Drug Development.

Background: Chronic innate neuroinflammation mediated by microglia and astrocytes in response to Aβ and pathological Tau species is a cardinal feature of AD that contributes to disease pathogenesis. Accumulating evidence now also highlight an instrumental role of T cells and peripheral-central immune crosstalk in the pathophysiology of AD. Both preclinical and clinical reports suggest the potential therapeutic interest of peripheral immunomodulatory approaches aimed at amplifying regulatory T cells (Tregs), e.

Imagine, Discover, Inspire: Proceedings of the 4th International Conference of the Trisomy 21 Research Society.

Down syndrome (DS) or trisomy 21 (T21) is present in a significant number of children and adults around the world and is associated with cognitive and medical challenges. Through research, the T21 Research Society (T21RS), established in 2014, unites a worldwide community dedicated to understanding the impact of T21 on biological systems and improving the quality of life of people with DS across the lifespan. T21RS hosts an international conference every two years to support collaboration, dissemination, and information sharing for this goal.

FLI1 and GATA1 govern transcription: new insights into FLI1-related platelet disorders.

Germline variants of FLI1, essential for megakaryopoiesis, are linked to bleeding disorders, platelet aggregation defects and mild thrombocytopenia. However, the mechanisms behind these abnormalities remain unclear. This study aims to elucidate the impact of FLI1 variants on human megakaryocytes and platelets.

A stratified treatment algorithm in psychiatry: a program on stratified pharmacogenomics in severe mental illness (Psych-STRATA): concept, objectives and methodologies of a multidisciplinary project funded by Horizon Europe.

Schizophrenia (SCZ), bipolar (BD) and major depression disorder (MDD) are severe psychiatric disorders that are challenging to treat, often leading to treatment resistance (TR). It is crucial to develop effective methods to identify and treat patients at risk of TR at an early stage in a personalized manner, considering their biological basis, their clinical and psychosocial characteristics. Effective translation of theoretical knowledge into clinical practice is essential for achieving this goal.

Predictive Factors for HBsAg Loss in Chronic HBeAg-Negative Hepatitis B Virus Infection: Insights From a 5-Year French Cohort.

Prognostic factors for the long-term evolution of chronic hepatitis B e antigen (HBeAg)-negative hepatitis B virus (HBV) infection may vary depending on local epidemiology. We aimed to identify these factors in France, where the epidemiology is influenced by diverse immigration. Hepatitis B surface antigen (HBsAg)-positive, HBeAg-negative adults with normal transaminase levels and viral loads < 20,000 IU/mL for 1 year, without viral co-infection or advanced liver disease, were enrolled for a 5-year follow-up.

Glucagon-Like Peptide-1 Receptor Agonist-Experienced Adults with Type 2 Diabetes Switching to Once-Weekly Semaglutide in a Real-World Setting: SURE Program Post Hoc Analysis.

Introduction: To investigate outcomes in adults with type 2 diabetes who switched to once-weekly (OW) semaglutide from another glucagon-like peptide-1 receptor agonist (GLP-1RA) in clinical practice.

Methods: This post hoc analysis used data from the SemaglUtide Real-world Evidence (SURE) program, which included nine observational studies investigating the initiation of OW semaglutide in people with type 2 diabetes in routine clinical practice. Using a random coefficient-adjusted mixed model for repeated measurements, changes in glycosylated hemoglobin (HbA), body weight, and body mass index were analyzed for GLP-1RA-experienced patients who had at least one documented HbA value within the 12 weeks before switching to OW semaglutide.

Optimizing Tris(2-Carboxyethyl)phosphine and Mercaptohexanol Concentrations for Thiolated Oligonucleotide Immobilization on Platinum Electrodes in Microfluidic Platforms.

In this study, we propose a strategy to explore the impact of the proportion of tris(2-carboxyethyl)phosphine (TCEP) and 6-mercaptohexanol (MCH) on the efficiency of oligonucleotide functionalization on PDMS microfluidic channels equipped with pairs of homemade microfabricated platinum microelectrodes. We identified an optimal concentration of these compounds that enables the effective orientation and distribution of probes, thereby facilitating subsequent target hybridization. The experiment included optimizing sample injection into microfluidic channels.

Modulation of the Immune Environment in Glioblastoma by the Gut Microbiota.

Studies increasingly support the role of the gut microbiota in glioma development and treatment, although the exact mechanisms remain unclear. Research indicates that the gut microbiota can influence glioma progression, response to therapies, and the effectiveness of treatments like immunotherapy, with certain microbial compositions being linked to better outcomes. Additionally, the gut microbiota impacts the tumor microenvironment, affecting both tumor growth and the response to treatment.

Effects of shear stress on mesenchymal stem cells of patients with osteogenesis imperfecta.

Introduction: Osteogenesis imperfecta (OI) is a rare genetic bone disorder, mainly caused by autosomal dominant mutations of the COL1A1 or COL1A2 genes that encode the alpha chains of type 1 collagen. In severe forms and in nonambulatory patients, for whom physical exercise is difficult, exposing the bone to mechanical stimuli by promoting movement, especially with physiotherapy and mobility aids, is an essential part of clinical practice. However, the effects of mechanical stimulation at the cellular level remain unknown for this disease.

Can the integration of new rules into a clinical decision support system reduce the incidence of acute kidney injury and hyperkalemia among hospitalized older adults: a protocol for a stepped-wedge, cluster-randomized trial (DETECT-IP).

Background: Clinical decision support systems (CDSSs) enable the automated, real-time detection of situations associated with a risk of adverse drug events (ADEs). However, the effectiveness of CDSS in reducing ADEs has yet to be demonstrated. We have chosen to focus on the detection of ADE such as hyperkalemia and/or acute kidney injury (AKI), which are common among hospitalized older adults.

