Systematic assessment of COVID-19 host genetics using whole genome sequencing data.

Courses of SARS-CoV-2 infections are highly variable, ranging from asymptomatic to lethal COVID-19. Though research has shown that host genetic factors contribute to this variability, cohort-based joint analyses of variants from the entire allelic spectrum in individuals with confirmed SARS-CoV-2 infections are still lacking. Here, we present the results of whole genome sequencing in 1,220 mainly vaccine-naïve individuals with confirmed SARS-CoV-2 infection, including 827 hospitalized COVID-19 cases.

Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype.

The mitochondrial ribosome (mitoribosome) synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA, and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders and frequently show combined oxidative phosphorylation deficiency.

Enforced CARD11/MALT1 signaling in dendritic cells triggers hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome fueled by uncontrolled mononuclear phagocyte activity, yet the innate immune mechanisms driving HLH pathogenesis remain elusive. Germline gain-of-function (GOF) mutations in CARD11, a pivotal regulator of lymphocyte antigen receptor signaling, cause the lymphoproliferative disease B-cell expansion with NF-κB and T-cell anergy, which is frequently associated with HLH development. Given that CARD11 is physiologically expressed not only in lymphocytes but also in dendritic cells (DCs), we explored whether enforced CARD11 signaling in DCs contributes to immunopathology.

Sex differences in insulin induced hippocampus functional connectivity during visual food cue presentation.

Aims: Central insulin has been shown to regulate eating behavior and cognitive processes in a sex-specific manner. Besides memory, the hippocampus is pivotal in the control of appetite. However, how insulin interacts with the hippocampal food cue response and the role of sex hormones in this context remain unclear.

Carrageenan and insulin resistance in humans: a randomised double-blind cross-over trial.

Background: The potential impact of specific food additives, common in Western diets, on the risk of developing type 2 diabetes is not well understood. This study focuses on carrageenan, a widely used food additive known to induce insulin resistance and gut inflammation in animal models, and its effects on human health.

Methods: In a randomised, double-blind, placebo-controlled, cross-over trial conducted at a university hospital metabolic study centre, 20 males (age 27.

DEP-1 is a brain insulin receptor phosphatase that prevents the simultaneous activation of counteracting metabolic pathways.

A healthy metabolism relies on precise regulation of anabolic and catabolic pathways. While insulin deficiency impairs anabolism, insulin resistance in obesity causes metabolic dysfunction, especially via altered brain insulin receptor (IR) activity. Density-enhanced phosphatase 1 (DEP-1) negatively modulates the IR in peripheral tissues.

The C-type lectin receptor MINCLE interferes with eosinophil function and protective intestinal immunity in Strongyloides ratti-infected mice.

Strongyloides ratti is a helminth parasite that displays tissue-migrating and intestinal life stages. Myeloid C-type lectin receptors (CLRs) are pattern recognition receptors that recognize pathogen-derived ligands and initiate immune responses. To date, the role of CLRs in S.

Omentin Increases Glucose Uptake, but Not Insulin Sensitivity in Human Myotubes Dependent on Extracellular Lactotransferrin.

Introduction: Omentin (intelectin-1) is an adipokine produced by the stromal vascular fraction of visceral adipose tissue and has been positively associated with insulin sensitivity. The underlying mechanism of action, however, is largely unknown. It has been described that omentin may increase insulin sensitivity and glucose uptake of adipocytes, but effects on other insulin-sensitive tissues such as skeletal muscle are unexplored.

Longitudinal analysis of astrocyte-derived protein levels in the blood of drug-naive and relapsed patients with schizophrenia.

The potential influence of astrocytes on neuronal circuitry and psychotic symptoms in schizophrenia have recently been highlighted. Human postmortem studies have observed reduced astrocyte numbers in schizophrenia, but whether this pathology is present at disease onset or accumulates progressively with further psychotic episodes remains unclear. Therefore, we analysed serum levels of the astrocyte-derived proteins glial fibrillary acidic protein (GFAP) and fatty acid-binding protein 7 (FABP7) in acutely ill first-episode (n = 60) and relapsed (n = 34) schizophrenia patients compared to 94 matched controls.

Expert-Guided Large Language Models for Clinical Decision Support in Precision Oncology.

Purpose: Rapidly expanding medical literature challenges oncologists seeking targeted cancer therapies. General-purpose large language models (LLMs) lack domain-specific knowledge, limiting their clinical utility. This study introduces the LLM system Medical Evidence Retrieval and Data Integration for Tailored Healthcare (MEREDITH), designed to support treatment recommendations in precision oncology.

A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes.

In a patient with permanent neonatal syndromic diabetes clinically similar to cases with ONECUT1 biallelic mutations, we identified a disease-causing deletion located upstream of ONECUT1. Through genetic, genomic, and functional studies, we identified a crucial regulatory region acting as an enhancer of ONECUT1 specifically during pancreatic development. This enhancer region contains a low-frequency variant showing a strong association with type 2 diabetes and other glycemic traits, thus extending the contribution of this region to common forms of diabetes.

