Development of a Polygenic Risk Score for Metabolic Dysfunction-Associated Steatotic Liver Disease Prediction in UK Biobank.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of liver-related morbidity and mortality. Although the invasive liver biopsy remains the golden standard for MASLD diagnosis, Magnetic Resonance Imaging-derived Proton Density Fat Fraction (MRI-PDFF) is an accurate, non-invasive method for the assessment of treatment response. This study aimed at developing a Polygenic Risk Score (PRS) to improve MRI-PDFF prediction using UK Biobank data to assess an individual's genetic liability to MASLD.

Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments.

Several human disorders, including Alzheimer's disease (AD), are characterized by the aberrant formation of amyloid fibrils. In many cases, the amyloid core is flanked by disordered regions, known as fuzzy coat. The structural properties of fuzzy coats, and their interactions with their environments, however, have not been fully described to date.

GABA/Glutamate Neuron Differentiation Imbalance and Increased AKT/mTOR Signaling in CNTNAP2 Cerebral Organoids.

Background: The polygenic nature of autism spectrum disorder (ASD) requires the identification of converging genetic pathways during early development to elucidate its complexity and varied manifestations.

Methods: We developed a human cerebral organoid model from induced pluripotent stem cells with targeted genome editing to abolish protein expression of the ASD risk gene.

Results: CNTNAP2 cerebral organoids displayed accelerated cell cycle, ventricular zone disorganization, and increased cortical folding.

Comprehensive histopathological analysis of gastric cancer in European and Latin America populations reveals differences in PDL1, HER2, p53 and MUC6 expression.

Introduction: Gastric cancer (GC) burden is currently evolving with regional differences associated with complex behavioural, environmental, and genetic risk factors. The LEGACy study is a Horizon 2020-funded multi-institutional research project conducted prospectively to provide comprehensive data on the tumour biological characteristics of gastroesophageal cancer from European and LATAM countries.

Material And Methods: Treatment-naïve advanced gastroesophageal adenocarcinoma patients were prospectively recruited in seven European and LATAM countries.

Elimination of High-grade Gliomas Through Induced Cytolysis, Elucidated by Two Patient Cases.

Background/aim: Glioblastoma multiforme (GBM) is the most common and aggressive form of primary malignant tumors in the central nervous system of adults. In practice, all patients with GBM experience relapse, and treatment options become limited following first-line therapy. We previously reported a new, successful treatment approach for a GBM patient, implemented in direct conjunction with surgical intervention.

Talin1 dysfunction is genetically linked to systemic capillary leak syndrome.

Systemic capillary leak syndrome (SCLS) is a rare life-threatening disorder due to profound vascular leak. The trigger and the cause of the disease are currently unknown and there is no specific treatment. Here, we identified a rare heterozygous splice-site variant in the TLN1 gene in a familial SCLS case, suggestive of autosomal dominant inheritance with incomplete penetrance.

Proteomic Changes of Glycolipid Pathways in Age-Related, Diabetic, and Post-Vitrectomy Cataracts.

: Alterations in glycolipid and glycosphingolipid pathways lead to compromised cell membranes and may be involved in cataract formation. However, the exact role of glycolipids in lens opacification is not completely understood. The aim of the current study is to investigate proteome complexity and the role of glycolipid and glycosphingolipid pathways in cataract formation.

VISTA Enhancer browser: an updated database of tissue-specific developmental enhancers.

Regulatory elements (enhancers) are major drivers of gene expression in mammals and harbor many genetic variants associated with human diseases. Here, we present an updated VISTA Enhancer Browser (https://enhancer.lbl.

Retrospective study of cisplatin plus radiotherapy toxicities in locally advanced squamous cell carcinoma of the head and neck - ReCisTT study.

Introduction: Squamous cell carcinoma of the head and neck (SCCHN) is a multifactorial disease involving genetic and environmental factors representing one of the most frequent cancer-related deaths worldwide. Tobacco and alcohol use account for most SCCHN, while a growing subset of oropharyngeal cancers is causally associated with human papillomavirus (HPV) infection. Despite improvements in overall survival, patients with HPV-negative locally advanced (LA) SCCHN continue to have a poor prognosis.

Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.

Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission.

Tear Proteomics in Children and Adolescents with Type 1 Diabetes: A Promising Approach to Biomarker Identification of Diabetes Pathogenesis and Complications.

The aim of the current study was to investigate the tear proteome in children and adolescents with type 1 diabetes (T1D) compared to healthy controls, and to identify differences in the tear proteome of children with T1D depending on different characteristics of the disease. Fifty-six children with T1D at least one year after diagnosis, aged 6-17 years old, and fifty-six healthy age- and sex-matched controls were enrolled in this cross-sectional study. The proteomic analysis was based on liquid chromatography tandem mass spectrometry (LC-MS/MS) enabling the identification and quantification of the protein content via Data-Independent Acquisition by Neural Networks (DIA-NN).

Exploration of isatin-based inhibitors of SARS-CoV-2 Nsp15 endoribonuclease.

