Abstract
Adenosine-to-inosine (A-to-I) RNA editing is a conserved posttranscriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules1. Although many editing sites have recently been discovered2-7, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood8-10. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of nonrepetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis-and trans-regulation of A-to-I editing.

Abstract
Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches. 2017 © The Authors.

Abstract
Background and purpose We evaluated two methods to identify mesial temporal sclerosis (MTS): visual inspection by experienced epilepsy neuroradiologists based on structural magnetic resonance imaging sequences and automated hippocampal volumetry provided by a processing pipeline based on the FMRIB Software Library. Methods This retrospective study included patients from the epilepsy monitoring unit database of our institution. All patients underwent brain magnetic resonance imaging in 1.5T and 3T scanners with protocols that included thin coronal T2, T1 and fluid-attenuated inversion recovery and isometric T1 acquisitions. Two neuroradiologists with experience in epilepsy and blinded to clinical data evaluated magnetic resonance images for the diagnosis of MTS. The diagnosis of MTS based on an automated method included the calculation of a volumetric asymmetry index between the two hippocampi of each patient and a threshold value to define the presence of MTS obtained through statistical tests (receiver operating characteristics curve). Hippocampi were segmented for volumetric quantification using the FIRST tool and fslstats from the FMRIB Software Library. Results The final cohort included 19 patients with unilateral MTS (14 left side): 14 women and a mean age of 43.4 ± 10.4 years. Neuroradiologists had a sensitivity of 100% and specificity of 73.3% to detect MTS (gold standard, k = 0.755). Automated hippocampal volumetry had a sensitivity of 84.2% and specificity of 86.7% (k = 0.704). Combined, these methods had a sensitivity of 84.2% and a specificity of 100% (k = 0.825). Conclusions Automated volumetry of the hippocampus could play an important role in temporal lobe epilepsy evaluation, namely on confirmation of unilateral MTS diagnosis in patients with radiological suggestive findings. © SAGE Publications.

Abstract
Gene expression is dependent on genetic and environmental factors. In the last decade, a large body of research has significantly improved our understanding of the genetic architecture of gene expression. However, it remains unclear whether genetic effects on gene expression remain stable over time. Here, we show, using longitudinal whole-blood gene expression data from a twin cohort, that the genetic architecture of a subset of genes is unstable over time. In addition, we identified 2213 genes differentially expressed across time points that we linked with aging within and across studies. Interestingly, we discovered that most differentially expressed genes were affected by a subset of 77 putative causal genes. Finally, we observed that putative causal genes and down-regulated genes were affected by a loss of genetic control between time points. Taken together, our data suggest that instability in the genetic architecture of a subset of genes could lead to widespread effects on the transcriptome with an aging signature. ©2017 Bryois et al.

Abstract
Given a retinal image, can we automatically determine whether it is of high quality (suitable for medical diagnosis)? Can we also explain our decision, pinpointing the region or regions that led to our decision? Images from human retinas are vital for the diagnosis of multiple health issues, like hypertension, diabetes, and Alzheimer's; low quality images may force the patient to come back again for a second scanning, wasting time and possibly delaying treatment. However, existing retinal image quality assessment methods are either black boxes without explanations of the results or depend heavily on feature engineering or on complex and error-prone anatomical structures' segmentation. Therefore, we propose EyeQual, that solves exactly this problem. EyeQual is novel, fast for inference, accurate and explainable, pinpointing low-quality regions on the image. We evaluated EyeQual on two real datasets where it achieved 100% accuracy taking just 36 milliseconds for each image.

Abstract
This paper describes a methodology for Diabetic Retinopathy detection from eye fundus images using a generalization of the Bag-of-Visual-Words (BoVW) method. We formulate the BoVW as two neural networks that can be trained jointly. Unlike the BoVW, our model is able to learn how to perform feature extraction, feature encoding and classification guided by the classification error. The model achieves 0.97 Area Under the Curve (AUC) on the DR2 dataset while the standard BoVW approach achieves 0.94 AUC. Also, it performs at the same level of the state-of-the-art on the Messidor dataset with 0.90 AUC.