Objective To determine whether microRNAs are differentially expressed in men with normal versus impaired spermatogenesis, and to find a biomarker for accurate diagnosis of male infertility. Design ...Microarray with real-time polymerase chain reaction (RT-PCR) validation. Setting University research and clinical institutes. Patient(s) Male partner of selected couples (n = 27) who were undergoing assisted reproduction techniques for infertility treatment. Intervention(s) None. Main Outcome Measure(s) Statistically significantly altered microRNA expression profiles in normozoospermic versus asthenozoospermic and oligoasthenozoospermic men. Result(s) There were 50 miRNAs up-regulated and 27 miRNAs down-regulated in asthenozoospermic males. In oligoasthenozoospermic males, 42 miRNAs were up-regulated and 44 miRNAs down-regulated when compared with normozoospermic males. The miRNAs that exhibited the highest fold changes and area under the receiver operating characteristic curve were miR-34b, miR-122, and miR-1973 in samples from asthenozoospermic men and miR-34b, miR-34b*, miR-15b, miR-34c-5p, miR-122, miR-449a, miR-1973, miR-16, and miR-19a in samples from oligoasthenozoospermic men. Furthermore, quantitative RT-PCR assays on specific miRNAs, including miR-141, miR-200a, miR-122, miR-34b, miR-34c-5p, and miR-16, yielded results that were largely consistent with the microarray data. Conclusion(s) Our results reveal an extended number of miRNAs that were differentially expressed in asthenozoospermic and oligoasthenozoospermic males compared with normozoospermic males. These data provide evidence for analysis of miRNA profiles as a future diagnosing tool for male infertility.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Information on miRNA targeting genes is growing rapidly. For high-throughput experiments, but also for targeted analyses of few genes or miRNAs, easy analysis with concise representation of results ...facilitates the work of life scientists. We developed miRTargetLink, a tool for automating respective analysis procedures that are frequently applied. Input of the web-based solution is either a single gene or single miRNA, but also sets of genes or miRNAs, can be entered. Validated and predicted targets are extracted from databases and an interaction network is presented. Users can select whether predicted targets, experimentally validated targets with strong or weak evidence, or combinations of those are considered. Central genes or miRNAs are highlighted and users can navigate through the network interactively. To discover the most relevant biochemical processes influenced by the target network, gene set analysis and miRNA set analysis are integrated. As a showcase for miRTargetLink, we analyze targets of five cardiac miRNAs. miRTargetLink is freely available without restrictions at www.ccb.uni-saarland.de/mirtargetlink.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
BACKGROUND:Biochemical DNA modification resembles a crucial regulatory layer among genetic information, environmental factors, and the transcriptome. To identify epigenetic susceptibility regions and ...novel biomarkers linked to myocardial dysfunction and heart failure, we performed the first multi-omics study in myocardial tissue and blood of patients with dilated cardiomyopathy and controls.
METHODS:Infinium human methylation 450 was used for high-density epigenome-wide mapping of DNA methylation in left-ventricular biopsies and whole peripheral blood of living probands. RNA deep sequencing was performed on the same samples in parallel. Whole-genome sequencing of all patients allowed exclusion of promiscuous genotype-induced methylation calls.
RESULTS:In the screening stage, we detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy (false discovery corrected P≤0.05), with 3 of them reaching epigenome-wide significance at P≤5×10. Twenty-seven (46%) of these loci could be replicated in independent cohorts, underlining the role of epigenetic regulation of key cardiac transcription regulators. Using a staged multi-omics study design, we link a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression. Furthermore, we identified distinct epigenetic methylation patterns that are conserved across tissues, rendering these CpGs novel epigenetic biomarkers for heart failure.
CONCLUSIONS:The present study provides to our knowledge the first epigenome-wide association study in living patients with heart failure using a multi-omics approach.
