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PubMed2024

Cohort Studies and Multi-omics Approaches to Low-Dose Ionizing Radiation-Induced Cardiovascular Disease: A Comprehensive Review.

The effect of low-dose ionizing radiation exposure on the risk of cardiovascular disease (CVD) represents a significant concern in the field of radiation protection. The prevailing approach to mitigating the adverse effects of low-dose or low-dose-rate radiation does not currently incorporate the potential risk of CVD, despite the possibility that such risk may be a substantial contributor to overall health hazards. Current evidence suggests a potential association between radiation exposure and CVD; however, the overall findings remain inconclusive. This is particularly due to the uncertainty surrounding the influence of significant non-radiation risk factors on the associations reported in epidemiological studies. It is difficult to discern the underlying connection in observational epidemiology when there is substantial variation in baseline risk factors. The paucity of epidemiological research in this domain is being partially offset by the advancement of multi-omics approaches. These methods assist in identifying radiosensitive targets, comprehending underlying biological processes, and pinpointing biomarkers. This, in turn, fortifies the evidence gleaned from epidemiological studies. In this review, we delve into the body of epidemiological research pertaining to CVD induced by low-dose ionizing radiation and the application of multi-omics techniques. The integration of these two methodologies holds the promise of identifying specific molecules or biological pathways that can be employed to validate endpoints related to radiation risk assessment.

Humans↗

PubMed1992

Bone hypertrophy and trabecular generation in Paget's disease and in fluoride-treated osteoporosis.

The replacement of lost trabeculae characteristic of postmenopausal osteoporosis is problematic, since a biological pathway has not been established for trabecular regeneration de novo in the healthy, intact, mature skeleton. Possible pathways for trabecular replacement may occur under pathological conditions, in particular those associated with bone hypertrophy. The topography of trabecular hypertrophy was compared in two groups of subjects with disease- or treatment-induced osteosclerosis following a period of atrophy. In Paget's disease and fluoride-treated osteoporosis a thickening of rarefied trabeculae in both was associated in Paget's disease only with an increase in the trabecular number and the transformation of a discontinuous arrangement into a more continuous network. The sequence seems to be a progression of intratrabecular resorption normally attendant upon a period of trabecular thickening. The failure of fluoride-treated bone in this respect, due to the unusual stability of the fluorotic skeleton, may provide insight to more effective anabolic regimens.

Adult↗

PubMed1986

Endometrial cancer and its precursors: a comparison of histological and clinical features.

In this study, the histological definition of endometrial cancer precursor (ECP) lesions is discussed and a comparison is made of clinical and histological parameters of ECP patients and endometrial cancer (EC) patients. ECP lesions were divided in 3 types: adenomatous hyperplasia, atypical hyperplasia and in situ adenocarcinoma. The following parameters were analyzed: age, menopausal status, gynecological and extragynecological familiar cancer incidence, other cancers in the proband, diabetes, obesity, primary infertility, fertility and previous estrogen therapy. Results give support to the hypothesis of the existence of a common biological pathway between ECP and EC. The high frequency of coexistence of both types of lesions in hysterectomy specimens from EC patients studied by step sections adds a confirmatory supporting argument. Measures for primary and secondary prevention of these lesions are proposed.

Adenocarcinoma↗

PubMed2025

Genetic analysis in African ancestry populations reveals genetic contributors to lung cancer susceptibility.

Striking disparities in lung cancer exist, with Black/African American individuals disproportionately affected by lung cancer, yet the genetic architecture in African ancestry individuals is poorly understood. We aimed to address this by performing a comprehensive genetic association study of lung cancer, incorporating local ancestry, across 6,490 African ancestry individuals (2,390 individuals with lung cancer and 4,100 control subjects). We identified a single genome-wide significant (p < 5 × 10-8) locus, 15q25.1 (lead SNP rs17486278, OR [95% CI] = 1.34 [1.23-1.45], p = 4.52 × 10-12), that has consistently shown a strong association with lung cancer across populations. Additionally, we identified nine suggestive (p < 1 × 10-6) loci. Four of these loci (3p12.1, 8q22.2, 14q11.2, and 18q22.3) have no prior reported associations with lung cancer. We performed a multi-ancestry lung cancer meta-analysis using prior large-scale summary statistics from European and Asian ancestry populations, incorporating our African ancestry results. The meta-analysis identified 17 genome-wide significant loci, including an association with locus 4q35.2 (p = 1.22 × 10-8), a genomic region that has been previously linked to forced expiratory volume. Genome-wide SNP-based heritability for lung cancer was 16% among African ancestry individuals. Follow-up in silico functional analyses identified genetically regulated gene expression (GReX) of nine genes (AC012184.3, ADK, CCDC12, CHRNA3, EML4, PSMA4, SNRNP200, TMEM50A, and ZYG11A) associated with lung cancer risk and biological pathways relevant to cancer and lung function. Cumulatively, these findings further elucidate the genetic architecture of lung cancer in African ancestry individuals, confirming prior loci and revealing new loci.

