Search Results (3,275)

Age-related macular degeneration (AMD) is an increasingly prevalent source of permanent visual impairment in the aging population and is widely accepted as a multi-factorial neurodegenerative disorder of the retina. While there has been significant progress in treating neovascular AMD, there are currently no effective disease-sparing treatments for dry AMD and geographic atrophy. To date, research has begun to reveal the complex relationship between the environment and genetic predisposition in AMD pathogenesis. Various environmental factors responsible for AMD include oxidative stress, mitochondrial dysfunction, inflammation, abnormal complement activation, and epigenetic regulation, which interact dynamically to drive disease progression. This review summarizes recent data and provides a comprehensive model for understanding how these interacting factors lead to the progression of AMD from an early stage to advanced stages with complications associated with the disease. We highlight the central role of retinal pigment epithelial mitochondrial failure and impaired stress resilience as upstream drivers that amplify inflammation and complement-mediated injuries. We also discuss how dysregulated miRNAs and proteomic network remodeling contribute to disease heterogeneity. Emerging therapeutic strategies are reviewed in the context of molecular endotyping and personalized intervention. Finally, we outline future directions toward precision medicine in AMD, emphasizing early disease modification, rational combination therapies, and the need to bridge the translational gaps between molecular discovery and clinical trial design. Full article

Background: Mammary ductal hyperplasia represents a spectrum of benign proliferative breast lesions, some of which pose elevated risks for malignant transformation into ductal carcinoma in situ and invasive breast cancer. This narrative review explores why only specific types, particularly those with atypia, exhibit higher progression potential, synthesizing epidemiologic, histopathologic, molecular, and environmental insights. Methods: We reviewed key literature from databases, including PubMed, focusing on classification, risk stratification, genetic/epigenetic mechanisms, tumor microenvironment dynamics, and modifiable factors influencing progression. Results: Benign breast lesions are categorized into non-proliferative, proliferative without atypia, and proliferative with atypia, such as atypical ductal hyperplasia and atypical lobular hyperplasia. Atypia represents a morphologic continuum toward low-grade ductal carcinoma in situ, driven by genetic alterations, epigenetic reprogramming, and changes in the tumor microenvironment, including stromal remodeling, immune infiltration, hypoxia-induced angiogenesis, and extracellular matrix degradation. Dietary factors, such as high-fat intake and obesity, exacerbate progression through inflammation, insulin resistance, and adipokine imbalance, while environmental toxins, including endocrine disruptors, pesticides, and ionizing radiation, amplify genomic instability. Conclusions: Understanding differential risks and mechanisms underscores the need for stratified surveillance, biomarker-driven interventions, and lifestyle modifications to mitigate progression. Future research should prioritize molecular profiling for personalized prevention in high-risk hyperplasia. Full article

Direct methods provide a model-free approach to solving the crystallographic phase problem and deliver unbiased atomic structures. However, conventional iterative projection algorithms such as Hybrid Input–Output (HIO) face two critical challenges: discontinuous density modification at the protein-solvent boundary and inaccurate molecular envelope reconstruction that fails to account for trapped solvent, particularly in crystals with solvent content approaching the lower limits of direct phasing applicability. We introduced four continuous iterative projection algorithms, including our improved continuous version, which implements smooth density modification at protein-solvent interfaces. To address envelope inaccuracy, we developed a two-step refined reconstruction scheme using sequential large-radius and small-radius Gaussian filters to identify trapped solvent molecules within surface cavities and internal channels. This scheme enhances the performance of both continuous and classical algorithms, including HIO, the difference map, and our improved versions. Benchmarking on 28 protein structures (solvent contents 55–78%, resolutions 1.46–3.2 Å, reported R-factor less than 0.22) showed that the refined envelope scheme increased average success rates of continuous algorithms by 45.7% and classical algorithms by 60.5%. The performance of continuous algorithms and improved classical algorithms proved comparable to the well-established HIO algorithm, forming a top-tier group that exceeded other classical algorithms. Integrating a genetic algorithm co-evolution strategy further enhanced average success rates by approximately 2.5-fold and accelerated convergence through population-wide information sharing. Although the success rate correlates with solvent content, our strategy improved success probability at any given solvent level, extending the practical boundaries of direct methods. The high success rate enabled averaging of multiple independent solutions, which reduced mean phase error by approximately 6.83° and yielded atomic models with backbone root-mean-square deviation (RMSD) typically below 0.5 Å relative to structures reported in the Protein Data Bank (PDB). This work introduces novel algorithms, a refined envelope reconstruction methodology, and an effective optimization strategy with genetic algorithm evolution. The complete framework enhances the capability and reliability of direct methods for phasing protein crystals with limited solvent content and provides a toolkit for addressing challenging cases in structural biology. Full article

