Our Publications

2022
Han, X. ; Yu, Z. ; Zhuo, Y. ; Zhao, B. ; Ren, Y. ; Lamm, L. ; Xue, X. ; Feng, J. ; Marr, C. ; Shan, F. ; Peng, T. ; Zhang, X.Y.
iScience 25:104227 (2022)
The respective value of clinical data and CT examinations in predicting COVID-19 progression is unclear, because the CT scans and clinical data previously used are not synchronized in time. To address this issue, we collected 119 COVID-19 patients with 341 longitudinal CT scans and paired clinical data, and developed an AI system for the prediction of COVID-19 deterioration. By combining features extracted from CT and clinical data with our system, we can predict whether a patient will develop severe symptoms during hospitalization. Complementary to clinical data, CT examinations show significant add-on values for the prediction of COVID-19 progression in the early stage of COVID-19, especially in the 6th to 8th day after the symptom onset, indicating that this is the ideal time window for the introduction of CT examinations. We release our AI system to provide clinicians with additional assistance to optimize CT usage in the clinical workflow.
Wissenschaftlicher Artikel
Scientific Article
Suls, J. ; Salive, M.E. ; Koroukian, S.M. ; Alemi, F. ; Silber, J.H. ; Kastenmüller, G. ; Klabunde, C.N.
J. Am. Geriatr. Soc., DOI: 10.1111/jgs.17914 (2022)
Older adults experience a higher prevalence of multiple chronic conditions (MCCs). Establishing the presence and pattern of MCCs in individuals or populations is important for healthcare delivery, research, and policy. This report describes four emerging approaches and discusses their potential applications for enhancing assessment, treatment, and policy for the aging population. The National Institutes of Health convened a 2-day panel workshop of experts in 2018. Four emerging models were identified by the panel, including classification and regression tree (CART), qualifying comorbidity sets (QCS), the multimorbidity index (MMI), and the application of omics to network medicine. Future research into models of multiple chronic condition assessment may improve understanding of the epidemiology, diagnosis, and treatment of older persons.
Wissenschaftlicher Artikel
Scientific Article
Kotlarz, D.M.
Gastroenterology 163, 527-528 (2022)
Sonstiges: Meinungsartikel
Other: Opinion
Iuso, A. ; Zhang, F. ; Rusha, E. ; Campbell, B. ; Dorn, T. ; Zanuttigh, E. ; Haas, D. ; Anikster, Y. ; Lederer, G. ; Pertek, A. ; Nteli, P. ; Laugwitz, K.L. ; Moretti, A.
Stem Cell Res. 61:102773 (2022)
Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the de novo coenzyme A (CoA) synthesis starting from pantothenate. Mutations in PPCS cause autosomal-recessive dilated cardiomyopathy, often fatal, without apparent neurodegeneration, whereas pathogenic variants in PANK2 and COASY, two other genes involved in the CoA synthesis, cause Neurodegeneration with Brain Iron Accumulation (NBIA). PPCS-deficiency is a relatively new disease with unclear pathogenesis and no targeted therapy. Here, we report the generation of induced pluripotent stem cells from fibroblasts of two PPCS-deficient patients. These cellular models could represent a platform for pathophysiological studies and testing of therapeutic compounds for PPCS-deficiency.
Wissenschaftlicher Artikel
Scientific Article
Milaneschi, Y. ; Arnold, M. ; Kastenmüller, G. ; Dehkordi, S.M. ; Krishnan, R.R. ; Dunlop, B.W. ; Rush, A.J. ; Penninx, B.W.J.H. ; Kaddurah-Daouk, R.
J. Affect. Disord. 307, 254-263 (2022)
Background: Altered metabolism of acylcarnitines – transporting fatty acids to mitochondria – may link cellular energy dysfunction to depression. We examined the potential causal role of acylcarnitine metabolism in depression by leveraging genomics and Mendelian randomization. Methods: Summary statistics were obtained from large GWAS: the Fenland Study (N = 9363), and the Psychiatric Genomics Consortium (246,363 depression cases and 561,190 controls). Two-sample Mendelian randomization analyses tested the potential causal link of 15 endogenous acylcarnitines with depression. Results: In univariable analyses, genetically-predicted lower levels of short-chain acylcarnitines C2 (odds ratio [OR] 0.97, 95% confidence intervals [CIs] 0.95–1.00) and C3 (OR 0.97, 95%CIs 0.96–0.99) and higher levels of medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.01–1.06) and C10 (OR 1.04, 95%CIs 1.02–1.06) were associated with increased depression risk. No reverse potential causal role of depression genetic liability on acylcarnitines levels was found. Multivariable analyses showed that the association with depression was driven by the medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.02–1.06) and C10 (OR 1.04, 95%CIs 1.02–1.06), suggesting a potential causal role in the risk of depression. Causal estimates for C8 (OR = 1.05, 95%CIs = 1.02–1.07) and C10 (OR = 1.05, 95%CIs = 1.02–1.08) were confirmed in follow-up analyses using genetic instruments derived from a GWAS meta-analysis including up to 16,841 samples. Discussion: Accumulation of medium-chain acylcarnitines is a signature of inborn errors of fatty acid metabolism and age-related metabolic conditions. Our findings point to a link between altered mitochondrial energy production and depression pathogenesis. Acylcarnitine metabolism represents a promising access point for the development of novel therapeutic approaches for depression.
Wissenschaftlicher Artikel
Scientific Article
Fiorentino, J. ; Scialdone, A.
PLoS Comput. Biol. 18:e1009552 (2022)
Cells can measure shallow gradients of external signals to initiate and accomplish a migration or a morphogenetic process. Recently, starting from mathematical models like the local-excitation global-inhibition (LEGI) model and with the support of empirical evidence, it has been proposed that cellular communication improves the measurement of an external gradient. However, the mathematical models that have been used have over-simplified geometries (e.g., they are uni-dimensional) or assumptions about cellular communication, which limit the possibility to analyze the gradient sensing ability of more complex cellular systems. Here, we generalize the existing models to study the effects on gradient sensing of cell number, geometry and of long- versus short-range cellular communication in 2D systems representing epithelial tissues. We find that increasing the cell number can be detrimental for gradient sensing when the communication is weak and limited to nearest neighbour cells, while it is beneficial when there is long-range communication. We also find that, with long-range communication, the gradient sensing ability improves for tissues with more disordered geometries; on the other hand, an ordered structure with mostly hexagonal cells is advantageous with nearest neighbour communication. Our results considerably extend the current models of gradient sensing by epithelial tissues, making a step further toward predicting the mechanism of communication and its putative mediator in many biological processes.
Wissenschaftlicher Artikel
Scientific Article
Ogris, C. ; Castresana-Aguirre, M. ; Sonnhammer, E.L.L.
Bioinformatics 38, 2659-2660 (2022)
MOTIVATION: Pathway annotation tools are indispensable for the interpretation of a wide range of experiments in life sciences. Network-based algorithms have recently been developed which are more sensitive than traditional overlap-based algorithms, but there is still a lack of good online tools for network-based pathway analysis. RESULTS: We present PathwAX II-a pathway analysis web tool based on network crosstalk analysis using the BinoX algorithm. It offers several new features compared to the first version, including interactive graphical network visualization of the crosstalk between a query gene set and an enriched pathway, and the addition of Reactome pathways. AVAILABILITY: PathwAX II is available at http://pathwax.sbc.su.se. SUPPLEMENTARY INFORMATION: Supplementary materials are available at Bioinformatics online.
Wissenschaftlicher Artikel
Scientific Article
Christensen, M.B. ; Levy, A.M. ; Mohammadi, N.A. ; Niceta, M. ; Kaiyrzhanov, R. ; Dentici, M.L. ; Al Alam, C. ; Alesi, V. ; Benoit, V. ; Bhatia, K.P. ; Bierhals, T. ; Boßelmann, C.M. ; Buratti, J. ; Callewaert, B. ; Ceulemans, B. ; Charles, P. ; De Wachter, M. ; Dehghani, M. ; D'haenens, E. ; Doco-Fenzy, M. ; Geßner, M. ; Gobert, C. ; Guliyeva, U. ; Haack, T.B. ; Hammer, T.B. ; Heinrich, T. ; Hempel, M. ; Herget, T. ; Hoffmann, U. ; Horvath, J. ; Houlden, H. ; Keren, B. ; Kresge, C. ; Kumps, C. ; Lederer, D.J. ; Lermine, A. ; Magrinelli, F. ; Maroofian, R. ; Vahidi Mehrjardi, M.Y. ; Moudi, M. ; Müller, A.J. ; Oostra, A.J. ; Pletcher, B.A. ; Ros-Pardo, D. ; Samarasekera, S. ; Tartaglia, M. ; Van Schil, K. ; Vogt, J. ; Wassmer, E. ; Winkelmann, J. ; Zaki, M.S. ; Zech, M. ; Lerche, H. ; Radio, F.C. ; Gómez-Puertas, P. ; Møller, R.S. ; Tümer, Z.
Clin. Genet. 102, 98-109 (2022)
Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.
Wissenschaftlicher Artikel
Scientific Article
Gomari, D.P. ; Schweickart, A. ; Cerchietti, L. ; Paietta, E. ; Fernandez, H.H. ; Al-Amin, H. ; Suhre, K. ; Krumsiek, J.
Comm. Biol. 5:645 (2022)
Dimensionality reduction approaches are commonly used for the deconvolution of high-dimensional metabolomics datasets into underlying core metabolic processes. However, current state-of-the-art methods are widely incapable of detecting nonlinearities in metabolomics data. Variational Autoencoders (VAEs) are a deep learning method designed to learn nonlinear latent representations which generalize to unseen data. Here, we trained a VAE on a large-scale metabolomics population cohort of human blood samples consisting of over 4500 individuals. We analyzed the pathway composition of the latent space using a global feature importance score, which demonstrated that latent dimensions represent distinct cellular processes. To demonstrate model generalizability, we generated latent representations of unseen metabolomics datasets on type 2 diabetes, acute myeloid leukemia, and schizophrenia and found significant correlations with clinical patient groups. Notably, the VAE representations showed stronger effects than latent dimensions derived by linear and non-linear principal component analysis. Taken together, we demonstrate that the VAE is a powerful method that learns biologically meaningful, nonlinear, and transferrable latent representations of metabolomics data.
Wissenschaftlicher Artikel
Scientific Article
Garavaglia, B. ; Vallian, S. ; Romito, L.M. ; Straccia, G. ; Capecci, M. ; Invernizzi, F. ; Andrenelli, E. ; Kazemi, A. ; Boesch, S. ; Kopajtich, R. ; Olfati, N. ; Shariati, M. ; Shoeibi, A. ; Sadr-Nabavi, A. ; Prokisch, H. ; Winkelmann, J. ; Zech, M.
Parkinsonism Relat. Disord. 97, 52-56 (2022)
INTRODUCTION: The genetic basis of autosomal-recessive dystonia remains poorly understood. Our objective was to report identification of additional individuals with variants in AOPEP, a recently described gene for recessively inherited dystonic disorders (OMIM:619565). METHODS: Ongoing analysis on a high-throughput genetic platform and international case-recruitment efforts were undertaken. RESULTS: Novel biallelic, likely pathogenic loss-of-function alleles were identified in two pedigrees of different ethnic background. Two members of a consanguineous Iranian family shared a homozygous c.1917-1G>A essential splice-site variant and featured presentations of adolescence-onset generalized dystonia. An individual of Chinese descent, homozygous for the nonsense variant c.1909G>T (p.Glu637*), displayed childhood-onset generalized dystonia combined with later-manifesting parkinsonism. One additional Iranian patient with adolescence-onset generalized dystonia carried an ultrarare, likely protein-damaging homozygous missense variant (c.1201C>T [p.Arg401Trp]). CONCLUSIONS: These findings support the implication of AOPEP in recessive forms of generalized dystonia and dystonia-parkinsonism. Biallelic AOPEP variants represent a worldwide cause of dystonic movement-disorder phenotypes and should be considered in dystonia molecular testing approaches.
Wissenschaftlicher Artikel
Scientific Article
Reuter, M.S. ; Zech, M. ; Hempel, M. ; Altmüller, J. ; Heung, T. ; Pölsler, L. ; Santer, R. ; Thiele, H. ; Trost, B. ; Kubisch, C. ; Scherer, S.W. ; Rudnik-Schöneborn, S. ; Bassett, A.S. ; Lessel, D.
Eur. J. Hum. Genet. 30, 611-618 (2022)
PAN2 encodes a subunit of a deadenylation complex with important functions in mRNA stability and post-transcriptional regulation of gene expression. A homozygous frameshift deletion in PAN2 was reported in a single affected individual with developmental delay and multiple congenital anomalies. Here, we describe five additional individuals from three unrelated families with homozygous predicted loss-of-function variants in PAN2. The affected individuals presented with significant overlap in their clinical features, including mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck. Our data confirm that biallelic predicted loss-of-function variants in PAN2 cause a syndrome with multiple congenital anomalies, and suggest an important role of mRNA polyA tail length for proper organ formation.
Wissenschaftlicher Artikel
Scientific Article
Ebert, K. ; Haffner, I. ; Zwingenberger, G. ; Keller, S. ; Raimúndez, E. ; Geffers, R. ; Wirtz, R. ; Barbaria, E. ; Hollerieth, V. ; Arnold, R. ; Walch, A.K. ; Hasenauer, J. ; Maier, D. ; Lordick, F. ; Luber, B.
BMC Cancer 22:254 (2022)
BACKGROUND: The standard treatment for patients with advanced HER2-positive gastric cancer is a combination of the antibody trastuzumab and platin-fluoropyrimidine chemotherapy. As some patients do not respond to trastuzumab therapy or develop resistance during treatment, the search for alternative treatment options and biomarkers to predict therapy response is the focus of research. We compared the efficacy of trastuzumab and other HER-targeting drugs such as cetuximab and afatinib. We also hypothesized that treatment-dependent regulation of a gene indicates its importance in response and that it can therefore be used as a biomarker for patient stratification. METHODS: A selection of gastric cancer cell lines (Hs746T, MKN1, MKN7 and NCI-N87) was treated with EGF, cetuximab, trastuzumab or afatinib for a period of 4 or 24 h. The effects of treatment on gene expression were measured by RNA sequencing and the resulting biomarker candidates were tested in an available cohort of gastric cancer patients from the VARIANZ trial or functionally analyzed in vitro. RESULTS: After treatment of the cell lines with afatinib, the highest number of regulated genes was observed, followed by cetuximab and trastuzumab. Although trastuzumab showed only relatively small effects on gene expression, BMF, HAS2 and SHB could be identified as candidate biomarkers for response to trastuzumab. Subsequent studies confirmed HAS2 and SHB as potential predictive markers for response to trastuzumab therapy in clinical samples from the VARIANZ trial. AREG, EREG and HBEGF were identified as candidate biomarkers for treatment with afatinib and cetuximab. Functional analysis confirmed that HBEGF is a resistance factor for cetuximab. CONCLUSION: By confirming HAS2, SHB and HBEGF as biomarkers for anti-HER therapies, we provide evidence that the regulation of gene expression after treatment can be used for biomarker discovery. TRIAL REGISTRATION: Clinical specimens of the VARIANZ study (NCT02305043) were used to test biomarker candidates.
Wissenschaftlicher Artikel
Scientific Article
Efendiyev, M.A. ; Vougalter, V.
J. Dyn. Differ. Equ., DOI: 10.1007/s10884-022-10147-0 (2022)
We establish the existence in the sense of sequences of solutions for some integro-differential type equations containing the drift term and the square root of the one dimensional negative Laplacian, on the whole real line or on a finite interval with periodic boundary conditions in the corresponding H2 spaces. The argument relies on the fixed point technique when the elliptic equations involve first order differential operators with and without Fredholm property. It is proven that, under the reasonable technical assumptions, the convergence in L1 of the integral kernels implies the existence and convergence in H2 of solutions.
Wissenschaftlicher Artikel
Scientific Article
Škorvánek, M. ; Jech, R. ; Winkelmann, J. ; Zech, M.
Ann. Clin. Transl. Neurol. 9, 577-581 (2022)
An association between movement disorders and immune-system dysfunction has been described in the context of rare genetic diseases such as ataxia telangiectasia as well as infectious encephalopathies. We encountered a male patient who presented immunodeficiency of unknown etiology since childhood. A medication-refractory, progressive choreodystonic movement disorder emerged at the age of 42 years and prompted an exome-wide molecular testing approach. This revealed a pathogenic hemizygous variant in CD40LG, the gene implicated in X-linked hyper-IgM syndrome. Only two prior reports have specifically suggested a causal relationship between CD40LG mutations and involuntary hyperkinetic movements. Our findings thus confirm the existence of a particular CD40LG-related condition, combining features of compromised immunity with neurodegenerative movement abnormalities. Establishing the diagnosis is crucial because of potential life-threatening immunological complications.
Wissenschaftlicher Artikel
Scientific Article
Bohnacker, S. ; Hartung, F. ; Henkel, F. ; Quaranta, A. ; Kolmert, J. ; Priller, A. ; Ud-Dean, M. ; Giglberger, J. ; Kugler, L.M. ; Pechtold, L. ; Yazici, S. ; Lechner, A. ; Erber, J. ; Protzer, U. ; Lingor, P. ; Knolle, P. ; Chaker, A. ; Schmidt-Weber, C.B. ; Wheelock, C.E. ; Esser-von Bieren, J.
Mucosal Immunol. 15, 515–524 (2022)
Monocyte-derived macrophages (MDM) drive the inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and they are a major source of eicosanoids in airway inflammation. Here we report that MDM from SARS-CoV-2-infected individuals with mild disease show an inflammatory transcriptional and metabolic imprint that lasts for at least 5 months after SARS-CoV-2 infection. MDM from convalescent SARS-CoV-2-infected individuals showed a downregulation of pro-resolving factors and an increased production of pro-inflammatory eicosanoids, particularly 5-lipoxygenase-derived leukotrienes. Leukotriene synthesis was further enhanced by glucocorticoids and remained elevated at 3–5 months, but had returned to baseline at 12 months post SARS-CoV-2 infection. Stimulation with SARS-CoV-2 spike protein or LPS triggered exaggerated prostanoid-, type I IFN-, and chemokine responses in post COVID-19 MDM. Thus, SARS-CoV-2 infection leaves an inflammatory imprint in the monocyte/ macrophage compartment that drives aberrant macrophage effector functions and eicosanoid metabolism, resulting in long-term immune aberrations in patients recovering from mild COVID-19.
Wissenschaftlicher Artikel
Scientific Article
Fritz, C. ; Dorigatti, E. ; Rügamer, D.
Sci. Rep. 12:3930 (2022)
During 2020, the infection rate of COVID-19 has been investigated by many scholars from different research fields. In this context, reliable and interpretable forecasts of disease incidents are a vital tool for policymakers to manage healthcare resources. In this context, several experts have called for the necessity to account for human mobility to explain the spread of COVID-19. Existing approaches often apply standard models of the respective research field, frequently restricting modeling possibilities. For instance, most statistical or epidemiological models cannot directly incorporate unstructured data sources, including relational data that may encode human mobility. In contrast, machine learning approaches may yield better predictions by exploiting these data structures yet lack intuitive interpretability as they are often categorized as black-box models. We propose a combination of both research directions and present a multimodal learning framework that amalgamates statistical regression and machine learning models for predicting local COVID-19 cases in Germany. Results and implications: the novel approach introduced enables the use of a richer collection of data types, including mobility flows and colocation probabilities, and yields the lowest mean squared error scores throughout the observational period in the reported benchmark study. The results corroborate that during most of the observational period more dispersed meeting patterns and a lower percentage of people staying put are associated with higher infection rates. Moreover, the analysis underpins the necessity of including mobility data and showcases the flexibility and interpretability of the proposed approach.
Wissenschaftlicher Artikel
Scientific Article
Kukacka, J. ; Metz, S. ; Dehner, C. ; Muckenhuber, A. ; Paul-Yuan, K. ; Karlas, A. ; Fallenberg, E.M. ; Rummeny, E. ; Jüstel, D. ; Ntziachristos, V.
Photoacoustics 26, 100343 (2022)
Background: Since the initial breast transillumination almost a century ago, breast cancer imaging using light has been considered in different implementations aiming to improve diagnostics, minimize the number of available biopsies, or monitor treatment. However, due to strong photon scattering, conventional optical imaging yields low resolution images, challenging quantification and interpretation. Optoacoustic imaging addresses the scattering limitation and yields high-resolution visualization of optical contrast, offering great potential value for breast cancer imaging. Nevertheless, the image quality of experimental systems remains limited due to a number of factors, including signal attenuation with depth and partial view angle and motion effects, particularly in multi-wavelength measurements. Methods: We developed data analytics methods to improve the accuracy of handheld optoacoustic breast cancer imaging, yielding second-generation optoacoustic imaging performance operating in tandem with ultrasonography. Results: We produced the most advanced images yet with handheld optoacoustic examinations of the human breast and breast cancer, in terms of resolution and contrast. Using these advances, we examined optoacoustic markers of malignancy, including vasculature abnormalities, hypoxia, and inflammation, on images obtained from breast cancer patients. Conclusions: We achieved a new level of quality for optoacoustic images from a handheld examination of the human breast, advancing the diagnostic and theranostic potential of the hybrid optoacoustic-ultrasound (OPUS) examination over routine ultrasonography.
Wissenschaftlicher Artikel
Scientific Article
Malek, A. ; Zeraati, T. ; Sadr-Nabavi, A. ; Abbaszadegan, M.R. ; Vakili, N.
Case Rep. Rheumatol. 2022:8334375 (2022)
Familial Mediterranean fever (FMF) typically presents with recurrent attacks of fever and serosal inflammation with peritoneum, pleura, and synovium. We usually do not expect pericardial involvement at the early stages. FMF is an autoinflammatory disease, usually inherited with an autosomal recessive pattern. The patients typically have biallelic mutations in the MEFV gene, located on chromosome 16. Colchicine is the first-line treatment of FMF, which not only plays a crucial prophylactic role regarding the attack episodes, but also prevents amyloidosis. Colchicine resistance and intolerance in FMF patients have been rarely reported. Alternative anti-inflammatory agents are understood to be helpful in such cases. We describe a 13-year-old boy referred to our pediatric department complaining of chest pain, dyspnea, and tachycardia. Due to the massive pericardial and pleural effusion, a pericardiocentesis was performed, and a chest tube was inserted. Cardiac tamponade was considered as the initial diagnosis. After a month, he faced another episode of pleuritic chest pain, fever, tachycardia, and pleural and pericardial effusion. Evaluation for probable differential diagnoses including infection, malignancy, and collagen vascular disease showed no remarkable results. Finally, the mutation found by whole exome sequencing was confirmed by direct Sanger sequencing revealing a heterozygote c.44G > C (p.Glu148Gln) mutation in exon 2, confirming the clinical diagnosis of familial Mediterranean fever. Since he seemed to be nonresponsive to the maximum standard dose of colchicine, 100 mg of daily dapsone was added to his treatment regimen, which controlled the attack episodes well. FMF, while rarely initiated with cardiac manifestation, should be considered in patients with any early signs and symptoms of cardiovascular involvement.
Wissenschaftlicher Artikel
Scientific Article
Peymani, F. ; Farzeen, A. ; Prokisch, H.
Pediatr. Investig. 6, 29-35 (2022)
Although whole-exome sequencing and whole-genome sequencing has tremendously improved our understanding of the genetic etiology of human disorders, about half of the patients still do not receive a molecular diagnosis. The high fraction of variants with uncertain significance and the challenges of interpretation of noncoding variants have urged scientists to implement RNA sequencing (RNA-seq) in the diagnostic approach as a high throughput assay to complement genomic data with functional evidence. RNA-seq data can be used to identify aberrantly spliced genes, detect allele-specific expression, and identify gene expression outliers. Amongst eight studies utilizing RNA-seq, a mean diagnostic uplift of 15% has been reported. Here, we provide an overview of how RNA-seq has been implemented to aid in identifying the causal variants of Mendelian disorders.
Review
Review
Pardo, M. ; Offer, S. ; Hartner, E. ; Di Bucchianico, S. ; Bisig, B. ; Bauer, S. ; Pantzke, J. ; Zimmermann, E. ; Cao, X. ; Binder, S. ; Kuhn, E. ; Huber, A. ; Jeong, S. ; Käfer, U. ; Schneider, E. ; Mesceriakovas, A. ; Bendl, J. ; Brejcha, R. ; Buchholz, A. ; Gat, D. ; Hohaus, T. ; Rastak, N. ; Karg, E.W. ; Jakobi, G. ; Kalberer, M. ; Kanashova, T. ; Hu, Y. ; Ogris, C. ; Marsico, A. ; Theis, F.J. ; Shalit, T. ; Gröger, T.M. ; Rüger, C.P. ; Oeder, S. ; Orasche, J. ; Paul, A. ; Ziehm, T. ; Zhang, Z.H. ; Adam, T. ; Sippula, O. ; Sklorz, M. ; Schnelle-Kreis, J. ; Czech, H. ; Kiendler-Scharr, A. ; Zimmermann, R. ; Rudich, Y.
Environ. Int. 166:107366 (2022)
The health effects of exposure to secondary organic aerosols (SOAs) are still limited. Here, we investigated and compared the toxicities of soot particles (SP) coated with β-pinene SOA (SOAβPin-SP) and SP coated with naphthalene SOA (SOANap-SP) in a human bronchial epithelial cell line (BEAS-2B) residing at the air-liquid interface. SOAβPin-SP mostly contained oxygenated aliphatic compounds from β-pinene photooxidation, whereas SOANap-SP contained a significant fraction of oxygenated aromatic products under similar conditions. Following exposure, genome-wide transcriptome responses showed an Nrf2 oxidative stress response, particularly for SOANap-SP. Other signaling pathways, such as redox signaling, inflammatory signaling, and the involvement of matrix metalloproteinase, were identified to have a stronger impact following exposure to SOANap-SP. SOANap-SP also induced a stronger genotoxicity response than that of SOAβPin-SP. This study elucidated the mechanisms that govern SOA toxicity and showed that, compared to SOAs derived from a typical biogenic precursor, SOAs from a typical anthropogenic precursor have higher toxicological potency, which was accompanied with the activation of varied cellular mechanisms, such as aryl hydrocarbon receptor. This can be attributed to the difference in chemical composition; specifically, the aromatic compounds in the naphthalene-derived SOA had higher cytotoxic potential than that of the β-pinene-derived SOA.
Wissenschaftlicher Artikel
Scientific Article
Cadby, G. ; Giles, C. ; Melton, P.E. ; Huynh, K. ; Mellett, N.A. ; Duong, T. ; Nguyen, A. ; Cinel, M. ; Smith, A. ; Olshansky, G. ; Wang, T. ; Brozynska, M. ; Inouye, M. ; McCarthy, N.S. ; Ariff, A. ; Hung, J. ; Hui, J. ; Beilby, J. ; Dubé, M.P. ; Watts, G.F. ; Shah, S. ; Wray, N.R. ; Lim, W.L.F. ; Chatterjee, P. ; Martins, I. ; Laws, S.M. ; Porter, T. ; Vacher, M. ; Bush, A.I. ; Rowe, C.C. ; Villemagne, V.L. ; Ames, D. ; Masters, C.L. ; Taddei, K. ; Arnold, M. ; Kastenmüller, G. ; Nho, K. ; Saykin, A.J. ; Han, X. ; Kaddurah-Daouk, R. ; Martins, R.N. ; Blangero, J. ; Meikle, P.J. ; Moses, E.K.
Nat. Commun. 13:3124 (2022)
We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10-3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.
Wissenschaftlicher Artikel
Scientific Article
Lopez, J.P. ; Luecken, M. ; Brivio, E. ; Karamihalev, S. ; Kos, A. ; De Donno, C. ; Benjamin, A. ; Yang, H. ; Dick, A.L.W. ; Stoffel, R. ; Flachskamm, C. ; Ressle, A. ; Roeh, S. ; Huettl, R.E. ; Parl, A. ; Eggert, C. ; Novak, B. ; Yan, Y. ; Yeoh, K. ; Holzapfel, M. ; Hauger, B. ; Harbich, D. ; Schmid, B. ; Di Giaimo, R. ; Turck, C.W. ; Schmidt, M.V. ; Deussing, J.M. ; Eder, M. ; Dine, J. ; Theis, F.J. ; Chen, A.
Neuron 110, 2283-2298.e9 (2022)
A single sub-anesthetic dose of ketamine produces a rapid and sustained antidepressant response, yet the molecular mechanisms responsible for this remain unclear. Here, we identified cell-type-specific transcriptional signatures associated with a sustained ketamine response in mice. Most interestingly, we identified the Kcnq2 gene as an important downstream regulator of ketamine action in glutamatergic neurons of the ventral hippocampus. We validated these findings through a series of complementary molecular, electrophysiological, cellular, pharmacological, behavioral, and functional experiments. We demonstrated that adjunctive treatment with retigabine, a KCNQ activator, augments ketamine's antidepressant-like effects in mice. Intriguingly, these effects are ketamine specific, as they do not modulate a response to classical antidepressants, such as escitalopram. These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.
Wissenschaftlicher Artikel
Scientific Article
Drovandi, S. ; Lipska-Ziętkiewicz, B.S. ; Ozaltin, F. ; Emma, F. ; Gulhan, B. ; Boyer, O. ; Trautmann, A. ; Xu, H. ; Shen, Q. ; Rao, J. ; Riedhammer, K.M. ; Heemann, U. ; Hoefele, J. ; Stenton, S. ; Tsygin, A.N. ; Ng, K.H. ; Fomina, S. ; Benetti, E. ; Aurelle, M. ; Prikhodina, L. ; Schreuder, M.F. ; Tabatabaeifar, M. ; Jankowski, M. ; Baiko, S. ; Mao, J. ; Feng, C. ; Liu, C. ; Sun, S. ; Deng, F. ; Wang, X. ; Clavé, S. ; Stańczyk, M. ; Bałasz-Chmielewska, I. ; Fila, M. ; Durkan, A.M. ; Levart, T.K. ; Dursun, I. ; Esfandiar, N. ; Haas, D. ; Bjerre, A. ; Anarat, A. ; Benz, M.R. ; Talebi, S. ; Hooman, N. ; Ariceta, G. ; Schaefer, F.
Kidney Int., DOI: 10.1016/j.kint.2022.04.029 (2022)
Primary Coenzyme Q10 (CoQ10) deficiency is an ultra-rare disorder caused by defects in genes involved in CoQ10 biosynthesis leading to multidrug-resistant nephrotic syndrome as the hallmark kidney manifestation. Promising early results have been reported anecdotally with oral CoQ10 supplementation. However, the long-term efficacy and optimal prescription remain to be established. In a global effort, we collected and analyzed information from 116 patients who received CoQ10 supplements for primary CoQ10 deficiency due to biallelic pathogenic variants in either the COQ2, COQ6 or COQ8B genes. Median duration of follow up on treatment was two years. The effect of treatment on proteinuria was assessed, and kidney survival was analyzed in 41 patients younger than 18 years with chronic kidney disease stage 1-4 at the start of treatment compared with that of an untreated cohort matched by genotype, age, kidney function, and proteinuria. CoQ10 supplementation was associated with a substantial and significant sustained reduction of proteinuria by 88% at 12 months. Complete remission of proteinuria was more frequently observed in COQ6 disease. CoQ10 supplementation led to significantly better preservation of kidney function (5-year kidney failure-free survival 62% vs. 19%) with an improvement in general condition and neurological manifestations. Side effects of treatment were uncommon and mild. Thus, our findings indicate that all patients diagnosed with primary CoQ10 deficiency should receive early and life-long CoQ10 supplementation to decelerate the progression of kidney disease and prevent further damage to other organs.
Wissenschaftlicher Artikel
Scientific Article
Straka, I. ; Švantnerová, J. ; Minár, M. ; Stanková, S. ; Zech, M.
Mov. Disord., DOI: 10.1002/mds.29125 (2022)
Letter to the Editor
Letter to the Editor
Kreitmaier, P. ; Suderman, M. ; Southam, L. ; Coutinho de Almeida, R. ; Hatzikotoulas, K. ; Meulenbelt, I. ; Steinberg, J. ; Relton, C.L. ; Wilkinson, J.M. ; Zeggini, E.
Am. J. Hum. Genet. 109, 1255-1271 (2022)
Osteoarthritis is a complex degenerative joint disease. Here, we investigate matched genotype and methylation profiles of primary chondrocytes from macroscopically intact (low-grade) and degraded (high-grade) osteoarthritis cartilage and from synoviocytes collected from 98 osteoarthritis-affected individuals undergoing knee replacement surgery. We perform an epigenome-wide association study of knee cartilage degeneration and report robustly replicating methylation markers, which reveal an etiologic mechanism linked to the migration of epithelial cells. Using machine learning, we derive methylation models of cartilage degeneration, which we validate with 82% accuracy in independent data. We report a genome-wide methylation quantitative trait locus (mQTL) map of articular cartilage and synovium and identify 18 disease-grade-specific mQTLs in osteoarthritis cartilage. We resolve osteoarthritis GWAS loci through causal inference and colocalization analyses and decipher the epigenetic mechanisms that mediate the effect of genotype on disease risk. Together, our findings provide enhanced insights into epigenetic mechanisms underlying osteoarthritis in primary tissues.
Wissenschaftlicher Artikel
Scientific Article
Schultze, J.L. ; Büttner, M. ; Becker, M.
Nat. Rev. Immunol. 22, 401–403 (2022)
Sonstiges: Meinungsartikel
Other: Opinion
Mertes, C. ; Scheller, I.F. ; Yépez, V.A. ; Çelik, M.H. ; Liang, Y. ; Kremer, L.S. ; Gusic, M. ; Prokisch, H. ; Gagneur, J.
Nat. Commun. 13:3474 (2022)
Klotz, S. ; Riederer, F. ; Hergovich, N. ; Schlager, T. ; Steinkellner, L. ; Fertl, E. ; Baumgartner, C. ; Wagner, M. ; Zimprich, A. ; Gelpi, E.
Clin. Neuropathol. 41, 145-146 (2022)
Letter to the Editor
Letter to the Editor
Krenn, M. ; Tomschik, M. ; Wagner, M. ; Zulehner, G. ; Weng, R. ; Rath, J. ; Klotz, S. ; Gelpi, E. ; Bsteh, G. ; Keritam, O. ; Colonna, I. ; Paternostro, C. ; Jäger, F. ; Lindeck-Pozza, E. ; Iglseder, S. ; Grinzinger, S. ; Schönfelder, M. ; Hohenwarter, C. ; Freimüller, M. ; Embacher, N. ; Wanschitz, J. ; Topakian, R. ; Töpf, A. ; Straub, V. ; Quasthoff, S. ; Zimprich, F. ; Löscher, W.N. ; Cetin, H.
Eur. J. Neurol. 29, 1815-1824 (2022)
BACKGROUND: Hereditary myopathies with limb-girdle muscular weakness (LGW) are a genetically heterogeneous group of disorders, in which molecular diagnosis remains challenging. Our aim was to present a detailed clinical and genetic characterisation of a large cohort of patients with LGW. METHODS: This nationwide cohort study included patients with LGW suspected to be associated with hereditary myopathies. Parameters associated with specific genetic aetiologies were evaluated, and we further assessed how they predicted the detection of causative variants by genetic analyses. RESULTS: Molecular diagnoses were identified in 62.0% (75/121) of the cohort, with a higher proportion of patients diagnosed by next-generation sequencing (NGS) than by single gene testing (77.3% vs. 22.7% of solved cases). Median time from onset to genetic diagnosis was 8.9 years (IQR 3.7-19.9) and 17.8 years (IQR 7.9-27.8) for single gene testing and NGS, respectively. The most common diagnoses were myopathies associated with variants in CAPN3 (n = 9), FKRP (n = 9), ANO5 (n = 8), DYSF (n = 8) and SGCA (n = 5), together accounting for 32.2% of the cohort. Younger age at disease onset (p = 0.043), >10x elevated CK activity levels (p = 0.024) and myopathic electromyography findings (p = 0.007) were significantly associated with the detection of causative variants. CONCLUSIONS: Our findings suggest an earlier use of NGS in patients with LGW to avoid long diagnostic delays. We further present parameters predictive of a molecular diagnosis that may help to select patients for genetic analyses, especially in centres with limited access to sequencing.
Wissenschaftlicher Artikel
Scientific Article
Filbir, F. ; Schroeder, K. ; Veselovska, A.
Numer. Funct. Anal. Optim. 43, 755-795 (2022)
We study the problem of recovering an atomic measure on the unit 2-sphere (Formula presented.) given finitely many moments with respect to spherical harmonics. The analysis relies on the formulation of this problem as an optimization problem on the space of bounded Borel measures on (Formula presented.) as it was considered by Y. de Castro & F. Gamboa (J. Math. Anal. Appl. 395(1):336–354, 2012) and E. Candés & C. Fernandez-Granda (J. Fourier Anal. Appl. 19(6):1229–1254, 2013). We construct a dual certificate using a kernel given in an explicit form and make a concrete analysis of the interpolation problem. Numerical examples are provided and analyzed.
Wissenschaftlicher Artikel
Scientific Article
Erber, J. ; Kappler, V. ; Haller, B. ; Mijočević, H. ; Galhoz, A. ; da Costa, C.P. ; Gebhardt, F. ; Graf, N. ; Hoffmann, D. ; Thaler, M. ; Lorenz, E. ; Roggendorf, H. ; Kohlmayer, F. ; Henkel, A. ; Menden, M. ; Ruland, J. ; Spinner, C.D. ; Protzer, U. ; Knolle, P. ; Lingor, P.
Emerg. Infect. Dis 28, 572-581 (2022)
Hospital staff are at high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease (COVID-19) pandemic. This cross-sectional study aimed to determine the prevalence of SARS-CoV-2 infection in hospital staff at the University Hospital rechts der Isar in Munich, Germany, and identify modulating factors. Overall seroprevalence of SARS-CoV-2-IgG in 4,554 participants was 2.4%. Staff engaged in direct patient care, including those working in COVID-19 units, had a similar probability of being seropositive as non–patient-facing staff. Increased probability of infection was observed in staff reporting interactions with SARS-CoV-2-infected coworkers or private contacts or exposure to COVID-19 patients without appropriate personal protective equipment. Analysis of spatiotemporal trajectories identified that distinct hotspots for SARS-CoV-2-positive staff and patients only partially overlap. Patient-facing work in a healthcare facility during the SARS-CoV-2 pandemic might be safe as long as adequate personal protective equipment is used and infection prevention practices are followed inside and outside the hospital.
Wissenschaftlicher Artikel
Scientific Article
Biller, A.M. ; Molenda, C. ; Obster, F. ; Zerbini, G. ; Förtsch, C. ; Roenneberg, T. ; Winnebeck, E.C.
Sci. Rep. 12:3178 (2022)
The mismatch between teenagers' late sleep phase and early school start times results in acute and chronic sleep reductions. This is not only harmful for learning but may reduce career prospects and widen social inequalities. Delaying school start times has been shown to improve sleep at least short-term but whether this translates to better achievement is unresolved. Here, we studied whether 0.5-1.5 years of exposure to a flexible school start system, with the daily choice of an 8 AM or 8:50 AM-start, allowed secondary school students (n = 63-157, 14-21 years) to improve their quarterly school grades in a 4-year longitudinal pre-post design. We investigated whether sleep, changes in sleep or frequency of later starts predicted grade improvements. Mixed model regressions with 5111-16,724 official grades as outcomes did not indicate grade improvements in the flexible system per se or with observed sleep variables nor their changes-the covariates academic quarter, discipline and grade level had a greater effect in our sample. Importantly, our finding that intermittent sleep benefits did not translate into detectable grade changes does not preclude improvements in learning and cognition in our sample. However, it highlights that grades are likely suboptimal to evaluate timetabling interventions despite their importance for future success.
Wissenschaftlicher Artikel
Scientific Article
Efendiyev, M.A. ; Vougalter, V.
Electron. Res. Arch. 30, 515-534 (2022)
In this survey we discuss the recent results on the existence in the sense of sequences of solutions for certain elliptic problems containing the non-Fredholm operators. First of all, we deal with the solvability in the sense of sequences for some fourth order non-Fredholm operators, such that the methods of the spectral and scattering theory for Schrödinger type operators are used for the analysis. Moreover, we present the easily verifiable necessary condition of the preservation of the nonnegativity of the solutions of a system of parabolic equations in the case of the anomalous diffusion with the negative Laplacian in a fractional power in one dimension, which imposes the necessary form of such system of equations that must be studied mathematically. This class of systems of PDEs has a wide range of applications. We conclude the survey with several new results nowhere published concerning the solvability in the sense of sequences for the generalized Poisson type equation with a scalar potential.
Wissenschaftlicher Artikel
Scientific Article
Dal Toso, L. ; Chalampalakis, Z. ; Buvat, I. ; Comtat, C. ; Cook, G. ; Goh, V. ; Schnabel, J.A. ; Marsden, P.K.
Phys. Med. Biol. 67, DOI: 10.1088/1361-6560/ac65d6 (2022)
Objective. In clinical positron emission tomography (PET) imaging, quantification of radiotracer uptake in tumours is often performed using semi-quantitative measurements such as the standardised uptake value (SUV). For small objects, the accuracy of SUV estimates is limited by the noise properties of PET images and the partial volume effect. There is need for methods that provide more accurate and reproducible quantification of radiotracer uptake. Approach. In this work, we present a deep learning approach with the aim of improving quantification of lung tumour radiotracer uptake and tumour shape definition. A set of simulated tumours, assigned with 'ground truth' radiotracer distributions, are used to generate realistic PET raw data which are then reconstructed into PET images. In this work, the ground truth images are generated by placing simulated tumours characterised by different sizes and activity distributions in the left lung of an anthropomorphic phantom. These images are then used as input to an analytical simulator to simulate realistic raw PET data. The PET images reconstructed from the simulated raw data and the corresponding ground truth images are used to train a 3D convolutional neural network. Results. When tested on an unseen set of reconstructed PET phantom images, the network yields improved estimates of the corresponding ground truth. The same network is then applied to reconstructed PET data generated with different point spread functions. Overall the network is able to recover better defined tumour shapes and improved estimates of tumour maximum and median activities. Significance. Our results suggest that the proposed approach, trained on data simulated with one scanner geometry, has the potential to restore PET data acquired with different scanners.
Wissenschaftlicher Artikel
Scientific Article
Lutz, K. ; Musumeci, A. ; Sie, C. ; Dursun, E. ; Winheim, E. ; Bagnoli, J. ; Ziegenhain, C. ; Rausch, L. ; Bergen, V. ; Luecken, M. ; Oostendorp, R.A.J. ; Schraml, B.U. ; Theis, F.J. ; Enard, W. ; Korn, T. ; Krug, A.B.
Nat. Commun. 13:3456 (2022)
Plasmacytoid and conventional dendritic cells (pDC and cDC) are generated from progenitor cells in the bone marrow and commitment to pDCs or cDC subtypes may occur in earlier and later progenitor stages. Cells within the CD11c+MHCII-/loSiglec-H+CCR9lo DC precursor fraction of the mouse bone marrow generate both pDCs and cDCs. Here we investigate the heterogeneity and commitment of subsets in this compartment by single-cell transcriptomics and high-dimensional flow cytometry combined with cell fate analysis: Within the CD11c+MHCII-/loSiglec-H+CCR9lo DC precursor pool cells expressing high levels of Ly6D and lacking expression of transcription factor Zbtb46 contain CCR9loB220hi immediate pDC precursors and CCR9loB220lo (lo-lo) cells which still generate pDCs and cDCs in vitro and in vivo under steady state conditions. cDC-primed cells within the Ly6DhiZbtb46- lo-lo precursors rapidly upregulate Zbtb46 and pass through a Zbtb46+Ly6D+ intermediate stage before acquiring cDC phenotype after cell division. Type I IFN stimulation limits cDC and promotes pDC output from this precursor fraction by arresting cDC-primed cells in the Zbtb46+Ly6D+ stage preventing their expansion and differentiation into cDCs. Modulation of pDC versus cDC output from precursors by external factors may allow for adaptation of DC subset composition at later differentiation stages.
Wissenschaftlicher Artikel
Scientific Article
Sanin, V. ; Schmieder, R. ; Ates, S. ; Schlieben, L.D. ; Wiehler, J. ; Sun, R. ; Decker, M. ; Sander, M. ; Holdenrieder, S. ; Kohlmayer, F. ; Friedmann, A. ; Mall, V. ; Feiler, T. ; Dreßler, A. ; Strom, T.M. ; Prokisch, H. ; Meitinger, T. ; von Scheidt, M. ; Koenig, W. ; Leipold, G. ; Schunkert, H.
Eur. J. Public Health 32, 422-428 (2022)
BACKGROUND: Heterozygous familial hypercholesterolemia (FH) represents the most frequent monogenic disorder with an estimated prevalence of 1:250 in the general population. Diagnosis during childhood enables early initiation of preventive measures, reducing the risk of severe consecutive atherosclerotic manifestations. Nevertheless, population-based screening programs for FH are scarce. METHODS: In the VRONI study, children aged 5-14 years in Bavaria are invited to participate in an FH screening program during regular pediatric visits. The screening is based on low-density lipoprotein cholesterol measurements from capillary blood. If exceeding 130 mg/dl (3.34 mmol/l), i.e. the expected 95th percentile in this age group, subsequent molecular genetic analysis for FH is performed. Children with FH pathogenic variants enter a registry and are treated by specialized pediatricians. Furthermore, qualified training centers offer FH-focused training courses to affected families. For first-degree relatives, reverse cascade screening is recommended to identify and treat affected family members. RESULTS: Implementation of VRONI required intensive prearrangements for addressing ethical, educational, data safety, legal and organizational aspects, which will be outlined in this article. Recruitment started in early 2021, within the first months, more than 380 pediatricians screened over 5200 children. Approximately 50 000 children are expected to be enrolled in the VRONI study until 2024. CONCLUSIONS: VRONI aims to test the feasibility of a population-based screening for FH in children in Bavaria, intending to set the stage for a nationwide FH screening infrastructure. Furthermore, we aim to validate genetic variants of unclear significance, detect novel causative mutations and contribute to polygenic risk indices (DRKS00022140; August 2020).
Wissenschaftlicher Artikel
Scientific Article
Sanin, V. ; Schmieder, R. ; Ates, S. ; Schlieben, L.D. ; Wiehler, J. ; Sun, R. ; Decker, M. ; Sander, M. ; Holdenrieder, S. ; Kohlmayer, F. ; Friedmann, A. ; Mall, V. ; Feiler, T. ; Dressler, A. ; Strom, T.M. ; Prokisch, H. ; Meitinger, T. ; von Scheidt, M. ; Koenig, W. ; Leipold, G. ; Schunkert, H.
Med. Genet. 34, 41-51 (2022)
Familial hypercholesterolemia (FH) is the most frequent monogenic disorder (prevalence 1:250) in the general population. Early diagnosis during childhood enables pre-emptive treatment, thus reducing the risk of severe atherosclerotic manifestations later in life. Nonetheless, FH screening programs are scarce. VRONI offers all children aged 5-14 years in Bavaria a FH screening in the context of regular pediatric visits. LDL-cholesterol (LDL-C) is measured centrally, followed by genetic analysis for FH if exceeding the age-specific 95th percentile (130 mg/dl, 3.34 mmol/l). Children with FH pathogenic variants are treated by specialized pediatricians and offered a FH-focused training course by a qualified training center. Reverse cascade screening is recommended for all first-degree relatives. VRONI aims to prove the feasibility of a population-based FH screening in children and to lay the foundation for a nationwide screening program.
Wissenschaftlicher Artikel
Scientific Article
Spielmann, N. ; Miller, G. ; Oprea, T.I. ; Hsu, C.-W. ; Fobo, G. ; Frishman, G. ; Montrone, C. ; Hasel Mashhadi, H. ; Mason, J. ; Munoz Fuentes, V. ; Leuchtenberger, S. ; Ruepp, A. ; Wagner, M. ; Westphal, D.S. ; Wolf, C. ; Görlach, A. ; Sanz-Moreno, A. ; Cho, Y.-L. ; Teperino, R. ; Brandmaier, S. ; Sharma, S. ; Galter, I.R. ; Östereicher, M.A. ; Zapf, L. ; Mayer-Kuckuk, P. ; Rozman, J. ; Teboul, L. ; Bunton, R.K.A. ; Cater, H. ; Stewart, M. ; Christou, S. ; Westerberg, H. ; Willet, A.M. ; Wotton, J.M. ; Roper, W.B. ; Christiansen, A.E. ; Ward, C.S. ; Heaney, J.D. ; Reynolds, C.L. ; Prochazka, J. ; Bower, L. ; Clary, D. ; Selloum, M. ; Bou About, G. ; Wendling, O. ; Jacobs, H. ; Leblanc, S. ; Meziane, H. ; Sorg, T. ; Audain, E. ; Gilly, A. ; Rayner, N.W. ; Hitz, M.-P. ; Zeggini, E. ; Wolf, E. ; Sedlacek, R. ; Murray, S.A. ; Svenson, K.L. ; Braun, R.E. ; White, J.K. ; Kelsey, L. ; Gao, X. ; Shiroishi, T. ; Xu, Y. ; Seong, J.K. ; Mammano, F. ; Tocchini-Valentini, G.P. ; Beaudet, A.L. ; Meehan, T.F. ; Parkinson, H. ; Smedley, D. ; Mallon, A.-M. ; Wells, S.E. ; Grallert, H. ; Wurst, W. ; Marschall, S. ; Fuchs, H. ; Brown, S.D.M. ; Flenniken, A.M. ; Nutter, L.M.J. ; McKerlie, C. ; Herault, Y. ; Lloyd, K.C.K. ; Dickinson, M.E. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; IMPC Consortium (Aguilar-Pimentel, J.A. ; Becker, L. ; Garrett, L. ; Hölter, S.M. ; Amarie, O.V. ; Calzada-Wack, J. ; Klein-Rodewald, T. ; Lengger, C. ; Stöger, C. ; Gerlini, R. ; Rathkolb, B. ; Seisenberger, C. ; Bürger, A. ; Giesert, F.)
Nat. Cardio. Res. 1, 157-173 (2022)
Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease.
Wissenschaftlicher Artikel
Scientific Article
Brunet, T. ; Berutti, R. ; Dill, V. ; Hecker, J.S. ; Choukair, D. ; Andres, S. ; Deschauer, M. ; Diehl-Schmid, J. ; Krenn, M. ; Eckstein, G. ; Graf, E. ; Gasser, T. ; Strom, T.M. ; Hoefele, J. ; Götze, K.S. ; Meitinger, T. ; Wagner, M.
Hum. Mol. Genet., DOI: 10.1093/hmg/ddac034:ddac034 (2022)
Clonal hematopoiesis due to somatic mutations in hematopoietic stem/progenitor cells is an age-related phenomenon and commonly observed when sequencing blood DNA in elderly individuals. Several genes that are implicated in clonal hematopoiesis are also associated with Mendelian disorders when mutated in the germline, potentially leading to variant misinterpretation. We performed a literature search to identify genes associated with age-related clonal hematopoiesis followed by an OMIM query to identify the subset of genes in which germline variants are associated with Mendelian disorders. We retrospectively screened for diagnostic cases in which the presence of age-related clonal hematopoiesis confounded exome sequencing data interpretation. We found 58 genes in which somatic mutations are implicated in clonal hematopoiesis while germline variants in the same genes are associated with Mendelian (mostly neurodevelopmental) disorders. Using five selected cases of individuals with suspected monogenic disorders, we illustrate how clonal hematopoiesis in either variant databases or exome sequencing datasets poses a pitfall, potentially leading to variant misclassification and erroneous conclusions regarding gene-disease associations.
Wissenschaftlicher Artikel
Scientific Article
Indelicato, E. ; Zech, M. ; Amprosi, M. ; Boesch, S.
Orphanet J. Rare Dis. 17:55 (2022)
BACKGROUND: The genetic landscape of neurodevelopmental disorders is constantly expanding and children with early-onset neurological phenotypes increasingly receive a genetic diagnosis. Nonetheless, the awareness of the chronic course of these conditions, and consequently their recognition and management in the adult population, is still limited. RESULTS: Herein, we describe four patients with rare neurodevelopmental disorders (SON, ZMYND11, DNMT1 and YY1-related diseases), who received a genetic assignment only in the adulthood. All these patients had an early developmental delay and displayed a movement disorder (dystonia/ataxia/tremor) which manifested for the first time, or worsened, in the adulthood, prompting the referral to a neurologist. This phenotypic combination led eventually to the genetic testing. We report previously unrecognized features and highlight the peculiarities of the adult presentation of four neurodevelopmental disorders. CONCLUSIONS: This report expands the current knowledge on four rare neurodevelopmental disorders (SON, ZMYND11, DNMT1 and YY1), which was mainly based on reports from paediatric cases. This case series emphasize the importance of a tight neurological surveillance extending beyond the childhood.
Wissenschaftlicher Artikel
Scientific Article
Biller, A.M. ; Molenda, C. ; Zerbini, G. ; Roenneberg, T. ; Winnebeck, E.C.
Sci. Rep. 12:2787 (2022)
Early school times fundamentally clash with the late sleep of teenagers. This mismatch results in chronic sleep deprivation posing acute and long-term health risks and impairing students' learning. Despite immediate short-term benefits for sleep, the long-term effects of later starts remain unresolved. In a pre-post design over 1 year, we studied a unique flexible school start system, in which 10-12th grade students chose daily between an 8:00 or 8:50AM-start. Missed study time (8:00-8:50) was compensated for during gap periods or after classes. Based on 2 waves (6-9 weeks of sleep diary each), we found that students maintained their ~ 1-h-sleep gain on later days, longitudinally (n = 28) and cross-sectionally (n = 79). This gain was independent of chronotype and frequency of later starts but attenuated for boys after 1 year. Students showed persistently better sleep quality and reduced alarm-driven waking and reported psychological benefits (n = 93) like improved motivation, concentration, and study quality on later days. Nonetheless, students chose later starts only infrequently (median 2 days/week), precluding detectable sleep extensions in the flexible system overall. Reasons for not choosing late starts were the need to make up lost study time, preference for extra study time and transport issues. Whether flexible systems constitute an appealing alternative to fixed delays given possible circadian and psychological advantages warrants further investigation.
Wissenschaftlicher Artikel
Scientific Article
Doleckova, K. ; Roth, J. ; Stellmachova, J. ; Gescheidt, T. ; Sigut, V. ; Houska, P. ; Jech, R. ; Zech, M. ; Vyhnalek, M. ; Vyhnalkova, E. ; Seeman, P. ; Meszarosova, A.U.
Neurol. Res., DOI: 10.1080/01616412.2021.1975224 (2022)
SPG11 is one of the most frequent autosomal recessively inherited types of hereditary spastic paraplegias (HSP or SPG). We describe the first seven patients from the Czech Republic with biallelic pathogenic variants in the SPG11. The typical HSP neurological findings are present in all the described patients in that the signs of a complicated phenotype develop slowly. The speed of disease progression, and the severity of gait impairment, was fast in all patients but the phenotype varied from patient to patient. Thin corpus callosum was not observed in two patients. Two Czech SPG11 patients had unusual late onset of disease and both were compound heterozygotes for the c.5381T>C variant. Therefore, we looked for a potential ralationship between the type of variant in the SPG11 gene and the age of disease onset. By reviewing all described SPG11 patients carrying at least one missense pathogenic variant in the SPG11 gene we did not found any relationship between the age of onset and the type of variant. Together twelve pathogenic variants, including gross deletions, were found in the SPG11 gene the Czech SPG11 patients, the c.3454-2A>G variant is novel.
Review
Review
Vogel, F.D. ; Krenn, M. ; Westphal, D.S. ; Graf, E. ; Wagner, M. ; Leiz, S. ; Koniuszewski, F. ; Augé-Stock, M. ; Kramer, G. ; Scholze, P. ; Ernst, M.
Epilepsia 63, e35-e41 (2022)
Variants in γ-aminobutyric acid A (GABAA) receptor genes cause different forms of epilepsy and neurodevelopmental disorders. To date, GABRA4, encoding the α4-subunit, has not been associated with a monogenic condition. However, preclinical evidence points toward seizure susceptibility. Here, we report a de novo missense variant in GABRA4 (c.899C>T, p.Thr300Ile) in an individual with early-onset drug-resistant epilepsy and neurodevelopmental abnormalities. An electrophysiological characterization of the variant, which is located in the pore-forming domain, shows accelerated desensitization and a lack of seizure-protective neurosteroid function. In conclusion, our findings strongly suggest an association between de novo variation in GABRA4 and a neurodevelopmental disorder with epilepsy.
Wissenschaftlicher Artikel
Scientific Article
Kolářová, H. ; Tan, J. ; Strom, T.M. ; Meitinger, T. ; Wagner, M. ; Klopstock, T.
EBioMedicine 77:103869 (2022)
Background: Neurodegeneration with brain iron accumulation (NBIA) are a group of clinically and genetically heterogeneous diseases characterized by iron overload in basal ganglia and progressive neurodegeneration. Little is known about the epidemiology of NBIA disorders. In the absence of large-scale population-based studies, obtaining reliable epidemiological data requires innovative approaches. Methods: All pathogenic variants were collected from the 13 genes associated with autosomal recessive NBIA (PLA2G6, PANK2, COASY, ATP13A2, CP, AP4M1, FA2H, CRAT, SCP2, C19orf12, DCAF17, GTPBP2, REPS1). The allele frequencies of these disease-causing variants were assessed in exome/genome collections: the Genome Aggregation Database (gnomAD) and our in-house database. Lifetime risks were calculated from the sum of allele frequencies in the respective genes under assumption of Hardy-Weinberg equilibrium. Findings: The combined estimated lifetime risk of all 13 investigated NBIA disorders is 0.88 (95% confidence interval 0.70–1.10) per 100,000 based on the global gnomAD dataset (n = 282,912 alleles), 0.92 (0.65–1.29) per 100,000 in the European gnomAD dataset (n = 129,206), and 0.90 (0.48–1.62) per 100,000 in our in-house database (n = 44,324). Individually, the highest lifetime risks (>0.15 per 100,000) are found for disorders caused by variants in PLA2G6, PANK2 and COASY. Interpretation: This population-genetic estimation on lifetime risks of recessive NBIA disorders reveals frequencies far exceeding previous population-based numbers. Importantly, our approach represents lifetime risks from conception, thus including prenatal deaths. Understanding the true lifetime risk of NBIA disorders is important in estimating disease burden, allocating resources and targeting specific interventions.
Wissenschaftlicher Artikel
Scientific Article
Katsoula G. ; Steinberg, J. ; Tuerlings, M. ; de Almeida, R.C. ; Southam, L. ; Swift, D. ; Meulenbelt, I. ; Wilkinson, J.M. ; Zeggini, E.
Hum. Mol. Genet. 31, 2090-2105 (2022)
Osteoarthritis is a prevalent joint disease and a major cause of disability worldwide with no curative therapy. Development of disease-modifying therapies requires a better understanding of the molecular mechanisms underpinning disease. A hallmark of osteoarthritis is cartilage degradation. To define molecular events characterising osteoarthritis at the whole transcriptome level, we performed deep RNA sequencing in paired samples of low- and high-osteoarthritis grade knee cartilage derived from 124 patients undergoing total joint replacement. We detected differential expression between low- and high-osteoarthritis grade articular cartilage for 365 genes and identified a 38-gene signature in osteoarthritis cartilage by replicating our findings in an independent dataset. We also found differential expression for 25 novel long non-coding RNA genes (lncRNAs) and identified potential lncRNA interactions with RNA-binding proteins in osteoarthritis. We assessed alterations in the relative usage of individual gene transcripts and identified differential transcript usage for 82 genes, including ABI3BP, coding for an extracellular matrix protein, AKT1S1, a negative regulator of the mTOR pathway, and TPRM4, coding for a transient receptor potential channel. We further assessed genome-wide differential splicing, for the first time in osteoarthritis, and detected differential splicing for 209 genes, which were enriched for extracellular matrix, proteoglycans and integrin surface interactions terms. In the largest study of its kind in osteoarthritis, we find that isoform and splicing changes, in addition to extensive differences in both coding and non-coding sequence expression, are associated with disease and demonstrate a novel layer of genomic complexity to osteoarthritis pathogenesis.
Wissenschaftlicher Artikel
Scientific Article
Grimalt, J.O. ; Garí, M. ; Santa-Marina, L. ; Ibarluzea, J. ; Sunyer, J.
Environ. Res. 209:112783 (2022)
BACKGROUND: Transplacental transfer and breastfeeding are the main transport routes of organic pollutants into children at the beginning of life. Although pollutant transmission through these mechanisms primarily depends on the maternal pollution burden, its impact may be modulated by physiological effects. OBJECTIVES: We have examined whether gestational weight gain (GWG) exerts an influence on the content of lipophilic low volatile pollutants in breast milk. RESULTS: Colostrum from mothers from the INMA cohorts of Sabadell and Gipuzkoa (n = 256 and 119, respectively) with low GWG as defined by the Institute of Medicine (IOM) from the US National Academies of Sciences, Engineering and Medicine had significantly higher concentrations of polychlorobiphenyls (PCBs) and 4,4'-DDE than colostrum in mothers who gained weight within IOM recommendations or in those who exceeded this threshold. Statistically significant differences were also found in the colostrum:maternal serum ratios of these compounds. Women with low GWG retained higher pollutant amounts in colostrum. These observations are consistent with previously described higher concentrations of these pollutants in infant cord blood from mothers with low GWG by IOM standards. They indicate that mobilization of lipophilic organic pollutants by metabolic pregnant changes not only leads to higher fetal transfer but to higher accumulation into the mammary system upon low GWG. CONCLUSIONS: The present results show that insufficient GWG, besides increasing in utero exposure, also enhances pollutant transfer to infants during breastfeeding which considerably extends the significance of this physiological change for the pollutant children intake in early life.
Wissenschaftlicher Artikel
Scientific Article
Ugurlu, D. ; Puyol-Antón, E. ; Ruijsink, B. ; Young, A. ; Machado, I. ; Hammernik, K. ; King, A.P. ; Schnabel, J.A.
In: (STACOM 2021: Statistical Atlases and Computational Models of the Heart. Multi-Disease, Multi-View, and Multi-Center Right Ventricular Segmentation in Cardiac MRI Challenge, 27 September 2021, Strasbourg). 2022. 57-65 (Lect. Notes Comput. Sc. ; 13131 LNCS)
Domain shift refers to the difference in the data distribution of two datasets, normally between the training set and the test set for machine learning algorithms. Domain shift is a serious problem for generalization of machine learning models and it is well-established that a domain shift between the training and test sets may cause a drastic drop in the model’s performance. In medical imaging, there can be many sources of domain shift such as different scanners or scan protocols, different pathologies in the patient population, anatomical differences in the patient population (e.g. men vs women) etc. Therefore, in order to train models that have good generalization performance, it is important to be aware of the domain shift problem, its potential causes and to devise ways to address it. In this paper, we study the effect of domain shift on left and right ventricle blood pool segmentation in short axis cardiac MR images. Our dataset contains short axis images from 4 different MR scanners and 3 different pathology groups. The training is performed with nnUNet. The results show that scanner differences cause a greater drop in performance compared to changing the pathology group, and that the impact of domain shift is greater on right ventricle segmentation compared to left ventricle segmentation. Increasing the number of training subjects increased cross-scanner performance more than in-scanner performance at small training set sizes, but this difference in improvement decreased with larger training set sizes. Training models using data from multiple scanners improved cross-domain performance.
Machado, I. ; Puyol-Antón, E. ; Hammernik, K. ; Cruz, G. ; Ugurlu, D. ; Ruijsink, B. ; Castelo-Branco, M. ; Young, A. ; Prieto, C. ; Schnabel, J.A. ; King, A.P.
In: (Statistical Atlases and Computational Models of the Heart. Multi-Disease, Multi-View, and Multi-Center Right Ventricular Segmentation in Cardiac MRI Challenge). 2022. 12-20 (Lect. Notes Comput. Sc. ; 13131 LNCS)
Cine cardiac MRI is routinely acquired for the assessment of cardiac health, but the imaging process is slow and typically requires several breath-holds to acquire sufficient k-space profiles to ensure good image quality. Several undersampling-based reconstruction techniques have been proposed during the last decades to speed up cine cardiac MRI acquisition. However, the undersampling factor is commonly fixed to conservative values before acquisition to ensure diagnostic image quality, potentially leading to unnecessarily long scan times. In this paper, we propose an end-to-end quality-aware cine short-axis cardiac MRI framework that combines image acquisition and reconstruction with downstream tasks such as segmentation, volume curve analysis and estimation of cardiac functional parameters. The goal is to reduce scan time by acquiring only a fraction of k-space data to enable the reconstruction of images that can pass quality control checks and produce reliable estimates of cardiac functional parameters. The framework consists of a deep learning model for the reconstruction of 2D+t cardiac cine MRI images from undersampled data, an image quality-control step to detect good quality reconstructions, followed by a deep learning model for bi-ventricular segmentation, a quality-control step to detect good quality segmentations and automated calculation of cardiac functional parameters. To demonstrate the feasibility of the proposed approach, we perform simulations using a cohort of selected participants from the UK Biobank (n = 270), 200 healthy subjects and 70 patients with cardiomyopathies. Our results show that we can produce quality-controlled images in a scan time reduced from 12 to 4 s per slice, enabling reliable estimates of cardiac functional parameters such as ejection fraction within 5% mean absolute error.
Katsoula G. ; Steinberg, J. ; Tuerlings, M. ; de Almeida, R.C. ; Southam, L. ; Swift, D. ; Wilkinson, J.M. ; Zeggini, E.
Eur. J. Hum. Genet. 30, 557-557 (2022)
Meeting abstract
Meeting abstract
Gehlert, S. ; Weinisch, P. ; Römisch-Margl, W. ; Jaspers, R.T. ; Artati, A. ; Adamski, J. ; Dyar, K.A. ; Aussieker, T. ; Jacko, D. ; Bloch, W. ; Wackerhage, H. ; Kastenmüller, G.
Metabolites 12:445 (2022)
Resistance training promotes metabolic health and stimulates muscle hypertrophy, but the precise routes by which resistance exercise (RE) conveys these health benefits are largely unknown. Aim: To investigate how acute RE affects human skeletal muscle metabolism. Methods: We collected vastus lateralis biopsies from six healthy male untrained volunteers at rest, before the first of 13 RE training sessions, and 45 min after the first and last bouts of RE. Biopsies were analysed using untargeted mass spectrometry-based metabolomics. Results: We measured 617 metabolites covering a broad range of metabolic pathways. In the untrained state RE altered 33 metabolites, including increased 3-methylhistidine and N-lactoylvaline, suggesting increased protein breakdown, as well as metabolites linked to ATP (xanthosine) and NAD (N1-methyl-2-pyridone-5-carboxamide) metabolism; the bile acid chenodeoxycholate also increased in response to RE in muscle opposing previous findings in blood. Resistance training led to muscle hypertrophy, with slow type I and fast/intermediate type II muscle fibre diameter increasing by 10.7% and 10.4%, respectively. Comparison of post-exercise metabolite levels between trained and untrained state revealed alterations of 46 metabolites, including decreased N-acetylated ketogenic amino acids and increased beta-citrylglutamate which might support growth. Only five of the metabolites that changed after acute exercise in the untrained state were altered after chronic training, indicating that training induces multiple metabolic changes not directly related to the acute exercise response. Conclusion: The human skeletal muscle metabolome is sensitive towards acute RE in the trained and untrained states and reflects a broad range of adaptive processes in response to repeated stimulation.
Wissenschaftlicher Artikel
Scientific Article
Pieschner, S. ; Hasenauer, J. ; Fuchs, C.
J. Math. Biol. 84:56 (2022)
Mechanistic models are a powerful tool to gain insights into biological processes. The parameters of such models, e.g. kinetic rate constants, usually cannot be measured directly but need to be inferred from experimental data. In this article, we study dynamical models of the translation kinetics after mRNA transfection and analyze their parameter identifiability. That is, whether parameters can be uniquely determined from perfect or realistic data in theory and practice. Previous studies have considered ordinary differential equation (ODE) models of the process, and here we formulate a stochastic differential equation (SDE) model. For both model types, we consider structural identifiability based on the model equations and practical identifiability based on simulated as well as experimental data and find that the SDE model provides better parameter identifiability than the ODE model. Moreover, our analysis shows that even for those parameters of the ODE model that are considered to be identifiable, the obtained estimates are sometimes unreliable. Overall, our study clearly demonstrates the relevance of considering different modeling approaches and that stochastic models can provide more reliable and informative results.
Wissenschaftlicher Artikel
Scientific Article
Shaikh, B. ; Smith, L.P. ; Vasilescu, D. ; Marupilla, G. ; Wilson, M. ; Agmon, E. ; Agnew, H. ; Andrews, S.S. ; Anwar, A. ; Beber, M.E. ; Bergmann, F.T. ; Brooks, D. ; Brusch, L. ; Calzone, L. ; Choi, K. ; Cooper, J. ; Detloff, J. ; Drawert, B. ; Dumontier, M. ; Ermentrout, G.B. ; Faeder, J.R. ; Freiburger, A.P. ; Fröhlich, F. ; Funahashi, A. ; Garny, A. ; Gennari, J.H. ; Gleeson, P. ; Goelzer, A. ; Haiman, Z. ; Hasenauer, J. ; Hellerstein, J.L. ; Hermjakob, H. ; Hoops, S. ; Ison, J.C. ; Jahn, D. ; Jakubowski, H.V. ; Jordan, R. ; Kalaš, M. ; König, M. ; Liebermeister, W. ; Sheriff, R.S.M. ; Mandal, S. ; McDougal, R. ; Medley, J.K. ; Mendes, P. ; Müller, R. ; Myers, C.J. ; Naldi, A. ; Nguyen, T.V.N. ; Nickerson, D.P. ; Olivier, B.G. ; Patoliya, D. ; Paulevé, L. ; Petzold, L.R. ; Priya, A. ; Rampadarath, A.K. ; Rohwer, J.M. ; Saglam, A.S. ; Singh, D. ; Sinha, A. ; Snoep, J.D. ; Sorby, H. ; Spangler, R. ; Starruß, J. ; Thomas, P.J. ; van Niekerk, D. ; Weindl, D. ; Zhang, F. ; Zhukova, A. ; Goldberg, A.P. ; Schaff, J.C. ; Blinov, M.L. ; Sauro, H.M. ; Moraru, I.I. ; Karr, J.R.
Nucleic Acids Res. 50, W108-W114 (2022)
Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed through a distinct interface. To help investigators find and use simulation tools, we developed BioSimulators (https://biosimulators.org), a central registry of the capabilities of simulation tools and consistent Python, command-line and containerized interfaces to each version of each tool. The foundation of BioSimulators is standards, such as CellML, SBML, SED-ML and the COMBINE archive format, and validation tools for simulation projects and simulation tools that ensure these standards are used consistently. To help modelers find tools for particular projects, we have also used the registry to develop recommendation services. We anticipate that BioSimulators will help modelers exchange, reproduce, and combine simulations.
Wissenschaftlicher Artikel
Scientific Article
Drovandi, S. ; Lipska-Ziętkiewicz, B.S. ; Ozaltin, F. ; Emma, F. ; Gulhan, B. ; Boyer, O. ; Trautmann, A. ; Zietkiewicz, S. ; Xu, H. ; Shen, Q. ; Rao, J.L. ; Riedhammer, K.M. ; Heemann, U. ; Hoefele, J. ; Stenton, S. ; Tsygin, A.N. ; Ng, K.H. ; Fomina, S. ; Benetti, E. ; Aurelle, M. ; Prikhodina, L. ; Schijvens, A.M. ; Tabatabaeifar, M. ; Jankowski, M. ; Baiko, S. ; Mao, J. ; Feng, C. ; Deng, F. ; Rousset-Rouviere, C. ; Stańczyk, M. ; Bałasz-Chmielewska, I. ; Fila, M. ; Durkan, A.M. ; Levart, T.K. ; Dursun, I. ; Esfandiar, N. ; Haas, D. ; Bjerre, A. ; Anarat, A. ; Benz, M.R. ; Talebi, S. ; Hooman, N. ; Ariceta, G. ; Schaefer, F.
Kidney Int., DOI: 10.1016/j.kint.2022.02.040 (2022)
Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, MitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.
Wissenschaftlicher Artikel
Scientific Article
Mutsch, B. ; Heiber, M. ; Grätz, F. ; Hain, R. ; Schönfelder, M. ; Kaps, S. ; Schranner, D. ; Kähler, C.J. ; Wackerhage, H.
Proc. Natl. Acad. Sci. U.S.A. 119:e2202521119 (2022)
SignificanceAirborne transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or other pathogens is probably increased during indoor exercise, but data on the emission of aerosol particles by an exercising individual are lacking. Here, we report that aerosol particle emission increases on average 132-fold from 580 ± 489 particles/min at rest to 76,200 ± 48,000 particles/min during maximal exercise. Aerosol particle emission increases moderately up to an exercise intensity of ≈2 W/kg and exponentially at higher exercise intensities. These data not only explain SARS-CoV-2 transmissions during indoor group exercise but also can be used to design better targeted mitigation measures for physical activity indoors such as physical education in school, dance events during weddings, or high-intensity gym classes such as spinning.
