Spatiotemporal subtypes of brain and spinal cord atrophy in neuromyelitis optica spectrum disorders and multiple sclerosis.

Background: Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) are autoimmune demyelinating diseases with overlapping clinical features but distinct patterns of brain and spinal cord atrophy. The precise atrophy subtypes specific to each disease remain elusive. This study aimed to identify shared and distinct atrophy subtypes in NMOSD and MS, using neuroimaging to explore their clinical significance and potential implications for tailored treatment strategies.

The function of GPCRs in different bone cells.

G protein-coupled receptors (GPCRs) are recognized as critical therapeutic targets in bone disorders, owing to their multifaceted regulatory roles across diverse bone cell lineages. This review systematically catalogs GPCR expression and functional heterogeneity in key bone cells: 12 GPCRs in mesenchymal stem cells (MSCs) orchestrate lineage specification; 21 GPCRs in osteoblasts/osteocytes mediate matrix mineralization and mechanotransduction; 23 GPCRs in macrophages/osteoclasts regulate inflammatory bone resorption; 31 GPCRs in chondrocytes govern endochondral ossification and osteoarthritis pathogenesis; and 8 GPCRs in other cell types modulate bone-related physiological processes. By integrating canonical signaling axes-cAMP/PKA-dependent transcriptional networks, PLC-β/IP3-driven calcium signaling, and NF-κB-modulated immuno-skeletal interactions-we elucidate how GPCRs dynamically coordinate cellular plasticity to maintain skeletal homeostasis.

Recent advances in tumor immunotherapy based on NK cells.

Immunotherapy has emerged as the established fourth pillar of cancer treatment following surgery, radiotherapy, and chemotherapy, representing a cutting-edge research domain in translational medicine and clinical oncology. Natural killer (NK) cells, a type of innate cytotoxic lymphocyte, possess unique antitumor properties that are independent of major histocompatibility complex (MHC) restrictions, making them promising candidates for "off-the-shelf" therapeutic products. NK cells can eliminate tumor cells through various mechanisms.

Blood plasma proteome-wide association study implicates new proteins in type 2 diabetes mellitus pathogenesis.

The pathophysiological mechanisms underlying type 2 diabetes mellitus (T2DM) remain incompletely understood, and the disease continues to impose a substantial burden on global health. In this study, we integrated the data from the largest genome-wide association study (GWAS; N = 898,130) of T2DM with human plasma protein quantitative trait locus (pQTL; N = 53,022) data to conduct the first proteome-wide association study (PWAS) of T2DM. Following Mendelian randomization and colocalization analyses, we identified nine independent putatively causal proteins.

Blood plasma proteome-wide association study implicates novel proteins in the pathogenesis of multiple cardiovascular diseases.

Background: Cardiovascular diseases (CVD) are the leading cause of global mortality, yet current treatments benefit only a subset of patients. To identify new potential treatment targets, we conducted the first proteome wide association study (PWAS) for 26 CVDs using plasma proteomics data from the largest cohort to date (53,022 individuals in the UK Biobank Pharma Proteomics Project (UKB-PPP)).

Methods And Results: We calculated single nucleotide polymorphism (SNP)-protein weights using the UKB-PPP dataset and integrated these weights with genome-wide association study (GWAS) summary statistics for 26 CVDs across three categories (16 cardiac, 5 venous, and 5 cerebrovascular diseases) in up to 1,308,460 individuals.

Long noncoding RNA LINC00339 promotes osteoporosis development via modulating of regulator CDC42 by binding PARP1.

Background: Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass and microarchitectural deterioration of bone tissue. Our previous investigation provided preliminary evidence that single nucleotide polymorphisms (SNPs) may functionally interact with the LINC00339, potentially contributing to the pathogenesis and progression of osteoporosis through undefined molecular pathways. However, the exact mechanistic basis of LINC00339's involvement in osteoporotic bone remodeling remains incompletely characterized and warrants systematic exploration.