Sesame (Sesamum indicum L.) is a nutrient-rich oilseed crop whose improvement can be accelerated by unlocking untapped genetic variation in African landraces. We integrated a global meta-quantitative trait loci (QTL) analysis with a genome-wide association study (GWAS) of Ethiopian germplasm to identify molecular markers for plant height and seed coat color. Meta-analysis of eight available data sources revealed six conserved QTL hotspots on chromosomes 3, 4, 6, 8, 9, and 11. Subsequently, GWAS on 200 Ethiopian accessions, represented by 3683 SNPs, detected 36 significant associations, including novel loci on chromosomes 12 and 13 not reported in Asian-focused research. Candidate genes assigned to these loci implicated key hormonal and transcriptional mechanisms: brassinosteroid biosynthesis (CYP90B1) and ethylene signaling (AP2/ERF) probably regulate plant architecture, while transcription factors (WRKY23, DOF3.1, and SBP-like) modulate flavonoid pathways controlling seed coat pigmentation. Analyses of population structure revealed two distinct groups (K = 2), and linkage disequilibrium (LD) decayed rapidly (~190 kb), which allows fine-mapping. The present study presents validated molecular markers and candidate genes for marker-assisted selection in sesame breeding. Full article

Neospora caninum, the causative agent of abortion in cattle, has a major economic impact worldwide. This review aims to provide an overview of key advances over the last 10 years in understanding host−pathogen interactions, molecular mechanisms, and emerging control strategies and puts them into a context with previously published important findings. More recently, novel diagnostic tools with improved sensitivity and specificity have been developed. These have supplemented the already existing methods to detect infection in clinical cases and are essential for investigations on parasite distribution, disease incidence and prevalence, and transmission of N. caninum. Epidemiological studies have revealed the influence of environmental, genetic, and ecological factors on parasite transmission dynamics, and emphasized the importance of integrated “One Health” strategies. Characteristics of different Neospora strains have been elucidated through animal models and molecular tools such as clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9)-based gene editing, high-throughput sequencing, and advanced proteomics, aiming to shed light on stage-specific gene regulation and virulence factors, contributing to the development of interventions against neosporosis. Insights into immune modulation, immune evasion, and parasite persistence contributed to the efforts towards vaccine development. In terms of therapeutics, both repurposed drugs and more targeted inhibitors have shown promising efficacy in reducing parasite burden and mitigating vertical transmission in laboratory models. Here, more recent innovations in nanoparticle-based drug delivery systems and immunomodulatory strategies are prone to enhancing therapeutic outcomes. However, a significant challenge remains the integration of molecular and immunological insights into practical applications. Full article

Vitamin D, a fat-soluble secosteroid traditionally recognized for skeletal health, exerts pleiotropic effects on cardiovascular physiology and disease. Circulating 25-hydroxyvitamin D [25(OH)D], the principal biomarker of vitamin D status, is frequently suboptimal worldwide, particularly in older adults, individuals with darker skin pigmentation, and populations at higher latitudes. Observational studies consistently associate low 25(OH)D concentrations with increased risk of hypertension, atherosclerosis, myocardial infarction, heart failure, arrhythmias, stroke, and cardiovascular mortality. Mechanistic investigations have revealed that vitamin D modulates cardiomyocyte calcium handling, endothelial function, vascular smooth muscle proliferation, inflammation, oxidative stress, and renin–angiotensin–aldosterone system activity, establishing biologically plausible links to cardiovascular outcomes. Despite these associations, large randomized trials of vitamin D supplementation have failed to demonstrate reductions in major cardiovascular events, likely due to heterogeneity in baseline status, dosing regimens, intervention timing, genetic variability, and underlying comorbidities. Vitamin D may function more effectively as a biomarker of cardiovascular risk rather than a universal therapeutic agent, with deficiency reflecting systemic vulnerability rather than acting as a dominant causal factor. Emerging evidence supports precision approaches targeting individuals with severe deficiency, high renin activity, early endothelial dysfunction, or specific genetic profiles, potentially in combination with lifestyle or pharmacologic interventions. Future research should focus on defining optimal dosing strategies, intervention timing, and mechanistic biomarkers to identify subpopulations most likely to benefit, integrating vitamin D therapy into multifaceted cardiovascular prevention frameworks. This systematic review synthesizes molecular, observational, and clinical trial evidence, critically evaluating the current understanding of vitamin D in cardiovascular medicine and highlighting opportunities for targeted, personalized interventions. Vitamin D represents a complex, context-dependent modulator of cardiovascular health, offering both prognostic insight and potential therapeutic value when appropriately applied. Full article

