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PubMed2001

TrkB-like immunoreactivity is present on geniculocortical afferents in layer IV of kitten primary visual cortex.

Exogenous administration of the neurotrophins brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5 (NT-4/5), or blockade of their endogenous actions, have been reported to affect the anatomic organization and physiological responses of neurons in developing mammalian primary visual cortex. Experimental alteration of levels of these neurotrophic factors can also influence the morphology of the geniculocortical afferents that project from the lateral geniculate nucleus (LGN) to primary visual cortex. BDNF and NT-4/5 are ligands of the TrkB tyrosine kinase receptor. Although multiple populations of cortical neurons express TrkB, it is not known whether geniculocortical afferents express this receptor on their axon branches in visual cortex. We have anatomically labeled geniculocortical afferents of postnatal day 40 kittens with the anterograde neuronal tracer Phaseolus vulgaris leucoagglutinin (PHA-L) and performed double-label immunofluorescence with a panel of anti-TrkB antibodies. Confocal microscopy and object-based colocalization analysis were used to measure levels of TrkB-like immunoreactivity (IR) on geniculocortical afferents in layer IV of primary visual cortex. By using a conservative analysis involving a comparison of measured colocalization with the amount of colocalization expected based on random overlap of TrkB puncta and PHA-L--labeled afferents, 3 of 5 anti-TrkB antibodies tested showed significant colocalization with the geniculocortical axons. Results for the other two antibodies were indeterminate. The indices obtained for colocalization of TrkB and geniculocortical afferents were also compared with the equivalent index obtained for GAD65, a protein that has a similar overall expression pattern to that of TrkB but is not expressed on geniculocortical axons. This analysis indicated that TrkB was present on geniculocortical axons for all five TrkB antibodies tested. TrkB-like IR was also observed on neuronal somata in the LGN. These results indicate that TrkB receptors on geniculocortical afferents are potential mediators of the actions of BDNF and NT-4/5 in developing visual cortex.

Animals↗

PubMed2026

Multi-ancestry multi-trait analysis reveals shared genetics across major psychiatric disorders and Alzheimer's disease.

The clinical overlap between major psychiatric disorders (MPDs) and Alzheimer's disease (AD) implicates complex shared etiology. Previous studies demonstrated that both diseases are genetically complex and highly heritable, suggesting that more endeavors are necessary to be made from the very bottom to understand their genetic basis. With the advance of post-genomic analysis, multi-ancestry meta-analysis allows the generalizability of the genetic architecture across different populations to uncover ancestry-specific variants, while multi-trait analysis enables the discovery of the co-colocalized risk genomic regions across diseases. Therefore, in this study, we leveraged published GWAS summary statistics from European, East Asian, Hispanic and African American populations to report schizophrenia, major depressive disorders, and Alzheimer's disease risk loci and further fine-mapping to credible sets with >95% PP inclusion of the causal variant. We distilled 2871 potential traits from publicly available and found 134 traits significantly genetically correlated with both MPDs and AD using batch LD score regression. We then prioritized the identified loci from multi-ancestry results for cross-trait colocalization analysis to assess shared genetic etiology and further nominated 2 colocalized loci across both conditions, including rs2532240 and rs6504163. In the end, we finalized our analysis by validation and functional inference of the underlying susceptibility genes as well as putative mechanisms using evidence from multiple resources, including FIVEx, Open Targets, and scQTLbase.

Humans↗

PubMed1998

Cytoskeletal targeting of calponin in differentiated, contractile smooth muscle cells of the ferret.

1. Biochemical and quantitative image analysis methods were used to investigate the anatomical basis for the previously described agonist-induced redistribution of calponin. 2. At 140 nm resolution, the quantitative distribution of calponin in resting cells was statistically indistinguishable from that of filament bundles containing alpha-smooth muscle actin and myosin, but was significantly different from that of filaments containing beta-non-muscle actin. Conversely, in stimulated cells, the distribution of calponin was not significantly different from that of beta-actin filaments in the subplasmalemmal cell cortex but was significantly different from the distribution of alpha-actin- and myosin-containing filamentous bundles. 3. The distribution of calponin significantly differed from that of the intermediate filament proteins vimentin and desmin as well as that of the dense body protein alpha-actinin either by ratio analysis of the subcellular distribution or by colocalization analysis. 4. The imaging results, although limited to 140 nm spatial resolution, suggested the hypothesis that the agonist-induced redistribution involves the binding of calponin to isoform-specific actin filaments. This hypothesis was tested by quantifying the relative affinity of calponin for purified alpha- and beta-actin. Light scattering measurements showed that calponin induces bundle formation with beta-actin more readily than alpha-actin, indicating that calponin may be preferentially sequestered by beta-actin under appropriate conditions. 5. These results are consistent with a model whereby agonist activation decreases calponin's binding to filaments, but the tighter binding to beta-actin filaments results in a spatial redistribution of calponin to the submembranous cortex.

