Search Results (1,031)

Aging of the central nervous system (CNS) involves widespread transcriptional and structural remodeling, prominently marked by synaptic loss, impaired neurogenesis, and glial dysfunction. While age-related gene expression changes have been documented for decades, recent genome-wide next-generation sequencing studies emphasize the importance of epigenetic mechanisms—such as DNA methylation and histone modification—in shaping these profiles. Notably, these modifications are potentially reversible, making them promising targets for therapeutic intervention. However, the mechanisms by which age-associated factors, such as inflammation and oxidative stress, orchestrate these epigenetic alterations across distinct CNS cell types remain poorly understood. In this review, we propose a framework for understanding how aging and neuroinflammation are regulated by epigenetic mechanisms, contributing to brain dysfunction and disease vulnerability. Full article

Background: Physical conditioning is essential to meet the operational demands of military environments. However, high-intensity exercise provokes muscle microinjuries resulting in exercise-induced muscle damage. This condition is typically monitored using serum biomarkers such as creatine kinase (CK), myoglobin (MYO), and lactate dehydrogenase (LDH). Nevertheless, individual variability and genetic factors complicate the interpretation. In this context, the rs1815739 variant (ACTN3), the most common variant related to exercise phenotypes, hypothetically could interfere with the muscle physiological response. This study aimed to evaluate the kinetics of serum biomarkers during a high-intensity activity and their potential association with rs1815739 polymorphism. Materials and Methods: 32 male cadets were selected during the Army Paratrooper Course. Serum was obtained at six distinct moments while they performed regular course tests and recovery time. Borg scale was assessed in 2 moments (~11 and ~17). Results: Serum levels of CK, CK-MB, MYO, and LDH significantly increase after exercise, proportionally to Borg’s level, following the applicability of longitudinal studies to understand biomarker levels in response to exercise. R allele carriers (ACTN3) were only slightly associated with greater levels of MYO and CK, mainly in relative kinetic levels, and especially at moments of greater physical demand/recovery. Although the ACTN3 was slightly related to different biomarker levels in our investigation, the success or healthiness in military activities is multifactorial and does not depend only on interindividual variability or physical capacity. Conclusions: Monitoring biomarkers and multiple genomic regions can generate more efficient exercise-related phenotype interventions. Full article

The negative strand of the human immunodeficiency virus-1 (HIV-1) proviral genome contains an antisense open reading frame encoding a protein (ASP) with no known homologs. The presence of immune responses to ASP in people living with HIV-1 (PLWH) demonstrates its expression in vivo. Further, the predicted hydrophobicity of ASP is consistent with its association with the plasma membrane and viral envelope. Despite this body of evidence, the role of ASP in HIV-1 replication remains unknown. In this report, we investigated the hypothesis that the presence of ASP on the viral surface enhances HIV-1 entry into target cells. We generated an ASP-knockout replication-competent HIV-1 molecular clone in the NL4-3 background, which we used to perform cell–cell fusion, viral entry, and viral replication assays. Our results suggest that the presence of ASP on the plasma membrane of infected cells and the envelope of HIV-1 virions enhances viral transmission. Overall, our studies provide first evidence that ASP plays a role in the HIV-1 replication cycle. Further investigation into these observations may lead to the identification of new HIV-1 vulnerabilities that may be the target of novel interventions. Full article

Background: Colorectal cancer (CRC) represents a major global health challenge, characterized by rising incidence and mortality rates, necessitating improved diagnostic and therapeutic approaches. This study aimed to elucidate the expression and functional role of PAK6, a protein linked to cancer progression, as a potential biomarker for CRC. Methods: Utilizing comprehensive analyses of transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we performed differential expression assessments, survival analyses, and functional enrichment studies. Results: Our findings demonstrate a significant upregulation of PAK6 in CRC tissues compared to adjacent normal tissues (p < 0.001), with a diagnostic AUC of 0.855, indicating its potential utility as a reliable biomarker for early detection. High PAK6 expression was significantly associated with aggressive clinicopathological features, including poor differentiation, residual tumor presence and reduced overall survival (HR = 1.72, p = 0.004). Functional enrichment analyses revealed PAK6’s involvement in critical biological processes such as cell cycle regulation, alongside its correlation with immune infiltration, particularly NK and CD8⁺ T cells. Moreover, PAK6 expression positively correlated with chemokines involved in immune cell recruitment, suggesting its role in modulating the tumor immune microenvironment. Conclusions: Our study underscores the significance of PAK6 as a diagnostic and prognostic biomarker in CRC, with the potential to inform targeted therapeutic strategies and enhance patient outcomes. Future research should focus on validating these findings in larger cohorts and exploring PAK6-targeted interventions to improve immunotherapeutic responses in CRC patients Full article