Wissenschaftlicher Artikel
Scientific Article
Muhammad, M.H. ; Prakash, J. ; Liapis, E. ; Ntziachristos, V. ; Jüstel, D.
J. Biophotonics 15:e202100334 (2022)
Acoustic heterogeneities in biological samples are known to cause artefacts in tomographic optoacoustic (photoacoustic) image reconstruction. A statistical weighted model-based reconstruction approach was previously introduced to mitigate such artefacts. However, this approach does not reliably provide high-quality reconstructions for partial-view imaging systems, which are common in preclinical and clinical optoacoustics. In this paper, the capability of the weighted model-based algorithm is extended to generate optoacoustic reconstructions with less distortions for partial-view geometry data. This is achieved by manipulating the weighting scheme based on the detector geometry. Using partial-view optoacoustic tomography data from a tissue-mimicking phantom containing a strong acoustic reflector, tumors grafted onto mice, and a mouse brain with intact skull, the proposed partial-view-corrected weighted model-based algorithm is shown to mitigate reflection artefacts in reconstructed images without distorting structures or boundaries, compared to both conventional model-based and the weighted model-based algorithms. It is also demonstrated that the partial-view-corrected weighted model-based algorithm has the additional advantage of suppressing streaking artefacts due to the partial-view geometry itself in the presence of a very strong optoacoustic chromophore. Due to its enhanced performance, the partial-view-corrected weighted model-based algorithm may prove useful for improving the quality of partial-view multispectral optoacoustic tomography, leading to enhanced visualization of functional parameters such as tissue oxygenation. This article is protected by copyright. All rights reserved.
Wissenschaftlicher Artikel
Scientific Article
Brydges, C.R. ; Bhattacharyya, S. ; Dehkordi, S.M. ; Milaneschi, Y. ; Penninx, B. ; Jansen, R. ; Kristal, B.S. ; Han, X. ; Arnold, M. ; Kastenmüller, G. ; Bekhbat, M. ; Mayberg, H.S. ; Craighead, W.E. ; Rush, A.J. ; Fiehn, O. ; Dunlop, B.W. ; Kaddurah-Daouk, R.
Brain Behav. Immun. 102, 42-52 (2022)
BACKGROUND: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions. METHODS: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism. RESULTS: The IMD clinical dimension and the inflammatory index were positively correlated (r=0.19, p=.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids. CONCLUSION: The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.
Wissenschaftlicher Artikel
Scientific Article
Li, L. ; Zimmer, V.A. ; Schnabel, J.A. ; Zhuang, X.
Med. Image Anal. 77:102360 (2022)
Late gadolinium enhancement magnetic resonance imaging (LGE MRI) is commonly used to visualize and quantify left atrial (LA) scars. The position and extent of LA scars provide important information on the pathophysiology and progression of atrial fibrillation (AF). Hence, LA LGE MRI computing and analysis are essential for computer-assisted diagnosis and treatment stratification of AF patients. Since manual delineations can be time-consuming and subject to intra- and inter-expert variability, automating this computing is highly desired, which nevertheless is still challenging and under-researched. This paper aims to provide a systematic review on computing methods for LA cavity, wall, scar, and ablation gap segmentation and quantification from LGE MRI, and the related literature for AF studies. Specifically, we first summarize AF-related imaging techniques, particularly LGE MRI. Then, we review the methodologies of the four computing tasks in detail and summarize the validation strategies applied in each task as well as state-of-the-art results on public datasets. Finally, the possible future developments are outlined, with a brief survey on the potential clinical applications of the aforementioned methods. The review indicates that the research into this topic is still in the early stages. Although several methods have been proposed, especially for the LA cavity segmentation, there is still a large scope for further algorithmic developments due to performance issues related to the high variability of enhancement appearance and differences in image acquisition.
Review
Review
Sommer, A. ; Peters, A. ; Rommel, M. ; Cyrys, J. ; Grallert, H. ; Haller, D. ; Müller, C. ; Bind, M.C.
PLoS Comput. Biol. 18:e1010044 (2022)
Statistical analysis of microbial genomic data within epidemiological cohort studies holds the promise to assess the influence of environmental exposures on both the host and the host-associated microbiome. However, the observational character of prospective cohort data and the intricate characteristics of microbiome data make it challenging to discover causal associations between environment and microbiome. Here, we introduce a causal inference framework based on the Rubin Causal Model that can help scientists to investigate such environment-host microbiome relationships, to capitalize on existing, possibly powerful, test statistics, and test plausible sharp null hypotheses. Using data from the German KORA cohort study, we illustrate our framework by designing two hypothetical randomized experiments with interventions of (i) air pollution reduction and (ii) smoking prevention. We study the effects of these interventions on the human gut microbiome by testing shifts in microbial diversity, changes in individual microbial abundances, and microbial network wiring between groups of matched subjects via randomization-based inference. In the smoking prevention scenario, we identify a small interconnected group of taxa worth further scrutiny, including Christensenellaceae and Ruminococcaceae genera, that have been previously associated with blood metabolite changes. These findings demonstrate that our framework may uncover potentially causal links between environmental exposure and the gut microbiome from observational data. We anticipate the present statistical framework to be a good starting point for further discoveries on the role of the gut microbiome in environmental health.
Wissenschaftlicher Artikel
Scientific Article
Ayhan, M.S. ; Kuemmerle, L. ; Kühlewein, L. ; Inhoffen, W. ; Aliyeva, G. ; Ziemssen, F. ; Berens, P.
Med. Image Anal. 77:102364 (2022)
Deep neural networks (DNNs) have achieved physician-level accuracy on many imaging-based medical diagnostic tasks, for example classification of retinal images in ophthalmology. However, their decision mechanisms are often considered impenetrable leading to a lack of trust by clinicians and patients. To alleviate this issue, a range of explanation methods have been proposed to expose the inner workings of DNNs leading to their decisions. For imaging-based tasks, this is often achieved via saliency maps. The quality of these maps are typically evaluated via perturbation analysis without experts involved. To facilitate the adoption and success of such automated systems, however, it is crucial to validate saliency maps against clinicians. In this study, we used three different network architectures and developed ensembles of DNNs to detect diabetic retinopathy and neovascular age-related macular degeneration from retinal fundus images and optical coherence tomography scans, respectively. We used a variety of explanation methods and obtained a comprehensive set of saliency maps for explaining the ensemble-based diagnostic decisions. Then, we systematically validated saliency maps against clinicians through two main analyses — a direct comparison of saliency maps with the expert annotations of disease-specific pathologies and perturbation analyses using also expert annotations as saliency maps. We found the choice of DNN architecture and explanation method to significantly influence the quality of saliency maps. Guided Backprop showed consistently good performance across disease scenarios and DNN architectures, suggesting that it provides a suitable starting point for explaining the decisions of DNNs on retinal images.
Wissenschaftlicher Artikel
Scientific Article
Matek, C.
Patterns 3:100426 (2022)
Label-efficient algorithms are of central importance for machine learning applications in many medical fields, where obtaining expert annotations is often expensive and time-consuming. Soni et al. show how contrastive learning can help build classifiers for one of the oldest and most revered methods of clinical medicine: auscultation of heart and lung sounds.
Editorial
Editorial
Cuschieri, S. ; Borg, D. ; Agius, S. ; Scherb, H. ; Grech, V.
J. Egypt. Public Health Assoc. 97:7 (2022)
BACKGROUND: COVID-19 has severely impacted global healthcare services. Malta has only one acute state hospital, Mater Dei Hospital (MDH), and at the time of writing is the most vaccinated country in Europe. Malta thus provides an ideal setting to assess the impact of COVID-19 on healthcare services at population level, including the impact of vaccination on hospital admissions. METHODS: Hospital data was obtained as anonymised totals from MDH's Clinical Performance Unit and the European Centre for Disease Prevention and Control. COVID-19-related data was obtained from the Ministry of Health dashboard. Comparative assessments were performed to explore associations between the COVID-19 situation, vaccination, and hospital activity. Poisson regression was used to model the counts of monthly accident and emergency (A&E), outpatient clinics attendances and hospital admissions. RESULTS: A&E, hospital admissions, and outpatient clinics attendances declined (31.88%; 23.89%; 29.57%; p < 0.01 respectively) with onset of COVID-19 till April 2021 when compared to pre-COVID years (2017-2019). Admissions due to COVID-19 initially increased in parallel to the population's COVID positivity. Vaccination rollout led to a decline in COVID-19 admissions. CONCLUSIONS: The drastic drop in admissions and outpatient attendees was expected but not for A&E attendees as acutely ill patients should still have attended. This is of public health concern since delayed or deferred medical management increases population morbidity, mortality and increases the eventual burden on the healthcare system. Mass vaccination saw the return to normality with an increase in A&E burden.
Wissenschaftlicher Artikel
Scientific Article
Kuchenbaecker, K. ; Gilly, A. ; Suveges, D. ; Southam, L. ; Giannakopoulou, O. ; Kilian, B. ; Tsafantakis, E. ; Karaleftheri, M. ; Farmaki, A.E. ; Gurdasani, D. ; Kundu, K. ; Sandhu, M.S. ; Danesh, J. ; Butterworth, A. ; Barroso, I. ; Dedoussis, G. ; Zeggini, E.
Sci. Rep. 12:1131 (2022)
Haematological traits are linked to cardiovascular, metabolic, infectious and immune disorders, as well as cancer. Here, we examine the role of genetic variation in shaping haematological traits in two isolated Mediterranean populations. Using whole-genome sequencing data at 22× depth for 1457 individuals from Crete (MANOLIS) and 1617 from the Pomak villages in Greece, we carry out a genome-wide association scan for haematological traits using linear mixed models. We discover novel associations (p < 5 × 10–9) of five rare non-coding variants with alleles conferring effects of 1.44–2.63 units of standard deviation on red and white blood cell count, platelet and red cell distribution width. Moreover, 10.0% of individuals in the Pomak population and 6.8% in MANOLIS carry a pathogenic mutation in the Haemoglobin Subunit Beta (HBB) gene. The mutational spectrum is highly diverse (10 different mutations). The most frequent mutation in MANOLIS is the common Mediterranean variant IVS-I-110 (G>A) (rs35004220). In the Pomak population, c.364C>A (“HbO-Arab”, rs33946267) is most frequent (4.4% allele frequency). We demonstrate effects on haematological and other traits, including bilirubin, cholesterol, and, in MANOLIS, height and gestation age. We find less severe effects on red blood cell traits for HbS, HbO, and IVS-I-6 (T>C) compared to other b+ mutations. Overall, we uncover allelic diversity of HBB in Greek isolated populations and find an important role for additional rare variants outside of HBB.
Wissenschaftlicher Artikel
Scientific Article
Maddu, S. ; Sturm, D. ; Müller, C. ; Sbalzarini, I.F.
Mach. Learn.: Sci. Technol. 3:015026 (2022)
We characterize and remedy a failure mode that may arise from multi-scale dynamics with scale imbalances during training of deep neural networks, such as physics informed neural networks (PINNs). PINNs are popular machine-learning templates that allow for seamless integration of physical equation models with data. Their training amounts to solving an optimization problem over a weighted sum of data-fidelity and equation-fidelity objectives. Conflicts between objectives can arise from scale imbalances, heteroscedasticity in the data, stiffness of the physical equation, or from catastrophic interference during sequential training. We explain the training pathology arising from this and propose a simple yet effective inverse Dirichlet weighting strategy to alleviate the issue. We compare with Sobolev training of neural networks, providing the baseline of analytically epsilon-optimal training. We demonstrate the effectiveness of inverse Dirichlet weighting in various applications, including a multi-scale model of active turbulence, where we show orders of magnitude improvement in accuracy and convergence over conventional PINN training. For inverse modeling using sequential training, we find that inverse Dirichlet weighting protects a PINN against catastrophic forgetting.
Wissenschaftlicher Artikel
Scientific Article
Gomez, A. ; Zimmer, V.A. ; Wheeler, G. ; Toussaint, N. ; Deng, S. ; Wright, R. ; Skelton, E. ; Matthew, J. ; Kainz, B. ; Hajnal, J. ; Schnabel, J.A.
SoftwareX 17:100959 (2022)
We present PRETUS — a Plugin-based Real Time UltraSound software platform for live ultrasound image analysis and operator support. The software is lightweight; functionality is brought in via independent plug-ins that can be arranged in sequence. The software allows to capture the real-time stream of ultrasound images from virtually any ultrasound machine, applies computational methods and visualizes the results on-the-fly. Plug-ins can run concurrently without blocking each other. They can be implemented in C++ and Python. A graphical user interface can be implemented for each plug-in, and presented to the user in a compact way. The software is free and open source, and allows for rapid prototyping and testing of real-time ultrasound imaging methods in a manufacturer-agnostic fashion. The software is provided with input, output and processing plug-ins, as well as with tutorials to illustrate how to develop new plug-ins for PRETUS.
Wissenschaftlicher Artikel
Scientific Article
Krenn, M. ; Kepa, S. ; Kasprian, G. ; Riedhammer, K.M. ; Wagner, M. ; Goedl-Fleischhacker, U. ; Milenkovic, I.
Eur. J. Med. Genet. 65:104423 (2022)
Variants in CSDE1, a gene encoding a constrained RNA-binding protein, have recently been associated with a spectrum of neurodevelopmental conditions encompassing autism, seizures and ocular abnormalities. According to previously reported individuals, pathogenic variants in CSDE1 are typically associated with developmental delay and intellectual disability. Here, we report one individual with normal neurodevelopment and adult-onset neuropsychiatric features (i.e., acute psychosis) due to the novel de novo truncating variant c.2272C  >  T, p.(Gln758*) in CSDE1 (NM_001242891.1). Neuropsychological assessment confirmed deficits regarding verbal fluency, semantic memory, executive function and processing speed. Overall, our findings expand the phenotypic spectrum of CSDE1-related disorder towards the mild end.
Wissenschaftlicher Artikel
Scientific Article
Falkai, P. ; Koutsouleris, N. ; Bertsch, K. ; Bialas, M. ; Binder, E. ; Bühner, M. ; Buyx, A. ; Cai, N. ; Cappello, S. ; Ehring, T. ; Gensichen, J. ; Hamann, J. ; Hasan, A. ; Henningsen, P. ; Leucht, S. ; Möhrmann, K.H. ; Nagelstutz, E. ; Padberg, F. ; Peters, A. ; Pfäffel, L. ; Reich-Erkelenz, D. ; Riedl, V. ; Rueckert, D. ; Schmitt, A. ; Schulte-Körne, G. ; Scheuring, E. ; Schulze, T.G. ; Starzengruber, R. ; Stier, S. ; Theis, F.J. ; Winkelmann, J. ; Wurst, W. ; Priller, J.
Front. Psychiatr. 13:815718 (2022)
The Federal Ministry of Education and Research (BMBF) issued a call for a new nationwide research network on mental disorders, the German Center of Mental Health (DZPG). The Munich/Augsburg consortium was selected to participate as one of six partner sites with its concept "Precision in Mental Health (PriMe): Understanding, predicting, and preventing chronicity." PriMe bundles interdisciplinary research from the Ludwig-Maximilians-University (LMU), Technical University of Munich (TUM), University of Augsburg (UniA), Helmholtz Center Munich (HMGU), and Max Planck Institute of Psychiatry (MPIP) and has a focus on schizophrenia (SZ), bipolar disorder (BPD), and major depressive disorder (MDD). PriMe takes a longitudinal perspective on these three disorders from the at-risk stage to the first-episode, relapsing, and chronic stages. These disorders pose a major health burden because in up to 50% of patients they cause untreatable residual symptoms, which lead to early social and vocational disability, comorbidities, and excess mortality. PriMe aims at reducing mortality on different levels, e.g., reducing death by psychiatric and somatic comorbidities, and will approach this goal by addressing interdisciplinary and cross-sector approaches across the lifespan. PriMe aims to add a precision medicine framework to the DZPG that will propel deeper understanding, more accurate prediction, and personalized prevention to prevent disease chronicity and mortality across mental illnesses. This framework is structured along the translational chain and will be used by PriMe to innovate the preventive and therapeutic management of SZ, BPD, and MDD from rural to urban areas and from patients in early disease stages to patients with long-term disease courses. Research will build on platforms that include one on model systems, one on the identification and validation of predictive markers, one on the development of novel multimodal treatments, one on the regulation and strengthening of the uptake and dissemination of personalized treatments, and finally one on testing of the clinical effectiveness, utility, and scalability of such personalized treatments. In accordance with the translational chain, PriMe's expertise includes the ability to integrate understanding of bio-behavioral processes based on innovative models, to translate this knowledge into clinical practice and to promote user participation in mental health research and care.
Review
Review
Loh, M. ; Zhang, W. ; Ng, H.K. ; Schmid, K. ; Lamri, A. ; Tong, L. ; Ahmad, M. ; Lee, J.J. ; Ng, M.C.Y. ; Petty, L.E. ; Spracklen, C.N. ; Takeuchi, F. ; Islam, M.T. ; Jasmine, F. ; Kasturiratne, A. ; Kibriya, M.G. ; Mohlke, K.L. ; Paré, G. ; Prasad, G. ; Shahriar, M. ; Chee, M.L. ; de Silva, H.J. ; Engert, J.C. ; Gerstein, H.C. ; Mani, K.R. ; Sabanayagam, C. ; Vujkovic, M.R. ; Wickremasinghe, A.R. ; Wong, T.Y. ; Yajnik, C.S. ; Yusuf, S. ; Ahsan, H. ; Bharadwaj, D. ; Anand, S.S. ; Below, J.E. ; Boehnke, M. ; Bowden, D.W. ; Chandak, G.R. ; Cheng, C.Y. ; Kato, N. ; Mahajan, A. ; Sim, X. ; McCarthy, M.I. ; Morris, A.P. ; Kooner, J.S. ; Saleheen, D.
Comm. Biol. 5:329 (2022)
South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10-8 to 5.2 × 10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.
Wissenschaftlicher Artikel
Scientific Article
Stirm, L. ; Huypens, P. ; Sass, S. ; Batra, R. ; Fritsche, L. ; Brucker, S. ; Abele, H. ; Hennige, A.M. ; Theis, F.J. ; Beckers, J. ; Hrabě de Angelis, M. ; Fritsche, A. ; Häring, H.-U. ; Staiger, H.
Sci. Rep. 12:6793 (2022)
This Article contains an error in Table 1 where the mean value and standard deviation of pregnancy week for the "screening group:NGT women" was incorrectly given as 23.0 +/- 9.5. The correct numbers are 26.5 +/- 2.1. Incorrect: (Table presented.) Correct: (Table presented.).
Loh, M. ; Zhang, W. ; Ng, H.K. ; Schmid, K. ; Lamri, A. ; Tong, L. ; Ahmad, M. ; Lee, J.J. ; Ng, M.C.Y. ; Petty, L.E. ; Spracklen, C.N. ; Takeuchi, F. ; Islam, M.T. ; Jasmine, F. ; Kasturiratne, A. ; Kibriya, M.G. ; Mohlke, K.L. ; Paré, G. ; Prasad, G. ; Shahriar, M. ; Chee, M.L. ; de Silva, H.J. ; Engert, J.C. ; Gerstein, H.C. ; Mani, K.R. ; Sabanayagam, C. ; Vujkovic, M.R. ; Wickremasinghe, A.R. ; Wong, T.Y. ; Yajnik, C.S. ; Yusuf, S. ; Ahsan, H. ; Bharadwaj, D. ; Anand, S.S. ; Below, J.E. ; Boehnke, M. ; Bowden, D.W. ; Chandak, G.R. ; Cheng, C.Y. ; Kato, N. ; Mahajan, A. ; Sim, X. ; McCarthy, M.I. ; Morris, A.P. ; Kooner, J.S. ; Saleheen, D.
Comm. Biol. 5:441 (2022)
Rospleszcz, S. ; Starnecker, F. ; Linkohr, B. ; von Scheidt, M. ; Gieger, C. ; Schunkert, H. ; Peters, A. ; DigiMed Bayern Consortium (Adam, J.) ; DigiMed Bayern Consortium (Berutti, R.) ; DigiMed Bayern Consortium (Brandmaier, S.)
Diagnostics 12:965 (2022)
The Framingham Risk Score to predict 30-year risk (FRS30y) of cardiovascular disease (CVD) constitutes an important tool for long-term risk prediction. However, due to its complex statistical properties and the paucity of large population-based cohorts with appropriate data, validation of the FRS30y is lacking. A population-based cohort from Southern Germany (N = 3110, 1516 (48.7%) women) was followed up for a median time of 29.5 [18.7, 31.2] years. Discrimination and calibration were assessed for the original, recalibrated and refitted FRS30y version. During follow up, 620 incident CVD events (214 in women) occurred. The FRS30y showed adequate discrimination (original and recalibrated version: Area under the curve (AUC): 78.4 for women and 74.9 for men) but overestimated actual CVD risk (original version: discordance 45.4% for women and 37.3% for men, recalibrated version: 37.6% and 28.6%, respectively). Refitting showed substantial improvement in neither discrimination nor calibration. The performance of FRS30y is adequate for long-term CVD risk prediction and could serve as an important tool in risk communication, especially for younger audiences.
Wissenschaftlicher Artikel
Scientific Article
Ruiz Tejada Segura, M.L. ; Abou Moussa, E. ; Garabello, E. ; Nakahara, T.S. ; Makhlouf, M. ; Mathew, L.S. ; Wang, L. ; Valle, F. ; Huang, S.S.Y. ; Mainland, J.D. ; Caselle, M. ; Osella, M. ; Lorenz, S. ; Reisert, J. ; Logan, D.W. ; Malnic, B. ; Scialdone, A. ; Saraiva, L.R.
Cell Rep. 38:110547 (2022)
The sense of smell helps us navigate the environment, but its molecular architecture and underlying logic remain understudied. The spatial location of odorant receptor genes (Olfrs) in the nose is thought to be independent of the structural diversity of the odorants they detect. Using spatial transcriptomics, we create a genome-wide 3D atlas of the mouse olfactory mucosa (OM). Topographic maps of genes differentially expressed in space reveal that both Olfrs and non-Olfrs are distributed in a continuous and overlapping fashion over at least five broad zones in the OM. The spatial locations of Olfrs correlate with the mucus solubility of the odorants they recognize, providing direct evidence for the chromatographic theory of olfaction. This resource resolves the molecular architecture of the mouse OM and will inform future studies on mechanisms underlying Olfr gene choice, axonal pathfinding, patterning of the nervous system, and basic logic for the peripheral representation of smell.
Wissenschaftlicher Artikel
Scientific Article
Günsel, G.G. ; Conlon, T.M. ; Jeridi, A. ; Kim, R. ; Ertüz, Z. ; Lang, N.J. ; Ansari, M. ; Novikova, M. ; Jiang, D. ; Strunz, M. ; Gaianova, M. ; Hollauer, C. ; Gabriel, C. ; Angelidis, I. ; Doll, S. ; Pestoni, J. ; Edelmann, S.L. ; Kohlhepp, M.S. ; Guillot, A. ; Bassler, K. ; Van Eeckhoutte, H.P. ; Kayalar, Ö. ; Konyalilar, N. ; Kanashova, T. ; Rodius, S. ; Ballester-Lopez, C. ; Genes Robles, C.M. ; Smirnova, N.F. ; Rehberg, M. ; Agarwal, C. ; Krikki, I. ; Piavaux, B. ; Verleden, S.E. ; Vanaudenaerde, B. ; Königshoff, M. ; Dittmar, G. ; Bracke, K.R. ; Schultze, J.L. ; Watz, H. ; Eickelberg, O. ; Stöger, T. ; Burgstaller, G. ; Tacke, F. ; Heissmeyer, V. ; Rinkevich, Y. ; Bayram, H. ; Schiller, H. B. ; Conrad, M. ; Schneider, R. ; Yildirim, A.Ö.
Nat. Commun. 13:1303 (2022)
Extravasation of monocytes into tissue and to the site of injury is a fundamental immunological process, which requires rapid responses via post translational modifications (PTM) of proteins. Protein arginine methyltransferase 7 (PRMT7) is an epigenetic factor that has the capacity to mono-methylate histones on arginine residues. Here we show that in chronic obstructive pulmonary disease (COPD) patients, PRMT7 expression is elevated in the lung tissue and localized to the macrophages. In mouse models of COPD, lung fibrosis and skin injury, reduced expression of PRMT7 associates with decreased recruitment of monocytes to the site of injury and hence less severe symptoms. Mechanistically, activation of NF-κB/RelA in monocytes induces PRMT7 transcription and consequential mono-methylation of histones at the regulatory elements of RAP1A, which leads to increased transcription of this gene that is responsible for adhesion and migration of monocytes. Persistent monocyte-derived macrophage accumulation leads to ALOX5 over-expression and accumulation of its metabolite LTB4, which triggers expression of ACSL4 a ferroptosis promoting gene in lung epithelial cells. Conclusively, inhibition of arginine mono-methylation might offer targeted intervention in monocyte-driven inflammatory conditions that lead to extensive tissue damage if left untreated.
Wissenschaftlicher Artikel
Scientific Article
Stenton, S. ; Tesarova, M. ; Sheremet, N.L. ; Catarino, C. ; Carelli, V. ; Ciara, E. ; Curry, K. ; Engvall, M. ; Fleming, L.R. ; Freisinger, P. ; Iwanicka-Pronicka, K. ; Jurkiewicz, E. ; Klopstock, T. ; Koenig, M.K. ; Kolářová, H. ; Kousal, B. ; Krylova, T. ; La Morgia, C. ; Nosková, L. ; Piekutowska-Abramczuk, D. ; Russo, S.N. ; Stránecký, V. ; Tóthová, I. ; Träisk, F. ; Prokisch, H.
Brain, DOI: 10.1093/brain/awac052 (2022)
The recent description of biallelic DNAJC30 variants in Leber hereditary optic neuropathy (LHON) and Leigh syndrome (LS) challenged the longstanding assumption for LHON to be exclusively maternally inherited and broadened the genetic spectrum of LS, the most frequent paediatric mitochondrial disease. Herein, we characterise 28 so far unreported individuals from 26 families carrying a homozygous DNAJC30 p.Tyr51Cys founder variant, 24 manifesting with LHON, two manifesting with LS, and two remaining asymptomatic. This collection of unreported variant carriers confirms sex-dependent incomplete penetrance of the homozygous variant given a significant male predominance of disease and the report of asymptomatic homozygous variant carriers. The autosomal recessive LHON (arLHON) patients demonstrate an earlier age of disease onset and a higher rate of idebenone-treated and spontaneous recovery of vision in comparison to reported figures for maternally inherited disease (mtLHON). Moreover, the report of two additional patients with childhood- or adult-onset LS further evidences the association of DNAJC30 with LS, previously only reported in a single childhood-onset case.
Wissenschaftlicher Artikel
Scientific Article
Brunner, A.D. ; Thielert, M. ; Vasilopoulou, C.G. ; Ammar, C. ; Coscia, F. ; Mund, A. ; Hoerning, O.B. ; Bache, N. ; Apalategui, A. ; Lubeck, M. ; Richter, S. ; Fischer, D.S. ; Raether, O. ; Park, M.A. ; Meier, F. ; Theis, F.J. ; Mann, M.
Mol. Syst. Biol. 18:e10798 (2022)
Single-cell technologies are revolutionizing biology but are today mainly limited to imaging and deep sequencing. However, proteins are the main drivers of cellular function and in-depth characterization of individual cells by mass spectrometry (MS)-based proteomics would thus be highly valuable and complementary. Here, we develop a robust workflow combining miniaturized sample preparation, very low flow-rate chromatography, and a novel trapped ion mobility mass spectrometer, resulting in a more than 10-fold improved sensitivity. We precisely and robustly quantify proteomes and their changes in single, FACS-isolated cells. Arresting cells at defined stages of the cell cycle by drug treatment retrieves expected key regulators. Furthermore, it highlights potential novel ones and allows cell phase prediction. Comparing the variability in more than 430 single-cell proteomes to transcriptome data revealed a stable-core proteome despite perturbation, while the transcriptome appears stochastic. Our technology can readily be applied to ultra-high sensitivity analyses of tissue material, posttranslational modifications, and small molecule studies from small cell counts to gain unprecedented insights into cellular heterogeneity in health and disease.
Wissenschaftlicher Artikel
Scientific Article
Giehrl-Schwab, J. ; Giesert, F. ; Rauser, B. ; Lao, C.L. ; Hembach, S. ; Lefort, S. ; Ibarra Del Rio, I.A. ; Koupourtidou; C. ; Luecken, M. ; Truong, D.-J.J. ; Fischer-Sternjak, J. ; Masserdotti, G. ; Prakash, N. ; Ninkovic, J. ; Hölter, S.M. ; Vogt Weisenhorn, D.M. ; Theis, F.J. ; Götz, M. ; Wurst, W.
EMBO Mol. Med.:e14797 (2022)
Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock-in mouse line carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV-based strategy carrying intein-split-dCas9 in combination with activators (AAV-dCAS). Both approaches were successful in reprogramming striatal astrocytes into induced GABAergic neurons confirmed by single-cell transcriptome analysis of reprogrammed neurons in vivo. These GABAergic neurons functionally integrate into striatal circuits, alleviating voluntary motor behavior aspects in a 6-OHDA Parkinson's disease model. Our results suggest a novel intervention strategy beyond the restoration of dopamine levels. Thus, the AAV-dCAS approach might enable an alternative route for clinical therapies of Parkinson's disease.
Wissenschaftlicher Artikel
Scientific Article
Tessadori, F. ; Duran, K. ; Knapp, K. ; Fellner, M. ; Smithson, S. ; Beleza Meireles, A. ; Elting, M.W. ; Waisfisz, Q. ; O'Donnell-Luria, A. ; Nowak, C. ; Douglas, J. ; Ronan, A. ; Brunet, T. ; Kotzaeridou, U. ; Svihovec, S. ; Saenz, M.S. ; Thiffault, I. ; Del Viso, F. ; Devine, P. ; Rego, S. ; Tenney, J. ; van Haeringen, A. ; Ruivenkamp, C.A.L. ; Koene, S. ; Robertson, S.P. ; Deshpande, C. ; Pfundt, R. ; Verbeek, N. ; van de Kamp, J.M. ; Weiss, J.M.M. ; Ruiz, A. ; Gabau, E. ; Banne, E. ; Pepler, A. ; Bottani, A. ; Laurent, S. ; Guipponi, M. ; Bijlsma, E. ; Bruel, A.L. ; Sorlin, A. ; Willis, M. ; Powis, Z. ; Smol, T. ; Vincent-Delorme, C. ; Baralle, D. ; Colin, E. ; Revencu, N. ; Calpena, E. ; Wilkie, A.O.M. ; Chopra, M. ; Cormier-Daire, V. ; Keren, B. ; Afenjar, A. ; Niceta, M. ; Terracciano, A. ; Specchio, N. ; Tartaglia, M. ; Rio, M. ; Barcia, G. ; Rondeau, S. ; Colson, C. ; Bakkers, J. ; Mace, P.D. ; Bicknell, L.S. ; van Haaften, G.
Am. J. Hum. Genet. 109, 750-758 (2022)
Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.
Wissenschaftlicher Artikel
Scientific Article
Yépez, V.A. ; Gusic, M. ; Kopajtich, R. ; Mertes, C. ; Smith, N.H. ; Alston, C.L. ; Ban, R. ; Beblo, S. ; Berutti, R. ; Blessing, H. ; Ciara, E. ; Distelmaier, F. ; Freisinger, P. ; Häberle, J. ; Hayflick, S.J. ; Hempel, M. ; Itkis, Y.S. ; Kishita, Y. ; Klopstock, T. ; Krylova, T.D. ; Lamperti, C. ; Lenz, D. ; Makowski, C. ; Mosegaard, S. ; Müller, M.F. ; Muñoz-Pujol, G. ; Nadel, A. ; Ohtake, A. ; Okazaki, Y. ; Procopio, E. ; Schwarzmayr, T. ; Smet, J. ; Staufner, C. ; Stenton, S. ; Strom, T.-M. ; Terrile, C. ; Tort, F. ; van Coster, R. ; Vanlander, A. ; Wagner, M. ; Xu, M. ; Fang, F. ; Ghezzi, D. ; Mayr, J.A. ; Piekutowska-Abramczuk, D. ; Ribes, A. ; Rötig, A. ; Taylor, R.W. ; Wortmann, S.B. ; Murayama, K. ; Meitinger, T. ; Gagneur, J. ; Prokisch, H.
Genome Med. 14:38 (2022)
BACKGROUND: Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics. METHODS: We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage. RESULTS: We detected on average 12,500 genes per sample including around 60% of all disease genes-a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions. CONCLUSION: Together, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics.
Wissenschaftlicher Artikel
Scientific Article
Iturbide Martinez De Albeniz, A. ; Ruiz Tejada Segura, M.L. ; Noll, C. ; Schorpp, K.K. ; Rothenaigner, I. ; Lubatti, G. ; Agami, A. ; Hadian, K. ; Scialdone, A. ; Torres-Padilla, M.E.
Nat. Struct. Mol. Biol. 29:282 (2022)
In the version of this article initially published, the surname of author Mayra L. Ruiz Tejada Segura was misspelled as Ruiz Tejeda Segura. The error has been corrected in the online version of the article.
Yang, Z. ; Macdonald-Dunlop, E. ; Chen, J. ; Zhai, R. ; Li, T. ; Richmond, A. ; Klaric, L. ; Pirastu, N. ; Ning, Z. ; Zheng, C. ; Wang, Y. ; Huang, T. ; He, Y. ; Guo, H. ; Ying, K. ; Gustafsson, S. ; Prins, B. ; Ramisch, A. ; Dermitzakis, E.T. ; Png, G. ; Eriksson, N. ; Haessler, J. ; Hu, X. ; Zanetti, D. ; Boutin, T. ; Hwang, S.J. ; Wheeler, E. ; Pietzner, M. ; Raffield, L.M. ; Kalnapenkis, A. ; Peters, J.E. ; Viñuela, A. ; Gilly, A. ; Elmståhl, S. ; Dedoussis, G. ; Petrie, J.R. ; Polasek, O. ; Folkersen, L. ; Chen, Y. ; Yao, C. ; Võsa, U. ; Pairo-Castineira, E. ; Clohisey, S. ; Bretherick, A.D. ; Rawlik, K. ; Esko, T. ; Enroth, S. ; Johansson, Å ; Gyllensten, U. ; Langenberg, C. ; Levy, D. ; Hayward, C. ; Assimes, T.L. ; Kooperberg, C. ; Manichaikul, A.W. ; Siegbahn, A. ; Wallentin, L. ; Lind, L. ; Zeggini, E. ; Schwenk, J.M. ; Butterworth, A.S. ; Michaelsson, K. ; Pawitan, Y. ; Joshi, P.K. ; Baillie, J.K. ; Mälarstig, A. ; Reiner, A.P. ; Wilson, J.F. ; Shen, X.
Circulation 145, 1398-1411 (2022)
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, enters human cells using the angiotensin-converting enzyme 2 (ACE2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biologic systems. However, the genetic basis of the ACE2 protein levels is not well understood. Methods: We conduct so far the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals of the SCALLOP Consortium. We summarize the cross-sectional epidemiologic correlates of circulating ACE2. Using the summary-statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 disease severity using Mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. Results: We identified ten loci, including eight novel, capturing 30% of the protein's heritability. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-pQTL-based Mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio (OR), 1.63; 95% CI, 1.10 to 2.42; P = 0.01), hospitalization (OR, 1.52; 95% CI, 1.05 to 2.21; P = 0.03), and infection (OR, 1.60; 95% CI, 1.08 to 2.37; P = 0.02). Tissue- and cell-type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.
Wissenschaftlicher Artikel
Scientific Article
Katsoula G. ; Steinberg, J. ; Tuerlings, M. ; de Almeida, R.C. ; Southam, L. ; Swift, D. ; Meulenbelt, I. ; Wilkinson, J.M. ; Zeggini, E.
Osteoarthr. Cartil. 30, S352-S352 (2022)
Meeting abstract
Meeting abstract
Hsieh, T.C. ; Bar-Haim, A. ; Moosa, S. ; Ehmke, N. ; Gripp, K.W. ; Pantel, J.T. ; Danyel, M. ; Mensah, M.A. ; Horn, D. ; Rosnev, S. ; Fleischer, N. ; Bonini, G. ; Hustinx, A. ; Schmid, A. ; Knaus, A. ; Javanmardi, B. ; Klinkhammer, H. ; Lesmann, H. ; Sivalingam, S. ; Kamphans, T. ; Meiswinkel, W. ; Ebstein, F. ; Kruger, E. ; Küry, S. ; Bézieau, S. ; Schmidt, A. ; Peters, S. ; Engels, H. ; Mangold, E. ; Kreiß, M. ; Cremer, K. ; Perne, C. ; Betz, R.C. ; Bender, T. ; Grundmann-Hauser, K. ; Haack, T.B. ; Wagner, M. ; Brunet, T. ; Bentzen, H.B. ; Averdunk, L. ; Coetzer, K.C. ; Lyon, G.J. ; Spielmann, M. ; Schaaf, C.P. ; Mundlos, S. ; Nöthen, M.M. ; Krawitz, P.M.
Nat. Genet. 54, 349-357 (2022)
Many monogenic disorders cause a characteristic facial morphology. Artificial intelligence can support physicians in recognizing these patterns by associating facial phenotypes with the underlying syndrome through training on thousands of patient photographs. However, this ‘supervised’ approach means that diagnoses are only possible if the disorder was part of the training set. To improve recognition of ultra-rare disorders, we developed GestaltMatcher, an encoder for portraits that is based on a deep convolutional neural network. Photographs of 17,560 patients with 1,115 rare disorders were used to define a Clinical Face Phenotype Space, in which distances between cases define syndromic similarity. Here we show that patients can be matched to others with the same molecular diagnosis even when the disorder was not included in the training set. Together with mutation data, GestaltMatcher could not only accelerate the clinical diagnosis of patients with ultra-rare disorders and facial dysmorphism but also enable the delineation of new phenotypes.
Wissenschaftlicher Artikel
Scientific Article
Nakatani, T. ; Lin, J. ; Ji, F. ; Ettinger, A. ; Pontabry, J. ; Tokoro, M. ; Altamirano-Pacheco, L. ; Fiorentino, J. ; Mahammadov, E. ; Hatano, Y. ; Van Rechem, C. ; Chakraborty, D. ; Ruiz-Morales, E.R. ; Scialdone, A. ; Yamagata, K. ; Whetstine, J.R. ; Sadreyev, R.I. ; Torres-Padilla, M.E.
Nat. Genet. 54, 318–327 (2022)
Totipotency emerges in early embryogenesis, but its molecular underpinnings remain poorly characterized. In the present study, we employed DNA fiber analysis to investigate how pluripotent stem cells are reprogrammed into totipotent-like 2-cell-like cells (2CLCs). We show that totipotent cells of the early mouse embryo have slow DNA replication fork speed and that 2CLCs recapitulate this feature, suggesting that fork speed underlies the transition to a totipotent-like state. 2CLCs emerge concomitant with DNA replication and display changes in replication timing (RT), particularly during the early S-phase. RT changes occur prior to 2CLC emergence, suggesting that RT may predispose to gene expression changes and consequent reprogramming of cell fate. Slowing down replication fork speed experimentally induces 2CLCs. In vivo, slowing fork speed improves the reprogramming efficiency of somatic cell nuclear transfer. Our data suggest that fork speed regulates cellular plasticity and that remodeling of replication features leads to changes in cell fate and reprogramming.
Wissenschaftlicher Artikel
Scientific Article
Gayoso, A. ; Lopez, R. ; Xing, G. ; Boyeau, P. ; Valiollah Pour Amiri, V. ; Hong, J. ; Wu, K. ; Jayasuriya, M. ; Mehlman, E. ; Langevin, M. ; Liu, Y. ; Samaran, J. ; Misrachi, G. ; Nazaret, A. ; Clivio, O. ; Xu, C. ; Ashuach, T. ; Gabitto, M. ; Lotfollahi, M. ; Svensson, V. ; da Veiga Beltrame, E. ; Kleshchevnikov, V. ; Talavera-López, C. ; Pachter, L. ; Theis, F.J. ; Streets, A. ; Jordan, M.I. ; Regier, J. ; Yosef, N.
Nat. Biotechnol. 40, 163-166 (2022)
Letter to the Editor
Letter to the Editor
Stenton, S. ; Zou, Y. ; Cheng, H. ; Liu, Z. ; Wang, J. ; Shen, D. ; Jin, H. ; Ding, C. ; Tang, X. ; Sun, S. ; Han, H. ; Ma, Y. ; Zhang, W. ; Jin, R. ; Wang, H. ; Sun, D. ; Lv, J.L. ; Prokisch, H. ; Fang, F.
Ann. Neurol. 91, 466-482 (2022)
OBJECTIVE: Leigh syndrome (LS) is a heterogeneous neurodegenerative disease and the most frequent pediatric manifestation of mitochondrial disease. In the largest patient collection to date, this study aimed to provide new insights into the clinical and genetic spectrum of LS, defect-specific associations, and predictors of disease course and survival. METHODS: Clinical, metabolic, neuroimaging, onset, and survival data were collected from the medical records of 209 patients referred to the Beijing Children's Hospital with symmetrical basal ganglia and/or brainstem neuroimaging changes indicative of LS by 30 centers from the Chinese network of mitochondrial disease (mitoC-NET) between January 2013 and July 2021 for exploratory analysis. RESULTS: Pathogenic variants were identified in 52 genes, most frequently MT-ATP6, SURF1, and PDHA1. Maternally inherited variants accounted for 42% (heteroplasmy level ≥ 90% in 64%). Phenotypes spanned 92 Human Phenotype Ontology terms. Elevated serum lactate (144/195), global developmental delay (142/209), and developmental regression (103/209) were most frequent. Discriminating neuroimaging and/or clinical features were identified for MT-ATP6 (m.9176 T > C), MT-ND5, PDHA1, SUCLG1, and SURF1. Poorest survival was associated with MT-ND5, MT-ATP6 (m.8993 T > C and m.9176 T > C), SURF1, and ALDH5A1 (≤50% 3 year survival), in contrast to milder defects with specific treatment (ECHS1 and SLC19A3, 100% 3 year survival). INTERPRETATION: Our data define phenotype, onset, and survival of LS in a defect-specific manner, identifying features discriminating between genetic defects and predictive of disease outcome. These findings are essential to early diagnosis, in optimizing family counselling, and to the design and monitoring of future clinical trials, the next frontier of LS research. This article is protected by copyright. All rights reserved.
Wissenschaftlicher Artikel
Scientific Article
Palla, G. ; Spitzer, H. ; Klein, M. ; Fischer, D.S. ; Schaar, A. ; Kuemmerle, L. ; Rybakov, S. ; Ibarra Del Rio, I.A. ; Holmberg, O. ; Virshup, I. ; Lotfollahi, M. ; Richter, S. ; Theis, F.J.
Nat. Methods 19, 171–178 (2022)
Spatial omics data are advancing the study of tissue organization and cellular communication at an unprecedented scale. Flexible tools are required to store, integrate and visualize the large diversity of spatial omics data. Here, we present Squidpy, a Python framework that brings together tools from omics and image analysis to enable scalable description of spatial molecular data, such as transcriptome or multivariate proteins. Squidpy provides efficient infrastructure and numerous analysis methods that allow to efficiently store, manipulate and interactively visualize spatial omics data. Squidpy is extensible and can be interfaced with a variety of already existing libraries for the scalable analysis of spatial omics data.
Wissenschaftlicher Artikel
Scientific Article
Romer, P. ; Filbir, F. ; Krahmer, F.
In: (55th Asilomar Conference on Signals, Systems and Computers, ACSSC 2021, 31 October - 3 November 2021, Virtual, Pacific Grov). 2022. 847-851 ( ; 2021-October)
We investigate a variant of the randomized Kaczmarz algorithm as a method for solving the phase retrieval problem. The main contribution of this paper is a recovery guarantee for phase retrieval from measurements perturbed with additive noise via the randomized Kaczmarz algorithm. We consider the scenario that the measurement vectors are drawn independently and uniformly at random from the unit sphere and that the number of measurements is a sufficiently large multiple of the dimension. We show that, with high probability, the randomized Kaczmarz algorithm converges to a neighborhood around the ground-truth solution whose radius depends on the noise level.
Offer, S. ; Hartner, E. ; Di Bucchianico, S. ; Bisig, B. ; Bauer, S. ; Pantzke, J. ; Zimmermann, E. ; Cao, X. ; Binder, S. ; Kuhn, E. ; Huber, A. ; Jeong, S. ; Käfer, U. ; Martens, P. ; Mesceriakovas, A. ; Bendl, J. ; Brejcha, R. ; Buchholz, A. ; Gat, D. ; Hohaus, T. ; Rastak, N. ; Jakobi, G. ; Kalberer, M. ; Kanashova, T. ; Hu, Y. ; Ogris, C. ; Marsico, A. ; Theis, F.J. ; Pardo, M. ; Gröger, T.M. ; Oeder, S. ; Orasche, J. ; Paul, A. ; Ziehm, T. ; Zhang, Z.H. ; Adam, T. ; Sippula, O. ; Sklorz, M. ; Schnelle-Kreis, J. ; Czech, H. ; Kiendler-Scharr, A. ; Rudich, Y. ; Zimmermann, R.
Environ. Health Perspect. 130:27003 (2022)
BACKGROUND: Secondary organic aerosols (SOAs) formed from anthropogenic or biogenic gaseous precursors in the atmosphere substantially contribute to the ambient fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5)] burden, which has been associated with adverse human health effects. However, there is only limited evidence on their differential toxicological impact. OBJECTIVES: We aimed to discriminate toxicological effects of aerosols generated by atmospheric aging on combustion soot particles (SPs) of gaseous biogenic (β-pinene) or anthropogenic (naphthalene) precursors in two different lung cell models exposed at the air-liquid interface (ALI). METHODS: Mono- or cocultures of lung epithelial cells (A549) and endothelial cells (EA.hy926) were exposed at the ALI for 4 h to different aerosol concentrations of a photochemically aged mixture of primary combustion SP and β-pinene (SOAβPIN-SP) or naphthalene (SOANAP-SP). The internally mixed soot/SOA particles were comprehensively characterized in terms of their physical and chemical properties. We conducted toxicity tests to determine cytotoxicity, intracellular oxidative stress, primary and secondary genotoxicity, as well as inflammatory and angiogenic effects. RESULTS: We observed considerable toxicity-related outcomes in cells treated with either SOA type. Greater adverse effects were measured for SOANAP-SP compared with SOAβPIN-SP in both cell models, whereas the nano-sized soot cores alone showed only minor effects. At the functional level, we found that SOANAP-SP augmented the secretion of malondialdehyde and interleukin-8 and may have induced the activation of endothelial cells in the coculture system. This activation was confirmed by comet assay, suggesting secondary genotoxicity and greater angiogenic potential. Chemical characterization of PM revealed distinct qualitative differences in the composition of the two secondary aerosol types. DISCUSSION: In this study using A549 and EA.hy926 cells exposed at ALI, SOA compounds had greater toxicity than primary SPs. Photochemical aging of naphthalene was associated with the formation of more oxidized, more aromatic SOAs with a higher oxidative potential and toxicity compared with β-pinene. Thus, we conclude that the influence of atmospheric chemistry on the chemical PM composition plays a crucial role for the adverse health outcome of emissions. https://doi.org/10.1289/EHP9413.
Wissenschaftlicher Artikel
Scientific Article
Grech, V. ; Scherb, H.
Med. Princ. Pract. 31, 83-87 (2022)
OBJECTIVE: In humans, males are born slightly in excess of females. Many factors have been shown to affect this ratio, including stressful events such as terrorist attacks. Two shootings occurred in early August 2019 in the Oregon District in Dayton, Montgomery County, Ohio, and in El Paso County, Texas, in the USA. This study was carried out in order to identify whether there were any effects on sex ratio at birth at the state or county level 3-5 months later. SUBJECT AND METHODS: Births by sex, month of birth (2015-2019), and county were obtained for Ohio and Texas from the website of the Centers for Disease Control and Prevention. Ordinary linear logistic regression was used to assess the time trend in the probability of boys and to investigate changes in the trend functions. Poisson regression (SAS GENMOD) and linear logistic regression using SAS procedure LOGISTIC was applied. RESULTS: This study analyzed 2,623,714 live births, 1,939,938 in Texas (sex odds [SO] 1.044) and 683,776 in Ohio (SO 1.045). The only significant effect noted was seasonality (month) at the state level. CONCLUSION: It has been postulated that male fetal loss in pregnant women during stressful periods may occur in accordance with the Trivers-Willard hypothesis. Several studies have found significant effects after terrorist attacks in the USA (as well as in other countries), but this study did not reveal such effects. This may be due to several reasons including underpowered datasets and the possibility that populations may be becoming relatively immured to these events.
Wissenschaftlicher Artikel
Scientific Article
Wörheide, M. ; Krumsiek, J. ; Kastenmüller, G. ; Kaddurah-Daouk, R.F. ; Arnold, M.
Alzheimers Dement. 17, 3:e056673 (2022)
BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disorder for which there currently are no disease-modifying treatments available. To accelerate the path to effective intervention strategies, drug repositioning - the application of available compounds in a novel disease context - has gained increasing attention as a promising alternative to de novo drug development. Rich multi-omics data, generated by large international and interdisciplinary AD consortia, is now enabling the implementation of novel methods that have the potential to drive the computational identification and prioritization of promising repositioning candidates. METHOD: We recently developed the AD atlas, a web-based multi-omics resource that integrates multiple layers of heterogenous data from different studies and cohorts, including omics QTLs, transcriptomic, proteomic and metabolomic correlation networks, as well as genetic and multi-omics associations with AD and associated biomarkers/endophenotypes. Using this atlas, we generated and analyzed molecular context networks surrounding AD-associated genes as well as those targeted by drug repositioning candidates proposed in the literature. Subsequent enrichment analysis on AD subnetworks was used to identify drugs with overlapping molecular signatures on the gene expression level, while target networks of repositioning candidates were investigated for their potential involvement in AD pathogenesis. RESULT: We found ample evidence for the potential of integrative multi-omics approaches for drug repositioning in AD. For instance, enrichment analysis of the context network surrounding the AD-associated genes APOE and CLU identified multiple repositioning candidates, where the top hits were drugs that were either previously proposed as promising or already subjected to clinical trials, such as fluoxetine, rosiglitazone, and valproate. Investigating candidate drugs, the exploration of the context network targeted by statins revealed functional links to TYROBP/TREM2 signaling, suggesting a potential protective effect of this drug class through modulation of neuroinflammatory pathways. CONCLUSION: Our results highlight multiple opportunities to advance drug repositioning efforts in AD by integrative analysis of comprehensive multi-omics data. Automation of our analyses using network-based machine learning approaches and extension of the AD atlas with multi-omics data from drug screens to resolve directionalities will allow us to globally identify molecular pathways disturbed in AD that are targetable by drug repositioning candidates.
Meeting abstract
Meeting abstract
Palla, G. ; Fischer, D.S. ; Regev, A. ; Theis, F.J.
Nat. Biotechnol. 40, 308–318 (2022)
Methods for profiling RNA and protein expression in a spatially resolved manner are rapidly evolving, making it possible to comprehensively characterize cells and tissues in health and disease. To maximize the biological insights obtained using these techniques, it is critical to both clearly articulate the key biological questions in spatial analysis of tissues and develop the requisite computational tools to address them. Developers of analytical tools need to decide on the intrinsic molecular features of each cell that need to be considered, and how cell shape and morphological features are incorporated into the analysis. Also, optimal ways to compare different tissue samples at various length scales are still being sought. Grouping these biological problems and related computational algorithms into classes across length scales, thus characterizing common issues that need to be addressed, will facilitate further progress in spatial transcriptomics and proteomics.
Review
Review
Caldi Gomes, L. ; Galhoz, A. ; Jain, G. ; Roser, A.E. ; Maass, F. ; Carboni, E. ; Barski, E. ; Lenz, C. ; Lohmann, K. ; Klein, C. ; Bähr, M. ; Fischer, A. ; Menden, M. ; Lingor, P.
Clin. Transl. Med. 12:e692 (2022)
BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The molecular mechanisms underpinning the pathophysiology of sporadic PD remain incompletely understood. Therefore, causative therapies are still elusive. To obtain a more integrative view of disease-mediated alterations, we investigated the molecular landscape of PD in human post-mortem midbrains, a region that is highly affected during the disease process. METHODS: Tissue from 19 PD patients and 12 controls were obtained from the Parkinson's UK Brain Bank and subjected to multi-omic analyses: small and total RNA sequencing was performed on an Illumina's HiSeq4000, while proteomics experiments were performed in a hybrid triple quadrupole-time of flight mass spectrometer (TripleTOF5600+) following quantitative sequential window acquisition of all theoretical mass spectra. Differential expression analyses were performed with customized frameworks based on DESeq2 (for RNA sequencing) and with Perseus v.1.5.6.0 (for proteomics). Custom pipelines in R were used for integrative studies. RESULTS: Our analyses revealed multiple deregulated molecular targets linked to known disease mechanisms in PD as well as to novel processes. We have identified and experimentally validated (quantitative real-time polymerase chain reaction/western blotting) several PD-deregulated molecular candidates, including miR-539-3p, miR-376a-5p, miR-218-5p and miR-369-3p, the valid miRNA-mRNA interacting pairs miR-218-5p/RAB6C and miR-369-3p/GTF2H3, as well as multiple proteins, such as CHI3L1, HSPA1B, FNIP2 and TH. Vertical integration of multi-omic analyses allowed validating disease-mediated alterations across different molecular layers. Next to the identification of individual molecular targets in all explored omics layers, functional annotation of differentially expressed molecules showed an enrichment of pathways related to neuroinflammation, mitochondrial dysfunction and defects in synaptic function. CONCLUSIONS: This comprehensive assessment of PD-affected and control human midbrains revealed multiple molecular targets and networks that are relevant to the disease mechanism of advanced PD. The integrative analyses of multiple omics layers underscore the importance of neuroinflammation, immune response activation, mitochondrial and synaptic dysfunction as putative therapeutic targets for advanced PD.
Wissenschaftlicher Artikel
Scientific Article
Luecken, M. ; Zaragosi, L.E. ; Madissoon, E. ; Sikkema, L. ; Firsova, A.B. ; De Domenico, E. ; Kuemmerle, L. ; Saglam, A. ; Berg, M. ; Gay, A.C.A. ; Schniering, J. ; Mayr, C. ; Abalo, X.M. ; Larsson, L. ; Sountoulidis, A. ; Teichmann, S. ; van Eunen, K. ; Koppelman, G.H. ; Saeb-Parsy, K. ; Leroy, S. ; Powell, P. ; Sarkans, U. ; Timens, W. ; Lundeberg, J. ; van den Berge, M. ; Nilsson, M. ; Horváth, P. ; Denning, J. ; Papatheodorou, I. ; Schultze, J.L. ; Schiller, H. B. ; Barbry, P. ; Petoukhov, I. ; Misharin, A.V. ; Adcock, I. ; von Papen, M. ; Theis, F.J. ; Samakovlis, C. ; Meyer, K.B. ; Nawijn, M.C.
Eur. Respir. J. 59:2102057 (2022)
The Human Cell Atlas (HCA) consortium aims to establish an atlas of all organs in the healthy human body at single-cell resolution to increase our understanding of basic biological processes that govern development, physiology and anatomy, and to accelerate diagnosis and treatment of disease. The lung biological network of the HCA aims to generate the Human Lung Cell Atlas as a reference for the cellular repertoire, molecular cell states and phenotypes, and the cell-cell interactions that characterise normal lung homeostasis in healthy lung tissue. Such a reference atlas of the healthy human lung will facilitate mapping the changes in the cellular landscape in disease. The discovAIR project is one of six pilot actions for the HCA funded by the European Commission in the context of the H2020 framework program. DiscovAIR aims to establish the first draft of an integrated Human Lung Cell Atlas, combining single-cell transcriptional and epigenetic profiling with spatially resolving techniques on matched tissue samples, as well as including a number of chronic and infectious diseases of the lung. The integrated Lung Cell Atlas will be available as a resource for the wider respiratory community, including basic and translational scientists, clinical medicine, and the private sector, as well as for patients with lung disease and the interested lay public. We anticipate that the Lung Cell Atlas will be the founding stone for a more detailed understanding of the pathogenesis of lung diseases, guiding the design of novel diagnostics and preventive or curative interventions.
Review
Review
Han, S. ; Huang, J. ; Foppiano, F. ; Prehn, C. ; Adamski, J. ; Suhre, K. ; Li, Y. ; Matullo, G. ; Schliess, F. ; Gieger, C. ; Peters, A. ; Wang-Sattler, R.
Brief. Bioinform. 23:bbab535 (2022)
Large metabolomics datasets inevitably contain unwanted technical variations which can obscure meaningful biological signals and affect how this information is applied to personalized healthcare. Many methods have been developed to handle unwanted variations. However, the underlying assumptions of many existing methods only hold for a few specific scenarios. Some tools remove technical variations with models trained on quality control (QC) samples which may not generalize well on subject samples. Additionally, almost none of the existing methods supports datasets with multiple types of QC samples, which greatly limits their performance and flexibility. To address these issues, a non-parametric method TIGER (Technical variation elImination with ensemble learninG architEctuRe) is developed in this study and released as an R package (https://CRAN.R-project.org/package=TIGERr). TIGER integrates the random forest algorithm into an adaptable ensemble learning architecture. Evaluation results show that TIGER outperforms four popular methods with respect to robustness and reliability on three human cohort datasets constructed with targeted or untargeted metabolomics data. Additionally, a case study aiming to identify age-associated metabolites is performed to illustrate how TIGER can be used for cross-kit adjustment in a longitudinal analysis with experimental data of three time-points generated by different analytical kits. A dynamic website is developed to help evaluate the performance of TIGER and examine the patterns revealed in our longitudinal analysis (https://han-siyu.github.io/TIGER_web/). Overall, TIGER is expected to be a powerful tool for metabolomics data analysis.
Wissenschaftlicher Artikel
Scientific Article
Hawe, J. ; Wilson, R. ; Schmid, K. ; Zhou, L. ; Lakshmanan, L.N. ; Lehne, B.C. ; Kühnel, B. ; Scott, W.R. ; Wielscher, M. ; Yew, Y.W. ; Baumbach, C. ; Lee, D.P. ; Marouli, E. ; Bernard, M. ; Pfeiffer, L. ; Matias-Garcia, P.R. ; Autio, M.I. ; Bourgeois, S. ; Herder, C. ; Karhunen, V. ; Meitinger, T. ; Prokisch, H. ; Rathmann, W. ; Roden, M. ; Sebert, S. ; Shin, J. ; Strauch, K. ; Zhang, W. ; Tan, W.L.W. ; Hauck, S.M. ; Merl-Pham, J. ; Grallert, H. ; Barbosa, E.G.V. ; Illig, T. ; Peters, A. ; Paus, T. ; Pausova, Z. ; Deloukas, P. ; Foo, R.S.Y. ; Jarvelin, M.R. ; Kooner, J.S. ; Loh, M. ; Heinig, M. ; Gieger, C. ; Waldenberger, M. ; Chambers, J.C.
Nat. Genet. 54, 18–29 (2022)
We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P < 10-14), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961 , chromatin immunoprecipitation followed by sequencing (ChIP-seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+ T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.
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Scientific Article
Esch, T. ; Brzoska, E. ; Dech, S. ; Leutner, B. ; Palacios-Lopez, D. ; Metz-Marconcini, A. ; Marconcini, M. ; Roth, A. ; Zeidler, J.
Remote Sens. Environ. 270:112877 (2022)
Settlements, and in particular cities, are at the center of key future challenges related to global change and sustainable development. Widely used indicators to assess the efficiency and sustainability of settlement development are the compactness and density of the built-up area. However, at global scale, a temporally consistent and spatially detailed survey of the distribution and concentration of the building stock – meaning the total area and volume of buildings within a defined spatial unit or settlement, commonly referred to as building density – does not yet exist. To fill this data and knowledge gap, an approach was developed to map key characteristics of the world's building stock in a so far unprecedented level of spatial detail for every single settlement on our planet. The resulting World Settlement Footprint 3D dataset quantifies the fraction, total area, average height, and total volume of buildings for a measuring grid with 90 m cell size. The World Settlement Footprint 3D is generated using a modified version of the World Settlement Footprint human settlements mask derived from Sentinel-1 and Sentinel-2 satellite imagery at 10 m spatial resolution, in combination with 12 m digital elevation data and radar imagery collected by the TanDEM-X mission. The underlying, automated processing framework includes three basic workflows: one estimating the mean building height based on an analysis of height differences along potential building edges, a second module determining the building fraction and total building area within each 90 m cell, and a third part combining the height information and building area in order to determine the average height and total built-up volume at 90 m gridding. Optionally, a simple 3D building model (level of detail 1) can be generated for regions where data on the building footprints is available. A comprehensive validation campaign based on 3D building models obtained for 19 regions (~86,000 km2) and street-view samples indicating the number of floors for >130,000 individual buildings in 15 additional cities documents that the novel World Settlement Footprint 3D data provides valuable and, for the first time, globally consistent information on key characteristics of the building stock in both, large urban agglomerations as well as small-scale rural settlements. Thus, the new dataset represents a promising baseline dataset for a wide range of previously impossible environmental, socioeconomic, and climatological studies worldwide.
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Scientific Article
Lange, M. ; Bergen, V. ; Klein, M. ; Setty, M. ; Reuter, B. ; Bakhti, M. ; Lickert, H. ; Ansari, M. ; Schniering, J. ; Schiller, H. B. ; Pe'er, D. ; Theis, F.J.
Nat. Methods 19, 159–170 (2022)
Computational trajectory inference enables the reconstruction of cell state dynamics from single-cell RNA sequencing experiments. However, trajectory inference requires that the direction of a biological process is known, largely limiting its application to differentiating systems in normal development. Here, we present CellRank ( https://cellrank.org ) for single-cell fate mapping in diverse scenarios, including regeneration, reprogramming and disease, for which direction is unknown. Our approach combines the robustness of trajectory inference with directional information from RNA velocity, taking into account the gradual and stochastic nature of cellular fate decisions, as well as uncertainty in velocity vectors. On pancreas development data, CellRank automatically detects initial, intermediate and terminal populations, predicts fate potentials and visualizes continuous gene expression trends along individual lineages. Applied to lineage-traced cellular reprogramming data, predicted fate probabilities correctly recover reprogramming outcomes. CellRank also predicts a new dedifferentiation trajectory during postinjury lung regeneration, including previously unknown intermediate cell states, which we confirm experimentally.
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Scientific Article
Magaletta, M.E. ; Lobo, M. ; Kernfeld, E.M. ; Aliee, H. ; Huey, J.D. ; Parsons, T.J. ; Theis, F.J. ; Maehr, R.
Nat. Commun. 13:457 (2022)
Maldevelopment of the pharyngeal endoderm, an embryonic tissue critical for patterning of the pharyngeal region and ensuing organogenesis, ultimately contributes to several classes of human developmental syndromes and disorders. Such syndromes are characterized by a spectrum of phenotypes that currently cannot be fully explained by known mutations or genetic variants due to gaps in characterization of critical drivers of normal and dysfunctional development. Despite the disease-relevance of pharyngeal endoderm, we still lack a comprehensive and integrative view of the molecular basis and gene regulatory networks driving pharyngeal endoderm development. To close this gap, we apply transcriptomic and chromatin accessibility single-cell sequencing technologies to generate a multi-omic developmental resource spanning pharyngeal endoderm patterning to the emergence of organ-specific epithelia in the developing mouse embryo. We identify cell-type specific gene regulation, distill GRN models that define developing organ domains, and characterize the role of an immunodeficiency-associated forkhead box transcription factor.
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Scientific Article
Assum, I. ; Krause, J. ; Scheinhardt, M.O. ; Müller, C. ; Hammer, E. ; Börschel, C.S. ; Völker, U. ; Conradi, L. ; Geelhoed, B. ; Zeller, T. ; Schnabel, R.B. ; Heinig, M.
Nat. Commun. 13:441 (2022)
Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, refined multi-omics approaches are needed for deciphering the underlying molecular networks. Here, we integrate genomics, transcriptomics, and proteomics of human atrial tissue in a cross-sectional study to identify widespread effects of genetic variants on both transcript (cis-eQTL) and protein (cis-pQTL) abundance. We further establish a novel targeted trans-QTL approach based on polygenic risk scores to determine candidates for AF core genes. Using this approach, we identify two trans-eQTLs and five trans-pQTLs for AF GWAS hits, and elucidate the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and AF. Altogether, we present an integrative multi-omics method to uncover trans-acting networks in small datasets and provide a rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization.
Wissenschaftlicher Artikel
Scientific Article
Wang, T. ; Huynh, K. ; Giles, C. ; Mellett, N.A. ; Duong, T. ; Nguyen, A. ; Lim, W.L.F. ; Smith, A.A.T. ; Olshansky, G. ; Cadby, G. ; Hung, J. ; Hui, J. ; Beilby, J. ; Watts, G.F. ; Chatterjee, P. ; Martins, I. ; Laws, S.M. ; Bush, A.I. ; Rowe, C.C. ; Villemagne, V.L. ; Ames, D. ; Masters, C.L. ; Taddei, K. ; Doré, V. ; Fripp, J. ; Arnold, M. ; Kastenmüller, G. ; Nho, K. ; Saykin, A.J. ; Baillie, R. ; Han, X. ; Martins, R.N. ; Moses, E.K. ; Kaddurah-Daouk, R. ; Meikle, P.J.
Alzheimers Dement., DOI: 10.1002/alz.12538 (2022)
Introduction: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.
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Scientific Article
Ringeling, F.R. ; Chakraborty, S. ; Vissers, C. ; Reiman, D. ; Patel, A.M. ; Lee, K.H. ; Hong, A. ; Park, C.W. ; Reska, T. ; Gagneur, J. ; Chang, H. ; Spletter, M.L. ; Yoon, K.J. ; Ming, G.l. ; Song, H. ; Canzar, S.
Nat. Biotechnol. 40, 741–750 (2022)
The accuracy of methods for assembling transcripts from short-read RNA sequencing data is limited by the lack of long-range information. Here we introduce Ladder-seq, an approach that separates transcripts according to their lengths before sequencing and uses the additional information to improve the quantification and assembly of transcripts. Using simulated data, we show that a kallisto algorithm extended to process Ladder-seq data quantifies transcripts of complex genes with substantially higher accuracy than conventional kallisto. For reference-based assembly, a tailored scheme based on the StringTie2 algorithm reconstructs a single transcript with 30.8% higher precision than its conventional counterpart and is more than 30% more sensitive for complex genes. For de novo assembly, a similar scheme based on the Trinity algorithm correctly assembles 78% more transcripts than conventional Trinity while improving precision by 78%. In experimental data, Ladder-seq reveals 40% more genes harboring isoform switches compared to conventional RNA sequencing and unveils widespread changes in isoform usage upon m6A depletion by Mettl14 knockout.
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Scientific Article
Stapor, P. ; Schmiester, L. ; Wierling, C. ; Merkt, S. ; Pathirana, D. ; Lange, B.M.H. ; Weindl, D. ; Hasenauer, J.
Nat. Commun. 13:34 (2022)
Quantitative dynamic models are widely used to study cellular signal processing. A critical step in modelling is the estimation of unknown model parameters from experimental data. As model sizes and datasets are steadily growing, established parameter optimization approaches for mechanistic models become computationally extremely challenging. Mini-batch optimization methods, as employed in deep learning, have better scaling properties. In this work, we adapt, apply, and benchmark mini-batch optimization for ordinary differential equation (ODE) models, thereby establishing a direct link between dynamic modelling and machine learning. On our main application example, a large-scale model of cancer signaling, we benchmark mini-batch optimization against established methods, achieving better optimization results and reducing computation by more than an order of magnitude. We expect that our work will serve as a first step towards mini-batch optimization tailored to ODE models and enable modelling of even larger and more complex systems than what is currently possible.
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Scientific Article
Sherman, E. ; Alejo, D. ; Wood-Doughty, Z. ; Sussman, M. ; Schena, S. ; Ong, C.S. ; Etchill, E. ; Dinatale, J. ; Ahmidi, N. ; Shpitser, I. ; Whitman, G.
Ann. Thorac. Surg., DOI: 10.1016/j.athoracsur.2021.11.011 (2022)
Background: Hospital readmission within 30 days of discharge is a well-studied outcome. Predicting readmission after cardiac surgery, however, is notoriously challenging; the best-performing models in the literature have areas under the curve around .65. A reliable predictive model would enable clinicians to identify patients at risk for readmission and to develop prevention strategies. Methods: We analyzed The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database at our institution, augmented with electronic medical record data. Predictors included demographics, preoperative comorbidities, proxies for intraoperative risk, indicators of postoperative complications, and time series-derived variables. We trained several machine learning models, evaluating each on a held-out test set. Results: Our analysis cohort consisted of 4924 cases from 2011 to 2016. Of those, 723 (14.7%) were readmitted within 30 days of discharge. Our models included 141 STS-derived and 24 electronic medical records-derived variables. A random forest model performed best, with test area under the curve 0.76 (95% confidence interval, 0.73 to 0.79). Using exclusively preoperative variables, as in STS calculated risk scores, degraded the area under the curve, to 0.64 (95% confidence interval, 0.60 to 0.68). Key predictors included length of stay (12.5 times more important than the average variable) and whether the patient was discharged to a rehabilitation facility (11.2 times). Conclusions: Our approach, augmenting STS variables with electronic medical records data and using flexible machine learning modeling, yielded state-of-the-art performance for predicting 30-day readmission. Separately, the importance of variables not directly related to inpatient care, such as discharge location, amplifies questions about the efficacy of assessing care quality by readmissions.
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Scientific Article
Škorvánek, M. ; Rektorová, I. ; Mandemakers, W. ; Wagner, M. ; Steinfeld, R. ; Orec, L. ; Han, V. ; Pavelekova, P. ; Lackova, A. ; Kulcsarová, K. ; Ostrozovičová, M. ; Gdovinova, Z. ; Plecko, B. ; Brunet, T. ; Berutti, R. ; Kuipers, D.J.S. ; Boumeester, V. ; Havránková, P. ; Tijssen, M.A.J. ; Kaiyrzhanov, R. ; Rizig, M. ; Houlden, H. ; Winkelmann, J. ; Bonifati, V. ; Zech, M. ; Jech, R.
Parkinsonism Relat. Disord. 94, 54-61 (2022)
INTRODUCTION: Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia. METHODS: Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed. RESULTS: A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonus-ataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patient-derived fibroblasts showed a markedly decreased expression of the full-length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity. CONCLUSIONS: This study expands the spectrum of the disease to later onset phenotypes of early-onset tremor-dominant parkinsonism and progressive myoclonus-ataxia phenotypes.
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Scientific Article
Castaneda, A.B. ; Petty, L.E. ; Scholz, M. ; Jansen, R. ; Weiss, S. ; Zhang, X. ; Schramm, K. ; Beutner, F. ; Kirsten, H. ; Schminke, U. ; Hwang, S.J. ; Marzi, C. ; Dhana, K. ; Seldenrijk, A. ; Krohn, K. ; Homuth, G. ; Wolf, P. ; Peters, M.J. ; Dörr, M. ; Peters, A. ; van Meurs, J.B.J. ; Uitterlinden, A.G. ; Kavousi, M. ; Levy, D. ; Herder, C. ; Grootheest, G. ; Waldenberger, M. ; Meisinger, C. ; Rathmann, W. ; Thiery, J. ; Polak, J.F. ; Koenig, W. ; Seissler, J. ; Bis, J.C. ; Franceshini, N. ; Giambartolomei, C. ; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Subclinical Working Group ; Hofman, A. ; Franco, O.H. ; Penninx, B.W.J.H. ; Prokisch, H. ; Völzke, H. ; Loeffler, M. ; O'Donnell, C.J. ; Below, J.E. ; Dehghan, A. ; de Vries, P.S.
Hum. Mol. Genet. 31, 1171-1182 (2022)
Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent genome-wide association study on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD, and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL, and TLN2 as new candidate genes whose differential expression might modulate cIMT.
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Scientific Article
Meier, A.B. ; Raj Murthi, S. ; Rawat, H. ; Toepfer, C.N. ; Santamaria, G. ; Schmid, M. ; Mastantuono, E. ; Schwarzmayr, T. ; Berutti, R. ; Cleuziou, J. ; Ewert, P. ; Görlach, A. ; Klingel, K. ; Laugwitz, K.L. ; Seidman, C.E. ; Seidman, J.G. ; Moretti, A. ; Wolf, C.M.
iScience 25:103596 (2022)
Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality in early life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction, and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM.