Actins↗

PubMed2026

Shared Genetic Basis, Biological Function and Causal Relationship Between Sleep Traits and Hypothyroidism: Evidence from a Comprehensive Genetic Analysis.

BACKGROUND: This research attempts to clarify whether there are any genetic similarities between sleep traits and hypothyroidism based on publicly accessible large-scale genomewide association studies. METHODS: The methodology included colocalization analysis, cross-phenotype association analysis, and linkage disequilibrium score regression analysis to find common genetic overlap. Through tissue function specificity and functional mapping, we were able to identify the shared genetic level. Genetic instrumental factors were used for causal inference in two-sample univariate and multivariable Mendelian randomization analyses. RESULTS: A hereditary correlation between hypothyroidism and napping during the day and getting up in the morning (rg= -0.0982, P= 0.0007; rg= -0.101, P= 0.0001). MAGI3, and HLA-DRB1 BX296568.1 may be potential targets for shared treatments. Colocalization and tissue-specific analysis demonstrated that the common genes and SNPs were identified in the thyroid, lung, brain, and lymphatic tissues. Functional analysis emphasized the importance of these common genes in processes like as protein transport, inflammatory response, and MHC class II protein synthesis. Furthermore, an association has been established between hypothyroidism and sleep duration (IVW, OR 1.5208; 95% CI 1.1142-2.0758, P=0.0082) and getting up in the morning (IVW, OR 1.8375; 95%CI: 1.4502-2.3284, P=4.73E-07). Furthermore, the reverse MR analysis revealed no causal connection between aberrant sleep traits and hypothyroidism. The enduring impact of insomnia on hypothyroidism persists despite controlling for alcohol consumption and smoking habits. CONCLUSION: Certain genetic correlations between sleep traits and hypothyroidism have been emphasized. These findings may elucidate the origin of comorbidity and have implications for future clinical trials.

Humans↗

PubMed2026

Multi-omics identification of therapeutic targets of compound sappan decoction in hepatocellular carcinoma.

BACKGROUND: Compound sappan decoction (CSD) is a multi-herbal traditional Chinese medicine formulation with clinical relevance in hepatocellular carcinoma (HCC). However, its therapeutic mechanisms remain unclear. METHODS: Bioactive compounds of CSD were identified and standardized using pharmacological and chemical databases. Potential targets were predicted via multiple target inference platforms. HCC-related genes were curated from comprehensive disease databases. Summary-data-based Mendelian randomization (SMR) was conducted to infer causal relationships between compound targets and HCC risk using large-scale quantitative trait loci (QTL) datasets and HCC genome-wide association study data. Colocalization analysis, protein-protein interaction (PPI) network construction, and GO/KEGG enrichment were performed on SMR-identified targets. Molecular docking evaluated binding affinities of representative compounds to prioritized targets. RESULTS: A total of 784 overlapping genes between predicted CSD targets and HCC-related genes were subjected to SMR analysis. Among these, 22 targets were significantly associated with HCC risk based on transcriptomic or proteomic QTLs and showed colocalization evidence. Notably, four targets (ADRB2, APOE, SYK, and PGF) were supported by both replication in an independent cohort and strong colocalization. These 22 targets were enriched in apoptosis, PI3K-Akt signaling, redox metabolism, and detoxification pathways. PPI analysis revealed central hubs including MMP9, BCL2, CASP1, and MCL1. Molecular docking demonstrated strong binding of APOE to quercetin, PGF to luteolin-7-olate, and SYK to kaempferol. CONCLUSIONS: CSD may exert therapeutic effects on HCC through modulation of genetically validated targets involved in tumor progression, inflammation, and metabolic reprogramming, supporting its potential clinical utility as an adjunctive treatment strategy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12672-026-04740-8.