(1) Background: IgA nephropathy (IgAN) is a leading cause of chronic kidney disease worldwide. Despite its prevalence, the molecular mechanisms of IgAN remain poorly understood, partly due to limited research scale. Identifying key genes involved in IgAN’s pathogenesis is critical for novel diagnostic and therapeutic strategies. (2) Methods: We identified differentially expressed genes (DEGs) by analyzing public datasets from the Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to elucidate the biological roles of DEGs. Hub genes were screened using weighted gene co-expression network analysis combined with machine learning algorithms. Immune infiltration analysis was conducted to explore associations between hub genes and immune cell profiles. The hub genes were validated using receiver operating characteristic curves and area under the curve. (3) Results: We identified 165 DEGs associated with IgAN and revealed pathways such as IL-17 signaling and complement and coagulation cascades, and biological processes including response to xenobiotic stimuli. Four hub genes were screened: three downregulated (FOSB, SLC19A2, PER1) and one upregulated (SOX17). The AUC values for identifying IgAN in the training and testing set ranged from 0.956 to 0.995. Immune infiltration analysis indicated that hub gene expression correlated with immune cell abundance, suggesting their involvement in IgAN’s immune pathogenesis. (4) Conclusion: This study identifies FOSB, SLC19A2, PER1, and SOX17 as novel hub genes with high diagnostic accuracy for IgAN. These genes, linked to immune-related pathways such as IL-17 signaling and complement activation, offer promising targets for diagnostic development and therapeutic intervention, enhancing our understanding of IgAN’s molecular and immune mechanisms. Full article

Assembling high-quality fungal genomes, specifically telomere-to-telomere (T2T) gapless assemblies, often necessitates the integration of multiple sequencing platforms. This requirement poses a limitation on the number of fungal genomes that can feasibly be generated within a single project. Here, we demonstrate that haplotype-aware error correction (HERRO) of Oxford Nanopore simplex reads enables the generation of high-quality assemblies from a single sequencing platform. We present an automated Snakemake workflow that, without manual intervention, produced gapless genome assemblies for industrially relevant strains: Neurospora intermedia NRRL 2884, Trichoderma asperellum TA1, and Aspergillus oryzae CBS 466.91, each achieving complete BUSCO (Benchmarking Universal Single-Copy Orthologs) scores exceeding 98%. Among these, only the T. asperellum assembly yielded a fully telomere-to-telomere gapless genome, while the N. intermedia and A. oryzae assemblies were gapless but near-telomere-to-telomere. Manual curation was required for the mitochondrial genome assembly of N. intermedia. Full article

Drug-resistant Mycobacterium tuberculosis remains a significant global public health threat. While whole-genome sequencing (WGS) holds immense promise for understanding transmission dynamics and drug resistance mechanisms, its integration into routine surveillance remains limited. Additionally, insights from WGS are increasingly contributing to vaccine discovery by identifying novel antigenic targets and understanding pathogen evolution. The COVID-19 pandemic catalyzed an unprecedented expansion of genomic capacity in many low- and middle-income countries (LMICs), with public health institutions acquiring next-generation sequencing (NGS) platforms and developing local expertise in real-time pathogen surveillance. This hard-won capacity now represents a transformative opportunity to accelerate TB control enabling rapid detection of drug-resistant strains and high-resolution mapping of transmission networks that are critical for timely, targeted interventions. Furthermore, the integration of machine learning with genomic and clinical data offers a powerful avenue to improve the prediction of drug resistance and to tailor patient-specific TB management strategies. This article examines the practical challenges, emerging opportunities, and policy considerations necessary to embed genomic epidemiology within national TB control programs, particularly in high-burden, resource-constrained settings. Full article