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Scientific Article
Zech, M. ; Kopajtich, R. ; Steinbrücker, K. ; Bris, C. ; Gueguen, N. ; Feichtinger, R.G. ; Achleitner, M.T. ; Duzkale, N. ; Périvier, M. ; Koch, J. ; Engelhardt, H. ; Freisinger, P. ; Wagner, M. ; Brunet, T. ; Berutti, R. ; Smirnov, D. ; Navaratnarajah, T. ; Rodenburg, R.J.T. ; Pais, L.S. ; Austin-Tse, C. ; O'Leary, M. ; Boesch, S. ; Jech, R. ; Bakhtiari, S. ; Jin, S.C. ; Wilbert, F. ; Kruer, M.C. ; Wortmann, S.B. ; Eckenweiler, M. ; Mayr, J.A. ; Distelmaier, F. ; Steinfeld, R. ; Winkelmann, J. ; Prokisch, H.
Ann. Neurol. 91, 225-237 (2022)
OBJECTIVE: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. METHODS: Whole-exome sequencing in cohorts with 2,962 mitochondrial-disease- and/or dystonia-diagnosed individuals and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from five patients. RESULTS: We present ten total individuals with biallelic or de-novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de-novo heterozygous missense variants in ATP5F1A, whereas another three were heterozygous for ATP5MC3 de-novo missense changes. Bioinformatics methods and populational data supported the variants` pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in cells bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). INTERPRETATION: Our results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. This article is protected by copyright. All rights reserved.
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Scientific Article
Luecken, M. ; Büttner, M. ; Chaichoompu, K. ; Danese, A. ; Interlandi, M. ; Müller, M.F. ; Strobl, D.C. ; Zappia, L. ; Dugas, M. ; Colomé-Tatché, M. ; Theis, F.J.
Nat. Methods 19, 41-50 (2022)
Single-cell atlases often include samples that span locations, laboratories and conditions, leading to complex, nested batch effects in data. Thus, joint analysis of atlas datasets requires reliable data integration. To guide integration method choice, we benchmarked 68 method and preprocessing combinations on 85 batches of gene expression, chromatin accessibility and simulation data from 23 publications, altogether representing >1.2 million cells distributed in 13 atlas-level integration tasks. We evaluated methods according to scalability, usability and their ability to remove batch effects while retaining biological variation using 14 evaluation metrics. We show that highly variable gene selection improves the performance of data integration methods, whereas scaling pushes methods to prioritize batch removal over conservation of biological variation. Overall, scANVI, Scanorama, scVI and scGen perform well, particularly on complex integration tasks, while single-cell ATAC-sequencing integration performance is strongly affected by choice of feature space. Our freely available Python module and benchmarking pipeline can identify optimal data integration methods for new data, benchmark new methods and improve method development.
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Scientific Article
Biller, A.M. ; Meissner, K. ; Winnebeck, E.C. ; Zerbini, G.
Sleep Med. Rev. 61:101582 (2022)
Early school times clash with the late sleep of adolescents, leading to wide-spread sleep restriction in students. Evidence suggests that delaying school starts is beneficial for sleep and recent studies investigated whether this also translates into improved academic achievement. We thus conducted a systematic review of the literature on school start times, grades and test scores in middle and high-school students. We reviewed 21 studies following the PRISMA guidelines and assessed the evidence quality using a pre-defined risk of bias tool. Nine studies reported no association of later starts with achievement, while the remaining reported mixed (5), positive (5), negative (1) or unclear (1) results. Considering the heterogeneity in academic outcomes, study types, amount of delay and exposure, and the substantial risk of bias, a meta-analysis was not warranted - instead we provide grouped reviews and discussion. Overall, no generalisable improvements in achievement with later starts emerge beyond the level of single studies. This does not necessarily preclude improvements in students’ learning but highlights shortcomings of the literature and the challenges of using grades and test scores to operationalise academic achievement. Given other previously reported positive outcomes, our results suggest that schools could start later while achievement is likely maintained.
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Scientific Article
Clavijo, J.M. ; Glaysher, P. ; Jitsev, J. ; Katzy, J.M.
Mach. Learn.: Sci. Technol. 3:015014 (2022)
We apply adversarial domain adaptation in unsupervised setting to reduce sample bias in a supervised high energy physics events classifier training. We make use of a neural network containing event and domain classifier with a gradient reversal layer to simultaneously enable signal versus background events classification on the one hand, while on the other hand minimizing the difference in response of the network to background samples originating from different Monte Carlo models via adversarial domain classification loss. We show the successful bias removal on the example of simulated events at the Large Hadron Collider with t (t) over barH signal versus t (t) over barb (b) over bar background classification and discuss implications and limitations of the method.
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Scientific Article
Mou, L. ; Saha, S. ; Hua, Y. ; Bovolo, F. ; Bruzzone, L. ; Zhu, X.X.
IEEE Trans. Geosci. Remote Sens. 60, DOI: 10.1109/TGRS.2021.3067096 (2022)
Band selection refers to the process of choosing the most relevant bands in a hyperspectral image. By selecting a limited number of optimal bands, we aim at speeding up model training, improving accuracy, or both. It reduces redundancy among spectral bands while trying to preserve the original information of the image. By now, many efforts have been made to develop unsupervised band selection approaches, of which the majorities are heuristic algorithms devised by trial and error. In this article, we are interested in training an intelligent agent that, given a hyperspectral image, is capable of automatically learning policy to select an optimal band subset without any hand-engineered reasoning. To this end, we frame the problem of unsupervised band selection as a Markov decision process, propose an effective method to parameterize it, and finally solve the problem by deep reinforcement learning. Once the agent is trained, it learns a band-selection policy that guides the agent to sequentially select bands by fully exploiting the hyperspectral image and previously picked bands. Furthermore, we propose two different reward schemes for the environment simulation of deep reinforcement learning and compare them in experiments. This, to the best of our knowledge, is the first study that explores a deep reinforcement learning model for hyperspectral image analysis, thus opening a new door for future research and showcasing the great potential of deep reinforcement learning in remote sensing applications. Extensive experiments are carried out on four hyperspectral data sets, and experimental results demonstrate the effectiveness of the proposed method. The code is publicly available.
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Scientific Article
Hrovatin, K. ; Fischer, D.S. ; Theis, F.J.
Mol. Metab. 57:101396 (2022)
Background: Single-cell metabolic studies bring new insights into cellular function, which can often not be captured on other omics layers. Metabolic information has wide applicability, such as for the study of cellular heterogeneity or for the understanding of drug mechanisms and biomarker development. However, metabolic measurements on single-cell level are limited by insufficient scalability and sensitivity, as well as resource intensiveness, and are currently not possible in parallel with measuring transcript state, commonly used to identify cell types. Nevertheless, because omics layers are strongly intertwined, it is possible to make metabolic predictions based on measured data of more easily measurable omics layers together with prior metabolic network knowledge. Scope of review: We summarize the current state of single-cell metabolic measurement and modeling approaches, motivating the use of computational techniques. We review three main classes of computational methods used for prediction of single-cell metabolism: pathway-level analysis, constraint-based modeling, and kinetic modeling. We describe the unique challenges arising when transitioning from bulk to single-cell modeling. Finally, we propose potential model extensions and computational methods that could be leveraged to achieve these goals. Major conclusions: Single-cell metabolic modeling is a rising field that provides a new perspective for understanding cellular functions. The presented modeling approaches vary in terms of input requirements and assumptions, scalability, modeled metabolic layers, and newly gained insights. We believe that the use of prior metabolic knowledge will lead to more robust predictions and will pave the way for mechanistic and interpretable machine-learning models.
Review
Review
Saha, S. ; Zhu, X.X.
IEEE Geosci. Remote S. 19:6504405 (2022)
Change detection (CD) is critical for analyzing data collected by planetary exploration missions, e.g., for identification of new impact craters. However, CD is still a relatively new topic in the context of planetary exploration. Sheer variation of planetary data makes CD much more challenging than in the case of Earth observation (EO). Unlike CD for EO, patch-level decision is preferred in planetary exploration as it is difficult to obtain perfect pixelwise alignment/coregistration between the bi-temporal planetary images. Lack of labeled bi-temporal data impedes supervised CD. To overcome these challenges, we propose an unsupervised CD method that exploits a pretrained feature extractor to obtain bi-temporal deep features that are further processed using global max-pooling to obtain patch-level feature description. Bi-temporal patch-level features are further analyzed based on difference to determine whether a patch is changed. Additionally, a self-supervised method is proposed to estimate the decision boundary between the changed and unchanged patches. Experimental results on three planetary CD datasets from two different planetary bodies (Mars and Moon) demonstrate that the proposed method often outperforms supervised planetary CD methods. Code is available at https://gitlab.lrz.de/ai4eo/cd/-/tree/main/planetaryCDUnsup.
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Scientific Article
Lam, D. ; Williams, R.H. ; Lujan, E. ; Tanabe, K. ; Huber, G. ; Saw, N.L. ; Merl-Pham, J. ; Salminen, A.V. ; Lohse, D. ; Spendiff, S. ; Plastini, M.J. ; Zech, M. ; Lochmüller, H. ; Geerlof, A. ; Hauck, S.M. ; Shamloo, M. ; Wernig, M. ; Winkelmann, J.
J. Neurosci. 42, 1557-1573 (2022)
Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen α3 (VI) (COL6A3) C-terminal domain (CTD). These Col6a3 CTT mice showed a recessive dystonia-like phenotype in both sexes. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3 CTT mice of both sexes have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3 CTT mice of both sexes was improved by CB1R agonist treatment. Our findings identify a readily therapeutically addressable synaptic mechanism for motor control.SIGNIFICANCE STATEMENTDystonia is a movement disorder characterized by involuntary movements. We previously identified genetic variants affecting a specific domain of the COL6A3 protein as a cause of dystonia. Here, we created mice lacking the affected domain and observed an analogous movement disorder. Using a protein interaction screen, we found that the affected COL6A3 domain mediates an interaction with the cannabinoid receptor CB1R. Concordantly, our COL6A3-deficient mice showed a deficit in synaptic plasticity linked to a deficit in cannabinoid signaling. Pharmacological cannabinoid augmentation rescued the motor impairment of the mice. Thus, cannabinoid augmentation could be a promising avenue for treating dystonia, and we have identified a possible molecular mechanism mediating this.
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Scientific Article
Li, L. ; Zimmer, V.A. ; Schnabel, J.A. ; Zhuang, X.
Med. Image Anal. 76:102303 (2022)
Left atrial (LA) and atrial scar segmentation from late gadolinium enhanced magnetic resonance imaging (LGE MRI) is an important task in clinical practice. The automatic segmentation is however still challenging due to the poor image quality, the various LA shapes, the thin wall, and the surrounding enhanced regions. Previous methods normally solved the two tasks independently and ignored the intrinsic spatial relationship between LA and scars. In this work, we develop a new framework, namely AtrialJSQnet, where LA segmentation, scar projection onto the LA surface, and scar quantification are performed simultaneously in an end-to-end style. We propose a mechanism of shape attention (SA) via an implicit surface projection to utilize the inherent correlation between LA cavity and scars. In specific, the SA scheme is embedded into a multi-task architecture to perform joint LA segmentation and scar quantification. Besides, a spatial encoding (SE) loss is introduced to incorporate continuous spatial information of the target in order to reduce noisy patches in the predicted segmentation. We evaluated the proposed framework on 60 post-ablation LGE MRIs from the MICCAI2018 Atrial Segmentation Challenge. Moreover, we explored the domain generalization ability of the proposed AtrialJSQnet on 40 pre-ablation LGE MRIs from this challenge and 30 post-ablation multi-center LGE MRIs from another challenge (ISBI2012 Left Atrium Fibrosis and Scar Segmentation Challenge). Extensive experiments on public datasets demonstrated the effect of the proposed AtrialJSQnet, which achieved competitive performance over the state-of-the-art. The relatedness between LA segmentation and scar quantification was explicitly explored and has shown significant performance improvements for both tasks. The code has been released via https://zmiclab.github.io/projects.html.
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Scientific Article
Katsoula G. ; Kreitmaier, P. ; Zeggini, E.
Curr. Opin. Rheumatol. 34, 79-90 (2022)
PURPOSE OF REVIEW: To provide an overview of recent developments in the field of osteoarthritis research with a focus on insights gleaned from the application of different -omic technologies. RECENT FINDINGS: We searched for osteoarthritis-relevant studies focusing on transcriptomics, epigenomics, proteomics and metabolomics, published since November of 2019. Study designs showed a trend towards characterizing the genomic profile of osteoarthritis-relevant tissues with high resolution, for example either by using single-cell technologies or by considering several -omic levels and disease stages. SUMMARY: Multitissue interactions (cartilage-subchondral bone; cartilage-synovium) are prevalent in the pathophysiology of osteoarthritis, which is characterized by substantial matrix remodelling in an inflammatory milieu. Subtyping approaches using -omic technologies have contributed to the identification of at least two osteoarthritis endotypes. Studies using data integration approaches have provided molecular maps that are tissue-specific for osteoarthritis and pave the way for expanding these data integration approaches towards a more comprehensive view of disease aetiopathogenesis.
Review
Review
Xu, M. ; Kopajtich, R. ; Elstner, M. ; Li, H. ; Liu, Z. ; Wang, J. ; Prokisch, H. ; Fang, F.
Mitochondrion 62, 13-23 (2022)
Leigh syndrome (LS) is one of the most common mitochondrial diseases in children, for which at least 90 causative genes have been identified. However, many LS patients have no genetic diagnosis, indicating that more disease-related genes remain to be identified. In this study, we identified a novel variant, m.3955G > A, in mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) in two unrelated LS patients, manifesting as infancy-onset frequent seizures, neurodegeneration, elevated lactate levels, and bilateral symmetrical lesions in the brainstem, basal ganglia, and thalamus. Transfer of the mutant mtDNA with m.3955G > A into cybrids disturbed the MT-ND1 expression and CI assembly, followed by remarkable mitochondrial dysfunction, reactive oxygen species production, and mitochondrial membrane potential reduction. Our findings demonstrated the pathogenicity of the novel m.3955G > A variant, and extend the spectrum of pathogenic mtDNA variants.
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Scientific Article
Chetnik, K. ; Benedetti, E. ; Gomari, D.P. ; Schweickart, A. ; Batra, R. ; Buyukozkan, M. ; Wang, Z. ; Arnold, M. ; Zierer, J. ; Suhre, K. ; Krumsiek, J.
Bioinformatics 38, 1168-1170 (2022)
This paper presents maplet, an open-source R package for the creation of highly customizable, fully reproducible statistical pipelines for metabolomics data analysis. It builds on the SummarizedExperiment data structure to create a centralized pipeline framework for storing data, analysis steps, results, and visualizations. maplet's key design feature is its modularity, which offers several advantages, such as ensuring code quality through the maintenance of individual functions and promoting collaborative development by removing technical barriers to code contribution. With over 90 functions, the package includes a wide range of functionalities, covering many widely used statistical approaches and data visualization techniques. AVAILABILITY: The maplet package is implemented in R and freely available at https://github.com/krumsieklab/maplet.
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Scientific Article
Villaverde, A.F. ; Pathirana, D. ; Fröhlich, F. ; Hasenauer, J. ; Banga, J.R.
Brief. Bioinform. 23:bbab387 (2022)
Ordinary differential equation models are nowadays widely used for the mechanistic description of biological processes and their temporal evolution. These models typically have many unknown and nonmeasurable parameters, which have to be determined by fitting the model to experimental data. In order to perform this task, known as parameter estimation or model calibration, the modeller faces challenges such as poor parameter identifiability, lack of sufficiently informative experimental data and the existence of local minima in the objective function landscape. These issues tend to worsen with larger model sizes, increasing the computational complexity and the number of unknown parameters. An incorrectly calibrated model is problematic because it may result in inaccurate predictions and misleading conclusions. For nonexpert users, there are a large number of potential pitfalls. Here, we provide a protocol that guides the user through all the steps involved in the calibration of dynamic models. We illustrate the methodology with two models and provide all the code required to reproduce the results and perform the same analysis on new models. Our protocol provides practitioners and researchers in biological modelling with a one-stop guide that is at the same time compact and sufficiently comprehensive to cover all aspects of the problem.
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Scientific Article
Zacharias, H.U. ; Altenbuchinger, M. ; Schultheiss, U.T. ; Raffler, J. ; Kotsis, F. ; Ghasemi, S. ; Ali, I. ; Kollerits, B. ; Metzger, M. ; Steinbrenner, I. ; Sekula, P. ; Massy, Z.A. ; Combe, C. ; Kalra, P.A. ; Kronenberg, F. ; Stengel, B. ; Eckardt, K.U. ; Köttgen, A. ; Schmid, M. ; Gronwald, W. ; Oefner, P.J.
Am. J. Kidney Dis. 79, 217-230.e1 (2022)
RATIONALE & OBJECTIVE: Stratification of chronic kidney disease (CKD) patients at risk for progressing to end-stage kidney disease (ESKD) requiring kidney replacement therapy (KRT) is important for clinical decision-making and trial enrollment. STUDY DESIGN: Four independent prospective observational cohort studies. SETTING & PARTICIPANTS: The development cohort was comprised of 4,915 CKD patients and three independent validation cohorts were comprised of a total of 3,063. Patients were followed-up for approximately five years. NEW PREDICTORS & ESTABLISHED PREDICTORS: 22 demographic, anthropometric and laboratory variables commonly assessed in CKD patients. OUTCOMES: Progression to ESKD requiring KRT. ANALYTICAL APPROACH: A Least Absolute Shrinkage and Selection Operator (LASSO) Cox proportional hazards model was fit to select laboratory variables that best identified patients at high risk for ESKD. Model discrimination and calibration were assessed and compared against the 4-variable Tangri (T4) risk equation. Both used a resampling approach within the development cohort and in the validation cohorts using cause-specific concordance (C) statistics, net reclassification improvement, and calibration graphs. RESULTS: The newly derived 6-variable (Z6) risk score included serum creatinine, albumin, cystatin C and urea, as well as hemoglobin and the urine albumin-to-creatinine ratio. Based on the resampling approach, Z6 achieved a median C value of 0.909 (95% CI, 0.868-0.937) at two years after the baseline visit, whereas the T4 achieved a median C value of 0.855 (95% CI, 0.799-0.915). In the three independent validation cohorts, Z6 C values were 0.894, 0.921, and 0.891, whereas the T4 C values were 0.882, 0.913, and 0.862. LIMITATIONS: The Z6 was both derived and tested only in White European cohorts. CONCLUSIONS: A new risk equation, based on six routinely available laboratory tests facilitates identification of patients with CKD who are at high risk of progressing to ESKD.
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Scientific Article
Zeng, L. ; Moser, S. ; Mirza-Schreiber, N. ; Lamina, C. ; Coassin, S. ; Nelson, C.P. ; Annilo, T. ; Franzén, O. ; Kleber, M.E. ; Mack, S. ; Andlauer, T.F.M. ; Jiang, B. ; Stiller, B. ; Li, L. ; Willenborg, C. ; Munz, M. ; Kessler, T. ; Kastrati, A. ; Laugwitz, K.L. ; Erdmann, J. ; Moebus, S. ; Nöthen, M.M. ; Peters, A. ; Strauch, K. ; Müller-Nurasyid, M. ; Gieger, C. ; Meitinger, T. ; Steinhagen-Thiessen, E. ; März, W. ; Metspalu, A. ; Björkegren, J.L.M. ; Samani, N.J. ; Kronenberg, F. ; Müller-Myhsok, B. ; Schunkert, H.
Cardiovasc. Res. 118, 1088–1102 (2022)
AIMS: Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic-effects might be responsible for part of the unaccounted genetic variance. Here we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD. METHODS AND RESULTS: We tested for epistatic interactions in ten CAD case-control studies and UK Biobank with focus on 8,068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD (odds ratio [OR]=1.37, p = 1.07 × 10-11), peripheral arterial disease (OR = 1.22, p = 2.32 × 10-4), aortic stenosis (OR = 1.47, p = 6.95 × 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, p = 1.41 × 10-8), and Lp(a) serum levels (beta = 0.58, p = 8.7 × 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, p = 9.97 × 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, p = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele. CONCLUSIONS: These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases. TRANSLATIONAL PERSPECTIVE: Genetic variants identified by GWAS studies explain about a quarter of the heritability of coronary artery disease by additive genetic effects. Our study demonstrates that non-additive effects contribute to the genetic architecture of the disease as well and identifies complex interaction patterns at the LPA locus, which affect LPA expression, Lp(a) plasma levels and risk of atherosclerosis. This proof-of-concept study encourages systematic searches for epistatic interactions in further studies to shed new light on the aetiology of the disease.
Wissenschaftlicher Artikel
Scientific Article
2021
Muñoz, C. ; Ellis, S. ; Nekolla, S.G. ; Kunze, K.P. ; Vitadello, T. ; Neji, R. ; Botnar, R.M. ; Schnabel, J.A. ; Reader, A.J. ; Prieto, C.
J. Nucl. Med. 62, 1768-1774 (2021)
Simultaneous PET/MRI has shown potential for the comprehensive assessment of myocardial health from a single examination. Furthermore, MRI-derived respiratory motion information, when incorporated into the PET image reconstruction, has been shown to improve PET image quality. Separately, MRI-based anatomically guided PET image reconstruction has been shown to effectively denoise images, but this denoising has so far been demonstrated mainly in brain imaging. To date, the combined benefits of motion compensation and anatomic guidance have not been demonstrated for myocardial PET/MRI. This work addressed this lack by proposing a single cardiac PET/MR image reconstruction framework that fully utilizes MRI-derived information to allow both motion compensation and anatomic guidance within the reconstruction. Methods: Fifteen patients underwent an18F-FDG cardiac PET/MRI scan with a previously introduced acquisition framework. The MRI data processing and image reconstruction pipeline produces respiratory motion fields and a high-resolution respiratory motion-corrected MR image with good tissue contrast. This MRI-derived information was then included in a respiratory motion- corrected, cardiac-gated, anatomically guided image reconstruction of the simultaneously acquired PET data. Reconstructions were evaluated by measuring myocardial contrast and noise and were compared with images from several comparative intermediate methods using the components of the proposed framework separately. Results: Including respiratory motion correction, cardiac gating, and anatomic guidance significantly increased contrast. In particular, myocardium- to-blood pool contrast increased by 143% on average (P < 0.0001), compared with conventional uncorrected, non guided PET images. Furthermore, anatomic guidance significantly reduced image noise, by 16.1%, compared with nonguided image reconstruction (P < 0.0001). Conclusion: The proposed framework for MRI-derived motion compensation and anatomic guidance of cardiac PET data significantly improvedimagequalitycomparedwithalternativereconstructionmethods. Each component of the reconstruction pipeline had a positive impact on the final image quality. These improvements have the potential to improve clinical interpretability and diagnosis based on cardiac PET/MR images. COPYRIGHT
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Scientific Article
Ostaszewski, M. ; Niarakis, A. ; Mazein, A. ; Kuperstein, I. ; Phair, R. ; Orta-Resendiz, A. ; Singh, V. ; Aghamiri, S.S. ; Acencio, M.L. ; Glaab, E. ; Ruepp, A. ; Fobo, G. ; Montrone, C. ; Brauner, B. ; Frishman, G. ; Monraz Gómez, L.C. ; Somers, J. ; Hoch, M. ; Kumar Gupta, S. ; Scheel, J. ; Borlinghaus, H. ; Czauderna, T. ; Schreiber, F. ; Montagud, A. ; Ponce de Leon, M. ; Funahashi, A. ; Hiki, Y. ; Hiroi, N. ; Yamada, T.G. ; Dräger, A. ; Renz, A. ; Naveez, M. ; Bocskei, Z. ; Messina, F. ; Börnigen, D. ; Fergusson, L. ; Conti, M. ; Rameil, M. ; Nakonecnij, V. ; Vanhoefer, J. ; Schmiester, L. ; Wang, M. ; Ackerman, E.E. ; Shoemaker, J.E. ; Zucker, J. ; Oxford, K. ; Teuton, J. ; Kocakaya, E. ; Summak, G.Y. ; Hanspers, K. ; Kutmon, M. ; Coort, S. ; Eijssen, L. ; Ehrhart, F. ; Rex, D.A.B. ; Slenter, D. ; Martens, M. ; Pham, N. ; Haw, R. ; Jassal, B. ; Matthews, L. ; Orlic-Milacic, M. ; Senff-Ribeiro, A. ; Rothfels, K. ; Shamovsky, V. ; Stephan, R. ; Sevilla, C. ; Varusai, T. ; Ravel, J. ; Fraser, R. ; Ortseifen, V. ; Marchesi, S. ; Gawron, P. ; Smula, E. ; Heirendt, L. ; Satagopam, V. ; Wu, G. ; Riutta, A. ; Golebiewski, M. ; Owen, S. ; Goble, C. ; Hu, X. ; Overall, R.W. ; Maier, D. ; Bauch, A. ; Gyori, B.M. ; Bachman, J.A. ; Vega, C. ; Grouès, V. ; Vázquez, M.J. ; Porras, P. ; Licata, L. ; Iannuccelli, M. ; Sacco, F. ; Nesterova, A. ; Yuryev, A. ; de Waard, A. ; Türei, D. ; Luna, A. ; Babur, O. ; Soliman, S. ; Valdeolivas, A. ; Esteban-Medina, M. ; Peña-Chilet, M. ; Rian, K. ; Helikar, T. ; Puniya, B.L. ; Módos, D. ; Treveil, A. ; Ölbei, M. ; De Meulder, B. ; Ballereau, S. ; Dugourd, A. ; Naldi, A. ; Noël, V. ; Calzone, L. ; Sander, C. ; Demir, E. ; Korcsmáros, T. ; Freeman, T.C. ; Augé, F. ; Beckmann, J.S. ; Hasenauer, J. ; Wolkenhauer, O. ; Willighagen, E.L. ; Pico, A.R. ; Evelo, C.T. ; Gillespie, M.E. ; Stein, L.D. ; Hermjakob, H. ; D'Eustachio, P. ; Saez-Rodriguez, J. ; Dopazo, J. ; Valencia, A. ; Kitano, H. ; Barillot, E. ; Auffray, C. ; Balling, R. ; Schneider, R.
Mol. Syst. Biol. 17:e10851 (2021)
Efendiyev, M.A. ; Muradova, A. ; Muradov, N. ; Zischka, H.
Adv. Math. Sci. Appl. 30, 377-385 (2021)
In this paper, we consider deterministic, continuous, nonlocal models for the mitochondrial permeability transition, i.e. mitochondrial swelling. Based on seminal papers [1], [2], [3], [5] and the book [4], in which ODE-PDE and PDE-PDE local models for the swelling of mitochondria have been considered, we suggest here new nonlocal models for this process. This new nonlocal deterministic continuous model for mitochondrial swelling scenario contains nonlocal diffusion, nonlocal chemotaxis, as well as nonlocal source term. We would like to especially emphasize that some of the new nonlocal models that we consider in this paper do not have local counterparts in the literature.
Wissenschaftlicher Artikel
Scientific Article
Hawe, J.
München, Technische Universität, Fakultät für Informatik, Diss., 2021, 210 S.
We investigated molecular networks to further our understanding of how complex traits arise from genetic and epigenetic factors in humans. To this end, we leveraged genome-wide statistical associations between genetic variants and quantitative molecular traits derived from large-scale human population cohorts. By devising a novel strategy for genomic data integration and applying state-of-the-art network analysis and inference methods we gained novel insights into regulatory patterns underlying genome regulation and complex traits. 
Karollus, A. ; Avsec, Ž. ; Gagneur, J.
PLoS Comput. Biol. 17, e1008982 (2021)
The 5' untranslated region plays a key role in regulating mRNA translation and consequently protein abundance. Therefore, accurate modeling of 5'UTR regulatory sequences shall provide insights into translational control mechanisms and help interpret genetic variants. Recently, a model was trained on a massively parallel reporter assay to predict mean ribosome load (MRL)-a proxy for translation rate-directly from 5'UTR sequence with a high degree of accuracy. However, this model is restricted to sequence lengths investigated in the reporter assay and therefore cannot be applied to the majority of human sequences without a substantial loss of information. Here, we introduced frame pooling, a novel neural network operation that enabled the development of an MRL prediction model for 5'UTRs of any length. Our model shows state-of-the-art performance on fixed length randomized sequences, while offering better generalization performance on longer sequences and on a variety of translation-related genome-wide datasets. Variant interpretation is demonstrated on a 5'UTR variant of the gene HBB associated with beta-thalassemia. Frame pooling could find applications in other bioinformatics predictive tasks. Moreover, our model, released open source, could help pinpoint pathogenic genetic variants.
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Scientific Article
Baloni, P. ; Nho, K. ; Arnold, M. ; Louie, G. ; Kueider-Paisley, A. ; Saykin, A.J. ; Ekroos, K. ; Funk, C. ; Hood, L. ; Price, N.D. ; Baillie, R. ; Kastenmüller, G. ; Han, X. ; Kaddurah-Daouk, R.F.
Alzheimers Dement. 17:e056647 (2021)
BACKGROUND: L-carnitine is present in the mammalian cells as free carnitine (FC) and acylcarnitine and the adult human brain contains almost 10% of long chain acylcarnitine. Acylcarnitines are functionally involved in β-oxidation of fatty acids and are also known for their role in neuroprotection. Levels of plasma acylcarnitines are known to decreased on aging. It is important to understand the association of acylcarnitines with cognitive impairment in Alzheimer's disease (AD). METHOD: We integrated the transcriptome data from 1000 post-mortem brain samples from ROS/MAP, Mayo clinic and Mount Sinai Brain bank cohort with the brain region-specific metabolic networks. We calculated the metabolic fluxes for the reactions in the model and identified those that showed differential fluxes in AD samples. We filtered the reactions that are involved in acylcarnitine synthesis and transport namely carnitine transport, fatty acid oxidation, citric acid cycle, and glutathione metabolism. RESULT: We found differences in metabolic fluxes for reactions involved in the acetylcarnitine transport to mitochondria (ACRNtm), carnitine palmitoyl transferase 1 and 2 (CPT1 and CPT2) as well as acyl-CoA dehydrogenase short and medium chain (ACADS, ACADM) located in mitochondria in AD samples. Using gene-based association analysis in participants of the AD Neuroimaging Initiative (ADNI) phases 1, GO and 2, we identified genetic variants linked to CPT1, CPT2, ACADM and ACADS genes suggested from the metabolic flux analysis. CONCLUSION: Our findings suggest that acylcarnitine synthesis and transport is altered in AD. Altered metabolism of short and medium chain acylcarnitines can be used as metabolic features of AD.
Meeting abstract
Meeting abstract
Raffin, A. ; Hill, A. ; Gleave, A. ; Kanervisto, A. ; Ernestus, M. ; Dormann, N.
J. Mach. Learn. Res. 22, accepted (2021)
Stable-Baselines3 provides open-source implementations of deep reinforcement learning (RL) algorithms in Python. The implementations have been benchmarked against reference codebases, and automated unit tests cover 95% of the code. The algorithms follow a consistent interface and are accompanied by extensive documentation, making it simple to train and compare different RL algorithms. Our documentation, examples, and source-code are available at https://github.com/DLR-RM/stable-baselines3.
Wissenschaftlicher Artikel
Scientific Article
Moore, S.R. ; Halldorsdottir, T. ; Martins, J. ; Lucae, S. ; Müller-Myhsok, B. ; Müller, N.S. ; Piechaczek, C. ; Feldmann, L. ; Freisleder, F.J. ; Greimel, E. ; Schulte-Körne, G. ; Binder, E.B. ; Knauer-Arloth, J.
Transl. Psychiatry 11:632 (2021)
Substantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. Here, we explore the genomic variants in 93 females and 196 males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation. Gene expression levels in peripheral blood were obtained before and after GR-stimulation with the selective GR agonist dexamethasone to identify differential expression following GR-activation. Sex stratified analyses revealed that while the transcripts responsive to GR-stimulation were mostly overlapping between males and females, the quantitative trait loci (eQTLs) regulation differential transcription to GR-stimulation was distinct. Sex-stratified eQTL SNPs (eSNPs) were located in different functional genomic elements and sex-stratified transcripts were enriched within postmortem brain transcriptional profiles associated with Major Depressive Disorder (MDD) specifically in males and females in the cingulate cortex. Female eSNPs were enriched among SNPs linked to MDD in genome-wide association studies. Finally, transcriptional sensitive genetic profile scores derived from sex-stratified eSNPS regulating differential transcription to GR-stimulation were predictive of depression status and depressive symptoms in a sex-concordant manner in a child and adolescent cohort (n = 584). These results suggest the potential of eQTLs regulating differential transcription to GR-stimulation as biomarkers of sex-specific biological risk for stress-related psychiatric disorders.
Wissenschaftlicher Artikel
Scientific Article
Mcharo, R. ; Lennemann, T. ; France, J. ; Torres, L. ; Garí, M. ; Mbuya, W. ; Mwalongo, W. ; Mahenge, A. ; Bauer, A.J. ; Mnkai, J. ; Glasmeyer, L. ; Judick, M. ; Paul, M. ; Schroeder, N. ; Msomba, B. ; Sembo, M. ; Chiwerengo, N. ; Hoelscher, M. ; Geisenberger, O. ; Lelle, R.J. ; Saathoff, E. ; Maboko, L. ; Chachage, M. ; Kroidl, A. ; Geldmacher, C.
Front. Oncol. 11:763717 (2021)
Background: Women living with HIV in sub-Saharan Africa are at increased risk to develop cervical cancer (CC), which is caused by persistent infection with 13 oncogenic human papilloma viruses (HR-HPVs). It is important to accurately identify and target HIV-positive women at highest risk to develop CC for early therapeutic intervention. Methods: A total of 2,134 HIV+ and HIV− women from South-West Tanzania were prospectively screened for cervical cancer and precancerous lesions. Women with cervical cancer (n=236), high- and low-grade squamous intraepithelial lesions (HSIL: n=68, LSIL: n=74), and without lesion (n=426) underwent high-resolution HPV genotyping. Results: Eighty percent of women who were diagnosed with HSIL or LSIL were living with HIV. Any lesion, young age, HIV status, and depleted CD4 T cell counts were independent risk factors for HPV infections, which were predominantly caused by HR-HPV types. While multiple HR-HPV type infections were predominant in HIV+ women with HSIL, single-type infections predominated in HIV+ CC cases (p=0.0006). HPV16, 18, and 45 accounted for 85% (68/80) and 75% (82/110) of HIV+ and HIV− CC cases, respectively. Of note, HPV35, the most frequent HPV type in HSIL-positive women living with HIV, was rarely detected as a single-type infection in HSIL and cancer cases. Conclusion: HPV16, 18, and 45 should receive special attention for molecular diagnostic algorithms during CC prevention programs for HIV+ women from sub-Saharan Africa. HPV35 may have a high potential to induce HSIL in women living with HIV, but less potential to cause cervical cancer in single-type infections.
Wissenschaftlicher Artikel
Scientific Article
Wendisch, D. ; Dietrich, O. ; Mari, T. ; von Stillfried, S. ; Ibarra Del Rio, I.A. ; Mittermaier, M. ; Mache, C. ; Chua, R.L. ; Knöll, R. ; Timm, S. ; Brumhard, S. ; Krammer, T. ; Zauber, H. ; Hiller, A.L. ; Pascual-Reguant, A. ; Mothes, R. ; Bülow, R.D. ; Schulze, J. ; Leipold, A.M. ; Djudjaj, S. ; Erhard, F. ; Geffers, R. ; Pott, F. ; Kazmierski, J. ; Radke, J. ; Pergantis, P. ; Baßler, K. ; Conrad, C. ; Aschenbrenner, A.C. ; Sawitzki, B. ; Landthaler, M. ; Wyler, E. ; Horst, D. ; Hippenstiel, S. ; Hocke, A.C. ; Heppner, F.L. ; Uhrig, A. ; Garcia, C. ; Machleidt, F. ; Herold, S. ; Elezkurtaj, S. ; Thibeault, C. ; Witzenrath, M. ; Cochain, C. ; Suttorp, N. ; Drosten, C. ; Goffinet, C. ; Kurth, F. ; Schultze, J.L. ; Radbruch, H. ; Ochs, M. ; Eils, R. ; Müller-Redetzky, H. ; Hauser, A.E. ; Luecken, M. ; Theis, F.J. ; Wolff, T. ; Boor, P. ; Selbach, M. ; Saliba, A.E. ; Sander, L.E.
Cell 184, 6243-6261.e27 (2021)
COVID-19-induced “acute respiratory distress syndrome” (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.
Wissenschaftlicher Artikel
Scientific Article
Schalk, A. ; Cousin, M.A. ; Challman, T.D. ; Wain, K.E. ; Powis, Z. ; Minks, K. ; Trimouille, A. ; Lasseaux, E. ; Lacombre, D. ; Angelini, C. ; Michaud, V. ; Van-Gils, J. ; Spataro, N. ; Ruiz, A. ; Gabau, E. ; Stolerman, E. ; Washington, C. ; Louie, R.J. ; Lanpher, B.C. ; Kemppainen, J.L. ; Innes, A.M. ; Kooy, R.F. ; Meuwissen, M. ; Goldenberg, A. ; Lecoquierre, F. ; Vera, G. ; Diderich, K.E.M. ; Sheidley, B.R. ; El Achkar, C.M. ; Park, M. ; Hamdan, F.F. ; Michaud, J.L. ; Lewis, A.J. ; Zweier, C. ; Reis, A. ; Wagner, M. ; Weigand, H. ; Journel, H. ; Keren, B. ; Passemard, S. ; Mignot, C. ; van Gassen, K.L. ; Brilstra, E.H. ; Itzikowitz, G. ; O'Heir, E. ; Allen, J. ; Donald, K.A. ; Korf, B.R. ; Skelton, T. ; Thompson, M.L. ; Robin, N.H. ; Rudy, N. ; Dobyns, W.B. ; Foss, K. ; Zarate, Y.A. ; Bosanko, K.A. ; Alembik, Y. ; Durand, B. ; Mau-them, F.T. ; Ranza, E. ; Blanc, X. ; Antonarakis, S.E. ; McWalter, K. ; Torti, E. ; Millan, F. ; Dameron, A. ; Tokita, M.J. ; Zimmermann, M.T. ; Klee, E.W. ; Piton, A. ; Gérard, B.
J. Med. Genet., DOI: 10.1136/jmedgenet-2021-107751 (2021)
Background High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). Methods This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). Results A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations. Conclusion Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.
Wissenschaftlicher Artikel
Scientific Article
Hartley, A. ; Sanderson, E. ; Granell, R. ; Paternoster, L. ; Zheng, J. ; Smith, G.D. ; Southam, L. ; Hatzikotoulas, K. ; Boer, C.G. ; van Meurs, J. ; Zeggini, E. ; Genetics of Osteoarthritis Consortium ; Gregson, C.L. ; Tobias, J.H.
Int. J. Epidemiol., DOI: 10.1093/ije/dyab251 (2021)
OBJECTIVES: Observational analyses suggest that high bone mineral density (BMD) is a risk factor for osteoarthritis (OA); it is unclear whether this represents a causal effect or shared aetiology and whether these relationships are body mass index (BMI)-independent. We performed bidirectional Mendelian randomization (MR) to uncover the causal pathways between BMD, BMI and OA. METHODS: One-sample (1S)MR estimates were generated by two-stage least-squares regression. Unweighted allele scores instrumented each exposure. Two-sample (2S)MR estimates were generated using inverse-variance weighted random-effects meta-analysis. Multivariable MR (MVMR), including BMD and BMI instruments in the same model, determined the BMI-independent causal pathway from BMD to OA. Latent causal variable (LCV) analysis, using weight-adjusted femoral neck (FN)-BMD and hip/knee OA summary statistics, determined whether genetic correlation explained the causal effect of BMD on OA. RESULTS: 1SMR provided strong evidence for a causal effect of BMD estimated from heel ultrasound (eBMD) on hip and knee OA {odds ratio [OR]hip = 1.28 [95% confidence interval (CI) = 1.05, 1.57], p = 0.02, ORknee = 1.40 [95% CI = 1.20, 1.63], p = 3 × 10-5, OR per standard deviation [SD] increase}. 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional (βhip = 1.10 [95% CI = 0.36, 1.84], p = 0.003, βknee = 4.16 [95% CI = 2.74, 5.57], p = 8 × 10-9, β = SD increase per doubling in risk). MVMR identified a BMI-independent causal pathway between eBMD and hip/knee OA. LCV suggested that genetic correlation (i.e. shared genetic aetiology) did not fully explain the causal effects of BMD on hip/knee OA. CONCLUSIONS: These results provide evidence for a BMI-independent causal effect of eBMD on OA. Despite evidence of bidirectional effects, the effect of BMD on OA did not appear to be fully explained by shared genetic aetiology, suggesting a direct action of bone on joint deterioration.
Wissenschaftlicher Artikel
Scientific Article
Schlosser, P. ; Tin, A. ; Matias-Garcia, P.R. ; Thio, C.H.L. ; Joehanes, R. ; Liu, H. ; Weihs, A. ; Yu, Z. ; Hoppmann, A. ; Grundner-Culemann, F. ; Min, J.L. ; Adeyemo, A.A. ; Agyemang, C. ; Ärnlöv, J. ; Aziz, N.A. ; Baccarelli, A. ; Bochud, M. ; Brenner, H. ; Breteler, M.M.B. ; Carmeli, C. ; Chaker, L. ; Chambers, J.C. ; Cole, S.A. ; Coresh, J. ; Corre, T. ; Correa, A. ; Cox, S.R. ; de Klein, N. ; Delgado, G.E. ; Domingo-Relloso, A. ; Eckardt, K.U. ; Ekici, A.B. ; Endlich, K. ; Evans, K.L. ; Floyd, J.S. ; Fornage, M. ; Franke, L. ; Fraszczyk, E. ; Gao, X. ; Ghanbari, M. ; Ghasemi, S. ; Gieger, C. ; Greenland, P. ; Grove, M.L. ; Harris, S.E. ; Hemani, G. ; Henneman, P. ; Herder, C. ; Horvath, S. ; Hou, L. ; Hurme, M.A. ; Hwang, S.J. ; Jarvelin, M.R. ; Kardia, S.L.R. ; Kasela, S. ; Kleber, M.E. ; Koenig, W. ; Kooner, J.S. ; Kramer, H. ; Kronenberg, F. ; Kühnel, B. ; Lehtimäki, T. ; Lind, L. ; Liu, D. ; Liu, Y. ; Lloyd-Jones, D.M. ; Lohman, K. ; Lorkowski, S. ; Lu, A.T. ; Marioni, R.E. ; März, W. ; McCartney, D.L. ; Meeks, K.A.C. ; Milani, L. ; Mishra, P.P. ; Nauck, M. ; Navas-Acien, A. ; Nowak, C. ; Peters, A. ; Prokisch, H. ; Psaty, B.M. ; Raitakari, O.T. ; Ratliff, S.M. ; Reiner, A.P. ; Rosas, S.E. ; Schöttker, B. ; Schwartz, J. ; Sedaghat, S. ; Smith, J.A. ; Sotoodehnia, N. ; Stocker, H.R. ; Stringhini, S. ; Sundström, J. ; Swenson, B.R. ; Tellez-Plaza, M. ; van Meurs, J.B.J. ; van Vliet-Ostaptchouk, J.V. ; Venema, A. ; Verweij, N. ; Walker, R.M. ; Wielscher, M. ; Winkelmann, J. ; Wolffenbuttel, B.H.R. ; Zhao, W. ; Zheng, Y. ; Estonian Biobank Research Team ; Genetics of DNA Methylation Consortium ; Loh, M. ; Snieder, H. ; Levy, D. ; Waldenberger, M. ; Susztak, K. ; Köttgen, A. ; Teumer, A.
Nat. Commun. 12:7174 (2021)
Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
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Scientific Article
Tin, A. ; Schlosser, P. ; Matias-Garcia, P.R. ; Thio, C.H.L. ; Joehanes, R. ; Liu, H. ; Yu, Z. ; Weihs, A. ; Hoppmann, A. ; Grundner-Culemann, F. ; Min, J.L. ; Kuhns, V.L.H. ; Adeyemo, A.A. ; Agyemang, C. ; Ärnlöv, J. ; Aziz, N.A. ; Baccarelli, A. ; Bochud, M. ; Brenner, H. ; Bressler, J. ; Breteler, M.M.B. ; Carmeli, C. ; Chaker, L. ; Coresh, J. ; Corre, T. ; Correa, A. ; Cox, S.R. ; Delgado, G.E. ; Eckardt, K.U. ; Ekici, A.B. ; Endlich, K. ; Floyd, J.S. ; Fraszczyk, E. ; Gao, X. ; Gelber, A.C. ; Ghanbari, M. ; Ghasemi, S. ; Gieger, C. ; Greenland, P. ; Grove, M.L. ; Harris, S.E. ; Hemani, G. ; Henneman, P. ; Herder, C. ; Horvath, S. ; Hou, L. ; Hurme, M.A. ; Hwang, S.J. ; Kardia, S.L.R. ; Kasela, S. ; Kleber, M.E. ; Koenig, W. ; Kooner, J.S. ; Kronenberg, F. ; Kühnel, B. ; Ladd-Acosta, C. ; Lehtimäki, T. ; Lind, L. ; Liu, D. ; Lloyd-Jones, D.M. ; Lorkowski, S. ; Lu, A.T. ; Marioni, R.E. ; März, W. ; McCartney, D.L. ; Meeks, K.A.C. ; Milani, L. ; Mishra, P.P. ; Nauck, M. ; Nowak, C. ; Peters, A. ; Prokisch, H. ; Psaty, B.M. ; Raitakari, O.T. ; Ratliff, S.M. ; Reiner, A.P. ; Schöttker, B. ; Schwartz, J. ; Sedaghat, S. ; Smith, J.A. ; Sotoodehnia, N. ; Stocker, H.R. ; Stringhini, S. ; Sundström, J. ; Swenson, B.R. ; van Meurs, J.B.J. ; van Vliet-Ostaptchouk, J.V. ; Venema, A. ; Völker, U. ; Winkelmann, J. ; Wolffenbuttel, B.H.R. ; Zhao, W. ; Zheng, Y. ; Estonian Biobank Research Team ; Genetics of DNA Methylation Consortium ; Loh, M. ; Snieder, H. ; Waldenberger, M. ; Levy, D. ; Akilesh, S. ; Woodward, O.M. ; Susztak, K. ; Teumer, A. ; Köttgen, A.
Nat. Commun. 12:7173 (2021)
Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
Wissenschaftlicher Artikel
Scientific Article
Azodi, C.B ; Zappia, L. ; Oshlack, A. ; McCarthy, D.J.
Genome Biol. 22:341 (2021)
Population-scale single-cell RNA sequencing (scRNA-seq) is now viable, enabling finer resolution functional genomics studies and leading to a rush to adapt bulk methods and develop new single-cell-specific methods to perform these studies. Simulations are useful for developing, testing, and benchmarking methods but current scRNA-seq simulation frameworks do not simulate population-scale data with genetic effects. Here, we present splatPop, a model for flexible, reproducible, and well-documented simulation of population-scale scRNA-seq data with known expression quantitative trait loci. splatPop can also simulate complex batch, cell group, and conditional effects between individuals from different cohorts as well as genetically-driven co-expression.
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Scientific Article
Gjaltema, R.A.F. ; Schwämmle, T. ; Kautz, P. ; Robson, M. ; Schöpflin, R. ; Ravid Lustig, L. ; Brandenburg, L.O. ; Dunkel, I. ; Vechiatto, C. ; Ntini, E. ; Mutzel, V. ; Schmiedel, V. ; Marsico, A. ; Mundlos, S. ; Schulz, E.G.
Mol. Cell 82, 190-208.e17 (2021)
Developmental genes such as Xist, which initiates X chromosome inactivation, are controlled by complex cis-regulatory landscapes, which decode multiple signals to establish specific spatiotemporal expression patterns. Xist integrates information on X chromosome dosage and developmental stage to trigger X inactivation in the epiblast specifically in female embryos. Through a pooled CRISPR screen in differentiating mouse embryonic stem cells, we identify functional enhancer elements of Xist at the onset of random X inactivation. Chromatin profiling reveals that X-dosage controls the promoter-proximal region, while differentiation cues activate several distal enhancers. The strongest distal element lies in an enhancer cluster associated with a previously unannotated Xist-enhancing regulatory transcript, which we named Xert. Developmental cues and X-dosage are thus decoded by distinct regulatory regions, which cooperate to ensure female-specific Xist upregulation at the correct developmental time. With this study, we start to disentangle how multiple, functionally distinct regulatory elements interact to generate complex expression patterns in mammals.
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Scientific Article
Jin, K.X. ; Zuo, R. ; Anastassiadis, K. ; Klungland, A. ; Marr, C. ; Filipczyk, A.A.
Proc. Natl. Acad. Sci. U.S.A. 118:e2105192118 (2021)
N6-methyladenosine (m6A) deposition on messenger RNA (mRNA) controls embryonic stem cell (ESC) fate by regulating the mRNA stabilities of pluripotency and lineage transcription factors (TFs) [P. J. Batista et al., Cell Stem Cell 15, 707-719 (2014); Y. Wang et al., Nat. Cell Biol. 16, 191-198 (2014); and S. Geula et al., Science 347, 1002-1006 (2015)]. If the mRNAs of these two TF groups become stabilized, it remains unclear how the pluripotency or lineage commitment decision is implemented. We performed noninvasive quantification of Nanog and Oct4 TF protein levels in reporter ESCs to define cell-state dynamics at single-cell resolution. Long-term single-cell tracking shows that immediate m6A depletion by Mettl3 knock-down in serum/leukemia inhibitory factor supports both pluripotency maintenance and its departure. This is mediated by differential and opposing signaling pathways. Increased FGF5 mRNA stability activates pErk, leading to Nanog down-regulation. FGF5-mediated coactivation of pAkt reenforces Nanog expression. In formative stem cells poised toward differentiation, m6A depletion activates both pErk and pAkt, increasing the propensity for mesendodermal lineage induction. Stable m6A depletion by Mettl3 knock-out also promotes pErk activation. Higher pErk counteracts the pluripotency exit delay exhibited by stably m6A-depleted cells upon differentiation. At single-cell resolution, we illustrate that decreasing m6A abundances activates pErk and pAkt-signaling, regulating pluripotency departure.
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Scientific Article
Trenker, S. ; Grunenberg, L. ; Banerjee, T. ; Savasci, G. ; Poller, L.M. ; Muggli, K.I.M. ; Haase, F. ; Ochsenfeld, C. ; Lotsch, B.V.
Chem. Sci. 12, 15143-15150 (2021)
Covalent organic frameworks (COFs) offer a number of key properties that predestine them to be used as heterogeneous photocatalysts, including intrinsic porosity, long-range order, and light absorption. Since COFs can be constructed from a practically unlimited library of organic building blocks, these properties can be precisely tuned by choosing suitable linkers. Herein, we report the construction and use of a novel COF (FEAx-COF) photocatalyst, inspired by natural flavin cofactors. We show that the functionality of the alloxazine chromophore incorporated into the COF backbone is retained and study the effects of this heterogenization approach by comparison with similar molecular photocatalysts. We find that the integration of alloxazine chromophores into the framework significantly extends the absorption spectrum into the visible range, allowing for photocatalytic oxidation of benzylic alcohols to aldehydes even with low-energy visible light. In addition, the activity of the heterogeneous COF photocatalyst is less dependent on the chosen solvent, making it more versatile compared to molecular alloxazines. Finally, the use of oxygen as the terminal oxidant renders FEAx-COF a promising and "green" heterogeneous photocatalyst.
Wissenschaftlicher Artikel
Scientific Article
Li, Q. ; Mou, L. ; Hua, Y. ; Shi, Y. ; Zhu, X.X.
IEEE Trans. Geosci. Remote Sens., DOI: 10.1109/TGRS.2021.3109844 (2021)
Building footprint generation is a vital task in a wide range of applications, including, to name a few, land use management, urban planning and monitoring, and geographical database updating. Most existing approaches addressing this problem fall back on convolutional neural networks (CNNs) to learn semantic masks of buildings. However, one limitation of their results is blurred building boundaries. To address this, we propose to learn attraction field representation for building boundaries, which is capable of providing an enhanced representation power. Our method comprises two elemental modules: an Img2AFM module and an AFM2Mask module. More specifically, the former aims at learning an attraction field representation conditioned on an input image, which is capable of enhancing building boundaries and suppressing the background. The latter module predicts segmentation masks of buildings using the learned attraction field map. The proposed method is evaluated on three datasets with different spatial resolutions: the ISPRS dataset, the INRIA dataset, and the Planet dataset. From experimental results, we find that the proposed framework can well preserve geometric shapes and sharp boundaries of buildings, which brings significant improvements over other competitors. The trained model and code are available at https://github.com/lqycrystal/AFM_building.
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Scientific Article
Saha, S. ; Ebel, P. ; Zhu, X.X.
IEEE Trans. Geosci. Remote Sens., DOI: 10.1109/TGRS.2021.3109957 (2021)
Most change detection (CD) methods assume that prechange and postchange images are acquired by the same sensor. However, in many real-life scenarios, e.g., natural disasters, it is more practical to use the latest available images before and after the occurrence of incidence, which may be acquired using different sensors. In particular, we are interested in the combination of the images acquired by optical and synthetic aperture radar (SAR) sensors. SAR images appear vastly different from the optical images even when capturing the same scene. Adding to this, CD methods are often constrained to use only target image-pair, no labeled data, and no additional unlabeled data. Such constraints limit the scope of traditional supervised machine learning and unsupervised generative approaches for multisensor CD. The recent rapid development of self-supervised learning methods has shown that some of them can even work with only few images. Motivated by this, in this work, we propose a method for multisensor CD using only the unlabeled target bitemporal images that are used for training a network in a self-supervised fashion by using deep clustering and contrastive learning. The proposed method is evaluated on four multimodal bitemporal scenes showing change, and the benefits of our self-supervised approach are demonstrated. Code is available at https://gitlab.lrz.de/ai4eo/cd/-/tree/main/sarOpticalMultisensorTgrs2021.
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Scientific Article
Hua, Y. ; Mou, L. ; Jin, P. ; Zhu, X.X.
IEEE Trans. Geosci. Remote Sens., DOI: 10.1109/TGRS.2021.3110314 (2021)
Aerial scene recognition is a fundamental research problem in interpreting high-resolution aerial imagery. Over the past few years, most studies focus on classifying an image into one scene category, while in real-world scenarios, it is more often that a single image contains multiple scenes. Therefore, in this article, we investigate a more practical yet underexplored task--multiscene recognition in single images. To this end, we create a large-scale dataset, called MultiScene, composed of 100,000 unconstrained high-resolution aerial images. Considering that manually labeling such images is extremely arduous, we resort to low-cost annotations from crowdsourcing platforms, e.g., OpenStreetMap (OSM). However, OSM data might suffer from incompleteness and incorrectness, which introduce noise into image labels. To address this issue, we visually inspect 14,000 images and correct their scene labels, yielding a subset of cleanly annotated images, named MultiScene-Clean. With it, we can develop and evaluate deep networks for multiscene recognition using clean data. Moreover, we provide crowdsourced annotations of all images for the purpose of studying network learning with noisy labels. We conduct experiments with extensive baseline models on both MultiScene-Clean and MultiScene to offer benchmarks for multiscene recognition in single images and learning from noisy labels for this task, respectively. To facilitate progress, we make our dataset and trained models available on https://gitlab.lrz.de/ai4eo/reasoning/multiscene.
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Scientific Article
Von Heßberg, A. ; Jentsch, A. ; Berauer, B.J. ; Ewald, J. ; Fütterer, S. ; Görgen, A. ; Kluth, S. ; Krämer, A. ; Köllner, T.G. ; Scharmann, M. ; Schloter, M. ; Schmitt, T. ; Schödl, M. ; Schuchardt, M. ; Schucknecht, A. ; Steinberger, S. ; Vidal, A. ; Voith, J. ; Wiesmeier, M. ; Dannenmann, M.
Naturschutz und Landschaftsplanung 53, 28-36 (2021)
The abandonment of traditional alpine farming on high mountain pastures (Alms) is the strongest land use change in the European Alps. Besides the loss of a centuries-to millennia-old cultural landscape, such abandonment leads to undesired changes in soil functions and a loss of biodiversity as well as recreational ecosystem services. Recently, climate change has been facilitating faster woody encroachment onto abandoned Alms and, ultimately, reforestation. In 2018, we started to restore Brunnenkopfalm in the Ammergau Alps after 63 years of abandonment. By resuming an extensive grazing regime with traditional cattle breeds (Murnau-Werdenfelser, Tiroler Grauvieh), we are currently assessing the impacts of revitalization on soil func-tions, fresh water quality, recreational services, and plant and animal diversity. Here we synthesize the first results after two years of extensive re-graz-ing. Apart from positive impacts on recreation and tourism, we would like to highlight the activities at Brunnenkopfalm as an important and unique aspect of the entire biodiversity of the Ammergau Alps. Soil bio-chemical cycles and freshwater quality remained unchanged so far, although we expect long term changes. Thus far, the revitalization of abandoned Alms seems to be a valuable approach for preserving biodiversity and conserving traditional cultural landscapes in general.
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Scientific Article
Klopstock, T. ; Priglinger, C. ; Yilmaz, A. ; Kornblum, C. ; Distelmaier, F. ; Prokisch, H.
Dtsch. Arztebl. Int. 118, 741-748 (2021)
BACKGROUND: Mitochondrial disorders are among the most common heritable diseases, with an overall lifetime risk of approximately one in 1500. Nonetheless, their diagnosis is often missed because of their extreme phenotypic and genotypic heterogeneity. METHODS: This review is based on publications retrieved by a selective literature search on the clinical features, genetics, pathogenesis, diagnosis, and treatment of mitochondrial diseases. RESULTS: Pathogenic defects of energy metabolism have been described to date in over 400 genes. Only a small number of these genes lie in the mitochondrial DNA; the corresponding diseases are either maternally inherited or of sporadic distribution. The remaining diseaseassociated genes are coded in nuclear DNA and cause diseases that are inherited according to Mendelian rules, mostly autosomal recessive. The most severely involved organs are generally those with the highest energy requirements, including the brain, the sensory epithelia, and the extraocular, cardiac, and skeletal musculature. Typical manifestations include epileptic seizures, stroke-like episodes, hearing loss, retinopathy, external ophthalmoparesis, exercise intolerance, and diabetes mellitus. More than two manifestations of these types should arouse suspicion of a disease of energy metabolism. The severity of mitochondrial disorders ranges from very severe disease, already evident in childhood, to relatively mild disease arising in late adulthood. The diagnosis is usually confirmed with molecular-genetic methods. Symptomatic treatment can improve patients' quality of life. The only disease-modifying treatment that has been approved to date is idebenone for the treatment of Leber hereditary optic neuropathy. Intravitreal gene therapy has also been developed for the treatment of this disease; its approval by the European Medicines Agency is pending. CONCLUSION: Patients with mitochondrial diseases have highly varied manifestations and can thus present to physicians in practically any branch of medicine. A correct diagnosis is the prerequisite for genetic counseling and for the initiation of personalized treatment.
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Scientific Article
Lam, D. ; Nikolic, A.A. ; Zhao, C. ; Mirza-Schreiber, N. ; Krezel, W. ; Oexle, K. ; Winkelmann, J.
Hum. Mol. Genet. 31, 1733-1746 (2021)
A highly evolutionarily conserved MEIS1 intronic region is strongly associated with restless legs syndrome (RLS) and insomnia. To understand its regulatory function, we dissected the region by analyzing chromatin accessibility, enhancer-promoter contacts, DNA methylation, and eQTLs in different human neural cell types and tissues. We observed specific activity with respect to cell type and developmental maturation, indicating a prominent role for distinct highly conserved intronic elements in forebrain inhibitory neuron differentiation. Two elements were hypomethylated in neural cells with higher MEIS1 expression, suggesting a role of enhancer demethylation in gene regulation. MEIS1 eQTLs showed a striking modular chromosomal distribution, with forebrain eQTLs clustering in intron 8/9. CRISPR interference targeting of individual elements in this region attenuated MEIS1 expression, revealing a complex regulatory interplay of distinct elements. In summary, we found that MEIS1 regulation is organized in a modular pattern. Disease-associated intronic regulatory elements control MEIS1 expression with cell type and maturation stage specificity, particularly in the inhibitory neuron lineage. The precise spatiotemporal activity of these elements likely contributes to the pathogenesis of insomnia and RLS.
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Scientific Article
Holmberg, O. ; Lenz, T. ; Koch, V. ; Alyagoob, A. ; Utsch, L. ; Rank, A. ; Sabic, E. ; Seguchi, M. ; Xhepa, E. ; Kufner, S. ; Cassese, S. ; Kastrati, A. ; Marr, C. ; Joner, M. ; Nicol, P.
Front. Cardiovasc. Med. 8:779807 (2021)
Background: Optical coherence tomography is a powerful modality to assess atherosclerotic lesions, but detecting lesions in high-resolution OCT is challenging and requires expert knowledge. Deep-learning algorithms can be used to automatically identify atherosclerotic lesions, facilitating identification of patients at risk. We trained a deep-learning algorithm (DeepAD) with co-registered, annotated histopathology to predict atherosclerotic lesions in optical coherence tomography (OCT). Methods: Two datasets were used for training DeepAD: (i) a histopathology data set from 7 autopsy cases with 62 OCT frames and co-registered histopathology for high quality manual annotation and (ii) a clinical data set from 51 patients with 222 OCT frames in which manual annotations were based on clinical expertise only. A U-net based deep convolutional neural network (CNN) ensemble was employed as an atherosclerotic lesion prediction algorithm. Results were analyzed using intersection over union (IOU) for segmentation. Results: DeepAD showed good performance regarding the prediction of atherosclerotic lesions, with a median IOU of 0.68 ± 0.18 for segmentation of atherosclerotic lesions. Detection of calcified lesions yielded an IOU = 0.34. When training the algorithm without histopathology-based annotations, a performance drop of >0.25 IOU was observed. The practical application of DeepAD was evaluated retrospectively in a clinical cohort (n = 11 cases), showing high sensitivity as well as specificity and similar performance when compared to manual expert analysis. Conclusion: Automated detection of atherosclerotic lesions in OCT is improved using a histopathology-based deep-learning algorithm, allowing accurate detection in the clinical setting. An automated decision-support tool based on DeepAD could help in risk prediction and guide interventional treatment decisions.
Wissenschaftlicher Artikel
Scientific Article
Graham, S.E. ; Clarke, S.L. ; Wu, K.H. ; Kanoni, S. ; Zajac, G.J.M. ; Ramdas, S. ; Surakka, I. ; Ntalla, I. ; Vedantam, S. ; Winkler, T.W. ; Locke, A.E. ; Marouli, E. ; Hwang, M.Y. ; Han, S. ; Narita, A. ; Choudhury, A. ; Bentley, A.R. ; Ekoru, K. ; Verma, A. ; Trivedi, B. ; Martin, H.C. ; Hunt, K.A. ; Hui, Q. ; Klarin, D. ; Zhu, X. ; Thorleifsson, G. ; Helgadottir, A. ; Gudbjartsson, D.F. ; Holm, H. ; Olafsson, I. ; Akiyama, M. ; Sakaue, S. ; Terao, C. ; Kanai, M. ; Zhou, W. ; Brumpton, B.M. ; Rasheed, H. ; Ruotsalainen, S.E. ; Havulinna, A.S. ; Veturi, Y. ; Feng, Q. ; Rosenthal, E.A. ; Lingren, T. ; Pacheco, J.A. ; Pendergrass, S.A. ; Haessler, J. ; Giulianini, F. ; Bradford, Y. ; Miller, J.E. ; Campbell, A. ; Lin, K. ; Millwood, I.Y. ; Hindy, G. ; Rasheed, A. ; Faul, J.D. ; Zhao, W. ; Weir, D.R. ; Turman, C. ; Huang, H. ; Graff, M. ; Mahajan, A. ; Brown, M.R. ; Zhang, W. ; Yu, K. ; Schmidt, E.M. ; Pandit, A. ; Gustafsson, S. ; Yin, X. ; Luan, J. ; Zhao, J.H. ; Matsuda, F. ; Jang, H.M. ; Yoon, K. ; Medina-Gomez, C. ; Pitsillides, A. ; Hottenga, J.J. ; Willemsen, G. ; Wood, A.R. ; Ji, Y. ; Gao, Z. ; Haworth, S. ; Mitchell, R.E. ; Chai, J.F. ; Aadahl, M. ; Yao, J. ; Manichaikul, A. ; Warren, H.R. ; Ramirez, J. ; Bork-Jensen, J. ; Kårhus, L.L. ; Goel, A. ; Sabater-Lleal, M. ; Noordam, R. ; Sidore, C. ; Fiorillo, E. ; McDaid, A.F. ; Marques-Vidal, P. ; Wielscher, M. ; Trompet, S. ; Sattar, N. ; Møllehave, L.T. ; Thuesen, B.H. ; Munz, M. ; Zeng, L. ; Huang, J. ; Yang, B. ; Poveda, A. ; Kurbasic, A. ; Lamina, C. ; Forer, L. ; Scholz, M. ; Galesloot, T.E. ; Bradfield, J.P. ; Daw, E.W. ; Zmuda, J.M. ; Mitchell, J.S. ; Fuchsberger, C. ; Christensen, H. ; Brody, J.A. ; Feitosa, M.F. ; Wojczynski, M.K. ; Preuss, M. ; Mangino, M. ; Christofidou, P. ; Verweij, N. ; Engmann, J. ; Kember, R.L. ; Slieker, R.C. ; Lo, K.S. ; Zilhao, N.R. ; Le, P. ; Kleber, M.E. ; Delgado, G.E. ; Huo, S. ; Ikeda, D.D. ; Iha, H. ; Yang, J. ; Liu, J. ; Leonard, H.L. ; Marten, J. ; Schmidt, B. ; Arendt, M. ; Smyth, L.J. ; Cañadas-Garre, M. ; Wang, C. ; Nakatochi, M. ; Wong, A. ; Hutri-Kähönen, N. ; Sim, X. ; Xia, R. ; Huerta-Chagoya, A. ; Fernandez-Lopez, J.C. ; Lyssenko, V. ; Ahmed, M. ; Jackson, A.U. ; Irvin, M.R. ; Oldmeadow, C. ; Kim, H.N. ; Ryu, S. ; Timmers, P.R.H.J. ; Arbeeva, L. ; Dorajoo, R. ; Lange, L.A. ; Chai, X. ; Prasad, G. ; Lorés-Motta, L. ; Pauper, M. ; Long, J. ; Li, X. ; Theusch, E. ; Takeuchi, F. ; Spracklen, C.N. ; Loukola, A. ; Bollepalli, S. ; Warner, S.C. ; Wang, Y.X. ; Wei, W.B. ; Nutile, T. ; Ruggiero, D. ; Sung, Y.J. ; Hung, Y.J. ; Chen, S. ; Liu, F. ; Kentistou, K.A. ; Gorski, M. ; Brumat, M. ; Meidtner, K. ; Bielak, L.F. ; Smith, J.A. ; Hebbar, P. ; Farmaki, A.E. ; Hofer, E. ; Lin, M. ; Xue, C. ; Zhang, J. ; Concas, M.P. ; Vaccargiu, S. ; van der Most, P.J. ; Pitkänen, N. ; Cade, B.E. ; Lee, J. ; van der Laan, S.W. ; Chitrala, K.N. ; Weiss, S. ; Zimmermann, M.E. ; Lee, J.Y. ; Choi, H.S. ; Nethander, M. ; Freitag-Wolf, S. ; Southam, L. ; Rayner, N.W. ; Wang, C.A. ; Lin, S.Y. ; Wang, J.S. ; Couture, C. ; Lyytikäinen, L.P. ; Nikus, K. ; Cuellar-Partida, G. ; Vestergaard, H. ; Hildalgo, B. ; Giannakopoulou, O. ; Cai, Q. ; Obura, M.O. ; van Setten, J. ; Schwander, K. ; Terzikhan, N. ; Shin, J.H. ; Jackson, R.D. ; Reiner, A.P. ; Martin, L.W. ; Chen, Z. ; Li, L. ; Highland, H.M. ; Young, K.L. ; Kawaguchi, T. ; Thiery, J. ; Bis, J.C. ; Nadkarni, G.N. ; Launer, L.J. ; Li, H. ; Nalls, M.A. ; Raitakari, O.T. ; Ichihara, S. ; Wild, S.H. ; Nelson, C.P. ; Campbell, H. ; Jäger, S. ; Nabika, T. ; Al-Mulla, F. ; Niinikoski, H. ; Braund, P.S. ; Kolcic, I. ; Kovacs, P. ; Giardoglou, T. ; Katsuya, T. ; Bhatti, K.F. ; de Kleijn, D.P. ; de Borst, G.J. ; Kim, E.K. ; Adams, H.H.H. ; Ikram, M.A. ; Asselbergs, F.W. ; Kraaijeveld, A.O. ; Beulens, J.W.J. ; Shu, X.O. ; Rallidis, L.S. ; Pedersen, O. ; Hansen, T. ; Mitchell, P. ; Hewitt, A.W. ; Kähönen, M. ; Perusse, L. ; Bouchard, C. ; Tönjes, A. ; Chen, Y.I. ; Pennell, C.E. ; Mori, T.A. ; Lieb, W. ; Franke, A. ; Ohlsson, C. ; Mellström, D. ; Cho, Y.S. ; Lee, H. ; Yuan, J.M. ; Koh, W.P. ; Rhee, S.Y. ; Woo, J.T. ; Heid, I.M. ; Stark, K.J. ; Völzke, H. ; Homuth, G. ; Evans, M.K. ; Zonderman, A.B. ; Polasek, O. ; Pasterkamp, G. ; Hoefer, I.E. ; Redline, S. ; Pahkala, K. ; Oldehinkel, A.J. ; Snieder, H. ; Biino, G. ; Schmidt, R. ; Schmidt, H. ; Chen, Y.E. ; Bandinelli, S. ; Dedoussis, G. ; Thanaraj, T.A. ; Kardia, S.L.R. ; Kato, N. ; Schulze, M.B. ; Girotto, G. ; Jung, B. ; Böger, C.A. ; Joshi, P.K. ; Bennett, D.A. ; de Jager, P.L. ; Lu, X. ; Mamakou, V. ; Brown, M. ; Caulfield, M.J. ; Munroe, P.B. ; Guo, X. ; Ciullo, M. ; Jonas, J.B. ; Samani, N.J. ; Kaprio, J. ; Pajukanta, P. ; Adair, L.S. ; Bechayda, S.A. ; de Silva, H.J. ; Wickremasinghe, A.R. ; Krauss, R.M. ; Wu, J.Y. ; Zheng, W. ; den Hollander, A.I. ; Bharadwaj, D. ; Correa, A. ; Wilson, J.G. ; Lind, L. ; Heng, C.K. ; Nelson, A.E. ; Golightly, Y.M. ; Wilson, J.F. ; Penninx, B. ; Kim, H.L. ; Attia, J. ; Scott, R.J. ; Rao, D.C. ; Arnett, D.K. ; Walker, M. ; Koistinen, H.A. ; Chandak, G.R. ; Yajnik, C.S. ; Mercader, J.M. ; Tusié-Luna, T. ; Aguilar-Salinas, C.A. ; Villalpando, C.G. ; Orozco, L. ; Fornage, M. ; Tai, E.S. ; van Dam, R.M. ; Lehtimäki, T. ; Chaturvedi, N. ; Yokota, M. ; Reilly, D.F. ; McKnight, A.J. ; Kee, F. ; Jöckel, K.H. ; McCarthy, M.I. ; Palmer, C.N.A. ; Vitart, V. ; Hayward, C. ; Simonsick, E. ; van Duijn, C.M. ; Lu, F. ; Qu, J. ; Hishigaki, H. ; Lin, X. ; März, W. ; Parra, E.J. ; Cruz, M. ; Gudnason, V. ; Tardif, J.C. ; Lettre, G. ; 't Hart, L.M. ; Elders, P.J.M. ; Damrauer, S.M. ; Kumari, M. ; Kivimaki, M. ; van der Harst, P. ; Spector, T.D. ; Loos, R.J.F. ; Province, M.A. ; Psaty, B.M. ; Brandslund, I. ; Pramstaller, P.P. ; Christensen, K. ; Ripatti, S. ; Widen, E. ; Hakonarson, H. ; Grant, S.F.A. ; Kiemeney, L.A.L.M. ; de Graaf, J. ; Loeffler, M. ; Kronenberg, F. ; Gu, D. ; Erdmann, J. ; Schunkert, H. ; Franks, P.W. ; Linneberg, A. ; Jukema, J.W. ; Khera, A.V. ; Männikkö, M. ; Jarvelin, M.R. ; Kutalik, Z. ; Cucca, F. ; Mook-Kanamori, D.O. ; van Dijk, K.W. ; Watkins, H. ; Strachan, D.P. ; Grarup, N. ; Sever, P. ; Poulter, N. ; Rotter, J.I. ; Dantoft, T.M. ; Karpe, F. ; Neville, M.J. ; Timpson, N.J. ; Cheng, C.Y. ; Wong, T.Y. ; Khor, C.C. ; Sabanayagam, C. ; Peters, A. ; Gieger, C. ; Hattersley, A.T. ; Pedersen, N.L. ; Magnusson, P.K.E. ; Boomsma, D.I. ; de Geus, E.J.C. ; Cupples, L.A. ; van Meurs, J.B.J. ; Ghanbari, M. ; Gordon-Larsen, P. ; Huang, W. ; Kim, Y.J. ; Tabara, Y. ; Wareham, N.J. ; Langenberg, C. ; Zeggini, E. ; Kuusisto, J. ; Laakso, M. ; Ingelsson, E. ; Abecasis, G. ; Chambers, J.C. ; Kooner, J.S. ; de Vries, P.S. ; Morrison, A.C. ; North, K.E. ; Daviglus, M. ; Kraft, P. ; Martin, N.G. ; Whitfield, J.B. ; Abbas, S. ; Saleheen, D. ; Walters, R.G. ; Holmes, M.V. ; Black, C. ; Smith, B.H. ; Justice, A.E. ; Baras, A. ; Buring, J.E. ; Ridker, P.M. ; Chasman, D.I. ; Kooperberg, C. ; Wei, W.Q. ; Jarvik, G.P. ; Namjou, B. ; Hayes, M.G. ; Ritchie, M.D. ; Jousilahti, P. ; Salomaa, V. ; Hveem, K. ; Asvold, B.O. ; Kubo, M. ; Kamatani, Y. ; Okada, Y. ; Murakami, Y. ; Thorsteinsdottir, U. ; Stefansson, K. ; Ho, Y.L. ; Lynch, J.A. ; Rader, D.J. ; Tsao, P.S. ; Chang, K.M. ; Cho, K. ; O'Donnell, C.J. ; Gaziano, J.M. ; Wilson, P.F. ; Rotimi, C.N. ; Hazelhurst, S. ; Ramsay, M. ; Trembath, R.C. ; van Heel, D.A. ; Tamiya, G. ; Yamamoto, M. ; Kim, B.J. ; Mohlke, K.L. ; Frayling, T.M. ; Hirschhorn, J.N. ; Kathiresan, S. ; VA Million Veteran Program ; Global Lipids Genetics Consortium* ; Boehnke, M. ; Natarajan, P. ; Peloso, G.M. ; Brown, C.D. ; Morris, A.P. ; Assimes, T.L. ; Deloukas, P. ; Sun, Y.V. ; Willer, C.J.