Caesalpinia↗

PubMed2026

Large-Scale Proteomic Profiling of Incident Heart Failure and Its Subtypes in Older Adults.

BACKGROUND: Heart failure (HF) and its main subtypes, heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF), impose an enormous health burden on elders. Assessment of the circulating proteome to illuminate pathogenesis could open new opportunities for treatment. METHODS: We conducted a plasma proteomics screen of incident HF and its subtypes in 2 older population-based cohorts, the CHS (Cardiovascular Health Study) and the AGES-RS (Aging, Gene/Environment Susceptibility-Reykjavik Study). The 2 studies used SomaLogic platforms, with 4404 aptamers in common. Multivariable Cox models were fit to evaluate individual-protein associations with HF, HFpEF, and HFrEF separately in each cohort, and study-specific associations were combined by fixed-effects meta-analysis. Replication was performed in the ARIC (Atherosclerosis Risk in Communities) cohort. Two-sample Mendelian randomization of HF and its subtypes, along with colocalization analysis, was performed to support causal inference. RESULTS: Among 8599 participants, 1590 experienced incident HF (536 HFpEF, 471 HFrEF). There were 119 proteins associated with HF, 15 proteins with HFpEF, and 11 proteins with HFrEF, at Bonferroni-corrected significance. Among these, 9 have never previously been identified for cardiovascular diseases, and another 61 represent new associations with incident HF or its subtypes. Of these 70 proteins, 55 of the 66 available replicated externally. Mendelian randomization analysis revealed 7 proteins genetically associated with HF at nominal significance; 2 were separately associated with HFpEF, and another 2 with HFrEF. Seven of these 9 proteins (NPDC1 [neural proliferation differentiation and control protein 1], APOF [apolipoprotein F], LMAN2 [lectin, mannose-binding 2], ADIPOQ [adiponectin], CD14 [cluster of differentiation 14], ARHGAP1 [Rho GTPase-activating protein 1], C9 [complement 9]) showed new, possibly causal associations, although we did not detect evidence for colocalization. CONCLUSIONS: In this large-scale proteomic study involving 3 longitudinal cohorts of older adults, we identified and replicated 55 novel protein markers of HF or its subtypes, and 7 new, possibly causal proteins. These proteins may enhance risk prediction, improve understanding of pathobiology, and help prioritize targets for therapeutic development of these foremost disorders in elders.

Humans↗

PubMed2002

WAC, a novel WW domain-containing adapter with a coiled-coil region, is colocalized with splicing factor SC35.

WW domains mediate protein-protein interactions in many intracellular processes. In pre-mRNA splicing, WW domains participate in cross-intron bridging. These WW domains are characterized by a central aromatic block of three tyrosine residues. We identified a novel protein containing the same type of WW domain. The gene encoding the protein, named WAC, is located in human chromosome 10p11.2-10p12.1. A Drosophila melanogaster WAC homolog (CG8949) was identified as a Rosetta stone protein. Domain fusion analysis of the Rosetta stone protein linked WAC to splicing factor SNRP70. WAC existed mainly in a tyrosine-phosphorylated form. Immunofluorescence analysis colocalized WAC with SC35, the marker for pre-mRNA splicing machinery. Our analysis suggests that WAC represents a novel member of WW-domain-containing proteins for RNA processing.

Amino Acid Sequence↗

PubMed2026

Integrative multi-omics quantitative trait loci prioritize CASP7 as a candidate protective gene for cataract.

Cataracts are the leading cause of vision loss worldwide. Despite surgery being the only effective treatment, its economic burden highlights the necessity of exploring the pathogenesis of cataracts. In this study, we analyzed 4 large-scale GWAS (genome-wide association study) datasets for cataracts and performed SMR analysis along with heterogeneity in dependent instruments (HEIDI) testing to explore the effects of methylation, expression, and protein QTLs on cataracts. We further validated shared genetic variants through COLOC analysis. Additionally, we searched datasets related to cataracts from the Gene Expression Omnibus (GEO) database for differentially expressed genes (DEGs) and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses. By integrating summary-based Mendelian randomization (SMR) results with bioinformatics findings, CASP7 showed a consistent protective-direction association with cataract risk (mQTL: OR [95% CI] = 0.959 [0.941-0.977], FDR-adjusted P = .039; eQTL: OR [95% CI] = 0.897 [0.860-0.937], FDR-adjusted P = .0046; pQTL: OR [95% CI] = 0.597 [0.483-0.738], FDR-adjusted P = .00083). GEO-based analyses provided transcriptomic support for CASP7 involvement in cataract-related lens biology. These findings prioritize CASP7 as a genetically supported candidate protective gene associated with cataract risk. Because this study is based on public summary-level and transcriptomic datasets, the results should be interpreted cautiously and require functional validation in human lens-relevant systems.

