GPCR Promiscuity Reshapes Islet Physiology.

The family of proglucagon peptides Includes glucagon and glucagon-like peptide 1 (GLP-1), two unique peptides derived from the same prohormone. Despite numerous similarities between the peptides, these have long been viewed as having opposing actions on metabolism. GLP-1 is described as a postprandial hormone that stimulates anabolic actions via insulin, while glucagon is viewed as a fasting hormone that drives catabolic actions to maintain euglycemia.

Normal Pregnancy-Induced Islet Beta Cell Proliferation in Mouse Models That Are Deficient in Serotonin-Signaling.

During mouse pregnancy placental lactogens stimulate prolactin receptors on pancreatic islet beta cells to induce expression of the tryptophan hydroxylase , resulting in the synthesis and secretion of serotonin. Presently, the functional relevance of this phenomenon is unclear. One hypothesis is that serotonin-induced activation of 5-HT receptors on beta cells stimulates beta cell proliferation during pregnancy.

Vascular and Liver Homeostasis in Juvenile Mice Require Endothelial Cyclic AMP-Dependent Protein Kinase A.

During vascular development, endothelial cAMP-dependent protein kinase A (PKA) regulates angiogenesis by controlling the number of tip cells, and PKA inhibition leads to excessive angiogenesis. Whether this role of endothelial PKA is restricted to embryonic and neonatal development or is also required for vascular homeostasis later on is unknown. Here, we show that perinatal (postnatal days P1-P3) of later (P28-P32) inhibition of endothelial PKA using dominant-negative PKA expressed under the control of endothelial-specific Cdh5-CreERT2 recombinase (dnPKA mice) leads to severe subcutaneous edema, hypoalbuminemia, hypoglycemia and premature death.

Sequencing refractory regions in bird genomes are hotspots for accelerated protein evolution.

Background: Approximately 1000 protein encoding genes common for vertebrates are still unannotated in avian genomes. Are these genes evolutionary lost or are they not yet found for technical reasons? Using genome landscapes as a tool to visualize large-scale regional effects of genome evolution, we reexamined this question.

Results: On basis of gene annotation in non-avian vertebrate genomes, we established a list of 15,135 common vertebrate genes.

Comparing lung ultrasound: extensive versus short in COVID-19 (CLUES): a multicentre, observational study at the emergency department.

Background: Bedside lung ultrasound (LUS) is an affordable diagnostic tool that could contribute to identifying COVID-19 pneumonia. Different LUS protocols are currently used at the emergency department (ED) and there is a need to know their diagnostic accuracy.

Design: A multicentre, prospective, observational study, to compare the diagnostic accuracy of three commonly used LUS protocols in identifying COVID-19 pneumonia at the ED.

Regional effect on the molecular clock rate of protein evolution in Eutherian and Metatherian genomes.

Background: Different types of proteins diverge at vastly different rates. Moreover, the same type of protein has been observed to evolve with different rates in different phylogenetic lineages. In the present study we measured the rates of protein evolution in Eutheria (placental mammals) and Metatheria (marsupials) on a genome-wide basis and we propose that the gene position in the genome landscape has an important influence on the rate of protein divergence.

Assessing COVID-19 pneumonia-Clinical extension and risk with point-of-care ultrasound: A multicenter, prospective, observational study.

Background: Assessing the extent of lung involvement is important for the triage and care of COVID-19 pneumonia. We sought to determine the utility of point-of-care ultrasound (POCUS) for characterizing lung involvement and, thereby, clinical risk determination in COVID-19 pneumonia.

Methods: This multicenter, prospective, observational study included patients with COVID-19 who received 12-zone lung ultrasound and chest computed tomography (CT) scanning in the emergency department (ED).

[Lung ultrasound in patients with symptoms of covid-19].

The SARS-CoV-2 pandemic presents a challenge for healthcare worldwide. In this context, rapid, correct diagnosis and early isolation of infected persons is of great importance. Pneumonia as an expression of COVID-19 is responsible for the most part of morbidity and mortality.

Diagnosing COVID-19 pneumonia in a pandemic setting: Lung Ultrasound CT (LUVCT) - a multicentre, prospective, observational study.

Background: In this coronavirus disease 2019 (COVID-19) pandemic, fast and accurate testing is needed to profile patients at the emergency department (ED) and efficiently allocate resources. Chest imaging has been considered in COVID-19 workup, but evidence on lung ultrasound (LUS) is sparse. We therefore aimed to assess and compare the diagnostic accuracy of LUS and computed tomography (CT) in suspected COVID-19 patients.

Loss of in β-Cells Induces an mTORC1-ATF4 Anabolic Pathway That Leads to β-Cell Dysfunction.

FURIN is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, but its specific role in pancreatic β-cells is largely unknown. The aim of this study was to determine the role of FURIN in glucose homeostasis.

Vitamin D Binding Protein: A Historic Overview.

Vitamin D and all its metabolites are bound to a specific vitamin D binding protein, DBP. This protein was originally first discovered by its worldwide polymorphism and called Group-specific Component (GC). We now know that DBP and GC are the same protein and appeared early in the evolution of vertebrates.

Development and validation of a peripheral blood mRNA assay for the assessment of antibody-mediated kidney allograft rejection: A multicentre, prospective study.

Background: Antibody-mediated rejection, a leading cause of renal allograft graft failure, is diagnosed by histological assessment of invasive allograft biopsies. Accurate non-invasive biomarkers are not available.

