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PubMed2026

Risk stratification in aortic stenosis: exercise haemodynamics to refine risk in early cardiac damage stages.

AIMS: To describe exercise haemodynamics across cardiac damage stages and evaluate the incremental prognostic impact of cardiac damage stage and exercise-induced pulmonary hypertension (exPHT) in patients with symptomatic moderate aortic stenosis (AS) and asymptomatic severe AS. METHODS AND RESULTS: A total of 436 consecutive patients with ≥ moderate AS (74 ± 10 years, 32% women, 56% severe AS) underwent cardiopulmonary exercise testing with echocardiography. The primary endpoint was heart failure (HF) death and HF hospitalizations. Cardiac damage stage was 0 in 93 patients, 1 (LV damage) in 135, 2 (LA/mitral damage) in 135, and 3-4 (pulmonary vasculature/tricuspid or RV damage) in 73. Higher stages were associated with worse exercise capacity and haemodynamics. Over a median follow-up of 37 months, 65 patients met the primary endpoint. After adjustment for age, AS severity, and aortic valve replacement, cardiac damage stage and exPHT were independently associated with HF outcomes [HR per stage increase 1.51 (1.26-1.82); P < 0.001; exPHT HR 2.36 (1.10-5.07); P = 0.03]. exPHT improved risk stratification in early-stage disease (stages 1-2), conferring an approximately five-fold higher risk of HF events in patients with exPHT [HR 4.45 (1.58-12.59); P < 0.01]. CONCLUSION: In patients with ≥ moderate AS and discordant symptoms, cardiac damage stage and exPHT independently refined HF risk stratification. ExPHT provides incremental prognostic value in early damage stages (1-2), representing over half of the cohort, supporting a stepwise approach of routine damage staging with selective with exPHT assessment with exercise echocardiography in this subgroup to guide more personalized management and potentially optimize AVR timing.

Humans↗

PubMed2026

L-glutamine supplementation improves porcine sperm quality and early embryo development during in vitro fertilization.

L-glutamine (Gln), as a key additive in porcine sperm capacitation medium and in vitro fertilization (IVF) systems, has been shown to significantly improve sperm motility and survival rates. However, its precise roles during porcine IVF and subsequent early embryonic development remain elusive. This study utilized an IVF model in pigs to investigate the effects of glutamine on sperm quality and embryonic development. We found that Gln supplementation during sperm treatment significantly improved sperm quality, as evidenced by reduced reactive oxygen species (ROS) production and early apoptosis, while enhancing calcium ion levels and endoplasmic reticulum activity. Supplementing glutamine during embryo culture reduced polyspermy rates, promoted zygotic genome activation (ZGA) and accumulation of 5-ethynyluridine (EU) and histone modifications (H3K4me3 and H3K27ac) at the two-cell and four-cell stages, increased blastocyst formation rates and total cell numbers, while simultaneously reducing DNA damage and early apoptosis during the blastocyst stage. In summary, these findings demonstrate that Gln enhances porcine IVF outcomes by improving sperm quality, reducing polyspermy, and facilitating early embryonic development, thereby providing a basis for optimizing culture systems.

Animals↗

PubMed2026

Effects of passive blood flow restriction on muscle function following exercise-induced muscle damage in recreationally active males.

This investigation examined the effects of passive blood flow restriction (pBFR) on indices of exercise-induced muscle damage (EIMD) in recreationally active males. Fifteen males completed six consecutive visits (±2 hours). Participants completed 3 × 25 maximal, unilateral, isokinetic (60°·s-1), concentric-eccentric leg extensions on both legs. Each leg was randomly assigned to receive pBFR (80% arterial occlusion pressure) or sham (20 mmHg) at 0, 24, 48, 72, and 96 hours post-EIMD. Perceived muscle soreness, range of motion (ROM), pain pressure threshold (PPT), concentric peak torque (CPT), and maximal voluntary isometric contraction (MVIC) torque were assessed and analyzed using separate linear mixed-effects models. Perceived muscle soreness increased at 24 hours (mean difference [meandiff] = 4.9 au; p < 0.001) and recovered by 96 hours (p = 0.482), with no differences between conditions (p = 0.450). ROM (meandiff = -3.1°; p = 0.040), PPT (meandiff = -1.63 kgf; p < 0.001), CPT (meandiff = -27.7 Nm; p < 0.001), and MVIC torque (meandiff = -30.8 Nm; p < 0.001) decreased at 24 hours, with recovery occurring between 48-96 hours. Condition-specific differences were observed for ROM (meandiff = 2.5°; p < 0.001), PPT (meandiff = 0.49 kgf; p = 0.005), CPT (meandiff = 6.2 Nm; p = 0.020), and MVIC torque (meandiff = 7.1 Nm; p = 0.044), which were greater in pBFR than sham. These findings suggested that pBFR may reduce impairments in ROM, PPT, CPT, and MVIC torque following EIMD, despite a similar recovery trajectory between conditions.