Aging is a complex, multifactorial process characterized by progressive physiological decline and increased vulnerability to chronic diseases and syndromes. Recent studies have highlighted nine interrelated hallmarks of aging, emerging primarily from an understanding of cellular homeostasis, health, and senescence, such as genomic instability, telomere attrition, and cellular senescence. These hallmarks provide a conceptual framework for advancing pharmacotherapeutic interventions. In this review, we present an overview of old and new pharmacotherapeutic interventions that are being developed using these hallmarks of aging to enhance healthspan delay and ameliorate age-related pathologies. We classify these strategies into five broad categories, including senolytics, senomorphics, NAD⁺ precursors, mTOR inhibitors, and metabolic modifiers, such as metformin, and review the mechanisms by which they act, preclinical evidence for efficacy, and their translational potential to a clinical context. In addition, we consider the clinical landscape and report the important trials that are currently underway and some of the main obstacles, including key challenges such as biomarker identification, safety issues, and regulatory challenges. Overall, we discuss ahead-of-time gerotherapeutics and the important role of a collective, mechanism-focused basis for therapeutically targeting aging biology. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the pathological aggregation of α-synuclein (α-syn), the loss of dopaminergic neurons, and the appearance of both motor and non-motor symptoms. Emerging evidence suggests a bidirectional influence of the microbiota–gut–brain axis in PD pathogenesis, where gut dysbiosis contributes to increased intestinal barrier permeability, immune activation, chronic inflammation, oxidative stress, α-syn misfolding, and neurotransmitter imbalance. These findings are increasing interest in probiotics as microbiota-targeted interventions that restore intestinal and systemic homeostasis. Lactiplantibacillus plantarum, a probiotic species with remarkable environmental adaptability and genomic plasticity, has emerged as a promising candidate for PD management. Preclinical studies demonstrate that specific Lpb. plantarum strains, such as PS128 or CCFM405, can beneficially modulate gut microbial communities, reinforce barrier integrity, regulate bile acid metabolism, attenuate neuroinflammatory responses, and improve motor deficits in PD-like mice. In addition, Lpb. plantarum DP189 or SG5 interventions can significantly reduce α-syn aggregation in the brain via suppression of oxidative stress, modulation of neuroinflammatory responses, and activation of neurotrophic factors. Recent evidence even suggests that Lpb. plantarum-derived extracellular vesicles may possess anti-PD activity by influencing host gene expression, neuronal function, and immune modulation. Although robust clinical data are still limited, preliminary clinical trials indicate that supplementation with PS128 or certain Lpb. plantarum-contained consortiums can alleviate constipation, improve gastrointestinal function, reduce systemic inflammation, and even ameliorate motor symptoms when used alongside standard dopaminergic therapies. In this review, we provide an integrated overview of preclinical, clinical, and mechanistic insights, and evaluate the translational potential of Lpb. plantarum as a safe and diet-based strategy to target the microbiota-gut–brain axis in PD. Full article

Child growth in South America results from a complex interplay of genetic, environmental, and socioeconomic factors. The region’s high ancestral diversity—stemming from Native American, European, and African admixture—shapes growth patterns in ways not fully captured by international standard curves such as World Health Organization (WHO) charts, which are primarily based on European population. This mismatch may cause misclassification, especially among Native American and other underrepresented groups, and reduce the effectiveness of interventions like growth hormone (GH) therapy. Evidence from national surveys, cohort studies, and genetic analyses reveals persistent ethnic and socioeconomic disparities, with Native American children showing higher stunting prevalence even after adjusting for wealth and residence. Differences between WHO and national growth curves further contribute to inconsistent prevalence estimates due to methodological and contextual variants. Regional genomic studies, although limited, have identified population-specific variants, such as FBN1 (E1297G) in Peru, and modulators of GH therapy response, including GHR exon 3 deletion, ACAN, and NPR2, highlighting the role of genetic background, treatment timing, and adherence in height outcomes. These findings underscore the need to move toward precision growth medicine, integrating anthropometry, genetic, environmental, and socioeconomic data to design population-specific growth references, optimize pharmacogenetic approaches, and reduce inequities in pediatric growth care. Full article