Histomorphological scoring of murine colitis models: A practical guide for the evaluation of colitis and colitis-associated cancer.

Background And Aims: Histomorphology is a powerful and cost-efficient tool for evaluating inflammatory and neoplastic conditions. Inflammatory bowel disease (IBD) is a widespread condition with globally rising incidences, and a lot of research is done to better understand the pathogenesis of IBD and to identify potential therapeutic approaches. However, standardized and reproducible scores for the histomorphological evaluation of murine IBD models are lacking.

TGF-β2, EGF and FGF21 influence the suckling rat intestinal maturation.

Some of the growth factors present in breast milk, such as transforming growth factor-β (TGF-β), epidermal growth factor (EGF) and fibroblast growth factor 21 (FGF21), play important roles in the development of the intestinal tract. The aim of this study was to determine the effect of a supplementation with TGF-β2, EGF and FGF21 on suckling rats intestinal maturation. For this purpose, Wistar rats were supplemented daily with TGF-β2, EGF or FGF21 throughout the suckling period.

Biallelic variants in result in reduced assembly of the mitoribosomal small subunit with altered intrinsic and extrinsic apoptosis and a Perrault syndrome-spectrum phenotype.

The mitoribosome synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders, and frequently show combined oxidative phosphorylation deficiency.

Dynamic interplay of cortisol and BDNF in males under acute and chronic psychosocial stress - A randomized controlled study.

The neurotrophic protein brain-derived neurotrophic factor (BDNF) plays a pivotal role in brain function and is affected by acute and chronic stress. We here investigate the patterns of BDNF and cortisol stress reactivity and recovery under the standardized stress protocol of the TSST and the effect of perceived chronic stress on the basal BDNF levels in healthy young men. Twenty-nine lean young men underwent the Trier Social Stress Test (TSST) and a resting condition.

Evaluation of a host-protein signature score for differentiating between bacterial and viral infections: real-life evidence from a German tertiary hospital.

Purpose: A host-protein signature score, consisting of serum-concentrations of C-reactive protein, tumour necrosis factor-related apoptosis-inducing ligand, and interferon gamma-induced protein 10, was validated for distinguishing between bacterial and viral infections as an antimicrobial stewardship measure for routine clinical practice among adult patients in a German tertiary hospital.

Methods: This single-centre, explorative study prospectively assessed the host-protein signature score, comparing it with serum procalcitonin (PCT) in patients with blood stream infections (BSI) and evaluating its efficacy in patients with viral infections against the standard of care (SOC) to assess the need for antibiotics due to suspected bacterial super/coinfection. Manufacturer-specified threshold scores were used to differentiate viral (< 35) and bacterial (> 65) infections.

Management of patients with reduced dihydropyrimidine dehydrogenase activity receiving combined 5-fluoruracil-/capecitabine-based chemoradiotherapy.

Background: 5‑Fluoruracil (5-FU) and its oral prodrug capecitabine are mainstays in combined chemoradiotherapy regimens. They are metabolized by dihydropyrimidine dehydrogenase (DPYD). Pathogenic variants of the DPYD gene cause a reduction in DPYD activity, leading to possibly severe toxicities.

B-cell intrinsic RANK signaling cooperates with TCL1 to induce lineage-dependent B-cell transformation.

B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), remain incurable, with MM particularly prone to relapse. Our study introduces a novel mouse model with active RANK signaling and the TCL1 oncogene, displaying both CLL and MM phenotypes. In younger mice, TCL1 and RANK expression expands CLL-like B1-lymphocytes, while MM originates from B2-cells, becoming predominant in later stages and leading to severe disease progression and mortality.

Blood coagulation in Prediabetes clusters-impact on all-cause mortality in individuals undergoing coronary angiography.

Background: Metabolic clusters can stratify subgroups of individuals at risk for type 2 diabetes mellitus and related complications. Since obesity and insulin resistance are closely linked to alterations in hemostasis, we investigated the association between plasmatic coagulation and metabolic clusters including the impact on survival.

Methods: Utilizing data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, we assigned 917 participants without diabetes to prediabetes clusters, using oGTT-derived glucose and insulin, high-density lipoprotein cholesterol, triglycerides, and anthropometric data.

The Causal Effect of Intrapancreatic Fat Deposition on Acute and Chronic Pancreatitis: A Mendelian Randomization Study.

Introduction: Recent associative studies have linked intrapancreatic fat deposition (IPFD) with risk of pancreatitis, but the causal relationship remains unclear.

Methods: Using Mendelian randomization, we evaluated the causal association between genetically predicted IPFD and pancreatitis. This approach used genetic variants from genomewide association studies of IPFD (n = 25,617), acute pancreatitis (n = 6,787 cases/361,641 controls), and chronic pancreatitis (n = 3,875 cases/361,641 controls).