Humans↗

PubMed2026

To longevity and beyond: A systems view of aging and stress resilience.

Aging is a dynamic and time-dependent process characterized by progressive functional decline across biological systems. Key hallmarks, including genomic instability, telomere attrition, loss of proteostasis, mitochondrial dysfunction, and immunosenescence, have been widely described, each reflecting distinct yet interconnected mechanistic frameworks. Rather than acting in isolation, these processes arise from complex interactions among cellular stressors, impaired repair mechanisms, and the cumulative burden of maladaptive responses. This system-level perspective explains the inter-individual variability in aging trajectories. Centenarians represent an extreme and informative model of successful aging, in which the balance between damage accumulation and repair is shifted toward the maintenance of physiological function. Their exceptional longevity is supported by coordinated genetic, epigenetic, metabolic, and immunological adaptations that enhance resilience to age-related stressors. Here, we summarize the biological drivers and theoretical frameworks of aging within an integrative context, focusing on mechanisms associated with extended healthspan in centenarians. We also examine the contribution of major animal models, highlighting their complementary roles in elucidating conserved and species-specific aging pathways. Overall, aging outcomes reflect a dynamic equilibrium between damage and repair processes. Understanding how this balance is modulated in long-lived individuals may inform strategies to promote healthy aging and delay the onset of age-related diseases.

Humans↗

PubMed2026

Nebivolol treatment improves hypertension-induced endothelial cell dysfunction by reducing TGF-β1-dependent senescence and normalizing mitochondrial indices.

OBJECTIVES: Serum from patients with hypertension (HT) causes endothelial cell (EC) damage, leading to senescence and dysfunctional phenotype. This study investigated whether serum from patients treated with the antihypertensive drugs could normalize EC activity. METHODS: This study involved 71 patients with newly diagnosed HT, who were randomly assigned to one of three groups based on the antihypertensive treatment: amlodipine, nebivolol, or perindopril. Serum samples collected before and 6 weeks after treatment were applied to ECs in vitro to assess their angiogenic activity, cellular senescence, mitochondrial metabolism, and oxidative stress. RESULTS: Results showed that exposure of ECs to serum from patients treated for 6 weeks significantly altered EC function, with varying effects among the drugs. Serum from nebivolol-treated patients produced the most consistent benefits, reducing EC proliferation and HIF-1α expression, likely due to lower levels of angiogenic factors such as angiopoietin-1, basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). Additionally, this serum contained reduced levels of pro-inflammatory cytokines (E-selectin, P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNFα)) and lower TGF-β1, which are linked to HT-related EC senescence. Nebivolol treatment decreased senescence biomarkers such as SA-β-Gal, 53BP1, and p16, with SA-β-Gal reduction comparable to that of TGF-β1 neutralizing antibodies. Oxidative stress was reduced, indicated by lower oxidized DNA product levels. CONCLUSIONS: Nebivolol was the most effective at reducing the factors, associated with HT induced cellular senescence of endothelium, through reducing TGF-β1.

Humans↗

PubMed2026

ScRNA-seq analysis reveals the effects of nitrite stress on the endocrine system of the eyestalk in Litopenaeus vannamei.