Over the past two decades, advances in the understanding of epigenetic mechanisms—driven by the rapid expansion of omics technologies—have catalyzed a major paradigm shift in biology: from the genetic determinism and linear causality of the Central Dogma toward the dynamic, networked complexity of systems biology and multilevel regulation. This reconceptualization extends to inheritance itself, highlighting the crucial role of the epigenome as a molecular interface between the genome and the exposome—the cumulative set of internal and external environmental influences experienced across the lifespan. Within this evolving framework, neurodevelopmental disorders exemplify the deep entanglement between genetic predisposition, environmental exposure, and epigenetic modulation. Their increasing global prevalence and frequent comorbidities underscore the need for an integrated etiological understanding that transcends reductionist models. This review tries to synthesize current evidence on the shared molecular and systemic mechanisms underlying neurodevelopmental spectrum disorders and examines how environmental and epigenetic factors jointly shape neurodevelopmental trajectories across generations. Finally, it discusses the broader implications of this paradigm shift for early diagnosis, prevention, and public health policies aimed at fostering healthy brain development in future generations. Full article

Background: Multiple sclerosis (MS) is a neuroinflammatory disease characterized by autoimmune-driven inflammation in the central nervous system that damages axons and destroys myelin. It is difficult to diagnose multiple sclerosis due to its complexity, and different people may react differently to different treatments. While the exact cause of multiple sclerosis (MS) and the reasons for its increasing prevalence remain unclear, it is widely believed that a combination of genetic predisposition and environmental influences plays a significant role. Methods: Finding biomarkers for complicated diseases like multiple sclerosis (MS) is made more promising by the emergence of network and system biology technologies. Currently, using tools like Network Analyst to apply network-based gene expression profiling provides a novel approach to finding potential medication targets followed by molecular docking and MD Simulations. Results: There were 1200 genes found to be differentially expressed, with CD44 showing the highest degree score of 15, followed by CDC42 and SNAP25 genes, each with a degree score of 14. To explore the regulatory kinases involved in the protein–protein interaction network, we utilized the X2K online tool. The present study examines the binding interactions and the dynamic stability of four ligands (Obeticholic acid, Chlordiazepoxide, Dextromethorphan, and Hyaluronic acid) in the Hyaluronan binding site of the human CD44 receptor using molecular docking and molecular dynamics (MD) simulations. Docking studies demonstrated a significant docking score for Obeticholic acid (−6.3 kcal/mol), underscoring its medicinal potential. MD simulations conducted over a 100 ns period corroborated these results, revealing negligible structural aberrations (RMSD 1.3 Å) and consistent residue flexibility (RMSF 0.7 Å). Comparative examinations of RMSD, RMSF, Rg, and β-factor indicated that Obeticholic acid exhibited enhanced stability and compactness, establishing it as the most promising choice. Conclusions: This integrated method underscores the significance of dynamic validations for dependable drug design aimed at CD44 receptor-mediated pathways. Future experimental techniques are anticipated to further hone these findings, which further advance our understanding of putative biomarkers in multiple sclerosis (MS). Full article