Female↗

PubMed2026

Handgrip strength and risk of common infections and sepsis: Two prospective cohorts with proteomic mediation analysis.

BACKGROUND: Recent evidence links adiposity with the risk of severe infections, but whether muscle strength may also be an independent risk factor is less studied. We investigated the association between handgrip strength and risk of common infections and sepsis and explored potential mediation by plasma proteomic biomarkers. METHODS: We analyzed data from 405,451 UK Biobank participants and replicated the main findings in 4474 Chinese adults from the Hong Kong Osteoporosis Study (HKOS). Baseline handgrip strength was measured by a dynamometer. Cox models were used to estimate its association with incidence of pneumonia, urinary tract infection (UTI), skin infection, and sepsis, adjusting for sociodemographic, lifestyle, and health-related factors. Mediation analyses were performed using 2912 plasma proteins in a UK Biobank subsample (n = 42,414) to identify biological pathways. RESULTS: In UK Biobank (median follow-up 13.6-15.3 years), lower handgrip strength was associated with significantly increased risk of pneumonia (hazard ratio per 5-kg decrement=1.10; 95% CI=1.09-1.11), UTI (1.10; 1.09-1.11), skin infection (1.05; 1.04-1.05), and sepsis (1.08; 1.07-1.10). Associations were largely consistent in HKOS, and the relative risks associated with low grip strength were generally most pronounced in underweight individuals. GDF15 and PLAUR were identified as the most important proteins which mediated 12-14% of these associations. CONCLUSION: Low handgrip strength is associated with increased risks of common infections and sepsis, particularly in underweight individuals, with partial mediation by proteins related to inflammation and immune-related pathways. Handgrip strength assessment may provide prognostic value beyond body mass index for clinical risk stratification.

Humans↗

PubMed2026

Unraveling causal links between chronic rhinosinusitis and peripheral artery diseases: insights from genetic correlations through genome-wide association studies.

OBJECTIVES: Chronic Rhinosinusitis (CRS) shares epidemiological links with Cardiovascular Diseases (CVDs), however, their shared genetic basis remains unclear. We hypothesized that pleiotropic genetic variants underlie CRS-CVDs links via distinct biological pathways. METHODS: Using large-scale GWAS data from European-ancestry individuals, we assessed global and local genetic correlations. We applied Genomic Structural Equation Modeling (Genomic SEM) to dissect shared genetic architecture, performed bidirectional Mendelian Randomization (MR) to infer causality, and conducted cis-eQTL colocalization to identify shared genetic signals. Finally, in vitro endothelial models (HUVECs) validated the functional dynamics of candidate genes under CRS-mimicking inflammatory stress. RESULTS: CRS showed significant genetic correlations with multiple CVDs. Genomic SEM revealed a latent factor structuring shared genetic risk through three pathways: artery diseases, myocardial diseases, and heart failure. Local genetic correlations identified significant local genetic correlations specifically between CRS and Peripheral Atherosclerosis (PAS)/Peripheral Artery Disease (PAD) specifically within the chr6: 31.57‒33.24 Mb locus. MR demonstrated causal effects of CRS on PAD (OR = 1.23, p = 0.022) and PAS (OR = 1.21, p = 0.011), but not vice versa. Genetically predicted HLA-DRB1, APOM, and COL11A2 expression conferred protection, while HLA-DQA2 increased risk. Crucially, in vitro validation corroborated these pathogenic trajectories, inflammatory stress significantly downregulated the protective APOM and upregulated the risk-associated HLA-DQA2 alongside pro-atherogenic VCAM-1, while HLA-DRB1 exhibited a compensatory upregulation (p < 0.05). CONCLUSION: CRS shares global genetic liability with CVDs, structured through three primary etiological pathways. Causal effects of CRS on peripheral artery diseases are mediated by immune and lipid-related genes within the chr6 locus, revealing divergent pleiotropic mechanisms. Our integrated genetic and in vitro evidence provides a mechanistic framework wherein chronic mucosal inflammation contributes to systemic endothelial vulnerability, thereby highlighting candidate targets for mechanism-directed therapy.