The global health crisis caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) urges the development of new antiviral agents with broad coronavirus coverage. Due to its key role in viral evasion from the host innate immune response, the coronavirus Nsp15 uridine-specific endoribonuclease (EndoU) is of high interest as a drug target. Considering that the isatin scaffold is well-known for its versatile pharmacological properties, we synthesized and evaluated a series of compounds carrying an isatin core.

Biomimetic CO Capture Unlocked through Enzyme Mining: Discovery of a Highly Thermo- and Alkali-Stable Carbonic Anhydrase.

Taking immediate action to combat the urgent threat of CO-driven global warming is crucial for ensuring a habitable planet. Decarbonizing the industrial sector requires implementing sustainable carbon-capture technologies, such as biomimetic hot potassium carbonate capture (BioHPC). BioHPC is superior to traditional amine-based strategies due to its eco-friendly nature.

BioTextQuest v2.0: An evolved tool for biomedical literature mining and concept discovery.

The process of navigating through the landscape of biomedical literature and performing searches or combining them with bioinformatics analyses can be daunting, considering the exponential growth of scientific corpora and the plethora of tools designed to mine PubMed(®) and related repositories. Herein, we present BioTextQuest v2.0, a tool for biomedical literature mining.

Interplay between bone marrow adiposity and bone resorption in RANKL-mediated modelled osteoporosis.

Bone marrow adipose tissue (BMAT) accrues in osteoporosis, whereas its contribution to the progression of bone resorption remains insufficiently understood. To understand the mechanisms that promote BMAT expansion in osteoporosis, in the present study, we performed extensive analysis of the spatiotemporal pattern of BMAT expansion during the progression of bone resorption in TgRANKL transgenic mouse models of osteoporosis expressing human RANKL (receptor activator of nuclear factor-κB ligand). Our results showed that TgRANKL mice of both sexes developed dramatically increased BMAT expansion compared to wild-type (WT) littermates, that was analogous to the levels of RANKL expression and the severity of the bone loss phenotype.

A Dietary Intervention in Adults with Overweight or Obesity Leads to Weight Loss Irrespective of Macronutrient Composition.

Obesity is a critical public health issue, necessitating effective weight loss interventions. While various dietary regimens have been explored, individual responses to interventions often vary. This study involved a 3-month dietary intervention aiming at assessing the role of macronutrient composition and the potential role of genetic predisposition in weight loss among Greek adults.

drive synovial hyperplasia and arthritis by targeting cell cycle inhibitors and chromatin remodeling components.

miRNAs constitute fine-tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA); however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. Previous studies have shown that expression is upregulated in RA SFs.

Identification of a serum proteomic biomarker panel using diagnosis specific ensemble learning and symptoms for early pancreatic cancer detection.

Background: The grim (<10% 5-year) survival rates for pancreatic ductal adenocarcinoma (PDAC) are attributed to its complex intrinsic biology and most often late-stage detection. The overlap of symptoms with benign gastrointestinal conditions in early stage further complicates timely detection. The suboptimal diagnostic performance of carbohydrate antigen (CA) 19-9 and elevation in benign hyperbilirubinaemia undermine its reliability, leaving a notable absence of accurate diagnostic biomarkers.

Cyld restrains the hyperactivation of synovial fibroblasts in inflammatory arthritis by regulating the TAK1/IKK2 signaling axis.

TNF is a potent cytokine known for its involvement in physiology and pathology. In Rheumatoid Arthritis (RA), persistent TNF signals cause aberrant activation of synovial fibroblasts (SFs), the resident cells crucially involved in the inflammatory and destructive responses of the affected synovial membrane. However, the molecular switches that control the pathogenic activation of SFs remain poorly defined.

Kidney whole-transcriptome profiling in primary antiphospholipid syndrome reveals complement, interferons and NETs-related gene expression.

Objective: Pathogenesis of antiphospholipid syndrome (APS) remains poorly elucidated. We aimed to evaluate for the first time kidney transcriptome profiles in primary APS vs systemic lupus erythematosus (SLE) and control subjects.

Methods: We performed RNA sequencing on archival formalin-fixed paraffin-embedded kidney biopsies from APS (n = 4), SLE (n = 5) and control (n = 3) individuals, differential gene expression analysis (DGEA) and enrichment analysis using gene ontology (GO) and CORUM, KEGG and Reactome pathway databases.

Longitudinal proteomics of leptin treatment in humans with acute and chronic energy deficiency-induced hypoleptinemia reveal novel, mainly immune-related, pleiotropic effects.

Background: Leptin is known for its metabolic, immunomodulatory and neuroendocrine properties, but the full spectrum of molecules downstream of leptin and relevant underlying mechanisms remain to be fully clarified. Our objective was to identify proteins and pathways influenced by leptin through untargeted proteomics in two clinical trials involving leptin administration in lean individuals.

Methods: We performed untargeted liquid chromatography-tandem mass spectrometry serum proteomics across two studies a) Short-term randomized controlled crossover study of lean male and female humans undergoing a 72-h fast with concurrent administration of either placebo or high-dose leptin; b) Long-term (36-week) randomized controlled trial of leptin replacement therapy in human females with acquired relative energy deficiency and hypoleptinemia.