Nature 600, 675-679 (2021)
Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.
Wissenschaftlicher Artikel
Scientific Article
Yang, C. ; Starnecker, F. ; Pang, S. ; Chen, Z. ; Güldener, U. ; Li, L. ; Heinig, M. ; Schunkert, H.
BMC Cardiovasc. Disord. 21:586 (2021)
BACKGROUND: Epidemiological studies have repeatedly observed a markedly higher risk for coronary artery disease (CAD) in Scotland as compared to England. Up to now, it is unclear whether environmental or genetic factors might explain this phenomenon. METHODS: Using UK Biobank (UKB) data, we assessed CAD risk, based on the Framingham risk score (FRS) and common genetic variants, to explore the respective contribution to CAD prevalence in Scotland (n = 31,963) and England (n = 317,889). We calculated FRS based on sex, age, body mass index (BMI), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), antihypertensive medication, smoking status, and diabetes. We determined the allele frequency of published genome-wide significant risk CAD alleles and a weighted genetic risk score (wGRS) for quantifying genetic CAD risk. RESULTS: Prevalence of CAD was 16% higher in Scotland as compared to England (8.98% vs. 7.68%, P < 0.001). However, the FRS only predicted a marginally higher CAD risk (less than 1%) in Scotland (12.5 ± 10.5 vs.12.6 ± 10.6, P = 0.03). Likewise, the overall number of genome-wide significant variants affecting CAD risk (157.6 ± 7.7 and 157.5 ± 7.7; P = 0.12) and a wGRS for CAD (2.49 ± 0.25 in both populations, P = 0.14) were remarkably similar in the English and Scottish population. Interestingly, we observed substantial differences in the allele frequencies of individual risk variants. Of the previously described 163 genome-wide significant variants studied here, 35 variants had higher frequencies in Scotland, whereas 37 had higher frequencies in England (P < 0.001 each). CONCLUSIONS: Neither the traditional risk factors included in the FRS nor a genetic risk score (GRS) based on established common risk alleles explained the higher CAD prevalence in Scotland. However, we observed marked differences in the distribution of individual risk alleles, which emphasizes that even geographically and ethnically closely related populations may display relevant differences in the genetic architecture of a common disease.
Wissenschaftlicher Artikel
Scientific Article
Key, J. ; Torres-Odio, S. ; Bach, N.C. ; Gispert, S. ; Koepf, G. ; Reichlmeir, M. ; West, A.P. ; Prokisch, H. ; Freisinger, P. ; Newman, W.G. ; Shalev, S. ; Sieber, S.A. ; Wittig, I. ; Auburger, G.
Cells 10:3354 (2021)
Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with pro-gressive neurological deficits. Mouse models showed that accumulations of (i) its main protein in-teractor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fi-broblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence.
Wissenschaftlicher Artikel
Scientific Article
Dreher, S.I. ; Höckele, S. ; Huypens, P. ; Irmler, M. ; Hoffmann, C. ; Jeske, T. ; Hastreiter, M. ; Moller, A. ; Birkenfeld, A.L. ; Häring, H.-U. ; Peter, A. ; Beckers, J. ; Hrabě de Angelis, M. ; Weigert, C.
Cells 10:3443 (2021)
Physical training improves insulin sensitivity and can prevent type 2 diabetes (T2D). However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a possible upstream regulator involved in this low response, is also a potent regulator of microRNAs (miRNAs). The aim of this study was to elucidate the potential impact of TGF-β-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-β1-treated human skeletal muscle cells corroborated the effects of TGF-β1 on muscle cell differentiation, the induction of extracellular matrix components, and identified several TGF-β1-regulated miRNAs. qPCR validated a potent upregulation of miR-143-3p/145-5p and miR-181a2-5p by TGF-β1 in both human myoblasts and differentiated myotubes. Healthy subjects who were overweight or obese participated in a supervised 8-week endurance training intervention (n = 40) and were categorized as responder or low responder in glycemic control based on fold change ISIMats (≥+1.1 or <+1.1, respectively). In skeletal muscle biopsies of low responders, TGF-β signaling and miR-143/145 cluster levels were induced by training at much higher rates than among responders. Target-mining revealed HDACs, MYHs, and insulin signaling components INSR and IRS1 as potential miR-143/145 cluster targets. All these targets were down-regulated in TGF-β1-treated myotubes. Transfection of miR-143-3p/145-5p mimics in differentiated myotubes validated MYH1, MYH4, and IRS1 as miR-143/145 cluster targets. Elevated TGF-β signaling and miR-143/145 cluster induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: by a negative impact of miR-143-3p on muscle cell fusion and myofiber functionality and by directly impairing insulin signaling via a reduction in INSR by TGF-β and finetuned IRS1 suppression by miR-143-3p.
Wissenschaftlicher Artikel
Scientific Article
Neiburga, K.D. ; Vilne, B. ; Bauer, S. ; Bongiovanni, D. ; Ziegler, T. ; Lachmann, M. ; Wengert, S. ; Hawe, J.S. ; Güldener, U. ; Westerlund, A. ; Li, L. ; Pang, S. ; Yang, C. ; Saar, K. ; Huebner, N. ; Maegdefessel, L. ; Lange, R. ; Krane, M. ; Schunkert, H. ; von Scheidt, M.
Biomolecules 11, New Approaches for the Treatment of Civilization Diseases:1683 (2021)
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Non-coding RNAs have already been linked to CVD development and progression. While microR-NAs (miRs) have been well studied in blood samples, there is little data on tissue-specific miRs in cardiovascular relevant tissues and their relation to cardiovascular risk factors. Tissue-specific miRs derived from Arteria mammaria interna (IMA) from 192 coronary artery disease (CAD) patients undergoing coronary artery bypass grafting (CABG) were analyzed. The aims of the study were 1) to establish a reference atlas which can be utilized for identification of novel diagnostic biomarkers and potential therapeutic targets, and 2) to relate these miRs to cardiovascular risk factors. Overall, 393 individual miRs showed sufficient expression levels and passed quality control for further analysis. We identified 17 miRs–miR-10b-3p, miR-10-5p, miR-17-3p, miR-21-5p, miR-151a-5p, miR-181a-5p, miR-185-5p, miR-194-5p, miR-199a-3p, miR-199b-3p, miR-212-3p, miR-363-3p, miR-548d-5p, miR-744-5p, miR-3117-3p, miR-5683 and miR-5701–significantly correlated with cardiovascular risk factors (correlation coefficient >0.2 in both directions, p-value (p < 0.006, false discovery rate (FDR)
Wissenschaftlicher Artikel
Scientific Article
Heilbronner, U. ; Streit, F. ; Vogl, T. ; Senner, F. ; Schaupp, S.K. ; Reich-Erkelenz, D. ; Papiol, S. ; Oraki Kohshour, M. ; Klöhn-Saghatolislam, F. ; Kalman, J.L. ; Heilbronner, M. ; Gade, K. ; Comes, A.L. ; Budde, M. ; Andlauer, T.F.M. ; Anderson-Schmidt, H. ; Adorjan, K. ; Stürmer, T. ; Loerbroks, A. ; Amelang, M. ; Poisel, E. ; Foo, J.C. ; Heilmann-Heimbach, S. ; Forstner, A.J. ; Degenhardt, F. ; Zimmermann, J. ; Wiltfang, J. ; von Hagen, M. ; Spitzer, C. ; Schmauss, M. ; Reininghaus, E. ; Reimer, J. ; Konrad, C. ; Juckel, G. ; Lang, F.U. ; Jäger, M. ; Figge, C. ; Fallgatter, A.J. ; Dietrich, D.E. ; Dannlowski, U. ; Baune, B.T. ; Arolt, V. ; Anghelescu, I.G. ; Nöthen, M.M. ; Witt, S.H. ; Andreassen, O.A. ; Chen, C.H. ; Falkai, P. ; Rietschel, M. ; Schulze, T.G. ; Schulte, E.C.
BJPsych Open 7:e188 (2021)
Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, with its impact on our way of life, is affecting our experiences and mental health. Notably, individuals with mental disorders have been reported to have a higher risk of contracting SARS-CoV-2. Personality traits could represent an important determinant of preventative health behaviour and, therefore, the risk of contracting the virus. Aims: We examined overlapping genetic underpinnings between major psychiatric disorders, personality traits and susceptibility to SARS-CoV-2 infection. Method: Linkage disequilibrium score regression was used to explore the genetic correlations of coronavirus disease 2019 (COVID-19) susceptibility with psychiatric disorders and personality traits based on data from the largest available respective genome-wide association studies (GWAS). In two cohorts (the PsyCourse (n = 1346) and the HeiDE (n = 3266) study), polygenic risk scores were used to analyse if a genetic association between, psychiatric disorders, personality traits and COVID-19 susceptibility exists in individual-level data. Results: We observed no significant genetic correlations of COVID-19 susceptibility with psychiatric disorders. For personality traits, there was a significant genetic correlation for COVID-19 susceptibility with extraversion (P = 1.47 × 10-5; genetic correlation 0.284). Yet, this was not reflected in individual-level data from the PsyCourse and HeiDE studies. Conclusions: We identified no significant correlation between genetic risk factors for severe psychiatric disorders and genetic risk for COVID-19 susceptibility. Among the personality traits, extraversion showed evidence for a positive genetic association with COVID-19 susceptibility, in one but not in another setting. Overall, these findings highlight a complex contribution of genetic and non-genetic components in the interaction between COVID-19 susceptibility and personality traits or mental disorders.
Wissenschaftlicher Artikel
Scientific Article
Syga, S. ; David-Rus, D. ; Schälte, Y. ; Hatzikirou, H. ; Deutsch, A.
Sci. Rep. 11:21913 (2021)
Countries around the world implement nonpharmaceutical interventions (NPIs) to mitigate the spread of COVID-19. Design of efficient NPIs requires identification of the structure of the disease transmission network. We here identify the key parameters of the COVID-19 transmission network for time periods before, during, and after the application of strict NPIs for the first wave of COVID-19 infections in Germany combining Bayesian parameter inference with an agent-based epidemiological model. We assume a Watts–Strogatz small-world network which allows to distinguish contacts within clustered cliques and unclustered, random contacts in the population, which have been shown to be crucial in sustaining the epidemic. In contrast to other works, which use coarse-grained network structures from anonymized data, like cell phone data, we consider the contacts of individual agents explicitly. We show that NPIs drastically reduced random contacts in the transmission network, increased network clustering, and resulted in a previously unappreciated transition from an exponential to a constant regime of new cases. In this regime, the disease spreads like a wave with a finite wave speed that depends on the number of contacts in a nonlinear fashion, which we can predict by mean field theory.
Wissenschaftlicher Artikel
Scientific Article
Saha, S. ; Kondmann, L. ; Song, Q. ; Zhu, X.X.
14, 11029-11041 (2021)
Deep transfer-learning-based change detection methods are dependent on the availability of sensor-specific pretrained feature extractors. Such feature extractors are not always available due to lack of training data, especially for hyperspectral sensors and other hyperdimensional images. Moreover models trained on easily available multispectral (RGB/RGB-NIR) images cannot be reused on such hyperdimensional images due to their irregular number of bands. While hyperdimensional images show large number of spectral bands, they generally show much less spatial complexity, thus reducing the requirement of large receptive fields of convolution filters. Recent works in the computer vision have shown that even untrained deep models can yield remarkable result in some tasks like super-resolution and surface reconstruction. This motivates us to make a bold proposition that untrained lightweight deep model, initialized with some weight initialization strategy, can be used to extract useful semantic features from bi-temporal hyperdimensional images. Based on this proposition, we design a novel change detection framework for hyperdimensional images by extracting bitemporal features using an untrained model and further comparing the extracted features using deep change vector analysis to distinguish changed pixels from the unchanged ones. We further use the deep change hypervectors to cluster the changed pixels into different semantic groups. We conduct experiments on four change detection datasets: three hyperspectral datasets and a hyperdimensional polarimetric synthetic aperture radar dataset. The results clearly demonstrate that the proposed method is suitable for change detection in hyperdimensional remote sensing data.
Wissenschaftlicher Artikel
Scientific Article
Mertins, J. ; Finke, J. ; Sies, R. ; Rink, K.M. ; Hasenauer, J. ; Lang, T.
eLife 10, 2624-2624 (2021)
SNARE proteins have been described as the effectors of fusion events in the secretory pathway more than two decades ago. The strong interactions between SNARE domains are clearly important in membrane fusion, but it is unclear whether they are involved in any other cellular processes. Here, we analyzed two classical SNARE proteins, syntaxin 1A and SNAP25. Although they are supposed to be engaged in tight complexes, we surprisingly find them largely segregated in the plasma membrane. Syntaxin 1A only occupies a small fraction of the plasma membrane area. Yet, we find it is able to redistribute the far more abundant SNAP25 on the mesoscale by gathering crowds of SNAP25 molecules onto syntaxin clusters in a SNARE-domain-dependent manner. Our data suggest that SNARE domain interactions are not only involved in driving membrane fusion on the nanoscale, but also play an important role in controlling the general organization of proteins on the mesoscale. Further, we propose these mechanisms preserve active syntaxin 1A-SNAP25 complexes at the plasma membrane.
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Scientific Article
Aboulmaouahib, B. ; Kastenmüller, G. ; Suhre, K. ; Zöllner, S. ; Weissensteiner, H. ; Gieger, C. ; Wang-Sattler, R. ; Lichtner, P. ; Strauch, K. ; Flaquer, A.
Hum. Mol. Genet., DOI: 10.1093/hmg/ddab312 (2021)
INTRODUCTION: In the era of personalized medicine with more and more patient specific targeted therapies being used, we need reliable, dynamic, faster, and sensitive biomarkers both to track the causes of disease and to develop and evolve therapies during the course of treatment. Metabolomics recently has shown substantial evidence to support its emerging role in disease diagnosis and prognosis. Aside from biomarkers and development of therapies, it is also an important goal to understand the involvement of mitochondrial DNA mtDNA in metabolic regulation, aging, and disease development. Somatic mutations of the mitochondrial genome are also heavily implicated in age-related disease and aging. The general hypothesis is that an alteration in the concentration of metabolite profiles (possibly conveyed by lifestyle and environmental factors) influences the increase of mutation rate in the mtDNA, and thereby contributes to a range of pathophysiological alterations observed in complex diseases. METHODS: We performed an inverted mitochondrial genome wide association analysis between mitochondrial nucleotide variants (mtSNVs) and concentration of metabolites. We used 151 metabolites and the whole sequenced mitochondrial genome from 2718 individuals to identify genetic variants associated with metabolite profiles. Because of the high coverage, next generation sequencing-based analysis of the mitochondrial genome allows for an accurate detection of mitochondrial heteroplasmy and for identification of variants associated with the metabolome. RESULTS: The strongest association was found for mt715G > A located in the MT-12SrRNA with the metabolite ratio C2/C10:1 (p-value = 6.82*10-09, β = 0.909). The second most significant mtSNV was found for mt3714A > G located in the MT-ND1 with the metabolite ratio PC ae C42:5/PC ae C44:5 (p-value = 1.02*10-08, β = 3.631). A large number of significant metabolite ratios were observed involving PC aa C36:6 and the variant mt10689G > A, located in the MT-ND4L gene. CONCLUSION: These results show an important interconnection between mitochondria and metabolite concentrations. Considering that some of the significant metabolites found in this study have been previously related to complex diseases such as neurological disorders and metabolic conditions, these associations found here might play a crucial role for further investigations of such complex diseases. Understanding the mechanisms that control human health and disease, in particular the role of genetic predispositions and their interaction with environmental factors is a prerequisite for the development of safe and efficient therapies for complex disorders.
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Scientific Article
Brydges, C.R. ; Fiehn, O. ; Mayberg, H.S. ; Schreiber, H. ; Dehkordi, S.M. ; Bhattacharyya, S. ; Cha, J. ; Choi, K.S. ; Craighead, W.E. ; Krishnan, R.R. ; Rush, A.J. ; Dunlop, B.W. ; Kaddurah-Daouk, R. ; Mood Disorders Precision Medicine Consortium (Kastenmüller, G.) ; Mood Disorders Precision Medicine Consortium (Arnold, M.)
Sci. Rep. 11:21011 (2021)
It is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety. Serum samples (baseline, 12 weeks) were drawn from participants (n = 196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder. Baseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolite’s effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, and changes in symptoms were not correlated with changes in indole concentrations. These results suggest that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to modulation of indoles derived from gut microbiota; it remains possible that treatment-related improvement stems from their impact on other aspects of the gut microbiome. A peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches. Given the exploratory nature of this study, findings should be replicated in confirmatory studies. Clinical trial NCT00360399 “Predictors of Antidepressant Treatment Response: The Emory CIDAR” https://clinicaltrials.gov/ct2/show/NCT00360399.
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Scientific Article
Ostner, J. ; Carcy, S. ; Müller, C.
Front. Genet. 12:766405 (2021)
Accurate generative statistical modeling of count data is of critical relevance for the analysis of biological datasets from high-throughput sequencing technologies. Important instances include the modeling of microbiome compositions from amplicon sequencing surveys and the analysis of cell type compositions derived from single-cell RNA sequencing. Microbial and cell type abundance data share remarkably similar statistical features, including their inherent compositionality and a natural hierarchical ordering of the individual components from taxonomic or cell lineage tree information, respectively. To this end, we introduce a Bayesian model for tree-aggregated amplicon and single-cell compositional data analysis (tascCODA) that seamlessly integrates hierarchical information and experimental covariate data into the generative modeling of compositional count data. By combining latent parameters based on the tree structure with spike-and-slab Lasso penalization, tascCODA can determine covariate effects across different levels of the population hierarchy in a data-driven parsimonious way. In the context of differential abundance testing, we validate tascCODA’s excellent performance on a comprehensive set of synthetic benchmark scenarios. Our analyses on human single-cell RNA-seq data from ulcerative colitis patients and amplicon data from patients with irritable bowel syndrome, respectively, identified aggregated cell type and taxon compositional changes that were more predictive and parsimonious than those proposed by other schemes. We posit that tascCODA1 constitutes a valuable addition to the growing statistical toolbox for generative modeling and analysis of compositional changes in microbial or cell population data.
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Scientific Article
Büttner, M. ; Ostner, J. ; Müller, C. ; Theis, F.J. ; Schubert, B.
Nat. Commun. 12:6876 (2021)
Compositional changes of cell types are main drivers of biological processes. Their detection through single-cell experiments is difficult due to the compositionality of the data and low sample sizes. We introduce scCODA ( https://github.com/theislab/scCODA ), a Bayesian model addressing these issues enabling the study of complex cell type effects in disease, and other stimuli. scCODA demonstrated excellent detection performance, while reliably controlling for false discoveries, and identified experimentally verified cell type changes that were missed in original analyses.
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Scientific Article
Dzinovic, I. ; Serranová, T. ; Prouteau, C. ; Colin, E. ; Ziegler, A. ; Winkelmann, J. ; Jech, R. ; Zech, M.
Neurogenetics, DOI: 10.1007/s10048-021-00641-w (2021)
The affiliation of author Robert Jech was incorrectly indicated in the originally published version of this paper.
Png, G. ; Barysenka, A. ; Repetto, L. ; Navarro, P. ; Shen, X. ; Pietzner, M. ; Wheeler, E. ; Wareham, N.J. ; Langenberg, C. ; Tsafantakis, E. ; Karaleftheri, M. ; Dedoussis, G. ; Mälarstig, A. ; Wilson, J.F. ; Gilly, A. ; Zeggini, E.
Nat. Commun. 12:7042 (2021)
Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer's disease, GPNMB and Parkinson's disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.
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Scientific Article
Peng, Y. ; Felce, S.L. ; Dong, D. ; Penkava, F. ; Mentzer, A.J. ; Yao, X. ; Liu, G. ; Yin, Z. ; Chen, J.L. ; Lu, Y. ; Wellington, D. ; Wing, P.A.C. ; Dominey-Foy, D.C.C. ; Jin, C. ; Wang, W. ; Hamid, M.A. ; Fernandes, R.A. ; Wang, B. ; Fries, A. ; Zhuang, X. ; Ashley, N. ; Rostron, T. ; Waugh, C. ; Sopp, P. ; Hublitz, P. ; Beveridge, R. ; Tan, T.K. ; Dold, C. ; Kwok, A.J. ; Rich-Griffin, C. ; Dejnirattisa, W. ; Liu, C. ; Kurupati, P. ; Nassiri, I. ; Watson, R.A. ; Tong, O. ; Taylor, C.A. ; Kumar Sharma, P. ; Sun, B. ; Curion, F. ; Revale, S. ; Garner, L.C. ; Jansen, K. ; Ferreira, R.C. ; Attar, M. ; Fry, J.W. ; Russell, R.A. ; COMBAT Consortium ; Stauss, H.J. ; James, W. ; Townsend, A.J. ; Ho, J.-P. ; Klenerman, P. ; Mongkolsapaya, J. ; Screaton, G.R. ; Dendrou, C. ; Sansom, S.N. ; Bashford-Rogers, R. ; Chain, B. ; Smith, G.L. ; McKeating, J.A. ; Fairfax, B.P. ; Bowness, P. ; McMichael, A.J. ; Ogg, G. ; Knight, J.C. ; Dong, T.
Nat. Immunol., DOI: 10.1038/s41590-021-01084-z (2021)
NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.
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Scientific Article
Gudina, E.K. ; Ali, S. ; Girma, E. ; Gize, A. ; Tegene, B. ; Hundie, G.B. ; Sime, W.T. ; Ambachew, R. ; Gebreyohanns, A. ; Bekele, M. ; Bakuli, A. ; Elsbernd, K. ; Merkt, S. ; Contento, L. ; Hoelscher, M. ; Hasenauer, J. ; Wieser, A. ; Kroidl, A.
Lancet Glob. Health 9, e1517-e1527 (2021)
Background: Over 1 year since the first reported case, the true COVID-19 burden in Ethiopia remains unknown due to insufficient surveillance. We aimed to investigate the seroepidemiology of SARS-CoV-2 among front-line hospital workers and communities in Ethiopia. Methods: We did a population-based, longitudinal cohort study at two tertiary teaching hospitals involving hospital workers, rural residents, and urban communities in Jimma and Addis Ababa. Hospital workers were recruited at both hospitals, and community participants were recruited by convenience sampling including urban metropolitan settings, urban and semi-urban settings, and rural communities. Participants were eligible if they were aged 18 years or older, had provided written informed consent, and were willing to provide blood samples by venepuncture. Only one participant per household was recruited. Serology was done with Elecsys anti-SARS-CoV-2 anti-nucleocapsid assay in three consecutive rounds, with a mean interval of 6 weeks between tests, to obtain seroprevalence and incidence estimates within the cohorts. Findings: Between Aug 5, 2020, and April 10, 2021, we did three survey rounds with a total of 1104 hospital workers and 1229 community residents participating. SARS-CoV-2 seroprevalence among hospital workers increased strongly during the study period: in Addis Ababa, it increased from 10·9% (95% credible interval [CrI] 8·3–13·8) in August, 2020, to 53·7% (44·8–62·5) in February, 2021, with an incidence rate of 2223 per 100 000 person-weeks (95% CI 1785–2696); in Jimma Town, it increased from 30·8% (95% CrI 26·9–34·8) in November, 2020, to 56·1% (51·1–61·1) in February, 2021, with an incidence rate of 3810 per 100 000 person-weeks (95% CI 3149–4540). Among urban communities, an almost 40% increase in seroprevalence was observed in early 2021, with incidence rates of 1622 per 100 000 person-weeks (1004–2429) in Jimma Town and 4646 per 100 000 person-weeks (2797–7255) in Addis Ababa. Seroprevalence in rural communities increased from 18·0% (95% CrI 13·5–23·2) in November, 2020, to 31·0% (22·3–40·3) in March, 2021. Interpretation: SARS-CoV-2 spread in Ethiopia has been highly dynamic among hospital worker and urban communities. We can speculate that the greatest wave of SARS-CoV-2 infections is currently evolving in rural Ethiopia, and thus requires focused attention regarding health-care burden and disease prevention. Funding: Bavarian State Ministry of Sciences, Research, and the Arts; Germany Ministry of Education and Research; EU Horizon 2020 programme; Deutsche Forschungsgemeinschaft; and Volkswagenstiftung.
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Scientific Article
Baltatzis, V. ; Bintsi, K.M. ; Folgoc, L.L. ; Martinez Manzanera, O.E. ; Ellis, S. ; Nair, A. ; Desai, S. ; Glocker, B. ; Schnabel, J.A.
In: (4th International Workshop on Predictive Intelligence in Medicine, PRIME 2021, 1 October 2021, Virtual, Online). 2021. 201-211 (Lect. Notes Comput. Sc. ; 12928 LNCS)
Using publicly available data to determine the performance of methodological contributions is important as it facilitates reproducibility and allows scrutiny of the published results. In lung nodule classification, for example, many works report results on the publicly available LIDC dataset. In theory, this should allow a direct comparison of the performance of proposed methods and assess the impact of individual contributions. When analyzing seven recent works, however, we find that each employs a different data selection process, leading to largely varying total number of samples and ratios between benign and malignant cases. As each subset will have different characteristics with varying difficulty for classification, a direct comparison between the proposed methods is thus not always possible, nor fair. We study the particular effect of truthing when aggregating labels from multiple experts. We show that specific choices can have severe impact on the data distribution where it may be possible to achieve superior performance on one sample distribution but not on another. While we show that we can further improve on the state-of-the-art on one sample selection, we also find that on a more challenging sample selection, on the same database, the more advanced models underperform with respect to very simple baseline methods, highlighting that the selected data distribution may play an even more important role than the model architecture. This raises concerns about the validity of claimed methodological contributions. We believe the community should be aware of these pitfalls and make recommendations on how these can be avoided in future work.
Elstner, M. ; Olszewski, K. ; Prokisch, H. ; Klopstock, T. ; Murgia, M.
Int. J. Mol. Sci. 22:11080 (2021)
Mitochondrial DNA deletions affect energy metabolism at tissue-specific and cell-specific threshold levels, but the pathophysiological mechanisms determining cell fate remain poorly under-stood. Chronic progressive external ophthalmoplegia (CPEO) is caused by mtDNA deletions and characterized by a mosaic distribution of muscle fibers with defective cytochrome oxidase (COX) activity, interspersed among fibers with retained functional respiratory chain. We used diagnostic histochemistry to distinguish COX-negative from COX-positive fibers in nine muscle biopsies from CPEO patients and performed laser capture microdissection (LCM) coupled to genome-wide gene expression analysis. To gain molecular insight into the pathogenesis, we applied network and pathway analysis to highlight molecular differences of the COX-positive and COX-negative fiber transcriptome. We then integrated our results with proteomics data that we previously obtained comparing COX-positive and COX-negative fiber sections from three other patients. By virtue of the combination of LCM and a multi-omics approach, we here provide a comprehensive resource to tackle the pathogenic changes leading to progressive respiratory chain deficiency and disease in mitochondrial deletion syndromes. Our data show that COX-negative fibers upregulate transcripts involved in translational elongation and protein synthesis. Furthermore, based on functional annotation analysis, we find that mitochondrial transcripts are the most enriched among those with significantly different expression between COX-positive and COX-negative fibers, indicating that our unbiased large-scale approach resolves the core of the pathogenic changes. Further enrich-ments include transcripts encoding LIM domain proteins, ubiquitin ligases, proteins involved in RNA turnover, and, interestingly, cell cycle arrest and cell death. These pathways may thus have a functional association to the molecular pathogenesis of the disease. Overall, the transcriptome and proteome show a low degree of correlation in CPEO patients, suggesting a relevant contribution of post-transcriptional mechanisms in shaping this disease phenotype.
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Scientific Article
Farnoud, A. ; Tofighian, H. ; Baumann, I. ; Martin, A.R. ; Rashidi, M.M. ; Menden, M. ; Schmid, O.
Front. Pharmacol. 12:76420 (2021)
The nasal olfactory region is a potential route for non-invasive delivery of drugs directly from the nasal epithelium to the brain, bypassing the often impermeable blood-brain barrier. However, efficient aerosol delivery to the olfactory region is challenging due to its location in the nose. Here we explore aerosol delivery with bi-directional pulsatile flow conditions for targeted drug delivery to the olfactory region using a computational fluid dynamics (CFD) model on the patient-specific nasal geometry. Aerosols with aerodynamic diameter of 1 µm, which is large enough for delivery of large enough drug doses and yet potentially small enough for non-inertial aerosol deposition due to, e.g., particle diffusion and flow oscillations, is inhaled for 1.98 s through one nostril and exhaled through the other one. The bi-directional aerosol delivery with steady flow rate of 4 L/min results in deposition efficiencies (DEs) of 50.9 and 0.48% in the nasal cavity and olfactory region, respectively. Pulsatile flow with average flow rate of 4 L/min (frequency: 45 Hz) reduces these values to 34.4 and 0.12%, respectively, and it mitigates the non-uniformity of right-left deposition in both the cavity (from 1.77- to 1.33-fold) and the olfactory region (from 624- to 53.2-fold). The average drug dose deposited in the nasal cavity and the olfactory epithelium region is very similar in the right nasal cavity independent of pulsation conditions (inhalation side). In contrast, the local aerosol dose in the olfactory region of the left side is at least 100-fold lower than that in the nasal cavity independent of pulsation condition. Hence, while pulsatile flow reduces the right-left (inhalation-exhalation) imbalance, it is not able to overcome it. However, the inhalation side (even with pulsation) allows for relatively high olfactory epithelium drug doses per area reaching the same level as in the total nasal cavity. Due to the relatively low drug deposition in olfactory region on the exhalation side, this allows either very efficient targeting of the inhalation side, or uniform drug delivery by performing bidirectional flow first from the one and then from the other side of the nose.
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Scientific Article
Winheim, E. ; Rinke, L. ; Lutz, K. ; Reischer, A. ; Leutbecher, A. ; Wolfram, L. ; Rausch, L. ; Kranich, J. ; Wratil, P.R. ; Huber, J.E. ; Baumjohann, D. ; Rothenfußer, S. ; Schubert, B. ; Hilgendorff, A. ; Hellmuth, J.C. ; Scherer, C. ; Muenchhoff, M. ; von Bergwelt-Baildon, M. ; Stark, K. ; Straub, T. ; Brocker, T. ; Keppler, O.T. ; Subklewe, M. ; Krug, A.B.
PLoS Pathog. 17:e1009742 (2021)
Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage-HLADR+ cells lacking DC markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.
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Scientific Article
Cruceanu, C. ; Dony, L. ; Krontira, A.C. ; Fischer, D.S. ; Roeh, S. ; Di Giaimo, R. ; Kyrousi, C. ; Kaspar, L. ; Knauer-Arloth, J. ; Czamara, D. ; Martinelli, S. ; Wehner, S. ; Breen, M.S. ; Koedel, M. ; Sauer, S. ; Sportelli, V. ; Rex-Haffner, M. ; Cappello, S. ; Theis, F.J. ; Binder, E.B.
Am. J. Psychiatry 179, 375-387 (2021)
OBJECTIVE: A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with disturbances influencing many health outcomes. In utero, glucocorticoids have been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type-specific effects. An in vitro model of fetal human brain development, induced human pluripotent stem cell (hiPSC)-derived cerebral organoids, was used to test whether cerebral organoids are suitable for studying the impact of prenatal glucocorticoid exposure on the developing brain. METHODS: The GR was activated with the synthetic glucocorticoid dexamethasone, and the effects were mapped using single-cell transcriptomics across development. RESULTS: The GR was expressed in all cell types, with increasing expression levels through development. Not only did its activation elicit translocation to the nucleus and the expected effects on known GR-regulated pathways, but also neurons and progenitor cells showed targeted regulation of differentiation- and maturation-related transcripts. Uniquely in neurons, differentially expressed transcripts were significantly enriched for genes associated with behavior-related phenotypes and disorders. This human neuronal glucocorticoid response profile was validated across organoids from three independent hiPSC lines reprogrammed from different source tissues from both male and female donors. CONCLUSIONS: These findings suggest that excessive glucocorticoid exposure could interfere with neuronal maturation in utero, leading to increased disease susceptibility through neurodevelopmental processes at the interface of genetic susceptibility and environmental exposure. Cerebral organoids are a valuable translational resource for exploring the effects of glucocorticoids on early human brain development.
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Scientific Article
Aliee, H. ; Massip, F. ; Qi, C. ; Stella de Biase, M. ; van Nijnatten, J. ; Kersten, E.T.G. ; Kermani, N.Z. ; Khuder, B. ; Vonk, J.M. ; Vermeulen, R.C.H. ; U-BIOPRED study group ; Cambridge Lung Cancer Early Detection Programme ; INER-Ciencias Mexican Lung Program ; Neighbors, M. ; Tew, G.W. ; Grimbaldeston, M.A. ; Ten Hacken, N.H.T. ; Hu, S. ; Guo, Y. ; Zhang, X. ; Sun, K. ; Hiemstra, P.S. ; Ponder, B.A. ; Makela, M.J. ; Malmström, K. ; Rintoul, R.C. ; Reyfman, P.A. ; Theis, F.J. ; Brandsma, C.A. ; Adcock, I.M. ; Timens, W. ; Xu, C.J. ; van den Berge, M. ; Schwarz, R.F. ; Koppelman, G.H. ; Nawijn, M.C. ; Faiz, A.
Allergy, DOI: 10.1111/all.15152 (2021)
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Scientific Article
Horgusluoglu, E. ; Neff, R. ; Song, W.M. ; Wang, M. ; Wang, Q. ; Arnold, M. ; Krumsiek, J. ; Galindo-Prieto, B. ; Ming, C. ; Nho, K. ; Kastenmüller, G. ; Han, X. ; Baillie, R. ; Zeng, Q. ; Andrews, S. ; Cheng, H. ; Hao, K. ; Goate, A. ; Bennett, D.A. ; Saykin, A.J. ; Kaddurah-Daouk, R. ; Zhang, B.
Alzheimers Dement., DOI: 10.1002/alz.12468 (2021)
Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD-specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co-expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short-chain acylcarnitines/amino acids and medium/long-chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP-AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co-expression network analysis of the AMP-AD brain RNA-seq data suggests the CPT1A- and ABCA1-centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short-chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large-scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis.
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Scientific Article
Schmid, K. ; Höllbacher, B. ; Cruceanu, C. ; Böttcher, A. ; Lickert, H. ; Binder, E.B. ; Theis, F.J. ; Heinig, M.
Nat. Commun. 12:6625 (2021)
Single cell RNA-seq has revolutionized transcriptomics by providing cell type resolution for differential gene expression and expression quantitative trait loci (eQTL) analyses. However, efficient power analysis methods for single cell data and inter-individual comparisons are lacking. Here, we present scPower; a statistical framework for the design and power analysis of multi-sample single cell transcriptomic experiments. We modelled the relationship between sample size, the number of cells per individual, sequencing depth, and the power of detecting differentially expressed genes within cell types. We systematically evaluated these optimal parameter combinations for several single cell profiling platforms, and generated broad recommendations. In general, shallow sequencing of high numbers of cells leads to higher overall power than deep sequencing of fewer cells. The model, including priors, is implemented as an R package and is accessible as a web tool. scPower is a highly customizable tool that experimentalists can use to quickly compare a multitude of experimental designs and optimize for a limited budget.
Wissenschaftlicher Artikel
Scientific Article
Janzen, A. ; Kogan, R.V. ; Meles, S.K. ; Sittig, E. ; Renken, R.J. ; Geibl, F.F. ; Booij, J. ; Stormezand, G. ; Luster, M. ; Mayer, G. ; Leenders, K.L. ; Oertel, W.H.
Mov. Disord., DOI: 10.1002/mds.28859 (2021)
Background: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for α-synucleinopathies. Objective: The aim of this study was to determine whether pathological cardiac [123I]meta-iodobenzylguanidine scintigraphy ([123I]MIBG) is associated with progression of [18F]fluorodeoxyglucose-positron emission tomography–based Parkinson's disease (PD)-related brain pattern (PDRP) expression in iRBD. Methods: Seventeen subjects with iRBD underwent [18F]fluorodeoxyglucose-positron emission tomography brain imaging twice ~3.6 years apart. In addition, [123I]MIBG and [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computed tomography ([123I]FP-CIT-SPECT) at baseline were performed. Olfactory, cognitive, and motor functions were tested annually. Results: Twelve of 17 subjects had pathological [123I]MIBG. At baseline, 6 of 12 of these expressed the PDRP (suprathreshold PDRP z score). At follow-up, 12 of 17 subjects had suprathreshold PDRP z scores, associated with pathological [123I]MIBG in 92% and with pathological [123I]FP-CIT-SPECT in 75%. Subjects with pathological [123I]MIBG had higher PDRP z score change per year (P = 0.027). Three subjects phenoconverted to PD; all had pathological [123I]MIBG and [123I]FP-CIT-SPECT, suprathreshold baseline PDRP z scores, and hyposmia. Conclusions: Pathological [123I]MIBG was associated with progressive and suprathreshold PDRP z scores at follow-up. Abnormal [123I]MIBG likely identifies iRBD as prodromal PD earlier than pathological [123I]FP-CIT-SPECT. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Wissenschaftlicher Artikel
Scientific Article
Reddy, K.D. ; Lan, A. ; Boudewijn, I.M. ; Rathnayake, S.N.H. ; Koppelman, G.H. ; Aliee, H. ; Theis, F.J. ; Oliver, B.G. ; van den Berge, M. ; Faiz, A.
Am. J. Respir. Cell Mol. Biol. 65, 366-377 (2021)
Current smoking contributes to worsened asthma prognosis and more severe symptoms and limits the beneficial effects of corticosteroids. As the nasal epithelium can reflect smoking-induced changes in the lower airways, it is a relevant source to investigate changes in gene expression and DNA methylation. This study explores gene expression and DNA methylation changes in current and ex-smokers with asthma. Matched gene expression and epigenome-wide DNA methylation samples collected from nasal brushings of 55 patients enrolled in a clinical trial investigation of current and ex-smoker patients with asthma were analyzed. Differential gene expression and DNA methylation analyses were conducted comparing current smokers with ex-smokers. Expression quantitative trait methylation (eQTM) analysis was completed to explore smoking-relevant genes by CpG sites that differ between current and ex-smokers. To investigate the relevance of the smoking-associated DNA methylation changes for the lower airways, significant CpG sites were explored in bronchial biopsies from patients who had stopped smoking. A total of 809 genes and 18,814 CpG sites were differentially associated with current smoking in the nose. The cis-eQTM analysis uncovered 171 CpG sites with a methylation status associated with smoking-related gene expression, including AHRR, ALDH3A1, CYP1A1, and CYP1B1. The methylation status of CpG sites altered by current smoking reversed with 1 year of smoking cessation. We confirm that current smoking alters epigenetic patterns and affects gene expression in the nasal epithelium of patients with asthma, which is partially reversible in bronchial biopsies after smoking cessation. We demonstrate the ability to discern molecular changes in the nasal epithelium, presenting this as a tool in future investigations into disease-relevant effects of tobacco smoke.
Wissenschaftlicher Artikel
Scientific Article
Scharr, H. ; Rademske, P. ; Alonso, L. ; Cogliati, S. ; Rascher, U.
Remote Sens. Environ. 267:112718 (2021)
We propose a signal deconvolution procedure for imaging spectrometer data, where a measured point spread function (PSF) is deconvolved itself before being used for deconvolution of the signal. We evaluate the effectiveness of our procedure for improvement of the spatio-spectral signal, as well as our target application, i.e. estimation of sun-induced fluorescence (SIF). Imaging spectrometers are well established instruments for remote sensing. When used for scientific purposes these instruments are usually calibrated on a regular basis. In our case the point spread function of the optics is measured in an elaborate procedure with a tunable monochromator point light source. PSFs are measured at different pixel positions of the imaging sensor, i.e. at different spatio-spectral locations, and averaged in order to get an as accurate PSF as possible. We investigate error sources in this calibration process by simulating the procedure in silico. Averaging as well as the spectral and spatial width of the point source introduce some smoothness in the measured PSF. We propose corrective measures, i.e. deconvolution of the PSF itself and median instead of mean averaging, leading to a set of sharper PSFs. We test the performance of these PSFs in deconvolving simulated as well as real hyperspectral images. For deconvolution we test a set of well-known, off the shelf deconvolution algorithms. Quantitatively in terms of PSNR (Peak Signal to Noise Ratio) a combination of Wiener filtering and sharpened PSFs yields strongest improvements, while using Wiener filtering with non-sharpened PSFs even deteriorates the signal. Comparing deconvolution results of the simulated data with results of real data reveals, that visually very similar effects can be observed. This well supports the assumption, that our findings are also valid for real spatio-spectral data. Surprisingly, the choice of PSF, sharpened or not, is of little effect for SIF estimation with the iFLD algorithm in the O2A band. Quantitatively we find that deconvolution reduces the overall error of SIF by a factor of 3.8, when using Wiener filtering instead of the currently used 1 iteration of vanCittert's method. For SIF estimation in the O2B band we observe a totally different behavior, where all deconvolution methods yield unreliable results with mostly well above 200% relative error and high standard deviations. In the discussion we can only speculate on possible reasons for this unreliability. As conclusion we therefore propose to use the O2A band for SIF estimation together with classic Wiener filtering for deconvolution of spatio-spectral data.
Wissenschaftlicher Artikel
Scientific Article
Richard, E.M. ; Bakhtiari, S. ; Marsh, A.P.L. ; Kaiyrzhanov, R. ; Wagner, M. ; Shetty, S. ; Pagnozzi, A. ; Nordlie, S.M. ; Guida, B.S. ; Cornejo, P. ; Magee, H. ; Liu, J. ; Norton, B.Y. ; Webster, R.I. ; Worgan, L. ; Hakonarson, H. ; Li, J. ; Guo, Y. ; Jain, M. ; Blesson, A. ; Rodan, L.H. ; Abbott, M.A. ; Comi, A. ; Cohen, J.S. ; Alhaddad, B. ; Meitinger, T. ; Lenz, D. ; Ziegler, A. ; Kotzaeridou, U. ; Brunet, T. ; Chassevent, A. ; Smith-Hicks, C. ; Ekstein, J. ; Weiden, T. ; Hahn, A. ; Zharkinbekova, N. ; Turnpenny, P. ; Tucci, A. ; Yelton, M. ; Horvath, R. ; Gungor, S. ; Hiz, S. ; Oktay, Y. ; Lochmüller, H. ; Zollino, M. ; Morleo, M. ; Marangi, G. ; Nigro, V. ; Torella, A. ; Pinelli, M. ; Amenta, S. ; Husain, R.A. ; Grossmann, B. ; Rapp, M. ; Steen, C. ; Marquardt, I. ; Grimmel, M. ; Grasshoff, U. ; Korenke, G.C. ; Owczarek-Lipska, M. ; Neidhardt, J. ; Radio, F.C. ; Mancini, C. ; Claps Sepulveda, D.J. ; McWalter, K. ; Begtrup, A. ; Crunk, A. ; Guillen Sacoto, M.J. ; Person, R. ; Schnur, R.E. ; Mancardi, M.M. ; Kreuder, F. ; Striano, P. ; Zara, F. ; Chung, W.K. ; Marks, W.A. ; van Eyk, C.L. ; Webber, D.L. ; Corbett, M.A. ; Harper, K. ; Berry, J.G. ; MacLennan, A.H. ; Gecz, J. ; Tartaglia, M. ; Salpietro, V. ; Christodoulou, J. ; Kaslin, J. ; Padilla-Lopez, S. ; Bilguvar, K. ; Munchau, A. ; Ahmed, Z.M. ; Hufnagel, R.B. ; Fahey, M.C. ; Maroofian, R. ; Houlden, H. ; Sticht, H. ; Mane, S.M. ; Rad, A. ; Vona, B. ; Jin, S.C. ; Haack, T.B. ; Makowski, C. ; Hirsch, Y. ; Riazuddin, S. ; Kruer, M.C.
Am. J. Hum. Genet. 108, 2006-2016 (2021)
Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.
Wissenschaftlicher Artikel
Scientific Article
Ostaszewski, M. ; Niarakis, A. ; Mazein, A. ; Kuperstein, I. ; Phair, R. ; Orta-Resendiz, A. ; Singh, V. ; Aghamiri, S.S. ; Acencio, M.L. ; Glaab, E. ; Ruepp, A. ; Fobo, G. ; Montrone, C. ; Brauner, B. ; Frishman, G. ; Monraz Gómez, L.C. ; Somers, J. ; Hoch, M. ; Kumar Gupta, S. ; Scheel, J. ; Borlinghaus, H. ; Czauderna, T. ; Schreiber, F. ; Montagud, A. ; Ponce de Leon, M. ; Funahashi, A. ; Hiki, Y. ; Hiroi, N. ; Yamada, T.G. ; Dräger, A. ; Renz, A. ; Naveez, M. ; Bocskei, Z. ; Messina, F. ; Börnigen, D. ; Fergusson, L. ; Conti, M. ; Rameil, M. ; Nakonecnij, V. ; Vanhoefer, J. ; Schmiester, L. ; Wang, M. ; Ackerman, E.E. ; Shoemaker, J.E. ; Zucker, J. ; Oxford, K. ; Teuton, J. ; Kocakaya, E. ; Summak, G.Y. ; Hanspers, K. ; Kutmon, M. ; Coort, S. ; Eijssen, L. ; Ehrhart, F. ; Rex, D.A.B. ; Slenter, D. ; Martens, M. ; Pham, N. ; Haw, R. ; Jassal, B. ; Matthews, L. ; Orlic-Milacic, M. ; Senff Ribeiro, A. ; Rothfels, K. ; Shamovsky, V. ; Stephan, R. ; Sevilla, C. ; Varusai, T. ; Ravel, J.M. ; Fraser, R. ; Ortseifen, V. ; Marchesi, S. ; Gawron, P. ; Smula, E. ; Heirendt, L. ; Satagopam, V.P. ; Wu, G. ; Riutta, A. ; Golebiewski, M. ; Owen, S. ; Goble, C. ; Hu, X. ; Overall, R.W. ; Maier, D. ; Bauch, A. ; Gyori, B.M. ; Bachman, J.A. ; Vega, C. ; Grouès, V. ; Vázquez, M.J. ; Porras, P. ; Licata, L. ; Iannuccelli, M. ; Sacco, F. ; Nesterova, A. ; Yuryev, A. ; de Waard, A. ; Turei, D. ; Luna, A. ; Babur, O. ; Soliman, S. ; Valdeolivas, A. ; Esteban-Medina, M. ; Peña-Chilet, M. ; Rian, K. ; Helikar, T. ; Lal Puniya, B. ; Módos, D. ; Treveil, A. ; Olbei, M. ; De Meulder, B. ; Ballereau, S. ; Dugourd, A. ; Naldi, A. ; Noël, V. ; Calzone, L. ; Sander, C. ; Demir, E. ; Korcsmáros, T. ; Freeman, T.C. ; Augé, F. ; Beckmann, J.S. ; Hasenauer, J. ; Wolkenhauer, O. ; Wilighagen, E.L. ; Pico, A.R. ; Evelo, C.T. ; Gillespie, M.E. ; Stein, L.D. ; Hermjakob, H. ; D'Eustachio, P. ; Saez-Rodriguez, J. ; Dopazo, J. ; Valencia, A. ; Kitano, H. ; Barillot, E. ; Auffray, C. ; Balling, R. ; Schneider, R.
Mol. Syst. Biol. 17:e10387 (2021)
We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.
Wissenschaftlicher Artikel
Scientific Article
Way, G.P. ; Greene, C.S. ; Carninci, P. ; Carvalho, B.S. ; de Hoon, M. ; Finley, S. ; Gosline, S.J.C. ; Le Cao, K.A. ; Lee, J.S.H. ; Marchionni, L. ; Robine, N. ; Sindi, S.S. ; Theis, F.J. ; Yang, J.Y.H. ; Carpenter, A.E. ; Fertig, E.J.
PLoS Biol. 19:e3001419 (2021)
Evo:lvPinlegaisnecsoynnfcirwmitthhatthalelhceoamdipnugtleavtieolnsarreevreopluretisoenntoevdecor rtrheectplya:st 30 years, computational biology has emerged as a mature scientific field. While the field has made major contributions toward improving scientific knowledge and human health, individual computational biology practitioners at various institutions often languish in career development. As optimistic biologists passionate about the future of our field, we propose solutions for both eager and reluctant individual scientists, institutions, publishers, funding agencies, and educators to fully embrace computational biology. We believe that in order to pave the way for the next generation of discoveries, we need to improve recognition for computational biologists and better align pathways of career success with pathways of scientific progress. With 10 outlined steps, we call on all adjacent fields to move away from the traditional individual, single-discipline investigator research model and embrace multidisciplinary, data-driven, team science.
Review
Review
Stegelmann, F. ; Wille, K. ; Busen, H. ; Fuchs, C. ; Schauer, S. ; Sadjadian, P. ; Becker, T. ; Kolatzki, V. ; Döhner, H. ; Stadler, R. ; Döhner, K. ; Griesshammer, M.
Leukemia, DOI: 10.1038/s41375-021-01366-3 (2021)
The article Significant association of cutaneous adverse events with hydroxyurea: results from a prospective non-interventional study in BCR-ABL1-negative myeloproliferative neoplasms (MPN) - on behalf of the German Study Group-MPN, written by Frank Stegelmann, Kai Wille, Hannah Busen, Christiane Fuchs, Stefanie Schauer, Parvis Sadjadian, Tatjana Becker, Vera Kolatzki, Hartmut Döhner, Rudolf Stadler, German Study Group-MPN, Konstanze Döhner & Martin Griesshammer, was originally published Online First without Open Access. After publication in volume 35, page 628–631 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution. FUNDING Open Access funding enabled and organized by Projekt DEAL.
Sadafi, A. ; Makhro, A. ; Livshits, L. ; Navab, N. ; Bogdanova, A. ; Albarqouni, S. ; Marr, C.
In: (3rd MICCAI Workshop on Domain Adaptation and Representation Transfer, DART 2021, 27 September-01 October 2021, Virtual, Online). 2021. 216-225 (Lect. Notes Comput. Sc. ; 12968 LNCS)
Sickle cell disease (SCD) is a severe genetic hemoglobin disorder that results in premature destruction of red blood cells. Assessment of the severity of the disease is a challenging task in clinical routine, since the causes of broad variance in SCD manifestation despite the common genetic cause remain unclear. Identification of biomarkers that would predict the severity grade is of importance for prognosis and assessment of responsiveness of patients to therapy. Detection of the changes in red blood cell (RBC) density by means of separation of Percoll density gradients could be such a marker as it allows to resolve intercellular differences and follow the most damaged dense cells prone to destruction and vasoocclusion. Quantification and interpretation of the images obtained from the distribution of RBCs in Percoll gradients is an important prerequisite for establishment of this approach. Here, we propose a novel approach combining a graph convolutional network, a convolutional neural network, fast Fourier transform, and recursive feature elimination to predict the severity of SCD directly from a Percoll image. Two important but expensive laboratory blood test parameters are used for training the graph convolutional network. To make the model independent from such tests during prediction, these two parameters are estimated by a neural network from the Percoll image directly. On a cohort of 216 subjects, we achieve a prediction performance that is only slightly below an approach where the groundtruth laboratory measurements are used. Our proposed method is the first computational approach for the difficult task of SCD severity prediction. The two-step approach relies solely on inexpensive and simple blood analysis tools and can have a significant impact on the patients’ survival in low resource regions where access to medical instruments and doctors is limited.
Schiffer, C. ; Harmeling, S. ; Amunts, K. ; Dickscheid, T.
In: (24th International Conference on Medical Image Computing and Computer Assisted Intervention, MICCAI 2021, 27 September-01 October 2021, Virtual, Online). 2021. 395-404 (Lect. Notes Comput. Sc. ; 12908 LNCS)
Cytoarchitecture describes the spatial organization of neuronal cells in the brain, including their arrangement into layers and columns with respect to cell density, orientation, or presence of certain cell types. It allows to segregate the brain into cortical areas and subcortical nuclei, links structure with connectivity and function, and provides a microstructural reference for human brain atlases. Mapping boundaries between areas requires to scan histological sections at microscopic resolution. While recent high-throughput scanners allow to scan a complete human brain in the order of a year, it is practically impossible to delineate regions at the same pace using the established gold standard method. Researchers have recently addressed cytoarchitectonic mapping of cortical regions with deep neural networks, relying on image patches from individual 2D sections for classification. However, the 3D context, which is needed to disambiguate complex or obliquely cut brain regions, is not taken into account. In this work, we combine 2D histology with 3D topology by reformulating the mapping task as a node classification problem on an approximate 3D midsurface mesh through the isocortex. We extract deep features from cortical patches in 2D histological sections which are descriptive of cytoarchitecture, and assign them to the corresponding nodes on the 3D mesh to construct a large attributed graph. By solving the brain mapping problem on this graph using graph neural networks, we obtain significantly improved classification results. The proposed framework lends itself nicely to integration of additional neuroanatomical priors for mapping.
Wagner, S.J. ; Khalili, N. ; Sharma, R. ; Boxberg, M. ; Marr, C. ; de Back, W. ; Peng, T.
In: (24th International Conference on Medical Image Computing and Computer Assisted Intervention, MICCAI 2021, 27 September-01 October 2021, Virtual, Online). 2021. 257-266 (Lect. Notes Comput. Sc. ; 12908 LNCS)
In digital pathology, different staining procedures and scanners cause substantial color variations in whole-slide images (WSIs), especially across different laboratories. These color shifts result in a poor generalization of deep learning-based methods from the training domain to external pathology data. To increase test performance, stain normalization techniques are used to reduce the variance between training and test domain. Alternatively, color augmentation can be applied during training leading to a more robust model without the extra step of color normalization at test time. We propose a novel color augmentation technique, HistAuGAN, that can simulate a wide variety of realistic histology stain colors, thus making neural networks stain-invariant when applied during training. Based on a generative adversarial network (GAN) for image-to-image translation, our model disentangles the content of the image, i.e., the morphological tissue structure, from the stain color attributes. It can be trained on multiple domains and, therefore, learns to cover different stain colors as well as other domain-specific variations introduced in the slide preparation and imaging process. We demonstrate that HistAuGAN outperforms conventional color augmentation techniques on a classification task on the publicly available dataset Camelyon17 and show that it is able to mitigate present batch effects (Code and model weights are available at https://github.com/sophiajw/HistAuGAN.).
Nguyen, B.H.P. ; Ohnmacht, A. ; Galhoz, A. ; Büttner, M. ; Theis, F.J. ; Menden, M.
Diabetologe, DOI: 10.1007/s11428-021-00817-w (2021)
HintergrundDiabetes mellitus entwickelt sich zu einem globalen Gesundheitsproblem, das eine Transformation der Forschung und der medizinischen Praxis für ein besseres Patientenmanagement erfordert. Diesbezüglich bieten die Fülle an Daten und die Fortschritte in der Technologie und der künstlichen Intelligenz Möglichkeiten für ein solches Unterfangen.ZieleDiese Übersichtsarbeit soll einen Überblick über künstliche Intelligenz und die aktuelle Forschung in ihrer Anwendung im Bereich Diabetes geben, insbesondere zur Risikovorhersage, Diagnose, Prognose und Vorhersage von Komplikationen.FazitKünstliche Intelligenz transformiert die Diabetesforschung in vielen technischen und organisatorischen Aspekten. Obwohl ihr Einsatz noch begrenzt und mit vielen Herausforderungen konfrontiert ist, wird sie wahrscheinlich künftig die medizinische Behandlung beeinflussen, indem sie eine automatisierte und personalisierte Gesundheitsversorgung für Erkrankte bietet.
Review
Review
Paasche, H. ; Gross, M. ; Lüttgau, J. ; Greenberg, D.S. ; Weigel, T.
Geosci. Data J., DOI: 10.1002/gdj3.132 (2021)
The current handling of data in earth observation, modelling and prediction measures gives cause for critical consideration, since we all too often carelessly ignore data uncertainty. We think that Earth scientists are generally aware of the importance of linking data to quantitative uncertainty measures. But we also think that uncertainty quantification of Earth observation data too often fails at very early stages. We claim that data acquisition without uncertainty quantification is not sustainable and machine learning and computational modelling cannot unfold their potential when analysing complex natural systems like the Earth. Current approaches such as stochastic perturbation of parameters or initial conditions cannot quantify uncertainty or bias arising from the choice of model, limiting scientific progress. We need incentives stimulating the honest treatment of uncertainty starting during data acquisition, continuing through analysis methodology and prediction results. Computational modellers and machine learning experts have a critical role, since they enjoy high esteem from stakeholders and their methodologies and their results critically depend on data uncertainty. If both want to advance their uncertainty assessment of models and predictions of complex systems like the Earth, they have a common problem to solve. Together, computational modellers and machine learners could develop new strategies for bias identification and uncertainty quantification offering a more all-embracing uncertainty quantification than any known methodology. But since it starts for computational modellers and machine learners with data and their uncertainty, the fundamental first step in such a development would be leveraging shareholder esteem to insistently advocate for reduction of ignorance when it comes to uncertainty quantification of data.
Letter to the Editor
Letter to the Editor
Welz, L. ; Kakavand, N. ; Hang, X. ; Laue, G. ; Ito, G. ; Silva, M.G. ; Plattner, C. ; Mishra, N. ; Tengen, F. ; Ogris, C. ; Jesinghaus, M. ; Wottawa, F. ; Arnold, P. ; Kaikkonen, L. ; Stengel, S. ; Tran, F. ; Das, S. ; Kaser, A. ; Trajanoski, Z. ; Blumberg, R. ; Roecken, C. ; Saur, D. ; Tschurtschenthaler, M. ; Schreiber, S. ; Rosenstiel, P. ; Aden, K.
Gastroenterology 162, 223-237.e11 (2021)
BACKGROUND AIMS: Throughout life, the intestinal epithelium undergoes constant self-renewal from intestinal stem cells. Together with genotoxic stressors and failing DNA repair, this self-renewal causes susceptibility towards malignant transformation. X-box binding protein 1 (XBP1) is a stress sensor involved in the unfolded protein response (UPR). We hypothesized that XBP1 acts as a signaling hub to regulate epithelial DNA damage responses. METHODS: Data from the TCGA were analyzed for association of XBP1 with CRC survival and molecular interactions between XBP1 andp53 pathway activity. The role of XBP1 in orchestrating p53-driven DNA damage response was tested in-vitro, in mouse models of chronic intestinal epithelial DNA damage (Xbp1/H2bfl/fl, Xbp1ΔIEC, H2bΔIEC, H2b/Xbp1ΔIEC) and via orthotopic tumor organoid transplantation. Transcriptome analysis of intestinal organoids was performed to identify molecular targets of Xbp1-mediated DNA damage response. RESULTS: In the TCGA dataset of CRC, low XBP1 expression was significantly associated with poor overall survival (OS) and reduced p53 pathway activity. In-vivo, H2b/Xbp1ΔIEC mice developed spontaneous intestinal carcinomas. Orthotopic tumor organoid transplantation revealed a metastatic potential of H2b/Xbp1ΔIEC-derived tumors. RNA sequencing of intestinal organoids (H2b/Xbp1fl/fl, H2bΔIEC, H2b/Xbp1ΔIEC, H2b/p53ΔIEC) identified a transcriptional program downstream of p53, in which XBP1 directs DNA damage-induced Ddit4l expression. DDIT4L inhibits mTOR-mediated phosphorylation of 4E-BP1. Pharmacological mTOR inhibition suppressed epithelial hyperproliferation via 4E-BP1. CONCLUSIONS: Our data suggest a crucial role for XBP1 in coordinating epithelial DNA damage responses and stem cell function via a p53-DDIT4L-dependent feedback mechanism.
Wissenschaftlicher Artikel
Scientific Article
Zech, M. ; Kumar, K.R. ; Reining, S. ; Reunert, J. ; Tchan, M. ; Riley, L.G. ; Drew, A.P. ; Adam, R.J. ; Berutti, R. ; Biskup, S. ; Derive, N. ; Bakhtiari, S. ; Jin, S.C. ; Kruer, M.C. ; Bardakjian, T.M. ; Gonzalez-Alegre, P. ; Keller Sarmiento, I.J. ; Mencacci, N.E. ; Lubbe, S.J. ; Kurian, M.A. ; Clot, F. ; Méneret, A. ; de Sainte Agathe, J.M. ; Fung, V.S.C. ; Vidailhet, M. ; Baumann, M. ; Marquardt, T. ; Winkelmann, J. ; Boesch, S.
Mov. Disord., DOI: 10.1002/mds.28804 (2021)
BACKGROUND: Monogenic causes of isolated dystonia are heterogeneous. Assembling cohorts of affected individuals sufficiently large to establish new gene-disease relationships can be challenging. OBJECTIVE: We sought to expand the catalogue of monogenic etiologies for isolated dystonia. METHODS: After the discovery of a candidate variant in a multicenter exome-sequenced cohort of affected individuals with dystonia, we queried online platforms and genomic data repositories worldwide to identify subjects with matching genotypic profiles. RESULTS: Seven different biallelic loss-of-function variants in AOPEP were detected in five probands from four unrelated families with strongly overlapping phenotypes. In one proband, we observed a homozygous nonsense variant (c.1477C>T [p.Arg493*]). A second proband harbored compound heterozygous nonsense variants (c.763C>T [p.Arg255*]; c.777G>A [p.Trp259*]), whereas a third proband possessed a frameshift variant (c.696_697delAG [p.Ala234Serfs*5]) in trans with a splice-disrupting alteration (c.2041-1G>A). Two probands (siblings) from a fourth family shared compound heterozygous frameshift alleles (c.1215delT [p.Val406Cysfs*14]; c.1744delA [p.Met582Cysfs*6]). All variants were rare and expected to result in truncated proteins devoid of functionally important amino acid sequence. AOPEP, widely expressed in developing and adult human brain, encodes a zinc-dependent aminopeptidase, a member of a class of proteolytic enzymes implicated in synaptogenesis and neural maintenance. The probands presented with disabling progressive dystonia predominantly affecting upper and lower extremities, with variable involvement of craniocervical muscles. Dystonia was unaccompanied by any additional symptoms in three families, whereas the fourth family presented co-occurring late-onset parkinsonism. CONCLUSIONS: Our findings suggest a likely causative role of predicted inactivating biallelic AOPEP variants in cases of autosomal recessive dystonia. Additional studies are warranted to understand the pathophysiology associated with loss-of-function variation in AOPEP.
Wissenschaftlicher Artikel
Scientific Article
Mirza-Schreiber, N. ; Zech, M. ; Wilson, R. ; Brunet, T. ; Wagner, M. ; Jech, R. ; Boesch, S. ; Škorvánek, M. ; Necpál, J. ; Weise, D. ; Weber, S. ; Mollenhauer, B. ; Trenkwalder, C. ; Maier, E.M. ; Borggraefe, I. ; Vill, K. ; Hackenberg, A. ; Pilshofer, V. ; Kotzaeridou, U. ; Schwaibold, E.M.C. ; Hoefele, J. ; Waldenberger, M. ; Gieger, C. ; Peters, A. ; Meitinger, T. ; Schormair, B. ; Winkelmann, J. ; Oexle, K.
Brain, DOI: 10.1093/brain/awab360 (2021)
Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1x log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (p = 0.003) - being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.
Wissenschaftlicher Artikel
Scientific Article
Wille, K. ; Huenerbein, K. ; Jagenberg, E. ; Sadjadian, P. ; Becker, T. ; Kolatzki, V. ; Meixner, R. ; Marchi, H. ; Fuchs, C. ; Griesshammer, M.
Eur. J. Haematol., DOI: 10.1111/ejh.13721 (2021)
In patients with bcr-abl-negative myeloproliferative neoplasms (MPN), concerns are often raised about the use of anticoagulants because of an increased bleeding risk. However, there are few MPN studies focusing on bleeding. To investigate bleeding complications in MPN, we report our retrospective, single-center study of 829 patients with a median follow-up of 5.5 years (range: 0.1-35.6). A first bleeding event occurred in 143 of 829 patients (17.2%), corresponding to an incidence rate of 2.29% per patient/year. During the follow-up period, one out of 829 patients (0.1%) died due to bleeding. Regarding anticoagulation, most bleeding occurred in patients on antiplatelet therapies (60.1%), followed by patients on anticoagulation therapies (20.3%) and patients not on anticoagulation (19.6%). In multivariate analysis, administration of antiplatelet (HR 2.31 [1.43, 3.71]) and anticoagulation therapies (HR 4.06 [2.32, 7.09]), but not age, gender or mutation status, was associated with an increased bleeding risk. Comparing the "probability of bleeding-free survival" between the MPN subtypes, no significant difference was observed (p=0.91, log-rank test). Our retrospective study shows that antiplatelet and anticoagulation therapies significantly increase the risk of bleeding in MPN patients without affecting mortality. However, there is no reason to refrain from guideline-conform primary or secondary anticoagulation in MPN patients.
Wissenschaftlicher Artikel
Scientific Article
Baltatzis, V. ; Le Folgoc, L. ; Ellis, S. ; Manzanera, O.E.M. ; Bintsi, K.M. ; Nair, A. ; Desai, S. ; Glocker, B. ; Schnabel, J.A.
In: (4th International Workshop on Interpretability of Machine Intelligence in Medical Image Computing, iMIMIC 2020 and 1st International Workshop on Topological Data Analysis and Its Applications for Medical Data, TDA4MedicalData 2021 held in conjunction, 27 September 2021, Strasbourg). 2021. 56-64 (Lect. Notes Comput. Sc. ; 12929 LNCS)
Convolutional Neural Networks (CNNs) are widely used for image classification in a variety of fields, including medical imaging. While most studies deploy cross-entropy as the loss function in such tasks, a growing number of approaches have turned to a family of contrastive learning-based losses. Even though performance metrics such as accuracy, sensitivity and specificity are regularly used for the evaluation of CNN classifiers, the features that these classifiers actually learn are rarely identified and their effect on the classification performance on out-of-distribution test samples is insufficiently explored. In this paper, motivated by the real-world task of lung nodule classification, we investigate the features that a CNN learns when trained and tested on different distributions of a synthetic dataset with controlled modes of variation. We show that different loss functions lead to different features being learned and consequently affect the generalization ability of the classifier on unseen data. This study provides some important insights into the design of deep learning solutions for medical imaging tasks.
Zappia, L. ; Theis, F.J.
Genome Biol. 22:301 (2021)
Recent years have seen a revolution in single-cell RNA-sequencing (scRNA-seq) technologies, datasets, and analysis methods. Since 2016, the scRNA-tools database has cataloged software tools for analyzing scRNA-seq data. With the number of tools in the database passing 1000, we provide an update on the state of the project and the field. This data shows the evolution of the field and a change of focus from ordering cells on continuous trajectories to integrating multiple samples and making use of reference datasets. We also find that open science practices reward developers with increased recognition and help accelerate the field.
Review
Review
Chen, Y. ; Kassam, I. ; Lau, S.H. ; Kooner, J.S. ; Wilson, R. ; Peters, A. ; Winkelmann, J. ; Chow, V.T. ; Khor, C.C. ; van Dam, R.M. ; Teo, Y.Y. ; Loh, M. ; Sim, X.
Clin. Epigenet. 13:195 (2021)
Background: The prevalence of obesity and its related chronic diseases have been increasing especially in Asian countries. Obesity-related genetic variants have been identified, but these explain little of the variation in BMI. Recent studies reported associations between DNA methylation and obesity, mostly in non-Asian populations. Methods: We performed an epigenome-wide association study (EWAS) on general adiposity (body mass index, BMI) and abdominal adiposity (waist circumference, WC) in 409 multi-ethnic Asian individuals and replicated BMI and waist-associated DNA methylation CpGs identified in other populations. The cross-lagged panel model and Mendelian randomization were used to assess the temporal relationship between methylation and BMI. The temporal relationship between the identified CpGs and inflammation and metabolic markers was also examined. Results: EWAS identified 116 DNA methylation CpGs independently associated with BMI and eight independently associated with WC at false discovery rate PFDR < 0.05 in 409 Asian samples. We replicated 110 BMI-associated CpGs previously reported in Europeans and identified six novel BMI-associated CpGs and two novel WC-associated CpGs. We observed high consistency in association direction of effect compared to studies in other populations. Causal relationship analyses indicated that BMI was more likely to be the cause of DNA methylation alteration, rather than the consequence. The causal analyses using BMI-associated methylation risk score also suggested that higher levels of the inflammation marker IL-6 were likely the consequence of methylation change. Conclusion: Our study provides evidence of an association between obesity and DNA methylation in multi-ethnic Asians and suggests that obesity can drive methylation change. The results also suggested possible causal influence that obesity-related methylation changes might have on inflammation and lipoprotein levels.
Wissenschaftlicher Artikel
Scientific Article
Westerlund, A. ; Hawe, J.S. ; Heinig, M. ; Schunkert, H.
Int. J. Mol. Sci. 22:10291 (2021)
Cardiovascular diseases (CVD) annually take almost 18 million lives worldwide. Most lethal events occur months or years after the initial presentation. Indeed, many patients experience repeated complications or require multiple interventions (recurrent events). Apart from affecting the individual, this leads to high medical costs for society. Personalized treatment strategies aiming at prediction and prevention of recurrent events rely on early diagnosis and precise prognosis. Complementing the traditional environmental and clinical risk factors, multi-omics data provide a holistic view of the patient and disease progression, enabling studies to probe novel angles in risk stratification. Specifically, predictive molecular markers allow insights into regulatory networks, pathways, and mechanisms underlying disease. Moreover, artificial intelligence (AI) represents a powerful, yet adaptive, framework able to recognize complex patterns in large-scale clinical and molecular data with the potential to improve risk prediction. Here, we review the most recent advances in risk prediction of recurrent cardiovascular events, and discuss the value of molecular data and biomarkers for understanding patient risk in a systems biology context. Finally, we introduce explainable AI which may improve clinical decision systems by making predictions transparent to the medical practitioner.
Review
Review
Oala, L. ; Murchison, A.G. ; Balachandran, P. ; Choudhary, S. ; Fehr, J. ; Leite, A.W. ; Goldschmidt, P.G. ; Johner, C. ; Schörverth, E.D.M. ; Nakasi, R. ; Meyer, M. ; Cabitza, F. ; Baird, P. ; Prabhu, C. ; Weicken, E. ; Liu, X. ; Wenzel, M. ; Vogler, S. ; Akogo, D. ; Alsalamah, S. ; Kazim, E. ; Koshiyama, A. ; Piechottka, S. ; Macpherson, S. ; Shadforth, I. ; Geierhofer, R. ; Matek, C. ; Krois, J. ; Sanguinetti, B. ; Arentz, M. ; Bielik, P. ; Calderon-Ramirez, S. ; Abbood, A. ; Langer, N. ; Haufe, S. ; Kherif, F. ; Pujari, S. ; Samek, W. ; Wiegand, T.