Small non-coding RNAs, especially microRNAs, are discussed as promising biomarkers for a substantial number of human pathologies. A broad understanding in which solid tissues, cell types or body ...fluids a microRNA is expressed helps also to understand and to improve the suitability of miRNAs as non- or minimally-invasive disease markers. We recently reported the Human miRNA Tissue Atlas (
http://www.ccb.uni-saarland.de/tissueatlas
) containing 105 miRNA profiles of 31 organs from 2 corpses. We subsequently added miRNA profiles measured by others and us using the same array technology as for the first version of the Human miRNA Tissue Atlas. The latter profiles stem from 163 solid organs including lung, prostate and gastric tissue, from 253 whole blood samples and 66 fractioned blood cell isolates, from body fluids including 72 serum samples, 278 plasma samples, 29 urine samples, and 16 saliva samples and from different collection and storage conditions. While most miRNAs are ubiquitous abundant in solid tissues and whole blood, we also identified miRNAs that are rather specific for tissues. Our web-based repository now hosting 982 full miRNomes all of which are measured by the same microarray technology. The knowledge of these variant abundances of miRNAs in solid tissues, in whole blood and in other body fluids is essential to judge the value of miRNAs as biomarker.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
In many research disciplines, ordered lists are compared. One example is to compare a subset of all significant genes or proteins in a primary study to those in a replication study. Often, the top of ...the lists are compared using Venn diagrams, ore more precisely Euler diagrams (set diagrams showing logical relations between a finite collection of different sets). If different cohort sizes, different techniques or algorithms for evaluation were applied, a direct comparison of significant genes with a fixed threshold can however be misleading and approaches comparing lists would be more appropriate.
We developed DynaVenn, a web-based tool that incrementally creates all possible subsets from two or three ordered lists and computes for each combination a p-value for the overlap. Respectively, dynamic Venn diagrams are generated as graphical representations. Additionally an animation is generated showing how the most significant overlap is reached by backtracking. We demonstrate the improved performance of DynaVenn over an arbitrary cut-off approach on an Alzheimer's Disease biomarker set.
DynaVenn combines the calculation of the most significant overlap of different cohorts with an intuitive visualization of the results. It is freely available as a web service at http://www.ccb.uni-saarland.de/dynavenn.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this paper we examine the influence of foreign direct investment (FDI) inflows on energy intensities of developing countries empirically. We first replicate a simple ordinary least squares (OLS) ...estimation, as it is found in the literature, that suggests energy-intensity reductions from FDI inflows. However, the OLS estimation turns out to be spurious and only a starting point for further research. In our regressions we use macro-level panel data on 60 developing countries for the period 1975–2004, including other potential determinants of energy intensities, and carry out robustness checks with more specific data. The results do not confirm the hypothesis that aggregate FDI inflows reduce energy intensity of developing countries. Rather, foreign development aid seems to be related to energy efficiency gains.
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BFBNIB, CEKLJ, NUK, PNG, UL, UM, UPUK
Abstract
We present GeneTrail 3, a major extension of our web service GeneTrail that offers rich functionality for the identification, analysis, and visualization of deregulated biological processes. ...Our web service provides a comprehensive collection of biological processes and signaling pathways for 12 model organisms that can be analyzed with a powerful framework for enrichment and network analysis of transcriptomic, miRNomic, proteomic, and genomic data sets. Moreover, GeneTrail offers novel workflows for the analysis of epigenetic marks, time series experiments, and single cell data. We demonstrate the capabilities of our web service in two case-studies, which highlight that GeneTrail is well equipped for uncovering complex molecular mechanisms. GeneTrail is freely accessible at: http://genetrail.bioinf.uni-sb.de.
Chemosensory receptor genes encode G protein-coupled receptors with which animals sense their chemical environment. The large number of chemosensory receptor genes in the genome and their extreme ...genetic variability pose unusual challenges for understanding their evolution and function. Two articles in BMC Genomics explore the genetic variation of chemosensory receptor gene repertoires in humans and mice and provide unparalleled insight into the causes and consequences of this variability.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes.
Left ventricular non-compaction ...cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome.
In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays.
Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome.
For eosinophilic esophagitis (EoE), a substantial diagnostic delay is still a clinically relevant phenomenon. Deep learning-based algorithms have demonstrated potential in medical image analysis. ...Here we establish a convolutional neuronal network (CNN)-based approach that can distinguish the appearance of EoE from normal findings and candida esophagitis.
We trained and tested a CNN using 484 real-world endoscopic images from 134 subjects consisting of three classes (normal, EoE, and candidiasis). Images were split into two completely independent datasets. The proposed approach was evaluated against three trainee endoscopists using the test set. Model-explainability was enhanced by deep Taylor decomposition.
Global accuracy (0.915 95 % confidence interval (CI) 0.880-0.940), sensitivity (0.871 95 %CI 0.819-0.910), and specificity (0.936 95 %CI 0.910-0.955) were significantly higher than for the endoscopists on the test set. Global area under the receiver operating characteristic curve was 0.966 95 %CI 0.954-0.975. Results were highly reproducible. Explainability analysis found that the algorithm identified the characteristic signs also used by endoscopists.
Complex endoscopic classification tasks including more than two classes can be solved by CNN-based algorithms. Therefore, our algorithm may assist clinicians in making the diagnosis of EoE.
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