Nitrite is a harmful substance generated in Litopenaeus vannamei farming systems, largely originating from the inadequate breakdown of surplus feed and shrimp feces. Its accumulation in the water can affect the growth and physiological functions of shrimp, damage the immune system, and even cause mass mortality, thus becoming a key environmental factor restricting the green development of the industry. Under nitrite stress, the eyestalk, as an important neuroendocrine regulatory center in crustaceans, participates in the stress adaptation of the organism and exerts a protective effect by regulating energy metabolism and immune function. However, the molecular regulatory mechanism of the eyestalk in response to nitrite stress remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) technology was used to analyze the heterogeneity of eyestalk cells in L. vannamei under nitrite stress. A total of 18, 394 high-quality cells were obtained, and six major cell subpopulations, including Neurosecretory cell, Motor neuron, Sensory neuron, Interneuron, Neurogliocyte, and Support cell, were identified. Differential expression analysis identified 839 differentially expressed genes, and different cell types showed distinct specific responses to nitrite stress. Functional enrichment analysis indicated that pathways such as glycolysis, oxidative phosphorylation, ribosome function, and endoplasmic reticulum protein processing were significantly activated, while signal transduction and DNA repair-related pathways were inhibited. Further analysis revealed that nitrite stress could induce mitochondrial function changes and trigger oxidative stress, thereby affecting the neuroendocrine system function of the eyestalk. This study provided insights into transcriptomic responses of the eyestalk to nitrite stress at the single-cell level, laying a theoretical foundation for the management of aquaculture environments.

Animals↗

PubMed2026

Hydroxyl Radical Inactivation of Vesicle-Cloaked and Free Murine Norovirus: Linking Biomolecular Oxidation to Lifecycle Disruption and Infectivity Loss.

Hydroxyl radicals (•OH) play a central role in inactivating human viruses during advanced oxidation processes for water and wastewater treatment, solar disinfection, and natural attenuation in sunlit aquatic environments. Human norovirus, a leading cause of gastroenteritis, is efficiently transmitted through water and exhibits strong environmental persistence. The recent discovery of vesicle-cloaked virus clusters (viral vesicles) further challenges water treatment and reuse, particularly for norovirus elimination. We investigated •OH inactivation kinetics and mechanisms of murine norovirus 1 (MNV-1), a human norovirus surrogate, in free-virus and vesicle-cloaked forms. •OH rapidly inactivated both MNV-1 vesicles and free MNV-1 with second rate constants of ∼1010 M-1 s-1; however, the vesicle membrane provided a 2.24-fold protective effect to cloaked MNV-1, resulting in slower inactivation kinetics than those of free MNV-1. •OH oxidized viral capsid proteins and genomes together with vesicle proteins and lipids, resulting in impaired CD300lf receptor and cell-based binding, disrupted genome replication, and diminished viral assembly. Despite these biochemical and functional impairments, most vesicle structures remained largely intact following •OH exposure. This study establishes a quantitative framework linking biomolecular damage to viral infectivity loss through functional impairment and lifecycle disruption, providing mechanistic insights into advance water disinfection strategies and public health protection.

Norovirus↗

PubMed2026

Exploring the Role of DNA Methylation in the Epigenetic Landscape of Cancer.

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Cancer epigenetic↗

PubMed2026

Distinct functions of mammalian RAD51 paralogs in genome maintenance.

RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) are evolutionarily conserved essential proteins for cell survival and genome maintenance. RAD51 paralogs were originally identified to play a role in homologous recombination-mediated repair of DNA double-strand breaks (DSBs). However, investigations over the last decade have uncovered new roles of RAD51 paralogs beyond DSB repair in replication stress responses, including replication fork progression, fork stability, and its restart. Recent structural studies have not only uncovered the molecular architecture of previously known RAD51 paralog complexes but also identified novel paralog complex assemblies, providing mechanistic insights into their various genome-maintenance functions. Additionally, a role for RAD51 paralogs in resolving R-loops has been identified, and studies with cancer-associated variants suggest that RAD51 paralogs are potential determinants of cancer susceptibility and therapeutic responses. In the present review, we highlight the recently deciphered structures and novel functions of RAD51 paralog complexes and discuss the clinical and therapeutic implications.

Rad51 Recombinase↗

PubMed2026

Longitudinal comparison of treat-to-target states and clinical outcomes in patients with late-onset versus early-onset systemic lupus erythematosus.