Plasma Metabolomics and Machine Learning Reveals Metabolic Alterations and Diagnostic Biomarkers for Deep Venous Thrombosis in Hypertensive Patients after Traumatic Fracture.

We aimed to explore the metabolic dysregulations and diagnostic biomarkers for post-traumatic deep venous thrombosis (pt-DVT) in hypertensive (HPT) patients after fracture. An untargeted ultraperformance liquid chromatography-mass spectrometry-based metabolomics approach was employed to perform a comprehensive metabolic analysis of plasma samples of 80 patients with post-traumatic deep venous thrombosis and hypertension (pt-DVT&HPT) and 117 patients with hypertension only (HPT). Thirty-seven (37) differential metabolites were identified between pt-DVT&HPT and HPT patients.

Genetic transcriptional regulation profiling of cartilage reveals pathogenesis of osteoarthritis.

Background: Genome-wide association studies (GWAS) have identified more than one hundred risk loci for osteoarthritis (OA). Identifying the effector genes and deciphering the underlying regulatory mechanisms are of great importance but remains challenging due to limited availability of OA-related tissue data. This study aims to address this issue by generating a cartilage expression quantitative trait loci (eQTLs) and a functional fine-mapping resource.

Allantoin Serves as a Novel Risk Factor for the Progression of MASLD.

Uric acid (UA), traditionally recognized as an extracellular antioxidant, exhibits paradoxical associations with metabolic disorders such as metabolic dysfunction-associated steatotic liver disease (MASLD), though its mechanistic contributions remain elusive. Here, we integrate multi-modal evidence to explore the role of UA and its oxidative metabolite, allantoin, in MASLD progression. Analysis of UK Biobank data revealed a strong association between elevated UA levels and increased risks of MASLD and type 2 diabetes (T2D).

Exploring the research hotspots and trends in genetic education reform.

Genetics, as a core discipline of life sciences, has broad applications in medicine, agriculture, and environmental protection. With the rapid development in biotechnology, genetic education is facing new challenges and demands. Traditional teaching models have gradually revealed limitations in cultivating students' innovative abilities, practical skills, and comprehensive qualities.

Systematic functional characterization of non-coding regulatory SNPs associated with central obesity.

Central obesity is associated with higher risk of developing a wide range of diseases independent of overall obesity. Genome-wide association studies (GWASs) have identified more than 300 susceptibility loci associated with central obesity. However, the functional understanding of these loci is limited by the fact that most loci are in non-coding regions.

RUNX2 Phase Separation Mediates Long-Range Regulation Between Osteoporosis-Susceptibility Variant and XCR1 to Promote Osteoblast Differentiation.

GWASs have identified many loci associated with osteoporosis, but the underlying genetic regulatory mechanisms and the potential drug target need to be explored. Here, a new regulatory mechanism is found that a GWAS intergenic SNP (rs4683184) functions as an enhancer to influence the binding affinity of transcription factor RUNX2, whose phase separation can mediate the long-range chromatin interaction between enhancer and target gene XCR1 (a member of the GPCR family), leading to changes of XCR1 expression and osteoblast differentiation. Bone-targeting AAV of Xcr1 can improve bone formation in osteoporosis mice, suggesting that XCR1 can be a new susceptibility gene for osteoporosis.

Synovial transcriptome-wide association study implicates novel genes underlying rheumatoid arthritis risk.

Objectives: This study aimed to address the lack of gene expression regulation data in synovial tissues and to identify genes associated with rheumatoid arthritis (RA) in the synovium, a primary target tissue for RA.

Methods: Gene expression prediction models were built for synovial tissue using matched genotype and gene expression data from 202 subjects. Using this model, we conducted a transcriptome-wide association study (TWAS), utilizing the largest rheumatoid arthritis (RA) genome-wide association study (GWAS) meta-analysis data (n = 276 020).

