Search Results (10,265)

Background: Alzheimer’s disease (AD) represents a significant therapeutic challenge, largely attributed to the complex interplay of genetic and non-genetic mechanisms. Among the latter, metabolic dysregulation has emerged as a critical factor influencing disease progression. This study proposes a paradigm shift in our understanding of the role of phosphoglycerate dehydrogenase (PHGDH), a key metabolic enzyme, which, under pathological conditions associated with AD, transitions from a protective role to a pathogenic influence through alterations in its cellular localization and function. Methods: To elucidate the impact of exercise on PHGDH dynamics, a narrative review methodology was employed. We conducted comprehensive searches across bibliographic databases, including PubMed, Scopus, and Web of Science, focusing on peer-reviewed articles that detail the relationship between exercise, PHGDH activity, and AD-related neuroinflammation. The review was structured around specific inclusion criteria, which prioritized studies elucidating the mechanisms underlying PHGDH’s dual role in AD pathology and the influence of exercise on this process. Results: Our findings reveal that under AD-associated stress, PHGDH translocates to the nucleus, facilitating the activation of pro-inflammatory genes such as IKKα and HMGB1, while simultaneously suppressing autophagy and enhancing amyloid beta (Aβ) deposition. However, exercise induces the release of the myokine irisin, which inhibits PHGDH nuclear translocation through AMPK/PGC-1α signaling pathways. Additionally, peripheral effects of exercise are observed in hepatic Kupffer cells, where exercise attenuates PHGDH activity, leading to reduced systemic IL-1β release and neuroinflammation. Conclusions: This study underscores the potential of exercise as a precision intervention in AD management, highlighting its capacity to modulate PHGDH activity and mitigate neuroinflammatory processes. The therapeutic implications of these findings are profound, paving the way for novel diagnostic tools, such as PET probes for assessing PHGDH compartmentalization, and promoting a synergistic approach to “exercise–pharmacotherapy” in the treatment of Alzheimer’s disease. Future research should aim to further delineate the mechanisms by which exercise influences metabolic pathways in the context of neurodegeneration. Full article

Background: Keloid scarring is a fibroproliferative disorder driven by a complex interplay of genetic, epigenetic, and environmental factors, resulting in significant cosmetic and functional impairment. Despite its high prevalence in African, Asian, and Hispanic populations, the molecular mechanisms underlying ancestry-dependent susceptibility remain incompletely understood. Methods: This narrative review synthesizes current genomic, epigenetic, and multi-omic evidence related to keloid scarring. Relevant literature was identified through a targeted, structured, non-systematic search of PubMed, Scopus, Web of Science, SciELO, and Google Scholar up to August 2025, focusing on genetic susceptibility loci, epigenetic regulation, and ancestry-related differences. PRISMA-ScR guidelines were used as a reporting framework to enhance transparency, without implying a formal systematic review methodology. Results: This synthesis identifies recurrent susceptibility loci at 1q41, 3q22.3, and 15q21.3 across multiple populations. Variants in NEDD4 and regulatory regions near BMP2 emerge as key modulators of profibrotic signaling pathways, including TGF-β/SMAD and NF-κB. Additionally, epigenetic reprogramming and long non-coding RNA networks, such as CACNA1G-AS1, appear to sustain fibroblast hyperactivation. A persistent limitation is the marked underrepresentation of Latin American populations in current genomic studies. Conclusions: Integrating ancestry-specific genomic variation with epigenetic markers is essential for advancing precision diagnostic and therapeutic strategies in keloid scarring. Future research should prioritize diverse, multicenter cohorts and integrative multi-omics approaches to improve risk stratification and enable targeted interventions for this disfiguring condition. Full article

Background: BRAF is a core component of the RAS–MAPK signaling pathway and an established oncogenic driver in several solid tumors and selected hematologic malignancies. In myeloid neoplasms, BRAF mutations are rare, and their prevalence, molecular context, and clinical significance remain incompletely defined. Available evidence is scattered across heterogeneous reports involving acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative neoplasms, and overlap myelodysplastic/myeloproliferative neoplasms, with variable descriptions of mutation subtypes, co-mutational profiles, cytogenetic associations, therapeutic approaches, and clinical outcomes. To address these gaps, this review synthesizes data from the published literature up to 2025, summarizing the distribution, genetic landscape, and clinical impact of molecularly confirmed BRAF mutations across the spectrum of myeloid neoplasms. Results: Across published cohorts, BRAF mutations occurred in less than 1% of unselected myeloid neoplasms, with enrichment in chronic myelomonocytic leukemia and therapy-related or secondary acute myeloid leukemia. Both V600E and non-V600E variants were observed, typically within a complex genomic background involving ASXL1, TET2, DNMT3A, SRSF2, and RAS-pathway mutations. Acute myeloid leukemia cases showed poor prognosis, with median overall survival measured in months, whereas myelodysplastic syndromes and chronic myelomonocytic leukemia demonstrated relatively longer survival. Targeted MAPK inhibition produced hematologic responses in selected cases but rarely resulted in durable molecular clearance. Conclusions: BRAF mutations in myeloid neoplasms are rare, heterogeneous, and usually represent secondary events in clonal evolution. Although mutation clearance appears prognostically relevant, current targeted approaches provide limited durability, underscoring the need for prospective studies in this setting. Full article

