Search Results (21,073)

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a rising incidence and a poor prognosis that largely reflects late-stage diagnosis. Although most cases are sporadic, approximately 5–10% of PCs occur in the context of inherited cancer susceptibility, including hereditary pancreatic cancer (HPC) syndromes and familial pancreatic cancer (FPC). Germline pathogenic variants in genes involved in DNA damage repair, cell-cycle regulation, and genomic stability—such as BRCA1, BRCA2, PALB2, ATM, CDKN2A, STK11, mismatch repair genes, and TP53—contribute to PC risk and may influence disease biology. This review provides an overview of the genetic landscape of hereditary and FPC, focusing on established cancer predisposition syndromes and emerging susceptibility genes. Current evidence regarding the prevalence, penetrance, and clinical relevance of germline pathogenic variants (PGVs) is summarized, together with the challenges associated with identifying individuals at increased risk. Contemporary recommendations for germline genetic testing, including the use of multigene panel approaches and limitations in real-world implementation, are also discussed. In addition, surveillance strategies for PDAC in high-risk individuals (HRI) are reviewed, and the available data on the outcomes and limitations of surveillance programs are examined. Finally, the therapeutic implications of inherited alterations, particularly in DNA repair-deficient PC, are outlined with reference to genotype-informed systemic treatment approaches. Full article

Background: Ischemic stroke remains a leading cause of mortality and long-term disability worldwide, with complex and heterogeneous pathophysiological processes. Single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) has been increasingly applied to investigate cellular heterogeneity at high resolutions. Methods: We systematically searched PubMed, Web of Science, and Embase to identify studies that applied sc/snRNA-seq in ischemic stroke research. Based on the retrieved literature, we summarized the bioinformatic analytical methods and application strategies reported in these studies, focusing on how sc/snRNA-seq has been utilized across different research contexts. Results: The application of sc/snRNA-seq in ischemic stroke has expanded rapidly across species and sample types. A wide range of downstream bioinformatic analyses have been employed, including clustering, differential expression analysis, trajectory inference, gene regulatory network analysis, and cell–cell communication analysis. These approaches have been applied to investigate diverse biological processes in ischemic stroke. In addition, these analytical strategies have been extended to multiple biological contexts, including extracerebral tissues, stroke-related modifiers, and their associated complications. Furthermore, integrative analytical approaches that combine multiple datasets, bulk transcriptomics, and other omics data have been increasingly utilized. Advances in temporal and spatial resolutions have enabled analyses across different stages and anatomical regions. Conclusions: This review systematically summarizes the analytical methods and application strategies of sc/snRNA-seq in ischemic stroke. These approaches provide a structured perspective for understanding the application of single-cell technologies in this field. Future studies may benefit from standardized designs and coordinated analytical strategies to facilitate more systematic investigations. Full article

Waterlogging-induced hypoxic stress severely impairs vegetative growth and crop yield of melon (Cucumis melo L.). The formation of adventitious roots represents a critical morphological adaptive strategy for melon seedlings to alleviate hypoxic damage and maintain viability under waterlogging conditions. Nevertheless, the synergistic molecular regulatory mechanisms governing waterlogging-triggered adventitious root development in melon remain largely uncharacterized at the proteomic and metabolomic layers. In this study, the waterlogging-tolerant melon line ‘L8’ with superior adventitious root production capacity was exposed to waterlogging treatment, and hypocotyl tissues were harvested at 0, 24, 48 and 72 h post-waterlogging for untargeted metabolomic and proteomic analyses. A total of 1337 differentially accumulated metabolites (DAMs) and 2898 differentially expressed proteins (DEPs) were identified across the pairwise comparisons. Functional enrichment analyses of DAMs and DEPs indicated that pathways related to linoleic acid metabolism, α-linolenic acid metabolism, phenylpropanoid biosynthesis, biosynthesis of secondary metabolites, and glutathione metabolism were centrally implicated in adventitious rooting induced by waterlogging. At the protein level, pivotal functional proteins associated with anaerobic respiration (pyruvate decarboxylase, alcohol dehydrogenase), ethylene biosynthesis (1-aminocyclopropane- 1-carboxylate oxidase), cell wall remodeling and antioxidant defense were significantly up-regulated throughout adventitious root development. In addition, three transcription factors, namely the GRAS family protein MELO3C025904.1, MYB-related protein MELO3C007640.1, and ZF-HD protein MELO3C022921.1, exhibited differential expression across different time points compared to the control. Moreover, metabolomic profiling identified three prominent metabolites with regulatory functions, encompassing the terpenoid acorusnol, the piperidine alkaloid 1,4′-bipiperidine- 1′-carboxylic acid, and the flavonoid 4′,7-dihydroxy-2′-methoxy-3′-prenylisoflavan. Omics correlation analysis revealed extensive concordance between metabolomic and proteomic profiles. Nine core DAMs, including N-methylserotonin, Val-Val and glyuranolide, were tightly correlated with hundreds of DEPs and key transcription factors, constructing a complex regulatory network governing waterlogging stress acclimation and adventitious root morphogenesis. This study systematically characterizes the coordinated proteomic and metabolomic reprogramming underlying waterlogging-induced adventitious root formation in melon. These findings deepen our understanding of the molecular mechanism of waterlogging tolerance and provide valuable candidate genes and metabolic targets for genetic improvement of waterlogging resistance in melon. Full article

