Allele imputation for the killer cell immunoglobulin-like receptor KIR3DL1/S1.

Highly polymorphic interaction of KIR3DL1 and KIR3DS1 with HLA class I ligands modulates the effector functions of natural killer (NK) cells and some T cells. This genetically determined diversity affects severity of infections, immune-mediated diseases, and some cancers, and impacts the course of immunotherapies, including transplantation. KIR3DL1 is an inhibitory receptor, and KIR3DS1 is an activating receptor encoded by the KIR3DL1/S1 gene that has more than 200 diverse and divergent alleles.

Calprotectin Expressing Donor-Derived Macrophages Increase in Acute Gastrointestinal Graft-Versus-Host Disease.

Acute graft versus host disease (GVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). GVHD is therefore the main obstacle for a more widespread use of this highly effective and potentially curative therapy. Although donor T cells are believed to be key mediators in the pathogenesis of acute GVHD, recent reports have suggested that monocyte-derived macrophages also contribute.

Cross disorder comparisons of brain structure in schizophrenia, bipolar disorder, major depressive disorder, and 22q11.2 deletion syndrome: A review of ENIGMA findings.

This review compares the main brain abnormalities in schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and 22q11.2 Deletion Syndrome (22q11DS) determined by ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium investigations. We obtained ranked effect sizes for subcortical volumes, regional cortical thickness, cortical surface area, and diffusion tensor imaging abnormalities, comparing each of these disorders relative to healthy controls.

Effects of a Novel UGT2B Haplotype and UGT1A4*3 Allele Variants on Glucuronidation of Clozapine In vivo.

Background: Glucuronidation is an important metabolic pathway of clozapine (CLZ), but the impact of various uridine 5'diphospho-glucuronosyltransferases (UGT) polymorphisms on the exposure and metabolism of CLZ in vivo is unclear.

Objective: The objective of this study was to investigate the impact of UGT2B haplotype and UGT1A4*3 allele variants on the formation of CLZ glucuronide metabolites (5N- and N+-glucuronide) and CLZ exposure in patients' serum after adjusting for sex, age, and smoking habits.

Methods: The study was based on serum samples from CLZ-treated patients (n=79) subjected to routine therapeutic drug monitoring (TDM) at Diakonhjemmet Hospital, Oslo, Norway.

Affective lability and social functioning in severe mental disorders.

Social functioning is impaired in severe mental disorders despite clinical remission, illustrating the need to identify other mechanisms that hinder psychosocial recovery. Affective lability is elevated and associated with an increased clinical burden in psychosis spectrum disorders. We aimed to investigate putative associations between affective lability and social functioning in 293 participants with severe mental disorders (schizophrenia- and bipolar spectrum), and if such an association was independent of well-established predictors of social impairments.

Structural basis of T cell receptor specificity and cross-reactivity of two HLA-DQ2.5-restricted gluten epitopes in celiac disease.

Celiac disease is a T cell-mediated chronic inflammatory condition often characterized by human leukocyte antigen (HLA)-DQ2.5 molecules presenting gluten epitopes derived from wheat, barley, and rye. Although some T cells exhibit cross-reactivity toward distinct gluten epitopes, the structural basis underpinning such cross-reactivity is unclear.

TCRpower: quantifying the detection power of T-cell receptor sequencing with a novel computational pipeline calibrated by spike-in sequences.

T-cell receptor (TCR) sequencing has enabled the development of innovative diagnostic tests for cancers, autoimmune diseases and other applications. However, the rarity of many T-cell clonotypes presents a detection challenge, which may lead to misdiagnosis if diagnostically relevant TCRs remain undetected. To address this issue, we developed TCRpower, a novel computational pipeline for quantifying the statistical detection power of TCR sequencing methods.

Healthcare use in 700 000 children and adolescents for six months after covid-19: before and after register based cohort study.

Objectives: To explore whether and for how long use of healthcare services is increased among children and adolescents after covid-19.

Design: Before and after register based study.

Setting: General population of Norway.

External Validation of the Patient-Reported Villalta Scale for the Diagnosis of Postthrombotic Syndrome.

Introduction:  The Villalta scale is the endorsed tool to diagnose and grade the severity of postthrombotic syndrome (PTS); however, assessing presence and severity of PTS is time-consuming and relies on both the clinician and patient's assessments. The patient-reported Villalta scale version 2 (PRV2) is a visually assisted form that enables patients to self-assess presence and severity of PTS. Herein, we report on external validation of this tool.

Association between myocardial fibrosis, as assessed with cardiac magnetic resonance T1 mapping, and persistent dyspnea after pulmonary embolism.

Background: Persistent dyspnea is a common symptom after pulmonary embolism (PE). However, the pathophysiology of persistent dyspnea is not fully clarified. This study aimed to explore possible associations between diffuse myocardial fibrosis, as assessed by cardiac magnetic resonance (CMR) T1 mapping, and persistent dyspnea in patients with a history of PE.

Causal association of cognitive reserve on Alzheimer's disease with putative sex difference.

Introduction: Sex-dependent risk factors may underlie sex differences in Alzheimer's disease (AD).

Methods: Using sex-stratified genome-wide association studies (GWAS) of AD, we evaluated associations of 12 traits with AD through polygenic risk scores (PRS) and Mendelian randomization (MR), and explored joint genetic architecture among significant traits by genomic structural equation modeling and network analysis.

Results: AD was associated with lower PRS for premorbid cognitive performance, intelligence, and educational attainment.

Strategies to gain novel Alzheimer's disease diagnostics and therapeutics using modulators of ABCA transporters.