Methods: In the multicentre, prospective BIOMARGIN study, blood samples were prospectively collected at time of renal allograft biopsies between June 2011 and August 2016 and analyzed in three phases.

GC content of vertebrate exome landscapes reveal areas of accelerated protein evolution.

Background: Rapid accumulation of vertebrate genome sequences render comparative genomics a powerful approach to study macro-evolutionary events. The assessment of phylogenic relationships between species routinely depends on the analysis of sequence homology at the nucleotide or protein level.

Results: We analyzed mRNA GC content, codon usage and divergence of orthologous proteins in 55 vertebrate genomes.

COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.

Objective: Cytochrome c oxidase (COX) deficiency is a major mitochondrial respiratory chain defect that has vast genetic and phenotypic heterogeneity. This study aims to identify novel causative genes of COX deficiency with only striated muscle-specific symptoms.

Methods: Whole exome sequencing was performed in 2 unrelated individuals who were diagnosed with congenital myopathy and presented COX deficiency in muscle pathology.

Functional peroxisomes are required for β-cell integrity in mice.

Objectives: Peroxisomes play a crucial role in lipid and reactive oxygen species metabolism, but their importance for pancreatic β-cell functioning is presently unknown. To examine the contribution of peroxisomal metabolism to β-cell homeostasis in mice, we inactivated PEX5, the import receptor for peroxisomal matrix proteins, in an inducible and β-cell restricted manner (Rip-Pex5 mice).

Methods: After tamoxifen-induced recombination of the Pex5 gene at the age of 6 weeks, mice were fed either normal chow or a high-fat diet for 12 weeks and were subsequently phenotyped.

Gene and Mirna Regulatory Networks During Different Stages of Crohn's Disease.

Background And Aims: Early treatment of Crohn's disease [CD] is required in order to optimize patient outcomes. To this end, we need to gain a better understanding of the molecular changes at the onset of CD.

Methods: As a model for the earliest mucosal CD lesions, we study post-operative recurrent CD [Rutgeerts score ≥ i2b].

Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation.

Despite partial elucidation of the pathophysiology of antibody-mediated rejection (ABMR) after kidney transplantation, it remains largely unclear which of the involved immune cell types determine disease activity and outcome. We used microarray transcriptomic data from a case-control study (n=95) to identify genes that are differentially expressed in ABMR. Given the co-occurrence of ABMR and T-cell-mediated rejection (TCMR), we built a bioinformatics pipeline to distinguish ABMR-specific mRNA markers.

Adrenal hormones mediate disease tolerance in malaria.

Malaria reduces host fitness and survival by pathogen-mediated damage and inflammation. Disease tolerance mechanisms counter these negative effects without decreasing pathogen load. Here, we demonstrate that in four different mouse models of malaria, adrenal hormones confer disease tolerance and protect against early death, independently of parasitemia.

Transgenic Artifacts Caused by Passenger Human Growth Hormone.

The minigene encoding human growth hormone (hGH) has been incorporated into over 300 transgenic mouse lines to improve transgene expression. However, unexpected and functional hGH expression can drastically alter physiology. We list here the mouse lines in which ectopic hGH has been confirmed, and we provide a wiki for lines awaiting analysis.

Genetic and Transcriptomic Bases of Intestinal Epithelial Barrier Dysfunction in Inflammatory Bowel Disease.

Background: Intestinal barrier defects are common in patients with inflammatory bowel disease (IBD). To identify which components could underlie these changes, we performed an in-depth analysis of epithelial barrier genes in IBD.

Methods: A set of 128 intestinal barrier genes was selected.

How stable is repression of disallowed genes in pancreatic islets in response to metabolic stress?

The specific phenotype of mature differentiated beta cells not only depends on the specific presence of genes that allow beta cell function but also on the selective absence of housekeeping genes ("disallowed genes") that would interfere with this function. Recent studies have shown that both histone modifications and DNA methylation via the de novo methyltransferase DNMT3A are involved in repression of disallowed genes in neonatal beta cells when these cells acquire their mature phenotype. It is unknown, however, if the environmental influence of advanced age, pregnancy and the metabolic stress of high fat diet or diabetes could alter the repression of disallowed genes in beta cells.

Steviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity.

Steviol glycosides (SGs), such as stevioside and rebaudioside A, are natural, non-caloric sweet-tasting organic molecules, present in extracts of the scrub plant Stevia rebaudiana, which are widely used as sweeteners in consumer foods and beverages. TRPM5 is a Ca-activated cation channel expressed in type II taste receptor cells and pancreatic β-cells. Here we show that stevioside, rebaudioside A and their aglycon steviol potentiate the activity of TRPM5.

Early differences in islets from prediabetic NOD mice: combined microarray and proteomic analysis.

Aims/hypothesis: Type 1 diabetes is an endocrine disease where a long preclinical phase, characterised by immune cell infiltration in the islets of Langerhans, precedes elevated blood glucose levels and disease onset. Although several studies have investigated the role of the immune system in this process of insulitis, the importance of the beta cells themselves in the initiation of type 1 diabetes is less well understood. The aim of this study was to investigate intrinsic differences present in the islets from diabetes-prone NOD mice before the onset of insulitis.

Effect of vedolizumab (anti-α4β7-integrin) therapy on histological healing and mucosal gene expression in patients with UC.

Objective: Lymphocyte recruitment to the inflamed gut is increased in UC. Inhibition of this cell trafficking by vedolizumab (VDZ) was successful in inducing and maintaining remission and in induction of endoscopic mucosal healing. There are no data on histological healing with VDZ.