Background/Objectives: Ceftazidime-avibactam (CAZ/AVI) and cefiderocol (FDC) retain activity against most clinical isolates of KPC-producing Klebsiella pneumoniae (KPC-Kp). Nevertheless, the emergence of cross-resistance between both agents has become an increasing clinical concern. In this study, the development of resistance to both CAZ/AVI and FDC was retrospectively investigated in KPC-Kp isolates recovered from patients treated with CAZ/AVI between 2014 and 2023. Methods: Twenty-two isolates (pre- and post-therapy) obtained from nine patients were included. Demographic and clinical data were collected. FDC susceptibility testing was determined for both clinical isolates and E. coli TOP10 transformants by reference broth microdilution using iron-depleted medium, and MICs were interpreted according to EUCAST breakpoints. Resistance mechanisms were characterized using whole genome sequencing. Results: Cross-resistance to both CAZ/AVI and FDC emerged in six patients (66.7%) during CAZ/AVI therapy, after a median treatment duration of 12.8 ± 7.6 days. The presence of different KPC-3 variants in the CAZ/AVI-FDC resistant isolates was revealed by genomic analysis. Furthermore, the role of KPC-28, KPC-31, KPC-47, KPC-94, KPC-95, and KPC-148 in mediating reduced susceptibility to CAZ/AVI and FDC was confirmed by AST of transformants carrying bla_KPC variants. However, differences in MIC values compared with those obtained for the corresponding clinical isolates supported the relevance of additional mechanisms of co-resistance. The presence of ferric citrate transport (FEC) system was also associated with higher FDC MICs. Mutations in genes coding siderophore-iron transporter, PBPs, sensor histidine kinase or Tol-Pal system were also found in some of the isolates. Conclusions: These findings highlight the ability of KPC-Kp to develop co-resistance to both CAZ/AVI and FDC during CAZ/AVI therapy. Full article

The activator protein-1 (AP-1) transcription factor is a regulatory dimeric transcription factor complex, that responds to a wide range of intracellular and extracellular stimuli and controls gene expression involved in tumor initiation and progression. Comprised primarily of members of Jun and Fos protein subfamilies, AP-1 is activated downstream of major oncogenic signaling pathways such as the mitogen-activated protein kinase (MAPK) pathway and controls cellular processes including differentiation, invasion, proliferation and apoptosis. In various cancer types, AP-1 contributes to tumor growth by promoting tumor-like phenotypes and facilitating metastatic behavior. Furthermore, AP-1 can affect the tumor microenvironment by modulating inflammation and interaction with immune cells. AP-1 deregulation is linked to tumor heterogeneity and resistance to chemotherapy and radiation. Therefore, AP-1 has emerged as a potential therapeutic target. In preclinical models, direct and indirect targeting via upstream pathways of AP-1 components has demonstrated encouraging results. In addition, combinatorial approaches targeting AP-1 and other regulators may improve the effectiveness of treatment and overcome therapy resistance. In this review, we highlight the AP-1’s role as a critical hub in tumorigenesis that links oncogenic signaling to transcriptional regulation. We also focus on its regulation, function in the tumor microenvironment, and therapeutic potential in combating tumors. Full article