OBJECTIVE: We compared demographic and clinical characteristics between patients with late-onset (LO) and early-onset (EO) systemic lupus erythematosus (SLE) and examined their longitudinal associations with treatment targets and long-term outcomes, irreversible organ damage accrual and health-related quality of life (HRQoL). METHODS: We analyzed prospectively collected data from patients enrolled in the Asia Pacific Lupus Collaboration cohort. Patients diagnosed with SLE at age >50 years were classified as LO-SLE and compared with those diagnosed at age ≤50 years (EO-SLE). Longitudinal associations with treatment targets (LLDAS and DORIS remission), organ damage accrual (SLICC/ACR Damage Index), and HRQoL (SF36v2 physical and mental component summary (PCS and MCS) scores) were examined using multivariable multilevel logistic, recurrent-event survival, and linear mixed-effects models, respectively. Disease activity, flares, medication exposure, and other clinical characteristics were also compared between groups. RESULTS: Among 3,917 patients studied, 346 (8.8%) had LO-SLE. Compared with EO-SLE, patients with LO-SLE had lower disease activity, lower glucocorticoid and immunosuppressant exposure, and higher attainment of treatment targets; LO-SLE was associated with higher odds of attaining LLDAS (OR: 2.33 (1.66, 3.28)) and DORIS remission (OR: 2.22 (1.45, 3.38)). However, they were at a greater risk of damage accrual (HR:1.82 (1.50, 2.21)) and lower PCS scores, meaning poorer physical health (regression coefficient (RC) = -3.63 (-4.58, -2.68)) but not MCS (RC= 0.68 (-.50, 1.86)). CONCLUSION: Despite higher attainment of treatment targets, patients with LO-SLE experienced greater damage accrual and poorer physical health, suggesting that disease activity targets alone may not fully capture outcome risk in LO-SLE.

Journal Article↗

PubMed2026

The impact of sex, age, and genetic ancestry on DNA methylation across tissues.

Understanding the consequences of individual DNA methylation variation is crucial for advancing our knowledge of human biology and disease, yet the collective impact of individual traits on DNA methylation and their downstream effects on gene expression across human tissues remains poorly understood. Here, we quantify the contributions of sex, age, genetic ancestry, and BMI on autosomal DNA methylation variation across nine human tissues and 424 individuals from the Genotype-Tissue Expression project. We show that genetic ancestry and age have a greater impact on DNA methylation compared with sex, with aging effects being more widespread but less pronounced. On average, <10% of the gene expression variation in sex, age, and ancestry is mediated by DNA methylation differences, with ancestry showing the largest proportion of mediation. We further show that ancestry-associated DNA methylation differences accumulate at CpG sites with extreme methylation states and are largely under genetic control. The female autosomal genome exhibits consistent hypermethylation across tissues at Polycomb-repressed regions. Ultimately, we show that age-related Polycomb target hypermethylation is observed across multiple tissues but not in the gonads. Our multi-individual, multitissue approach defines the key drivers of human DNA methylation variation in healthy conditions, establishing a baseline for the interpretation of DNA methylation changes in disease contexts.

Humans↗

PubMed2026

An RPA-assisted homogeneous electrochemical DNA sensor for on-site eDNA detection toward early warning of crown-of-thorns starfish outbreaks.

Crown-of-thorns starfish (COTS) outbreaks seriously threaten coral reef ecosystems, while conventional monitoring approaches are time-consuming and often lack sufficient sensitivity for early warning. Existing electrochemical DNA sensors usually require complex electrode-surface immobilization procedures, which can lead to uneven probe distribution, significant steric hindrance, and poor stability. Meanwhile, the low concentration of environmental DNA (eDNA) in marine environments further complicates detection. To overcome these challenges, this study developed a homogeneous electrochemical DNA sensor assisted by recombinase polymerase amplification (RPA) for COTS eDNA detection. Target DNA was first amplified by RPA, and the amplification products were then hybridized in solution with capture probe (CP)-modified magnetic beads (MB) and biotin-labeled signal probe (SP) to form sandwich-structured MB complexes. These complexes were subsequently magnetically enriched and immobilized on the electrode surface for electrochemical signal readout. Under optimized conditions, the sensor displayed a linear response to COTS genomic DNA from 3.77 fg/μL to 1 ng/μL, with an LOD of 2.02 fg/μL and an LOQ of 3.77 fg/μL. The sensor was applied to Xisha Islands samples, and the results agreed with droplet digital PCR (ddPCR) (P > 0.05), demonstrating its potential for sensitive and reliable on-site COTS eDNA detection.