Breast cancer (BC) is a highly heterogeneous genetic disease, comprising several subtypes with distinct features that significantly influence prognosis and treatment outcomes. Among these subtypes, triple-negative breast cancer (TNBC) is particularly aggressive and makes it resistant to many standard therapies. Epigenetic mechanisms, including acetylation and deacetylation, are crucial in regulating gene expression and maintaining normal cellular functions and are closely associated with BC progression. In this context, the histone deacetylases sirtuins (SIRT1-7) regulate key biological processes like genomic stability, inflammation, cellular senescence, and metabolic functions, increasingly linked to cancer. In particular, SIRT1 shows dual roles, functioning both as a tumor suppressor or an oncogene, contributing to cancer initiation, progression, and metastasis as well as chemotherapy resistance. Despite extensive research in the past decade, the exact role of SIRT1 in BC, especially in TNBC, remains controversial. Recent findings suggest that SIRT1 can be modulated not only through pharmacological approaches but also using natural extracts, offering potential alternative or complementary therapeutic strategies. Additionally, SIRT1 activity is regulated by a complex network of miRNAs, highlighting the need for further investigation. This review aims to summarize recent studies to identify key insights into the role of SIRT1 and explore it as a potential therapeutic target in BC. Full article

Next-generation sequencing (NGS) and antisense oligonucleotide (ASO) technologies are converging to transform the diagnosis and treatment of rare monogenic disorders. NGS enables comprehensive, single-test molecular diagnoses through targeted panels, whole-exome sequencing, and whole-genome sequencing, which together reveal pathogenic variants across coding, intronic, and structural domains. Integration with transcriptomic analyses, including RNA sequencing, further refines genotype–phenotype correlations and identifies splicing aberrations amenable to correction by ASOs. Therapeutic advances now span RNase H1-dependent gapmers for transcript knockdown, splice-modulating phosphorodiamidate morpholino oligomers (PMOs), and peptide/antibody-conjugated PMOs that enhance muscle and cardiac delivery. These platforms underpin the rise in N-of-1 ASO therapies—customized drugs developed for individual patients with unique pathogenic variants. Landmark cases such as Milasen and Atipeksen illustrate the clinical feasibility and ethical complexities of personalized RNA therapeutics, while updated FDA guidance supports expedited, patient-specific investigational pathways. Despite progress, challenges persist in delivery efficiency, long-term efficacy, and equitable access. Emerging approaches—including long-read sequencing, AI-driven oligo design, and improved delivery—promise to extend ASO precision and reach. This review synthesizes current advances linking genomic diagnosis to individualized RNA-targeted interventions, outlining how integrated NGS-ASO pipelines are reshaping the therapeutic landscape for rare genetic diseases. Full article

Inflammatory bowel disease (IBD) is triggered by genetic predisposition and chronic inflammation, with aberrant activation of the innate immune complex NLRP3 inflammasome playing a pivotal role in its pathogenesis. In this study, we investigated the effects of a hot water extract from the brown alga Endarachne binghamiae (EB-WE) on the inhibition of NLRP3 inflammasome activation, with a focus on its antioxidant properties, in various inflammation models. In bone marrow-derived macrophages (BMDMs), NLRP3 inflammasome activation was induced using LPS and ATP, and EB-WE pretreatment (100, 200 µg/mL) significantly reduced the secretion of IL-1β and IL-18. Confocal immunofluorescence analysis further confirmed that EB-WE suppressed the formation of the NLRP3-ASC/caspase-1 complex. Furthermore, the in vivo anti-IBD efficacy of EB-WE was assessed using a DSS-induced mouse model, in which colonic inflammation and NLRP3-mediated responses were prominent. Oral administration of EB-WE (2 or 5 mg/day) markedly ameliorated clinical symptoms, such as weight loss, diarrhea, and rectal bleeding, and significantly reduced the disease activity index (DAI). EB-WE also decreased serum pro-inflammatory cytokine levels and the expression of NLRP3 inflammasome-related molecules in colon tissue at both the gene and protein levels. In both BMDMs and the IBD mouse model, we further analyzed the upstream regulatory pathway involving NOX2-iNOS. EB-WE efficiently inhibited the activation of the NOX-iNOS axis and NF-κB phosphorylation, thereby alleviating inflammasome activation associated with DSS-induced oxidative stress and neutrophil/macrophage infiltration. Collectively, these results demonstrate that EB-WE effectively suppresses the formation and activation of the NLRP3 inflammasome by modulating the NOX-iNOS axis and the NF-κB pathway via antioxidant mechanisms. These findings suggest that EB-WE holds promise as a novel marine-derived natural therapeutic agent for the treatment of chronic inflammatory diseases. Full article