Quantitative Trait Loci↗

PubMed2025

Soluble Immune Checkpoint Protein and Lipid Network Associations with All-Cause Mortality Risk: Trans-Omics for Precision Medicine (TOPMed) Program.

Adverse cardiovascular events are emerging with the use of immune checkpoint therapies in oncology. Using datasets in the Trans-Omics for Precision Medicine program (Multi-Ethnic Study of Atherosclerosis, Jackson Heart Study [JHS], and Framingham Heart Study), we examined the association of immune checkpoint plasma proteins with each other, their associated protein network with high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), and the association of HDL-C- and LDL-C-associated protein networks with all-cause mortality risk. Plasma levels of LAG3 and HAVCR2 showed statistically significant associations with mortality risk. Colocalization analysis using genome wide-association studies of HDL-C or LDL-C and protein quantitative trait loci from JHS and the Atherosclerosis Risk in Communities identified TFF3 rs60467699 and CD36 rs3211938 variants as significantly colocalized with HDL-C; in contrast, none colocalized with LDL-C. The measurement of plasma LAG3, HAVCR2, and associated proteins plus targeted genotyping may identify patients at increased mortality risk.

Journal Article↗

PubMed2026

Cell-type-specific genetic associations in Lewy body dementia identified using single-cell eQTL-based Mendelian randomization.

BACKGROUND: Lewy body dementia (LBD) is a complex neurodegenerative disorder marked by α-synuclein aggregation and dual impairment of cognitive and motor function.While genome-wide association studies have identified risk loci, the cellular mechanisms linking genetic variation to disease susceptibility remain largely unexplored. METHODS: We performed single-cell transcriptome-wide Mendelian randomization using brain cell-type-specific eQTLs across eight major cell types. Genetic associations were evaluated using inverse-variance weighted models, followed by Bayesian colocalization analysis. Replication was performed in independent stratified LBD cohorts based on APOE ε4 carrier status. Phenome-wide association analysis was included as a supplementary, descriptive assessment of cross-trait associations. RESULTS: Expression of ANKRD65 in excitatory neurons was significantly associated with reduced LBD risk (odds ratio = 0.65, 95 % CI: 0.52-0.81, p = 0.00013). This association passed a false discovery rate of 0.1 and showed strong evidence of colocalization (posterior probability = 0.93). Effect direction was consistent across APOE ε4+ and ε4- LBD subgroups in independent cohorts. No genome-wide significant associations were observed with non-neurological traits in the phenome-wide analysis. CONCLUSIONS: Our findings identify a genetically supported, cell-type-resolved association between ANKRD65 expression in excitatory neurons and LBD risk. This study demonstrates the value of integrating cell-resolved transcriptomic regulation with genetic inference to pinpoint functionally relevant targets in neurodegenerative diseases.

Humans↗

PubMed1999

Quantitative analysis of neuronal nitric oxide synthase-immunoreactive neurons in the mouse hippocampus with optical disector.