Animals↗

PubMed2026

Accurate quantification of canine mitochondrial DNA copy number from canine blood and brain samples.

Acute brain injury is difficult to evaluate in veterinary medicine and tools to investigate the potential involvement of mitochondrial involvement are limited. The brain is highly enriched in mitochondria and contains thousands of copies of mitochondrial DNA (mtDNA) per cell, but robust methods for quantifying mitochondrial DNA copy number (mtDNA-CN) in canine tissues are lacking. We describe the development of a quantitative real-time PCR assay for absolute measurement of mtDNA-CN which was validated in canine blood and brain tissue. To minimize amplification of nuclear mitochondrial insertion sequences (NumtS) and repetitive regions, species-specific oligonucleotide primers were designed following in silico genomic filtering. The assay was applied to a small pilot cohort comprising blood samples from dogs with and without acute brain injury (n = 4-6 per group) and cerebral cortex samples (n = 1 per group) to assess feasibility and biological plausibility. In non-brain injury dogs, blood mtDNA-CN ranged from 98 to 288 copies per nuclear genome (mean 193 ± 72), while values in brain-injured cases ranged from 163 to 228 copies per genome (mean 200 ± 33). Cerebral cortex samples exhibited higher mtDNA-CN than blood, consistent with known tissue-specific mitochondrial enrichment. In a single brain-injured case with serial sampling, mtDNA-CN increased over five days. This study presents a validated assay and pilot data for mtDNA-CN quantification in canine samples. While not powered for biomarker evaluation, this method may enable future studies of mitochondrial dynamics in canine brain injury and metabolic disease.

Animals↗

PubMed2026

Urinary Small Extracellular Vesicle DNA as a Biomarker for the Non-Invasive Diagnosis of Bladder Cancer.

Existing diagnostic technologies for bladder cancer (BC) suffer from low sensitivity, low specificity, or a lack of validation. Therefore, validated, non-invasive diagnostic biomarkers with high sensitivity and specificity for early detection of BC are needed to complement and improve upon the limitations of existing diagnostic methods. We used low-pass whole genome sequencing (LP-WGS) technology to detect copy number variations (CNVs) in small extracellular vesicle (sEV) DNA isolated from urine samples of patients. Based on these results, we constructed and validated a diagnostic model to differentiate between benign and malignant bladder lesions. We conducted a receiver operating characteristic analysis and calculated the area under the curve (AUC) to evaluate the performance of the diagnostic model. The urine sEV-DNA LP-WGS data revealed CNV differences between benign and malignant samples. The diagnostic model achieved an AUC of 0.953, a sensitivity of 86.7%, and a specificity of 100% in the training cohort and an AUC of 0.985, a sensitivity of 90%, and a specificity of 100% in the validation cohort. Even at the lowest coverage depth of 0.01X, the performance of the diagnostic model remained relatively robust. Notably, the performance of this diagnostic model surpassed that of the biomarker neuron-specific enolase (sensitivity: 85.7% vs. 64.3%; specificity: 100% vs. 87.5%) and urinary cytology (sensitivity: 100% vs. 66.7%; specificity: 100% vs. 94.1%). Our study demonstrates that urine sEV-DNA exhibits high discriminatory power in distinguishing between benign and malignant bladder lesions, making it a promising tool for auxiliary diagnosis of BC.

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

Integrative analysis of transcriptome and DNA methylome dynamics during caudal fin regeneration in silver pomfret (Pampus argenteus).