Efficient UAV logistics in complex urban airspaces requires a synergistic approach to task allocation and path planning. However, traditional methods often decouple these two phases, leading to physically infeasible or sub-optimal delivery schedules. This paper proposes a Dual-Layer Optimization Framework (D-LOF) to address the Multi-UAV delivery problem in 3D urban environments. The upper layer utilizes an improved Genetic Algorithm (GA) with a specialized constraint repair operator to optimize task sequences for a heterogeneous UAV fleet. The lower layer employs an altitude-aware A* algorithm that dynamically balances vertical energy costs and horizontal cruise efficiency across multiple altitude layers. Unlike conventional models, our framework iteratively feeds precise 3D flight costs from the lower layer back to the upper layer to guide evolutionary search. Simulation results demonstrate that the D-LOF consistently achieves global convergence within 20 generations. Compared to single-altitude planning and rule-based strategies, the proposed method can reduce total operational costs and maintains zero time-window violations in high-density obstacle scenarios. This study provides a robust decision-making tool for “last-mile” urban logistics by navigating the trade-offs between 3D spatial constraints and delivery punctuality. Full article

Efficient aero-acoustic regression is critical for unmanned aerial vehicle (UAV) design and urban air mobility operations, where noise mitigation is essential for regulatory compliance and public acceptance. While data-driven fuzzy Takagi–Sugeno–Kang (TSK) systems have shown potential for modeling complex aero-acoustic behaviors in UAV applications, their performance is strongly affected by input dimensionality and rule-base complexity. This work extends previous research on dimensionality reduction for genetic algorithm-optimized fuzzy systems by conducting a comparative benchmark on an aero-acoustic database regression task relevant to drone propulsion noise prediction. Several TSK architectures are evaluated, including zero- and first-order models, different membership function granularities, and clustering-based rule-generation strategies. In addition, a physics-based heuristic TSK rule system incorporating aero-acoustic knowledge is introduced and compared against data-driven fuzzy configurations. Model performance is primarily assessed through graphical regression analysis and optimization convergence behavior, with a focus on computational efficiency, structural complexity, and qualitative prediction trends—critical considerations for onboard UAV systems and real-time acoustic monitoring. The results highlight the trade-offs between data-driven learning and physics-informed rule construction, demonstrating that physics-based heuristics can reduce optimization complexity while preserving physically consistent behavior. This study provides practical insights into the design of interpretable and efficient fuzzy regression models for UAV aero-acoustic applications, supporting next-generation drone acoustic signature management. Full article

Background: The origin of hallux abducto valgus (HAV) is considered to be multifactorial; however, evidence regarding the factors involved in its development is scattered and often contradictory. Understanding the factors that contribute to the onset of HAV is crucial for informing both prevention and clinical management strategies. This review aims to explore the etiological factors associated with the development of HAV. Methods: A literature search was conducted in PubMed, Embase, Web of Science and Scopus. The search included observational studies that investigated etiological or risk factors related to the development of HAV. Methodological quality was assessed using the Joanna Briggs Institute (JBI) checklists, and the level of evidence was classified according to the Oxford Centre for Evidence-Based Medicine (OCEBM). Results: A total of 36 observational studies (20 cross-sectional and 16 case–control) were included, involving 14,500 participants, predominantly females. Genetic evidence indicated strong familial aggregation and variants in collagen- and extracellular matrix-related genes as potential hereditary determinants. The most consistent biomechanical factors were first-ray hypermobility, abnormal foot pronation and reduced activity of the abductor hallucis muscle. Additionally, female sex, older age and prolonged use of narrow or inadequate footwear were identified as recurring predictive variables. Overall, the findings support a complex etiological model based on the interaction of intrinsic and extrinsic factors. Conclusions: The development of HAV appears to be determined by the interaction of genetic, structural and biomechanical factors that alter first-ray stability and forefoot function. Current evidence supports a multifactorial etiological model with a strong hereditary component and higher susceptibility in women. Longitudinal studies employing standardized methods are needed to establish causal relationships and quantify the relative contribution of each factor. Full article

