Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of ß-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.

Chicdiff: a computational pipeline for detecting differential chromosomal interactions in Capture Hi-C data.

SUMMARY: Capture Hi-C is a powerful approach for detecting chromosomal interactions involving, at least on one end, DNA regions of interest, such as gene promoters. We present Chicdiff, an R package for robust detection of differential interactions in Capture Hi-C data. Chicdiff enhances a state-of-the-art differential testing approach for count data with bespoke normalization and multiple testing procedures that account for specific statistical properties of Capture Hi-C. We validate Chicdiff on published Promoter Capture Hi-C data in human Monocytes and CD4+ T cells, identifying multitudes of cell type-specific interactions, and confirming the overall positive association between promoter interactions and gene expression. AVAILABILITY AND IMPLEMENTATION: Chicdiff is implemented as an R package that is publicly available at https://github.com/RegulatoryGenomicsGroup/chicdiff. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SliDL: A toolbox for processing whole-slide images in deep learning.

The inspection of stained tissue slides by pathologists is essential for the early detection, diagnosis and monitoring of disease. Recently, deep learning methods for the analysis of whole-slide images (WSIs) have shown excellent performance on these tasks, and have the potential to substantially reduce the workload of pathologists. However, WSIs present a number of unique challenges for analysis, requiring special consideration of image annotations, slide and image artefacts, and evaluation of WSI-trained model performance. Here we introduce SliDL, a Python library for performing pre- and post-processing of WSIs. SliDL makes WSI data handling easy, allowing users to perform essential processing tasks in a few simple lines of code, bridging the gap between standard image analysis and WSI analysis. We introduce each of the main functionalities within SliDL: from annotation and tile extraction to tissue detection and model evaluation. We also provide 'code snippets' to guide the user in running SliDL. SliDL has been designed to interact with PyTorch, one of the most widely used deep learning libraries, allowing seamless integration into deep learning workflows. By providing a framework in which deep learning methods for WSI analysis can be developed and applied, SliDL aims to increase the accessibility of an important application of deep learning.

Rare case of Capnocytophaga canimorsus meningitis in a man without risk factors.

Capnocytophaga canimorsus meningitis is an uncommon but potentially serious cause of meningitis, which is considered particularly rare in healthy and immunocompetent individuals. We present a case of C. canimorsus meningitis in a young, immunocompetent patient which was acquired following a dog bite. We review the literature and propose that underdiagnosis of this condition is likely. To avoid misdiagnosis, and thus improper management, clinicians should ensure that they identify animal exposure in all meningitic patients, and adopt a higher clinical suspicion in the absence of classical risk factors.

Detecting chromosomal interactions in Capture Hi-C data with CHiCAGO and companion tools.

Capture Hi-C is widely used to obtain high-resolution profiles of chromosomal interactions involving, at least on one end, regions of interest such as gene promoters. Signal detection in Capture Hi-C data is challenging and cannot be adequately accomplished with tools developed for other chromosome conformation capture methods, including standard Hi-C. Capture Hi-C Analysis of Genomic Organization (CHiCAGO) is a computational pipeline developed specifically for Capture Hi-C analysis. It implements a statistical model accounting for biological and technical background components, as well as bespoke normalization and multiple testing procedures for this data type. Here we provide a step-by-step guide to the CHiCAGO workflow that is aimed at users with basic experience of the command line and R. We also describe more advanced strategies for tuning the key parameters for custom experiments and provide guidance on data preprocessing and downstream analysis using companion tools. In a typical experiment, CHiCAGO takes ~2-3 h to run, although pre- and postprocessing steps may take much longer.

Vitamin D in children with cystic fibrosis.

PURPOSE: The Cystic Fibrosis Trust in 2007 published a recommended target of 75-150 nmol/L for 25-hydroxyvitamin D (25-OHD). In 2008 we found that only 10% of pancreatic insufficient (PI) children met this target. An increase in supplementation was implemented and a repeat audit performed in 2010. METHODS: PI children ≥1 year under sole-care in our regional centre were included. Vitamin D3 supplementation increased by >450% to either 3800 IU/day liquid or 800 IU daily plus 20,000 IU weekly tablets. In 2010 pancreatic sufficient (PS) children were also audited separately. RESULTS: The median 25-OHD level increased from 51.5 nmol/L in 2008 (n=78, 10% >75 nmol/L) to 72 nmol/L in 2010 (n=72, 51% >75 nmol/L), p<0.0001. In PS children (n=15 in 2010) 87% had 25-OHD levels <75 nmol/L. CONCLUSIONS: A substantial increase in supplementation led to a significant increase in 25-OHD levels but around half still failed to reach the recommended target.