Intestinal interstitial fluid isolation provides novel insight into the human host-microbiome interface.

Aims: The gastrointestinal (GI) tract is composed of distinct sub-regions, which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health.

The proline-rich antimicrobial peptide Api137 disrupts large ribosomal subunit assembly and induces misfolding.

The proline-rich antimicrobial designer peptide Api137 inhibits protein expression in bacteria by binding simultaneously to the ribosomal polypeptide exit tunnel and the release factor (RF), depleting the cellular RF pool and leading to ribosomal arrest at stop codons. This study investigates the additional effect of Api137 on the assembly of ribosomes using an Escherichia coli reporter strain expressing one ribosomal protein per 30S and 50S subunit tagged with mCherry and EGFP, respectively. Separation of cellular extracts derived from cells exposed to Api137 in a sucrose gradient reveals elevated levels of partially assembled and not fully matured precursors of the 50S subunit (pre-50S).

Gonadal sex and temperature independently influence germ cell differentiation and meiotic progression in .

In species with genetic sex determination (GSD), the sex identity of the soma determines germ cell fate. For example, in mice, XY germ cells that enter an ovary differentiate as oogonia, whereas XX germ cells that enter a testis initiate differentiation as spermatogonia. However, numerous species lack a GSD system and instead display temperature-dependent sex determination (TSD).

Flow Cytometric Assessment of FcγRIIIa-V158F Polymorphisms and NK Cell Mediated ADCC Revealed Reduced NK Cell Functionality in Colorectal Cancer Patients.

Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells is a key mechanism in anti-cancer therapies with monoclonal antibodies, including cetuximab (EGFR-targeting) and avelumab (PDL1-targeting). Fc gamma receptor IIIa (FcγRIIIa) polymorphisms impact ADCC, yet their clinical relevance in NK cell functionality remains debated. We developed two complementary flow cytometry assays: one to predict the FcγRIIIa-V158F polymorphism using a machine learning model, and a 15-color flow cytometry panel to assess antibody-induced NK cell functionality and cancer-immune cell interactions.

Sex hormone-dependent host-microbiome interactions and cardiovascular risk (XCVD): design of a longitudinal multi-omics cohort study.

Introduction: Cardiovascular diseases (CVDs) present differently in women and men, influenced by host-microbiome interactions. The roles of sex hormones in CVD outcomes and gut microbiome in modifying these effects are poorly understood. The XCVD study examines gut microbiome mediation of sex hormone effects on CVD risk markers by observing transgender participants undergoing gender-affirming hormone therapy (GAHT), with findings expected to extrapolate to cisgender populations.

Transcript-specific enrichment enables profiling of rare cell states via single-cell RNA sequencing.

Single-cell genomics technologies have accelerated our understanding of cell-state heterogeneity in diverse contexts. Although single-cell RNA sequencing identifies rare populations that express specific marker transcript combinations, traditional flow sorting requires cell surface markers with high-fidelity antibodies, limiting our ability to interrogate these populations. In addition, many single-cell studies require the isolation of nuclei from tissue, eliminating the ability to enrich learned rare cell states based on extranuclear protein markers.

Aryl Hydrocarbon Receptor Activation Promotes Effector CD4+ T Cell Homeostasis and Restrains Salt-sensitive Hypertension.

Excess dietary salt and salt-sensitivity contribute to cardiovascular disease. Distinct T cell phenotypic responses to high salt and hypertension as well as influences from environmental cues are not well understood. The aryl hydrocarbon receptor (AhR) is activated by dietary ligands, promoting T cell and systemic homeostasis.

Generation of effective and specific human TCRs against tumor/testis antigen NY-ESO-1 in mice with humanized T cell recognition system.

Generation of high avidity T cell receptors (TCRs) reactive to tumor-associated antigens (TAA) is impaired by tolerance mechanisms, which is an obstacle to effective T cell therapies for cancer treatment. NY-ESO-1, a human cancer-testis antigen, represents an attractive target for such therapies due to its broad expression in different cancer types and the restricted expression in normal tissues. Utilizing transgenic mice with a diverse human TCR repertoire, we isolated effective TCRs against NY-ESO-1 restricted to HLA-A*02:01.

Effective Inhibitor Removal from Wastewater Samples Increases Sensitivity of RT-dPCR and Sequencing Analyses and Enhances the Stability of Wastewater-Based Surveillance.

Wastewater-based surveillance (WBS) is a proven tool for monitoring population-level infection events. Wastewater contains high concentrations of inhibitors, which contaminate the total nucleic acids (TNA) extracted from these samples. We found that TNA extracts from raw influent of Berlin wastewater treatment plants contained highly variable amounts of inhibitors that impaired molecular analyses like dPCR and next-generation sequencing (NGS).

Trace amine-associated receptor 1 agonist reduces aggression in brain serotonin-deficient tryptophan hydroxylase 2 knockout rats.

Introduction: Aggression and self-harm disproportionately occur in youths preoccupied with social status tracking. These pathological conditions are linked to a serotonin (5-HT) deficit in the brain. Ablation of 5-HT biosynthesis by tryptophan hydroxylase 2 knockout (TPH2-KO) increases aggression in rodents.

Gene-editing in patient and humanized-mice primary muscle stem cells rescues dysferlin expression in dysferlin-deficient muscular dystrophy.

Dystrophy-associated fer-1-like protein (dysferlin) conducts plasma membrane repair. Mutations in the DYSF gene cause a panoply of genetic muscular dystrophies. We targeted a frequent loss-of-function, DYSF exon 44, founder frameshift mutation with mRNA-mediated delivery of SpCas9 in combination with a mutation-specific sgRNA to primary muscle stem cells from two homozygous patients.