Listeria innocua is a bacterium frequently detected in food and food production plants (FPPs). Understanding the heterogeneity of L. innocua food isolates is essential for predicting potential food safety threats and developing preventive and control measures. This study aimed to characterize L. innocua isolated from raw drinking milk by investigating the genomic features related to virulence, antimicrobial resistance, and persistence using whole-genome sequencing (WGS), along with phenotypic antimicrobial susceptibility testing using the disk diffusion method. All ten isolates analyzed in this study belonged to sequence type (ST) 492 and were distantly related to the reference strain. A total of 80 virulence-associated genes were identified, including the complete Listeria Pathogenicity Islands-3 (LIPI-3) and LIPI-4 clusters typically found in virulent L. monocytogenes clones, as well as 66 additional genes involved in adhesion, invasion, motility, post-translational modification, regulation, immune modulation, and stress survival. Stress survival islet 2 (SSI-2) and genes encoding the Clp protease complex (clpC, clpE, clpP), which support both persistence and virulence, were also detected, whereas LIPI-1 and internalin genes were not detected. The antimicrobial resistance determinants included fosX, lin, norB, sul, and three multidrug efflux pumps (lde, mdrL and mdrM). Mobile genetic elements (plasmids, prophages, or transposons) were not detected. All isolates were phenotypically susceptible to benzylpenicillin, ampicillin, meropenem, erythromycin, and trimethoprim–sulfamethoxazole. These findings underscore the importance of ongoing genomic surveillance of L. innocua in food environments and highlight the need to assess the potential risk posed by specific lineages, such as ST492, to food safety. Full article

The genus Polygonatum encompasses numerous species with complex phenotypes, necessitating robust molecular markers for accurate species identification and superior germplasm screening. This study identified and developed SSR markers based on transcriptome analysis of three Polygonatum species to assess the genetic diversity of Polygonatum resources. The results showed that a total of 43,217 SSR loci were detected, and 31,703 primer pairs were successfully designed. Characterization of SSR motifs revealed mono-nucleotide repeats (SNRs) were the most frequent (59.45%). Unigenes containing SSRs were annotated across seven databases. In KEGG, 222 pathways were assigned, with genes annotated to carbohydrate metabolism being the most abundant. To validate and apply these markers, 100 primer pairs covering all eight SSR locus types were tested across 21 Polygonatum accessions. Of these, 49 polymorphic markers were identified, revealing high genetic diversity, with average expected heterozygosity (He) and polymorphism information content (PIC) values of 0.763 and 0.718, respectively, alongside significant population differentiation (Fst = 0.307). Cluster analysis grouped 21 accessions into three groups, which correlated with certain agronomic traits. Nine core markers were selected that effectively distinguished six species and intraspecific groups. Notably, the FB-9 marker, associated with polysaccharide biosynthesis, effectively discriminated among six Polygonatum species and also distinguished distinct germplasm resources within P. kingianum var. grandifolium. Overall, the transcriptome-derived SSR markers validated in this study constitute valuable resources for gene function analysis, population genetics research, and variety identification and genetic improvement of Polygonatum. Full article

Background/Objectives: This study assesses the genetic basis of fetal congenital heart disease (CHD), which exhibits a complex etiology, by using chromosomal microarray analysis (CMA); it also elucidates perinatal outcomes and postnatal development to support prenatal diagnosis and genetic counseling. Methods: Pregnant women (n = 1195) who were diagnosed with fetal CHD based on echocardiography were selected along with those having an interventional prenatal diagnosis, all of whom underwent CMA. Depending on the gestational age, amniotic fluid or umbilical cord blood samples were collected. Patients were included if they were diagnosed with fetal CHD based on echocardiography. Those who could not consent to amniocentesis or umbilical vein puncture or who had contraindications for amniocentesis or umbilical vein puncture were excluded. Patients were studied until May 2025. Results: Of the 1195 fetuses with CHD, 140 had pathogenic copy number variation (pCNV). The pCNV detection rate in cases with a single CHD was 3.17%, whereas it was 13.51% in the group with multiple CHDs. The detection rate for pCNVs in patients with extracardiac abnormalities was 28.62%. The fetal and postnatal mortality rates were highest for fetuses with multiple CHDs. The survival rate was highest for fetuses with a single CHD. Early detection of CHD and timely genetic testing can inform clinical management of CHD-affected pregnancies; however, larger prospective studies are needed to establish their impact on perinatal outcomes. Conclusions: CMA provides valuable information for genetic counselling, as it identifies pathogenic variants associated with CHD. However, prognostic predictions should consider multiple clinical factors. Full article