J. Med. Syst. 45:105 (2021)
Developers proposing new machine learning for health (ML4H) tools often pledge to match or even surpass the performance of existing tools, yet the reality is usually more complicated. Reliable deployment of ML4H to the real world is challenging as examples from diabetic retinopathy or Covid-19 screening show. We envision an integrated framework of algorithm auditing and quality control that provides a path towards the effective and reliable application of ML systems in healthcare. In this editorial, we give a summary of ongoing work towards that vision and announce a call for participation to the special issue  Machine Learning for Health: Algorithm Auditing & Quality Control in this journal to advance the practice of ML4H auditing.
Review
Review
Vidali, S. ; Gerlini, R. ; Thompson, K. ; Urquhart, J.E. ; Meisterknecht, J. ; Aguilar-Pimentel, J.A. ; Amarie, O.V. ; Becker, L. ; Breen, C. ; Calzada-Wack, J. ; Chhabra, N.F. ; Cho, Y.-L. ; da Silva Buttkus, P. ; Feichtinger, R.G. ; Gampe, K. ; Garrett, L. ; Hoefig, K.P. ; Hölter, S.M. ; Jameson, E. ; Klein-Rodewald, T. ; Leuchtenberger, S. ; Marschall, S. ; Mayer-Kuckuk, P. ; Miller, G. ; Oestereicher, M.A. ; Pfannes, K. ; Rathkolb, B. ; Rozman, J. ; Sanders, C. ; Spielmann, N. ; Stöger, C. ; Szibor, M. ; Treise, I. ; Walter, J.H. ; Wurst, W. ; Mayr, J.A. ; Fuchs, H. ; Gärtner, U. ; Wittig, I. ; Taylor, R.W. ; Newman, W.G. ; Prokisch, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M.
EMBO Mol. Med.:e14397 (2021)
Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh−/−), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh−/− mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (SXL), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh−/− mouse is a valuable model for future studies of human CIII deficiency.
Wissenschaftlicher Artikel
Scientific Article
Borkowski, K. ; Taha, A.Y. ; Pedersen, T.L. ; de Jager, P.L. ; Bennett, D.A. ; Arnold, M. ; Kaddurah-Daouk, R. ; Newman, J.W.
Sci. Rep. 11:18964 (2021)
Cognitive decline is associated with both normal aging and early pathologies leading to dementia. Here we used quantitative profiling of metabolites involved in the regulation of inflammation, vascular function, neuronal function and energy metabolism, including oxylipins, endocannabinoids, bile acids, and steroid hormones to identify metabolic biomarkers of mild cognitive impairment (MCI). Serum samples (n = 212) were obtained from subjects with or without MCI opportunistically collected with incomplete fasting state information. To maximize power and stratify the analysis of metabolite associations with MCI by the fasting state, we developed an algorithm to predict subject fasting state when unknown (n = 73). In non-fasted subjects, linoleic acid and palmitoleoyl ethanolamide levels were positively associated with perceptual speed. In fasted subjects, soluble epoxide hydrolase activity and tauro-alpha-muricholic acid levels were negatively associated with perceptual speed. Other cognitive domains showed associations with bile acid metabolism, but only in the non-fasted state. Importantly, this study shows unique associations between serum metabolites and cognitive function in the fasted and non-fasted states and provides a fasting state prediction algorithm based on measurable metabolites.
Wissenschaftlicher Artikel
Scientific Article
Manconi, M. ; García-Borreguero, D. ; Schormair, B. ; Videnovic, A. ; Berger, K. ; Ferri, R. ; Dauvilliers, Y.
Nat. Rev. Dis. Primers 7:80 (2021)
Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by an urge to move that appears during rest or is exacerbated by rest, that occurs in the evening or night and that disappears during movement or is improved by movement. Symptoms vary considerably in age at onset, frequency and severity, with severe forms affecting sleep, quality of life and mood. Patients with RLS often display periodic leg movements during sleep or resting wakefulness. RLS is considered to be a complex condition in which predisposing genetic factors, environmental factors and comorbidities contribute to the expression of the disorder. RLS occurs alone or with comorbidities, for example, iron deficiency and kidney disease, but also with cardiovascular diseases, diabetes mellitus and neurological, rheumatological and respiratory disorders. The pathophysiology is still unclear, with the involvement of brain iron deficiency, dysfunction in the dopaminergic and nociceptive systems and altered adenosine and glutamatergic pathways as hypotheses being investigated. RLS is poorly recognized by physicians and it is accordingly often incorrectly diagnosed and managed. Treatment guidelines recommend initiation of therapy with low doses of dopamine agonists or α2δ ligands in severe forms. Although dopaminergic treatment is initially highly effective, its long-term use can result in a serious worsening of symptoms known as augmentation. Other treatments include opioids and iron preparations.
Review
Review
Bortoluzzi, S. ; Dashtsoodol, N. ; Engleitner, T. ; Drees, C. ; Helmrath, S. ; Mir, J. ; Toska, A. ; Flossdorf, M. ; Öllinger, R. ; Solovey, M. ; Colomé-Tatché, M. ; Kalfaoglu, B. ; Ono, M. ; Buch, T. ; Ammon, T. ; Rad, R. ; Schmidt-Supprian, M.
Immunity 54, 2497-2513.e9 (2021)
Innate-like T cell populations expressing conserved TCRs play critical roles in immunity through diverse developmentally acquired effector functions. Focusing on the prototypical lineage of invariant natural killer T (iNKT) cells, we sought to dissect the mechanisms and timing of fate decisions and functional effector differentiation. Utilizing induced expression of the semi-invariant NKT cell TCR on double positive thymocytes, an initially highly synchronous wave of iNKT cell development was triggered by brief homogeneous TCR signaling. After reaching a uniform progenitor state characterized by IL-4 production potential and proliferation, effector subsets emerged simultaneously, but then diverged toward different fates. While NKT17 specification was quickly completed, NKT1 cells slowly differentiated and expanded. NKT2 cells resembled maturing progenitors, which gradually diminished in numbers. Thus, iNKT subset diversification occurs in dividing progenitor cells without acute TCR input but utilizes multiple active cytokine signaling pathways. These data imply a two-step model of iNKT effector differentiation.
Wissenschaftlicher Artikel
Scientific Article
Wagner, M. ; Lorenz, G. ; Volk, A.E. ; Brunet, T. ; Edbauer, D. ; Berutti, R. ; Zhao, C. ; Anderl-Straub, S. ; Bertram, L. ; Danek, A. ; Deschauer, M. ; Dill, V. ; Fassbender, K. ; Fliessbach, K. ; Götze, K.S. ; Jahn, H. ; Kornhuber, J. ; Landwehrmeyer, B. ; Lauer, M. ; Obrig, H. ; Prudlo, J. ; Schneider, A. ; Schroeter, M.L. ; Uttner, I. ; Vukovich, R. ; Wiltfang, J. ; Winkler, A.S. ; Zhou, Q. ; Ludolph, A.C. ; Oexle, K. ; Otto, M. ; Diehl-Schmid, J. ; Winkelmann, J.
Mol. Psychiatry, DOI: 10.1038/s41380-021-01271-2 (2021)
Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.
Wissenschaftlicher Artikel
Scientific Article
Krane, M. ; Dreßen, M. ; Santamaria, G. ; My, I. ; Schneider, C.M. ; Dorn, T. ; Laue, S. ; Mastantuono, E. ; Berutti, R. ; Rawat, H. ; Gilsbach, R. ; Schneider, P. ; Lahm, H. ; Schwarz, S. ; Doppler, S.A. ; Paige, S. ; Puluca, N. ; Doll, S. ; Neb, I. ; Brade, T. ; Zhang, Z. ; Abou-Ajram, C. ; Northoff, B. ; Holdt, L.M. ; Sudhop, S. ; Sahara, M. ; Goedel, A. ; Dendorfer, A. ; Tjong, F.V.Y. ; Rijlaarsdam, M.E. ; Cleuziou, J. ; Lang, N. ; Kupatt, C. ; Bezzina, C.R. ; Lange, R. ; Bowles, N.E. ; Mann, M. ; Gelb, B.D. ; Crotti, L. ; Hein, L. ; Meitinger, T. ; Wu, S. ; Sinnecker, D. ; Gruber, P.J. ; Laugwitz, K.L. ; Moretti, A.
Circulation 144, 1409-1428 (2021)
BACKGROUND: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. METHODS: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. RESULTS: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. CONCLUSIONS: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.
Wissenschaftlicher Artikel
Scientific Article
Zerbini, G. ; Merrow, M. ; Winnebeck, E.C.
J. Pineal Res.:e12777 (2021)
We read with interest the commentary by Skeldon and Dijk about our article "Weekly, seasonal and chronotype-dependent variation of dim light melatonin onset". The discussion points raised by Skeldon and Dijk are currently among the most hotly debated in human circadian science. What external factors determine human phase of entrainment? How great is the contribution of natural versus artificial light, and sun time versus social time? Our intra-individual data adds to the still limited evidence from field studies in this matter. In their commentary, Skeldon and Dijk formulate two either-or-hypotheses, postulating that humans entrain either solely to the natural light-dark cycle (sun time referenced by midday) (H1) or solely to the light selected by local clock time and social constraints (H2). Neither hypothesis accounts for the effect of season on human light exposure. We interpreted our findings along more complex lines, speculating that the one-hour earlier melatonin rise in summer found in our sample is likely the combined result of daylight saving time (DST)-induced behavioral advances AND a stronger natural zeitgeber in summer (light exposure determined by social AND seasonal factors, Horiginal ). Here we show how the criticism by Skeldon and Dijk is based on two sentences quoted out of context (misrepresenting our hypothesis as H1) and that their hypothesis H2 leaves out important seasonal components in light exposure.
Sonstiges: Meinungsartikel
Other: Opinion
Pietzner, M. ; Wheeler, E. ; Carrasco-Zanini, J. ; Cortes, A. ; Koprulu, M. ; Wörheide, M. ; Oerton, E. ; Cook, J. ; Stewart, I.D. ; Kerrison, N.D. ; Luan, J. ; Raffler, J. ; Arnold, M. ; Arlt, W. ; O'Rahilly, S. ; Kastenmüller, G. ; Gamazon, E.R. ; Hingorani, A.D. ; Scott, R.A. ; Wareham, N.J. ; Langenberg, C.
Science 374:eabj1541 (2021)
Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3,892 plasma proteins to create a cis-anchored gene-protein-disease map of 1,859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to 1) connect etiologically related diseases, 2) provide biological context for new or emerging disorders, and 3) integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at GWAS loci, addressing a major barrier for experimental validation and clinical translation of genetic discoveries.
Wissenschaftlicher Artikel
Scientific Article
Neilson, D.E. ; Zech, M. ; Hufnagel, R.B. ; Slone, J. ; Wang, X. ; Homan, S. ; Gutzwiller, L.M. ; Leslie, E.J. ; Leslie, N.D. ; Xiao, J. ; Hedera, P. ; LeDoux, M.S. ; Gebelein, B. ; Wilbert, F. ; Eckenweiler, M. ; Winkelmann, J. ; Gilbert, D.L. ; Huang, T.
Mov. Disord., DOI: 10.1002/mds.28821 (2021)
BACKGROUND: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31. OBJECTIVE: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia. METHODS: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function. RESULTS: Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility. CONCLUSION: A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.
Wissenschaftlicher Artikel
Scientific Article
Rekik, I. ; Adeli, E. ; Park, S.H. ; Schnabel, J.A.
Lect. Notes Comput. Sc. 12928 LNCS, v-vii (2021)
Editorial
Editorial
Pfaff, F. ; Li, K. ; Hanebeck, U.D.
Sensors 21:6314 (2021)
The SE(2) domain can be used to describe the position and orientation of objects in planar scenarios and is inherently nonlinear due to the periodicity of the angle. We present a novel filter that involves splitting up the joint density into a (marginalized) density for the periodic part and a conditional density for the linear part. We subdivide the state space along the periodic dimension and describe each part of the state space using the parameters of a Gaussian and a grid value, which is the function value of the marginalized density for the periodic part at the center of the respective area. By using the grid values as weighting factors for the Gaussians along the linear dimensions, we can approximate functions on the SE(2) domain with correlated position and orientation. Based on this representation, we interweave a grid filter with a Kalman filter to obtain a filter that can take different numbers of parameters and is in the same complexity class as a grid filter for circular domains. We thoroughly compared the filters with other state-of-the-art filters in a simulated tracking scenario. With only little run time, our filter outperformed an unscented Kalman filter for manifolds and a progressive filter based on dual quaternions. Our filter also yielded more accurate results than a particle filter using one million particles while being faster by over an order of magnitude.
Wissenschaftlicher Artikel
Scientific Article
Eshetu, G.G. ; Zhang, H. ; Judez, X. ; Adenusi, H. ; Armand, M. ; Passerini, S. ; Figgemeier, E.
Nat. Commun. 12:5459 (2021)
Rechargeable Li-based battery technologies utilising silicon, silicon-based, and Si-derivative anodes coupled with high-capacity/high-voltage insertion-type cathodes have reaped significant interest from both academic and industrial sectors. This stems from their practically achievable energy density, offering a new avenue towards the mass-market adoption of electric vehicles and renewable energy sources. Nevertheless, such high-energy systems are limited by their complex chemistry and intrinsic drawbacks. From this perspective, we present the progress, current status, prevailing challenges and mitigating strategies of Li-based battery systems comprising silicon-containing anodes and insertion-type cathodes. This is accompanied by an assessment of their potential to meet the targets for evolving volume- and weight-sensitive applications such as electro-mobility.
Review
Review
Olbrich, L. ; Castelletti, N. ; Schälte, Y. ; Garí, M. ; Pütz, P. ; Bakuli, A. ; Pritsch, M. ; Kroidl, I. ; Saathoff, E. ; Guggenbüehl Noller, J.M. ; Fingerle, V. ; Le Gleut, R. ; Gilberg, L. ; Brand, I. ; Falk, P. ; Markgraf, A. ; Deák, F. ; Riess, F. ; Diefenbach, M. ; Eser, T. ; Weinauer, F. ; Martin, S. ; Quenzel, E.M. ; Becker, M. ; Durner, J. ; Girl, P. ; Müller, K. ; Radon, K. ; Fuchs, C. ; Wölfel, R. ; Hasenauer, J. ; Hoelscher, M. ; Wieser, A.
J. Gen. Virol. 102:001653 (2021)
A number of seroassays are available for SARS-CoV-2 testing; yet, head-to-head evaluations of different testing principles are limited, especially using raw values rather than categorical data. In addition, identifying correlates of protection is of utmost importance, and comparisons of available testing systems with functional assays, such as direct viral neutralisation, are needed.We analysed 6658 samples consisting of true-positives (n=193), true-negatives (n=1091), and specimens of unknown status (n=5374). For primary testing, we used Euroimmun-Anti-SARS-CoV-2-ELISA-IgA/IgG and Roche-Elecsys-Anti-SARS-CoV-2. Subsequently virus-neutralisation, GeneScriptcPass, VIRAMED-SARS-CoV-2-ViraChip, and Mikrogen-recomLine-SARS-CoV-2-IgG were applied for confirmatory testing. Statistical modelling generated optimised assay cut-off thresholds. Sensitivity of Euroimmun-anti-S1-IgA was 64.8%, specificity 93.3% (manufacturer's cut-off); for Euroimmun-anti-S1-IgG, sensitivity was 77.2/79.8% (manufacturer's/optimised cut-offs), specificity 98.0/97.8%; Roche-anti-N sensitivity was 85.5/88.6%, specificity 99.8/99.7%. In true-positives, mean and median Euroimmun-anti-S1-IgA and -IgG titres decreased 30/90 days after RT-PCR-positivity, Roche-anti-N titres decreased significantly later. Virus-neutralisation was 80.6% sensitive, 100.0% specific (≥1:5 dilution). Neutralisation surrogate tests (GeneScriptcPass, Mikrogen-recomLine-RBD) were >94.9% sensitive and >98.1% specific. Optimised cut-offs improved test performances of several tests. Confirmatory testing with virus-neutralisation might be complemented with GeneScriptcPassTM or recomLine-RBD for certain applications. Head-to-head comparisons given here aim to contribute to the refinement of testing strategies for individual and public health use.
Wissenschaftlicher Artikel
Scientific Article
Rubio-Acero, R. ; Beyerl, J. ; Muenchhoff, M. ; Roth, M.S. ; Castelletti, N. ; Paunovic, I. ; Radon, K. ; Springer, B. ; Nagel, C.H. ; Boehm, B. ; Böhmer, M.M. ; Graf, A. ; Blum, H. ; Krebs, S. ; Keppler, O.T. ; Osterman, A. ; Khan, Z.N. ; Hoelscher, M. ; Wieser, A. ; KoCo19-Study Group (Fuchs, C.) ; KoCo19-Study Group (Le Gleut, R.)
Sci. Total Environ. 797:149031 (2021)
Wastewater-based epidemiology (WBE) is a tool now increasingly proposed to monitor the SARS-CoV-2 burden in populations without the need for individual mass testing. It is especially interesting in metropolitan areas where spread can be very fast, and proper sewage systems are available for sampling with short flow times and thus little decay of the virus. We started in March 2020 to set up a once-a-week qualified spot sampling protocol in six different locations in Munich carefully chosen to contain primarily wastewater of permanent residential areas, rather than industry or hospitals. We used RT-PCR and sequencing to track the spread of SARS-CoV-2 in the Munich population with temporo-spatial resolution. The study became fully operational in mid-April 2020 and has been tracking SARS-CoV-2 RNA load weekly for one year. Sequencing of the isolated viral RNA was performed to obtain information about the presence and abundance of variants of concern in the Munich area over time. We demonstrate that the evolution of SARS-CoV-2 RNA loads (between <7.5 and 3874/ml) in these different areas within Munich correlates well with official seven day incidence notification data (between 0.0 and 327 per 100,000) obtained from the authorities within the respective region. Wastewater viral loads predicted the dynamic of SARS-CoV-2 local incidence about 3 weeks in advance of data based on respiratory swab analyses. Aligning with multiple different point-mutations characteristic for certain variants of concern, we could demonstrate the gradual increase of variant of concern B.1.1.7 in the Munich population beginning in January 2021, weeks before it became apparent in sequencing results of swabs samples taken from patients living in Munich. Overall, the study highlights the potential of WBE to monitor the SARS-CoV-2 pandemic, including the introduction of variants of concern in a local population.
Wissenschaftlicher Artikel
Scientific Article
Beyerl, J. ; Rubio-Acero, R. ; Castelletti, N. ; Paunovic, I. ; Kroidl, I. ; Khan, Z.N. ; Bakuli, A. ; Tautz, A. ; Oft, J. ; Hoelscher, M. ; Wieser, A. ; KoCo19 Study group (Fuchs, C.) ; KoCo19 Study group (Le Gleut, R.)
EBioMedicine 70:103502 (2021)
BACKGROUND: Since 2020 SARS-CoV-2 spreads pandemically, infecting more than 119 million people, causing >2·6 million fatalities. Symptoms of SARS-CoV-2 infection vary greatly, ranging from asymptomatic to fatal. Different populations react differently to the disease, making it very hard to track the spread of the infection in a population. Measuring specific anti-SARS-CoV-2 antibodies is an important tool to assess the spread of the infection or successful vaccinations. To achieve sufficient sample numbers, alternatives to venous blood sampling are needed not requiring medical personnel or cold-chains. Dried-blood-spots (DBS) on filter-cards have been used for different studies, but not routinely for serology. METHODS: We developed a semi-automated protocol using self-sampled DBS for SARS-CoV-2 serology. It was validated in a cohort of matched DBS and venous-blood samples (n = 1710). Feasibility is demonstrated with two large serosurveys with 10247 company employees and a population cohort of 4465 participants. FINDINGS: Sensitivity and specificity reached 99·20% and 98·65%, respectively. Providing written instructions and video tutorials, 99·87% (4465/4471) of the unsupervised home sampling DBS cards could be analysed. INTERPRETATION: DBS-sampling is a valid and highly reliable tool for large scale serosurveys. We demonstrate feasibility and accuracy with a large validation cohort including unsupervised home sampling. This protocol might be of big importance for surveillance in resource-limited settings, providing low-cost highly accurate serology data. FUNDING: Provided by Bavarian State Ministry of Science and the Arts, LMU University-Hospital; Helmholtz-Centre-Munich, German Ministry for Education and Research (project01KI20271); University of Bonn; University of Bielefeld; the Medical Biodefense Research Program of Bundeswehr-Medical-Service; Euroimmun, RocheDiagnostics provided discounted kits and machines.
Wissenschaftlicher Artikel
Scientific Article
Garí, M. ; Grzesiak, M. ; Krekora, M. ; Kaczmarek, P. ; Jankowska, A. ; Krol, A. ; Kaleta, D. ; Jerzyńska, J. ; Janasik, B. ; Kuraś, R. ; Tartaglione, A.M. ; Calamandrei, G. ; Hanke, W. ; Polanska, K.
Environ. Res. 204:112049 (2021)
Exposure to environmental factors, such as neurotoxic metals and micronutrients, during critical periods of development can contribute to long-term consequences in offspring's health, including neurodevelopmental outcomes. The aim of this study was to evaluate the association between simultaneous prenatal exposure to metals [lead (Pb), cadmium (Cd), mercury (Hg)] and micronutrients [selenium (Se), zinc (Zn), copper (Cu)] and neurodevelopmental outcomes in school-age children from the Polish Mother and Child Cohort (REPRO_PL). Metals and micronutrients concentrations were measured in cord blood (Pb, Cd, Se, Zn, Cu) and in maternal hair (Hg) collected during the 3rd trimester of pregnancy. Behavioral and emotional problems, as well as children's cognitive and psychomotor development, were assessed in 436 school-age children using the Strengths and Difficulties Questionnaire (SDQ, filled in by the mothers) and the Polish adaptation of the Intelligence and Development Scales (IDS, administered by trained psychologists). Multivariate regression models were applied after imputation of missing values, using two approaches: (i) a joint analysis taking into account all metals and micronutrients simultaneously, and (ii) an ExWAS study (single-exposure model). In the SDQ, Hyperactivity/Inattention problems and Total difficulties were associated with higher Hg concentrations in maternal hair (0.18, 95% CI: 0.05; 0.3; and 0.14, 95% CI: 0.01; 0.3, respectively), whereas Emotional symptoms were inversely associated with Se and Zn levels in cord blood (-0.13, 95% CI: 0.3; 0.004; and -0.10, 95% CI: 0.2; 0.02, respectively). In the IDS, cord blood Pb levels were found to be negatively associated with Fluid and Crystallized IQ (-0.12, 95% CI: 0.3; 0.02; and -0.14, 95% CI: 0.3; 0.007, respectively) as well as Mathematical skills (-0.15, 95% CI: 0.3; 0.01). The current research has been able to simultaneously assess the exposure to various interacting chemicals during the prenatal period. We demonstrate that prenatal co-exposures to Pb, Hg, Zn and Se have long-term influences on the neuropsychological outcome of school-age children.
Wissenschaftlicher Artikel
Scientific Article
Meles, S.K. ; Oertel, W.H. ; Leenders, K.L.
Mol. Med. 27:111 (2021)
Parkinson's disease (PD) commences several years before the onset of motor features. Pathophysiological understanding of the pre-clinical or early prodromal stages of PD are essential for the development of new therapeutic strategies. Two categories of patients are ideal to study the early disease stages. Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents a well-known prodromal stage of PD in which pathology is presumed to have reached the lower brainstem. The majority of patients with iRBD will develop manifest PD within years to decades. Another category encompasses non-manifest mutation carriers, i.e. subjects without symptoms, but with a known mutation or genetic variant which gives an increased risk of developing PD. The speed of progression from preclinical or prodromal to full clinical stages varies among patients and cannot be reliably predicted on the individual level. Clinical trials will require inclusion of patients with a predictable conversion within a limited time window. Biomarkers are necessary that can confirm pre-motor PD status and can provide information regarding lead time and speed of progression. Neuroimaging changes occur early in the disease process and may provide such a biomarker. Studies have focused on radiotracer imaging of the dopaminergic nigrostriatal system, which can be assessed with dopamine transporter (DAT) single photon emission computed tomography (SPECT). Loss of DAT binding represents an effect of irreversible structural damage to the nigrostriatal system. This marker can be used to monitor disease progression and identify individuals at specific risk for phenoconversion. However, it is known that changes in neuronal activity precede structural changes. Functional neuro-imaging techniques, such as 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography (18F-FDG PET) and functional magnetic resonance imaging (fMRI), can be used to model the effects of disease on brain networks when combined with advanced analytical methods. Because these changes occur early in the disease process, functional imaging studies are of particular interest in prodromal PD diagnosis. In addition, fMRI and 18F-FDG PET may be able to predict a specific future phenotype in prodromal cohorts, which is not possible with DAT SPECT. The goal of the current review is to discuss the network-level brain changes in pre-motor PD.
Review
Review
Wallach, D. ; Palosuo, T. ; Thorburn, P. ; Hochman, Z. ; Gourdain, E. ; Andrianasolo, F. ; Asseng, S. ; Basso, B. ; Buis, S. ; Crout, N. ; Dibari, C. ; Dumont, B. ; Ferrise, R. ; Gaiser, T. ; Garcia, C. ; Gayler, S. ; Ghahramani, A. ; Hiremath, S. ; Hoek, S. ; Horan, H. ; Hoogenboom, G. ; Huang, M. ; Jabloun, M. ; Jansson, P.E. ; Jing, Q. ; Justes, É. ; Kersebaum, K.C. ; Klosterhalfen, A. ; Launay, M. ; Lewan, E. ; Luo, Q. ; Maestrini, B. ; Mielenz, H. ; Moriondo, M. ; Zadeh, H.N. ; Padovan, G. ; Olesen, J.E. ; Poyda, A. ; Priesack, E. ; Pullens, J.W.M. ; Qian, B. ; Schuetze, N. ; Shelia, V. ; Souissi, A. ; Specka, X. ; Srivastava, A.K. ; Stella, T. ; Streck, T. ; Trombi, G. ; Wallor, E. ; Wang, J. ; Weber, T.K.D. ; Weihermueller, L. ; de Wit, A. ; Woehling, T. ; Xiao, L. ; Zhao, C. ; Zhu, Y. ; Seidel, S.J.
Environ. Modell. Softw. 145:105206 (2021)
Calibration, the estimation of model parameters based on fitting the model to experimental data, is among the first steps in many applications of process-based models and has an important impact on simulated values. We propose a novel method of developing guidelines for calibration of process-based models, based on development of recommendations for calibration of the phenology component of crop models. The approach was based on a multi-model study, where all teams were provided with the same data and asked to return simulations for the same conditions. All teams were asked to document in detail their calibration approach, including choices with respect to criteria for best parameters, choice of parameters to estimate and software. Based on an analysis of the advantages and disadvantages of the various choices, we propose calibration recommendations that cover a comprehensive list of decisions and that are based on actual practices.
Wissenschaftlicher Artikel
Scientific Article
Gergei, I. ; Zheng, J. ; Andlauer, T.F.M. ; Brandenburg, V. ; Mirza-Schreiber, N. ; Müller-Myhsok, B. ; Krämer, B.K. ; Richard, D. ; Falk, L. ; Movérare-Skrtic, S. ; Ohlsson, C. ; Smith, G.D. ; März, W. ; Voelkl, J. ; Tobias, J.H.
Hum. Mol. Genet., DOI: 10.1093/hmg/ddab263 (2021)
BACKGROUND: The protein α-Klotho acts as transmembrane the co-receptor for fibroblast growth factor 23 (FGF-23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a GWAS meta-analysis followed by Mendelian randomisation (MR) of circulating α-Klotho levels. METHODS: Plasma α-Klotho levels were measured by ELISA in the LURIC and ALSPAC (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. RESULTS: Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (p < 5 × 10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained > 9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF-23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes, followed by targeted MR suggested causal effects of liability of Crohn's disease risk [IVW beta = 0.059 (95% CI 0.026, 0.093)] and low-density lipoprotein cholesterol (LDL-C) levels [-0.198, (-0.332, -0.063)] on α-Klotho. CONCLUSIONS: Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively.
Wissenschaftlicher Artikel
Scientific Article
Võsa, U. ; Claringbould, A. ; Westra, H.J. ; Bonder, M.J. ; Deelen, P. ; Zeng, B. ; Kirsten, H. ; Saha, A. ; Kreuzhuber, R. ; Yazar, S. ; Brugge, H. ; Oelen, R. ; de Vries, D.H. ; van der Wijst, M.G.P. ; Kasela, S. ; Pervjakova, N. ; Alves, I. ; Favé, M.J. ; Agbessi, M. ; Christiansen, M.W. ; Jansen, R. ; Seppälä, I. ; Tong, L. ; Teumer, A. ; Schramm, K. ; Hemani, G. ; Verlouw, J. ; Yaghootkar, H. ; Sönmez Flitman, R. ; Brown, A. ; Kukushkina, V. ; Kalnapenkis, A. ; Rüeger, S. ; Porcu, E. ; Kronberg, J. ; Kettunen, J. ; Lee, B. ; Zhang, F. ; Qi, T. ; Hernandez, J.A. ; Arindrarto, W. ; Beutner, F. ; BIOS Consortium ; i2QTL Consortium ; Dmitrieva, J. ; Elansary, M. ; Fairfax, B.P. ; Georges, M. ; Heijmans, B.T. ; Hewitt, A.W. ; Kähönen, M. ; Kim, Y. ; Knight, J.C. ; Kovacs, P. ; Krohn, K. ; Li, S. ; Loeffler, M. ; Marigorta, U.M. ; Mei, H. ; Momozawa, Y. ; Müller-Nurasyid, M. ; Nauck, M. ; Nivard, M.G. ; Penninx, B.W.J.H. ; Pritchard, J.K. ; Raitakari, O.T. ; Rotzschke, O. ; Slagboom, E.P. ; Stehouwer, C.D.A. ; Stumvoll, M. ; Sullivan, P. ; 't Hoen, P.A.C. ; Thiery, J. ; Tönjes, A. ; van Dongen, J. ; van Iterson, M. ; Veldink, J.H. ; Völker, U. ; Warmerdam, R. ; Wijmenga, C. ; Swertz, M. ; Andiappan, A. ; Montgomery, G.W. ; Ripatti, S. ; Perola, M. ; Kutalik, Z. ; Dermitzakis, E. ; Bergmann, S. ; Frayling, T. ; van Meurs, J. ; Prokisch, H. ; Ahsan, H. ; Pierce, B.L. ; Lehtimäki, T. ; Boomsma, D.I. ; Psaty, B.M. ; Gharib, S.A. ; Awadalla, P. ; Milani, L. ; Ouwehand, W.H. ; Downes, K. ; Stegle, O. ; Battle, A. ; Visscher, P.M. ; Yang, J. ; Scholz, M. ; Powell, J. ; Gibson, G. ; Esko, T. ; Franke, L.
Nat. Genet. 53, 1300-1310 (2021)
Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
Wissenschaftlicher Artikel
Scientific Article
Oppenländer, L. ; Palit, S. ; Stemmer, K. ; Greisle, T. ; Sterr, M. ; Salinno, C. ; Bastidas-Ponce, A. ; Feuchtinger, A. ; Böttcher, A. ; Ansarullah ; Theis, F.J. ; Lickert, H.
Mol. Metab. 54:101330 (2021)
While the effectiveness of bariatric surgery in restoring β-cell function has been described in type-2 diabetes (T2D) patients and animal models for years, the mechanistic underpinnings are largely unknown. The possibility of vertical sleeve gastrectomy (VSG) to rescue a clinically-relevant, late-stage T2D condition and to promote β-cell recovery has not been investigated on a single-cell level. Nevertheless, characterization of the heterogeneity and functional states of β-cells after VSG is a fundamental step to understand mechanisms of glycaemic recovery and to ultimately develop alternative, less-invasive therapies. Here, we report that VSG was superior to calorie restriction in late-stage T2D and rapidly restored normoglycaemia in morbidly obese and overt diabetic db/db mice. Single-cell profiling of islets of Langerhans showed that VSG induced distinct, intrinsic changes in the β-cell transcriptome, but not in that of α-, δ-, and PP-cells. VSG triggered fast β-cell redifferentiation and functional improvement within only two weeks of intervention, which is not seen upon calorie restriction. Furthermore, VSG expanded β-cell area by means of redifferentiation and by creating a proliferation competent β-cell state. Collectively, our study reveals the superiority of VSG in the remission of far-progressed T2D and presents paths of β-cell regeneration and molecular pathways underlying the glycaemic benefits of VSG.
Wissenschaftlicher Artikel
Scientific Article
van der Ven, A.T. ; Johannsen, J. ; Kortüm, F. ; Wagner, M. ; Tsiakas, K. ; Bierhals, T. ; Lessel, D. ; Herget, T. ; Kloth, K. ; Lisfeld, J. ; Scholz, T. ; Obi, N. ; Wortmann, S.B. ; Prokisch, H. ; Kubisch, C. ; Denecke, J. ; Santer, R. ; Hempel, M.
Clin. Genet., DOI: 10.1111/cge.14061 (2021)
Neurological symptoms are frequent and often a leading feature of childhood-onset mitochondrial disorders (MD) but the exact incidence of MD in unselected neuropediatric patients is unknown. Their early detection is desirable due to a potentially rapid clinical decline and the availability of management options. In 491 children with neurological symptoms a comprehensive diagnostic work-up including exome sequencing was performed. The success rate in terms of a molecular genetic diagnosis within our cohort was 51%. Disease-causing variants in a mitochondria-associated gene were detected in 12% of solved cases. In order to facilitate the clinical identification of MDs within neuropediatric cohorts, we have created an easy-to-use bedside-tool, the MDC-NP. In our cohort, the MDC-NP predicted disease conditions related to MDs with a sensitivity of 0.83, and a specificity of 0.96.
Wissenschaftlicher Artikel
Scientific Article
Verdun, C.M. ; Fuchs, T. ; Harar, P. ; Elbrächter, D. ; Fischer, D.S. ; Berner, J. ; Grohs, P. ; Theis, F.J. ; Krahmer, F.
Front. Publ. Health 9:583377 (2021)
Background: Due to the ongoing COVID-19 pandemic, demand for diagnostic testing has increased drastically, resulting in shortages of necessary materials to conduct the tests and overwhelming the capacity of testing laboratories. The supply scarcity and capacity limits affect test administration: priority must be given to hospitalized patients and symptomatic individuals, which can prevent the identification of asymptomatic and presymptomatic individuals and hence effective tracking and tracing policies. We describe optimized group testing strategies applicable to SARS-CoV-2 tests in scenarios tailored to the current COVID-19 pandemic and assess significant gains compared to individual testing. Methods: We account for biochemically realistic scenarios in the context of dilution effects on SARS-CoV-2 samples and consider evidence on specificity and sensitivity of PCR-based tests for the novel coronavirus. Because of the current uncertainty and the temporal and spatial changes in the prevalence regime, we provide analysis for several realistic scenarios and propose fast and reliable strategies for massive testing procedures. Key Findings: We find significant efficiency gaps between different group testing strategies in realistic scenarios for SARS-CoV-2 testing, highlighting the need for an informed decision of the pooling protocol depending on estimated prevalence, target specificity, and high- vs. low-risk population. For example, using one of the presented methods, all 1.47 million inhabitants of Munich, Germany, could be tested using only around 141 thousand tests if the infection rate is below 0.4% is assumed. Using 1 million tests, the 6.69 million inhabitants from the city of Rio de Janeiro, Brazil, could be tested as long as the infection rate does not exceed 1%. Moreover, we provide an interactive web application, available at www.grouptexting.com, for visualizing the different strategies and designing pooling schemes according to specific prevalence scenarios and test configurations. Interpretation: Altogether, this work may help provide a basis for an efficient upscaling of current testing procedures, which takes the population heterogeneity into account and is fine-grained towards the desired study populations, e.g., mild/asymptomatic individuals vs. symptomatic ones but also mixtures thereof. Funding: German Science Foundation (DFG), German Federal Ministry of Education and Research (BMBF), Chan Zuckerberg Initiative DAF, and Austrian Science Fund (FWF).
Wissenschaftlicher Artikel
Scientific Article
Danese, A. ; Richter, M. ; Chaichoompu, K. ; Fischer, D.S. ; Theis, F.J. ; Colomé-Tatché, M.
Nat. Commun. 12:5228 (2021)
EpiScanpy is a toolkit for the analysis of single-cell epigenomic data, namely single-cell DNA methylation and single-cell ATAC-seq data. To address the modality specific challenges from epigenomics data, epiScanpy quantifies the epigenome using multiple feature space constructions and builds a nearest neighbour graph using epigenomic distance between cells. EpiScanpy makes the many existing scRNA-seq workflows from scanpy available to large-scale single-cell data from other -omics modalities, including methods for common clustering, dimension reduction, cell type identification and trajectory learning techniques, as well as an atlas integration tool for scATAC-seq datasets. The toolkit also features numerous useful downstream functions, such as differential methylation and differential openness calling, mapping epigenomic features of interest to their nearest gene, or constructing gene activity matrices using chromatin openness. We successfully benchmark epiScanpy against other scATAC-seq analysis tools and show its outperformance at discriminating cell types.
Wissenschaftlicher Artikel
Scientific Article
Efendiyev, M.A. ; Vougalter, V.
In: The Many Facets of Complexity Science. 2021. 185-192
The chapter deals with the easily verifiable necessary condition of the preservation of the nonnegativity of the solutions of a system of parabolic equations in the case of the mixed diffusion when the standard Laplacian in the first m variables is added to the Laplace operator in the rest of the variables in a fractional power in the space of an arbitrary dimension. This necessary condition is crucial for the applied analysis community since it imposes the necessary form of the system of equations that must be treated mathematically.
Zhu, F. ; Zhang, L. ; Wang, X. ; Dos Santos, F.J. ; Song, J. ; Mueller, T. ; Schmalzl, K. ; Schmidt, W.F. ; Ivanov, A.I. ; Park, J.T. ; Xu, J. ; Ma, J. ; Lounis, S. ; Blügel, S. ; Mokrousov, Y. ; Su, Y. ; Brückel, T.
Sci. Adv. 7:eabi7532 (2021)
The bosonic analogs of topological insulators have been proposed in numerous theoretical works, but their experimental realization is still very rare, especially for spin systems. Recently, two-dimensional (2D) honeycomb van der Waals ferromagnets have emerged as a new platform for topological spin excitations. Here, via a comprehensive inelastic neutron scattering study and theoretical analysis of the spin-wave excitations, we report the realization of topological magnon insulators in CrXTe3 (X = Si, Ge) compounds. The nontrivial nature and intrinsic tunability of the gap opening at the magnon band-crossing Dirac points are confirmed, while the emergence of the corresponding in-gap topological edge states is demonstrated theoretically. The realization of topological magnon insulators with intrinsic gap-unability in this class of remarkable 2D materials will undoubtedly lead to new and fascinating technological applications in the domain of magnonics and topological spintronics.
Wissenschaftlicher Artikel
Scientific Article
Deng, S. ; Wheeler, G. ; Toussaint, N. ; Munroe, L. ; Bhattacharya, S. ; Sajith, G. ; Lin, E. ; Singh, E. ; Chu, K.Y.K. ; Kabir, S. ; Pushparajah, K. ; Simpson, J.M. ; Schnabel, J.A. ; Gomez, A.
J. Imaging 7:151 (2021)
The intricate nature of congenital heart disease requires understanding of the complex, patient-specific three-dimensional dynamic anatomy of the heart, from imaging data such as three-dimensional echocardiography for successful outcomes from surgical and interventional procedures. Conventional clinical systems use flat screens, and therefore, display remains two-dimensional, which undermines the full understanding of the three-dimensional dynamic data. Additionally, the control of three-dimensional visualisation with two-dimensional tools is often difficult, so used only by imaging specialists. In this paper, we describe a virtual reality system for immersive surgery planning using dynamic three-dimensional echocardiography, which enables fast prototyping for visualisation such as volume rendering, multiplanar reformatting, flow visualisation and advanced interaction such as three-dimensional cropping, windowing, measurement, haptic feedback, automatic image orientation and multiuser interactions. The available features were evaluated by imaging and nonimaging clinicians, showing that the virtual reality system can help improve the understanding and communication of three-dimensional echocardiography imaging and potentially benefit congenital heart disease treatment.
Wissenschaftlicher Artikel
Scientific Article
Bergen, V. ; Soldatov, R.A. ; Kharchenko, P.V. ; Theis, F.J.
Mol. Syst. Biol. 17:e10282 (2021)
RNA velocity has enabled the recovery of directed dynamic information from single-cell transcriptomics by connecting measurements to the underlying kinetics of gene expression. This approach has opened up new ways of studying cellular dynamics. Here, we review the current state of RNA velocity modeling approaches, discuss various examples illustrating limitations and potential pitfalls, and provide guidance on how the ensuing challenges may be addressed. We then outline future directions on how to generalize the concept of RNA velocity to a wider variety of biological systems and modalities.
Review
Review
Kaiser, R. ; Leunig, A. ; Pekayvaz, K. ; Popp, O. ; Joppich, M. ; Polewka, V. ; Escaig, R. ; Anjum, A. ; Hoffknecht, M.L. ; Gold, C. ; Brambs, S. ; Engel, A. ; Stockhausen, S. ; Knottenberg, V. ; Titova, A. ; Haji, M. ; Scherer, C. ; Muenchhoff, M. ; Hellmuth, J.C. ; Saar, K. ; Schubert, B. ; Hilgendorff, A. ; Schulz, C. ; Kääb, S. ; Zimmer, R. ; Hübner, N. ; Massberg, S. ; Mertins, P. ; Nicolai, L. ; Stark, K.
JCI insight 6:e150862 (2021)
Neutrophils provide a critical line of defense in immune responses to various pathogens, but also inflict self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients suffering from COVID-19. Here, we utilize state-of-the art mass spectrometry-based proteomics, transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic interleukin-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophil-driven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8-CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8-like signaling reduces SARS-CoV-2 spike protein-induced, hACE2-dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil-IL-8-axis as promising therapeutic target in severe SARS-CoV-2 infection.
Wissenschaftlicher Artikel
Scientific Article
Matschinske, J. ; Alcaraz, N. ; Benis, A. ; Golebiewski, M. ; Grimm, D.G. ; Heumos, L. ; Kacprowski, T. ; Lazareva, O. ; List, M. ; Louadi, Z. ; Pauling, J.K. ; Pfeifer, N. ; Röttger, R. ; Schwämmle, V. ; Sturm, G. ; Traverso, A. ; van Steen, K. ; de Freitas, M.V. ; Villalba Silva, G.C. ; Wee, L. ; Wenke, N.K. ; Zanin, M. ; Zolotareva, O. ; Baumbach, J. ; Blumenthal, D.B.
Nat. Methods, DOI: 10.1038/s41592-021-01241-0 (2021)
We present the AIMe registry, a community-driven reporting platform for AI in biomedicine. It aims to enhance the accessibility, reproducibility and usability of biomedical AI models, and allows future revisions by the community.
Review
Review
Fischer, D.S. ; Dony, L. ; König, M. ; Moeed, A. ; Zappia, L. ; Heumos, L. ; Tritschler, S. ; Holmberg, O. ; Aliee, H. ; Theis, F.J.
Genome Biol. 22:248 (2021)
Single-cell RNA-seq datasets are often first analyzed independently without harnessing model fits from previous studies, and are then contextualized with public data sets, requiring time-consuming data wrangling. We address these issues with sfaira, a single-cell data zoo for public data sets paired with a model zoo for executable pre-trained models. The data zoo is designed to facilitate contribution of data sets using ontologies for metadata. We propose an adaption of cross-entropy loss for cell type classification tailored to datasets annotated at different levels of coarseness. We demonstrate the utility of sfaira by training models across anatomic data partitions on 8 million cells.
Wissenschaftlicher Artikel
Scientific Article
Garí, M. ; Moos, R. ; Bury, D. ; Kasper-Sonnenberg, M. ; Jankowska, A. ; Andysz, A. ; Hanke, W. ; Nowak, D. ; Bose-O'Reilly, S. ; Koch, H.M. ; Polanska, K.
Environ. Health 20:95 (2021)
BACKGROUND: Bisphenol A (BPA) is an industrial chemical mostly used in the manufacture of plastics, resins and thermal paper. Several studies have reported adverse health effects with BPA exposures, namely metabolic disorders and altered neurodevelopment in children, among others. The aim of this study was to explore BPA exposure, its socio-demographic and life-style related determinants, and its association with neurodevelopmental outcomes in early school age children from Poland. METHODS: A total of 250 urine samples of 7 year-old children from the Polish Mother and Child Cohort Study (REPRO_PL) were analyzed for BPA concentrations using high performance liquid chromatography with online sample clean-up coupled to tandem mass spectrometry (online-SPE-LC-MS/MS). Socio-demographic and lifestyle-related data was collected by questionnaires or additional biomarker measurements. Emotional and behavioral symptoms in children were assessed using mother-reported Strengths and Difficulties Questionnaire (SDQ). Cognitive and psychomotor development was evaluated by Polish adaptation of the Intelligence and Development Scales (IDS) performed by trained psychologists. RESULTS: Urinary BPA concentrations and back-calculated daily intakes (medians of 1.8 μg/l and 46.3 ng/kg bw/day, respectively) were similar to other European studies. Urinary cotinine levels and body mass index, together with maternal educational level and socio-economic status, were the main determinants of BPA levels in Polish children. After adjusting for confounding factors, BPA has been found to be positively associated with emotional symptoms (β: 0.14, 95% CI: 0.022; 0.27). Cognitive and psychomotor development were not found to be related to BPA levels. CONCLUSIONS: This study represents the first report of BPA levels and their determinants in school age children in Poland. The exposure level was found to be related to child emotional condition, which can have long-term consequences including social functioning and scholastic achievements. Further monitoring of this population in terms of overall chemical exposure is required.
Wissenschaftlicher Artikel
Scientific Article
Nguyen, B.H.P. ; Ohnmacht, A. ; Sharifli, S. ; Garnett, M.J. ; Menden, M.
Int. J. Mol. Sci. 22:10135 (2021)
Disparities between risk, treatment outcomes and survival rates in cancer patients across the world may be attributed to socioeconomic factors. In addition, the role of ancestry is frequently discussed. In preclinical studies, high‐throughput drug screens in cancer cell lines have empowered the identification of clinically relevant molecular biomarkers of drug sensitivity; however, the genetic ancestry from tissue donors has been largely neglected in this setting. In order to address this, here, we show that the inferred ancestry of cancer cell lines is conserved and may impact drug response in patients as a predictive covariate in high‐throughput drug screens. We found that there are differential drug responses between European and East Asian ancestries, especially when treated with PI3K/mTOR inhibitors. Our finding emphasizes a new angle in precision medicine, as cancer intervention strategies should consider the germline landscape, thereby reducing the failure rate of clinical trials.
Wissenschaftlicher Artikel
Scientific Article
Aliluev, A. ; Tritschler, S. ; Sterr, M. ; Oppenländer, L. ; Hinterdobler, J. ; Greisle, T. ; Irmler, M. ; Beckers, J. ; Sun, N. ; Walch, A.K. ; Stemmer, K. ; Kindt, A. ; Krumsiek, J. ; Tschöp, M.H. ; Luecken, M. ; Theis, F.J. ; Lickert, H. ; Böttcher, A.
Nat. Metab. 3, 1202-1216 (2021)
Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr-Igf1r-Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.
Wissenschaftlicher Artikel
Scientific Article
Boer, C.G. ; Hatzikotoulas, K. ; Southam, L. ; Stefansdottir, L. ; Zhang, Y. ; Coutinho de Almeida, R. ; Wu, T.T. ; Zheng, J. ; Hartley, A. ; Teder-Laving, M. ; Skogholt, A.H. ; Terao, C. ; Zengini, E. ; Alexiadis, G. ; Barysenka, A. ; Bjornsdottir, G. ; Gabrielsen, M.E. ; Gilly, A. ; Ingvarsson, T. ; Johnsen, M.B. ; Jonsson, H. ; Kloppenburg, M. ; Luetge, A. ; Lund, S.H. ; Mägi, R. ; Mangino, M. ; Nelissen, R.R.G.H.H. ; Shivakumar, M. ; Steinberg, J. ; Takuwa, H. ; Thomas, L.F. ; Tuerlings, M. ; arcOGEN Consortium ; HUNT All-In Pain ; ARGO Consortium ; Regeneron Genetics Center ; Babis, G.C. ; Cheung, J.P.Y. ; Kang, J.H. ; Kraft, P. ; Lietman, S.A. ; Samartzis, D. ; Slagboom, P.E. ; Stefansson, K. ; Thorsteinsdottir, U. ; Tobias, J.H. ; Uitterlinden, A.G. ; Winsvold, B. ; Zwart, J.A. ; Davey Smith, G. ; Sham, P.C. ; Thorleifsson, G. ; Gaunt, T.R. ; Morris, A.P. ; Valdes, A.M. ; Tsezou, A. ; Cheah, K.S.E. ; Ikegawa, S. ; Hveem, K. ; Esko, T. ; Wilkinson, J.M. ; Meulenbelt, I. ; Lee, M.T.M. ; van Meurs, J.B.J. ; Styrkarsdottir, U. ; Zeggini, E.
Cell 184, 4784-4818.e17 (2021)
Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.
Wissenschaftlicher Artikel
Scientific Article
Hoppel, F. ; Garcia-Souza, L.F. ; Kantner-Rumplmair, W. ; Burtscher, M. ; Gnaiger, E. ; Calabria, E.
Cells 10:2088 (2021)
Human blood cells may offer a minimally invasive strategy to study systemic alterations of mitochondrial function. Here we tested the reliability of a protocol designed to study mitochondrial respiratory control in human platelets (PLTs) in field studies, using high-resolution respirometry (HRR). Several factors may trigger PLT aggregation during the assay, altering the homogeneity of the cell suspension and distorting the number of cells added to the two chambers (A, B) of the Oroboros Oxygraph-2k (O2k). Thus, inter-chamber variability (∆ab) was calculated by normalizing oxygen consumption to chamber volume (JO2) or to a specific respiratory control state (flux control ratio, FCR) as a reliable parameter of experimental quality. The method's reliability was tested by comparing the ∆ab of laboratory-performed experiments (LAB, N = 9) to those of an ultramarathon field study (three sampling time-points: before competition (PRE, N = 7), immediately after (POST, N = 10) and 24 h after competition (REC; N = 10)). Our results show that ∆ab JO2 changed PRE-POST, but also for LAB-POST and LAB-REC, while all ∆ab FCR remained unchanged. Thus, we conclude that our method is reliable for assessing PLT mitochondrial function in LAB and field studies and after systemic stress conditions.
Wissenschaftlicher Artikel
Scientific Article
Brandstetter, A. ; Bolakhrif, N. ; Schiffer, C. ; Dickscheid, T. ; Mohlberg, H. ; Amunts, K.
In:. 2021. 22-32 (Lect. Notes Comput. Sc. ; 12339 LNCS)
The human lateral geniculate body (LGB) with its six sickle shaped layers (lam) represents the principal thalamic relay nucleus for the visual system. Cytoarchitectonic analysis serves as the groundtruth for multimodal approaches and studies exploring its function. This technique, however, requires experienced knowledge about human neuroanatomy and is costly in terms of time. Here we mapped the six layers of the LGB manually in serial, histological sections of the BigBrain, a high-resolution model of the human brain, whereby their extent was manually labeled in every 30th section in both hemispheres. These maps were then used to train a deep learning algorithm in order to predict the borders on sections in-between these sections. These delineations needed to be performed in 1 µm scans of the tissue sections, for which no exact cross-section alignment is available. Due to the size and number of analyzed sections, this requires to employ high-performance computing. Based on the serial section delineations, high-resolution 3D reconstruction was performed at 20 µm isotropic resolution of the BigBrain model. The 3D reconstruction shows the shape of the human LGB and its sublayers for the first time at cellular precision. It represents a use case to study other complex structures, to visualize their shape and relationship to neighboring structures. Finally, our results could provide reference data of the LGB for modeling and simulation to investigate the dynamics of signal transduction in the visual system.
Lotfollahi, M. ; Naghipourfar, M. ; Luecken, M. ; Khajavi, M. ; Büttner, M. ; Wagenstetter, M. ; Avsec, Z. ; Gayoso, A. ; Yosef, N. ; Interlandi, M. ; Rybakov, S. ; Misharin, A.V. ; Theis, F.J.
Nat. Biotechnol., DOI: 10.1038/s41587-021-01001-7 (2021)
Large single-cell atlases are now routinely generated to serve as references for analysis of smaller-scale studies. Yet learning from reference data is complicated by batch effects between datasets, limited availability of computational resources and sharing restrictions on raw data. Here we introduce a deep learning strategy for mapping query datasets on top of a reference called single-cell architectural surgery (scArches). scArches uses transfer learning and parameter optimization to enable efficient, decentralized, iterative reference building and contextualization of new datasets with existing references without sharing raw data. Using examples from mouse brain, pancreas, immune and whole-organism atlases, we show that scArches preserves biological state information while removing batch effects, despite using four orders of magnitude fewer parameters than de novo integration. scArches generalizes to multimodal reference mapping, allowing imputation of missing modalities. Finally, scArches retains coronavirus disease 2019 (COVID-19) disease variation when mapping to a healthy reference, enabling the discovery of disease-specific cell states. scArches will facilitate collaborative projects by enabling iterative construction, updating, sharing and efficient use of reference atlases.
Wissenschaftlicher Artikel
Scientific Article
Sekhri, R. ; Sadjadian, P. ; Becker, T. ; Kolatzki, V. ; Huenerbein, K. ; Meixner, R. ; Marchi, H. ; Wallmann, R. ; Fuchs, C. ; Griesshammer, M. ; Wille, K.
Ann. Hematol., DOI: 10.1007/s00277-021-04647-0 (2021)
Recently, there has been increased concern about a risk of secondary malignancies (SM) occurring in myelofibrosis (MF) patients receiving ruxolitinib (RUX). In polycythemia vera (PV), on the other hand, only limited data on the risk of SM under RUX treatment are available. To investigate the association between RUX therapy in PV and SM, we conducted a retrospective, single-center study that included 289 PV patients. RUX was administered to 32.9% (95/289) of patients for a median treatment duration of 48.0 months (range 1.0-101.6). Within a median follow-up of 97 months (1.0-395.0) after PV diagnosis, 24 SM occurred. Comparing the number of PV patients with RUX-associated SM (n = 10, 41.7%) with the 14 (58.3%) patients who developed SM without RUX, no significant difference (p = 0.34, chi square test) was found. No increased incidences of melanoma, lymphoma, or solid "non-skin" malignancies were observed with RUX (p = 0.31, p = 0.60, and p = 0.63, respectively, chi square test). However, significantly more NMSC occurred in association with RUX treatment (p = 0.03, chi-squared test). The "SM-free survival" was not significantly different by log rank test for all 289 patients (p = 0.65), for the patients (n = 208; 72%) receiving cytoreductive therapy (p = 0.48) or for different therapy sequences (p = 0.074). In multivariate analysis, advanced age at PV diagnosis (HR 1.062 [95% CI 1.028, 1.098]) but not administration of RUX (HR 1.068 [95% CI 0.468, 2.463]) was associated with an increased risk for SM (p = 0.005). According to this retrospective analysis, no increased risk of SM due to RUX treatment could be substantiated for PV.
Wissenschaftlicher Artikel
Scientific Article
Radon, K. ; Bakuli, A. ; Pütz, P. ; Le Gleut, R. ; Guggenbüehl Noller, J.M. ; Olbrich, L. ; Saathoff, E. ; Garí, M. ; Schälte, Y. ; Frahnow, T. ; Wölfel, R. ; Pritsch, M. ; Rothe, C. ; Pletschette, M. ; Rubio-Acero, R. ; Beyerl, J. ; Metaxa, D. ; Förster, F. ; Thiel, V. ; Castelletti, N. ; Rieß, F. ; Diefenbach, M.N. ; Fröschl, G. ; Bruger, J. ; Winter, S. ; Frese, J. ; Puchinger, K. ; Brand, I. ; Kroidl, I. ; Wieser, A. ; Hoelscher, M. ; Hasenauer, J. ; Fuchs, C.
BMC Infect. Dis. 21:925 (2021)
BACKGROUND: In the 2nd year of the COVID-19 pandemic, knowledge about the dynamics of the infection in the general population is still limited. Such information is essential for health planners, as many of those infected show no or only mild symptoms and thus, escape the surveillance system. We therefore aimed to describe the course of the pandemic in the Munich general population living in private households from April 2020 to January 2021. METHODS: The KoCo19 baseline study took place from April to June 2020 including 5313 participants (age 14 years and above). From November 2020 to January 2021, we could again measure SARS-CoV-2 antibody status in 4433 of the baseline participants (response 83%). Participants were offered a self-sampling kit to take a capillary blood sample (dry blood spot; DBS). Blood was analysed using the Elecsys® Anti-SARS-CoV-2 assay (Roche). Questionnaire information on socio-demographics and potential risk factors assessed at baseline was available for all participants. In addition, follow-up information on health-risk taking behaviour and number of personal contacts outside the household (N = 2768) as well as leisure time activities (N = 1263) were collected in summer 2020. RESULTS: Weighted and adjusted (for specificity and sensitivity) SARS-CoV-2 sero-prevalence at follow-up was 3.6% (95% CI 2.9-4.3%) as compared to 1.8% (95% CI 1.3-3.4%) at baseline. 91% of those tested positive at baseline were also antibody-positive at follow-up. While sero-prevalence increased from early November 2020 to January 2021, no indication of geospatial clustering across the city of Munich was found, although cases clustered within households. Taking baseline result and time to follow-up into account, men and participants in the age group 20-34 years were at the highest risk of sero-positivity. In the sensitivity analyses, differences in health-risk taking behaviour, number of personal contacts and leisure time activities partly explained these differences. CONCLUSION: The number of citizens in Munich with SARS-CoV-2 antibodies was still below 5% during the 2nd wave of the pandemic. Antibodies remained present in the majority of SARS-CoV-2 sero-positive baseline participants. Besides age and sex, potentially confounded by differences in behaviour, no major risk factors could be identified. Non-pharmaceutical public health measures are thus still important.
Wissenschaftlicher Artikel
Scientific Article
Doummar, D. ; Treven, M. ; Qebibo, L. ; Devos, D. ; Ghoumid, J. ; Ravelli, C. ; Kranz, G. ; Krenn, M. ; Demailly, D. ; Cif, L. ; Davion, J.B. ; Zimprich, F. ; Burglen, L. ; Zech, M.
Ann. Clin. Transl. Neurol., DOI: 10.1002/acn3.51444 (2021)
Originally described as a risk factor for autism, CHD8 loss-of-function variants have recently been associated with a wider spectrum of neurodevelopmental abnormalities. We further expand the CHD8-related phenotype with the description of two unrelated patients who presented with childhood-onset progressive dystonia. Whole-exome sequencing conducted in two independent laboratories revealed a CHD8 nonsense variant in one patient and a frameshift variant in the second. The patients had strongly overlapping phenotypes characterized by generalized dystonia with mild-to-moderate neurodevelopmental comorbidity. Deep brain stimulation led to clinical improvement in both cases. We suggest that CHD8 should be added to the growing list of neurodevelopmental disorder-associated genes whose mutations can also result in dystonia-dominant phenotypes.
Wissenschaftlicher Artikel
Scientific Article
Saha, S. ; Kondmann, L. ; Zhu, X.X.
In:. 2021. 311-316 (ISPRS Ann. Photogramm. Remote Sens. Spatial Info. Sci. ; 5)
Unsupervised deep transfer-learning based change detection (CD) methods require pre-trained feature extractor that can be used to extract semantic features from the target bi-temporal scene. However, it is difficult to obtain such feature extractors for hyperspectral images. Moreover, it is not trivial to reuse the models trained with the multispectral images for the hyperspectral images due to the significant difference in number of spectral bands. While hyperspectral images show large number of spectral bands, they generally show much less spatial complexity, thus reducing the requirement of large receptive fields of convolution filters. Recent works in the computer vision have shown that even untrained networks can yield remarkable result in different tasks like super-resolution and surface reconstruction. Motivated by this, we make a bold proposition that untrained deep model, initialized with some weight initialization strategy can be used to extract useful semantic features from bi-temporal hyperspectral images. Thus, we couple an untrained network with Deep Change Vector Analysis (DCVA), a popular method for unsupervised CD, to propose an unsupervised CD method for hyperspectral images. We conduct experiments on two hyperspectral CD data sets, and the results demonstrate advantages of the proposed unsupervised method over other competitors.
Adlung, L. ; Stapor, P. ; Tönsing, C. ; Schmiester, L. ; Schwarzmüller, L.E. ; Postawa, L. ; Wang, D. ; Timmer, J. ; Klingmüller, U. ; Hasenauer, J. ; Schilling, M.
Cell Rep. 36:109507 (2021)
Survival or apoptosis is a binary decision in individual cells. However, at the cell-population level, a graded increase in survival of colony-forming unit-erythroid (CFU-E) cells is observed upon stimulation with erythropoietin (Epo). To identify components of Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5) signal transduction that contribute to the graded population response, we extended a cell-population-level model calibrated with experimental data to study the behavior in single cells. The single-cell model shows that the high cell-to-cell variability in nuclear phosphorylated STAT5 is caused by variability in the amount of Epo receptor (EpoR):JAK2 complexes and of SHP1, as well as the extent of nuclear import because of the large variance in the cytoplasmic volume of CFU-E cells. 24–118 pSTAT5 molecules in the nucleus for 120 min are sufficient to ensure cell survival. Thus, variability in membrane-associated processes is sufficient to convert a switch-like behavior at the single-cell level to a graded population-level response.
Wissenschaftlicher Artikel
Scientific Article
Lakrisenko, P. ; Weindl, D.
Curr. Opin. Syst. Biol. 28:100358 (2021)
As metabolomics datasets are becoming larger and more complex, there is an increasing need for model-based data integration and analysis to optimally leverage these data. Dynamic models of metabolism allow for the integration of heterogeneous data and the analysis of dynamic phenotypes. Here, we review recent efforts in using dynamic metabolic models for data integration, focusing on approaches based on ordinary differential equations that are applicable to both time-resolved and steady-state measurements and that do not require flux distributions as inputs. Furthermore, we discuss recent advances and current challenges. We conclude that much progress has been made in various areas, such as the development of scalable simulation tools, and although challenges remain, dynamic modeling is a powerful tool for metabolomics data analysis that is not yet living up to its full potential.
Review
Review
Dzinovic, I. ; Škorvánek, M. ; Necpál, J. ; Boesch, S. ; Švantnerová, J. ; Wagner, M. ; Havránková, P. ; Pavelekova, P. ; Han, V. ; Janzarik, W.G. ; Berweck, S. ; Diebold, I. ; Kuster, A. ; Jech, R. ; Winkelmann, J. ; Zech, M.
Parkinsonism Relat. Disord. 90, 73-78 (2021)
Introduction: Although there has been increasing recognition of the occurrence of non-epileptic involuntary movements in developmental and epileptic encephalopathies (DEEs), the spectrum of dystonic presentations associated with these conditions remains poorly described. We sought to expand the catalogue of dystonia-predominant phenotypes in monogenic DEEs, building on the recently introduced concept of an epilepsy-movement disorder spectrum. Methods: Cases were identified from a whole-exome-sequenced cohort of 45 pediatric index patients with complex dystonia (67% sequenced as parent-child trios). Review of molecular findings in DEE-associated genes was performed. For five individuals with identified DEE-causing variants, detailed information about presenting phenotypic features and the natural history of disease was obtained. Results: De-novo pathogenic and likely pathogenic missense variants in GABRA1, GABBR2, GNAO1, and FOXG1 gave rise to infantile-onset persistent and paroxysmal dystonic manifestations, beginning in the limb or truncal musculature and progressing gradually to a generalized state. Coexisting, less prominent movement-disorder symptoms were observed and included myoclonic, ballistic, and stereotypic abnormal movements as well as choreoathetosis. Dystonia dominated over epileptic neurodevelopmental comorbidities in all four subjects and represented the primary indication for molecular genetic analysis. We also report the unusual case of an adult female patient with dystonia, tremor, and mild learning disability who was found to harbor a pathogenic frameshift variant in MECP2. Conclusions: Dystonia can be a leading clinical manifestation in different DEEs. A monogenic basis of disease should be considered on the association of dystonia and developmental delay-epilepsy presentations, justifying a molecular screening for variants in DEE-associated genes.
Wissenschaftlicher Artikel
Scientific Article
Zec, N. ; Mangiapia, G. ; Hendry, A.C. ; Barker, R. ; Koutsioubas, A. ; Frielinghaus, H. ; Campana, M. ; Ortega-Roldan, J.L. ; Busch, S. ; Moulin, J.F.
Membranes 11:507 (2021)
We showcase the combination of experimental neutron scattering data and molecular dynamics (MD) simulations for exemplary phospholipid membrane systems. Neutron and X-ray reflectometry and small-angle scattering measurements are determined by the scattering length density profile in real space, but it is not usually possible to retrieve this profile unambiguously from the data alone. MD simulations predict these density profiles, but they require experimental control. Both issues can be addressed simultaneously by cross-validating scattering data and MD results. The strengths and weaknesses of each technique are discussed in detail with the aim of optimizing the opportunities provided by this combination.
Wissenschaftlicher Artikel
Scientific Article
Serr, I. ; Drost, F. ; Schubert, B. ; Daniel, C.
Front. Immunol. 12:712870 (2021)
Regulatory T cells (Tregs) are key mediators of peripheral self-tolerance and alterations in their frequencies, stability, and function have been linked to autoimmunity. The antigen-specific induction of Tregs is a long-envisioned goal for the treatment of autoimmune diseases given reduced side effects compared to general immunosuppressive therapies. However, the translation of antigen-specific Treg inducing therapies for the treatment or prevention of autoimmune diseases into the clinic remains challenging. In this mini review, we will discuss promising results for antigen-specific Treg therapies in allergy and specific challenges for such therapies in autoimmune diseases, with a focus on type 1 diabetes (T1D). We will furthermore discuss opportunities for antigen-specific Treg therapies in T1D, including combinatorial strategies and tissue-specific Treg targeting. Specifically, we will highlight recent advances in miRNA-targeting as a means to foster Tregs in autoimmunity. Additionally, we will discuss advances and perspectives of computational strategies for the detailed analysis of tissue-specific Tregs on the single-cell level.
Review
Review
Efendiyev, M.A. ; Murley, J. ; Sivaloganathan, S.
Bull. Math. Biol. 83:95 (2021)
High intensity focussed ultrasound (HIFU) has emerged as a novel therapeutic modality, for the treatment of various cancers, that is gaining significant traction in clinical oncology. It is a cancer therapy that avoids many of the associated negative side effects of other more well-established therapies (such as surgery, chemotherapy and radiotherapy) and does not lead to the longer recuperation times necessary in these cases. The increasing interest in HIFU from biomedical researchers and clinicians has led to the development of a number of mathematical models to capture the effects of HIFU energy deposition in biological tissue. In this paper, we study the simplest such model that has been utilized by researchers to study temperature evolution under HIFU therapy. Although the model poses significant theoretical challenges, in earlier work, we were able to establish existence and uniqueness of solutions to this system of PDEs (see Efendiev et al. Adv Appl Math Sci 29(1):231-246, 2020). In the current work, we take the next natural step of studying the long-time dynamics of solutions to this model, in the case where the external forcing is quasi-periodic. In this case, we are able to prove the existence of uniform attractors to the corresponding evolutionary processes generated by our model and to estimate the Hausdorff dimension of the attractors, in terms of the physical parameters of the system.
Review
Review
Pachl, E. ; Zamanian, A. ; Stieler, M. ; Bahr, C. ; Ahmidi, N.
Appl. Sci. 11:6986 (2021)
The main intervention for coronary artery disease is stent implantation. We aim to predict post-intervention target lesion failure (TLF) months before its onset, an extremely challenging task in clinics. This post-intervention decision support tool helps physicians to identify at-risk patients much earlier and to inform their follow-up care. We developed a novel machine-learning model with three components: a TLF predictor at discharge via a combination of nine conventional models and a super-learner, a risk score predictor for time-to-TLF, and an update function to manage the size of the at-risk cohort. We collected data in a prospective study from 120 medical centers in over 25 countries. All 1975 patients were enrolled during Phase I (2016–2020) and were followed up for five years post-intervention. During Phase I, 151 patients (7.6%) developed TLF, which we used for training. Additionally, 12 patients developed TLF after Phase I (right-censored). Our algorithm successfully classifies 1635 patients as not at risk (TNR = 90.23%) and predicts TLF for 86 patients (TPR = 52.76%), outperforming its training by identifying 33% of the right-censored patients. We also compare our model against five state of the art models, outperforming them all. Our prediction tool is able to optimize for both achieving higher sensitivity and maintaining a reasonable size for the at-risk cohort over time.
Wissenschaftlicher Artikel
Scientific Article
Fischer, D.S. ; Ansari, M. ; Wagner, K.I. ; Jarosch, S. ; Huang, Y. ; Mayr, C. ; Strunz, M. ; Lang, N.J. ; D'Ippolito, E. ; Hammel, M. ; Mateyka, L. ; Weber, S. ; Wolff, L.S. ; Witter, K. ; Fernandez, I.E. ; Leuschner, G. ; Milger, K. ; Frankenberger, M. ; Nowak, L. ; Heinig-Menhard, K. ; Koch, I. ; Stoleriu, M.-G. ; Hilgendorff, A. ; Behr, J. ; Pichlmair, A. ; Schubert, B. ; Theis, F.J. ; Busch, D.H. ; Schiller, H. B. ; Schober, K.
Nat. Commun. 12:4515 (2021)
The in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for 'reverse phenotyping'. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.
Wissenschaftlicher Artikel
Scientific Article
Miglis, M.G. ; Adler, C.H. ; Antelmi, E. ; Arnaldi, D. ; Baldelli, L. ; Boeve, B.F. ; Cesari, M. ; Dall'Antonia, I. ; Diederich, N.J. ; Doppler, K. ; Dušek, P. ; Ferri, R. ; Gagnon, J.F. ; Gan-Or, Z. ; Hermann, W. ; Hoegl, B. ; Hu, M.T. ; Iranzo, A. ; Janzen, A. ; Kuzkina, A. ; Lee, J. ; Leenders, K.L. ; Lewis, S.J.G. ; Liguori, C. ; Liu, J. ; Lo, C. ; Martens, K.A.E ; Nepozitek, J. ; Plazzi, G. ; Provini, F. ; Puligheddu, M. ; Rolinski, M. ; Rusz, J. ; Stefani, A. ; Summers, R.L.S. ; Yoo, D. ; Zitser, J. ; Oertel, W.H.
Lancet Neurol. 20, 671-684 (2021)
Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving alpha-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal alpha-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest alpha-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of alpha-synucleinopathy patients with isolated RBD might develop.
Review
Review
Williams, R.H. ; Riedemann, T.
Int. J. Mol. Sci. 22:9297 (2021)
In the mammalian brain, cortical interneurons (INs) are a highly diverse group of cells. A key neurophysiological question concerns how each class of INs contributes to cortical circuit function and whether specific roles can be attributed to a selective cell type. To address this question, researchers are integrating knowledge derived from transcriptomic, histological, electrophysiological, developmental, and functional experiments to extensively characterise the different classes of INs. Our hope is that such knowledge permits the selective targeting of cell types for therapeutic endeavours. This review will focus on two of the main types of INs, namely the parvalbumin (PV+) or somatostatin (SOM+)-containing cells, and summarise the research to date on these classes.
Review
Review
Nho, K. ; Kueider-Paisley, A. ; Arnold, M. ; MahmoudianDehkordi, S. ; Risacher, S.L. ; Louie, G. ; Blach, C. ; Baillie, R. ; Han, X. ; Kastenmüller, G. ; Doraiswamy, P.M. ; Kaddurah-Daouk, R. ; Saykin, A.J.
Brain Commun. 3:fcab139 (2021)
Metabolomics in the Alzheimer's Disease Neuroimaging Initiative cohort provides a powerful tool for mapping biochemical changes in Alzheimer's disease, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-β deposition in Alzheimer's disease. We examined 140 serum metabolites and their associations with brain amyloid-β deposition, cognition and conversion from mild cognitive impairment to Alzheimer's disease in the Alzheimer's Disease Neuroimaging Initiative. Processed [18F] Florbetapir PET images were used to perform a voxel-wise statistical analysis of the effect of metabolite levels on amyloid-β accumulation across the whole brain. We performed a multivariable regression analysis using age, sex, body mass index, apolipoprotein E ε4 status and study phase as covariates. We identified nine metabolites as significantly associated with amyloid-β deposition after multiple comparison correction. Higher levels of one acylcarnitine (C3; propionylcarnitine) and one biogenic amine (kynurenine) were associated with decreased amyloid-β accumulation and higher memory scores. However, higher levels of seven phosphatidylcholines (lysoPC a C18:2, PC aa C42:0, PC ae C42:3, PC ae C44:3, PC ae C44:4, PC ae C44:5 and PC ae C44:6) were associated with increased brain amyloid-β deposition. In addition, higher levels of PC ae C44:4 were significantly associated with lower memory and executive function scores and conversion from mild cognitive impairment to Alzheimer's disease dementia. Our findings suggest that dysregulation of peripheral phosphatidylcholine metabolism is associated with earlier pathological changes noted in Alzheimer's disease as measured by brain amyloid-β deposition as well as later clinical features including changes in memory and executive functioning. Perturbations in phosphatidylcholine metabolism may point to issues with membrane restructuring leading to the accumulation of amyloid-β in the brain. Additional studies are needed to explore whether these metabolites play a causal role in the pathogenesis of Alzheimer's disease or if they are biomarkers for systemic changes during preclinical phases of the disease.