Bovine mastitis is one of the most prevalent and economically significant diseases affecting dairy cows worldwide, with Escherichia coli (E. coli) recognized as one of the principal pathogens causing acute mastitis. The innate immune system plays a crucial role in the defense of the bovine mammary gland, serving as the first line of defense against pathogen invasion. This study elucidated the pathological mechanisms and immune response-related molecular regulatory networks involved in E. coli-induced bovine mastitis. Histopathological and apoptosis analyses of mammary tissues were performed using hematoxylin-eosin (HE) staining and TUNEL staining, respectively, while RNA sequencing (RNA-seq) was conducted to identify differentially expressed genes (DEGs) and their associated signaling pathways. HE staining revealed typical inflammatory lesions in the mammary glands of mastitis cows. TUNEL staining further confirmed that the level of apoptosis in the mastitis group was significantly higher than in the healthy control group (p < 0.0001). RNA-seq analysis identified 2717 DEGs, with 2238 upregulated and 479 downregulated genes. The top 20 significantly upregulated genes (e.g., S100A12, IL1RN, IL1R2, CXCL8, SAA3, S100A8, S100A9, TREML2, TREM1, M-SAA3.2, PTX3, MMP9) were predominantly involved in inflammatory immune regulation, acute phase responses (e.g., HP, SAA3), and cellular signal transduction (e.g., PLEK, LPAR3). Gene Ontology (GO) enrichment analysis revealed that these DEGs were mainly associated with biological processes, such as signal transduction, immune response, inflammatory response, and transcriptional regulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these DEGs were significantly enriched in key inflammatory and immune regulatory pathways, including the TNF signaling pathway, C-type lectin receptor signaling pathway, Chemokine signaling pathway, NOD-like receptor signaling pathway, NF-κ B signaling pathway, and IL-17 signaling pathway, suggesting that these pathways play central roles in the mammary immune defense against E. coli infection. In conclusion, this study demonstrated at the histopathological, cellular apoptosis, and transcriptomic levels that E. coli infection induces mammary tissue damage and apoptosis by activating immune and inflammation-related genes (S100A12, IL1RN, IL1R2, CXCL8, SAA3, S100A8, S100A9, TREML2, TREM1, M-SAA3.2, PTX3, MMP9) and key signaling pathways (TNF signaling pathway, C-type lectin receptor signaling pathway, Chemokine signaling pathway, NOD-like receptor signaling pathway, NF-κ B signaling pathway, IL-17 signaling pathway). The findings of this study provide a theoretical basis for probing into the pathogenesis of bovine mastitis and the development of targeted interventions. Full article

Background: Pregnancy-induced hypertension (PIH) affects approximately 10% of pregnancies worldwide, representing a leading cause of maternal and perinatal morbidity and mortality. The relationship between plasma selenium levels and PIH remains controversial, with observational studies limited by confounding factors. Selenoprotein S (SELENOS) has emerged as a potential biomarker for PIH risk. As one of the carrier proteins for dietary selenium, SELENOS plays a crucial role in oxidative stress and inflammatory pathways. However, the causal relationship between the plasma levels of the SELENOS and PIH development remains unclear. This study employed Mendelian randomization (MR) to investigate the causal link between the plasma levels of the SELENOS and PIH risk, providing evidence for preventive strategies. Methods: We conducted a two-sample MR analysis using genome-wide association study (GWAS) summary statistics from the INTERVAL study and FinnGen consortium. The analysis included individuals of European ancestry, utilizing the inverse-variance weighted (IVW) method as the primary approach. Comprehensive sensitivity analyses were performed to address potential pleiotropy and strengthen causal inference. Results: The analysis encompassed 3301 samples for the plasma levels of the SELENOS and 7686 PIH cases, 1109 pre-existing hypertension (PEH) cases, 4255 gestational hypertension (GH) cases, and 83 preeclampsia (PE) cases superimposed on chronic hypertension, alongside approximately 115,000 controls. Genetic variabilities that have been found to be accompanied by elevated levels of plasma selenioprotein levels showed significant associations with increased risk of PIH [odds ratio (OR) 1.078, 95% confidence interval (CI) 1.031–1.126, p = 0.001], PEH (OR 1.232, 95% CI 1.105–1.373, p < 0.001), and GH (OR 1.111, 95% CI 1.047–1.180, p = 0.001), with suggestive associations for preeclampsia superimposed on chronic hypertension (OR 1.590, 95% CI 1.078–2.344, p = 0.019). Conclusions: This study provides robust genetic evidence for a causal relationship between the plasma levels of the SELENOS and PIH risk, establishing SELENOS as a potential modifiable risk factor with significant clinical implications. These findings support the development of personalized selenium management strategies during pregnancy and highlight the potential for early screening and targeted interventions to improve maternal and fetal outcomes. Full article