Humans↗

PubMed2026

Comprehensive mass spectrometry screening-derived atlas of HDAC inhibitors reveals histone-specific acetylation changes.

Histone deacetylase inhibitors (HDACis) have emerged as valuable therapeutics for cancer and other diseases; however, their effects on histone post-translational modification remain poorly characterized. Here, we applied quantitative mass spectrometry and high-throughput sequencing to systematically profile site-specific changes in histone modifications in response to a panel of HDACis. This platform enabled mapping of histone modification changes across hundreds of sites, including low-abundance histone marks. Furthermore, an integrative analysis of chromatin immunoprecipitation followed by sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) data identified genome-wide binding sites for the low-abundance histone modification of H2A.Z acetylation in HeLa and MDA-MB-231 breast cancer cells, highlighting the role of H2A.Z acetylation in regulating gene expression across diverse biological pathways, including specific genes involved in tumor suppressor pathways. Our findings provide a functional resource for identifying and quantifying histone modification changes and transcriptional regulation of histone H2A.Z acetylation following pharmacological perturbation.

Histone Deacetylase Inhibitors↗

PubMed2024

Gene expression patterns associated with PFOA exposure in Czech young men and women.

Perfluorooctanoic acid (PFOA), a member of per- and polyfluoroalkyl substances (PFASs), has been widely used in manufacturing for decades. Currently, PFOA is strictly regulated, but due to its high stability and persistence, it is detected in both environmental as well as in human matrices. To elucidate mechanisms of PFOA toxicity in humans, we determined the genome-wide transcriptomic changes of peripheral blood mononuclear cells (PBMC) responding to PFOA exposure in a sex-stratified analysis. This work employed samples from 145 female and 143 male participants of the CELSPAC: YA study to characterize PFOA-associated transcripts in a broader context using computational analysis. PFOA-associated gene expression differed significantly between men and women, as only 2 % of mapped genes were expressed in both sexes. Disease-specific enrichment analysis revealed cancer and immune-related disease terms as those most enriched in male and female populations. Patterns of enriched terms within the gene set enrichment analysis indicated three main targets of PFOA toxicity: i) lipid metabolism for women; ii) cell cycle regulation for men; and iii) immune system response for both sexes. In summary, our genome-wide transcriptomics analysis described sex-specific differences in PFOA-associated gene expression and provided evidence about biological pathways underlying PFOA toxicity in humans.

Humans↗

PubMed2026

Long-term (>7-year) parental consumption of genetically modified maize (Cry1Ab/Cry2Aj and EPSPS) induces no adverse sperm DNA methylation alterations across two generations of cynomolgus monkeys.

This study assessed the long-term safety of genetically modified (GM) maize from a male reproductive perspective, using a non-human primate model. We analyzed the sperm DNA methylation profiles in cynomolgus monkeys fed GM maize, non-GM parental maize, or a conventional diet over two generations (F0/F1). Whole-genome bisulfite sequencing (WGBS) revealed no significant differences in global methylation levels among groups. The identified differentially methylated regions (DMRs) were short, enriched in non-regulatory genomic areas, and did not cluster after treatment. Functional enrichment analysis showed that DMR-associated genes were consistently involved in the same core biological pathways (e.g., mTOR and Wnt signaling) across all dietary comparisons. These findings indicate that GM maize consumption did not induce specific adverse epigenetic alterations in sperm, with the observed changes reflecting common physiological adaptations to dietary variations rather than GM-related effects.

Animals↗

PubMed2026

Proteome Unravels Mechanism Differences in Embryogenesis Between Honey Bee Drone and Worker (Apis mellifera L.).