Wissenschaftlicher Artikel
Scientific Article
El-Gazzar, A. ; Mayr, J.A. ; Voraberger, B. ; Brügger, K. ; Blouin, S. ; Tischlinger, K. ; Duba, H.C. ; Prokisch, H. ; Fratzl-Zelman, N. ; Högler, W.
Bone Rep. 15:101110 (2021)
Osteogenesis imperfecta (OI) is an inherited genetic disorder characterized by frequent bone fractures and reduced bone mass. Most cases of OI are caused by dominantly inherited heterozygous mutations in one of the two genes encoding type I collagen, COL1A1 and COL1A2. Here we describe a five-year-old boy with typical clinical, radiological and bone ultrastructural features of OI type I. Establishing the molecular genetic cause of his condition proved difficult since clinical exome and whole exome analysis was repeatedly reported negative. Finally, manual analysis of exome data revealed a silent COL1A2 variant c.3597 T > A (NM_000089.4), which we demonstrate activates a cryptic splice site. The newly generated splice acceptor in exon 50 is much more accessible than the wild-type splice-site between the junction of exon 49 and 50, and results in an in-frame deletion of 24 amino acids of the C-terminal propeptide. In vitro collagen expression studies confirmed cellular accumulation and decreased COL1A2 secretion to 45%. This is the first report of a cryptic splice site within the coding region of COL1A2. which results in abnormal splicing causing OI. The experience from this case demonstrates that routine diagnostic approaches may miss cryptic splicing mutations in causative genes due to the lack of universally applicable algorithms for splice-site prediction. In exome-negative cases, in-depth analysis of common causative genes should be conducted and trio-exome analysis is recommended.
Wissenschaftlicher Artikel
Scientific Article
Weiel, M. ; Götz, M. ; Klein, A. ; Coquelin, D. ; Floca, R.O. ; Schug, A.
Nat. Mach. Intell., DOI: 10.1038/s42256-021-00366-3 (2021)
Molecular simulations are a powerful tool to complement and interpret ambiguous experimental data on biomolecules to obtain structural models. Such data-assisted simulations often rely on parameters, the choice of which is highly non-trivial and crucial to performance. The key challenge is weighting experimental information with respect to the underlying physical model. We introduce FLAPS, a self-adapting variant of dynamic particle swarm optimization, to overcome this parameter selection problem. FLAPS is suited for the optimization of composite objective functions that depend on both the optimization parameters and additional, a priori unknown weighting parameters, which substantially influence the search-space topology. These weighting parameters are learned at runtime, yielding a dynamically evolving and iteratively refined search-space topology. As a practical example, we show how FLAPS can be used to find functional parameters for small-angle X-ray scattering-guided protein simulations.
Wissenschaftlicher Artikel
Scientific Article
Schlund, R. ; Riesterer, J. ; Köpke, M. ; Kowalski, M. ; Tremper, P. ; Budde, M. ; Beigl, M.
In: (International Summit Smart City 360°). 2021. 596-614 (Lecture Notes Inst. Comp. Sci. Soc. Info. Telecomm. ; 372)
Urban air quality is an important problem of our time. Due to their high costs and therefore low spacial density, high precision monitoring stations cannot capture the temporal and spatial dynamics in the urban atmosphere, low-cost sensors must be used to setup dense measurement grids. However, low-cost sensors are imprecise, biased and susceptible to environmental influences. While neural networks have been explored for their calibration, issues include the amount of data needed for training, requiring sensors to be co-located with reference stations for extensive periods of time. Also re-calibrating them with new data can lead to catastrophic forgetting. We propose using Elastic Weight Consolidation (EWC) as an incremental calibration method. By exploiting the Fisher-Information-Matrix it enables the network to compensate for different sources of error, both pertaining to the sensor itself, as well as caused by varying environmental conditions. Models are pre-calibrated with data of 40 h measurement on a low-cost SDS011 PM sensor and then re-calibrated on another SDS011 sensor. Our evaluation on 1.5 years of real world data shows that a model using EWC with a time period of data of 6 h for re-calibration is more precise than models without EWC, even those with longer re-calibration periods. This demonstrates that EWC is suitable for on-the-fly collaborative calibration of low-cost sensors.
Ban, R. ; Liu, Z. ; Shimura, M. ; Tong, X. ; Wang, J. ; Yang, L. ; Xu, M. ; Xiao, J. ; Murayama, K. ; Elstner, M. ; Prokisch, H. ; Fang, F.
Front. Genet. 12:685035 (2021)
Objective: The cytochrome c oxidase assembly factor 7 (COA7) gene encodes a protein localized to mitochondria that is involved in the assembly of mitochondrial respiratory chain complex IV. Here, we report the clinical, genetic and biochemical analysis of a female patient with suspected mitochondrial disorder and novel variants in COA7, that presented with a considerably different phenotype and age of onset than the five COA7 patients reported to date. Methods: We performed trio-exome sequencing in the affected patient and both parents. To verify the pathogenicity of the detected variants in COA7, mitochondrial enzyme activities and oxygen consumption rate were investigated in fibroblasts of the patient and her parents. Results: A Chinese girl was referred at 9 months of age with a history of developmental delay and regression since 3 months of age. In the following months, she lost previously acquired skills and developed progressive spasticity of the lower extremities. Trio-exome sequencing revealed compound heterzygous variants in COA7 (c.511G > A/p.Ala171Thr and c.566A > G/p.Asn189Ser). Functional validation experiments revealed isolated complex IV deficiency and a significantly reduced mitochondrial respiration rate in patient-derived fibroblasts. Interpretation: Hitherto, characteristic features of COA7 patients were described as slowly progressing neuropathy and spinocerebellar ataxia, starting at the toddler age and progressing into adulthood. In contrast, our patient was reported to show developmental delay from 3 months of age, which was found to be due to a rapidly progressive encephalopathy and brain atrophy seen at 9 months of age. Unexpectedly, the genetic investigation revealed a COA7-associated mitochondrial disease, which was confirmed functionally. Thus, this report broadens the genetic and clinical spectrum of this heterogeneous mitochondriopathy and highlights the value of the presented unbiased approach.
Wissenschaftlicher Artikel
Scientific Article
Bien, J. ; Yan, X. ; Simpson, L. ; Müller, C.
Sci. Rep. 11:14505 (2021)
Modern high-throughput sequencing technologies provide low-cost microbiome survey data across all habitats of life at unprecedented scale. At the most granular level, the primary data consist of sparse counts of amplicon sequence variants or operational taxonomic units that are associated with taxonomic and phylogenetic group information. In this contribution, we leverage the hierarchical structure of amplicon data and propose a data-driven and scalable tree-guided aggregation framework to associate microbial subcompositions with response variables of interest. The excess number of zero or low count measurements at the read level forces traditional microbiome data analysis workflows to remove rare sequencing variants or group them by a fixed taxonomic rank, such as genus or phylum, or by phylogenetic similarity. By contrast, our framework, which we call trac (tree-aggregation of compositional data), learns data-adaptive taxon aggregation levels for predictive modeling, greatly reducing the need for user-defined aggregation in preprocessing while simultaneously integrating seamlessly into the compositional data analysis framework. We illustrate the versatility of our framework in the context of large-scale regression problems in human gut, soil, and marine microbial ecosystems. We posit that the inferred aggregation levels provide highly interpretable taxon groupings that can help microbiome researchers gain insights into the structure and functioning of the underlying ecosystem of interest.
Wissenschaftlicher Artikel
Scientific Article
Schmiester, L. ; Weindl, D. ; Hasenauer, J.
Bioinformatics 37, 4493-4500 (2021)
MOTIVATION: Unknown parameters of dynamical models are commonly estimated from experimental data. However, while various efficient optimization and uncertainty analysis methods have been proposed for quantitative data, methods for qualitative data are rare and suffer from bad scaling and convergence. RESULTS: Here, we propose an efficient and reliable framework for estimating the parameters of ordinary differential equation models from qualitative data. In this framework, we derive a semi-analytical algorithm for gradient calculation of the optimal scaling method developed for qualitative data. This enables the use of efficient gradient-based optimization algorithms. We demonstrate that the use of gradient information improves performance of optimization and uncertainty quantification on several application examples. On average, we achieve a speedup of more than one order of magnitude compared to gradient-free optimization. Additionally, in some examples, the gradient-based approach yields substantially improved objective function values and quality of the fits. Accordingly, the proposed framework substantially improves the parameterization of models from qualitative data. AVAILABILITY: The proposed approach is implemented in the open-source Python Parameter EStimation TOolbox (pyPESTO). pyPESTO is available at https://github.com/ICB-DCM/pyPESTO. All application examples and code to reproduce this study are available at https://doi.org/10.5281/zenodo.4507613. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Wissenschaftlicher Artikel
Scientific Article
Schwaibold, E.M.C. ; Brugger, M. ; Wagner, M.
Clin. Genet., DOI: 10.1111/cge.14034 (2021)
Wissenschaftlicher Artikel
Scientific Article
Marttila, S. ; Viiri, L.E. ; Mishra, P.P. ; Kühnel, B. ; Matias-Garcia, P.R. ; Lyytikäinen, L.P. ; Ceder, T. ; Mononen, N. ; Rathmann, W. ; Winkelmann, J. ; Peters, A. ; Kähönen, M. ; Hutri-Kähönen, N. ; Juonala, M. ; Aalto-Setälä, K. ; Raitakari, O. ; Lehtimäki, T. ; Waldenberger, M. ; Raitoharju, E.
Clin. Epigenet. 13:143 (2021)
BACKGROUND: Non-coding RNA 886 (nc886) is coded from a maternally inherited metastable epiallele. We set out to investigate the determinants and dynamics of the methylation pattern at the nc886 epiallele and how this methylation status associates with nc886 RNA expression. Furthermore, we investigated the associations between the nc886 methylation status or the levels of nc886 RNAs and metabolic traits in the YFS and KORA cohorts. The association between nc886 epiallele methylation and RNA expression was also validated in induced pluripotent stem cell (iPSC) lines. RESULTS: We confirm that the methylation status of the nc886 epiallele is mostly binomial, with individuals displaying either a non- or hemi-methylated status, but we also describe intermediately and close to fully methylated individuals. We show that an individual's methylation status is associated with the mother's age and socioeconomic status, but not with the individual's own genetics. Once established, the methylation status of the nc886 epiallele remains stable for at least 25 years. This methylation status is strongly associated with the levels of nc886 non-coding RNAs in serum, blood, and iPSC lines. In addition, nc886 methylation status associates with glucose and insulin levels during adolescence but not with the indicators of glucose metabolism or the incidence of type 2 diabetes in adulthood. However, the nc886-3p RNA levels also associate with glucose metabolism in adulthood. CONCLUSIONS: These results indicate that nc886 metastable epiallele methylation is tuned by the periconceptional conditions and it associates with glucose metabolism through the expression of the ncRNAs coded in the epiallele region.
Wissenschaftlicher Artikel
Scientific Article
Pollmann, T.R. ; Schönert, S. ; Müller, J. ; Pollmann, J. ; Resconi, E. ; Wiesinger, C. ; Haack, C. ; Shtembari, L. ; Turcati, A. ; Neumair, B. ; Meighen-Berger, S. ; Zattera, G. ; Neumair, M. ; Apel, U. ; Okolie, A.
EPJ Data Sci. 10:37 (2021)
Contact tracing is one of several strategies employed in many countries to curb the spread of SARS-CoV-2. Digital contact tracing (DCT) uses tools such as cell-phone applications to improve tracing speed and reach. We model the impact of DCT on the spread of the virus for a large epidemiological parameter space consistent with current literature on SARS-CoV-2. We also model DCT in combination with random testing (RT) and social distancing (SD). Modelling is done with two independently developed individual-based (stochastic) models that use the Monte Carlo technique, benchmarked against each other and against two types of deterministic models. For current best estimates of the number of asymptomatic SARS-CoV-2 carriers (approximately 40%), their contagiousness (similar to that of symptomatic carriers), the reproductive number before interventions ( R 0 at least 3) we find that DCT must be combined with other interventions such as SD and/or RT to push the reproductive number below one. At least 60% of the population would have to use the DCT system for its effect to become significant. On its own, DCT cannot bring the reproductive number below 1 unless nearly the entire population uses the DCT system and follows quarantining and testing protocols strictly. For lower uptake of the DCT system, DCT still reduces the number of people that become infected. When DCT is deployed in a population with an ongoing outbreak where O (0.1%) of the population have already been infected, the gains of the DCT intervention come at the cost of requiring up to 15% of the population to be quarantined (in response to being traced) on average each day for the duration of the epidemic, even when there is sufficient testing capability to test every traced person.
Wissenschaftlicher Artikel
Scientific Article
Cousin, M.A. ; Creighton, B.A. ; Breau, K.A. ; Spillmann, R.C. ; Torti, E. ; Dontu, S. ; Tripathi, S. ; Ajit, D. ; Edwards, R.J. ; Afriyie, S. ; Bay, J.C. ; Harper, K.M. ; Beltran, A.A. ; Munoz, L.J. ; Falcon Rodriguez, L. ; Stankewich, M.C. ; Person, R.E. ; Si, Y. ; Normand, E.A. ; Blevins, A. ; May, A.S. ; Bier, L. ; Aggarwal, V. ; Mancini, G.M.S. ; van Slegtenhorst, M.A. ; Cremer, K. ; Becker, J. ; Engels, H. ; Aretz, S. ; MacKenzie, J.J. ; Brilstra, E. ; van Gassen, K.L.I. ; van Jaarsveld, R.H. ; Oegema, R. ; Parsons, G.M. ; Mark, P. ; Helbig, I. ; McKeown, S.E. ; Stratton, R. ; Cogné, B. ; Isidor, B. ; Cacheiro, P. ; Smedley, D. ; Firth, H.V. ; Bierhals, T. ; Kloth, K. ; Weiss, D. ; Fairley, C. ; Shieh, J.T. ; Kritzer, A. ; Jayakar, P. ; Kurtz-Nelson, E. ; Bernier, R.A. ; Wang, T. ; Eichler, E.E. ; van de Laar, I.M.B.H. ; McConkie-Rosell, A. ; McDonald, M.T. ; Kemppainen, J. ; Lanpher, B.C. ; Schultz-Rogers, L.E. ; Gunderson, L.B. ; Pichurin, P.N. ; Yoon, G. ; Zech, M. ; Jech, R. ; Winkelmann, J. ; Beltran, A.S. ; Zimmermann, M.T. ; Temple, B. ; Moy, S.S. ; Klee, E.W. ; Tan, Q.K. ; Lorenzo, D.N.
Nat. Genet. 53, 1006-1021 (2021)
SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of βII-spectrin in the central nervous system.
Wissenschaftlicher Artikel
Scientific Article
Matek, C. ; Krappe, S. ; Münzenmayer, C. ; Haferlach, T. ; Marr, C.
Blood 138, 1917-1927 (2021)
Biomedical applications of deep learning algorithms rely on large, expert annotated data sets. The classification of bone marrow cell cytomorphology, an important cornerstone of hematological diagnosis, is still done manually thousands of times every day, due to a lack of datasets and trained models.We apply convolutional neural networks (CNNs) to a large dataset of 171,374 microscopic cytological images taken from bone marrow smears of 945 patients diagnosed with a variety of hematological diseases. The dataset is the largest expert-annotated pool of bone marrow cytology images available in the literature so far. It allows us to train high-quality classifiers of leukocyte cytomorphology that identify a wide range of diagnostically relevant cell species at high precision and recall.Our CNNs outcompete previous feature-based approaches and provide a proof-of-concept to the classification problem of single bone marrow cells.This work is a step towards automated evaluation of bone marrow cell morphology using state-of-the-art image classification algorithms. The underlying dataset represents both an educational resource as well as a reference for future AI-based approaches to bone marrow cytomorphology.
Wissenschaftlicher Artikel
Scientific Article
Aliee, H. ; Theis, F.J.
Cell Syst. 12, 706-715.e4 (2021)
Knowing cell-type proportions in a tissue is very important to identify which cells or cell types are targeted by a disease or perturbation. Hence, several deconvolution methods have been proposed to infer cell-type proportions from bulk RNA samples. Their performance with noisy reference profiles and closely correlated cell types highly depends on the set of genes undergoing deconvolution. In this work, we introduce AutoGeneS, a platform that automatically extracts discriminative genes and reveals the cellular heterogeneity of bulk RNA samples. AutoGeneS requires no prior knowledge about marker genes and selects genes by simultaneously optimizing multiple criteria: minimizing the correlation and maximizing the distance between cell types. AutoGeneS can be applied to reference profiles from various sources like single-cell experiments or sorted cell populations. Ground truth cell proportions analyzed by flow cytometry confirmed the accuracy of AutoGeneS in identifying cell-type proportions. AutoGeneS is available for use via a standalone Python package (https://github.com/theislab/AutoGeneS).
Wissenschaftlicher Artikel
Scientific Article
Scheibner, K. ; Schirge, S. ; Burtscher, I. ; Büttner, M. ; Sterr, M. ; Yang, D. ; Böttcher, A. ; Ansarullah ; Irmler, M. ; Beckers, J. ; Cernilogar, F.M. ; Schotta, G. ; Theis, F.J. ; Lickert, H.
Nat. Cell Biol., DOI: 10.1038/s41556-021-00735-5 (2021)
In the version of this Article originally published, text referencing ATAC-seq data was incorrectly retained. References to ATAC-seq data, which are not included in this study, should be removed from the text in the Results sections ‘In vitro-generated definitive endoderm forms by partial EMT’ and ‘Foxa2 suppresses a complete EMT during endoderm formation’, as well as from the author contributions section. The Methods subsection ‘ChIP-seq and ATAC-seq data visualization’ should also be completely removed. The errors have been corrected.
Wortmann, S.B. ; Zietkiewicz, S. ; Guerrero-Castillo, S. ; Feichtinger, R.G. ; Wagner, M. ; Russell, J. ; Ellaway, C. ; Mróz, D. ; Wyszkowski, H. ; Weis, D. ; Hannibal, I. ; von Stülpnagel, C. ; Cabrera-Orefice, A. ; Lichter-Konecki, U. ; Gaesser, J. ; Windreich, R. ; Myers, K.C. ; Lorsbach, R. ; Dale, R.C. ; Gersting, S. ; Prada, C.E. ; Christodoulou, J. ; Wolf, N.I. ; Venselaar, H. ; Mayr, J.A. ; Wevers, R.A.
Genet. Med., DOI: 10.1038/s41436-021-01280-0 (2021)
Unfortunately the funding information was not given. Funding is as follows: This work was funded by the ERA PerMed project PerMiM (Austrian Science Fund FWF, I4704-B) to S.B.W. This study was supported by a “Sonata Bis 5” grant of the National Science Center Poland (2015/18/E/NZ1/00673) to S.Z. and D.M.
Braun, F. ; Hentschel, A. ; Sickmann, A. ; Marteau, T. ; Hertel, S. ; Förster, F. ; Prokisch, H. ; Wagner, M. ; Wortmann, S. ; Della Marina, A. ; Kölbel, H. ; Roos, A. ; Schara‐Schmidt, U.
Int. J. Mol. Sci. 22:7835 (2021)
Mutations in the SPATA5 gene are associated with epilepsy, hearing loss and mental retardation syndrome (EHLMRS). While SPATA5 is ubiquitously expressed and is attributed a role within mitochondrial morphogenesis during spermatogenesis, there is only limited knowledge about the associated muscular and molecular pathology. This study reports on a comprehensive workup of muscular pathology, including proteomic profiling and microscopic studies, performed on an 8‐year‐old girl with typical clinical presentation of EHLMRS, where exome analysis revealed two clinically relevant, compound‐heterozygous variants in SPATA5. Proteomic profiling of a quadriceps biopsy showed the dysregulation of 82 proteins, out of which 15 were localized in the mitochondrion, while 19 were associated with diseases presenting with phenotypical overlap to EHLMRS. Histological staining of our patient’s muscle biopsy hints towards mitochondrial pathology, while the identification of dysregulated proteins attested to the vulnerability of the cell beyond the mitochondria. Through our study we provide insights into the molecular etiology of EHLMRS and provide further evidence for a muscle pathology associated with SPATA5 deficiency, including a pathological histochemical pattern accompanied by dysregulated protein expression.
Wissenschaftlicher Artikel
Scientific Article
Durso-Cain, K. ; Kumberger, P. ; Schälte, Y. ; Fink, T. ; Dahari, H. ; Hasenauer, J. ; Uprichard, S.L. ; Graw, F.
Viruses 13:1308 (2021)
The hepatitis C virus (HCV) is capable of spreading within a host by two different transmission modes: cell-free and cell-to-cell. However, the contribution of each of these transmission mechanisms to HCV spread is unknown. To dissect the contribution of these different transmission modes to HCV spread, we measured HCV lifecycle kinetics and used an in vitro spread assay to monitor HCV spread kinetics after a low multiplicity of infection in the absence and presence of a neutralizing antibody that blocks cell-free spread. By analyzing these data with a spatially explicit mathematical model that describes viral spread on a single-cell level, we quantified the contribution of cell-free, and cell-to-cell spread to the overall infection dynamics and show that both transmission modes act synergistically to enhance the spread of infection. Thus, the simultaneous occurrence of both transmission modes represents an advantage for HCV that may contribute to viral persistence. Notably, the relative contribution of each viral transmission mode appeared to vary dependent on different experimental conditions and suggests that viral spread is optimized according to the environment. Together, our analyses provide insight into the spread dynamics of HCV and reveal how different transmission modes impact each other.
Wissenschaftlicher Artikel
Scientific Article
Loft, A. ; Alfaro, A.J. ; Schmidt, S.F. ; Pedersen, F.B. ; Terkelsen, M.K. ; Puglia, M. ; Chow, K.K. ; Feuchtinger, A. ; Troullinaki, M. ; Maida, A. ; Wolff, G. ; Sakurai, M. ; Berutti, R. ; Ekim Üstünel, B. ; Nawroth, P.P. ; Ravnskjaer, K. ; Diaz, M.B. ; Blagoev, B. ; Herzig, S.
Cell Metab. 33, 1685-1700.e9 (2021)
Liver fibrosis is a strong predictor of long-term mortality in individuals with metabolic-associated fatty liver disease; yet, the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely understood. Using cell-type-resolved genomics, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a network of fibrosis-activated transcription factors, as exemplified by the transcription factor Elf-3 (ELF3) and zinc finger protein GLIS2 (GLIS2). Indeed, ELF3- and GLIS2-controlled fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell gene programs. Thus, interconnected transcription factor networks not only promoted hepatocyte dysfunction but also directed the intra-hepatic crosstalk necessary for NASH and fibrosis progression, implying that molecular "hub-centered" targeting strategies are superior to existing mono-target approaches as currently used in NASH therapy.
Wissenschaftlicher Artikel
Scientific Article
Ditz, B. ; Boekhoudt, J.G. ; Aliee, H. ; Theis, F.J. ; Nawijn, M.C. ; Brandsma, C.A. ; Hiemstra, P.S. ; Timens, W. ; Tew, G.W. ; Grimbaldeston, M.A. ; Neighbors, M. ; Guryev, V. ; van den Berge, M. ; Faiz, A.
ERJ Open Res. 7:00104-2021 (2021)
More DEGs are detected by RNA-Seq than microarrays in COPD lung biopsies and are associated with immunological pathways. Performing bulk tissue cell-type deconvolution in microarray lung samples, using the SVR method, reflects RNA-Seq results. https://bit.ly/2N8sY3s.
Wissenschaftlicher Artikel
Scientific Article
Post, J. ; Schaffrath, A. ; Gering, I. ; Hartwig, S. ; Lehr, S. ; Shah, N.J. ; Langen, K.J. ; Willbold, D. ; Kutzsche, J. ; Willuweit, A.
Int. J. Mol. Sci. 22:7066 (2021)
Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and plays a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been implicated as driver of disease progression and is observed in ALS patients, as well as in the transgenic SOD1G93A mouse model. Here, we explore and validate the therapeutic potential of the d-enantiomeric peptide RD2RD2 upon oral administration in SOD1G93A mice. Transgenic mice were treated daily with RD2RD2 or placebo for 10 weeks and phenotype progression was followed with several behavioural tests. At the end of the study, plasma cytokine levels and glia cell markers in brain and spinal cord were analysed. Treatment resulted in a significantly increased performance in behavioural and motor coordination tests and a decelerated neurodegenerative phenotype in RD2RD2-treated SOD1G93A mice. Additionally, we observed retardation of the average disease onset. Treatment of SOD1G93A mice led to significant reduction in glial cell activation and a rescue of neurons. Analysis of plasma revealed normalisation of several cytokines in samples of RD2RD2-treated SOD1G93A mice towards the levels of non-transgenic mice. In conclusion, these findings qualify RD2RD2 to be considered for further development and testing towards a disease modifying ALS treatment.
Wissenschaftlicher Artikel
Scientific Article
Schiffer, C. ; Spitzer, H. ; Kiwitz, K. ; Unger, N. ; Wagstyl, K. ; Evans, A.C. ; Harmeling, S. ; Amunts, K. ; Dickscheid, T.
Neuroimage 240:118327 (2021)
Human brain atlases provide spatial reference systems for data characterizing brain organization at different levels, coming from different brains. Cytoarchitecture is a basic principle of the microstructural organization of the brain, as regional differences in the arrangement and composition of neuronal cells are indicators of changes in connectivity and function. Automated scanning procedures and observer-independent methods are prerequisites to reliably identify cytoarchitectonic areas, and to achieve reproducible models of brain segregation. Time becomes a key factor when moving from the analysis of single regions of interest towards high-throughput scanning of large series of whole-brain sections. Here we present a new workflow for mapping cytoarchitectonic areas in large series of cell-body stained histological sections of human postmortem brains. It is based on a Deep Convolutional Neural Network (CNN), which is trained on a pair of section images with annotations, with a large number of un-annotated sections in between. The model learns to create all missing annotations in between with high accuracy, and faster than our previous workflow based on observer-independent mapping. The new workflow does not require preceding 3D-reconstruction of sections, and is robust against histological artefacts. It processes large data sets with sizes in the order of multiple Terabytes efficiently. The workflow was integrated into a web interface, to allow access without expertise in deep learning and batch computing. Applying deep neural networks for cytoarchitectonic mapping opens new perspectives to enable high-resolution models of brain areas, introducing CNNs to identify borders of brain areas.
Wissenschaftlicher Artikel
Scientific Article
Schumann, T. ; König, J. ; von Loeffelholz, C. ; Vatner, D.F. ; Zhang, D. ; Perry, R.J. ; Bernier, M. ; Chami, J. ; Henke, C. ; Kurzbach, A. ; El-Agroudy, N.N. ; Willmes, D.M. ; Pesta, D. ; de Cabo, R. ; O Sullivan, J.F. ; Simon, E. ; Shulman, G.I. ; Hamilton, B.S. ; Birkenfeld, A.L.
Comm. Biol. 4:826 (2021)
Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes. The SLC16A13 gene encodes SLC16A13/MCT13, a member of the solute carrier 16 family of monocarboxylate transporters. Despite its potential importance to diabetes development, the physiological function of SLC16A13 is unknown. Here, we validate Slc16a13 as a lactate transporter expressed at the plasma membrane and report on the effect of Slc16a13 deletion in a mouse model. We show that Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice. We propose a mechanism for improved hepatic insulin sensitivity in the context of Slc16a13 deficiency in which reduced intrahepatocellular lactate availability drives increased AMPK activation and increased mitochondrial respiration, while reducing hepatic lipid content. Slc16a13 deficiency thereby attenuates hepatic diacylglycerol-PKCε mediated insulin resistance in obese mice. Together, these data suggest that SLC16A13 is a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease.
Wissenschaftlicher Artikel
Scientific Article
Witte, F. ; Ruiz-Orera, J. ; Mattioli, C.C. ; Blachut, S. ; Adami, E. ; Schulz, J.F. ; Schneider-Lunitz, V. ; Hummel, O. ; Patone, G. ; Mücke, M.B. ; Silhavý, J. ; Heinig, M. ; Bottolo, L. ; Sanchis, D. ; Vingron, M. ; Chekulaeva, M. ; Pravenec, M. ; Hubner, N. ; Van Heesch, S.
Genome Biol. 22:191 (2021)
BACKGROUND: Little is known about the impact of trans-acting genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate the influence of such distant genetic loci on the efficiency of mRNA translation and define their contribution to the development of complex disease phenotypes within a panel of rat recombinant inbred lines. RESULTS: We identify several tissue-specific master regulatory hotspots that each control the translation rates of multiple proteins. One of these loci is restricted to hypertrophic hearts, where it drives a translatome-wide and protein length-dependent change in translational efficiency, altering the stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus across multiple congenic lines points to a translation machinery defect, characterized by marked differences in polysome profiles and misregulation of the small nucleolar RNA SNORA48. Strikingly, from yeast to humans, we observe reproducible protein length-dependent shifts in translational efficiency as a conserved hallmark of translation machinery mutants, including those that cause ribosomopathies. Depending on the factor mutated, a pre-existing negative correlation between protein length and translation rates could either be enhanced or reduced, which we propose to result from mRNA-specific imbalances in canonical translation initiation and reinitiation rates. CONCLUSIONS: We show that distant genetic control of mRNA translation is abundant in mammalian tissues, exemplified by a single genomic locus that triggers a translation-driven molecular mechanism. Our work illustrates the complexity through which genetic variation can drive phenotypic variability between individuals and thereby contribute to complex disease.
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Scientific Article
Zech, M. ; Seibt, A. ; Zumbaum, B. ; Klee, D. ; Meitinger, T. ; Winkelmann, J. ; Mayatpepek, E. ; Wagner, M. ; Distelmaier, F.
Brain 144:e72 (2021)
Wissenschaftlicher Artikel
Scientific Article
Schumann, T. ; König, J. ; von Loeffelholz, C. ; Vatner, D.F. ; Zhang, D. ; Perry, R.J. ; Bernier, M. ; Chami, J. ; Henke, C. ; Kurzbach, A. ; El-Agroudy, N.N. ; Willmes, D.M. ; Pesta, D. ; de Cabo, R. ; O Sullivan, J.F. ; Simon, E. ; Shulman, G.I. ; Hamilton, B.S. ; Birkenfeld, A.L.
Comm. Biol. 4:890 (2021)
The original published version of the Article contained an error in the abstract whereby the words “loss of” were inadvertently omitted from the following sentence: “We show that loss of Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice.” The error has been corrected in the HTML and PDF versions of the Article.
Richter, M. ; Deligiannis, I.K. ; Yin, K. ; Danese, A. ; Lleshi, E. ; Coupland, P. ; Vallejos, C.A. ; Matchett, K.P. ; Henderson, N.C. ; Colomé-Tatché, M. ; Martinez Jimenez, C.P.
Nat. Commun. 12:4264 (2021)
Single-cell RNA-seq reveals the role of pathogenic cell populations in development and progression of chronic diseases. In order to expand our knowledge on cellular heterogeneity, we have developed a single-nucleus RNA-seq2 method tailored for the comprehensive analysis of the nuclear transcriptome from frozen tissues, allowing the dissection of all cell types present in the liver, regardless of cell size or cellular fragility. We use this approach to characterize the transcriptional profile of individual hepatocytes with different levels of ploidy, and have discovered that ploidy states are associated with different metabolic potential, and gene expression in tetraploid mononucleated hepatocytes is conditioned by their position within the hepatic lobule. Our work reveals a remarkable crosstalk between gene dosage and spatial distribution of hepatocytes.
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Scientific Article
Ihsan, A.Z. ; Dessì, D. ; Alam, M.J. ; Sack, H. ; Sandfeld, S.
CEUR Workshop Proc. 2887, accepted (2021)
The field of Materials Science is concerned with, e.g., properties and performance of materials. An important class of materials are crystalline materials that usually contain "dislocations"-A line-like defect type. Dislocation decisively determine many important materials properties. Over the past decades, significant effort was put into understanding dislocation behavior across different length scales both with experimental characterization techniques as well as with simulations. However, for describing such dislocation structures there is still a lack of a common standard to represent and to connect dislocation domain knowledge across different but related communities. An ontology offers a common foundation to enable knowledge representation and data interoperability, which are important components to establish a âdigital twin". This paper outlines the first steps towards the design of an ontology in the dislocation domain and shows a connection with the already existing ontologies in the materials science and engineering domain.
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Scientific Article
Tuia, D. ; Roscher, R. ; Wegner, J.D. ; Jacobs, N. ; Zhu, X. ; Camps-Valls, G.
9, 88-104 (2021)
In past years, we have witnessed the fields of geosciences and remote sensing and artificial intelligence (AI) become closer. Thanks to the massive availability of observational data, improved simulations, and algorithmic advances, these disciplines have found common objectives and challenges to help advance the modeling and understanding of the Earth system. Despite such great opportunities, we have also observed a worrisome tendency to remain in disciplinary comfort zones, applying recent advances from AI on well-resolved remote sensing problems. Here, we take a position on the research directions for which we think the interface between these fields will have the most significant impact and become potential game changers. In our declared agenda for AI in Earth sciences, we aim to inspire researchers, especially the younger generations, to tackle these challenges for a real advance of remote sensing and the geosciences.
Wissenschaftlicher Artikel
Scientific Article
Hong, D. ; He, W. ; Yokoya, N. ; Yao, J. ; Gao, L. ; Zhang, L. ; Chanussot, J. ; Zhu, X.
9, 52-87 (2021)
Hyperspectral (HS) imaging, also known as image spectrometry, is a landmark technique in geoscience and remote sensing (RS). In the past decade, enormous efforts have been made to process and analyze these HS products, mainly by seasoned experts. However, with an ever-growing volume of data, the bulk of costs in manpower and material resources poses new challenges for reducing the burden of manual labor and improving efficiency. For this reason, it is urgent that more intelligent and automatic approaches for various HS RS applications be developed. Machine learning (ML) tools with convex optimization have successfully undertaken the tasks of numerous artificial intelligence (AI)-related applications; however, their ability to handle complex practical problems remains limited, particularly for HS data, due to the effects of various spectral variabilities in the process of HS imaging and the complexity and redundancy of higher-dimensional HS signals. Compared to convex models, nonconvex modeling, which is capable of characterizing more complex real scenes and providing model interpretability technically and theoretically, has proven to be a feasible solution that reduces the gap between challenging HS vision tasks and currently advanced intelligent data processing models.
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Scientific Article
Klaus, V. ; Schriever, S.C. ; Monroy Kuhn, J.M. ; Peter, A. ; Irmler, M. ; Tokarz, J. ; Prehn, C. ; Kastenmüller, G. ; Beckers, J. ; Adamski, J. ; Königsrainer, A. ; Müller, T.D. ; Heni, M. ; Tschöp, M.H. ; Pfluger, P.T. ; Lutter, D.
Mol. Metab. 53, 101295 (2021)
Technological advances have brought a steady increase in the availability of various types of omics data, from genomics to metabolomics. Integrating these multi-omics data is a chance and challenge for systems biology, yet tools to fully tap their potential remain scarce. We here present a fully unsupervised and versatile correlation-based method, termed Correlation guided Network Integration (CoNI), to integrate multi-omics data into a hypergraph structure that allows for the identification of effective modulators of metabolism. Our approach yields single transcripts of potential relevance that map to specific, densely connected metabolic sub-graphs or pathways. By applying our method on transcriptomics and metabolomics data from murine livers under standard Chow or high-fat diet, we identified eleven genes with potential regulatory effects on hepatic metabolism. Five candidates, including the hepatokine INHBE, were validated in human liver biopsies to correlate with diabetes-related traits such as overweight, hepatic fat content, and insulin resistance (HOMA-IR). Our method's successful application to an independent omics dataset confirmed that the novel CoNI framework is a transferable, entirely data-driven, flexible, and versatile tool for multiple omics data integration and interpretation.
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Scientific Article
Ahookhosh, K. ; Saidi, M. ; Mohammadpourfard, M. ; Aminfar, H. ; Hamishehkar, H. ; Farnoud, A. ; Schmid, O.
Eur. J. Pharm. Sci. 164:105911 (2021)
Inhalation therapy plays an important role in management or treatment of respiratory diseases such asthma and chronic obstructive pulmonary diseases (COPDs). For decades, pressurized metered dose inhalers (pMDIs) have been the most popular and prescribed drug delivery devices for inhalation therapy. The main objectives of the present computational work are to study flow structure inside a pMDI, as well as transport and deposition of micron-sized particles in a model of human tracheobronchial airways and their dependence on inhalation air flow rate and characteristic pMDI parameters. The upper airway geometry, which includes the extrathoracic region, trachea, and bronchial airways up to the fourth generation in some branches, was constructed based on computed tomography (CT) images of an adult healthy female. Computational fluid dynamics (CFD) simulation was employed using the k-ω model with low-Reynolds number (LRN) corrections to accomplish the objectives. The deposition results of the present study were verified with the in vitro deposition data of our previous investigation on pulmonary drug delivery using a hollow replica of the same airway geometry as used for CFD modeling. It was found that the flow structure inside the pMDI and extrathoracic region strongly depends on inhalation flow rate and geometry of the inhaler. In addition, regional aerosol deposition patterns were investigated at four inhalation flow rates between 30 and 120 L/min and for 60 L/min yielding highest deposition fractions of 24.4% and 3.1% for the extrathoracic region (EX) and the trachea, respectively. It was also revealed that particle deposition was larger in the right branches of the bronchial airways (right lung) than the left branches (left lung) for all of the considered cases. Also, optimization of spray characteristics showed that the optimum values for initial spray velocity, spray cone angle and spray duration were 100 m/s, 10∘ and 0.1 sec, respectively. Moreover, spray cone angle, more than any other of the investigated pMDI parameters can change the deposition pattern of inhaled particles in the airway model. In conclusion, the present investigation provides a validated CFD model for particle deposition and new insights into the relevance of flow structure for deposition of pMDI-emitted pharmaceutical aerosols in the upper respiratory tract.
Wissenschaftlicher Artikel
Scientific Article
Portero, V. ; Nicol, T. ; Podliesna, S. ; Marchal, G.A. ; Baartscheer, A. ; Casini, S. ; Tadros, R. ; Treur, J.L. ; Tanck, M.W.T. ; Cox, I.J. ; Probert, F. ; Hough, T.A. ; Falcone, S. ; Beekman, L. ; Müller-Nurasyid, M. ; Kastenmüller, G. ; Gieger, C. ; Peters, A. ; Kääb, S. ; Sinner, M.F. ; Blease, A. ; Verkerk, A.O. ; Bezzina, C.R. ; Potter, P.K. ; Remme, C.A.
Cardiovasc. Res. 118:1742–1757 (2021)
AIM: Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. METHODS AND RESULTS: We employed a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs - leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to ECG indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs) and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. CONCLUSIONS: Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome and heart failure. TRANSLATIONAL PERSPECTIVES: Development of efficient anti-arrhythmic strategies is hampered by incomplete knowledge of disease mechanisms. Using an unbiased approach, we here identified for the first time a pro-arrhythmic effect of increased levels of branched chain amino acids (BCAAs). This is of particular relevance for conditions associated with BCAA dysregulation and increased arrhythmia risk, including heart failure, obesity and diabetes, as well as for athletes supplementing their diet with BCAAs. Such metabolic dysregulation is potentially modifiable through dietary interventions, paving the way for novel preventive strategies. Our findings furthermore identify mTOR inhibition as a potential anti-arrhythmic strategy in patients with metabolic syndrome.
Wissenschaftlicher Artikel
Scientific Article
Wortmann, S.B. ; Zietkiewicz, S. ; Guerrero-Castillo, S. ; Feichtinger, R.G. ; Wagner, M. ; Russell, J. ; Ellaway, C. ; Mróz, D. ; Wyszkowski, H. ; Weis, D. ; Hannibal, I. ; von Stülpnagel, C. ; Cabrera-Orefice, A. ; Lichter-Konecki, U. ; Gaesser, J. ; Windreich, R. ; Myers, K.C. ; Lorsbach, R. ; Dale, R.C. ; Gersting, S. ; Prada, C.E. ; Christodoulou, J. ; Wolf, N.I. ; Venselaar, H. ; Mayr, J.A. ; Wevers, R.A.
Genet. Med. 23, 1705-1714 (2021)
PURPOSE: To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive. METHODS: We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing. RESULTS: In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1. CONCLUSION: Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1.
Wissenschaftlicher Artikel
Scientific Article
Schranner, D. ; Schönfelder, M. ; Römisch-Margl, W. ; Scherr, J. ; Schlegel, J. ; Zelger, O. ; Riermeier, A. ; Kaps, S. ; Prehn, C. ; Adamski, J. ; Söhnlein, Q. ; Stocker, F. ; Kreuzpointner, F. ; Halle, M. ; Kastenmüller, G. ; Wackerhage, H.
Physiol. Rep. 9:e14885 (2021)
Human metabolism is highly variable. At one end of the spectrum, defects of enzymes, transporters, and metabolic regulation result in metabolic diseases such as diabetes mellitus or inborn errors of metabolism. At the other end of the spectrum, favorable genetics and years of training combine to result in physiologically extreme forms of metabolism in athletes. Here, we investigated how the highly glycolytic metabolism of sprinters, highly oxidative metabolism of endurance athletes, and highly anabolic metabolism of natural bodybuilders affect their serum metabolome at rest and after a bout of exercise to exhaustion. We used targeted mass spectrometry-based metabolomics to measure the serum concentrations of 151 metabolites and 43 metabolite ratios or sums in 15 competitive male athletes (6 endurance athletes, 5 sprinters, and 4 natural bodybuilders) and 4 untrained control subjects at fasted rest and 5 minutes after a maximum graded bicycle test to exhaustion. The analysis of all 194 metabolite concentrations, ratios and sums revealed that natural bodybuilders and endurance athletes had overall different metabolite profiles, whereas sprinters and untrained controls were more similar. Specifically, natural bodybuilders had 1.5 to 1.8-fold higher concentrations of specific phosphatidylcholines and lower levels of branched chain amino acids than all other subjects. Endurance athletes had 1.4-fold higher levels of a metabolite ratio showing the activity of carnitine-palmitoyl-transferase I and 1.4-fold lower levels of various alkyl-acyl-phosphatidylcholines. When we compared the effect of exercise between groups, endurance athletes showed 1.3-fold higher increases of hexose and of tetradecenoylcarnitine (C14:1). In summary, physiologically extreme metabolic capacities of endurance athletes and natural bodybuilders are associated with unique blood metabolite concentrations, ratios, and sums at rest and after exercise. Our results suggest that long-term specific training, along with genetics and other athlete-specific factors systematically change metabolite concentrations at rest and after exercise.
Wissenschaftlicher Artikel
Scientific Article
Ji, Y. ; Lotfollahi, M. ; Wolf, F.A. ; Theis, F.J.
Cell Syst. 12, 522-537 (2021)
Cell biology is fundamentally limited in its ability to collect complete data on cellular phenotypes and the wide range of responses to perturbation. Areas such as computer vision and speech recognition have addressed this problem of characterizing unseen or unlabeled conditions with the combined advances of big data, deep learning, and computing resources in the past 5 years. Similarly, recent advances in machine learning approaches enabled by single-cell data start to address prediction tasks in perturbation response modeling. We first define objectives in learning perturbation response in single-cell omics; survey existing approaches, resources, and datasets (https://github.com/theislab/sc-pert); and discuss how a perturbation atlas can enable deep learning models to construct an informative perturbation latent space. We then examine future avenues toward more powerful and explainable modeling using deep neural networks, which enable the integration of disparate information sources and an understanding of heterogeneous, complex, and unseen systems.
Review
Review
Invernizzi, F. ; Legati, A. ; Nasca, A. ; Lamantea, E. ; Garavaglia, B. ; Gusic, M. ; Kopajtich, R. ; Prokisch, H. ; Zeviani, M. ; Lamperti, C. ; Ghezzi, D.
Brain 144:e74 (2021)
Wissenschaftlicher Artikel
Scientific Article
Lesch, S. ; Blumenberg, V. ; Stoiber, S. ; Gottschlich, A. ; Ogonek, J. ; Cadilha, B.L. ; Dantes, Z. ; Rataj, F. ; Dorman, K. ; Lutz, J. ; Karches, C.H. ; Heise, C. ; Kurzay, M. ; Larimer, B.M. ; Grassmann, S. ; Rapp, M. ; Nottebrock, A. ; Krüger, S. ; Tokarew, N. ; Metzger, P. ; Hoerth, C. ; Benmebarek, M.R. ; Dhoqina, D. ; Grünmeier, R. ; Seifert, M. ; Oener, A. ; Umut, Ö. ; Joaquina, S. ; Vimeux, L. ; Tran, T. ; Hank, T. ; Baba, T. ; Huynh, D. ; Megens, R.T.A. ; Janssen, K.P. ; Jastroch, M. ; Lamp, D. ; Ruehland, S. ; Di Pilato, M. ; Pruessmann, J.N. ; Thomas, M. ; Marr, C. ; Ormanns, S. ; Reischer, A. ; Hristov, M. ; Tartour, E. ; Donnadieu, E. ; Rothenfußer, S. ; Duewell, P. ; König, L.M. ; Schnurr, M. ; Subklewe, M. ; Liss, A.S. ; Halama, N. ; Reichert, M. ; Mempel, T.R. ; Endres, S. ; Kobold, S.
Nat. Bio. Eng., DOI: 10.1038/s41551-021-00737-6 (2021)
The efficacy of adoptive cell therapy for solid tumours is hampered by the poor accumulation of the transferred T cells in tumour tissue. Here, we show that forced expression of C-X-C chemokine receptor type 6 (whose ligand is highly expressed by human and murine pancreatic cancer cells and tumour-infiltrating immune cells) in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer. In mice with subcutaneous pancreatic tumours treated with T cells with either a transgenic T-cell receptor or a murine chimeric antigen receptor targeting the tumour-associated antigen epithelial cell adhesion molecule, and in mice with orthotopic pancreatic tumours or patient-derived xenografts treated with T cells expressing a chimeric antigen receptor targeting mesothelin, the T cells exhibited enhanced intratumoral accumulation, exerted sustained anti-tumoral activity and prolonged animal survival only when co-expressing C-X-C chemokine receptor type 6. Arming tumour-specific T cells with tumour-specific chemokine receptors may represent a promising strategy for the realization of adoptive cell therapy for solid tumours.
Wissenschaftlicher Artikel
Scientific Article
Tremblay-Laganière, C. ; Maroofian, R. ; Nguyen, T.T.M. ; Karimiani, E.G. ; Kirmani, S. ; Akbar, F. ; Ibrahim, S. ; Afroze, B. ; Doosti, M. ; Ashrafzadeh, F. ; Babaei, M. ; Efthymiou, S. ; Christoforou, M. ; Sultan, T. ; Ladda, R.L. ; McLaughlin, H.M. ; Truty, R. ; Mahida, S. ; Cohen, J.S. ; Baranano, K. ; Ismail, F.Y. ; Patel, M.S. ; Lehman, A. ; Edmondson, A.C. ; Nagy, A. ; Walker, M.A. ; Mercimek-Andrews, S. ; Maki, Y. ; Sachdev, R. ; Macintosh, R. ; Palmer, E.E. ; Mancini, G.M.S. ; Barakat, T.S. ; Steinfeld, R. ; Rüsch, C.T. ; Stettner, G.M. ; Wagner, M. ; Wortmann, S.B. ; Kini, U. ; Brady, A.F. ; Stals, K.L. ; Ismayilova, N. ; Ellard, S. ; Bernardo, D. ; Nugent, K. ; McLean, S.D. ; Antonarakis, S.E. ; Houlden, H. ; Kinoshita, T. ; Campeau, P.M. ; Murakami, Y.
Genet. Med., DOI: 10.1038/s41436-021-01215-9 (2021)
Purpose: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. Methods: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. Results: Phenotypic analysis of reported individuals reveals shared PIGG deficiency–associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. Conclusion: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.
Wissenschaftlicher Artikel
Scientific Article
Rüttgers, A. ; Petrarolo, A.
Exp. Fluids 62:136 (2021)
Local anomaly detection was applied to image data of hybrid rocket combustion tests for a better understanding of the complex flow phenomena. Novel techniques such as hybrid rockets that allow for cost reductions of space transport vehicles are of high importance in space flight. However, the combustion process in hybrid rocket engines is still a matter of ongoing research and not fully understood yet. Since 2013, combustion tests with different paraffin-based fuels have been performed at the German Aerospace Center (DLR) and the whole process has been recorded with a high-speed video camera. This has led to a huge amount of images for each test that needs to be automatically analyzed. In order to catch specific flow phenomena appearing during the combustion, potential anomalies have been detected by local outlier factor (LOF), an algorithm for local outlier detection. The choice of this particular algorithm is justified by a comparison with other established anomaly detection algorithms. Furthermore, a detailed investigation of different distance measures and an investigation of the hyperparameter choice in the LOF algorithm have been performed. As a result, valuable insights into the main phenomena appearing during the combustion of liquefying hybrid rocket fuels are obtained. In particular, fuel droplets entrained into the oxidizer flow and burning over the flame are clearly identified as outliers with respect to the main combustion process. Graphic abstract: [Figure not available: see fulltext.]
Wissenschaftlicher Artikel
Scientific Article
Hong, D. ; Hu, J. ; Yao, J. ; Chanussot, J. ; Zhu, X.X.
178, 68-80 (2021)
As remote sensing (RS) data obtained from different sensors become available largely and openly, multimodal data processing and analysis techniques have been garnering increasing interest in the RS and geoscience community. However, due to the gap between different modalities in terms of imaging sensors, resolutions, and contents, embedding their complementary information into a consistent, compact, accurate, and discriminative representation, to a great extent, remains challenging. To this end, we propose a shared and specific feature learning (S2FL) model. S2FL is capable of decomposing multimodal RS data into modality-shared and modality-specific components, enabling the information blending of multi-modalities more effectively, particularly for heterogeneous data sources. Moreover, to better assess multimodal baselines and the newly-proposed S2FL model, three multimodal RS benchmark datasets, i.e., Houston2013 – hyperspectral and multispectral data, Berlin – hyperspectral and synthetic aperture radar (SAR) data, Augsburg – hyperspectral, SAR, and digital surface model (DSM) data, are released and used for land cover classification. Extensive experiments conducted on the three datasets demonstrate the superiority and advancement of our S2FL model in the task of land cover classification in comparison with previously-proposed state-of-the-art baselines. Furthermore, the baseline codes and datasets used in this paper will be made available freely at https://github.com/danfenghong/ISPRS_S2FL.
Wissenschaftlicher Artikel
Scientific Article
Glauche, I. ; Marr, C.
Curr. Opin. Syst. Biol. 28, 100355 (2021)
Billions of functionally distinct blood cells emerge from a pool of hematopoietic stem cells in our bodies every day. This progressive differentiation process is hierarchically structured and remarkably robust. We provide an introductory review to mathematical approaches addressing the functional aspects of how lineage choice is potentially implemented on a molecular level. Emerging from studies on the mutual repression of key transcription factors we illustrate how those simple concepts have been challenged in recent years and subsequently extended. Especially the analysis of omics data on the single cell level with computational tools provide descriptive insights on a yet unknown level, while their embedding into a consistent mechanistic and mathematical framework is still incomplete.
Review
Review
Winter, B. ; Kramer, J. ; Meinhardt, T. ; Berner, D. ; Alt, K. ; Wenzel, M. ; Winkelmann, J. ; Zech, M.
Mov. Disord. 36, 2203-2204 (2021)
Wissenschaftlicher Artikel
Scientific Article
Matias-Garcia, P.R. ; Ward-Caviness, C.K. ; Raffield, L.M. ; Gao, X. ; Zhang, Y. ; Wilson, R. ; Nano, J. ; Bostom, A. ; Colicino, E. ; Correa, A. ; Coull, B. ; Eaton, C. ; Hou, L. ; Just, A.C. ; Kunze, S. ; Lange, L. ; Lange, E.M. ; Lin, X. ; Liu, S. ; Nwanaji-Enwerem, J.C. ; Reiner, A. ; Shen, J. ; Schöttker, B. ; Vokonas, P. ; Zheng, Y. ; Young, B. ; Schwartz, J. ; Horvath, S. ; Lu, A. ; Whitsel, E.A. ; Koenig, W. ; Adamski, J. ; Winkelmann, J. ; Brenner, H. ; Baccarelli, A.A. ; Gieger, C. ; Peters, A. ; Franceschini, N. ; Waldenberger, M.
Clin. Epigenet. 13:121 (2021)
BACKGROUND: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. RESULTS: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β =  - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E-06). The "first-generation" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. CONCLUSION: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.
Wissenschaftlicher Artikel
Scientific Article
Schiffer, C. ; Amunts, K. ; Harmeling, S. ; Dickscheid, T.
In: (2021 IEEE 18th International Symposium on Biomedical Imaging (ISBI), 13-16 April 2021, Nice, France). 2021. 603-606
Cytoarchitectonic maps provide microstructural reference parcellations of the brain, describing its organization in terms of the spatial arrangement of neuronal cell bodies as measured from histological tissue sections. Recent work provided the first automatic segmentations of cytoarchitectonic areas in the visual system using Convolutional Neural Networks. We aim to extend this approach to become applicable to a wider range of brain areas, envisioning a solution for mapping the complete human brain. Inspired by recent success in image classification, we propose a contrastive learning objective for encoding microscopic image patches into robust microstructural features, which are efficient for cytoarchitectonic area classification. We show that a model pre-trained using this learning task outperforms a model trained from scratch, as well as a model pre-trained on a recently proposed auxiliary task. We perform cluster analysis in the feature space to show that the learned representations form anatomically meaningful groups.
Chen, J. ; Spracklen, C.N. ; Marenne, G. ; Varshney, A. ; Corbin, L.J. ; Luan, J. ; Willems, S.M. ; Wu, Y. ; Zhang, X. ; Horikoshi, M. ; Boutin, T.S. ; Mägi, R. ; Waage, J. ; Li-Gao, R. ; Chan, K.H.K. ; Yao, J. ; Anasanti, M.D. ; Chu, A.Y. ; Claringbould, A. ; Heikkinen, J. ; Hong, J. ; Hottenga, J.J. ; Huo, S. ; Kaakinen, M.A. ; Louie, T. ; Marz, W. ; Moreno-Macias, H. ; Ndungu, A. ; Nelson, S.C. ; Nolte, I.M. ; North, K.E. ; Raulerson, C.K. ; Ray, D.W. ; Rohde, R. ; Rybin, D. ; Schurmann, C. ; Sim, X. ; Southam, L. ; Stewart, I.D. ; Wang, C.A. ; Wang, Y. ; Wu, P. ; Zhang, W. ; Ahluwalia, T.S. ; Appel, E.V.R. ; Bielak, L.F. ; Brody, J.A. ; Burtt, N.P. ; Cabrera, C.P. ; Cade, B.E. ; Chai, J.F. ; Chai, X. ; Chang, L.C. ; Chen, C.H. ; Chen, B.H. ; Chitrala, K.N. ; Chiu, Y.F. ; de Haan, H.G. ; Delgado, G.E. ; Demirkan, A. ; Duan, Q. ; Engmann, J. ; Fatumo, S.A. ; Gayán, J. ; Giulianini, F. ; Gong, J.H. ; Gustafsson, S. ; Hai, Y. ; Hartwig, F.P. ; He, J. ; Heianza, Y. ; Huang, T. ; Huerta-Chagoya, A. ; Hwang, M.Y. ; Jensen, R.A. ; Kawaguchi, T. ; Kentistou, K.A. ; Kim, Y.J. ; Kleber, M.E. ; Kooner, I.K. ; Lai, S. ; Lange, L.A. ; Langefeld, C.D. ; Lauzon, M. ; Li, M. ; Ligthart, S. ; Liu, J. ; Loh, M. ; Long, J. ; Lyssenko, V. ; Mangino, M. ; Marzi, C. ; Montasser, M.E. ; Nag, A. ; Nakatochi, M. ; Noce, D. ; Noordam, R. ; Pistis, G. ; Preuss, M. ; Raffield, L.M. ; Rasmussen-Torvik, L.J. ; Rich, S.S. ; Robertson, N.R. ; Rueedi, R. ; Ryan, K. ; Sanna, S. ; Saxena, R. ; Schraut, K.E. ; Sennblad, B. ; Setoh, K. ; Smith, A.V. ; Sparsø, T. ; Strawbridge, R.J. ; Takeuchi, F. ; Tan, J. ; Trompet, S. ; van den Akker, E. ; van der Most, P.J. ; Verweij, N. ; Vogel, M. ; Wang, H. ; Wang, C. ; Wang, N. ; Warren, H.R. ; Wen, W. ; Wilsgaard, T. ; Wong, A. ; Wood, A.R. ; Xie, T.Y. ; Zafarmand, M.H. ; Zhao, J.H. ; Zhao, W. ; Amin, N. ; Arzumanyan, Z. ; Astrup, A. ; Bakker, S.J.L. ; Baldassarre, D. ; Beekman, M. ; Bergman, R.N. ; Bertoni, A.G. ; Blüher, M. ; Bonnycastle, L.L. ; Bornstein, S.R. ; Bowden, D.W. ; Cai, Q. ; Campbell, A. ; Campbell, H. ; Chang, Y.C. ; de Geus, E.J.C. ; Dehghan, A. ; Du, S. ; Eiriksdottir, G. ; Farmaki, A.E. ; Frånberg, M. ; Fuchsberger, C. ; Gao, Y. ; Gjesing, A.P. ; Goel, A. ; Han, S. ; Hartman, C.A. ; Herder, C. ; Hicks, A.A. ; Hsieh, C.H. ; Hsueh, W.A. ; Ichihara, S. ; Igase, M. ; Ikram, M.A. ; Johnson, W.C. ; Jørgensen, M.E. ; Joshi, P.K. ; Kalyani, R.R. ; Kandeel, F.R. ; Katsuya, T. ; Khor, C.C. ; Kiess, W. ; Kolcic, I. ; Kuulasmaa, T. ; Kuusisto, J. ; Läll, K. ; Lam, K. ; Lawlor, D.A. ; Lee, N.R. ; Lemaitre, R.N. ; Li, H. ; Lifelines Cohort Study ; Lin, S.Y. ; Lindstrom, J. ; Linneberg, A. ; Lorenzo, C. ; Matsubara, T. ; Matsuda, F. ; Mingrone, G. ; Mooijaart, S.P. ; Moon, S. ; Nabika, T. ; Nadkarni, G.N. ; Nadler, J.L. ; Nelis, M. ; Neville, M.J. ; Norris, J.M. ; Ohyagi, Y. ; Peters, A. ; Peyser, P.A. ; Polasek, O. ; Qi, Q. ; Raven, D. ; Reilly, D.F. ; Reiner, A. ; Rivideneira, F. ; Roll, K. ; Rudan, I. ; Sabanayagam, C. ; Sandow, K. ; Sattar, N. ; Schürmann, A. ; Shi, J. ; Stringham, H.M. ; Taylor, K.D. ; Teslovich, T.M. ; Thuesen, B. ; Timmers, P.R.H.J. ; Tremoli, E. ; Tsai, M.Y. ; Uitterlinden, A. ; van Dam, R.M. ; van Heemst, D. ; van Hylckama Vlieg, A. ; van Vliet-Ostaptchouk, J.V. ; Vangipurapu, J. ; Vestergaard, H. ; Wang, T. ; Willems van Dijk, K. ; Zemunik, T. ; Abecasis, G.R. ; Adair, L.S. ; Aguilar-Salinas, C.A. ; Alarcón-Riquelme, M.E. ; An, P. ; Aviles-Santa, L. ; Becker, D.M. ; Beilin, L.J. ; Bergmann, S. ; Bisgaard, H. ; Black, C.-J. ; Boehnke, M. ; Boerwinkle, E. ; Böhm, B.O. ; Bønnelykke, K. ; Boomsma, D.I. ; Bottinger, E.P. ; Buchanan, T.A. ; Canouil, M. ; Caulfield, M.J. ; Chasman, D.I. ; Chen, Y.I. ; Cheng, C.Y. ; Collins, F.S. ; Correa, A. ; Cucca, F. ; de Silva, H.J. ; Dedoussis, G. ; Elmståhl, S. ; Evans, M.K. ; Ferrannini, E. ; Ferrucci, L. ; Florez, J.C. ; Franks, P.W. ; Frayling, T.M. ; Froguel, P. ; Gigante, B. ; Goodarzi, M.O. ; Gordon-Larsen, P. ; Grallert, H. ; Grarup, N. ; Grimsgaard, S. ; Groop, L. ; Gudnason, V. ; Guo, X. ; Hamsten, A. ; Hansen, T. ; Hayward, C. ; Heckbert, S.R. ; Horta, B.L. ; Huang, W. ; Ingelsson, E. ; James, P.S. ; Jarvelin, M.R. ; Jonas, J.B. ; Jukema, J.W. ; Kaleebu, P. ; Kaplan, R. ; Kardia, S.L.R. ; Kato, N. ; Keinanen-Kiukaanniemi, S.M. ; Kim, B.J. ; Kivimaki, M. ; Koistinen, H.A. ; Kooner, J.S. ; Körner, A. ; Kovacs, P. ; Kuh, D. ; Kumari, M. ; Kutalik, Z. ; Laakso, M. ; Lakka, T.A. ; Launer, L.J. ; Leander, K. ; Lin, X. ; Lind, L. ; Lindgren, C. ; Liu, S. ; Loos, R.J.F. ; Magnusson, P.K.E. ; Mahajan, A. ; Metspalu, A. ; Mook-Kanamori, D.O. ; Mori, T.A. ; Munroe, P.B. ; Njølstad, I. ; O'Connell, J.R. ; Oldehinkel, A.J. ; Ong, K.K. ; Padmanabhan, S. ; Palmer, C.N.A. ; Palmer, N.D. ; Pedersen, O. ; Pennell, C.E. ; Porteous, D.J. ; Pramstaller, P.P. ; Province, M.A. ; Psaty, B.M. ; Qi, L. ; Raffel, L.J. ; Rauramaa, R. ; Redline, S. ; Ridker, P.M. ; Rosendaal, F.R. ; Saaristo, T.E. ; Sandhu, M. ; Saramies, J. ; Schneiderman, N. ; Schwarz, P.E. ; Scott, L.J. ; Selvin, E. ; Sever, P. ; Shu, X.O. ; Slagboom, P.E. ; Small, K.S. ; Smith, B.H. ; Snieder, H. ; Sofer, T. ; Sørensen, T.I.A. ; Spector, T.D. ; Stanton, A. ; Steves, C.J. ; Stumvoll, M. ; Sun, L. ; Tabara, Y. ; Tai, E.S. ; Timpson, N.J. ; Tönjes, A. ; Tuomilehto, J. ; Tusie, T. ; Uusitupa, M. ; van der Harst, P. ; van Duijn, C.M. ; Vitart, V. ; Vollenweider, P. ; Vrijkotte, T.G.M. ; Wagenknecht, L.E. ; Walker, M. ; Wang, Y.X. ; Wareham, N.J. ; Watanabe, R.M. ; Watkins, H. ; Wei, W.B. ; Wickremasinghe, A.R. ; Willemsen, G. ; Wilson, J.F. ; Wong, T.Y. ; Wu, J.Y. ; Xiang, A.H. ; Yanek, L.R. ; Yengo, L. ; Yokota, M. ; Zeggini, E. ; Zheng, W. ; Zonderman, A.B. ; Rotter, J.I. ; Gloyn, A.L. ; Dupuis, J. ; Meigs, J.B. ; Scott, R.A. ; Prokopenko, I. ; Leong, A. ; Liu, C.T. ; Parker, S.C.J. ; Mohlke, K.L. ; Langenberg, C. ; Wheeler, E. ; Morris, A.P. ; Barroso, I.
Nat. Genet. 53, 840-860 (2021)
Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
Wissenschaftlicher Artikel
Scientific Article
Abel, M. ; Pfister, R. ; Hussein, I. ; Alsalloum, F. ; Onyinzo, C. ; Kappl, S. ; Zech, M. ; Demmel, W. ; Staudt, M. ; Kudernatsch, M. ; Berweck, S.
Front. Neurol. 12:662910 (2021)
Objective: KMT2B-related dystonia is a progressive childhood-onset movement disorder, evolving from lower-limb focal dystonia into generalized dystonia. With increasing age, children frequently show prominent laryngeal or facial dystonia manifesting in dysarthria. Bilateral deep brain stimulation of the globus pallidus internus (GPi-DBS) is reported to be an efficient therapeutic option. Especially improvement of dystonia and regaining of independent mobility is commonly described, but detailed information about the impact of GPi-DBS on dysarthria and speech is scarce. Methods: We report the 16-months outcome after bilateral GPi-DBS in an 8-year-old child with KMT2B-related dystonia caused by a de-novo c.3043C>T (p.Arg1015*) non-sense variant with special emphasis on dysarthria and speech. We compare the outcome of our patient with 59 patients identified through a PubMed literature search. Results: A remarkable improvement of voice, articulation, respiration and prosodic characteristics was seen 16 months after GPi-DBS. The patients' speech intelligibility improved. His speech became much more comprehensible not only for his parents, but also for others. Furthermore, his vocabulary and the possibility to express his feelings and wants expanded considerably. Conclusion: A positive outcome of GPi-DBS on speech and dysarthria is rarely described in the literature. This might be due to disease progression, non-effectiveness of DBS or due to inadvertent spreading of the electrical current to the corticobulbar tract causing stimulation induced dysarthria. This highlights the importance of optimal lead placement, the possibility of horizontal steering of the electrical field by applying directional stimulation with segmented leads as well as the use of the lowest possible effective stimulation intensity.
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Scientific Article
Dworschak, G.C. ; Punetha, J. ; Kalanithy, J.C. ; Mingardo, E. ; Erdem, H.B. ; Akdemir, Z.C. ; Karaca, E. ; Mitani, T. ; Marafi, D. ; Fatih, J.M. ; Jhangiani, S.N. ; Hunter, J.V. ; Dakal, T.C. ; Dhabhai, B. ; Dabbagh, O. ; Alsaif, H.S. ; Alkuraya, F.S. ; Maroofian, R. ; Houlden, H. ; Efthymiou, S. ; Dominik, N. ; Salpietro,V. ; Sultan, T. ; Haider, S. ; Bibi, F. ; Thiele, H. ; Hoefele, J. ; Riedhammer, K.M. ; Wagner, M. ; Guella, I. ; Demos, M. ; Keren, B. ; Buratti, J. ; Charles, P. ; Nava, C. ; Heron, D. ; Heide, S. ; Valkanas, E. ; Waddell, L.B. ; Jones, K.J. ; Oates, E.C. ; Cooper, S.T. ; MacArthur, D. ; Syrbe, S. ; Ziegler, A. ; Platzer, K. ; Okur, V. ; Chung, W.K. ; O'Shea, S.A. ; Alcalay, R. ; Fahn, S. ; Mark, P.R. ; Guerrini, R. ; Vetro, A. ; Hudson, B. ; Schnur, R.E. ; Hoganson, G.E. ; Burton, J.E. ; McEntagart, M. ; Lindenberg, T. ; Yilmaz, Ö. ; Odermatt, B. ; Pehlivan, D. ; Posey, J.E. ; Lupski, J.R. ; Reutter, H.
Genet. Med. 23, 1715–1725 (2021)
PURPOSE: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development. METHODS: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b. RESULTS: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye. CONCLUSION: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
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Scientific Article
Bauer, A. ; Zierer, A. ; Gieger, C. ; Büyüközkan, M. ; Müller-Nurasyid, M. ; Grallert, H. ; Meisinger, C. ; Strauch, K. ; Prokisch, H. ; Roden, M. ; Peters, A. ; Krumsiek, J. ; Herder, C. ; Koenig, W. ; Thorand, B. ; Huth, C.
Genet. Epidemiol. 45, 633-650 (2021)
It is still unclear how genetic information, provided as single-nucleotide polymorphisms (SNPs), can be most effectively integrated into risk prediction models for coronary heart disease (CHD) to add significant predictive value beyond clinical risk models. For the present study, a population-based case-cohort was used as a trainingset (451 incident cases, 1488 noncases) and an independent cohort as testset (160 incident cases, 2749 noncases). The following strategies to quantify genetic information were compared: A weighted genetic risk score including Metabochip SNPs associated with CHD in the literature (GRSMetabo ); selection of the most predictive SNPs among these literature-confirmed variants using priority-Lasso (PLMetabo ); validation of two comprehensive polygenic risk scores: GRSGola based on Metabochip data, and GRSKhera (available in the testset only) based on cross-validated genome-wide genotyping data. We used Cox regression to assess associations with incident CHD. C-index, category-free net reclassification index (cfNRI) and relative integrated discrimination improvement (IDIrel ) were used to quantify the predictive performance of genetic information beyond Framingham risk score variables. In contrast to GRSMetabo and PLMetabo , GRSGola significantly improved the prediction (delta C-index [95% confidence interval]: 0.0087 [0.0044, 0.0130]; IDIrel : 0.0509 [0.0131, 0.0894]; cfNRI improved only in cases: 0.1761 [0.0253, 0.3219]). GRSKhera yielded slightly worse prediction results than GRSGola .
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Scientific Article
Boniolo, F ; Dorigatti, E. ; Ohnmacht, A. ; Saur, D. ; Schubert, B. ; Menden, M.
Expert Opin. Drug Discov. 16, 991-1007 (2021)
Introduction: Precision medicine is the concept of treating diseases based on environmental factors, lifestyles, and molecular profiles of patients. This approach has been found to increase success rates of clinical trials and accelerate drug approvals. However, current precision medicine applications in early drug discovery use only a handful of molecular biomarkers to make decisions, whilst clinics gear up to capture the full molecular landscape of patients in the near future. This deep multi-omics characterization demands new analysis strategies to identify appropriate treatment regimens, which we envision will be pioneered by artificial intelligence.Areas covered: In this review, the authors discuss the current state of drug discovery in precision medicine and present our vision of how artificial intelligence will impact biomarker discovery and drug design.Expert opinion: Precision medicine is expected to revolutionize modern medicine; however, its traditional form is focusing on a few biomarkers, thus not equipped to leverage the full power of molecular landscapes. For learning how the development of drugs can be tailored to the heterogeneity of patients across their molecular profiles, artificial intelligence algorithms are the next frontier in precision medicine and will enable a fully personalized approach in drug design, and thus ultimately impacting clinical practice.
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Scientific Article
Cadilha, B.L. ; Benmebarek, M.R. ; Dorman, K. ; Oner, A. ; Lorenzini, T. ; Obeck, H. ; Vänttinen, M. ; Pilato, M.D. ; Pruessmann, J.N. ; Stoiber, S. ; Huynh, D. ; Märkl, F. ; Seifert, M. ; Manske, K. ; Suarez-Gosalvez, J. ; Zeng, Y. ; Lesch, S. ; Karches, C.H. ; Heise, C. ; Gottschlich, A. ; Thomas, M. ; Marr, C. ; Zhang, J. ; Pandey, D. ; Feuchtinger, T. ; Subklewe, M. ; Mempel, T.R. ; Endres, S. ; Kobold, S.
Sci. Adv. 7:eabi5781 (2021)
CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.
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Scientific Article
Hecker, J.S. ; Hartmann, L. ; Riviere, J. ; Buck, M.C. ; van der Garde, M. ; Rothenberg-Thurley, M. ; Fischer, L. ; Winter, S. ; Ksienzyk, B. ; Ziemann, F. ; Solovey, M. ; Rauner, M. ; Tsourdi, E. ; Sockel, K. ; Schneider, M. ; Kubasch, A.S. ; Nolde, M. ; Hausmann, D. ; Paulus, A.C. ; Lützner, J. ; Roth, A. ; Bassermann, F. ; Spiekermann, K. ; Marr, C. ; Hofbauer, L.C. ; Platzbecker, U. ; Metzeler, K.H. ; Götze, K.S.
Blood 138, 1727-1732 (2021)
Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of 'healthy' hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variants with allele frequencies [VAF] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF 1-2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%) and ASXL1 (3.5%). CHIP significantly associated with lower hemoglobin, higher mean corpuscular volume, prior/present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AID; multivariate adjusted odds ratio, 6.6; 95% confidence interval [1.7, 30]; p=0.0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for management of patients with OA and AID or mild anemia, and question use of hip bone-derived cells as 'healthy' experimental controls.