Blood metabolites, neurocognition and psychiatric disorders: a Mendelian randomization analysis to investigate causal pathways.

Background: Neurocognitive dysfunction is observationally associated with the risk of psychiatric disorders. Blood metabolites, which are readily accessible, may become highly promising biomarkers for brain disorders. However, the causal role of blood metabolites in neurocognitive function, and the biological pathways underlying their association with psychiatric disorders remain unclear.

Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression.

The human brain has been implicated in the pathogenesis of several complex diseases. Taking advantage of single-cell techniques, genome-wide association studies (GWAS) have taken it a step further and revealed brain cell-type-specific functions for disease loci. However, genetic causal associations inferred by Mendelian randomization (MR) studies usually include all instrumental variables from GWAS, which hampers the understanding of cell-specific causality.

Unveiling Promising Neuroimaging Biomarkers for Schizophrenia Through Clinical and Genetic Perspectives.

Schizophrenia is a complex and serious brain disorder. Neuroscientists have become increasingly interested in using magnetic resonance-based brain imaging-derived phenotypes (IDPs) to investigate the etiology of psychiatric disorders. IDPs capture valuable clinical advantages and hold biological significance in identifying brain abnormalities.

Two-sample Mendelian randomization analysis reveals causal relationships between blood lipids and venous thromboembolism.

Venous thromboembolism (VTE) is a complex disease that can be classified into two subtypes: deep vein thrombosis (DVT) and pulmonary embolism (PE). Previous observational studies have shown associations between lipids and VTE, but causality remains unclear. Hence, by utilizing 241 lipid-related traits as exposures and data from the FinnGen consortium on VTE, DVT, and PE as outcomes, we conducted two-sample Mendelian randomization (MR) analysis to investigate causal relationships between lipids and VTE, DVT and PE.

The Causal Relationships Between Gut Microbiota, Brain Volume, and Intelligence: A Two-Step Mendelian Randomization Analysis.

Background: Growing evidence indicates that dynamic changes in gut microbiome can affect intelligence; however, whether these relationships are causal remains elusive. We aimed to disentangle the poorly understood causal relationship between gut microbiota and intelligence.

Methods: We performed a 2-sample Mendelian randomization (MR) analysis using genetic variants from the largest available genome-wide association studies of gut microbiota (N = 18,340) and intelligence (N = 269,867).

A landscape of gene expression regulation for synovium in arthritis.

The synovium is an important component of any synovial joint and is the major target tissue of inflammatory arthritis. However, the multi-omics landscape of synovium required for functional inference is absent from large-scale resources. Here we integrate genomics with transcriptomics and chromatin accessibility features of human synovium in up to 245 arthritic patients, to characterize the landscape of genetic regulation on gene expression and the regulatory mechanisms mediating arthritic diseases predisposition.

Integrative high-throughput enhancer surveying and functional verification divulges a YY2-condensed regulatory axis conferring risk for osteoporosis.

The precise roles of chromatin organization at osteoporosis risk loci remain largely elusive. Here, we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated single-nucleotide polymorphisms (SNPs). We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) that linked to hundreds of candidate target genes through chromatin interactions across 146 loci.

Multi-tissue transcriptome-wide association study reveals susceptibility genes and drug targets for insulin resistance-relevant phenotypes.

Aim: Genome-wide association studies (GWAS) have identified multiple susceptibility loci associated with insulin resistance (IR)-relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify susceptibility genes for IR-relevant phenotypes via a transcriptome-wide association study.

High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes.

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac).

Assessment of bidirectional relationships between brain imaging-derived phenotypes and stroke: a Mendelian randomization study.

Background: Stroke is a major cause of mortality and long-term disability worldwide. Whether the associations between brain imaging-derived phenotypes (IDPs) and stroke are causal is uncertain.

Methods: We performed two-sample bidirectional Mendelian randomization (MR) analyses to explore the causal associations between IDPs and stroke.