The physiological and social behaviors differ widely between honeybee workers and drones. All the organ rudiments of adult bees are formed during the embryonic stage. The initial molecular bases at the proteomic level for both embryonic developments have been identified, but a comprehensive understanding of the significant events involved in embryonic establishment remains elusive. To elucidate the molecular regulatory mechanisms underlying tissue differentiation during the embryogenesis of drones and workers, we implemented a state-of-the-art approach that combines in-hive inspection and targeted sampling (at nine embryogenesis stages) with high-throughput proteomics technology to investigate the developmental differences. In-hive inspection of hatching timing revealed an average developmental gap of approximately 3.6 h between the two embryos. Furthermore, proteomic analyses indicate that drone and worker embryos adopt distinct developmental strategies. Notably, proteins involved in fatty acid metabolism and key biological pathways related to organ formation-such as the Hedgehog and Wnt signaling pathways-are activated earlier in drones, suggesting that tissue development begins sooner in drone embryos than in workers. Additionally, the upregulation of cytoskeletal proteins and antioxidants in drone embryos likely supports their larger cell size and higher metabolic stress, reflecting distinct molecular characteristics of male development. Ribosomal proteins essential for biosynthetic support remain consistently expressed throughout the late stages in male embryos, indicating that drone embryogenesis lasts longer than that of workers. This work provides novel insights into the molecular foundations of honeybee embryogenesis and lays both theoretical and practical groundwork for future research into the mechanisms driving embryonic development.

Animals↗

PubMed2026

Mapping the Immune cell-specific gene regulatory network in bipolar disorder: A framework from scTWMR to exploratory drug-target annotation.

BACKGROUND: Although the involvement of the immune system in the genetic susceptibility of bipolar disorder (BD) is widely acknowledged, the causal relationship between gene expression in specific immune cell subtypes and BD requires systematic elucidation. METHODS: We implemented an analytical framework integrating single-cell transcriptome-wide Mendelian randomization (scTWMR) with colocalization analysis. This approach utilized cis-expression quantitative trait loci (cis-eQTLs) derived from 14 distinct immune cell types as instrumental variables to interrogate BD genome-wide association study (GWAS) summary statistics (comprising 41,917 cases and 371,549 controls). Subsequent investigations encompassed functional enrichment analysis, protein-protein interaction (PPI) network construction, phenome-wide association study (PheWAS), and performed an exploratory drug-target annotation. RESULTS: Our analysis identified 33 gene-immune cell associations. Colocalization analysis provided robust evidence (PPH4 > 90%) for shared causal variants implicating the MAD1L1, APOM, and NFKBIL1 loci. Significantly enriched biological pathways included cell cycle regulation, circadian rhythm entrainment, and neuroinflammation. The PPI network revealed a core regulatory module centered on histone-encoding and immune-related genes. Exploratory drug-target annotation nominated compounds for further investigation for compounds targeting APOM, TMEM258, and NFKBIL1. CONCLUSION: This study systematically delineates a genetically supported regulatory network of immune cell-specific gene expression in BD, predominantly implicating CD8⁺ effector T cells, plasma cells, and B cells. The findings corroborate established pathological pathways while uncovering novel cell type-specific therapeutic targets, thereby providing a genetic framework for prioritizing candidate targets for future investigation.

Bipolar disorder↗

PubMed2026

Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.

Amino Acids, Branched-Chain↗

PubMed1977

Reductive dechlorination of DDT by haem proteins.

DDT1 is converted to DDD by reduced myoglobin (rapidly), cytochrome c oxidase, and a haem-containing undecapeptide derived from cytochrome c. Cytochrome c itself is inactive. This demonstrates that an accessible haem site is necessary for the reaction. Spectrophotometric evidence is presented for an interaction between DDT and the undecapeptide. These results cast light on one of the biological pathways for the breakdown of DDT.

Animals↗

PubMedDate not supplied

An IgG autoantibody which inactivates C1-inhibitor.

Antibodies are considered to play a specific pathogenic role in certain disease states such as myasthenia gravis, Graves' disease and autoimmune haemolytic anaemia. Autoantibodies which interfere with the function of enzyme cascade systems have also been described in diseases such as acquired haemophilia (anti-factor VIII antibodies) and glomerulonephritis (C3 nephritic factor). The identification of these autoantibodies is crucial to an understanding of the aetiology of such diseases and is also of importance in revealing the inter-relationships of the immune system with other biological pathways. This is the first report of an immunoglobulin G (IgG) autoantibody reactive with C1-inhibitor (C1-Inh), a pivotal inhibitor of the inflammatory response which is known to inactivate proteins of the complement, kinin, fibrinolytic and 'contact phase' systems. This autoantibody was isolated from a patient with a novel variant of acquired angioedema and C1-Inh dysfunction. This finding highlights the involvement of the immune system in the pathogenesis of disorders characterized by the presence of dysfunctional inflammatory response proteins.