Previous studies have considered the iridescent feathers of the peafowl as a classic example of structural coloration. The structural color is primarily attributed to a two-dimensional (2D) photonic crystal structure composed of melanin rods and air channels embedded in a keratin matrix. While previous optical models have successfully explained spectral tuning via geometric parameters such as lattice constants and cortex thickness, the potential contribution of auxiliary pigments to these complex hues has been largely overlooked. In this study, we combined high-sensitivity UPLC-MS and transcriptome analysis to elucidate the biochemical and genetic mechanisms underlying peafowl coloration. We identified trace amounts of the Xanthophyll lutein (one of the carotenoids) in iridescent train feathers, challenging the purely structural paradigm. Transcriptome analysis revealed significant differences in the expression of the melanin-related gene ASIP between iridescent and non-iridescent feather follicles. Furthermore, we observed significant expression differences in the carotenoid deposition-related gene GSTA2, correlating with the presence of lutein in iridescent regions. We conclude that while melanin provides the structural foundation for iridescence, lutein acts as an indispensable conditional modulator. The coordinated differential expression of melanin synthesis (ASIP) and carotenoid deposition (GSTA2) genes constitutes the genetic basis for the vibrant iridescent coloration of peafowl feathers. Full article

Background/Objectives: Mitochondrial Oxidative Phosphorylation (OXPHOS) is a critical metabolic dependency in many cancers. Targeting OXPHOS through Leucine-Rich PPR Motif-Containing Protein (LRPPRC) degrader-mediated OXPHOS Complex Biogenesis Inhibition (OCBI) has demonstrated promising anti-tumor activity. However, rational combination strategies to enhance therapeutic efficacy remain undefined. This study aims to identify FDA-approved drugs that synergize with LRPPRC inhibition and elucidate the underlying mechanism. Methods: We conducted a high-throughput screen of 1376 FDA-approved compounds using LRPPRC isogenic cancer cell models to identify agents that synergize with LRPPRC degrader-based OCBI therapy. The synergistic effects of the candidate compound were validated in multiple cancer cell lines with either genetic ablation or pharmacological inhibition of LRPPRC. Mechanistic studies were performed to investigate the impact on OXPHOS gene expression from both nuclear and mitochondrial genomes. Results: The clinically approved multi-kinase inhibitor Dasatinib was identified as a robust synergistic candidate, exhibiting heightened sensitivity in cancer cells with either LRPPRC knockout or pharmacological inhibition. Mechanistically, Dasatinib selectively suppressed nuclear-encoded OXPHOS genes, whereas LRPPRC inhibition preferentially impaired mitochondrial DNA-encoded OXPHOS genes, resulting in a coordinated dual-genome blockade of OXPHOS. Conclusions: This study uncovers a previously unrecognized synergistic anti-tumor effect between LRPPRC inhibition and Dasatinib, mediated by complementary suppression of nuclear- and mitochondrial genome-encoded OXPHOS pathways. These findings provide a strong mechanistic and translational rationale for combination therapies targeting LRPPRC-high tumors. Full article

Branch number is an important agronomic trait that determines the number of siliques per plant and yield in rapeseed (Brassica napus). However, the complex genetic and molecular mechanisms regulating the formation of branch number in rapeseed remain unclear. In a previous study, we isolated an EMS-induced multi-branching mutant (mbm1). Here, agronomic trait analysis showed that the mbm1 mutant produced more effective primary branches, total silique number, and yield per plant compared with the wild type. Genetic analysis indicated that the multi-branching trait of the mbm1 mutant is controlled by incompletely dominant gene(s) and follows nuclear inheritance. As a result of combined BSA-seq-based mapping and RNA-seq profiling, two candidate genes, BnaC03G0462000ZS (BnaC03.GAE6) and BnaC03G0491900ZS (BnaC03.MEE14), were identified based on sequence variation and expression differences. KASP marker analysis confirmed that there are significant associations between these two gene loci and the multi-branching trait. Hybrid progeny derived from crosses between the mbm1 mutant and commercial cultivars L329 and ZS11 showed significantly improved yield due to increased effective branch number. Together, these results provide important genetic resources and a theoretical foundation for further elucidating the genetic regulatory network of branching in rapeseed and for developing high-yielding rapeseed varieties with ideal plant architecture. Full article