Caudal fin regeneration in teleost fish is a complex, multi-stage process involving coordinated molecular and cellular changes. While the role of epigenetic regulation particularly DNA methylation has been studied in model freshwater species such as zebrafish, its contribution to regeneration in marine teleosts remains largely unexplored. In this study, we integrated transcriptomic and DNA methylomic data to characterize the temporal dynamics of gene expression and methylation during caudal fin regeneration in the silver pomfret (Pampus argenteus). Using RNA-sequencing and reduced representation bisulfite sequencing (RRBS) at three biologically critical time points 1, 3, and 7 days post-amputation (dpa), we characterized the spatiotemporal molecular landscape of caudal fin regeneration. These time points capture the key transitional phases of wound healing and inflammation (1 dpa), blastema formation and progenitor proliferation (3 dpa), and regenerative outgrowth with tissue remodeling (7 dpa), enabling robust detection of the major molecular programs underlying epimorphic regeneration. Concurrently, CG-methylome analysis identified thousands of dynamically changing differentially methylated regions (DMRs). A strong global inverse correlation was observed between promoter methylation and gene expression. Integrative analysis pinpointed key regeneration genes (fgf20a, msxb, sox9b) whose expression was associated with dynamic methylation changes in their promoters or gene bodies. We conclude that DNA methylation is a dynamic and key regulatory layer that acts in concert with transcriptional reprogramming to coordinate tissue regeneration, providing new insights into the epigenetic mechanisms underlying complex regenerative processes in teleosts.

Animals↗

PubMed2026

A genome-wide coverage-based pipeline for the identification of host-derived candidate DNA biomarkers from cell-free blood.

We have created a new data-analysis pipeline for the discovery of host-specific candidate DNA biomarkers derived from sequencing data of cell-free blood. Unlike approaches that rely on specific molecular or genetic signatures, our method leverages the coverage distribution of cell-free DNA sequences mapped to a reference genome, applying statistical analyses to identify informative short genomic regions for biomarker discovery. The pipeline is applicable to diverse diseases and can be used to analyze cell-free DNA sequences from plasma or serum to identify candidate biomarkers that are characteristic of disease states in mammals. Core functionalities were developed in Java and integrated with open-source software tools for the preprocessing of raw sequencing data, complemented by Python scripts for the machine-learning analysis and statistical validation. The pipeline is designed for HPC use and users can access the pipeline through a Galaxy workflow, which offers a user-friendly web interface for input selection prior to execution and analysis progress monitoring. Performance tests, carried out using duplicate sets of COVID-19 samples and controls, showed linear scalability of execution time with an increasing dataset size, as well as a substantial reduction in execution time through parallelized computation, whereby each HPC node is used to process the data of one chromosome. Further statistical tests confirmed the quality of the pipeline's results by showing that the set of identified candidate biomarkers remained stable across varying dataset sizes.

Biomarkers↗

PubMed2026

Apoptosis protein markers in comorbid type 2 diabetes mellitus and depression; relationships with cognitive performance, incident dementia, and white matter hyperintensities.

Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) are reciprocal risk factors, and both elevate dementia risk. Dysregulation of programmed cell death is implicated in T2DM, MDD, and neurodegeneration, but proteomic markers of apoptosis have yet to be studied as dementia predictors in people with T2DM and/or MDD. This study examines apoptosis markers in comorbid T2DM and MDD, and their associations with cognitive, dementia, and neuroimaging outcomes. The retrospective sample (n = 15,765) consisted of UK Biobank participants (MDD only n = 1230; T2DM only n = 3644; comorbid T2DM + MDD n = 721). Individuals with T2DM + MDD comorbidity had poorer cognitive performance, and a higher 15-year dementia incidence (HR = 4.44, 95% CI = [3.23,6.11]). Among 60 apoptosis-related proteins identified by Kyoto Encyclopedia of Genes and Genomes pathway enrichment, 41 were significantly up-regulated in comorbid T2DM + MDD relative to controls, and 4 were higher in the comorbid group than both T2DM alone and MDD alone. Tumor necrosis factor ligand superfamily member 10 (TNFSF10), growth arrest and DNA damage-inducible protein GADD45 beta, tumor necrosis factor ligand superfamily member 6, and RAC-gamma serine/threonine-protein kinase were associated with dementia risk. Nine proteins (e.g. apoptosis-inducing factor 1, mitochondrial, caspase-2, mitogen-activated protein kinase kinase kinase 5, TNFSF10), were associated with white matter hyperintensity volumes in comorbid T2DM + MDD after FDR correction, but none were associated with cognitive performance, atrophy, or white matter microstructural changes. These findings identify peripheral apoptosis markers that were further elevated in comorbid T2DM + MDD compared to either alone, pointing to an important pathophysiological element underlying adverse outcomes in the context of mood and metabolic comorbidity.

Humans↗