DNA double-strand breaks (DSBs), caused by various endogenous and exogenous factors, pose a significant threat to genomic stability. Several conserved repair pathways address DSBs, with homologous recombination (HR) being the only mechanism capable of accurately restoring the original DNA sequence. The BRCA1 gene plays a critical role in HR and is involved in maintaining genomic stability, cell cycle regulation, transcription, and tumor angiogenesis. Germline mutations in BRCA1 are strongly associated with increased risks of breast, ovarian, and other cancers. Dysfunction of BRCA1 leads to homologous recombination deficiency (HRD), forcing cells to rely on error-prone repair pathways, which promotes genomic instability and tumorigenesis. Besides hereditary mutations, HRD can also arise in sporadic cancers through epigenetic mechanisms such as promoter hypermethylation and reduced BRCA1 expression. Although BRCA1 deficiency is uncommon in lung cancer, BRCA1 status is considered a potential biomarker for sensitivity to platinum-based chemotherapy and other cytotoxic agents used in lung cancer treatment. However, the impact of BRCA1 on treatment response and prognosis in lung cancer remains controversial and not fully understood. This review summarizes current evidence on the role of BRCA1 in modulating chemotherapy response and disease outcomes in lung cancer patients, highlighting its potential as a biomarker for personalized therapy selection. Thus, in this context, the key unresolved issues critical for the development of personalized treatment strategies for lung cancer associated with BRCA1 alterations include the identification of molecular biomarkers most reliably associated with tumor sensitivity to chemotherapy. In addition, the development of methods for identifying patients with homologous recombination deficiency specifically in lung tumors appears to be of considerable importance, as does a better understanding of how the biological and therapeutic implications of BRCA1-related parameters in lung cancer differ from those observed in other tumor types. Addressing these challenges could substantially improve the efficacy of chemotherapy and patient outcomes, while also expanding the opportunities for a personalized approach to treatment selection in patients with lung cancer. Full article

Porcine reproductive and respiratory syndrome (PRRS), caused by PRRSV, causes substantial economic losses in the swine industry. Because viral variability and host genetic complexity limit conventional control, identifying host genetic factors associated with PRRS resistance through genomic approaches is important for disease-resistant breeding. In this study, 699 pigs were immunized with a PRRSV vaccine, 135 were selected for PRRSV infection experiments, and 133 were retained for whole-genome resequencing after two-stage phenotypic screening based on post-immunization and post-infection profiles. Genome-wide selection-signal analysis identified 12 highly differentiated regions (F_st > 0.15), annotated to 11 candidate genes: NFXL1, NIPAL1, CHIC2, LOC100623351, LOC100513671, LOC100513484, CENPC, STAP1, UBA6, GNRHR, and LOC100512727. The original exploratory GWAS identified candidate association signals, including signals annotated to PYGM, NFXL1, KIAA1324L, and FLNC; after PC1/PC2 adjustment, NFXL1 retained exploratory support, and additional exploratory signals were observed. Public PRRSV-related transcriptomic datasets provided additional expression-level evidence, with NIPAL1 and PYGM showing increased expression in PRRSV-infected porcine alveolar macrophages. Functional enrichment and variant-level analyses supported the biological relevance of the prioritized candidate gene set, particularly the chromosome 8 NFXL1 region, where the A-C-G haplotype was more frequent in resistant pigs. These findings provide useful genetic clues for further validation and PRRS resistance breeding. Full article