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Scientific Article
Matias-Garcia, P.R. ; Wilson, R. ; Guo, Q. ; Zaghlool, S. ; Eales, J. ; Xu, X. ; Charchar, F.J. ; Dormer, J. ; Maalmi, H. ; Schlosser, P. ; Elhadad, M.A. ; Nano, J. ; Sharma, S. ; Peters, A. ; Fornoni, A. ; Mook-Kanamori, D. ; Winkelmann, J. ; Danesh, J. ; di Angelantonio, E. ; Ouwehand, W. ; Watkins, N. ; Roberts, D. ; Petrera, A. ; Graumann, J. ; Koenig, W. ; Hveem, K. ; Jonasson, C. ; Köttgen, A. ; Butterworth, A. ; Prunotto, M. ; Hauck, S.M. ; Herder, C. ; Suhre, K. ; Gieger, C. ; Tomaszewski, M. ; Teumer, A. ; Waldenberger, M.
J. Am. Soc. Nephrol. 32, 1747-1763 (2021)
BACKGROUND: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. METHODS: A cross-sectional study of 993 plasma proteins among 2,882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified trans-ethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR . RESULTS: Fifty-seven plasma proteins were associated with eGFR, including one novel protein. Twenty-three of these were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. CONCLUSIONS: In a discovery-replication setting, we identified 57 proteins trans-ethnically associated with eGFR. The revealed causal relationships are an important stepping-stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.
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Scientific Article
Pacini, G. ; Dunkel, I. ; Mages, N. ; Mutzel, V. ; Timmermann, B. ; Marsico, A. ; Schulz, E.G.
Nat. Commun. 12:3638 (2021)
To ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediates chromosome-wide gene silencing. Cell differentiation, Xist upregulation and gene silencing are thought to be coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cell RNA-sequencing. Specifically, we assess the onset of random XCI in differentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploiting the inter-cellular heterogeneity of XCI onset, we identify putative Xist regulators. Moreover, we show that transient Xist upregulation from both X chromosomes results in biallelic gene silencing right before transitioning to the monoallelic state, confirming a prediction of the stochastic model of XCI. Finally, we show that genetic variation modulates the XCI process at multiple levels, providing a potential explanation for the long-known X-controlling element (Xce) effect, which leads to preferential inactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of the different levels of regulation that govern the initiation of XCI. The experimental and computational strategies we have developed here will allow us to profile random XCI in more physiological contexts, including primary human cells in vivo.
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Scientific Article
Doppler, K. ; Antelmi, E. ; Kuzkina, A. ; Donadio, V. ; Incensi, A. ; Plazzi, G. ; Pizza, F. ; Marelli, S. ; Ferini-Strambi, L. ; Tinazzi, M. ; Mayer, G. ; Sittig, E. ; Booij, J. ; Sedghi, A. ; Oertel, W.H. ; Volkmann, J. ; Sommer, C. ; Janzen, A. ; Liguori, R.
Parkinsonism Relat. Disord. 86, 108-113 (2021)
Objective/methods: Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017. Results: Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients. Conclusions: Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.
Wissenschaftlicher Artikel
Scientific Article
Scheibner, K. ; Schirge, S. ; Burtscher, I. ; Büttner, M. ; Sterr, M. ; Yang, D. ; Böttcher, A. ; Ansarullah ; Irmler, M. ; Beckers, J. ; Cernilogar, F.M. ; Schotta, G. ; Theis, F.J. ; Lickert, H.
Nat. Cell Biol. 23, 692-703 (2021)
It is generally accepted that epiblast cells ingress into the primitive streak by epithelial-to-mesenchymal transition (EMT) to give rise to the mesoderm; however, it is less clear how the endoderm acquires an epithelial fate. Here, we used embryonic stem cell and mouse embryo knock‐in reporter systems to combine time-resolved lineage labelling with high-resolution single-cell transcriptomics. This allowed us to resolve the morphogenetic programs that segregate the mesoderm from the endoderm germ layer. Strikingly, while the mesoderm is formed by classical EMT, the endoderm is formed independent of the key EMT transcription factor Snail1 by mechanisms of epithelial cell plasticity. Importantly, forkhead box transcription factor A2 (Foxa2) acts as an epithelial gatekeeper and EMT suppressor to shield the endoderm from undergoing a mesenchymal transition. Altogether, these results not only establish the morphogenetic details of germ layer formation, but also have broader implications for stem cell differentiation and cancer metastasis.
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Scientific Article
Iturbide Martinez De Albeniz, A. ; Ruiz Tejada Segura, M.L. ; Noll, C. ; Schorpp, K.K. ; Rothenaigner, I. ; Ruiz-Morales, E.R. ; Lubatti, G. ; Agami, A. ; Hadian, K. ; Scialdone, A. ; Torres-Padilla, M.E.
Nat. Struct. Mol. Biol. 28, 521-532 (2021)
Totipotent cells hold enormous potential for regenerative medicine. Thus, the development of cellular models recapitulating totipotent-like features is of paramount importance. Cells resembling the totipotent cells of early embryos arise spontaneously in mouse embryonic stem (ES) cell cultures. Such ‘2-cell-like-cells’ (2CLCs) recapitulate 2-cell-stage features and display expanded cell potential. Here, we used 2CLCs to perform a small-molecule screen to identify new pathways regulating the 2-cell-stage program. We identified retinoids as robust inducers of 2CLCs and the retinoic acid (RA)-signaling pathway as a key component of the regulatory circuitry of totipotent cells in embryos. Using single-cell RNA-seq, we reveal the transcriptional dynamics of 2CLC reprogramming and show that ES cells undergo distinct cellular trajectories in response to RA. Importantly, endogenous RA activity in early embryos is essential for zygotic genome activation and developmental progression. Overall, our data shed light on the gene regulatory networks controlling cellular plasticity and the totipotency program.
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Warnat-Herresthal, S. ; Schultze, H. ; Shastry, K.L. ; Manamohan, S. ; Mukherjee, S. ; Garg, V. ; Sarveswara, R. ; Händler, K. ; Pickkers, P. ; Aziz, N.A. ; Ktena, S. ; Tran, F. ; Bitzer, M. ; Ossowski, S. ; Casadei, N. ; Herr, C. ; Petersheim, D. ; Behrends, U. ; Kern, F. ; Fehlmann, T. ; Schommers, P. ; Lehmann, C. ; Augustin, M. ; Rybniker, J. ; Altmüller, J. ; Mishra, N. ; Bernardes, J.P. ; Krämer, B.F. ; Bonaguro, L. ; Schulte-Schrepping, J. ; De Domenico, E. ; Siever, C. ; Kraut, M. ; Desai, M. ; Monnet, B. ; Saridaki, M. ; Siegel, C.M. ; Drews, A. ; Nuesch-Germano, M. ; Theis, H. ; Heyckendorf, J. ; Schreiber, S. ; Kim-Hellmuth, S. ; Nattermann, J. ; Skowasch, D. ; Kurth, I. ; Keller, A. ; Bals, R. ; Nürnberg, P. ; Rieß, O. ; Rosenstiel, P. ; Netea, M.G. ; Theis, F.J. ; Backes, M. ; Aschenbrenner, A.C. ; Ulas, T. ; Deutsche COVID-19 Omics Initiative (DeCOI) (De La Rosa Velázquez, I.A.) ; Breteler, M.M.B. ; Giamarellos-Bourboulis, E.J. ; Kox, M. ; Beck, M. ; Cheran, S. ; Woodacre, M.S. ; Lim Goh, E. ; Schultze, J.L.
Nature (2021)
Fast and reliable detection of patients with severe and heterogeneous illnesses is a major goal of precision medicine . Patients with leukaemia can be identified using machine learning on the basis of their blood transcriptomes . However, there is an increasing divide between what is technically possible and what is allowed, because of privacy legislation . Here, to facilitate the integration of any medical data from any data owner worldwide without violating privacy laws, we introduce Swarm Learning—a decentralized machine-learning approach that unites edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator, thereby going beyond federated learning. To illustrate the feasibility of using Swarm Learning to develop disease classifiers using distributed data, we chose four use cases of heterogeneous diseases (COVID-19, tuberculosis, leukaemia and lung pathologies). With more than 16,400 blood transcriptomes derived from 127 clinical studies with non-uniform distributions of cases and controls and substantial study biases, as well as more than 95,000 chest X-ray images, we show that Swarm Learning classifiers outperform those developed at individual sites. In addition, Swarm Learning completely fulfils local confidentiality regulations by design. We believe that this approach will notably accelerate the introduction of precision medicine. 1,2 3 4,5
Wissenschaftlicher Artikel
Scientific Article
Usmani, M.A. ; Ahmed, Z.M. ; Pamela, M. ; Pienkowski, V.M. ; Rasmussen, K.J. ; Hernan, R. ; Rasheed, F. ; Hussain, M. ; Shahzad, M. ; Lanpher, B.C. ; Niu, Z. ; Lim, F.Y. ; Pippucci, T. ; Ploski, R. ; Kraus, V. ; Matuszewska, K. ; Palombo, F. ; Kianmahd, J. ; Martinez-Agosto, J.A. ; Lee, H. ; Colao, E. ; Motazacker, M.M. ; Brigatti, K.W. ; Puffenberger, E.G. ; Riazuddin, S.A. ; Gonzaga-Jauregui, C. ; Chung, W.K. ; Wagner, M. ; Schultz, M.J. ; Seri, M. ; Kievit, A.J.A. ; Perrotti, N. ; Wassink-Ruiter, J.S.K. ; van Bokhoven, H. ; Riazuddin, S.
Am. J. Hum. Genet. 108, 1330-1341 (2021)
Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.
Review
Review
Brand, I. ; Gilberg, L. ; Bruger, J. ; Garí, M. ; Wieser, A. ; Eser, T.M. ; Frese, J. ; Ahmed, M.I.M. ; Rubio-Acero, R. ; Guggenbüehl Noller, J.M. ; Castelletti, N. ; Diekmannshemke, J. ; Thiesbrummel, S. ; Huynh, D. ; Winter, S. ; Kroidl, I. ; Fuchs, C. ; Hoelscher, M. ; Roider, J. ; Kobold, S. ; Pritsch, M. ; Geldmacher, C.
Front. Immunol. 12:688436 (2021)
Background: Adaptive immune responses to structural proteins of the virion play a crucial role in protection against coronavirus disease 2019 (COVID-19). We therefore studied T cell responses against multiple SARS-CoV-2 structural proteins in a large cohort using a simple, fast, and high-throughput approach. Methods: An automated interferon gamma release assay (IGRA) for the Nucleocapsid (NC)-, Membrane (M)-, Spike-C-terminus (SCT)-, and N-terminus-protein (SNT)-specific T cell responses was performed using fresh whole blood from study subjects with convalescent, confirmed COVID-19 (n = 177, more than 200 days post infection), exposed household members (n = 145), and unexposed controls (n = 85). SARS-CoV-2-specific antibodies were assessed using Elecsys® Anti-SARS-CoV-2 (Ro-N-Ig) and Anti-SARS-CoV-2-ELISA (IgG) (EI-S1-IgG). Results: 156 of 177 (88%) previously PCR confirmed cases were still positive by Ro-N-Ig more than 200 days after infection. In T cells, most frequently the M-protein was targeted by 88% seropositive, PCR confirmed cases, followed by SCT (85%), NC (82%), and SNT (73%), whereas each of these antigens was recognized by less than 14% of non-exposed control subjects. Broad targeting of these structural virion proteins was characteristic of convalescent SARS-CoV-2 infection; 68% of all seropositive individuals targeted all four tested antigens. Indeed, anti-NC antibody titer correlated loosely, but significantly with the magnitude and breadth of the SARS-CoV-2-specific T cell response. Age, sex, and body mass index were comparable between the different groups. Conclusion: SARS-CoV-2 seropositivity correlates with broad T cell reactivity of the structural virus proteins at 200 days after infection and beyond. The SARS-CoV-2-IGRA can facilitate large scale determination of SARS-CoV-2-specific T cell responses with high accuracy against multiple targets.
Wissenschaftlicher Artikel
Scientific Article
Zacharias, H.U. ; Hertel, J. ; Johar, H. ; Pietzner, M. ; Lukaschek, K. ; Atasoy, S. ; Kunze, S. ; Völzke, H. ; Nauck, M. ; Friedrich, N. ; Kastenmüller, G. ; Grabe, H.J. ; Gieger, C. ; Krumsiek, J. ; Ladwig, K.-H.
Mol. Psychiatry 26, 7372–7383 (2021)
Depression constitutes a leading cause of disability worldwide. Despite extensive research on its interaction with psychobiological factors, associated pathways are far from being elucidated. Metabolomics, assessing the final products of complex biochemical reactions, has emerged as a valuable tool for exploring molecular pathways. We conducted a metabolome-wide association analysis to investigate the link between the serum metabolome and depressed mood (DM) in 1411 participants of the KORA (Cooperative Health Research in the Augsburg Region) F4 study (discovery cohort). Serum metabolomics data comprised 353 unique metabolites measured by Metabolon. We identified 72 (5.1%) KORA participants with DM. Linear regression tests were conducted modeling each metabolite value by DM status, adjusted for age, sex, body-mass index, antihypertensive, cardiovascular, antidiabetic, and thyroid gland hormone drugs, corticoids and antidepressants. Sensitivity analyses were performed in subcohorts stratified for sex, suicidal ideation, and use of antidepressants. We replicated our results in an independent sample of 968 participants of the SHIP-Trend (Study of Health in Pomerania) study including 52 (5.4%) individuals with DM (replication cohort). We found significantly lower laurylcarnitine levels in KORA F4 participants with DM after multiple testing correction according to Benjamini/Hochberg. This finding was replicated in the independent SHIP-Trend study. Laurylcarnitine remained significantly associated (p value < 0.05) with depression in samples stratified for sex, suicidal ideation, and antidepressant medication. Decreased blood laurylcarnitine levels in depressed individuals may point to impaired fatty acid oxidation and/or mitochondrial function in depressive disorders, possibly representing a novel therapeutic target.
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Scientific Article
Li, K. ; Pfaff, F. ; Hanebeck, U.D.
Sensors 21:2991 (2021)
In this work, we present a novel scheme for nonlinear hyperspherical estimation using the von Mises-Fisher distribution. Deterministic sample sets with an isotropic layout are exploited for the efficient and informative representation of the underlying distribution in a geometrically adaptive manner. The proposed deterministic sampling approach allows manually configurable sample sizes, considerably enhancing the filtering performance under strong nonlinearity. Furthermore, the progressive paradigm is applied to the fusing of measurements of non-identity models in conjunction with the isotropic sample sets. We evaluate the proposed filtering scheme in a nonlinear spherical tracking scenario based on simulations. Numerical results show the evidently superior performance of the proposed scheme over state-of-the-art von Mises-Fisher filters and the particle filter.
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Scientific Article
Hua, Y. ; Mou, L. ; Lin, J. ; Heidler, K. ; Zhu, X.X.
177, 89-102 (2021)
Aerial scene recognition is a fundamental visual task and has attracted an increasing research interest in the last few years. Most of current researches mainly deploy efforts to categorize an aerial image into one scene-level label, while in real-world scenarios, there often exist multiple scenes in a single image. Therefore, in this paper, we propose to take a step forward to a more practical and challenging task, namely multi-scene recognition in single images. Moreover, we note that manually yielding annotations for such a task is extraordinarily time- and labor-consuming. To address this, we propose a prototype-based memory network to recognize multiple scenes in a single image by leveraging massive well-annotated single-scene images. The proposed network consists of three key components: 1) a prototype learning module, 2) a prototype-inhabiting external memory, and 3) a multi-head attention-based memory retrieval module. To be more specific, we first learn the prototype representation of each aerial scene from single-scene aerial image datasets and store it in an external memory. Afterwards, a multi-head attention-based memory retrieval module is devised to retrieve scene prototypes relevant to query multi-scene images for final predictions. Notably, only a limited number of annotated multi-scene images are needed in the training phase. To facilitate the progress of aerial scene recognition, we produce a new multi-scene aerial image (MAI) dataset. Experimental results on variant dataset configurations demonstrate the effectiveness of our network. Our dataset and codes are publicly available.
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Scientific Article
Xu, M. ; Kopajtich, R. ; Elstner, M. ; Wang, Z. ; Liu, Z. ; Wang, J. ; Prokisch, H. ; Fang, F.
Front. Genet. 12:638749 (2021)
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disease. Most cases of MELAS are caused by the m.3243A > G variant in the MT-TL1 gene encoding tRNALeu((UUR)). However, the genetic cause in 10% of patients with MELAS is unknown. We investigated the pathogenicity of the novel mtDNA variant m.9396G > A/MT-CO3 (p.E64K), which affects an extremely conserved amino acid in the CO3 subunit of mitochondrial respiratory chain (MRC) complex IV (CIV) in a patient with MELAS. Biochemical assays of a muscle biopsy confirmed remarkable CIV deficiency, and pathological examination showed ragged red fibers and generalized COX non-reactive muscle fibers. Transfer of the mutant mtDNA into cybrids impaired CIV assembly, followed by remarkable mitochondrial dysfunction and ROS production. Our findings highlight the pathogenicity of a novel m.9396G > A variant and extend the spectrum of pathogenic mtDNA variants.
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Scientific Article
Stadler, M. ; Doebler, P. ; Mertins, B. ; Delucchi Danhier, R.
Behav. Res. Methods 53, 2650-2667 (2021)
This paper presents a model that allows group comparisons of gaze behavior while watching dynamic video stimuli. The model is based on the approach of Coutrot and Guyader (2017) and allows linear combinations of feature maps to form a master saliency map. The feature maps in the model are, for example, the dynamically salient contents of a video stimulus or predetermined areas of interest. The model takes into account temporal aspects of the stimuli, which is a crucial difference to other common models. The multi-group extension of the model introduced here allows to obtain relative importance plots, which visualize the effect of a specific feature of a stimulus on the attention and visual behavior for two or more experimental groups. These plots are interpretable summaries of data with high spatial and temporal resolution. This approach differs from many common methods for comparing gaze behavior between natural groups, which usually only include single-dimensional features such as the duration of fixation on a particular part of the stimulus. The method is illustrated by contrasting a sample of a group of persons with particularly high cognitive abilities (high achievement on IQ tests) with a control group on a psycholinguistic task on the conceptualization of motion events. In the example, we find no substantive differences in relative importance, but more exploratory gaze behavior in the highly gifted group. The code, videos, and eye-tracking data we used for this study are available online.
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Scientific Article
Amprosi, M. ; Zech, M. ; Lichtner, P. ; Eckstein, G.N. ; Unterberger, I. ; Eigentler, A. ; Indelicato, E. ; Puttinger, G. ; Nachbauer, W. ; Boesch, S.
Parkinsonism Relat. Disord. 87, 119-121 (2021)
Dentatorubral-pallidoluysian atrophy (DRPLA) is a CAG trinucleotide repeat expansion disorder with an autosomal-dominant mode of inheritance and very low prevalence in Europe. We herein report the clinical characteristics of the first Austrian DRPLA family. Genetic analysis revealed the presence of a common European haplotype, suggesting a founder mutation in Europe.
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Scientific Article
von Streitberg, A. ; Jäkel, S. ; Eugenin von Bernhardi, J. ; Straube, C. ; Buggenthin, F. ; Marr, C. ; Dimou, L.
Front. Cell Dev. Biol. 9:662056 (2021)
In the adult brain, NG2-glia represent a cell population that responds to injury. To further investigate if, how and why NG2-glia are recruited to the injury site, we analyzed in detail the long-term reaction of NG2-glia after a lesion by time-lapse two-photon in vivo microscopy. Live imaging over several weeks of GFP-labeled NG2-glia in the stab wounded cerebral cortex revealed their fast and heterogeneous reaction, including proliferation, migration, polarization, hypertrophy, or a mixed response, while a small subset of cells remained unresponsive. At the peak of the reaction, 2-4 days after the injury, NG2-glia accumulated around and within the lesion core, overcoming the homeostatic control of their density, which normalized back to physiological conditions only 4 weeks after the insult. Genetic ablation of proliferating NG2-glia demonstrated that this accumulation contributed beneficially to wound closure. Thus, NG2-glia show a fast response to traumatic brain injury (TBI) and participate in tissue repair.
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Scientific Article
Cathiard, L. ; Fraulob, V. ; Lam, D.D. ; Torres, M. ; Winkelmann, J. ; Krezel, W.
J. Sleep Res. 30:e13311 (2021)
Restless legs syndrome (RLS) is a common neurological disorder in which sensorimotor symptoms lead to sleep disturbances with substantial impact on life quality. RLS is caused by a combination of genetic and environmental factors, and Meis homeobox 1 (MEIS1) was identified as the main genetic risk factor. The efficacy of dopaminergic agonists, including dopamine D2 receptor (DRD2) agonists, for treating RLS led to the hypothesis of dopaminergic impairment. However, it remains unclear whether it is directly involved in the disease aetiology and what the role of MEIS1 is considering its developmental and postnatal expression in the striatum, a critical structure in motor control. We addressed the role of MEIS1 in striatal dopaminergic signalling in Meis1+/- mice, a valid animal model of RLS, and in Meis1Drd2-/- mice carrying a somatic null mutation of Meis1 in Drd2+ neurones. Motor behaviours, pharmacological exploration of DRD2 signalling, and quantitative analyses of DRD2+ and DRD1+ expressing neurones were investigated. Although Meis1+/- mice displayed an RLS-like phenotype, including motor hyperactivity at the beginning of the rest phase, no reduction of dopaminoceptive neurones was observed in the striatum. Moreover, the null mutation of Meis1 in DRD2+ cells did not lead to RLS-like symptoms and dysfunction of the DRD2 pathway. These data indicate that MEIS1 does not modulate DRD2-dependent signalling in a cell-autonomous manner. Thus, the efficiency of D2 -like agonists may reflect the involvement of other dopaminergic receptors or normalisation of motor circuit abnormalities downstream from defects caused by MEIS1 dysfunction.
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Scientific Article
Ostrozovičová, M. ; Jech, R. ; Steel, D. ; Pavelekova, P. ; Han, V. ; Gdovinova, Z. ; Lichtner, P. ; Kurian, M.A. ; Wiethoff, S. ; Houlden, H. ; Havránková, P. ; Winkelmann, J. ; Zech, M. ; Škorvánek, M.
Mov. Disord. 36, 1984-1985 (2021)
Wissenschaftlicher Artikel
Scientific Article
Esteve-Codina, A. ; Hofer, T.P. ; Burggraf, D. ; Heiss-Neumann, M.S. ; Gesierich, W. ; Boland, A. ; Olaso, R. ; Bihoreau, M.T. ; Deleuze, J.F. ; Möller, W. ; Schmid, O. ; Soler Artigas, M. ; Renner, K. ; Hohlfeld, J.M. ; Welte, T. ; Fuehner, T. ; Jerrentrup, L. ; Koczulla, A.R. ; Greulich, T. ; Prasse, A. ; Müller-Quernheim, J. ; Gupta, S. ; Brightling, C. ; Subramanian, D.R. ; Parr, D.G. ; Kolsum, U. ; Gupta, V. ; Barta, I. ; Döme, B. ; Strausz, J. ; Stendardo, M. ; Piattella, M. ; Boschetto, P. ; Korzybski, D. ; Gorecka, D. ; Nowinski, A. ; Dabad, M. ; Fernández-Callejo, M. ; Endesfelder, D. ; zu Castell, W. ; Hiemstra, P.S. ; Venge, P. ; Nößner, E. ; Griebel, T. ; Heath, S. ; Singh, D. ; Gut, I. ; Ziegler-Heitbrock, L.
Sci. Rep. 11:12848 (2021)
Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term "response to stress" was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females.
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Scientific Article
Schubert, B. ; Dorigatti, E. ; Felix, D.
Vortrag: ISMB/ECCB, 25-30 July 2021, virtual. (2021)
Wang, S.-H. ; Zissler, U.M. ; Büttner, M. ; Heine, S. ; Heldner, A. ; Kotz, S. ; Pechtold, L. ; Kau, J. ; Plaschke, M. ; Ullmann, J.T. ; Guerth, F. ; Oelsner, M. ; Alessandrini, F. ; Blank, S. ; Chaker, A. ; Schmidt-Weber, C.B. ; Jakwerth, C.A.
Allergy 76, 2827-2839 (2021)
BACKGROUND: Studies show that proallergic TH 2-cells decrease after successful allergen-specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergenexposure during AIT in mice and two independent patient cohorts. METHODS: OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion inlocal and systemic TH 2-cells was analyzed.In patients, the expression of exhaustion-associated surface markers on TH 2-cells was evaluated using flow cytometry in a cross-sectional grass pollen allergy cohort with and without AIT.The treatment effect was further studied in PBMC collected from a prospective long-termAIT cohort. RESULTS: The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on TH 2-cells upon OVA aerosol exposure in OVA-allergic compared to non-allergic mice. CTLA-4 and PD-1decreased after AIT, in particular on the surface oflocal lung TH 2-cells. Similarly, CTLA-4 and PD-1 expression were enhanced on TH 2-cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discoveredalate-differentiated TH 2 population expressing both markers that decreased during up-dosing but persisted long-term during the maintenance phase. CONCLUSIONS: This study shows that allergen exposure promotes CTLA-4 and PD-1 expression onTH 2-cells, andthat the dynamic change in frequencies of exhausted TH 2-cells exhibits a differential pattern during the up-dosing versus the maintenance phases of AIT.
Wissenschaftlicher Artikel
Scientific Article
Schulze-Makuch, D. ; Lipus, D. ; Arens, F.L. ; Baqué, M. ; Bornemann, T.L.V. ; Devere, J.P. ; Flury, M. ; Frösler, J. ; Heinz, J. ; Hwang, Y. ; Kounaves, S.P. ; Mangelsdorf, K. ; Meckenstock, R.U. ; Pannekens, M. ; Probst, A.J. ; Sáenz, J.S. ; Schirmack, J. ; Schloter, M. ; Schmitt-Kopplin, P. ; Schneider, B. ; Uhl, J. ; Vestergaard, G. ; Valenzuela, B. ; Zamorano, P. ; Wagner, D.
Microorganisms 9:1038 (2021)
The existence of microbial activity hotspots in temperate regions of Earth is driven by soil heterogeneities, especially the temporal and spatial availability of nutrients. Here we investigate whether microbial activity hotspots also exist in lithic microhabitats in one of the most arid regions of the world, the Atacama Desert in Chile. While previous studies evaluated the total DNA fraction to elucidate the microbial communities, we here for the first time use a DNA separation approach on lithic microhabitats, together with metagenomics and other analysis methods (i.e., ATP, PLFA, and metabolite analysis) to specifically gain insights on the living and potentially active microbial community. Our results show that hypolith colonized rocks are microbial hotspots in the desert environment. In contrast, our data do not support such a conclusion for gypsum crust and salt rock environments, because only limited microbial activity could be observed. The hypolith community is dominated by phototrophs, mostly Cyanobacteria and Chloroflexi, at both study sites. The gypsum crusts are dominated by methylotrophs and heterotrophic phototrophs, mostly Chloroflexi, and the salt rocks (halite nodules) by phototrophic and halotolerant endoliths, mostly Cyanobacteria and Archaea. The major environmental constraints in the organic-poor arid and hyperarid Atacama Desert are water availability and UV irradiation, allowing phototrophs and other extremophiles to play a key role in desert ecology.
Wissenschaftlicher Artikel
Scientific Article
Necpál, J. ; Zech, M. ; Winkelmann, J. ; Jech, R.
Neurol. Sci. 42, 3883-3884 (2021)
Wissenschaftlicher Artikel
Scientific Article
Giacopelli, B. ; Wang, M. ; Cleary, A. ; Wu, Y.Z. ; Schultz, A.R. ; Schmutz, M. ; Blachly, J.S. ; Eisfeld, A.K. ; Mundy-Bosse, B. ; Vosberg, S. ; Greif, P.A. ; Claus, R. ; Bullinger, L. ; Garzon, R. ; Coombes, K.R. ; Bloomfield, C.D. ; Druker, B.J. ; Tyner, J.W. ; Byrd, J.C. ; Oakes, C.C.
Genome Res. 31, 747-761 (2021)
Acute myeloid leukemia (AML) is a molecularly complex disease characterized by heterogeneous tumor genetic profiles and involving numerous pathogenic mechanisms and pathways. Integration of molecular data types across multiple patient cohorts may advance current genetic approaches for improved subclassification and understanding of the biology of the disease. Here, we analyzed genome-wide DNA methylation in 649 AML patients using Illumina arrays and identified a configuration of 13 subtypes (termed "epitypes") using unbiased clustering. Integration of genetic data revealed that most epitypes were associated with a certain recurrent mutation (or combination) in a majority of patients, yet other epitypes were largely independent. Epitypes showed developmental blockage at discrete stages of myeloid differentiation, revealing epitypes that retain arrested hematopoietic stem-cell-like phenotypes. Detailed analyses of DNA methylation patterns identified unique patterns of aberrant hyper- and hypomethylation among epitypes, with variable involvement of transcription factors influencing promoter, enhancer, and repressed regions. Patients in epitypes with stem-cell-like methylation features showed inferior overall survival along with up-regulated stem cell gene expression signatures. We further identified a DNA methylation signature involving STAT motifs associated with FLT3-ITD mutations. Finally, DNA methylation signatures were stable at relapse for the large majority of patients, and rare epitype switching accompanied loss of the dominant epitype mutations and reversion to stem-cell-like methylation patterns. These results show that DNA methylation-based classification integrates important molecular features of AML to reveal the diverse pathogenic and biological aspects of the disease.
Wissenschaftlicher Artikel
Scientific Article
Stavsky, A. ; Stoler, O. ; Kostic, M. ; Katoshevsky, T. ; Assali, E.A. ; Savic, I. ; Amitai, Y. ; Prokisch, H. ; Leiz, S. ; Daumer-Haas, C. ; Fleidervish, I.A. ; Perocchi, F. ; Gitler, D. ; Sekler, I.
Comm. Biol. 4:666 (2021)
Calcium dynamics control synaptic transmission. Calcium triggers synaptic vesicle fusion, determines release probability, modulates vesicle recycling, participates in long-term plasticity and regulates cellular metabolism. Mitochondria, the main source of cellular energy, serve as calcium signaling hubs. Mitochondrial calcium transients are primarily determined by the balance between calcium influx, mediated by the mitochondrial calcium uniporter (MCU), and calcium efflux through the sodium/lithium/calcium exchanger (NCLX). We identified a human recessive missense SLC8B1 variant that impairs NCLX activity and is associated with severe mental retardation. On this basis, we examined the effect of deleting NCLX in mice on mitochondrial and synaptic calcium homeostasis, synaptic activity, and plasticity. Neuronal mitochondria exhibited basal calcium overload, membrane depolarization, and a reduction in the amplitude and rate of calcium influx and efflux. We observed smaller cytoplasmic calcium transients in the presynaptic terminals of NCLX-KO neurons, leading to a lower probability of release and weaker transmission. In agreement, synaptic facilitation in NCLX-KO hippocampal slices was enhanced. Importantly, deletion of NCLX abolished long term potentiation of Schaffer collateral synapses. Our results show that NCLX controls presynaptic calcium transients that are crucial for defining synaptic strength as well as short- and long-term plasticity, key elements of learning and memory processes.
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Scientific Article
Schlieben, L.D. ; Prokisch, H. ; Yépez, V.A.
Front. Mol. Biosci. 8:647277 (2021)
Rare diseases, although individually rare, collectively affect approximately 350 million people worldwide. Currently, nearly 6,000 distinct rare disorders with a known molecular basis have been described, yet establishing a specific diagnosis based on the clinical phenotype is challenging. Increasing integration of whole exome sequencing into routine diagnostics of rare diseases is improving diagnostic rates. Nevertheless, about half of the patients do not receive a genetic diagnosis due to the challenges of variant detection and interpretation. During the last years, RNA sequencing is increasingly used as a complementary diagnostic tool providing functional data. Initially, arbitrary thresholds have been applied to call aberrant expression, aberrant splicing, and mono-allelic expression. With the application of RNA sequencing to search for the molecular diagnosis, the implementation of robust statistical models on normalized read counts allowed for the detection of significant outliers corrected for multiple testing. More recently, machine learning methods have been developed to improve the normalization of RNA sequencing read count data by taking confounders into account. Together the methods have increased the power and sensitivity of detection and interpretation of pathogenic variants, leading to diagnostic rates of 10–35% in rare diseases. In this review, we provide an overview of the methods used for RNA sequencing and illustrate how these can improve the diagnostic yield of rare diseases.
Review
Review
Stavsky, A. ; Stoler, O. ; Kostic, M. ; Katoshevsky, T. ; Assali, E.A. ; Savic, I. ; Amitai, Y. ; Prokisch, H. ; Leiz, S. ; Daumer-Haas, C. ; Fleidervish, I.A. ; Perocchi, F. ; Gitler, D. ; Sekler, I.
Comm. Biol. 4:755 (2021)
The original version of this Article contained an error in the spelling of the author Fabiana Perocchi, which was incorrectly given as Fabiana Perrochi. This has now been corrected in both the PDF and HTML versions of the Article.
Friederich, M.W. ; Geddes, G.C. ; Wortmann, S.B. ; Punnoose, A. ; Wartchow, E. ; Knight, K.M. ; Prokisch, H. ; Creadon-Swindell, G. ; Mayr, J.A. ; van Hove, J.L.K.
Mol. Genet. Metab. 133, 362-371 (2021)
Cardiac dysfunction is a common phenotypic manifestation of primary mitochondrial disease with multiple nuclear and mitochondrial DNA pathogenic variants as a cause, including disorders of mitochondrial translation. To date, five patients have been described with pathogenic variants in MRPL44, encoding the ml44 protein which is part of the large subunit of the mitochondrial ribosome (mitoribosome). Three presented as infants with hypertrophic cardiomyopathy, mild lactic acidosis, and easy fatigue and muscle weakness, whereas two presented in adolescence with myopathy and neurological symptoms. We describe two infants who presented with cardiomyopathy from the neonatal period, failure to thrive, hypoglycemia and in one infant lactic acidosis. A decompensation of the cardiac function in the first year resulted in demise. Exome sequencing identified compound heterozygous variants in the MRPL44 gene including the known pathogenic variant c.467 T > G and two novel pathogenic variants. We document a combined respiratory chain enzyme deficiency with emphasis on complex I and IV, affecting heart muscle tissue more than skeletal muscle or fibroblasts. We show this to be caused by reduced mitochondrial DNA encoded protein synthesis affecting all subunits, and resulting in dysfunction of complex I and IV assembly. The degree of oxidative phosphorylation dysfunction correlated with the impairment of mitochondrial protein synthesis due to different pathogenic variants. These functional studies allow for improved understanding of the pathogenesis of MRPL44-associated mitochondrial disorder.
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Scientific Article
Denkena, J. ; Johannes, F. ; Colomé-Tatché, M.
Heredity 127, 190–202 (2021)
Failure to maintain DNA methylation patterns during plant development can occasionally give rise to so-called “spontaneous epimutations”. These stochastic methylation changes are sometimes heritable across generations and thus accumulate in plant genomes over time. Recent evidence indicates that spontaneous epimutations have a major role in shaping patterns of methylation diversity in plant populations. Using single CG dinucleotides as units of analysis, previous work has shown that the epimutation rate is several orders of magnitude higher than the genetic mutation rate. While these large rate differences have obvious implications for understanding genome-methylome co-evolution, the functional relevance of single CG methylation changes remains questionable. In contrast to single CG, solid experimental evidence has linked methylation gains and losses in larger genomic regions with transcriptional variation and heritable phenotypic effects. Here we show that such region-level changes arise stochastically at about the same rate as those at individual CG sites, are only marginal dependent on region size and cytosine density, but strongly dependent on chromosomal location. We also find consistent evidence that region-level epimutations are not restricted to CG contexts but also frequently occur in non-CG regions at the genome-wide scale. Taken together, our results support the view that many differentially methylated regions (DMRs) in natural populations originate from epimutation events and may not be effectively tagged by proximal SNPs. This possibility reinforces the need for epigenome-wide association studies (EWAS) in plants as a way to identify the epigenetic basis of complex traits.
Wissenschaftlicher Artikel
Scientific Article
Akagi, G. ; Melchionna, S. ; Stefanelli, U.
J. evol. equ. 21, 5203-5207 (2021)
In our paper [2], strong solutions of the Cauchy problem for the doubly nonlinear gradient flow posed on the dual space V* of a uniformly convex Banach space V.
Dieckmann, M.A. ; Beyvers, S. ; Nkouamedjo-Fankep, R.C. ; Hanel, P. ; Jelonek, L. ; Blom, J. ; Goesmann, A.
Nucleic Acids Res. 49, W185-W192 (2021)
The EDGAR platform, a web server providing databases of precomputed orthology data for thousands of microbial genomes, is one of the most established tools in the field of comparative genomics and phylogenomics. Based on precomputed gene alignments, EDGAR allows quick identification of the differential gene content, i.e. the pan genome, the core genome, or singleton genes. Furthermore, EDGAR features a wide range of analyses and visualizations like Venn diagrams, synteny plots, phylogenetic trees, as well as Amino Acid Identity (AAI) and Average Nucleotide Identity (ANI) matrices. During the last few years, the average number of genomes analyzed in an EDGAR project increased by two orders of magnitude. To handle this massive increase, a completely new technical backend infrastructure for the EDGAR platform was designed and launched as EDGAR3.0. For the calculation of new EDGAR3.0 projects, we are now using a scalable Kubernetes cluster running in a cloud environment. A new storage infrastructure was developed using a file-based high-performance storage backend which ensures timely data handling and efficient access. The new data backend guarantees a memory efficient calculation of orthologs, and parallelization has led to drastically reduced processing times. Based on the advanced technical infrastructure new analysis features could be implemented including POCP and FastANI genomes similarity indices, UpSet intersecting set visualization, and circular genome plots. Also the public database section of EDGAR was largely updated and now offers access to 24,317 genomes in 749 free-to-use projects. In summary, EDGAR 3.0 provides a new, scalable infrastructure for comprehensive microbial comparative gene content analysis. The web server is accessible at http://edgar3.computational.bio.
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Scientific Article
Klinger, E. ; Motta, A. ; Marr, C. ; Theis, F.J. ; Helmstaedter, M.
Nat. Commun. 12:2785 (2021)
With the availability of cellular-resolution connectivity maps, connectomes, from the mammalian nervous system, it is in question how informative such massive connectomic data can be for the distinction of local circuit models in the mammalian cerebral cortex. Here, we investigated whether cellular-resolution connectomic data can in principle allow model discrimination for local circuit modules in layer 4 of mouse primary somatosensory cortex. We used approximate Bayesian model selection based on a set of simple connectome statistics to compute the posterior probability over proposed models given a to-be-measured connectome. We find that the distinction of the investigated local cortical models is faithfully possible based on purely structural connectomic data with an accuracy of more than 90%, and that such distinction is stable against substantial errors in the connectome measurement. Furthermore, mapping a fraction of only 10% of the local connectome is sufficient for connectome-based model distinction under realistic experimental constraints. Together, these results show for a concrete local circuit example that connectomic data allows model selection in the cerebral cortex and define the experimental strategy for obtaining such connectomic data.
Wissenschaftlicher Artikel
Scientific Article
Monfrini, E. ; Zech, M. ; Steel, D. ; Kurian, M.A. ; Winkelmann, J. ; Di Fonzo, A.
Brain 144, 2610-2615 (2021)
The "homotypic fusion and protein sorting" (HOPS) complex is the structural bridge necessary for the fusion of late endosomes and autophagosomes with lysosomes. Recent publications linked mutations in genes encoding HOPS complex proteins with the etiopathogenesis of inherited dystonias (i.e., VPS16, VPS41, and VPS11). Functional and microstructural studies conducted on patient-derived fibroblasts carrying mutations of HOPS complex subunits displayed clear abnormalities of the lysosomal and autophagic compartments. We propose to name HOPS-associated Neurological Disorders (HOPSANDs) this group of diseases, which are mainly characterized by dystonic presentations. The delineation of HOPSANDs further confirms the connection of lysosomal and autophagic dysfunction with the pathogenesis of dystonia, prompting researchers to find innovative therapies targeting this pathway.
Review
Review
Butterfield, N.C. ; Curry, K.F. ; Steinberg, J. ; Dewhurst, H. ; Komla-Ebri, D. ; Mannan, N.S. ; Adoum, A.T. ; Leitch, V.D. ; Logan, J.G. ; Waung, J.A. ; Ghirardello, E. ; Southam, L. ; Youlten, S.E. ; Wilkinson, J.M. ; McAninch, E.A. ; Vancollie, V.E. ; Kussy, F. ; White, J.K. ; Lelliott, C.J. ; Adams, D.J. ; Jacques, R. ; Bianco, A.C. ; Boyde, A. ; Zeggini, E. ; Croucher, P.I. ; Williams, G.R. ; Bassett, J.H.D.
Nat. Commun. 12:3302 (2021)
The original version of this Article contained private information in the Data Availability statement, which was used by reviewers to access Proteomics datasets. This information has now been removed from both the PDF and HTML versions of this article.
Zech, M. ; Jech, R. ; Boesch, S. ; Škorvánek, M. ; Necpál, J. ; Švantnerová, J. ; Wagner, M. ; Sadr-Nabavi, A. ; Distelmaier, F. ; Krenn, M. ; Serranová, T. ; Rektorová, I. ; Havránková, P. ; Mosejová, A. ; Příhodová, I. ; Šarláková, J. ; Kulcsarová, K. ; Ulmanová, O. ; Bechyně, K. ; Ostrozovičová, M. ; Haň, V. ; Ventosa, J.R. ; Brunet, T. ; Berutti, R. ; Shariati, M. ; Shoeibi, A. ; Schneider, S.A. ; Kuster, A. ; Baumann, M. ; Weise, D. ; Wilbert, F. ; Janzarik, W.G. ; Eckenweiler, M. ; Mall, V. ; Haslinger, B. ; Berweck, S. ; Winkelmann, J. ; Oexle, K.
Mov. Disord. 36, 959-1964 (2021)
BACKGROUND: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications. OBJECTIVES: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity). METHODS: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses. RESULTS: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81. CONCLUSIONS: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols.
Wissenschaftlicher Artikel
Scientific Article
Loureiro, H. ; Becker, T. ; Bauer-Mehren, A. ; Ahmidi, N. ; Weberpals, J.
Front. Artif. Intell. 4:625573 (2021)
Introduction: Prognostic scores are important tools in oncology to facilitate clinical decision-making based on patient characteristics. To date, classic survival analysis using Cox proportional hazards regression has been employed in the development of these prognostic scores. With the advance of analytical models, this study aimed to determine if more complex machine-learning algorithms could outperform classical survival analysis methods. Methods: In this benchmarking study, two datasets were used to develop and compare different prognostic models for overall survival in pan-cancer populations: a nationwide EHR-derived de-identified database for training and in-sample testing and the OAK (phase III clinical trial) dataset for out-of-sample testing. A real-world database comprised 136K first-line treated cancer patients across multiple cancer types and was split into a 90% training and 10% testing dataset, respectively. The OAK dataset comprised 1,187 patients diagnosed with non-small cell lung cancer. To assess the effect of the covariate number on prognostic performance, we formed three feature sets with 27, 44 and 88 covariates. In terms of methods, we benchmarked ROPRO, a prognostic score based on the Cox model, against eight complex machine-learning models: regularized Cox, Random Survival Forests (RSF), Gradient Boosting (GB), DeepSurv (DS), Autoencoder (AE) and Super Learner (SL). The C-index was used as the performance metric to compare different models. Results: For in-sample testing on the real-world database the resulting C-index [95% CI] values for RSF 0.720 [0.716, 0.725], GB 0.722 [0.718, 0.727], DS 0.721 [0.717, 0.726] and lastly, SL 0.723 [0.718, 0.728] showed significantly better performance as compared to ROPRO 0.701 [0.696, 0.706]. Similar results were derived across all feature sets. However, for the out-of-sample validation on OAK, the stronger performance of the more complex models was not apparent anymore. Consistently, the increase in the number of prognostic covariates did not lead to an increase in model performance. Discussion: The stronger performance of the more complex models did not generalize when applied to an out-of-sample dataset. We hypothesize that future research may benefit by adding multimodal data to exploit advantages of more complex models.
Wissenschaftlicher Artikel
Scientific Article
Strasser, B. ; Rittweger, J. ; Burtscher, J. ; Burtscher, M.
Nutrients 13:1409 (2021)
Regular physical exercise and a healthy diet are major determinants of a healthy lifespan. Although aging is associated with declining endurance performance and muscle function, these components can favorably be modified by regular physical activity and especially by exercise training at all ages in both sexes. In addition, age-related changes in body composition and metabolism, which affect even highly trained masters athletes, can in part be compensated for by higher exercise metabolic efficiency in active individuals. Accordingly, masters athletes are often considered as a role model for healthy aging and their physical capacities are an impressive example of what is possible in aging individuals. In the present review, we first discuss physiological changes, performance and trainability of older athletes with a focus on sex differences. Second, we describe the most important hormonal alterations occurring during aging pertaining regulation of appetite, glucose homeostasis and energy expenditure and the modulatory role of exercise training. The third part highlights nutritional aspects that may support health and physical performance for older athletes. Key nutrition-related concerns include the need for adequate energy and protein intake for preventing low bone and muscle mass and a higher demand for specific nutrients (e.g., vitamin D and probiotics) that may reduce the infection burden in masters athletes. Fourth, we present important research findings on the association between exercise, nutrition and the microbiota, which represents a rapidly developing field in sports nutrition.
Review
Review
Youlten, S.E. ; Kemp, J.P. ; Logan, J.G. ; Ghirardello, E.J. ; Sergio, C.M. ; Dack, M.R.G. ; Guilfoyle, S.E. ; Leitch, V.D. ; Butterfield, N.C. ; Komla-Ebri, D. ; Chai, R.C. ; Corr, A.P. ; Smith, J.T. ; Mohanty, S.T. ; Morris, J.A. ; McDonald, M.M. ; Quinn, J.M.W. ; McGlade, A.R. ; Bartonicek, N. ; Jansson, M. ; Hatzikotoulas, K. ; Irving, M.D. ; Beleza-Meireles, A. ; Rivadeneira, F. ; Duncan, E. ; Richards, J.B. ; Adams, D.J. ; Lelliott, C.J. ; Brink, R. ; Phan, T.G. ; Eisman, J.A. ; Evans, D.M. ; Zeggini, E. ; Baldock, P.A. ; Bassett, J.H.D. ; Williams, G.R. ; Croucher, P.I.
Nat. Commun. 12:2444 (2021)
Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10-22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10-13) and osteoarthritis (P = 1.6 × 10-7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
Wissenschaftlicher Artikel
Scientific Article
Storath, M. ; Weinmann, A.
Info. Infern. 10, 195-230 (2021)
In this paper, we consider the variational regularization of manifold-valued data in the inverse problems setting. In particular, we consider total variation and total generalized variation regularization for manifold-valued data with indirect measurement operators. We provide results on the well-posedness and present algorithms for a numerical realization of these models in the manifold setup. Further, we provide experimental results for synthetic and real data to show the potential of the proposed schemes for applications.
Wissenschaftlicher Artikel
Scientific Article
Steinberg, J. ; Southam, L. ; Fontalis, A. ; Clark, M.J. ; Jayasuriya, R.L. ; Swift, D. ; Shah, K.M. ; Brooks, R.A. ; McCaskie, A.W. ; Wilkinson, J.M. ; Zeggini, E.
Ann. Rheum. Dis. 80, 1070-1074 (2021)
OBJECTIVES: To determine how gene expression profiles in osteoarthritis joint tissues relate to patient phenotypes and whether molecular subtypes can be reproducibly captured by a molecular classification algorithm. METHODS: We analysed RNA sequencing data from cartilage and synovium in 113 osteoarthritis patients, applying unsupervised clustering and Multi-Omics Factor Analysis to characterise transcriptional profiles. We tested the association of the molecularly defined patient subgroups with clinical characteristics from electronic health records. RESULTS: We detected two patient subgroups in low-grade cartilage (showing no/minimal degeneration, cartilage normal/softening only), with differences associated with inflammation, extracellular matrix-related and cell adhesion pathways. The high-inflammation subgroup was associated with female sex (OR 4.12, p=0.0024) and prescription of proton pump inhibitors (OR 4.21, p=0.0040). We identified two independent patient subgroupings in osteoarthritis synovium: one related to inflammation and the other to extracellular matrix and cell adhesion processes. A seven-gene classifier including MMP13, APOD, MMP2, MMP1, CYTL1, IL6 and C15orf48 recapitulated the main axis of molecular heterogeneity in low-grade knee osteoarthritis cartilage (correlation ρ=-0.88, p<10-10) and was reproducible in an independent patient cohort (ρ=-0.85, p<10-10). CONCLUSIONS: These data support the reproducible stratification of osteoarthritis patients by molecular subtype and the exploration of new avenues for tailored treatments.
Wissenschaftlicher Artikel
Scientific Article
Hummel, S. ; Weiss, A. ; Bonifacio, E. ; Agardh, D. ; Akolkar, B. ; Aronsson, C.A. ; Hagopian, W.A. ; Koletzko, S. ; Krischer, J.P. ; Lernmark, Å. ; Lynch, K. ; Norris, J.M. ; Rewers, M.J. ; She, J.X. ; Toppari, J. ; Uusitalo, U. ; Vehik, K. ; Virtanen, S.M. ; Beyerlein, A. ; Ziegler, A.-G.
Am. J. Clin. Nutr. 114, 134-142 (2021)
BACKGROUND: Breastfeeding has beneficial effects on numerous health outcomes. OBJECTIVES: We investigated whether breastfeeding duration is associated with the development of early childhood autoimmunity, allergies, or obesity in a multinational prospective birth cohort. METHODS: Infants with genetic susceptibility for type 1 diabetes (n = 8676) were followed for the development of autoantibodies to islet autoantigens or transglutaminase, allergies, and for anthropometric measurements to a median age of 8.3 y (IQR: 2.8-10.2 y). Information on breastfeeding was collected at 3 mo of age and prospectively thereafter. A propensity score for longer breastfeeding was calculated from the variables that were likely to influence any or exclusive breastfeeding. The risks of developing autoimmunity or allergy were assessed using Cox proportional hazards models, and the risk of obesity at 5.5 y of age was assessed using logistic regression with adjustment by the propensity score. RESULTS: Breastfeeding duration was not associated with a lower risk of either islet or transglutaminase autoimmunity (any breastfeeding >6 mo, adjusted HR: 1.07; 95% CI: 0.96, 1.19; exclusive breastfeeding >3 mo, adjusted HR: 1.03; 95% CI: 0.92, 1.15). Exclusive breastfeeding >3 mo was associated with a decreased risk of seasonal allergic rhinitis (adjusted HR: 0.70; 95% CI: 0.53, 0.92; P < 0.01). Any breastfeeding >6 mo and exclusive breastfeeding >3 mo were associated with decreased risk of obesity (adjusted OR: 0.62; 95% CI: 0.47, 0.81; P < 0.001; and adjusted OR: 0.68; 95% CI: 0.47, 0.95; P < 0.05, respectively). CONCLUSIONS: Longer breastfeeding was not associated with a lower risk of childhood (islet or transglutaminase) autoimmunity in genetically at-risk children but was associated with decreased risk of seasonal allergic rhinitis and obesity at 5.5 y of age.
Wissenschaftlicher Artikel
Scientific Article
Eberherr, A.C. ; Maaske, A. ; Wolf, C. ; Giesert, F. ; Berutti, R. ; Rusha, E. ; Pertek, A. ; Kastlmeier, M.T. ; Voss, C. ; Plummer, M. ; Sayed, A. ; Graf, E. ; Effner, R. ; Volz, T. ; Drukker, M. ; Strom, T.M. ; Meitinger, T. ; Stöger, T. ; Buyx, A.M. ; Hagl, B. ; Renner, E.D.
CRISPR J. 4, 178-190 (2021)
STAT3-hyper IgE syndrome (STAT3-HIES) is a primary immunodeficiency presenting with destructive lung disease along with other symptoms. CRISPR-Cas9-mediated adenine base editors (ABEs) have the potential to correct one of the most common STAT3-HIES causing heterozygous STAT3 mutations (c.1144C>T/p.R382W). As a proof-of-concept, we successfully applied ABEs to correct STAT3 p.R382W in patient fibroblasts and induced pluripotent stem cells (iPSCs). Treated primary STAT3-HIES patient fibroblasts showed a correction efficiency of 29% ± 7% without detectable off-target effects evaluated through whole-genome and high-throughput sequencing. Compared with untreated patient fibroblasts, corrected single-cell clones showed functional rescue of STAT3 signaling with significantly increased STAT3 DNA-binding activity and target gene expression of CCL2 and SOCS3. Patient-derived iPSCs were corrected with an efficiency of 30% ± 6% and differentiated to alveolar organoids showing preserved plasticity in treated cells. In conclusion, our results are supportive for ABE-based gene correction as a potential causative treatment of STAT3-HIES.
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Musacchio, T. ; Zech, M. ; Reich, M.M. ; Winkelmann, J. ; Volkmann, J.
Ann. Neurol. 89, 1257-1258 (2021)
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Scientific Article
Böttcher, A. ; Büttner, M. ; Tritschler, S. ; Sterr, M. ; Aliluev, A. ; Oppenländer, L. ; Burtscher, I. ; Sass, S. ; Irmler, M. ; Beckers, J. ; Ziegenhain, C. ; Enard, W. ; Schamberger, A.C. ; Verhamme, F.M. ; Eickelberg, O. ; Theis, F.J. ; Lickert, H.
Nat. Cell Biol. 23, 566-576 (2021)
A Correction to this paper has been published: https://doi.org/10.1038/s41556-021-00667-0.
Schulte-Sasse, R. ; Budach, S. ; Hnisz, D. ; Marsico, A.
Nat. Mach. Intell. 3, 513–526 (2021)
The increase in available high-throughput molecular data creates computational challenges for the identification of cancer genes. Genetic as well as non-genetic causes contribute to tumorigenesis, and this necessitates the development of predictive models to effectively integrate different data modalities while being interpretable. We introduce EMOGI, an explainable machine learning method based on graph convolutional networks to predict cancer genes by combining multiomics pan-cancer data—such as mutations, copy number changes, DNA methylation and gene expression—together with protein–protein interaction (PPI) networks. EMOGI was on average more accurate than other methods across different PPI networks and datasets. We used layer-wise relevance propagation to stratify genes according to whether their classification was driven by the interactome or any of the omics levels, and to identify important modules in the PPI network. We propose 165 novel cancer genes that do not necessarily harbour recurrent alterations but interact with known cancer genes, and we show that they correspond to essential genes from loss-of-function screens. We believe that our method can open new avenues in precision oncology and be applied to predict biomarkers for other complex diseases.
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Neuser, S. ; Brechmann, B. ; Heimer, G. ; Brösse, I. ; Schubert, S. ; O'Grady, L. ; Zech, M. ; Srivastava, S. ; Sweetser, D.A. ; Dincer, Y. ; Mall, V. ; Winkelmann, J. ; Behrends, C. ; Darras, B.T. ; Graham, R.J. ; Jayakar, P. ; Byrne, B. ; El Bar-Aluma, B. ; Haberman, Y. ; Szeinberg, A. ; Aldhalaan, H.M. ; Hashem, M. ; Tenaiji, A.A. ; Ismayl, O. ; Al Nuaimi, A.E. ; Maher, K. ; Ibrahim, S. ; Khan, F. ; Houlden, H. ; Ramakumaran, V.S. ; Pagnamenta, A.T. ; Posey, J.E. ; Lupski, J.R. ; Tan, W.H. ; ElGhazali, G. ; Herman, I. ; Muñoz, T. ; Repetto, G.M. ; Seitz, A. ; Krumbiegel, M. ; Cecilia Poli, M. ; Kini, U. ; Efthymiou, S. ; Meiler, J. ; Maroofian, R. ; Alkuraya, F.S. ; Jamra, R.A. ; Popp, B. ; Ben-Zeev, B. ; Ebrahimi-Fakhari, D.
Hum. Mutat. 42, 762-776 (2021)
Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through an international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections and central/nocturnal hypopnea as core manifestations. A review of brain MRI scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing β-propeller repeats. Despite constituting nearly half of disease associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1,221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.
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Scientific Article
Schouten, J.P.E. ; Matek, C. ; Jacobs, L.F.P. ; Buck, M.C. ; Bošnački, D. ; Marr, C.
Sci. Rep. 11:7995 (2021)
Convolutional neural networks (CNNs) excel as powerful tools for biomedical image classification. It is commonly assumed that training CNNs requires large amounts of annotated data. This is a bottleneck in many medical applications where annotation relies on expert knowledge. Here, we analyze the binary classification performance of a CNN on two independent cytomorphology datasets as a function of training set size. Specifically, we train a sequential model to discriminate non-malignant leukocytes from blast cells, whose appearance in the peripheral blood is a hallmark of leukemia. We systematically vary training set size, finding that tens of training images suffice for a binary classification with an ROC-AUC over 90%. Saliency maps and layer-wise relevance propagation visualizations suggest that the network learns to increasingly focus on nuclear structures of leukocytes as the number of training images is increased. A low dimensional tSNE representation reveals that while the two classes are separated already for a few training images, the distinction between the classes becomes clearer when more training images are used. To evaluate the performance in a multi-class problem, we annotated single-cell images from a acute lymphoblastic leukemia dataset into six different hematopoietic classes. Multi-class prediction suggests that also here few single-cell images suffice if differences between morphological classes are large enough. The incorporation of deep learning algorithms into clinical practice has the potential to reduce variability and cost, democratize usage of expertise, and allow for early detection of disease onset and relapse. Our approach evaluates the performance of a deep learning based cytology classifier with respect to size and complexity of the training data and the classification task.
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Scientific Article
Biagosch, C. ; Vidali, S. ; Faerberboeck, M. ; Hensler, S. ; Becker, L. ; Amarie, O.V. ; Aguilar-Pimentel, J.A. ; Garrett, L. ; Klein-Rodewald, T. ; Rathkolb, B. ; Zanuttigh, E. ; Calzada-Wack, J. ; da Silva Buttkus, P. ; Rozman, J. ; Treise, I. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Janik, D. ; Wurst, W. ; Mayr, J.A. ; Klopstock, T. ; Meitinger, T. ; Prokisch, H. ; Iuso, A.
Mamm. Genome 32, 332-349 (2021)
Pathogenic variants in the WDR45 (OMIM: 300,526) gene on chromosome Xp11 are the genetic cause of a rare neurological disorder characterized by increased iron deposition in the basal ganglia. As WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, the disease has been named Beta-Propeller Protein-Associated Neurodegeneration (BPAN). BPAN represents one of the four most common forms of Neurodegeneration with Brain Iron Accumulation (NBIA). In the current study, we generated and characterized a whole-body Wdr45 knock-out (KO) mouse model. The model, developed using TALENs, presents a 20-bp deletion in exon 2 of Wdr45. Homozygous females and hemizygous males are viable, proving that systemic depletion of Wdr45 does not impair viability and male fertility in mice. The in-depth phenotypic characterization of the mouse model revealed neuropathology signs at four months of age, neurodegeneration progressing with ageing, hearing and visual impairment, specific haematological alterations, but no brain iron accumulation. Biochemically, Wdr45 KO mice presented with decreased complex I (CI) activity in the brain, suggesting that mitochondrial dysfunction accompanies Wdr45 deficiency. Overall, the systemic Wdr45 KO described here complements the two mouse models previously reported in the literature (PMIDs: 26,000,824, 31,204,559) and represents an additional robust model to investigate the pathophysiology of BPAN and to test therapeutic strategies for the disease.
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Scientific Article
Yap, Z.Y. ; Park, Y.H. ; Wortmann, S.B. ; Gunning, A.C. ; Ezer, S. ; Lee, S. ; Duraine, L. ; Wilichowski, E. ; Wilson, K. ; Mayr, J.A. ; Wagner, M. ; Li, H. ; Kini, U. ; Black, E.D. ; Monaghan, K.G. ; Lupski, J.R. ; Ellard, S. ; Westphal, D.S. ; Harel, T. ; Yoon, W.H.
Genome Med. 13:55 (2021)
BACKGROUND: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans. METHODS: To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants. RESULTS: We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles. CONCLUSION: Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.
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Scientific Article
Camero, A. ; Wang, H. ; Alba, E. ; Bäck, T.
Appl. Soft. Comput. 106:107356 (2021)
Recurrent neural networks (RNNs) are a powerful approach for time series prediction. However, their performance is strongly affected by their architecture and hyperparameter settings. The architecture optimization of RNNs is a time-consuming task, where the search space is typically a mixture of real, integer and categorical values. To allow for shrinking and expanding the size of the network, the representation of architectures often has a variable length. In this paper, we propose to tackle the architecture optimization problem with a variant of the Bayesian Optimization (BO) algorithm. To reduce the evaluation time of candidate architectures the Mean Absolute Error Random Sampling (MRS), a training-free method to estimate the network performance, is adopted as the objective function for BO. Also, we propose three fixed-length encoding schemes to cope with the variable-length architecture representation. The result is a new perspective on accurate and efficient design of RNNs, that we validate on three problems. Our findings show that (1) the BO algorithm can explore different network architectures using the proposed encoding schemes and successfully designs well-performing architectures, and (2) the optimization time is significantly reduced by using MRS, without compromising the performance as compared to the architectures obtained from the actual training procedure.
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Scientific Article
Ecker, J. ; Benedetti, E. ; Kindt, A. ; Höring, M. ; Perl, M. ; Machmüller, A.C. ; Sichler, A. ; Plagge, J. ; Wang, Y. ; Zeissig, S. ; Shevchenko, A. ; Burkhardt, R. ; Krumsiek, J. ; Liebisch, G. ; Janssen, K.P.
Gastroenterology 161, 910-923.e19 (2021)
OBJECTIVE: Lipidomic changes were causally linked to metabolic diseases, but the scenario for colorectal cancer (CRC) is less clear. We investigated the CRC lipidome for putative tumour-specific alterations through analysis of three independent retrospective patient cohorts from two clinical centers, to derive a clinically useful signature. DESIGN: Quantitative comprehensive lipidomic analysis was performed by direct infusion electrospray ionization coupled to tandem mass spectrometry (ESI-MS/MS) and high-resolution mass spectrometry (HR-MS) on matched non-diseased mucosa and tumor tissue in a discovery cohort (n=106). Results were validated in two independent cohorts (n=28, and n=20), associated with genomic and clinical data, and lipidomic data from a genetic mouse tumor model (Apc1638N). RESULTS: Significant differences were found between tumor and normal tissue for glycero-, glycerophospho- and sphingolipids in the discovery cohort. Comparison to the validation collectives unveiled that glycerophospholipids showed high interpatient variation and were strongly affected by preanalytical conditions, whereas glycero- and sphingolipids appeared more robust. Signatures of sphingomyelin (SM) and triacylglycerol (TG) species significantly differentiated cancerous from non-diseased tissue in both validation studies. Moreover, lipogenic enzymes were significantly upregulated in CRC, and FASN gene expression was prognostically detrimental. The TG profile was significantly associated with post-operative disease-free survival and lymphovascular invasion, and was essentially conserved in murine digestive cancer, but not associated with microsatellite status, KRAS or BRAF mutations, or T-cell infiltration. CONCLUSION: Analysis of the CRC lipidome revealed a robust TG-species signature with prognostic potential. A better understanding of the cancer-associated glycerolipid and sphingolipid metabolism may lead to novel therapeutic strategies.
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Scientific Article
Kappelmann, N. ; Czamara, D. ; Rost, N. ; Moser, S. ; Schmoll, V. ; Trastulla, L. ; Stochl, J. ; Lucae, S. ; Binder, E.B. ; Khandaker, G.M. ; Knauer-Arloth, J.
Brain Behav. Immun. 95, 256-268 (2021)
BACKGROUND: About every fourth patient with major depressive disorder (MDD) shows evidence of systemic inflammation. Previous studies have shown inflammation-depression associations of multiple serum inflammatory markers and multiple specific depressive symptoms. It remains unclear, however, if these associations extend to genetic/lifetime predisposition to higher inflammatory marker levels and what role metabolic factors such as Body Mass Index (BMI) play. It is also unclear whether inflammation-symptom associations reflect direct or indirect associations, which can be disentangled using network analysis. METHODS: This study examined associations of polygenic risk scores (PRSs) for immuno-metabolic markers (C-reactive protein [CRP], interleukin [IL]-6, IL-10, tumour necrosis factor [TNF]-α, BMI) with seven depressive symptoms in one general population sample, the UK Biobank study (n=110,010), and two patient samples, the Munich Antidepressant Response Signature (MARS, n=1,058) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D, n=1,143) studies. Network analysis was applied jointly for these samples using fused graphical least absolute shrinkage and selection operator (FGL) estimation as primary analysis and, individually, using unregularized model search estimation. Stability of results was assessed using bootstrapping and three consistency criteria were defined to appraise robustness and replicability of results across estimation methods, network bootstrapping, and samples. RESULTS: Network analysis results displayed to-be-expected PRS-PRS and symptom-symptom associations (termed edges), respectively, that were mostly positive. Using FGL estimation, results further suggested 28, 29, and six PRS-symptom edges in MARS, STAR*D, and UK Biobank samples, respectively. Unregularized model search estimation suggested three PRS-symptom edges in the UK Biobank sample. Applying our consistency criteria to these associations indicated that only the association of higher CRP PRS with greater changes in appetite fulfilled all three criteria. Four additional associations fulfilled at least two consistency criteria; specifically, higher CRP PRS was associated with greater fatigue and reduced anhedonia, higher TNF-α PRS was associated with greater fatigue, and higher BMI PRS with greater changes in appetite and anhedonia. Associations of the BMI PRS with anhedonia, however, showed an inconsistent valence across estimation methods. CONCLUSIONS: Genetic predisposition to higher systemic inflammatory markers are primarily associated with somatic/neurovegetative symptoms of depression such as changes in appetite and fatigue, consistent with previous studies based on circulating levels of inflammatory markers. We extend these findings by providing evidence that associations are direct (using network analysis) and extend to genetic predisposition to immuno-metabolic markers (using PRSs). Our findings can inform selection of patients with inflammation-related symptoms into clinical trials of immune-modulating drugs for MDD.
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Scientific Article
Liu, Z. ; Zhang, L. ; Ren, C. ; Xu, M. ; Li, S. ; Ban, R. ; Wu, Y. ; Chen, L. ; Sun, S. ; Elstner, M. ; Shimura, M. ; Ogawa-Tominaga, M. ; Murayama, K. ; Shi, T. ; Prokisch, H. ; Fang, F.
J. Med. Genet. 59, 351-357 (2021)
BACKGROUND: Progressive cavitating leukoencephalopathy (PCL) is thought to result from mutations in nuclear genes affecting mitochondrial function and energy metabolism. To date, mutations in two subunits of complex I, NDUFS1 and NDUFV1, have been reported to be related to PCL. METHODS: Patients underwent clinical examinations, brain MRI, skin biopsy and muscle biopsy. Whole-genome or whole-exome sequencing was performed on the index patients from two unrelated families with PCL. The effects of the mutations were examined through complementation of the NDUFV2 mutation by cDNA expression. RESULTS: The common clinical features of the patients in this study were recurring episodes of acute or subacute developmental regression that appeared in the first years of life, followed by gradual remissions and prolonged periods of stability. MRI showed leukoencephalopathy with multiple cavities. Three novel NDUFV2 missense mutations were identified in these families. Complex I deficiency was confirmed in affected individuals' fibroblasts and a muscle biopsy. Functional and structural analyses revealed that these mutations affect the structural stability and function of the NDUFV2 protein, indicating that defective NDUFV2 function is responsible for the phenotypes in these individuals. CONCLUSIONS: Here, we report the clinical presentations, neuroimaging and molecular and functional analyses of novel mutations in NDUFV2 in two sibling pairs of two Chinese families presenting with PCL. We hereby expand the knowledge on the clinical phenotypes associated with mutations in NDUFV2 and the genotypes causative for PCL.
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Scientific Article
Fröhlich, F. ; Weindl, D. ; Schälte, Y. ; Pathirana, D. ; Paszkowski, L. ; Lines, G.T. ; Stapor, P. ; Hasenauer, J.
Bioinformatics 37, 3676-3677 (2021)
SUMMARY: Ordinary differential equation models facilitate the understanding of cellular signal transduction and other biological processes. However, for large and comprehensive models, the computational cost of simulating or calibrating can be limiting. AMICI is a modular toolbox implemented in C ++/Python/MATLAB that provides efficient simulation and sensitivity analysis routines tailored for scalable, gradient-based parameter estimation and uncertainty quantification. AVAILABILITY: AMICI is published under the permissive BSD-3-Clause license with source code publicly available on https://github.com/AMICI-dev/AMICI. Citeable releases are archived on Zenodo. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Scientific Article
Sanchez-Arcilla, A. ; Staneva, J. ; Cavaleri, L. ; Badger, M. ; Bidlot, J. ; Sorensen, J.T. ; Hansen, L.B. ; Martin, A. ; Saulter, A. ; Espino, M. ; Miglietta, M.M. ; Mestres, M. ; Bonaldo, D. ; Pezzutto, P. ; Schulz-Stellenfleth, J. ; Wiese, A. ; Larsen, X. ; Carniel, S. ; Bolanos, R. ; Abdalla, S. ; Tiesi, A.
Front. Mar. Sci. 8, DOI: 10.3389/fmars.2021.604741 (2021)
Recent advances in numerical modeling, satellite data, and coastal processes, together with the rapid evolution of CMEMS products and the increasing pressures on coastal zones, suggest the timeliness of extending such products toward the coast. The CEASELESS EU H2020 project combines Sentinel and in-situ data with high-resolution models to predict coastal hydrodynamics at a variety of scales, according to stakeholder requirements. These predictions explicitly introduce land discharges into coastal oceanography, addressing local conditioning, assimilation memory and anisotropic error metrics taking into account the limited size of coastal domains. This article presents and discusses the advances achieved by CEASELESS in exploring the performance of coastal models, considering model resolution and domain scales, and assessing error generation and propagation. The project has also evaluated how underlying model uncertainties can be treated to comply with stakeholder requirements for a variety of applications, from storm-induced risks to aquaculture, from renewable energy to water quality. This has led to the refinement of a set of demonstrative applications, supported by a software environment able to provide met-ocean data on demand. The article ends with some remarks on the scientific, technical and application limits for CMEMS-based coastal products and how these products may be used to drive the extension of CMEMS toward the coast, promoting a wider uptake of CMEMS-based predictions.
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Scientific Article
Türei, D. ; Valdeolivas, A. ; Gul, L. ; Palacio-Escat, N. ; Klein, M. ; Ivanova, O. ; Ölbei, M. ; Gábor, A. ; Theis, F.J. ; Módos, D. ; Korcsmáros, T. ; Saez-Rodriguez, J.
Mol. Syst. Biol. 17:e9923 (2021)
Molecular knowledge of biological processes is a cornerstone in omics data analysis. Applied to single-cell data, such analyses provide mechanistic insights into individual cells and their interactions. However, knowledge of intercellular communication is scarce, scattered across resources, and not linked to intracellular processes. To address this gap, we combined over 100 resources covering interactions and roles of proteins in inter- and intracellular signaling, as well as transcriptional and post-transcriptional regulation. We added protein complex information and annotations on function, localization, and role in diseases for each protein. The resource is available for human, and via homology translation for mouse and rat. The data are accessible via OmniPath's web service (https://omnipathdb.org/), a Cytoscape plug-in, and packages in R/Bioconductor and Python, providing access options for computational and experimental scientists. We created workflows with tutorials to facilitate the analysis of cell-cell interactions and affected downstream intracellular signaling processes. OmniPath provides a single access point to knowledge spanning intra- and intercellular processes for data analysis, as we demonstrate in applications studying SARS-CoV-2 infection and ulcerative colitis.
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Scientific Article
Haffner, I. ; Schierle, K. ; Raimúndez, E. ; Geier, B. ; Maier, D. ; Hasenauer, J. ; Luber, B. ; Walch, A.K. ; Kolbe, K. ; Riera Knorrenschild, J. ; Kretzschmar, A. ; Rau, B. ; Fischer von Weikersthal, L. ; Ahlborn, M. ; Siegler, G. ; Fuxius, S. ; Decker, T. ; Wittekind, C. ; Lordick, F.
