Search Results (199)

UNC13D, which encodes the Munc13–4 protein, is a critical gene implicated in type 3 familial hemophagocytic lymphohistiocytosis (HLH). While biallelic nucleotide variants in HLH-related genes, including UNC13D, are traditionally linked to recessive inheritance patterns in HLH, emerging evidence suggests that heterozygous variants may also contribute to the onset of adult-onset HLH. However, the pathogenicity of heterozygous UNC13D variants is still not fully understood. Here, we present a 29-year-old male patient with Epstein–Barr virus (EBV)-triggered adult-onset HLH, who was found to carry compound heterozygous variants in the UNC13D gene (c.2588G>A and c.1978_1979insATTACCG) with complete T/NK cytotoxicity dysfunction. We conducted NK-cell function assay in this pedigree to link the genotype to phenotype and demonstrated that the monoallelic UNC13D c.2588G>A variant could partially impair NK cell cytotoxicity, in contrast to the completely recessive inheritance observed with UNC13D c.1978_1979insATTACCG and other familial HLH-related variants. In addition, to explore the implication of UNC13D c.2588G>A variant in various diseases, we reviewed 16 published studies, including data on 35 patients carrying this variant. Data showed the heterozygous variant of UNC13D c.2588G>A might act as a genetic risk factor predisposing carriers to conditions like HLH, lymphoma, etc. This study underscores the pathogenic role of the UNC13D c.2588G>A variant and expands our understanding of the genetic basis of adult-onset HLH. Full article

Acrobeloides nanus is a cosmopolitan, parthenogenetic soil nematode that is widely distributed across various terrestrial environments, including forests, sand dunes, and agricultural lands. In Korea, this nematode was first isolated from soil collected from a potato farm. It has been used as a biological indicator for monitoring contamination caused by divalent metals such as copper and zinc. In this study, A. nanus was isolated from the soil collected from a cucumber farm, and its identity was confirmed using both morphological and molecular markers. Spray-induced gene silencing using double-stranded RNA (dsRNA) represents a promising new strategy for pest control. Here, we tested a spraying dsRNA that would specifically suppress the target genes in A. nanus. Three genes (Pat-10, Unc-87, and vATPase-B) were targeted, and their expression levels were assessed following treatment with their corresponding dsRNAs. The dsRNAs were sprayed onto the nematode diet. As the concentration of dsRNA increased, the expression levels of the target genes were significantly reduced, leading to notable nematode mortality. However, nematicidal activity varied among the three different dsRNAs. To practically assess these dsRNAs under field conditions, the dsRNAs were applied to the soil containing the nematodes by a drenching application. Significant mortality was observed in treatments with dsRNAs targeting vATPase-B or Pat-10, but not with dsRNA targeting Unc-87. To enhance nematicidal activity in soil, the dsRNAs were formulated with chitosan. This formulation significantly improved the stability of dsRNAs under soil conditions and increased their control efficacy against A. nanus. This study suggests that the drenching technique offers an effective strategy to the control of soil-dwelling nematode pests affecting agricultural crops. Full article

Background/Objectives: Multiple myeloma (MM) is the second most common hematological malignancy and remains incurable because of its complex and heterogeneous pathogenesis. UNC13B (unc-13 homolog B) encodes Munc13-2, a presynaptic protein that is involved in vesicle exocytosis. While its role has been explored in neurological diseases, its function in cancer biology remains largely uncharacterized. This study aimed to elucidate the role of UNC13B in regulating MM cell proliferation and apoptosis. Methods:UNC13B mRNA expression was assessed across human MM cell lines. ARD cells, which exhibited the highest UNC13B expression, were transduced with a UNC13B-specific shRNA via a lentiviral vector. Cell proliferation, apoptosis, and expression of associated proteins were evaluated by means of the Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and Western blot analysis. Results: UNC13B was significantly upregulated in MM cell lines. The knockdown of UNC13B in ARD cells markedly inhibited cell proliferation and induced apoptosis. These changes were accompanied by the downregulation of proliferation-related proteins and upregulation of pro-apoptotic markers. Western blot analysis suggests that UNC13B may exert its effects by modulating key regulatory proteins, including PINK1, CDK2, AKR7A3, and Bim. Conclusions: Our findings suggest that UNC13B supports MM cell survival and proliferation, potentially through the regulation of oncogenic and apoptotic signaling pathways. UNC13B may represent a novel therapeutic target in multiple myeloma. Full article

Molecular research for genetic variants underlying body weight (BW) provides crucial information for this important selected trait when developing productive poultry breeds, lines and crosses. We searched for molecular markers—single nucleotide polymorphisms (SNPs)—and candidate genes associated with this trait in 240 F₂ resource population Japanese quails (Coturnix japonica). This population was produced by crossing two breeds with contrasting growth phenotypes, i.e., Japanese (with lower growth) and Texas White (with higher growth). The birds were genotyped using the genotyping-by-sequencing method followed by a genome-wide association study (GWAS). Using 74,387 SNPs, GWAS resulted in 142 significant SNPs and 42 candidate genes associated with BW at the age of 1, 14, 28, 35, 42, 49 and 56 days. Hereby, 25 SNPs simultaneously associated with BW at more than one age were established that colocalized with nine prioritized candidate genes (PCGs), including ITM2B, SLC35F3, ADAM33, UNC79, LEPR, RPP14, MVK, ASTN2, and ZBTB16. Twelve PCGs were identified in the regions of two or more significant SNPs, including MARCHF6, EGFR, ADGRL3, ADAM33, NPC2, LTBP2, ZC2HC1C, SATB2, ASTN2, ZBTB16, ADAR, and LGR6. These SNPs and PCGs can serve as molecular genetic markers for the genomic selection of quails with desirable BW phenotypes to enhance growth rates and meat productivity. Full article