Plerixafor is a clinically approved CXCR4 antagonist that mobilizes hematopoietic stem cells by disrupting CXCL12/CXCR4 retention signaling. However, its biochemical effects on melanocytes and pigmentation remain unexplored. We investigated how Plerixafor modulates CXCR4 signaling in melanocytes and evaluated its potential as a pro-melanogenic agent using in vitro and in vivo approaches. Human PIG1 melanocytes were treated with 10 nM Plerixafor with or without hydroquinone (HQ), followed by qPCR for MITF and tyrosinase expression, flow cytometry for CXCR4/CXCR7 and integrin profiling, transwell migration assays, β-arrestin siRNA knockdown, Western blotting, subcellular fractionation, and ChIP-qPCR for β-catenin binding to MITF regulatory regions. A murine HQ-induced depigmentation model was used to test topical Plerixafor on pigmentation, hair follicles, melanogenic gene expression, and systemic safety markers. Plerixafor significantly increased MITF and tyrosinase mRNA and enhanced melanocyte migration while counteracting HQ-induced suppression of melanogenic genes. In addition, it reduced cell-surface CXCR4 (consistent with β-arrestin-mediated receptor internalization) without altering CXCR7, c-KIT, or N-cadherin. β-Arrestin knockdown abolished Plerixafor-induced ERK phosphorylation and melanogenic responses, confirming β-arrestin dependence. Plerixafor promoted β-catenin nuclear translocation and direct β-catenin occupancy at MITF promoter/enhancer TCF/LEF motifs. In vivo, topical Plerixafor restored HQ-induced depigmentation, increased hair follicle number and melanin content, and upregulated cutaneous MITF and tyrosinase without hepatic, renal, or inflammatory toxicity. Plerixafor functions as a biased CXCR4 ligand in melanocytes, influencing the β-arrestin–β-catenin–MITF signaling axis to drive melanogenesis and re-pigmentation. These findings identify β-arrestin-dependent CXCR4 signaling as a tractable pharmacologic mechanism for therapeutic re-pigmentation in pigmentary disorders. Full article

Pyruvate kinase (PK) is the terminal rate-limiting enzyme of glycolysis and occupies a central position in plant energy metabolism and carbon skeleton allocation. Plant PK isoenzymes comprise the cytosolic pyruvate kinase (PKc) and the plastidic pyruvate kinase (PKp), which differ markedly in gene origin, protein structure, subcellular localization, and physiological function, exhibiting independent evolutionary histories and functional diversification. Recent studies have revealed that PKc possesses dynamic subcellular distribution, allowing it to shuttle among the cytosol, mitochondria, and nucleus, where it participates in stress responses and epigenetic regulation through protein–protein interactions. PKp is localized to plastids and connects carbon metabolism with lipid biosynthesis and the methylerythritol phosphate (MEP) pathway by supplying pyruvate, thereby playing critical roles in seed development and oil accumulation. This review comprehensively summarizes recent advances in plant PKc and PKp concerning protein structure and subunit composition, tissue-specific expression, subcellular localization, protein interaction networks, activity regulation, and their effects on plant growth, development, and stress responses. In addition, phylogenetic tree, motif, and domain analyses of pyruvate kinase genes from Oryza sativa (rice), Glycine max (soybean), Gossypium hirsutum (cotton), Solanum tuberosum (potato), Arachis hypogaea (peanut), and Arabidopsis thaliana, as well as promoter cis-element analyses, are performed. This review aims to provide theoretical references for crop quality improvement and stress-resilient breeding. Full article

Rice tiller number is a key determinant of panicle number and yield, yet its genetic architecture is highly influenced by environmental variation. Identifying loci showing reproducible effects across multiple growing seasons at the same experimental site is important for improving the reliability of GWAS-based locus prioritization for breeding. In this study, 240 rice accessions from the Rice3K panel were evaluated for tiller number over three growing seasons (2021–2023) in Sanya, Hainan Province, representing the South China rice-growing region. Genome-wide association analyses using GLM and MLM, combined with BLUEs, identified reproducible genetic signals. Several previously reported tillering-related genes, such as NAL1, BON3, ANT1, MRG702, D27, WTG1, and VPE2, were detected across different analyses. Among them, NAL1 and ANT1 represented the most consistently associated loci across three growing seasons and statistical models. Gene-based association analysis identified the promoter variants Chr4:31203262 (C/T) in NAL1 and Chr7:7310528 (G/A) in ANT1 as the lead polymorphisms, with the favorable C and G alleles associated with increased tiller number, respectively. In addition, nine putative candidate loci showing suggestive associations across three growing seasons were identified as putative candidate breeding resources. These results highlight the importance of integrating multi-year phenotyping with GWAS to prioritize loci showing reproducible associations across three growing seasons and provide valuable candidate genetic resources for future molecular improvement of rice adapted to the South China rice-growing region. Full article