A detailed quantitative analysis of immunocytochemically identified nonprincipal neurons containing neuronal nitric oxide synthase (nNOS) was performed on the mouse hippocampus, with particular reference to the dorsoventral gradient. The present study applied two variations of a stereologic technique, the optical disector--one that used confocal laser-scanning microscope optical sections to examine colocalization of nNOS and glutamic acid decarboxylase 67 (GAD67), and the other that used conventional thick sections to examine numerical densities (NDs) and cell sizes of nNOS-immunoreactive (IR) neurons. Colocalization analysis indicated that practically all nNOS-IR neurons (97.6%) were GAD67-IR, whereas a part of the GAD67-IR neurons (about 30%) were nNOS-IR in the whole hippocampus at both dorsal and ventral levels. The percentages of GAD67-IR neurons containing nNOS were higher in the dentate gyrus (DG, about 50%), and lower in the Ammon's horn (about 20%). Laminar analysis revealed that the majority of GAD67-IR neurons contained nNOS in the stratum lacunosum-moleculare of the CA3 region (about 60%) and in the molecular layer of the DG (about 80%). The NDs of nNOS-IR neurons in the whole hippocampus showed a dorsoventral gradient, which increased from dorsal (1.6 x 10(3)/mm3) to ventral (2.2 x 10(3)/mm3) levels. The NDs were relatively higher in the principal cell layers, where about 40% of nNOS-IR neurons were situated both in the Ammon's horn and DG. The mean cell sizes of nNOS-IR neurons showed no remarkable laminar differences or dorsoventral gradient in the Ammon's horn, but they were extensively larger in the hilus of the DG than in other layers. These results indicate that nNOS-IR neurons in the mouse hippocampus represent a subpopulation of gamma-aminobutyric acid (GABA)ergic neurons and suggest that the laminar distributions of nNOS-IR neurons related to possible functional heterogeneity of GABAergic neurons in each hippocampal layer.

Animals↗

PubMed2025

Exploring the shared genetic basis of attention-deficit/hyperactivity disorder and obstructive sleep apnea: A multi-omics analysis.

BACKGROUND: Observational studies have suggested an association between attention-deficit/hyperactivity disorder (ADHD) and obstructive sleep apnea (OSA), but these findings are often inconsistent due to potential biases from medication use, and varying diagnostic criteria. Genetic analyses can help mitigate these confounding factors, providing additional evidence. METHODS: This study evaluated the genetic correlations between ADHD and OSA using Genome-wide association study (GWAS) summary data, applying linkage disequilibrium score regression (LDSC) and SUPER GeNetic cOVariance Analyzer (SUPERGNOVA). Cross-trait association and colocalization analysis identify potential pleiotropic loci. Tissue enrichment analysis and gene-level analysis of shared genes between OSA and ADHD was conducted. Additionally, bidirectional Mendelian randomization was used to assess potential causal relationships. RESULTS: We found significant genetic correlations between ADHD and OSA (rg = 0.309, p = 3.252E-27), and identified 8 novel pleiotropic loci through cross-trait association analysis. Tissue enrichment analysis showed that these shared genes were primarily concentrated in brain tissues, particularly in deep gray matter regions, and were associated with immune and inflammatory pathways. Forward Mendelian Randomization analysis showed that ADHD was significantly associated with the risk of OSA (OR 1.070, 95 % CI 1.013-1.130, p = 0.016), and reverse analysis showed that OSA was significantly associated with the risk of ADHD (OR 1.240, 95 % CI 1.106-1.390, p = 2.213E-4). CONCLUSION: The findings of this study show a significant positive genetic correlation between ADHD and OSA and each is a risk factor for the other. Inflammation in specific brain regions may be the underlying mechanism for their comorbidity.

Humans↗

PubMed2026

Linking cortical structure and delirium in the elderly: insights from cohort study and shared genetic risk analysis.

BACKGROUND: This study aimed to assess the association between regional cortical changes measured via baseline magnetic resonance imaging (MRI) and the incidence of delirium. METHODS: Observational associations were assessed using a prospective cohort from the UK Biobank and an independent clinical cohort. The population-based study included participants aged 60 years or older who had undergone structural brain MRI since 2014. Regional cortical volume, mean thickness, and surface area were extracted based on the Desikan-Killiany cortical atlas. Delirium was defined using ICD-10 diagnostic codes. Additionally, preoperative brain MRI images from participants in another cohort were collected and automatically segmented using deep learning algorithms to obtain cortical measurements. Logistic analysis was performed to investigate the associations between cerebral cortical structure and delirium risk. Lastly, genome-wide association study data derived from the ENIGMA Consortium and FinnGen Biobank were utilized to conduct conditional/conjunctional false discovery rate (cond/conjFDR) analyses to identify shared genetic loci associated with cortical structures and delirium. RESULTS: This observational analysis included 31,890 participants from the UK Biobank and 152 participants from an independent cohort. In the UK Biobank cohort, decreased cortical thickness in the 17 regions was associated with a significantly increased risk of delirium. Similarly, a preoperative reduction in cortical volume in 7 regions was associated with an increased risk of delirium in the independent cohort. Besides, 100 single-nucleotide polymorphisms (SNPs) were identified as significantly associated with cortical structures when conditioned on delirium. Finally, colocalization analysis demonstrated that these pleiotropic risk loci modulated the expression of NT5C2, RGP1, CCDC25, TPM2, EEF1AKMT2, IQANK1 and LHPP in blood and brain tissues. CONCLUSION: Regional cortical atrophy is associated with an increased risk of delirium in the elderly. Brain MRI examinations may be beneficial for preoperative delirium risk assessment in elderly individuals undergoing elective surgery.