Genetic factors are key determinants in the pathophysiology of obesity, regulating energy homeostasis. Monogenic non-syndromic obesity accounts for 2–3% of obesity in both children and adults and is most often attributable to mutations in genes encoding components of the leptin–melanocortin pathway. Genetic testing is indicated in children with severe obesity before age 5, hyperphagia, a family history of obesity, and neurodevelopmental delay or organ dysfunction. Mutations associated with monogenic obesity follow autosomal recessive (LEP, LEPR, POMC, and PCSK1) or autosomal dominant (MC4R, SH2B1, SIM1, GNAS) modes of inheritance. Other gene mutations in heterozygous states (MRAP2, MC3R, SRC1, KSR2) are associated with obesity and may exhibit autosomal dominant inheritance; however, the clinical phenotype depends on the degree of genetic penetrance and interactions with other genetic and/or environmental factors. No approved targeted pharmacotherapies are currently available for autosomal dominant monogenic obesity, and the frequent detection of variants of uncertain significance often hinders timely diagnostic confirmation. The review provides a comprehensive appraisal of autosomal dominant forms of monogenic non-syndromic obesity, analyzing genetic and molecular features, clinical presentations, and therapeutic strategies. Full article

This systematic review synthesizes evidence on upland rice (Oryza sativa L.) genotypes resistant to neck blast disease caused by Magnaporthe oryzae, focusing on resistant lines, screening methods, and genetic factors underlying resistance. Empirical studies published in English between 1980 and 2025 were identified through searches of PubMed, ScienceDirect, Google Scholar, and grey literature, with final searches completed on 31 October 2025. Eligible studies evaluated upland rice under upland or rainfed conditions. The risk of bias was assessed using a customized framework adapted from the ROBINS-I tool, and findings were synthesized narratively due to substantial methodological heterogeneity. Six studies from Asia and Africa, encompassing 248 genotypes, met the inclusion criteria. Twenty genotypes—including Kahei, Barkhe 1032, Barkhe 1035, Barkhe 2014, several NERICA lines, and BC1F4 backcross derivatives—demonstrated moderate to high resistance based on the IRRI 0–9 Standard Evaluation System. Two studies reported quantitative trait loci (qBFR4-1, qBl1, and qBl2) associated with durable resistance, highlighting the potential of QTL-based breeding. Despite limitations related to small sample sizes, heterogeneous methodologies, and limited molecular characterization, particularly for neck blast-specific resistance, this review underscores the promise of marker-assisted selection. Future research should prioritize neck blast-focused QTL validation, expanded genomic screening, harmonized screening protocols, and multi-location field trials to confirm resistance durability and agronomic performance across diverse upland environments. Full article

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, classically characterized by right ventricular outflow tract obstruction, ventricular septal defect, overriding aorta, and right ventricular hypertrophy. Recent advances in molecular and genomic research indicate that TOF is part of a phenotypic continuum encompassing Trilogy, Tetralogy, and Pentalogy of Fallot, in which the variability of anatomical presentation reflects shared genetic and epigenetic mechanisms with highly variable penetrance and expressivity. Variants in NOTCH1, FLT4, KDR, GATA6, and TBX1 highlight key pathways in conotruncal development and endothelial–mesenchymal transition, yet these well-known genes explain only a fraction of the genetic landscape. Emerging studies have identified additional candidate genes and networks involved in cardiac morphogenesis, including transcriptional regulators, signaling mediators, chromatin-remodeling factors, and splicing-associated genes such as PUF60 and DVL3. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA expression, further modulate phenotypic expressivity and contribute to variability along the Trilogy–Tetralogy–Pentalogy spectrum. This review integrates current genomic and clinical evidence to provide a comprehensive overview of the molecular architecture of Fallot-type conotruncal malformations, emphasizing the interplay between genetic and epigenetic mechanisms, genotype–phenotype correlations, and implications for diagnosis, risk stratification, counseling, and personalized management in the era of precision cardiology. Full article

Laryngeal squamous carcinoma is a major type of head and neck cancer. Despite a wide range of treatment options, it remains a challenge to identify which ones are the most effective for which groups of patients. One solution is to analyse selected biomarkers. In this paper, biomarkers are divided into distinctive groups according to the molecular pathways analysed or specific molecules within the cell or in tissue fluids. The paper provides a description of these groups, including genetic and apoptosis-associated factors, factors regulating angiogenesis, cell structure regulators, immune factors in the form of programmed cell death ligand (PD-L1), hormone receptors, molecules involved in growth factor pathways, and cell cycle regulators. Representative examples are discussed for each of these groups, indicating their potential usefulness in staging, assessing tumour aggressiveness, and making a prognosis. Full article