Black soybean is an important functional crop valued for its high anthocyanin content and associated health benefits, attracting increasing interest in plant breeding and mutation-based approaches to enhance its nutritional and agronomic traits. Here, we investigated a DT26 black seed-coat mutant (DT26BS) derived from the Vietnamese cultivar DT26 following gamma irradiation. Genetic analysis of F₂ populations indicated that the phenotype is controlled by a single recessive mutation, with additional epistatic interactions observed in other genetic backgrounds. MutMap analysis based on whole-genome sequencing of pooled F₂ individuals identified a candidate region on chromosome 8 corresponding to the I locus. A large deletion (~176 kb) was identified in this region, affecting multiple Chalcone Synthase (CHS) gene repeats, and which may disrupt RNAi-mediated silencing of CHS, thereby triggering anthocyanin restoration in the seed coat. PCR-based markers confirmed tight linkage between this deletion and the black seed-coat phenotype. Crosses with elite lines and further selection until F7 generations showed that the mutation has no adverse effects on major agronomic traits and is useful as a donor for developing improved lines with black seed coat, shorter maturity, high yield, and enhanced anthocyanin content for nutritional improvement. These results demonstrate the utility of MutMap for detecting irradiation-induced structural variants and extend its application to a non-reference elite tropical soybean background, providing a useful genetic resource for black soybean breeding. Full article

The carob tree (Ceratonia siliqua L., Fabaceae) is an ecologically and economically significant species of the Mediterranean basin, yet its cytogenetic and genomic organisation have remained largely uncharacterised. Here we present the first comprehensive molecular cytogenetic characterisation of C. siliqua, combining conventional karyotyping, fluorochrome banding, fluorescence in situ hybridisation (FISH), and flow cytometric genome size estimation across 29 accessions spanning the Mediterranean basin. A uniform diploid chromosome number of 2n = 24 was confirmed across all 14 populations examined, including Algerian, French, and Lebanese accessions, with no karyotypic variation detected regardless of geographic origin, altitude, or cultivation status. Karyotype analysis revealed a bimodal chromosome set comprising two large metacentric pairs and ten smaller pairs, with an intermediate asymmetry class (AsI = 60.09; R = 2.71). Physical mapping of ribosomal RNA gene families by FISH identified three chromosome pairs bearing 35S rDNA loci, all co-localising with GC-rich CMA₃-positive heterochromatin at satellite regions, and a single 5S rDNA locus at the telomeric region of a distinct chromosome pair, corresponding to the S-type arrangement. DAPI staining revealed an additional class of AT-rich constitutive heterochromatin at centromeric positions, compositionally and positionally independent of the rDNA arrays. Genome size was strikingly conserved across all 23 accessions assessed (2C = 1.10–1.23 pg; overall mean 1.14 ± 0.03 pg), with no significant variation attributable to geographic origin, altitude along an Algerian gradient (162–950 m a.s.l.), cultivation status, or sex. The near-identical genome sizes recorded in female and male individuals provide no cytometric evidence for heteromorphic sex chromosomes in this dioecious species. These results establish a stable genomic and cytogenetic baseline for C. siliqua across its Mediterranean range and provide a reference framework for future comparative cytogenetics, molecular marker development, and breeding programmes targeting this increasingly valued climate-resilient crop. Full article

Background/Objectives: The non-neuronal cardiac cholinergic system (NNCCS) is known to synthesize ACh independently of the parasympathetic nervous system, thereby regulating cardiac homeostasis, which includes sustainability of energy metabolism, anti-inflammatory and anti-ischemic properties, electrical stability, and mitochondrial calcium handling. Given these beneficial functions of NNCCS, we were prompted to search for an inducer. One such inducer is SNPiP, a novel low-molecular-weight chemical compound developed by us. SNPiP accelerates ACh synthesis in the heart via cGMP elevation and, intriguingly, enhances diastolic function, increasing cardiac output and end-systolic pressure without elevating heart rate. However, the pharmacokinetics of SNPiP remain unknown, which led us to conduct the present study. Methods and Results: We found that the half-life of SNPiP in the blood was extremely short, similar to that of a nitric oxide (NO) donor, S-nitroso-N-acetyl-DL-penicillamine. This short half-life is caused by the rapid distribution of SNPiP into organs, including the heart, kidney, and liver. In addition, once transferred into blood cells, SNPiP itself became stable and remained intact for up to 1 h. Moreover, the short half-life was partly explained by the rapid degradation of SNPiP and concomitant loss of the nitroso group in the blood. Notably, when rats were treated with SNPiP, NO levels in the heart elevated bimodally: immediately after administration and again about 12 h later, coinciding with the previous report of NNCCS upregulation and accelerated ACh synthesis with NO production. Importantly, our previous transcriptome analysis of SNPiP-treated hearts supports these findings, as it revealed upregulation of diastolic function-related genes and proteins. Conclusions: Collectively, these results clarify the pharmacokinetics of SNPiP and demonstrate that, despite a shorter half-life, SNPiP is efficiently distributed to the heart, where it confers beneficial effects through induction of NNCCS. Full article