Humans↗

PubMed1997

Differential induction of heat shock mRNA in oligodendrocytes, microglia, and astrocytes following hyperthermia.

A time course analysis of hsp70 mRNA induction in response to a physiologically relevant increase in body temperature of 2.6 degrees C was performed in the rabbit forebrain. A protocol that combined in situ hybridization and cytochemistry on the same tissue section was employed to identify reactive glial cell types. Cytochemical markers for astrocytes, microglia, and oligodendrocytes were utilized in combination with a DIG-labelled hsp70 riboprobe, which permitted mRNA localization at high resolution. Four glial cell body-enriched regions of the rabbit forebrain were examined, namely, cortical layer 1, hippocampal fissure, corpus callosum, and fimbria. Maximal hsp70 mRNA induction was observed in 2 and 3 h hyperthermic animals. The colocalization analysis demonstrated that hsp70 mRNA was induced in oligodendrocytes and microglia, but not in forebrain GFAP positive astrocytes. In addition, cell counts were performed which showed that almost all oligodendrocytes induced hsp70 mRNA while a subpopulation of microglial cells responded. These data are consistent with the notion that oligodendrocytes, microglia, and astrocytes exhibit distinct thresholds for activation of the heat shock response following a physiologically relevant increase in body temperature.

Animals↗

PubMed2001

Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis.

BACKGROUND: Angiogenesis is a prerequisite for airway remodeling in bronchial asthma. Several growth factors may play important roles in inflammation and angiogenesis through effects on inflammatory cell infiltration or neovascularization. OBJECTIVE: We sought to compare bronchial vascularity and expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin in bronchial biopsy specimens from asthmatic and healthy control subjects. METHODS: Bronchial biopsy specimens were obtained from 16 asthmatic subjects and 9 normal control subjects. The number of vessel profiles and the vascular area per unit area on a histologic section were estimated by using computerized image analysis after staining for type IV collagen in vessel walls. Numbers of VEGF+, bFGF+, and angiogenin+ cells were determined by means of immunoreactivity. RESULTS: The airways of asthmatic subjects had significantly more vessels (P < .05) and greater vascular area (P < .001) than that observed in control subjects. Asthmatic subjects exhibited higher VEGF and bFGF and angiogenin immunoreactivity in the submucosa than did control subjects (P < .001, respectively). Significant correlations were detected between the vascular area and the numbers of angiogenic factor-positive cells (VEGF: rs = 0.93, P < .001; bFGF: rs = 0.83, P < .001; angiogenin: rs = 0.88, P < .001) within the asthmatic airways. Furthermore, the degree of vascularity was inversely correlated with airway caliber and airway responsiveness. Colocalization analysis revealed that the angiogenic factor-positive cells were CD34+ cells, eosinophils, and macrophages. CONCLUSION: Our results suggest that increased vascularity of the bronchial mucosa in asthmatic subjects is closely related to the expression of angiogenic factors, which may then contribute to the pathogenesis of asthma.

Adolescent↗

PubMed2026

Genetic evidence that advanced COVID-19 accelerates longitudinal brain atrophy: A Mendelian randomization study.