Cancer health disparities represent profound inequalities in incidence, outcomes, and survivorship across populations. While traditionally examined through distinct lenses of either molecular biology or social epidemiology, these disparities arise from the complex interplay of genetic susceptibility, epigenetic dysregulation, and social determinants of health (SDoH). This review proposes that DNA damage and genomic instability serve as a critical mechanistic bridge, integrating exposures from the societal level to cellular dysfunction. We synthesize evidence demonstrating how SDoH—such as systemic inequities, environmental exposures, and chronic stress—converge with genetic and epigenetic factors to disproportionately increase DNA damage burden, impair repair mechanisms, and accelerate tumorigenesis in marginalized communities. Using the elevated gastrointestinal cancer rates among Native Hawaiians and Pacific Islanders (NH/PI) as a case study, we illustrate how historical, environmental, and socioeconomic factors interact with biological pathways to drive disparities. The review highlights key advances in DNA damage research—from somatic mutation theory to the modern understanding of chronic genomic stress—and explores how innovations in single-cell genomics, biomarker discovery, and computational modeling can unravel disparity etiologies. We argue that a translational framework linking social exposure data to molecular biomarkers of DNA damage is essential for moving beyond descriptive disparities to mechanistic understanding. Ultimately, addressing cancer equity requires interdisciplinary strategies that bridge molecular oncology, public health, and community-engaged research, targeting the root causes where social inequities become biologically embedded as genomic instability. Full article

Depression and osteoporosis frequently co-occur, presenting a significant and increasing clinical challenge, especially among older adults. Growing research highlights the bone–brain axis, a complex bidirectional communication network connecting the skeletal and central nervous systems, as a central mechanism linking these conditions. This review comprehensively examines the current knowledge of the molecular and cellular pathways within this axis that contribute to depression–osteoporosis interactions. It details how depression promotes bone loss through sustained hypothalamic–pituitary–adrenal axis activation, sympathetic nervous system overactivity, and chronic low-grade inflammation. This review also explores how bone-derived factors, including osteocalcin, lipocalin 2, and extracellular vesicles, cross the blood–brain barrier to influence brain function by regulating hippocampal neurogenesis, serotonin signaling, and neuroinflammation. This bidirectional communication is modulated by circadian rhythms and genetic factors. Understanding these pathways offers critical insights into the shared pathophysiology and reveals promising therapeutic targets. Interventions such as neuromodulation, customized exercise programs, and novel treatments focusing on bone-derived signals show potential for simultaneously addressing both mood disorders and bone health deterioration. This review emphasizes the need for an integrated system-based approach in clinical care that moves beyond traditional specialty-focused treatment to improve overall health outcomes, particularly for vulnerable elderly individuals. Full article

Improving fruit quality is one of the most critical core tasks in fruit tree breeding. However, the complexity of the constituent factors of fruit quality and their interrelationships, the significant influence of environmental factors on quality, and the diversity of consumer demands, among other factors, make quality breeding a more challenging endeavor than other breeding objectives. Essentially, fruit quality is defined by the delicate balance of sugar, acid, and aromas, which collectively influence the fruit’s flavor, consumer satisfaction, and economic value. While substantial progress has been made in the depiction of the metabolic pathways underlying these traits, the molecular mechanism coordinating carbon partitioning and competition between sugars, acids, and volatiles remains unknown. This review focuses on recent advances in understanding stone fruit metabolism and identifies key gaps in knowledge. We emphasize the need for integrated approaches combining spatial metabolomics, transcriptomics, genetics, and genomics to reveal the regulatory networks underlying metabolomic variation during fruit development and ripening. We also discuss the application of molecular tools, such as marker-assisted selection and metabolite-associated markers, to accelerate the breeding of flavor-balanced stone fruit cultivars. By adapting these advances in breeding practices, we can achieve coordinated improvement and precise regulation of various components of fruit quality, thereby developing elite stone fruit cultivars with improved flavor that meet prevailing consumer demands. Full article