Intact Fish Skin Graft to Treat Deep Diabetic Foot Ulcers.

Background: Diabetic foot ulcers are chronic, difficult to heal, and potentially life-threatening. Few medical devices have been studied in diabetic ulcers penetrating to bone or tendon.

Methods: We conducted an international, open-label randomized controlled trial, randomly assigning patients with diabetic ulcers penetrating to bone, joint, or tendon 1:1 to intact fish skin graft or standard wound care, with assigned treatment applied through 14 weeks.

Fully automated epicardial adipose tissue volume quantification with deep learning and relationship with CAC score and micro/macrovascular complications in people living with type 2 diabetes: the multicenter EPIDIAB study.

Background: The aim of this study (EPIDIAB) was to assess the relationship between epicardial adipose tissue (EAT) and the micro and macrovascular complications (MVC) of type 2 diabetes (T2D).

Methods: EPIDIAB is a post hoc analysis from the AngioSafe T2D study, which is a multicentric study aimed at determining the safety of antihyperglycemic drugs on retina and including patients with T2D screened for diabetic retinopathy (DR) (n = 7200) and deeply phenotyped for MVC. Patients included who had undergone cardiac CT for CAC (Coronary Artery Calcium) scoring after inclusion (n = 1253) were tested with a validated deep learning segmentation pipeline for EAT volume quantification.

Analysis of a Chronic Lateral Ankle Instability Model in the Rat: Conclusions and Suggestions for Future Research.

The purpose of this study was to evaluate potential osteoarthritic alterations within the ankle using a surgically-induced chronic lateral ankle instability (CLAI) model. Twelve rats were assigned randomly to either the control ( = 4) or CLAI group ( = 8). Surgery was performed on the right ankle.

Landing force reveals new form of motion-induced sound camouflage in a wild predator.

Predator-prey arms races have led to the evolution of finely tuned disguise strategies. While the theoretical benefits of predator camouflage are well established, no study has yet been able to quantify its consequences for hunting success in natural conditions. We used high-resolution movement data to quantify how barn owls () conceal their approach when using a sit-and-wait strategy.

Biosynthesis of a clickable pyoverdine via in vivo enzyme engineering of an adenylation domain.

The engineering of non ribosomal peptide synthetases (NRPS) for new substrate specificity is a potent strategy to incorporate non-canonical amino acids into peptide sequences, thereby creating peptide diversity and broadening applications. The non-ribosomal peptide pyoverdine is the primary siderophore produced by Pseudomonas aeruginosa and holds biomedical promise in diagnosis, bio-imaging and antibiotic vectorization. We engineered the adenylation domain of PvdD, the terminal NRPS in pyoverdine biosynthesis, to accept a functionalized amino acid.

Quantum Dot-Based FRET Nanosensors for Talin-Membrane Assembly and Mechanosensing.

Understanding the mechanisms of assembly and disassembly of macromolecular structures in cells relies on solving biomolecular interactions. However, those interactions often remain unclear because tools to track molecular dynamics are not sufficiently resolved in time or space. In this study, we present a straightforward method for resolving inter- and intra-molecular interactions in cell adhesive machinery, using quantum dot (QD) based Förster resonance energy transfer (FRET) nanosensors.

Strawberry phenotypic plasticity in flowering time is driven by the interaction between genetic loci and temperature.

Flowering time (FT), which determines when fruits or seeds can be harvested, is subject to phenotypic plasticity, that is, the ability of a genotype to display different phenotypes in response to environmental variation. Here, we investigated how the environment affects the genetic architecture of FT in cultivated strawberry (Fragaria × ananassa) and modifies its quantitative trait locus (QTL) effects. To this end, we used a bi-parental segregating population grown for 2 years at widely divergent latitudes (five European countries) and combined climatic variables with genomic data (Affymetrix SNP array).

Obesogenic diet induces sex-specific alterations of contextual fear memory and associated hippocampal activity in mice.

In addition to metabolic and cardiovascular disorders, obesity is associated with cognitive deficits in humans and animal models. We have previously shown that obesogenic high-fat and sugar diet intake during adolescence (adoHFSD) impairs hippocampus (HPC)-dependent memory in rodents. These results were obtained in males only and it remains to evaluate whether adoHFSD has similar effect in females.

The path to next-generation disease-modifying immunomodulatory combination therapies in Alzheimer's disease.

The cautious optimism following recent anti-amyloid therapeutic trials for Alzheimer's disease (AD) provides a glimmer of hope after years of disappointment. Although these encouraging results represent discernible progress, they also highlight the need to enhance further the still modest clinical efficacy of current disease-modifying immunotherapies. Here, we highlight crucial milestones essential for advancing precision medicine in AD.

Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema.

Primary lymphedema (PL), characterized by tissue swelling, fat accumulation, and fibrosis, results from defects in lymphatic vessels or valves caused by mutations in genes involved in development, maturation, and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor-like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms.

Automated deep learning segmentation of neuritic plaques and neurofibrillary tangles in Alzheimer disease brain sections using a proprietary software.

Neuropathological diagnosis of Alzheimer disease (AD) relies on semiquantitative analysis of phosphorylated tau-positive neurofibrillary tangles (NFTs) and neuritic plaques (NPs), without consideration of lesion heterogeneity in individual cases. We developed a deep learning workflow for automated annotation and segmentation of NPs and NFTs from AT8-immunostained whole slide images (WSIs) of AD brain sections. Fifteen WSIs of frontal cortex from 4 biobanks with varying tissue quality, staining intensity, and scanning formats were analyzed.