Eucommia ulmoides leaf extract (ELE) boasts a high concentration of bioactive components including flavonoids, chlorogenic acid, and polysaccharides. It exhibits multiple biological functions, including antioxidant, anti-inflammatory, and gut microbiota-modulating properties, showing great potential in enhancing immunity, maintaining intestinal health, and delaying cellular senescence. This study investigated the protective effects and underlying mechanisms of ELE against D-galactose-induced senescence in chick embryo primary intestinal epithelial cells (IECs). Using an in vitro model (200 mmol/L D-galactose), we found that 100 µg/mL ELE pretreatment significantly preserved cell viability, mitigated apoptosis, and delayed cellular senescence, as evidenced by cytological and biochemical assays. Furthermore, RNA-seq transcriptomic analysis identified seven key differentially expressed genes (DEGs) mediating these anti-aging effects. Mechanistic investigations revealed that ELE modulates ATP6V0D2 and NCF2 to activate autophagy signaling pathways. This ELE-induced promotion of autophagy effectively suppresses inflammatory responses in IECs, thereby delaying senescence progression. These findings elucidate the molecular mechanisms by which ELE antagonizes intestinal cellular senescence, providing a solid theoretical foundation for its development as a functional anti-aging additive in the food industry. Full article

Background: Depression-related liability is frequently accompanied by reduced physical function, yet the shared genetic architecture linking mood-related traits and physical-function decline remains incompletely characterized. Methods: We applied genomic structural equation modeling to European-ancestry GWAS summary statistics for five constituent phenotypes: depressive symptoms, depression diagnosis, grip strength, appendicular lean mass, and walking pace. A Depression–Physical Function shared genetic factor was constructed as a cross-trait genetic covariance dimension and evaluated using LDSC-based validation and leave-one-trait-out sensitivity analyses. We then performed factor GWAS, FUMA locus annotation, Bayesian fine-mapping, MAGMA gene-based analysis, transcriptome-wide association analysis, pathway enrichment, CELLECT/MAGMA cell-type specificity analysis, partitioned heritability analysis, and gsMap spatial transcriptomic mapping. Results: The shared factor showed good model fit and retained 755,397 quality-controlled variants for downstream analysis. The factor was positively genetically correlated with depression-related traits and negatively correlated with physical-function-related traits. FUMA identified 245 genome-wide significant SNPs, 44 lead SNPs, and 38 genomic risk loci, with 127 positional mapped genes. Fine-mapping prioritized one high-confidence locus. MAGMA identified 19 Bonferroni-significant genes and 326 FDR-significant genes, while TWAS identified 322 FDR-significant expression-associated genes. Integrating FUMA positional mapping, MAGMA gene-level association and TWAS expression-level association prioritized eight convergent genes: TMEM106B, CENPW, DRD2, LRFN5, NCAPG, DCAF16, SGIP1, and FAM120A. Functional enrichment highlighted postsynaptic structure, neuron spine, synaptic plasticity, and synapse organization. CELLECT/MAGMA prioritized brain non-myeloid neurons and glial populations, with additional endocrine-metabolic and immune-hematopoietic signals. Spatial transcriptomic mapping localized top signals to brain and spinal cord regions in the embryonic neuro-muscle reference. Partitioned heritability analysis showed enrichment in conserved, intronic, promoter, and chromatin-related genomic annotations. Conclusions: These findings support a shared polygenic covariance dimension linking depression-related liability with reduced physical-function-related genetic propensity. Downstream analyses prioritized candidate loci, genes, and biological contexts, with enrichment patterns consistent with neuronal, synaptic, and regulatory genomic processes. Full article