Autoantibodies↗

PubMed1992

The murine pallid mutation is a platelet storage pool disease associated with the protein 4.2 (pallidin) gene.

Pallid is one of 12 independent murine mutations with a prolonged bleeding time that are models for human platelet storage pool deficiencies in which several intracellular organelles are abnormal. We have mapped the murine gene for protein 4.2 (Epb4.2) to chromosome 2 where it co-localizes with pallid. Southern blot analyses suggest that pallid is a mutation in the Epb4.2 gene. Northern blot analyses demonstrate a smaller than normal Epb4.2 transcript in affected pallid tissues, such as kidney and skin. This is the first gene defect to be associated with a platelet storage pool deficiency, and may allow the identification of a novel structure or biological pathway that influences granulogenesis.

Animals↗

PubMed2026

Dissecting pleiotropy between major depressive disorder and physical disease comorbidities.

Major depressive disorder (MDD) is characterized by substantial comorbidity with medical conditions. To achieve better outcomes for patients with MDD, an improved understanding of the mechanisms underlying pervasive comorbidities is required. Here, to this end, we mapped patterns of pleiotropy by defining four clusters of physical diseases (cardiovascular, metabolic, gastrointestinal and immune) and analyzed their genetic relationships with MDD using genomic structural equation modeling. Three disease clusters exhibited independent associations with MDD and accounted for 47% of MDD h2SNP, with the gastrointestinal disease cluster having the strongest association (β = 0.63, s.e. = 0.05, P = 3.04 × 10-30). In addition, we identified independent loci associated with the shared genetic liability between each disease cluster and MDD, revealing different pleiotropic components. Characterization of these loci revealed previously unidentified associations with MDD and physical disease traits, along with unique biological pathways, drug groups, cell types and genes associated with each disease-MDD cluster. Our findings reveal genetic connections implicating the gut-brain axis as a key mechanism underlying the comorbidity of physical diseases in MDD. This work advances our understanding of MDD by highlighting unique and shared genetic components across different disease systems.

Major Depressive Disorder↗

PubMed2025

Horse model of spontaneous atrial fibrillation share proteomic changes with humans.

Horses and humans are among the few mammals susceptible to spontaneous atrial fibrillation (AF), both suffering from high recurrence rates after treatment. Treatment resistance is often attributed to progressive atrial remodeling, but current treatment options fail to effectively address this aspect. Here, we introduce a novel horse model of spontaneous AF to investigate the biological pathway changes in early stages of the disease. Through data-independent acquisition mass spectrometry on biopsies from the right and left atrium and left ventricular chamber of horses with early-stage persistent AF (n = 8) and controls (n = 8), we identify several differentially regulated proteins across all three chambers. Pathway enrichment analyses and histological stainings highlight a significant role of atrial extracellular matrix (ECM) remodeling in early AF. Other key proteomic changes relate to metabolism, contractility, and protein-folding, and overlap with findings from publicly available human datasets. Our results demonstrate that horses and humans share several AF-related proteomic changes, providing translational insights into the early atrial remodeling processes that are likely to contribute to treatment resistance. These protein-level changes could serve as biomarkers or pharmacological targets for preventing AF-associated atrial remodeling and improve treatment outcomes across species.

Atrial Fibrillation↗

PubMed1985

Characterization of rate-controlling steps in vivo by use of an adjustable expression vector.

Citrate synthase (EC 4.1.3.7) was varied from 10% to 5000% the level found in wild-type Escherichia coli by means of recombinant DNA techniques. When acetate was the sole carbon source, cell growth and carbon flow through the Krebs cycle were greatly affected by the under-production of citrate synthase. In contrast, when glucose was the main nutrient, the same underproduction of citrate synthase had little effect on either growth or carbon flux. When the enzyme was overproduced 50-fold, cultures would grow on glucose but cell division could be abruptly stopped by adding acetate to the medium. These results indicate that the regulatory properties of citrate synthase are highly dependent on the carbon-source composition of the medium. Furthermore, recombinant DNA technology can be used to alter rate-controlling steps in biological pathways and elucidate the regulatory properties of metabolic systems.

Citrate (si)-Synthase↗