Coronavirus disease 2019 (COVID-19) was reported to persist long-term in the brain and leave several long-term neurologic sequelae. However, the causal relationship between COVID-19 and brain aging is still unknown. The genome-wide association study (GWAS) data on COVID-19 phenotypes (susceptibility, hospitalization, and severity), involving a total of 5,779,391 participants, were collected from the COVID-19 Host Genetics Initiative. In addition, GWAS data on longitudinal changes in 15 brain structures, assessed via magnetic resonance imaging across the lifespan, were sourced from the ENIGMA Consortium and involved 15,640 participants. Two-sample Mendelian randomization was conducted to infer the causal relationship between COVID-19 and longitudinal brain changes. Multi-trait GWAS meta-analysis, colocalization, and fine-mapping analyses were performed to identify shared genetic etiologies. H3K27me3 ChIP-seq was used to evaluate the regulatory effect of colocalized loci. Two-step Mendelian randomization was applied to explore potential mediating mechanisms across multi-omics layers, including proteomics, metabolomics, and immunomics. Our results showed that COVID-19 hospitalization (β = -262.405, P = .041) and severity (β = -177.676, P = .049) were genetically associated with atrophied volume of total brain during longitudinal change. This suggests that individuals with advanced COVID-19 may be more susceptible to accelerated global brain aging. Caudate was genetically affected by all COVID-19 phenotypes. Seven variants were shared between advanced COVID-19 and global brain aging. rs117169628 was colocalized between advanced COVID-19 and global brain aging, and exerted an inhibitory effect on CDH15 expression, further strengthening the causality. Six metabolites, 1 protein, and 1 immune trait were identified as potential mediators. Our study indicates that advanced COVID-19 might be genetically associated with accelerated brain aging. Brain health should be paid more attention in long COVID-19.

Humans↗

PubMed2026

Colocalization and functional analyses identify GBE1 as a gene linking muscle strength and cardiometabolic fitness.

Handgrip strength is a proxy for muscular fitness, an indicator for general health status, and is associated with cardiometabolic health. The mechanisms connecting handgrip strength to skeletal muscle function are incompletely understood. We applied integrated linkage-disequilibrium-adjusted colocalization analysis of genome-wide association study summary statistics for handgrip strength, combined with expression and splicing quantitative trait loci from skeletal muscle, and identified glycogen branching enzyme 1 (GBE1) as a candidate gene for handgrip strength. CRISPR-interference knockdown of GBE1 in immortalized human skeletal muscle cells (HMCL-7304) demonstrated decreased glycogen content and accumulation of polyglucosan bodies. Knockdown of GBE1 led to increased oxygen consumption rate, oxidative stress, and changes in mitochondrial morphology. Transcriptomic profiling of GBE1 knockdown cells identified upregulation of the human superoxide dismutase 2 and enrichment of pathways related to muscle contraction and oxidative stress responses. These functional genomic analyses prioritize GBE1 as a muscle-relevant candidate gene for handgrip strength and provide mechanistic insights to muscle fitness.NEW & NOTEWORTHY Colocalization of genome-wide association study (GWAS) loci with quantitative trait loci (QTL) in skeletal muscle tissue identified GBE1 as a candidate for handgrip strength. Cellular phenotypes with GBE1 knockdown in immortalized human skeletal muscle cells include decreased glycogen content, accumulation of polyglucosan bodies, changes in mitochondrial function and morphology, and increased expression of reactive oxygen species (ROS) scavengers. Transcriptomic changes suggest a role for GBE1 in muscle contraction and oxidative stress-mediated responses.

Humans↗

PubMed1996

Coexistence of parvalbumin and GABA in nonpyramidal neurons of the rat entorhinal cortex.

The possible coexistence of the calcium-binding protein, parvalbumin, with the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), and its synthesizing enzyme, glutamate decarboxylase (GAD), was studied in nonpyramidal cells of the rat medial and lateral entorhinal cortex. The material was analyzed by two different methods, the first of which was a mirror techniques where the possible coexistence of two different antigens was analyzed from cells cut in half at the surface of the adjacent section. The other method consisted of analyzing double immunofluorescent-stained sections with a confocal microscope. The colocalization analysis revealed that all parvalbumin-immunoreactive neurons (mirror technique n = 688 and confocal microscopy n = 644) in all layers of the medial and lateral entorhinal cortex were also immunopositive for GABA or GAD. Parvalbumin-cells made up 52% of the GABA cells in most of the layers in the medial and lateral entorhinal cortex. In layer III of the entorhinal cortex, the proportion was about 40%. Thus, parvalbumin-containing neurons in the entorhinal cortex represent a large GABAergic cell population, which is likely to play an important role in controlling both the input and the output of the entorhinal cortex.

Animals↗