Adenosine-triphosphate-(ATP)-binding cassette (ABC) transport proteins are ubiquitously present membrane-bound efflux pumps that distribute endo- and xenobiotics across intra- and intercellular barriers. Discovered over 40 years ago, ABC transporters have been identified as key players in various human diseases, such as multidrug-resistant cancer and atherosclerosis, but also neurodegenerative diseases, such as Alzheimer's disease (AD). Most prominent and well-studied are ABCB1, ABCC1, and ABCG2, not only due to their contribution to the multidrug resistance (MDR) phenotype in cancer, but also due to their contribution to AD.

Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics.

The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer's disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of 'under-studied' ABC transporters that cannot be addressed by small-molecules.

Intranasal delivery of a cDC1 targeted influenza vaccine with poly(I:C) enhances T cell responses and protects against influenza infection.

Targeting antigens to dendritic cells represent a promising method for enhancing immune responses against specific antigens. However, many studies have focused on systemic delivery (intravenous or intraperitoneally) of targeted antigen, approaches that are not easily transferable to humans. Here we evaluate the efficacy of an influenza vaccine targeting Xcr1 cDC1 administered by intranasal immunization.

Chronic treatment with terbutaline increases glucose and oleic acid oxidation and protein synthesis in cultured human myotubes.

Objective: studies have reported several beneficial metabolic effects of β-adrenergic receptor agonist administration in skeletal muscle, including increased glucose uptake, fatty acid metabolism, lipolysis and mitochondrial biogenesis. Although these effects have been widely studied , the data are limited to mouse and rat cell lines. Therefore, we sought to discover the effects of the β-adrenergic receptor agonist terbutaline on metabolism and protein synthesis in human primary skeletal muscle cells.

Structural feature-driven pattern analysis for multitarget modulator landscapes.

Motivation: Multitargeting features of small molecules have been of increasing interest in recent years. Polypharmacological drugs that address several therapeutic targets may provide greater therapeutic benefits for patients. Furthermore, multitarget compounds can be used to address proteins of the same (or similar) protein families for their exploration as potential pharmacological targets.

Matrix M Adjuvanted H5N1 Vaccine Elicits Broadly Neutralizing Antibodies and Neuraminidase Inhibiting Antibodies in Humans That Correlate With Protection.

The highly pathogenic avian influenza H5N1 viruses constantly evolve and give rise to novel variants that have caused widespread zoonotic outbreaks and sporadic human infections. Therefore, vaccines capable of eliciting broadly protective antibody responses are desired and under development. We here investigated the magnitude, kinetics and protective efficacy of the multi-faceted humoral immunity induced by vaccination in healthy adult volunteers with a Matrix M adjuvanted virosomal H5N1 vaccine.

T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.

Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice.

Methotrexate Treatment of Newly Diagnosed RA Patients Is Associated With DNA Methylation Differences at Genes Relevant for Disease Pathogenesis and Pharmacological Action.

Background: Methotrexate (MTX) is the first line treatment of rheumatoid arthritis (RA), and methylation changes in bulk T cells have been reported after treatment with MTX. We have investigated cell-type specific DNA methylation changes across the genome in naïve and memory CD4 T cells before and after MTX treatment of RA patients. DNA methylation profiles of newly diagnosed RA patients (N=9) were assessed by reduced representation bisulfite sequencing.

JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles.

JASPAR (http://jaspar.genereg.net/) is an open-access database containing manually curated, non-redundant transcription factor (TF) binding profiles for TFs across six taxonomic groups.

Oxytocin-pathway polygenic scores for severe mental disorders and metabolic phenotypes in the UK Biobank.

Oxytocin is a neuromodulator and hormone that is typically associated with social cognition and behavior. In light of its purported effects on social cognition and behavior, research has investigated its potential as a treatment for psychiatric illnesses characterized by social dysfunction, such as schizophrenia and bipolar disorder. While the results of these trials have been mixed, more recent evidence suggests that the oxytocin system is also linked with cardiometabolic conditions for which individuals with severe mental disorders are at a higher risk for developing.

Covid-19 transmission in fitness centers in Norway - a randomized trial.

Background: Closed fitness centers during the Covid-19 pandemic may negatively impact health and wellbeing. We assessed whether training at fitness centers increases the risk of SARS-CoV-2 virus infection.

Methods: In a two-group parallel randomized controlled trial, fitness center members aged 18 to 64 without Covid-19-relevant comorbidities, were randomized to access to training at a fitness center or no-access.

Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies.

Diffuse midline glioma (DMG) is a deadly pediatric and adolescent central nervous system (CNS) tumor localized along the midline structures of the brain atop the spinal cord. With a median overall survival (OS) of just 9-11-months, DMG is characterized by global hypomethylation of histone H3 at lysine 27 (H3K27me3), driven by recurring somatic mutations in H3 genes including, HIST1H3B/C (H3.1K27M) or H3F3A (H3.

Plasma extracellular vesicles in people living with HIV and type 2 diabetes are related to microbial translocation and cardiovascular risk.

HIV and type 2 diabetes (T2D) are both associated with gut microbiota alterations, low-grade endotoxemia and increased cardiovascular risk. We investigated the potential role of plasma extracellular vesicles (EVs) in relation to these processes. Plasma EVs were isolated by size exclusion chromatography in fasting individuals with HIV and T2D (n = 16), T2D only (n = 14), HIV only (n = 20) or healthy controls (n = 19), and characterized by transmission electron microscopy, western blot, nanoparticle tracking analysis and quantitative proteomics.