J. Clin. Oncol. 39, 1468-1478 (2021)
PURPOSE: Trastuzumab is the only approved targeted drug for first-line treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic gastric cancer (mGC). However, not all patients respond and most eventually progress. The multicenter VARIANZ study aimed to investigate the background of response and resistance to trastuzumab in mGC. METHODS: Patients receiving medical treatment for mGC were prospectively recruited in 35 German sites and followed for up to 48 months. HER2 status was assessed centrally by immunohistochemistry and chromogenic in situ hybridization. In addition, HER2 gene expression was assessed using qPCR. RESULTS: Five hundred forty-eight patients were enrolled, and 77 had HER2+ mGC by central assessment (14.1%). A high deviation rate of 22.7% between central and local test results was seen. Patients who received trastuzumab for centrally confirmed HER2+ mGC (central HER2+/local HER2+) lived significantly longer as compared with patients who received trastuzumab for local HER2+ but central HER2- mGC (20.5 months, n = 60 v 10.9 months, n = 65; hazard ratio, 0.42; 95% CI, 8.2 to 14.4; P < .001). In the centrally confirmed cohort, significantly more tumor cells stained HER2+ than in the unconfirmed cohort, and the HER2 amplification ratio was significantly higher. A minimum of 40% HER2+ tumor cells and a HER2 amplification ratio of ≥ 3.0 were calculated as optimized thresholds for predicting benefit from trastuzumab. CONCLUSION: Significant discrepancies in HER2 assessment of mGC were found in tumor specimens with intermediate HER2 expression. Borderline HER2 positivity and heterogeneity of HER2 expression should be considered as resistance factors for HER2-targeting treatment of mGC. HER2 thresholds should be reconsidered. Detailed reports with quantification of HER2 expression and amplification levels may improve selection of patients for HER2-directed treatment.
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Scientific Article
Ogris, C. ; Hu, Y. ; Knauer-Arloth, J. ; Müller, N.S.
Sci. Rep. 11:6806 (2021)
Constantly decreasing costs of high-throughput profiling on many molecular levels generate vast amounts of multi-omics data. Studying one biomedical question on two or more omic levels provides deeper insights into underlying molecular processes or disease pathophysiology. For the majority of multi-omics data projects, the data analysis is performed level-wise, followed by a combined interpretation of results. Hence the full potential of integrated data analysis is not leveraged yet, presumably due to the complexity of the data and the lacking toolsets. We propose a versatile approach, to perform a multi-level fully integrated analysis: The Knowledge guIded Multi-Omics Network inference approach, KiMONo ( https://github.com/cellmapslab/kimono ). KiMONo performs network inference by using statistical models for combining omics measurements coupled to a powerful knowledge-guided strategy exploiting prior information from existing biological sources. Within the resulting multimodal network, nodes represent features of all input types e.g. variants and genes while edges refer to knowledge-supported and statistically derived associations. In a comprehensive evaluation, we show that our method is robust to noise and exemplify the general applicability to the full spectrum of multi-omics data, demonstrating that KiMONo is a powerful approach towards leveraging the full potential of data sets for detecting biomarker candidates.
Wissenschaftlicher Artikel
Scientific Article
Damialis, A. ; Gilles, S. ; Sofiev, M. ; Sofieva, V. ; Kolek, F. ; Bayr, D. ; Plaza, M.P. ; Leier-Wirtz, V. ; Kaschuba, S. ; Ziska, L.H. ; Bielory, L. ; Makra, L. ; del Mar Trigo, M. ; Traidl-Hoffmann, C.
Proc. Natl. Acad. Sci. U.S.A. 118:e2019034118 (2021)
Pollen exposure weakens the immunity against certain seasonal respiratory viruses by diminishing the antiviral interferon response. Here we investigate whether the same applies to the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is sensitive to antiviral interferons, if infection waves coincide with high airborne pollen concentrations. Our original hypothesis was that more airborne pollen would lead to increases in infection rates. To examine this, we performed a cross-sectional and longitudinal data analysis on SARS-CoV-2 infection, airborne pollen, and meteorological factors. Our dataset is the most comprehensive, largest possible worldwide from 130 stations, across 31 countries and five continents. To explicitly investigate the effects of social contact, we additionally considered population density of each study area, as well as lockdown effects, in all possible combinations: without any lockdown, with mixed lockdown−no lockdown regime, and under complete lockdown. We found that airborne pollen, sometimes in synergy with humidity and temperature, explained, on average, 44% of the infection rate variability. Infection rates increased after higher pollen concentrations most frequently during the four previous days. Without lockdown, an increase of pollen abundance by 100 pollen/m3 resulted in a 4% average increase of infection rates. Lockdown halved infection rates under similar pollen concentrations. As there can be no preventive measures against airborne pollen exposure, we suggest wide dissemination of pollen−virus coexposure dire effect information to encourage high-risk individuals to wear particle filter masks during high springtime pollen concentrations.
Wissenschaftlicher Artikel
Scientific Article
van Cromvoirt, A.M. ; Fenk, S. ; Sadafi, A. ; Melnikova, E.V. ; Lagutkin, D.A. ; Dey, K. ; Petrushanko, I.Y. ; Hegemann, I. ; Goede, J.S. ; Bogdanova, A.
Front. Physiol. 12:639722 (2021)
The ability of red blood cells (RBCs) to transport gases, their lifespan as well as their rheological properties invariably depend on the deformability, hydration, and membrane stability of these cells, which can be measured by Laser optical rotational red cell analyser (Lorrca® Maxsis, RR Mechatronics). The osmoscan mode of Lorrca is currently used in diagnosis of rare anemias in clinical laboratories. However, a broad range of normal values for healthy subjects reduces the sensitivity of this method for diagnosis of mild disease phenotype. In this pilot study, we explored the impact of age and gender of 45 healthy donors, as well as RBC age on the Lorrca indices. Whereas gender did not affect the Lorrca indices in our study, the age donors had a profound effect on the O_hyper parameter. To study the impact of RBC age on the osmoscan parameters, we have isolated low (L)-, medium (M)-, or high (H)- density fractions enriched with young, mature, and senescent RBCs, respectively, and evaluated the influence of RBC age-related properties, such as density, morphology, and redox state, on the osmoscan indices. As before, O_hyper was the most sensitive parameter, dropping markedly with an increase in RBC density and age. Senescence was associated with a decrease in deformability (EI_max) and tolerability to low and high osmolatites (Area). L-fraction was enriched with reticulocytes and cells with high projected area and EMA staining, but also contained a small number of cells small in projected area and most likely, terminally senescent. L-fraction was on average slightly less deformable than mature cells. The cells from the L-fraction produced more oxidants and NO than all other fractions. However, RBCs from the L-fraction contained maximal levels of reduced thiols compared to other fractions. Our study suggests that reference values for O_hyper should be age-stratified, and, most probably, corrected for the average RBC age. Further multi-center study is required to validate these suggestions before implementing them into clinical practice.
Wissenschaftlicher Artikel
Scientific Article
Kretzschmar, M. ; Müller, J.
eLife 10:e67417 (2021)
Analysing the characteristics of the SARS-CoV-2 virus makes it possible to estimate the length of quarantine that reduces the impact on society and the economy, while minimising infections.
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Wallach, D. ; Palosuo, T. ; Thorburn, P. ; Gourdain, E. ; Asseng, S. ; Basso, B. ; Buis, S. ; Crout, N. ; Dibari, C. ; Dumont, B. ; Ferrise, R. ; Gaiser, T. ; Garcia, C. ; Gayler, S. ; Ghahramani, A. ; Hochman, Z. ; Hoek, S. ; Hoogenboom, G. ; Horan, H. ; Huang, M. ; Jabloun, M. ; Jing, Q. ; Justes, É. ; Kersebaum, K.C. ; Klosterhalfen, A. ; Launay, M. ; Luo, Q. ; Maestrini, B. ; Mielenz, H. ; Moriondo, M. ; Zadeh, H.N. ; Olesen, J.E. ; Poyda, A. ; Priesack, E. ; Pullens, J.W.M. ; Qian, B. ; Schuetze, N. ; Shelia, V. ; Souissi, A. ; Specka, X. ; Srivastava, A.K. ; Stella, T. ; Streck, T. ; Trombi, G. ; Wallor, E. ; Wang, J. ; Weber, T.K.D. ; Weihermueller, L. ; de Wit, A. ; Woehling, T. ; Xiao, L. ; Zhao, C. ; Zhu, Y. ; Seidel, S.J.
Eur. J. Agron. 124:126195 (2021)
Predicting phenology is essential for adapting varieties to different environmental conditions and for crop management. Therefore, it is important to evaluate how well different crop modeling groups can predict phenology. Multiple evaluation studies have been previously published, but it is still difficult to generalize the findings from such studies since they often test some specific aspect of extrapolation to new conditions, or do not test on data that is truly independent of the data used for calibration. In this study, we analyzed the prediction of wheat phenology in Northern France under observed weather and current management, which is a problem of practical importance for wheat management. The results of 27 modeling groups are evaluated, where modeling group encompasses model structure, i.e. the model equations, the calibration method and the values of those parameters not affected by calibration. The data for calibration and evaluation are sampled from the same target population, thus extrapolation is limited. The calibration and evaluation data have neither year nor site in common, to guarantee rigorous evaluation of prediction for new weather and sites. The best modeling groups, and also the mean and median of the simulations, have a mean absolute error (MAE) of about 3 days, which is comparable to the measurement error. Almost all models do better than using average number of days or average sum of degree days to predict phenology. On the other hand, there are important differences between modeling groups, due to model structural differences and to differences between groups using the same model structure, which emphasizes that model structure alone does not completely determine prediction accuracy. In addition to providing information for our specific environments and varieties, these results are a useful contribution to a knowledge base of how well modeling groups can predict phenology, when provided with calibration data from the target population.
Wissenschaftlicher Artikel
Scientific Article
Amrhein, L. ; Fuchs, C.
BMC Bioinformatics 22:123 (2021)
Background: Tissues are often heterogeneous in their single-cell molecular expression, and this can govern the regulation of cell fate. For the understanding of development and disease, it is important to quantify heterogeneity in a given tissue. Results: We present the R package stochprofML which uses the maximum likelihood principle to parameterize heterogeneity from the cumulative expression of small random pools of cells. We evaluate the algorithm’s performance in simulation studies and present further application opportunities. Conclusion: Stochastic profiling outweighs the necessary demixing of mixed samples with a saving in experimental cost and effort and less measurement error. It offers possibilities for parameterizing heterogeneity, estimating underlying pool compositions and detecting differences between cell populations between samples.
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Scientific Article
Pietzner, M. ; Stewart, I.D. ; Raffler, J. ; Khaw, K.T. ; Michelotti, G.A. ; Kastenmüller, G. ; Wareham, N.J. ; Langenberg, C.
Nat. Med. 27, 471-479 (2021)
Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and across 27 incident noncommunicable diseases (NCDs) assessed using electronic health record hospitalization and cancer registry data from over 11,000 participants (219,415 person years). We identified 420 metabolites shared between at least 2 NCDs, representing 65.5% of all 640 significant metabolite-disease associations. We integrated baseline data on over 50 diverse clinical risk factors and characteristics to identify actionable shared pathways represented by those metabolites. Our study highlights liver and kidney function, lipid and glucose metabolism, low-grade inflammation, surrogates of gut microbial diversity and specific health-related behaviors as antecedents of common NCD multimorbidity with potential for early prevention. We integrated results into an open-access webserver ( https://omicscience.org/apps/mwasdisease/ ) to facilitate future research and meta-analyses.
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Scientific Article
Suwandhi, L. ; Altun, I. ; Karlina, R. ; Miok, V. ; Wiedemann, T. ; Fischer, D.S. ; Walzthoeni, T. ; Lindner, C. ; Böttcher, A. ; Heinzmann, S.S. ; Israel, A. ; Khalil, A. ; Braun, A. ; Pramme-Steinwachs, I. ; Burtscher, I. ; Schmitt-Kopplin, P. ; Heinig, M. ; Elsner, M. ; Lickert, H. ; Theis, F.J. ; Ussar, S.
Nat. Commun. 12:1588 (2021)
Adipose tissue expansion, as seen in obesity, is often metabolically detrimental causing insulin resistance and the metabolic syndrome. However, white adipose tissue expansion at early ages is essential to establish a functional metabolism. To understand the differences between adolescent and adult adipose tissue expansion, we studied the cellular composition of the stromal vascular fraction of subcutaneous adipose tissue of two and eight weeks old mice using single cell RNA sequencing. We identified a subset of adolescent preadipocytes expressing the mature white adipocyte marker Asc-1 that showed a low ability to differentiate into beige adipocytes compared to Asc-1 negative cells in vitro. Loss of Asc-1 in subcutaneous preadipocytes resulted in spontaneous differentiation of beige adipocytes in vitro and in vivo. Mechanistically, this was mediated by a function of the amino acid transporter ASC-1 specifically in proliferating preadipocytes involving the intracellular accumulation of the ASC-1 cargo D-serine.
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Scientific Article
Müller, J. ; Kretzschmar, M.
Nat. Phys. 17, 555–556 (2021)
Sonstiges: Meinungsartikel
Other: Opinion
Efendiyev, M.A. ; Vougalter, V.
J. Differ. Equations 284, 83-101 (2021)
We establish the existence in the sense of sequences of solutions for certain integro-differential type equations in two dimensions involving the normal diffusion in one direction and the anomalous diffusion in the other direction in H2(R2) via the fixed point technique. The elliptic equation contains a second order differential operator without the Fredholm property. It is proved that, under the reasonable technical conditions, the convergence in L1(R2) of the integral kernels implies the existence and convergence in H2(R2) of the solutions.
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Scientific Article
Torraco, A. ; Nasca, A. ; Verrigni, D. ; Pennisi, A. ; Zaki, M.S. ; Olivieri, G. ; Assouline, Z. ; Martinelli, D. ; Maroofian, R. ; Rizza, T. ; Di Nottia, M. ; Invernizzi, F. ; Lamantea, E. ; Longo, D. ; Houlden, H. ; Prokisch, H. ; Rötig, A. ; Dionisi-Vici, C. ; Bertini, E. ; Ghezzi, D. ; Carrozzo, R. ; Diodato, D.
Hum. Mutat. 42, 699-710 (2021)
Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature amongst mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and >80 monogenic causes have been involved in the disease. In this report, we describe 7 patients from four unrelated families harbouring novel NDUFA12 variants, 6 of them presenting with Leigh syndrome. Molecular genetic characterization was performed using next generation sequencing combined with the Sanger method. Biochemical and protein studies were achieved by enzymatic activities, blue native gel electrophoresis and Western blotting. All patients displayed novel homozygous mutations in the NDUFA12 gene leading to the virtual absence of the corresponding protein. Surprisingly, despite in none of the analyzed patients NDUFA12 protein was detected, they present a different onset and clinical course of the disease. Our report expands the array of genetic alterations in NDUFA12 and underlines phenotype variability associated with NDUFA12 defect.
Wissenschaftlicher Artikel
Scientific Article
Weberpals, J. ; Becker, T. ; Davies, J. ; Schmich, F. ; Rüttinger, D. ; Theis, F.J. ; Bauer-Mehren, A.
Epidemiology 32, 378-388 (2021)
BACKGROUND: Due to the non-randomized nature of real-world data, prognostic factors need to be balanced, which is often done by propensity scores (PS). This study aimed to investigate whether autoencoders, which are unsupervised deep learning architectures, might be leveraged to compute PS. METHODS: We selected patient-level data of 128,368 first-line treated cancer patients from the Flatiron Health EHR-derived de-identified database. We trained an autoencoder architecture to learn a lower-dimensional patient representation, which we used to compute PS. To compare the performance of an autoencoder-based PS with established methods, we performed a simulation study. We assessed the balancing and adjustment performance using standardized mean differences (SMD), root-mean-square-errors (RMSE), percent bias and confidence interval (CI) coverage. To illustrate the application of the autoencoder-based PS, we emulated the PRONOUNCE trial by applying the trial's protocol elements within an observational database setting, comparing two chemotherapy regimens. RESULTS: All methods but the manual variable selection approach led to well-balanced cohorts with average SMDs <0.1. LASSO yielded on average the lowest deviation of resulting estimates (RMSE 0.0205) followed by the autoencoder approach (RMSE 0.0248). Altering the hyperparameter setup in sensitivity analysis, the autoencoder approach led to similar results as LASSO (RMSE 0.0203 and 0.0205, respectively). In the case study, all methods provided a similar conclusion with point estimates clustered around the null (e.g. HRautoencoder 1.01 [95% CI 0.80-1.27] vs. HRPRONOUNCE 1.07 [0.83-1.36]). INTERPRETATION: Autoencoder-based PS computation was a feasible approach to control for confounding but did not perform better than some established approaches like LASSO.
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Scientific Article
Alston, C.L. ; Stenton, S. ; Hudson, G. ; Prokisch, H. ; Taylor, R.W.
J. Pathol. 254, 430-442 (2021)
Mitochondria play essential roles in numerous metabolic pathways including the synthesis of adenosine triphosphate through oxidative phosphorylation. Clinically, mitochondrial diseases occur when there is mitochondrial dysfunction - manifesting at any age and affecting any organ system; tissues with high energy requirements, such as muscle and the brain, are often affected. The clinical heterogeneity is parallel to the degree of genetic heterogeneity associated with mitochondrial dysfunction. Around 10% of human genes are predicted to have a mitochondrial function, and defects in over 300 genes are reported to cause mitochondrial disease. Some involve the mitochondrial genome (mtDNA), but the vast majority occur within the nuclear genome. Except for a few specific genetic defects, there remains no cure for mitochondrial diseases which means that a genetic diagnosis is imperative for genetic counselling and the provision of reproductive options for at-risk families. Next-generation sequencing strategies, particularly exome and whole-genome sequencing, have revolutionised mitochondrial diagnostics such that the traditional muscle biopsy has largely been replaced with a minimally-invasive blood sample for an unbiased approach to genetic diagnosis. Where these genomic approaches have not identified a causative defect, or where there is insufficient support for pathogenicity, additional functional investigations are required. The application of supplementary 'omics' technologies, including transcriptomics, proteomics, and metabolomics, has the potential to greatly improve diagnostic strategies. This review aims to demonstrate that, whilst a molecular diagnosis can be achieved for many cases through next-generation sequencing of blood DNA, the use of patient tissues and an integrated, multidisciplinary multi-omics approach is pivotal for diagnosing more challenging cases. Moreover, the analysis of clinically-relevant tissues from affected individuals remains crucial for understanding the molecular mechanisms underlying mitochondrial pathology. This article is protected by copyright. All rights reserved.
Review
Review
Salinno, C. ; Büttner, M. ; Cota, P. ; Tritschler, S. ; Tarquis-Medina, M. ; Bastidas-Ponce, A. ; Scheibner, K. ; Burtscher, I. ; Böttcher, A. ; Theis, F.J. ; Bakhti, M. ; Lickert, H.
Mol. Metab. 49:101188 (2021)
OBJECTIVE: Islets of Langerhans contain heterogeneous populations of insulin-producing β-cells. Surface markers and respective antibodies for isolation, tracking, and analysis are urgently needed to study β-cell heterogeneity and explore the mechanisms to harness the regenerative potential of immature β-cells. METHODS: We performed single-cell mRNA profiling of early postnatal mouse islets and re-analyzed several single-cell mRNA sequencing datasets from mouse and human pancreas and islets. We used mouse primary islets, iPSC-derived endocrine cells, Min6 insulinoma, and human EndoC-βH1 β-cell lines and performed FAC sorting, Western blotting, and imaging to support and complement the findings from the data analyses. RESULTS: We found that all endocrine cell types expressed the cluster of differentiation 81 (CD81) during pancreas development, but the expression levels of this protein were gradually reduced in β-cells during postnatal maturation. Single-cell gene expression profiling and high-resolution imaging revealed an immature signature of β-cells expressing high levels of CD81 (CD81high) compared to a more mature population expressing no or low levels of this protein (CD81low/-). Analysis of β-cells from different diabetic mouse models and in vitro β-cell stress assays indicated an upregulation of CD81 expression levels in stressed and dedifferentiated β-cells. Similarly, CD81 was upregulated and marked stressed human β-cells in vitro. CONCLUSIONS: We identified CD81 as a novel surface marker that labels immature, stressed, and dedifferentiated β-cells in the adult mouse and human islets. This novel surface marker will allow us to better study β-cell heterogeneity in healthy subjects and diabetes progression.
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Scientific Article
Brunet, T. ; Jech, R. ; Brugger, M. ; Kovacs, R. ; Alhaddad, B. ; Leszinski, G. ; Riedhammer, K.M. ; Westphal, D.S. ; Mahle, I. ; Mayerhanser, K. ; Škorvánek, M. ; Weber, S. ; Graf, E. ; Berutti, R. ; Necpál, J. ; Havránková, P. ; Pavelekova, P. ; Hempel, M. ; Kotzaeridou, U. ; Hoffmann, G.F. ; Leiz, S. ; Makowski, C. ; Roser, T. ; Schroeder, S.A. ; Steinfeld, R. ; Strobl-Wildemann, G. ; Hoefele, J. ; Borggraefe, I. ; Distelmaier, F. ; Strom, T.M. ; Winkelmann, J. ; Meitinger, T. ; Zech, M. ; Wagner, M.
Clin. Genet. 100, 14-28 (2021)
Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.
Wissenschaftlicher Artikel
Scientific Article
Pritsch, M. ; Radon, K. ; Bakuli, A. ; Le Gleut, R. ; Olbrich, L. ; Guggenbüehl Noller, J.M. ; Saathoff, E. ; Castelletti, N. ; Garí, M. ; Pütz, P. ; Schälte, Y. ; Frahnow, T. ; Wölfel, R. ; Rothe, C. ; Pletschette, M. ; Metaxa, D. ; Förster, F. ; Thiel, V. ; Rieß, F. ; Diefenbach, M.N. ; Fröschl, G. ; Bruger, J. ; Winter, S. ; Frese, J. ; Puchinger, K. ; Brand, I. ; Kroidl, I. ; Hasenauer, J. ; Fuchs, C. ; Wieser, A. ; Hoelscher, M.
Int. J. Environ. Res. Public Health 18:3572 (2021)
Given the large number of mild or asymptomatic SARS-CoV-2 cases, only population-based studies can provide reliable estimates of the magnitude of the pandemic. We therefore aimed to assess the sero-prevalence of SARS-CoV-2 in the Munich general population after the first wave of the pandemic. For this purpose, we drew a representative sample of 2994 private households and invited household members 14 years and older to complete questionnaires and to provide blood samples. SARS-CoV-2 seropositivity was defined as Roche N pan-Ig ≥ 0.4218. We adjusted the prevalence for the sampling design, sensitivity, and specificity. We investigated risk factors for SARS-CoV-2 seropositivity and geospatial transmission patterns by generalized linear mixed models and permutation tests. Seropositivity for SARS-CoV-2-specific antibodies was 1.82% (95% confidence interval (CI) 1.28–2.37%) as compared to 0.46% PCR-positive cases officially registered in Munich. Loss of the sense of smell or taste was associated with seropositivity (odds ratio (OR) 47.4; 95% CI 7.2–307.0) and infections clustered within households. By this first population-based study on SARS-CoV-2 prevalence in a large German municipality not affected by a superspreading event, we could show that at least one in four cases in private households was reported and known to the health authorities. These results will help authorities to estimate the true burden of disease in the population and to take evidence-based decisions on public health measures.
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Scientific Article
Kümmel, F. ; Kirchmayer, A. ; Solís, C. ; Hofmann, M. ; Neumeier, S. ; Gilles, R.
Metals 11:719 (2021)
Polycrystalline Ni-based superalloys are one of the most frequently used materials for high temperature load-bearing applications due to their superior mechanical strength and chemical resistance. In this paper, we presented an in situ diffraction study on the tensile deformation behavior of the polycrystalline Ni-based superalloy VDM® Alloy 780 at temperatures up to 500 °C performed at the STRESS-SPEC neutron diffractometer at the Heinz Maier-Leibnitz Zentrum. A detailed microstructural investigation was carried out by electron microscopy before and after testing. The results of these studies allowed us to determine the deformation mechanism in the differently orientated grains. It is shown that the deformation behavior, which is mainly dislocation motion and shearing of the γ′-precipitates, does not change at this temperature range. The deformation is strongly anisotropic and depends on the grain orientation. The macroscopic hardening can mainly be attributed to plastic deformation in grains, where the (200) lattice planes were orientated perpen-dicular to the loading direction. Accordingly, a remaining lattice strain and high dislocation density were detected predominantly in these grains.
Wissenschaftlicher Artikel
Scientific Article
Veerman, F. ; Popović, N. ; Marr, C.
Int. J. Nonlinear Sci., DOI: 10.1515/ijnsns-2019-0258 (2021)
Stochastic gene expression in regulatory networks is conventionally modelled via the chemical master equation (CME). As explicit solutions to the CME, in the form of so-called propagators, are oftentimes not readily available, various approximations have been proposed. A recently developed analytical method is based on a separation of time scales that assumes significant differences in the lifetimes of mRNA and protein in the network, allowing for the efficient approximation of propagators from asymptotic expansions for the corresponding generating functions. Here, we showcase the applicability of that method to simulated data from a ‘telegraph’ model for gene expression that is extended with an autoregulatory mechanism. We demonstrate that the resulting approximate propagators can be applied successfully for parameter inference in the non-regulated model; moreover, we show that, in the extended autoregulated model, autoactivation or autorepression may be refuted under certain assumptions on the model parameters. These results indicate that our approach may allow for successful parameter inference and model identification from longitudinal single cell data.
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Scientific Article
Maddu, S. ; Cheeseman, B.L. ; Müller, C. ; Sbalzarini, I.F.
Phys. Rev. E 103:042310 (2021)
We propose a statistical learning framework based on group-sparse regression that can be used to (i) enforce conservation laws, (ii) ensure model equivalence, and (iii) guarantee symmetries when learning or inferring differential-equation models from data. Directly learning interpretable mathematical models from data has emerged as a valuable modeling approach. However, in areas such as biology, high noise levels, sensor-induced correlations, and strong intersystem variability can render data-driven models nonsensical or physically inconsistent without additional constraints on the model structure. Hence, it is important to leverage prior knowledge from physical principles to learn biologically plausible and physically consistent models rather than models that simply fit the data best. We present the group iterative hard thresholding algorithm and use stability selection to infer physically consistent models with minimal parameter tuning. We show several applications from systems biology that demonstrate the benefits of enforcing priors in data-driven modeling.
Wissenschaftlicher Artikel
Scientific Article
Lo, C. ; Arora, S. ; Ben-Shlomo, Y. ; Barber, T.R. ; Lawton, M. ; Klein, J.C. ; Kanavou, S. ; Janzen, A. ; Sittig, E. ; Oertel, W.H. ; Grosset, D. ; Hu, M.T.
Neurology 96, e2016-e2027 (2021)
OBJECTIVE: We sought to identify an abbreviated test of impaired olfaction, amenable for use in busy clinical environments in prodromal (isolated REM sleep Behavior Disorder (iRBD)) and manifest Parkinson's disease (PD). METHODS: 890 PD and 313 control participants in the Discovery cohort study underwent Sniffin' stick odour identification assessment. Random forests were initially trained to distinguish individuals with poor (functional anosmia/hyposmia) and good (normosmia/super-smeller) smell ability using all 16 Sniffin' sticks. Models were retrained using the top 3 sticks ranked by order of predictor importance. One randomly selected 3-stick model was tested in a second independent PD dataset (n=452) and in two iRBD datasets (Discovery n=241; Marburg n=37) before being compared to previously described abbreviated Sniffin' stick combinations. RESULTS: In differentiating poor from good smell ability, the overall area under the curve (AUC) value associated with the top 3 sticks (Anise/Licorice/Banana) was 0.95 in the development dataset (sensitivity:90%, specificity:92%, positive predictive value:92%, negative predictive value:90%). Internal and external validation confirmed AUCs≥0.90. The combination of 3-stick model determined poor smell and an RBD screening questionnaire score of ≥5, separated iRBD from controls with a sensitivity, specificity, PPV and NPV of 65%, 100%, 100% and 30%. CONCLUSIONS: Our 3-Sniffin'-stick model holds potential utility as a brief screening test in the stratification of individuals with PD and iRBD according to olfactory dysfunction. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a 3-Sniffin'-stick model distinguishes individuals with poor and good smell ability and can be used to screen for individuals with iRBD.
Wissenschaftlicher Artikel
Scientific Article
MahmoudianDehkordi, S. ; Ahmed, A.T. ; Bhattacharyya, S. ; Han, X. ; Baillie, R.A. ; Arnold, M. ; Skime, M.K. ; John-Williams, L.S. ; Moseley, M.A. ; Thompson, J.W. ; Louie, G. ; Riva-Posse, P. ; Craighead, W.E. ; McDonald, W. ; Krishnan, R. ; Rush, A.J. ; Frye, M.A. ; Dunlop, B.W. ; Weinshilboum, R.M. ; Kaddurah-Daouk, R.
Transl. Psychiatry 11:153 (2021)
Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17 ≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD17). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics-including acylcarnitine metabolism, transport, and its link to β-oxidation-and lipid membrane remodeling may play roles in SSRI treatment response.
Wissenschaftlicher Artikel
Scientific Article
Waibel, D.J.E. ; Shetab Boushehri, S. ; Marr, C.
BMC Bioinformatics 22:103 (2021)
BACKGROUND: Deep learning contributes to uncovering molecular and cellular processes with highly performant algorithms. Convolutional neural networks have become the state-of-the-art tool to provide accurate and fast image data processing. However, published algorithms mostly solve only one specific problem and they typically require a considerable coding effort and machine learning background for their application. RESULTS: We have thus developed InstantDL, a deep learning pipeline for four common image processing tasks: semantic segmentation, instance segmentation, pixel-wise regression and classification. InstantDL enables researchers with a basic computational background to apply debugged and benchmarked state-of-the-art deep learning algorithms to their own data with minimal effort. To make the pipeline robust, we have automated and standardized workflows and extensively tested it in different scenarios. Moreover, it allows assessing the uncertainty of predictions. We have benchmarked InstantDL on seven publicly available datasets achieving competitive performance without any parameter tuning. For customization of the pipeline to specific tasks, all code is easily accessible and well documented. CONCLUSIONS: With InstantDL, we hope to empower biomedical researchers to conduct reproducible image processing with a convenient and easy-to-use pipeline.
Wissenschaftlicher Artikel
Scientific Article
Mayr, C. ; Simon, L. ; Leuschner, G. ; Ansari, M. ; Schniering, J. ; Geyer, P.E. ; Angelidis, I. ; Strunz, M. ; Singh, P. ; Kneidinger, N. ; Reichenberger, F. ; Silbernagel, E. ; Böhm, S. ; Adler, H. ; Lindner, M. ; Maurer, B. ; Hilgendorff, A. ; Prasse, A. ; Behr, J. ; Mann, M. ; Eickelberg, O. ; Theis, F.J. ; Schiller, H. B.
EMBO Mol. Med. 13:e12871 (2021)
The correspondence of cell state changes in diseased organs to peripheral protein signatures is currently unknown. Here, we generated and integrated single-cell transcriptomic and proteomic data from multiple large pulmonary fibrosis patient cohorts. Integration of 233,638 single-cell transcriptomes (n = 61) across three independent cohorts enabled us to derive shifts in cell type proportions and a robust core set of genes altered in lung fibrosis for 45 cell types. Mass spectrometry analysis of lung lavage fluid (n = 124) and plasma (n = 141) proteomes identified distinct protein signatures correlated with diagnosis, lung function, and injury status. A novel SSTR2+ pericyte state correlated with disease severity and was reflected in lavage fluid by increased levels of the complement regulatory factor CFHR1. We further discovered CRTAC1 as a biomarker of alveolar type-2 epithelial cell health status in lavage fluid and plasma. Using cross-modal analysis and machine learning, we identified the cellular source of biomarkers and demonstrated that information transfer between modalities correctly predicts disease status, suggesting feasibility of clinical cell state monitoring through longitudinal sampling of body fluid proteomes.
Wissenschaftlicher Artikel
Scientific Article
Henke, C. ; Haufe, S. ; Ziehl, D. ; Bornstein, S.R. ; Schulz-Menger, J. ; Heni, M. ; Engeli, S. ; Jordan, J. ; Birkenfeld, A.L.
ESC Heart Fail. 8, 938-942 (2021)
AIMS: Neprilysin (NEP), a zinc metallopeptidase, degrades a variety of bioactive peptides including natriuretic peptides terminating their biological action on arterial blood pressure and natriuresis. Pharmacological inhibition of NEP reduces mortality in patients with heart failure with reduced ejection fraction. Physiological interventions reducing NEP levels are unknown in humans. Because obesity leads to increased NEP levels and increases the risk for heart failure, we hypothesized that weight loss reduces NEP concentrations in plasma and tissue. METHODS AND RESULTS: We randomized overweight to obese human subjects to a low-fat or low-carbohydrate hypocaloric 6 month weight loss intervention. Soluble NEP was determined in plasma, and NEP mRNA was analysed from subcutaneous adipose tissue before and after diet. Low-fat diet-induced weight loss reduced soluble NEP levels from 0.83 ± 0.18 to 0.72 ± 0.18 μg/L (P = 0.038), while subcutaneous adipose tissue NEP mRNA expression was reduced by both dietary interventions [21% (P = 0.0057) by low-fat diet and 16% (P = 0.048) by low-carbohydrate diet]. We also analysed the polymorphisms of the gene coding for NEP, rs9827586 and rs701109, known to be associated with plasma NEP levels. For both single-nucleotide polymorphisms, minor allele carriers (A/A) had higher baseline plasma NEP levels (rs9827586: β = 0.53 ± 0.23, P < 0.0001; rs701109: β = 0.43 ± 0.22, P = 0.0016), and minor allele carriers of rs9827586 responded to weight loss with a larger NEP reduction (rs9827586: P = 0.0048). CONCLUSIONS: Our study identifies weight loss via a hypocaloric low-fat diet as the first physiological intervention in humans to reduce NEP in plasma and adipose tissue. Specific single-nucleotide polymorphisms further contribute to the decrease. Our findings may help to explain the beneficial effect of weight loss on cardiac function in patients with heart failure.
Wissenschaftlicher Artikel
Scientific Article
Steinberg, J. ; Southam, L. ; Roumeliotis, T.I. ; Clark, M.J. ; Jayasuriya, R.L. ; Swift, D. ; Shah, K.M. ; Butterfield, N.C. ; Brooks, R.A. ; McCaskie, A.W. ; Bassett, J.H.D. ; Williams, G.R. ; Choudhary, J.S. ; Wilkinson, J.M. ; Zeggini, E.
Nat. Commun. 12:1309 (2021)
Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.
Wissenschaftlicher Artikel
Scientific Article
Conlon, T.M. ; John-Schuster, G. ; Heide, D. ; Pfister, D. ; Lehmann, M. ; Hu, Y. ; Ertüz, Z. ; López, M.A. ; Ansari, M. ; Strunz, M. ; Mayr, C. ; Angelidis, I. ; Ciminieri, C. ; Costa, R. ; Kohlhepp, M.S. ; Guillot, A. ; Güneş, G. ; Jeridi, A. ; Funk, M.C. ; Beroshvili, G. ; Prokosch, S. ; Hetzer, J. ; Verleden, S.E. ; Alsafadi, H.N. ; Lindner, M. ; Burgstaller, G. ; Becker, L. ; Irmler, M. ; Dudek, M. ; Janzen, J. ; Goffin, E. ; Gosens, R. ; Knolle, P. ; Pirotte, B. ; Stöger, T. ; Beckers, J. ; Wagner, D.E. ; Singh, I. ; Theis, F.J. ; Hrabě de Angelis, M. ; O’Connor, T. ; Tacke, F. ; Boutros, M. ; Dejardin, E. ; Eickelberg, O. ; Schiller, H. B. ; Königshoff, M. ; Heikenwalder, M. ; Yildirim, A.Ö.
Nature 589, E6 (2021)
In the HTML version of this Article, owing to a typesetting error, the affiliations for author Indrabahadur Singh were incorrect. The correct affiliation is ‘Emmy Noether Research Group Epigenetic Machineries and Cancer, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany’. The PDF and print versions of the Article are correct. In addition, Ilias Angelidis should have been listed as an author, with the affiliation: ‘Comprehensive Pneumology Center (CPC), Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Neuherberg, Germany’. They designed, undertook, and analysed scRNA-seq experiments, and analysed and interpreted data (see ‘Author contributions’). Finally, in the original Article, authors Mathias Heikenwalder and Ali Önder Yildirim were listed as ‘jointly supervising’ authors instead of ‘equally contributing’ authors, alongside authors Thomas M. Conlon and Gerrit John-Schuster. The original Article has been corrected online.
Krenn, M. ; Schloegl, M. ; Pataraia, E. ; Gelpi, E. ; Schröder, S. ; Rauscher, C. ; Mayr, J.A. ; Kotzot, D. ; Zimprich, F. ; Meitinger, T. ; Wagner, M.
Seizure 87, 25-29 (2021)
OBJECTIVE: To further delineate the clinical and genetic spectrum of epileptic and neurodevelopmental conditions associated with variants in STX1B. METHODS: We screened our diagnostic in-house database (comprising >20,000 exome sequencing datasets) for pathogenic and likely pathogenic variants inSTX1B. The detected cases were phenotyped in detail, and the findings were compared to previously published case reports. RESULTS: We identified four unrelated individuals with pathogenic or likely pathogenic variants in STX1B (one missense and three loss-of-function variants). All patients displayed epileptic phenotypes, including epileptiform discharges on electroencephalography (without apparent seizures), developmental and epileptic encephalopathy and focal epilepsy. Three of the four patients had developmental delay. Febrile seizures occurred in two individuals. One patient with focal epilepsy underwent epilepsy surgery without lasting improvement. The neuropathological workup of brain tissue revealed a mild malformation of cortical development without alterations of cortical lamination or dysplastic neurons. CONCLUSIONS: Our findings confirm the wide clinical range ofSTX1B-related epileptic conditions and highlight the necessity of genetic testing prior to epilepsy surgery in cases with monogenic epilepsy. The identification of loss-of-function variants in very differently affected individuals suggests that no clear genotype-phenotype correlation can be established.
Wissenschaftlicher Artikel
Scientific Article
Dzinovic, I. ; Škorvánek, M. ; Pavelekova, P. ; Zhao, C. ; Keren, B. ; Whalen, S. ; Bakhtiari, S. ; Chih Jin, S. ; Kruer, M.C. ; Jech, R. ; Winkelmann, J. ; Zech, M.
Ann. Clin. Transl. Neurol. 8, 951-955 (2021)
The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G > A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by prominent motor dysfunction.
Wissenschaftlicher Artikel
Scientific Article
Gusic, M. ; Prokisch, H.
FEBS Lett. 595, 1132-1158 (2021)
Mitochondrial disorders are monogenic disorders characterized by a defect in oxidative phosphorylation and caused by pathogenic variants in one of over 340 different genes. The implementation of whole exome sequencing has led to a revolution in their diagnosis, duplicated the number of associated disease genes, and significantly increased the diagnosed fraction. However, the genetic etiology of a substantial fraction of patients exhibiting mitochondrial disorders remains unknown, highlighting limitations in variant detection and interpretation, which calls for improved computational and DNA sequencing methods, as well as the addition of OMICS tools. More intriguingly, this also suggests that some pathogenic variants lie outside of the protein-coding genes and that the mechanisms beyond the Mendelian inheritance and the mtDNA are of relevance. This review covers the current status of the genetic basis of mitochondrial diseases, discusses current challenges and perspectives, and explores the contribution of factors beyond the protein-coding regions and monogenic inheritance in the expansion of the genetic spectrum of disease.
Review
Review
Martínez, Y.A. ; Guo, X. ; Portales-Pérez, D.P. ; Rivera, G. ; Castañeda-Delgado, J.E. ; Garcia Perez, C. ; Enciso-Moreno, J.A. ; Lara-Ramírez, E.E.
PLoS ONE 16:e0246901 (2021)
The MERS-CoV, SARS-CoV, and SARS-CoV-2 are highly pathogenic viruses that can cause severe pneumonic diseases in humans. Unfortunately, there is a non-available effective treatment to combat these viruses. Domain-motif interactions (DMIs) are an essential means by which viruses mimic and hijack the biological processes of host cells. To disentangle how viruses achieve this process can help to develop new rational therapies. Data mining was performed to obtain DMIs stored as regular expressions (regexp) in 3DID and ELM databases. The mined regexp information was mapped on the coronaviruses’ proteomes. Most motifs on viral protein that could interact with human proteins are shared across the coronavirus species, indicating that molecular mimicry is a common strategy for coronavirus infection. Enrichment ontology analysis for protein domains showed a shared biological process and molecular function terms related to carbon source utilization and potassium channel regulation. Some of the mapped motifs were nested on B, and T cell epitopes, suggesting that it could be as an alternative way for reverse vaccinology. The information obtained in this study could be used for further theoretic and experimental explorations on coronavirus infection mechanism and development of medicines for treatment.
Wissenschaftlicher Artikel
Scientific Article
Dzinovic, I. ; Serranová, T. ; Prouteau, C. ; Colin, E. ; Ziegler, A. ; Winkelmann, J. ; Jech, R. ; Zech, M.
Neurogenetics 22, 137-141 (2021)
Intragenic rearrangements and sequence variants in the calmodulin-binding transcription activator 1 gene (CAMTA1) can result in a spectrum of clinical presentations, most notably congenital ataxia with or without intellectual disability. We describe for the first time a myoclonic dystonia-predominant phenotype associated with a novel CAMTA1 sequence variant. Furthermore, by identifying an additional, recurrent CAMTA1 sequence variant in an individual with a more typical neurodevelopmental disease manifestation, we contribute to the elucidation of phenotypic variability associated with CAMTA1 gene mutations.
Wissenschaftlicher Artikel
Scientific Article
Rajewsky, N. ; Almouzni, G. ; Gorski, S.A. ; Aerts, S. ; Amit, I. ; Bertero, M.G. ; Bock, C. ; Bredenoord, A.L. ; Cavalli, G. ; Chiocca, S. ; Clevers, H. ; de Strooper, B. ; Eggert, A. ; Ellenberg, J. ; Fernández, X.M. ; Figlerowicz, M. ; Gasser, S.M. ; Hubner, N. ; Kjems, J. ; Knoblich, J.A. ; Krabbe, G. ; Lichter, P. ; Linnarsson, S. ; Marine, J.C. ; Marioni, J.C. ; Marti-Renom, M.A. ; Netea, M.G. ; Nickel, D. ; Nollmann, M. ; Novak, H.R. ; Parkinson, H. ; Piccolo, S. ; Pinheiro, I. ; Pombo, A. ; Popp, C. ; Reik, W. ; Roman-Roman, S. ; Rosenstiel, P. ; Schultze, J.L. ; Stegle, O. ; Tanay, A. ; Testa, G. ; Thanos, D. ; Theis, F.J. ; Torres-Padilla, M.E. ; Valencia, A. ; Vallot, C. ; van Oudenaarden, A. ; Vidal, M. ; Voet, T. ; LifeTime Community (Schiller, H. B. ; Ziegler, A.-G.)
Nature 592:E8 (2021)
In this Perspective, owing to an error in the HTML, the surname of author Alejandro López-Tobón of the LifeTime Community Working Groups consortium was indexed as ‘Tobon’ rather than ‘López-Tobón’ and the accents were missing. The HTML version of the original Perspective has been corrected; the PDF and print versions were always correct. *A list of authors and their affiliations appears online.
Katsoula G. ; Southam, L. ; Steinberg, J. ; Zeggini, E. ; Tuerlings, M. ; Almeida, R. ; Swift, D. ; Meulenbelt, I. ; Wilkinson, J.M.
Vortrag: OARSI - Osteoarthritis Research Society International 2021, 29 April-01 May 2021, virtuell. (2021)
Peñuelas, J. ; Germain, J. ; Álvarez, E. ; Aparicio, E. ; Arús, P. ; Basnou, C. ; Blanché, C. ; Bonada, N. ; Canals, P. ; Capodiferro, M. ; Carceller, X. ; Casademunt, A. ; Casals, J. ; Casals, P. ; Casañas, F. ; Catalán, J. ; Checa, J. ; Cordero, P.J. ; Corominas, J. ; De Sostoa, A. ; Morral, J.M.E. ; Estrada, M. ; Folch, R. ; Franquesa, T. ; Garcia-Lozano, C. ; Garí, M. ; Geli, A.M. ; González-Guerrero, Ó. ; Gordillo, J. ; Gosálbez, J. ; Grimalt, J.O. ; Guàrdia, A. ; Isern, R. ; Jordana, J. ; Junqué, E. ; Lascurain, J. ; Lleonart, J. ; Llorente, G.A. ; Lloret, F. ; Lloret, J. ; Mallarach, J.M. ; Martín-Vide, J. ; Medir, R.M. ; Melero, Y. ; Montasell, J. ; Montori, A. ; Munné, A. ; Lo, O.N. ; Palazón, S. ; Palmero, M. ; Parés, M. ; Pino, J. ; Pintó, J. ; Planagumà, L. ; Pons, X. ; Prat, N. ; Puig, C. ; Puig, I. ; Puigdoménech, P. ; Pujol-Buxó, E. ; Roca, N. ; Rodrigo, J. ; Rodríguez-Teijeiro, J.D. ; Roig-Munar, F.X. ; Romanyà, J. ; Rovira, P. ; Sàez, L. ; Sauras-Yera, M.T. ; Serrat, D. ; Simó, J. ; Soler, J. ; Terradas, J. ; Vallejo, R. ; Vicente, P. ; Vilaplana, J.M. ; Vinyoles, D.
Land 10:144 (2021)
This paper provides an overview of the last 40 years of use, and in many cases abuse, of the natural resources in Catalonia, a country that is representative of European countries in general, and especially those in the Mediterranean region. It analyses the use of natural resources made by mining, agriculture, livestock, logging, fishing, nature tourism, and energy production and consumption. This use results in an ecological footprint, i.e., the productive land and sea surface required to generate the consumed resources and absorb the resulting waste, which is about seven times the amount available, a very high number but very similar to other European countries. This overexploitation of natural resources has a huge impact on land and its different forms of cover, air, and water. For the last 25 years, forests and urban areas have each gained almost 3% more of the territory at the expense of agricultural land; those municipalities bordering the sea have increased their number of inhabitants and activity, and although they only occupy 6.7% of the total surface area, they account for 43.3% of the population; air quality has stabilized since the turn of the century, and there has been some improvement in the state of aquatic ecosystems, but still only 36% are in good condition, while the remainder have suffered morphological changes and different forms of nonpoint source pollution; meanwhile the biodiversity of flora and fauna remains still under threat. Environmental policies do not go far enough so there is a need for revision of the legislation related to environmental impact and the protection of natural areas, flora, and fauna. The promotion of environmental research must be accompanied by environmental education to foster a society which ismore knowledgeable, has more control and influence over the decisions that deeply affect it. Indeed, nature conservation goes hand in hand with other social and economic challenges that require a more sustainable vision. Today’s problems with nature derive from the current economic model, which is environmentally unsustainable in that it does not take into account environmental impacts. Lastly, we propose a series of reasonable and feasible priority measures and actions related to each use made of the country’s natural resources, to the impacts they have had, and to their management, in the hope that these can contribute to improving the conservation and management of the environment and biodiversity and move towards sustainability.
Wissenschaftlicher Artikel
Scientific Article
Zech, M. ; Boesch, S. ; Škorvánek, M. ; Necpál, J. ; Švantnerová, J. ; Wagner, M. ; Dincer, Y. ; Sadr-Nabavi, A. ; Serranová, T. ; Rektorová, I. ; Havránková, P. ; Ganai, S. ; Mosejová, A. ; Příhodová, I. ; Šarláková, J. ; Kulcsarová, K. ; Ulmanová, O. ; Bechyně, K. ; Ostrozovičová, M. ; Haň, V. ; Ventosa, J.R. ; Shariati, M. ; Shoeibi, A. ; Weber, S. ; Mollenhauer, B. ; Trenkwalder, C. ; Berutti, R. ; Strom, T.M. ; Ceballos-Baumann, A. ; Mall, V. ; Haslinger, B. ; Jech, R. ; Winkelmann, J.
Parkinsonism Relat. Disord. 84, 129-134 (2021)
Introduction: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia. Methods: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource. Results: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone. Conclusions: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.
Wissenschaftlicher Artikel
Scientific Article
Bast, L. ; Buck, M.C. ; Hecker, J.S. ; Oostendorp, R.A.J. ; Götze, K.S. ; Marr, C.
iScience 24:102120 (2021)
Classically, hematopoietic stem cell (HSC) differentiation is assumed to occur via progenitor compartments of decreasing plasticity and increasing maturity in a specific, hierarchical manner. The classical hierarchy has been challenged in the past by alternative differentiation pathways. We abstracted experimental evidence into 10 differentiation hierarchies, each comprising 7 cell type compartments. By fitting ordinary differential equation models with realistic waiting time distributions to time-resolved data of differentiating HSCs from 10 healthy human donors, we identified plausible lineage hierarchies and rejected others. We found that, for most donors, the classical model of hematopoiesis is preferred. Surprisingly, multipotent lymphoid progenitor differentiation into granulocyte-monocyte progenitors is plausible in 90% of samples. An in silico analysis confirmed that, even for strong noise, the classical model can be identified robustly. Our computational approach infers differentiation hierarchies in a personalized fashion and can be used to gain insights into kinetic alterations of diseased hematopoiesis.
Wissenschaftlicher Artikel
Scientific Article
Perrin-Cocon, L. ; Vidalain, P.O. ; Jacquemin, C. ; Aublin-Gex, A. ; Olmstead, K. ; Panthu, B. ; Rautureau, G.J.P. ; André, P. ; Nyczka, P. ; Hütt, M.T. ; Amoedo, N. ; Rossignol, R. ; Filipp, F.V. ; Lotteau, V. ; Diaz, O.
Comm. Biol. 4:217 (2021)
During the cancerous transformation of normal hepatocytes into hepatocellular carcinoma (HCC), the enzyme catalyzing the first rate-limiting step of glycolysis, namely the glucokinase (GCK), is replaced by the higher affinity isoenzyme, hexokinase 2 (HK2). Here, we show that in HCC tumors the highest expression level of HK2 is inversely correlated to GCK expression, and is associated to poor prognosis for patient survival. To further explore functional consequences of the GCK-to-HK2 isoenzyme switch occurring during carcinogenesis, HK2 was knocked-out in the HCC cell line Huh7 and replaced by GCK, to generate the Huh7-GCK+/HK2− cell line. HK2 knockdown and GCK expression rewired central carbon metabolism, stimulated mitochondrial respiration and restored essential metabolic functions of normal hepatocytes such as lipogenesis, VLDL secretion, glycogen storage. It also reactivated innate immune responses and sensitivity to natural killer cells, showing that consequences of the HK switch extend beyond metabolic reprogramming.
Wissenschaftlicher Artikel
Scientific Article
Klöckner, C. ; Sticht, H. ; Zacher, P. ; Popp, B. ; Babcock, H.E. ; Bakker, D.P. ; Barwick, K. ; Bonfert, M.V. ; Bönnemann, C.G. ; Brilstra, E.H. ; Chung, W.K. ; Clarke, A.J. ; Devine, P. ; Donkervoort, S. ; Fraser, J.L. ; Friedman, J. ; Gates, A. ; Ghoumid, J. ; Hobson, E. ; Horvath, G. ; Keller-Ramey, J. ; Keren, B. ; Kurian, M.A. ; Lee, V. ; Leppig, K.A. ; Lundgren, J. ; McDonald, M.T. ; McLaughlin, H.M. ; McTague, A. ; Mefford, H.C. ; Mignot, C. ; Mikati, M.A. ; Nava, C. ; Raymond, F.L. ; Sampson, J.R. ; Sanchis-Juan, A. ; Shashi, V. ; Shieh, J.T.C. ; Shinawi, M. ; Slavotinek, A. ; Stödberg, T. ; Stong, N. ; Sullivan, J.A. ; Taylor, A.C. ; Toler, T.L. ; van den Boogaard, M.J. ; van der Crabben, S.N. ; van Gassen, K.L.I. ; van Jaarsveld, R.H. ; Van Ziffle, J. ; Wadley, A.F. ; Wagner, M. ; Wigby, K. ; Wortmann, S.B. ; Zarate, Y.A. ; Møller, R.S. ; Lemke, J.R. ; Platzer, K.
Genet. Med. 23:796 (2021)
Unfortunately, in the first sentence in the abstract, a spelling mistake was introduced during the production process after our proofreading. The wording was changed from “aims” to “aimsed.” Heather M. McLaughlin was not listed among the authors. The original article has been corrected.
Cheng, J. ; Çelik, M.H. ; Kundaje, A. ; Gagneur, J.
Genome Biol. 22:94 (2021)
We develop the free and open-source model Multi-tissue Splicing (MTSplice) to predict the effects of genetic variants on splicing of cassette exons in 56 human tissues. MTSplice combines MMSplice, which models constitutive regulatory sequences, with a new neural network that models tissue-specific regulatory sequences. MTSplice outperforms MMSplice on predicting tissue-specific variations associated with genetic variants in most tissues of the GTEx dataset, with largest improvements on brain tissues. Furthermore, MTSplice predicts that autism-associated de novo mutations are enriched for variants affecting splicing specifically in the brain. We foresee that MTSplice will aid interpreting variants associated with tissue-specific disorders.
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Cheng, J. ; Çelik, M.H. ; Kundaje, A. ; Gagneur, J.
Genome Biol. 22:107 (2021)
Following publication of the original paper [1], it was noticed that a typesetting error occurred. Julien Gagneur was mistakenly not indicated as a corresponding author. This has been corrected and the original article [1] has been updated.
Yao, C. ; Joehanes, R. ; Wilson, R. ; Tanaka, T. ; Ferrucci, L. ; Kretschmer, A. ; Prokisch, H. ; Schramm, K. ; Gieger, C. ; Peters, A. ; Waldenberger, M. ; Marzi, C. ; Herder, C. ; Levy, D.
Clin. Epigenet. 13:60 (2021)
BACKGROUND: DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. RESULTS: We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. CONCLUSIONS: Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.
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Yoon, G. ; Müller, C. ; Gaynanova, I.
J. Comput. Graph. Stat. 30, 1249-1256 (2021)
Latent Gaussian copula models provide a powerful means to perform multi-view data integration since these models can seamlessly express dependencies between mixed variable types (binary, continuous, zero-inflated) via latent Gaussian correlations. The estimation of these latent correlations, however, comes at considerable computational cost, having prevented the routine use of these models on high-dimensional data. Here, we propose a new computational approach for estimating latent correlations via a hybrid multilinear interpolation and optimization scheme. Our approach speeds up the current state of the art computation by several orders of magnitude, thus allowing fast computation of latent Gaussian copula models even when the number of variables p is large. We provide theoretical guarantees for the approximation error of our numerical scheme and support its excellent performance on simulated and real-world data. We illustrate the practical advantages of our method on high-dimensional sparse quantitative and relative abundance microbiome data as well as multi-view data from The Cancer Genome Atlas Project. Our method is implemented in the R package mixedCCA, available at https://github.com/irinagain/mixedCCA.
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Vural, S. ; Baumgartner, M. ; Lichtner, P. ; Eckstein, G.N. ; Hariry, H. ; Chen, W. ; Ruzicka, T. ; Melnik, B. ; Plewig, G. ; Wagner, M. ; Giehl, K.A.
J. Eur. Acad. Dermatol. Venereol. 35, 1386-1392 (2021)
BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease affecting apocrine gland-bearing skin in the axilla, groin and under the breasts. Mutations of the gamma-secretase gene complex, which is essential in the activation of Notch signalling pathways were shown in some families with HS and in a few sporadic cases. Although an imbalance in Notch signalling is implicated in the pathogenesis, the exact mechanism of HS development is yet unknown. OBJECTIVES: We aim to investigate the genetic basis of HS by determining the presence of mutations of gamma-secretase gene complex in a cohort of HS patients and by searching for a disease-causing pathogenic variant in a multi-generational HS family using parametric linkage analysis. METHODS: Thirty-eight patients clinically diagnosed with HS were included in this study. All exons and exon-intron boundaries of the genes encoding gamma-secretase complex consisting of six genes: APH1A, APH1B, PSENEN, NCSTN, PSEN1 and PSEN2 were sequenced by Sanger technique. Genetic mapping with parametric linkage analysis for the patients in the family was performed with eight affected and four healthy individuals. The logarithm of odds was calculated. RESULTS: In a sporadic patient with early-onset, severe lesions in axilla and groin, a novel single nucleotide deletion causing frameshift in exon 1 of the NCSTN gene was identified ((NM_015331.3): c.38delG, p.(Gly13Glufs*15)). The LOD score of 1.5 was never exceeded in any region of the genome, pointing towards intricate multigenic inheritance pattern within the affected family. CONCLUSIONS: The gamma-secretase gene complex mutations were rare in our cohort (3.2%). Besides, our analysis indicates a possible complex multigenic inheritance in a seemingly autosomal dominantly inherited large HS family. Genetics of both familial and sporadic HS may be complicated in most cases, and the role of other potential genes such as autoinflammatory and modifier genes as well as environmental factors may influence the pathogenesis.
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Filbir, F. ; Krahmer, F. ; Melnyk, O.
J. Fourier Anal. Appl. 27:31 (2021)
The angular synchronization problem of estimating a set of unknown angles from their known noisy pairwise differences arises in various applications. It can be reformulated as an optimization problem on graphs involving the graph Laplacian matrix. We consider a general, weighted version of this problem, where the impact of the noise differs between different pairs of entries and some of the differences are erased completely; this version arises for example in ptychography. We study two common approaches for solving this problem, namely eigenvector relaxation and semidefinite convex relaxation. Although some recovery guarantees are available for both methods, their performance is either unsatisfying or restricted to the unweighted graphs. We close this gap, deriving recovery guarantees for the weighted problem that are completely analogous to the unweighted version.
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Gebresilase, T. ; Finan, C. ; Suveges, D. ; Tessema, T.S. ; Aseffa, A. ; Davey, G. ; Hatzikotoulas, K. ; Zeggini, E. ; Newport, M.J. ; Tekola-Ayele, F.
Sci. Rep. 11:3285 (2021)
Podoconiosis, a debilitating lymphoedema of the leg, results from barefoot exposure to volcanic clay soil in genetically susceptible individuals. A previous genome-wide association study (GWAS) conducted in the Wolaita ethnic group from Ethiopia showed association between single nucleotide polymorphisms (SNPs) in the HLA class II region and podoconiosis. We aimed to conduct a second GWAS in a new sample (N = 1892) collected from the Wolaita and two other Ethiopian populations, the Amhara and the Oromo, also affected by podoconiosis. Fourteen SNPs in the HLA class II region showed significant genome-wide association (P < 5.0 × 10-8) with podoconiosis. The lead SNP was rs9270911 (P = 5.51 × 10-10; OR 1.53; 95% CI 1.34-1.74), located near HLA-DRB1. Inclusion of data from the first GWAS (combined N = 2289) identified 47 SNPs in the class II HLA region that were significantly associated with podoconiosis (lead SNP also rs9270911 (P = 2.25 × 10-12). No new loci outside of the HLA class II region were identified in this more highly-powered second GWAS. Our findings confirm the HLA class II association with podoconiosis suggesting HLA-mediated abnormal induction and regulation of immune responses may have a direct role in its pathogenesis.
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den Hoed, J. ; de Boer, E. ; Voisin, N. ; Dingemans, A.J.M. ; Guex, N. ; Wiel, L. ; Nellaker, C. ; Amudhavalli, S.M. ; Banka, S. ; Bena, F.S. ; Ben-Zeev, B. ; Bonagura, V.R. ; Bruel, A.L. ; Brunet, T. ; Brunner, H.G. ; Chew, H.B. ; Chrast, J. ; Cimbalistienė, L. ; Coon, H. ; Délot, E.C. ; Démurger, F. ; Denommé-Pichon, A.S. ; Depienne, C. ; Donnai, D. ; Dyment, D.A. ; Elpeleg, O. ; Faivre, L. ; Gilissen, C. ; Granger, L. ; Haber, B. ; Hachiya, Y. ; Abedi, Y.H. ; Hanebeck, J. ; Hehir-Kwa, J.Y. ; Horist, B. ; Itai, T. ; Jackson, A. ; Jewell, R. ; Jones, K.L. ; Joss, S. ; Kashii, H. ; Kato, M. ; Kattentidt-Mouravieva, A.A. ; Kok, F. ; Kotzaeridou, U. ; Krishnamurthy, V. ; Kučinskas, V. ; Kuechler, A. ; Lavillaureix, A. ; Liu, P. ; Manwaring, L. ; Matsumoto, N. ; Mazel, B. ; McWalter, K. ; Meiner, V. ; Mikati, M.A. ; Miyatake, S. ; Mizuguchi, T. ; Moey, L.H. ; Mohammed, S. ; Mor-Shaked, H. ; Mountford, H. ; Newbury-Ecob, R. ; Odent, S. ; Orec, L. ; Osmond, M. ; Palculict, T.B. ; Parker, M. ; Petersen, A.K. ; Pfundt, R. ; Preikšaitienė, E. ; Radtke, K. ; Ranza, E. ; Rosenfeld, J.A. ; Santiago-Sim, T. ; Schwager, C. ; Sinnema, M. ; Snijders Blok, L. ; Spillmann, R.C. ; Stegmann, A.P.A. ; Thiffault, I. ; Tran, L. ; Vaknin-Dembinsky, A. ; Vedovato-Dos-Santos, J.H. ; Schrier Vergano, S.A. ; Vilain, E. ; Vitobello, A. ; Wagner, M. ; Waheeb, A. ; Willing, M. ; Zuccarelli, B. ; Kini, U. ; Newbury, D.F. ; Kleefstra, T. ; Reymond, A. ; Fisher, S.E. ; Vissers, L.E.L.M.
Am. J. Hum. Genet. 108, 346-356 (2021)
Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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Raimúndez, E. ; Dudkin, E. ; Vanhoefer, J. ; Alamoudi, E. ; Merkt, S. ; Fuhrmann, L. ; Bai, F. ; Hasenauer, J.
Epidemics 34:100439 (2021)
Epidemiological models are widely used to analyze the spread of diseases such as the global COVID-19 pandemic caused by SARS-CoV-2. However, all models are based on simplifying assumptions and often on sparse data. This limits the reliability of parameter estimates and predictions. In this manuscript, we demonstrate the relevance of these limitations and the pitfalls associated with the use of overly simplistic models. We considered the data for the early phase of the COVID-19 outbreak in Wuhan, China, as an example, and perform parameter estimation, uncertainty analysis and model selection for a range of established epidemiological models. Amongst others, we employ Markov chain Monte Carlo sampling, parameter and prediction profile calculation algorithms. Our results show that parameter estimates and predictions obtained for several established models on the basis of reported case numbers can be subject to substantial uncertainty. More importantly, estimates were often unrealistic and the confidence/credibility intervals did not cover plausible values of critical parameters obtained using different approaches. These findings suggest, amongst others, that standard compartmental models can be overly simplistic and that the reported case numbers provide often insufficient information for obtaining reliable and realistic parameter values, and for forecasting the evolution of epidemics.
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Pietzner, M. ; Wheeler, E. ; Carrasco-Zanini, J. ; Raffler, J. ; Kerrison, N.D. ; Oerton, E. ; Auyeung, V.P.W. ; Luan, J. ; Finan, C. ; Casas, J.P. ; Ostroff, R. ; Williams, S.A. ; Kastenmüller, G. ; Ralser, M. ; Gamazon, E.R. ; Wareham, N.J. ; Hingorani, A.D. ; Langenberg, C.
Nat. Commun. 12:845 (2021)
The original version of this Article cited “Mehra, M. R., Desai, S. S., Kuy, S., Henry, T. D. & Patel, A. N. Cardiovascular disease, drug therapy, and mortality in Covid-19. N. Engl. J. Med. 382, e102 (2020)” as Ref. 20. The cited paper was retracted; accordingly, Ref. 20 has been replaced with "Grasselli G et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern. Med. 180, 1345–1355 (2020)”. This has been corrected in the PDF and HTML versions of the article.
Scherb, H.
Eur. J. Clin. Invest. 51:e13500 (2021)
Sars-CoV-2 positive rates showed delays of about 20 days to proportional counts of positive deaths, worldwide. Using German data for the period 2/24/20 to 1/19/2021, the association of positive deaths with lagged positive rates was updated with focus on temporal homogeneity. A temporal clustering of the association between positive deaths and lagged positive rate was observed. This finding indicates unknown biological or epidemiological determinants of the pandemic and/or highlights deficits in Sars-CoV-2 metrics and statistics.
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Schmiester, L. ; Schälte, Y. ; Bergmann, F.T. ; Camba, T. ; Dudkin, E. ; Egert, J. ; Fröhlich, F. ; Fuhrmann, L. ; Hauber, A.L. ; Kemmer, S. ; Lakrisenko, P. ; Loos, C. ; Merkt, S. ; Müller, W. ; Pathirana, D. ; Raimundez-Alvarez, E. ; Refisch, L. ; Rosenblatt, M. ; Stapor, P. ; Städter, P. ; Wang, D. ; Wieland, F.G. ; Banga, J.R. ; Timmer, J. ; Villaverde, A.F. ; Sahle, S. ; Kreutz, C. ; Hasenauer, J. ; Weindl, D.
PLoS Comput. Biol. 17:e1008646 (2021)
Reproducibility and reusability of the results of data-based modeling studies are essential. Yet, there has been-so far-no broadly supported format for the specification of parameter estimation problems in systems biology. Here, we introduce PEtab, a format which facilitates the specification of parameter estimation problems using Systems Biology Markup Language (SBML) models and a set of tab-separated value files describing the observation model and experimental data as well as parameters to be estimated. We already implemented PEtab support into eight well-established model simulation and parameter estimation toolboxes with hundreds of users in total. We provide a Python library for validation and modification of a PEtab problem and currently 20 example parameter estimation problems based on recent studies.
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Städter, P. ; Schälte, Y. ; Schmiester, L. ; Hasenauer, J. ; Stapor, P.
Sci. Rep. 11:2696 (2021)
Ordinary differential equation (ODE) models are a key tool to understand complex mechanisms in systems biology. These models are studied using various approaches, including stability and bifurcation analysis, but most frequently by numerical simulations. The number of required simulations is often large, e.g., when unknown parameters need to be inferred. This renders efficient and reliable numerical integration methods essential. However, these methods depend on various hyperparameters, which strongly impact the ODE solution. Despite this, and although hundreds of published ODE models are freely available in public databases, a thorough study that quantifies the impact of hyperparameters on the ODE solver in terms of accuracy and computation time is still missing. In this manuscript, we investigate which choices of algorithms and hyperparameters are generally favorable when dealing with ODE models arising from biological processes. To ensure a representative evaluation, we considered 142 published models. Our study provides evidence that most ODEs in computational biology are stiff, and we give guidelines for the choice of algorithms and hyperparameters. We anticipate that our results will help researchers in systems biology to choose appropriate numerical methods when dealing with ODE models.
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Lopez, J.P. ; Brivio, E. ; Santambrogio, A. ; De Donno, C. ; Kos, A. ; Peters, M. ; Rost, N. ; Czamara, D. ; Brückl, T.M. ; Roeh, S. ; Pöhlmann, M.L. ; Engelhardt, C. ; Ressle, A. ; Stoffel, R. ; Tontsch, A. ; Villamizar, J.M. ; Reincke, M. ; Riester, A. ; Sbiera, S. ; Fassnacht, M. ; Mayberg, H.S. ; Craighead, W.E. ; Dunlop, B.W. ; Nemeroff, C.B. ; Schmidt, M.V. ; Binder, E.B. ; Theis, F.J. ; Beuschlein, F. ; Andoniadou, C.L. ; Chen, A.
Sci. Adv. 7:eabe4497 (2021)
Chronic activation and dysregulation of the neuroendocrine stress response have severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. We provide the first unbiased, cell type-specific, molecular characterization of all three components of the hypothalamic-pituitary- adrenal axis, under baseline and chronic stress conditions. Among others, we identified a previously unreported subpopulation of Abcb1b+ cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing's syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism's nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders.
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Sorg, A.L. ; von Kries, R. ; Klemme, M. ; Gerstl, L. ; Beyerlein, A. ; Lack, N. ; Felderhoff-Müser, U. ; Dzietko, M.
Dev. Med. Child. Neurol. 63, 697-704 (2021)
Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press. Aim: To describe the incidence of term and preterm neonatal cerebral sinovenous thrombosis (CSVT) and identify perinatal risk factors. Method: This was a national capture-recapture calculation-corrected surveillance and nested case–control study. Infants born preterm and at term with magnetic resonance imaging-confirmed neonatal CSVT were identified by surveillance in all paediatric hospitals in Germany (2015–2017). Incidence was corrected for underreporting using a capture-recapture method in one federal state and then extrapolated nationwide. We reviewed PubMed for comparisons with previously reported incidence estimators. We used a population-based perinatal database for quality assurance to select four controls per case and applied univariate and multivariable regression for risk factor analysis. Results: Fifty-one newborn infants (34 males, 17 females; 14 born preterm) with neonatal CSVT were reported in the 3-year period. The incidence of term and preterm neonatal CSVT was 6.6 (95% confidence interval [CI] 4.4–8.7) per 100 000 live births. Median age at time of confirmation of the diagnosis was 9.95 days (range 0–39d). In the univariate analysis, male sex, preterm birth, hypoxia and related indicators (umbilical artery pH <7.1; 5-minute Apgar score <7; intubation/mask ventilation; perinatal asphyxia), operative vaginal delivery, emergency Caesarean section, and pathological fetal Doppler sonography were associated (p<0.05) with neonatal CSVT. Multivariable regression yielded hypoxia (odds ratio=20.3; 95% CI 8.1–50.8) as the independent risk factor. Interpretation: Incidence of neonatal CSVT was within the range of other population-based studies. The results suggest that hypoxia is an important perinatal risk factor for the aetiology of neonatal CSVT.
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Scherb, H. ; Grech, V.
Reprod. Toxicol. 100, 137-142 (2021)
In Europe, the male to female ratio at birth (secondary sex ratio: SSR; sex odds: SO) is 1.04-1.06, is influenced by many factors and is declining in industrialized countries. This study was carried out to identify possible impacts of fallout by atomic bomb tests or by the Chernobyl event on SSR in Italy. Italy is a country without commercial nuclear power generation for the last four decades and thus nearly free of radiological confounders. Counts of annual male and female live births in Italy are provided by the World Health Organization (WHO) and by the Italian Istituto Nazionale di Statistica (ISTAT). This study included 57.7 million live births (1940-2019) with overall SSR 1.05829. The Italian SSR trend was modelled with linear and non-linear logistic regression. Trend changes, i.e., periods with level shifts were estimated with Markov Chain Monte Carlo (MCMC). Two distinct idealized level shifts were identified superimposed on a uniform secular downward trend. The first one is seen towards the end of the 1960s with a jump sex odds ratio (SOR) 1.00681, p < 0.0001. The second one occurred in 1987 with SOR 1.00474, p < 0.0001. In each of the 3 periods separated by the two jumps, SSR uniformly decreased with trend SOR per 100 years of 0.98549, p < 0.0001. In conclusion, the secular trend in the Italian SSR showed two marked level shifts, at the end of the 1960s and from 1987 onward. These follow the release of radioactivity by atmospheric atomic bomb tests during the 1960s and by Chernobyl in 1986 and corroborate the hypothesis that ionizing radiation increases SSR.
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Kortüm, F. ; Kieninger, S. ; Mazzola, P. ; Kohl, S. ; Wissinger, B. ; Prokisch, H. ; Stingl, K. ; Weisschuh, N.
Int. J. Mol. Sci. 22:850 (2021)
We aimed to validate the effect of non-canonical splice site variants in the RPGR gene in five patients from four families diagnosed with retinitis pigmentosa. Four variants located in intron 2 (c.154 + 3_154 + 6del), intron 3 (c.247 + 5G>A), intron 7 (c.779-5T>G), and intron 13 (c.1573-12A>G), respectively, were analyzed by means of in vitro splice assays. Splicing analysis revealed different aberrant splicing events, including exon skipping and intronic nucleotide addition, which are predicted to lead either to an in-frame deletion affecting relevant protein domains or to a frameshift of the open reading frame. Our data expand the landscape of pathogenic variants in RPGR, thereby increasing the genetic diagnostic rate in retinitis pigmentosa and allowing patients harboring the analyzed variants to be enrolled in clinical trials.
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Spiegel, E ; Kneib, T. ; von Gablenz, P. ; Otto‐Sobotka, F.
Biom. J. 63, 1028-1051 (2021)
Expectile regression, in contrast to classical linear regression, allows for heteroscedasticity and omits a parametric specification of the underlying distribution. This model class can be seen as a quantile‐like generalization of least squares regression. Similarly as in quantile regression, the whole distribution can be modeled with expectiles, while still offering the same flexibility in the use of semiparametric predictors as modern mean regression. However, even with no parametric assumption for the distribution of the response in expectile regression, the model is still constructed with a linear relationship between the fitted value and the predictor. If the true underlying relationship is nonlinear then severe biases can be observed in the parameter estimates as well as in quantities derived from them such as model predictions. We observed this problem during the analysis of the distribution of a self‐reported hearing score with limited range. Classical expectile regression should in theory adhere to these constraints, however, we observed predictions that exceeded the maximum score. We propose to include a response function between the fitted value and the predictor similarly as in generalized linear models. However, including a fixed response function would imply an assumption on the shape of the underlying distribution function. Such assumptions would be counterintuitive in expectile regression. Therefore, we propose to estimate the response function jointly with the covariate effects. We design the response function as a monotonically increasing P‐spline, which may also contain constraints on the target set. This results in valid estimates for a self