Paracrine role of endothelial IGF-1 receptor in depot-specific adipose tissue adaptation in male mice.

During recent decades, changes in lifestyle have led to widespread nutritional obesity and its related complications. Remodelling adipose tissue as a therapeutic goal for obesity and its complications has attracted much attention and continues to be actively explored. The endothelium lines all blood vessels and is close to all cells, including adipocytes.

Loss of structural specificity in 3D genome organization upon viral infection is predicted by polymer physics.

In the last years, it has been proved that some viruses are able to re-structure chromatin organization and alter the epigenomic landscape of the host genome. In addition, they are able to affect the physical mechanisms shaping chromatin 3D structure, with a consequent impact on gene activity. Here, we investigate with polymer physics genome re-organization of the host genome upon SARS-CoV-2 viral infection and how it can impact structural variability within the population of single-cell chromatin configurations.

Microscopy image reconstruction with physics-informed denoising diffusion probabilistic model.

Light microscopy is a practical tool for advancing biomedical research and diagnostics, offering invaluable insights into the cellular and subcellular structures of living organisms. However, diffraction and optical imperfections actively hinder the attainment of high-quality images. In recent years, there has been a growing interest in applying deep learning techniques to overcome these challenges in light microscopy imaging.

Real-world multicentre cohort study on choices and effectiveness of immunotherapies in NMOSD and MOGAD.

Background: Recurrent attacks in neuromyelitis optica spectrum disorders (NMOSDs) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can lead to severe disability. We aimed to analyse the real-world use of immunotherapies in patients with NMOSD and MOGAD, focusing on changes in treatment strategies, effects on attack rates (ARR) and risk factors for attacks.

Methods: This longitudinal registry-based cohort study included 493 patients (320 with aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive NMOSD (65%), 44 with AQP4-IgG seronegative NMOSD (9%) and 129 MOGAD (26%)) with 1247 treatments from 19 German and one Austrian centre from the registry of the neuromyelitis optica study group (NEMOS).

High-resolution DNA methylation changes reveal biomarkers of heart failure with preserved ejection fraction versus reduced ejection fraction.

Novel biomarkers are needed to better identify-and distinguish-heart failure with preserved ejection fraction (HFpEF) from other clinical phenotypes. The goal of our study was to identify epigenetic-sensitive biomarkers useful to a more accurate diagnosis of HFpEF. We performed a network-oriented genome-wide DNA methylation study of circulating CD4 T lymphocytes isolated from peripheral blood using reduced representation bisulfite sequencing (RRBS) in two cohorts (i.

Impact of genetic test interpretation on a missense variant in Cohen syndrome.

Introduction: Cohen syndrome (CS) is an early-onset pediatric neurodevelopmental disorder characterized by postnatal microcephaly and intellectual disability. An accurate diagnosis for individuals with CS is crucial, particularly for their caretakers and future prospects. CS is predominantly caused by rare homozygous or compound heterozygous pathogenic variants in the vacuolar protein sorting-associated 13B () gene, which disrupt protein translation and lead to a loss of function (LoF) of the encoded VPS13B protein.

Distinguishing Transient From Persistent Brain Structural Changes in Pediatric Patients With Acute Disseminated Encephalomyelitis.

Background And Objectives: Pediatric patients with acute disseminated encephalomyelitis (ADEM) are at risk of impaired brain growth, with long-term neuropsychiatric consequences. We previously reported transient expansions of cerebral ventricle volume (VV) in experimental autoimmune encephalomyelitis, which subsequently normalized. In this study, we investigated changes in VV in ADEM in relation to other brain structures and clinical outcomes.

Blood-Based Biomarkers for Identifying Disease Activity in AQP4-IgG-Positive Neuromyelitis Optica Spectrum Disorder.

Importance: The temporal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) as biomarkers of disease activity for neuromyelitis optica spectrum disorder (NMOSD) remain underexplored.

Objective: To determine optimal timing for assessing sGFAP and sNfL, establish cutoff values differentiating between attacks and remissions in NMOSD, and evaluate these findings across independent cohorts.

Design, Setting, And Participants: This retrospective, longitudinal, multicenter cohort study was conducted among patients with aquaporin-4 antibody (AQP4-IgG)-positive NMOSD.

Hyperphenylalaninemia and serotonin deficiency in Dnajc12-deficient mice.

Serotonin exerts numerous neurological and physiological actions in the brain and in the periphery. It is generated by two different tryptophan hydroxylase enzymes, TPH1 and TPH2, in the periphery and in the brain, respectively, which are members of the aromatic amino acid hydroxylase (AAAH) family together with phenylalanine hydroxylase (PAH), degrading phenylalanine, and tyrosine hydroxylase (TH), generating dopamine. In this study, we show that the co-chaperone DNAJC12 is downregulated in serotonergic neurons in the brain of mice lacking TPH2 and thereby central serotonin.

A biomathematical model of SARS-CoV-2 in Syrian hamsters.

When infected with SARS-CoV-2, Syrian hamsters (Mesocricetus auratus) develop moderate disease severity presenting key features of human COVID-19. We here develop a biomathematical model of the disease course by translating known biological mechanisms of virus-host interactions and immune responses into ordinary differential equations. We explicitly describe the dynamics of virus population, affected alveolar epithelial cells, and involved relevant immune cells comprising for example CD4+ T cells, CD8+ T cells, macrophages, natural killer cells and B cells.