Human papillomavirus (HPV) integration is recognized as a hallmark event in cervical carcinogenesis. However, it does not represent a routine phase of the viral life cycle but rather a stochastic occurrence, often constituting a dead-end pathway for the virus. High-risk human papillomavirus (hr-HPV) exhibits a greater propensity for integration. The progression from initial infection to genomic integration constitutes a dynamic multi-step oncogenic process in the development of cervical cancer (CC). This process involves viral entry, immune evasion, persistent infection, and ultimately integration. This article innovatively provides a comprehensive overview of this multi-stage mechanism: HPV, via the L1/L2 proteins, mediates internalization and establishes infection. Subsequently, under the influence of factors such as the host’s genetic background, vaginal microbiota imbalance, and immune evasion, the host’s DNA damage response (DDR) pathways are activated. Viral DNA integrates into host genome vulnerable sites (e.g., 3q28 and 8q24) through microhomology-mediated end joining (MMEJ) or other alternative pathways. Following integration, the expression of viral oncogenes persists, triggering host genomic rearrangements, aberrant epigenetic modifications, and immune microenvironment remodeling, all of which collectively drive cervical cancer progression. The study further reveals the clinical potential of HPV integration as a highly specific molecular biomarker, offering new perspectives for precision screening and targeted therapy. This dynamic model deepens our understanding of the HPV carcinogenic mechanism and provides a theoretical basis for intervention strategies. Full article

Neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and Huntington’s disease, represent unmet medical and social needs. Still, no definitive cure exists for these illnesses, hence a therapeutic approach with molecules able to prevent/downtone/modify the disease seems highly attractive. Remarkably, a higher risk of neurodegenerative disease is associated with low vitamin D levels. Vitamin D is a multifaceted molecule able to target critical neuroinflammatory processes underlying neurodegeneration, acting through genomic or rapid signaling. This narrative review aims to focus on vitamin D’s potential to be an optimal neuroprotective molecule, based on its ability to target and counteract aberrant biomolecular processes involved in neuroinflammation/neurodegeneration. Noticeably, exercise can potentiate vitamin D’s protective effect through some anti-inflammatory actions exerted on shared biomolecular targets. Thus, although vitamin D is not strictly a drug, it could be potentially allocated within the therapeutic approach to neurodegenerative diseases in combination with adapted exercise, best as an early intervention. Topics on the complexity concerning the doses for supplementation and data discrepancy from trials are addressed. The urgent demand is to test and clarify vitamin D efficacy and safety, combined or not with exercise, in clinical settings. Full article

This review investigates genetic strategies aimed at improving robustness in pigs to enhance disease resistance and reduce reliance on antibiotics. Robustness refers to a pig’s ability to stay healthy and productive under stressful or challenging conditions. The review outlines current breeding practices focused on key traits such as maternal ability, growth, immune function, and survival, and highlights that these robustness-related traits show measurable heritability, making them suitable for genetic improvement. Special attention is given to resistance against porcine reproductive and respiratory syndrome (PRRS), a major disease in swine. We also evaluate breed-specific differences, environmental influences, and immune response profiles, emphasizing their impact on breeding outcomes. The development of robust pig lines emerges as a sustainable strategy to reduce antibiotic dependence and enhance herd health. A distinctive contribution of this work is the integration of genetic robustness and resilience strategies with antibiotic stewardship objectives. We link genomic selection, advanced phenotyping, and targeted management interventions within a One Health framework to outline actionable, system-level pathways for reducing antimicrobial inputs. To our knowledge, this combined genetic and public health perspective has not been comprehensively addressed previously. Full article