Background: In recent years, comprehensive analyses using a genome-wide association study (GWAS) have been conducted to identify genetic factors related to athletic performance. In this study, we investigated the association between genetic variants and elite wrestling status across multiple ethnic groups using a genome-wide genotyping approach. Methods: This study included 168 elite wrestlers (64 Japanese, 67 Turkish, and 36 Russian), all of whom had competed in international tournaments, including the Olympic Games. Control groups consisted of 306 Japanese, 137 Turkish, and 173 Russian individuals without elite athletic backgrounds. We performed a GWAS comparing allele frequencies of single-nucleotide polymorphisms (SNPs) between elite wrestlers and controls in each ethnic cohort. Cross-population analysis comprised (1) identifying SNPs with nominal significance (p < 0.05) in all three groups, then (2) meta-analyzing overlapped SNPs to assess effect consistency and combined significance. Finally, we investigated whether the most significant SNPs were associated with gene expression in skeletal muscle in 23 physically active men. Results: The GWAS identified 328,388 (Japanese), 23,932 (Turkish), and 30,385 (Russian) SNPs reaching nominal significance. Meta-analysis revealed that the ATP2A3 rs6502758 and UNC5C rs265061 polymorphisms were associated (p < 0.0001) with elite wrestling status across all three populations. Both variants are located in intronic regions and influence the expression of their respective genes in skeletal muscle. Conclusions: This is the first study to investigate gene polymorphisms associated with elite wrestling status in a multi-ethnic cohort. ATP2A3 rs6502758 and UNC5C rs265061 polymorphisms may represent important genetic factors associated with achieving an elite status in wrestling, irrespective of ethnicity. Full article

Background/Objectives: The consumption of opioids is a public health problem that significantly affects quality of life. In Spain, 7585 people are enrolled in the Methadone Maintenance Programme (MMP), which is an effective intervention with a low adherence rate. In this study, factors associated with the quality of life of MMP users, especially perceived social support and treatment adherence, were analysed. We hypothesised that low levels of adherence and social support would be associated with poorer quality of life. Methods: This was a cross-sectional observational study with an analytical approach. Quality of life (WHOQoL-BREF), perceived social support (DUKE-UNC-11), and treatment adherence (MMAS-8) among MMP users were studied, and data on sociodemographic and clinical characteristics were collected through ad hoc questionnaires and a review of electronic medical records. Linear and logistic regression models were used. Results: A total of 70 individuals were included in this study. The mean age was 56.9 years, and 83% of the participants were male. The perceived quality of life was low in the four domains evaluated (range of 47.4–48.2). A total of 38.57% of the participants had low perceived social support. Treatment adherence was low or moderate in 77.1% of the participants. Greater perceived social support was associated with better quality of life in all domains (p < 0.05). Quality of social life was negatively associated with the use of nonbenzodiazepine neuroleptics and HIV status. Treatment adherence was lower in insulin therapy users. Conclusions: Social support is a key determinant of the quality of life of MMP users. Health policies should promote social support networks as a strategy to improve the well-being of this population. Full article

Native bean genotypes (Phaseolus vulgaris L.) play a crucial role in ensuring food security in the Andean region. However, their cultivation faces challenges, such as low yields and a high dependence on nitrogen fertilizers. Addressing these issues requires the development of sustainable strategies to enhance productivity. This study evaluated the interaction between Rhizobium phaseoli inoculation and three levels of phosphorus (P) and potassium (K) fertilization on the growth, yield, and nutritional profile of the ‘Tiachos bayo’ native bean variety under Andean field conditions. Two R. phaseoli strains (UNC-1 and CIAT-2) were tested in combination with three levels of chemical fertilization (0%, 50%, and 100%) using a factorial design under field conditions. Parameters assessed included nodule number, plant height, phenology, yield, and proximal grain composition. Results indicated that inoculation and fertilization levels significantly influenced nodulation, phenological phases, and crop yield. The highest yield (2172 kg·ha⁻¹) and nodule number (78) were observed with the combined treatment of R. phaseoli CIAT-2 strain with 100% fertilization. It was concluded that R. phaseoli inoculation, when integrated with appropriate fertilization, enhances the productivity of native beans. Full article

Rotator cuff tears are a leading cause of shoulder pain and dysfunction, yet the molecular mechanisms that link tendon injury to inflammation and nociceptive signaling remain poorly understood. Netrin-1, a classical axon guidance cue signaling through dependence receptors UNC5B and Neogenin-1, has been implicated in both neuronal plasticity and inflammatory processes, but its role in tendon pathology has not been explored. A rat supraspinatus tear model was employed to assess, in vivo, the expression of genes encoding netrin-1 (Ntn1) and its receptors (Unc5b and Neo1) at 0, 7, 14, 28, and 56 days post-injury (n = 10 per time point). Primary rat tenocytes isolated from rotator cuff tissue were treated in vitro with recombinant netrin-1, and transcriptional changes in genes encoding TNF-α (Tnfa), IL-6 (Il6), MMP-1 (Mmp1), and MMP-3 (Mmp3) were quantified by qRT-PCR. Separately, human iPSC-derived sensory neurons were exposed to netrin-1, and dose- and time-dependent effects on neurite outgrowth were measured at 4 and 14 days in culture. In injured tendons, Ntn1 mRNA increased significantly at day 14 (p = 0.010) and 28 (p = 0.042), Unc5b at day 7 (p = 0.002) and 14 (p < 0.001), and Neo1 at day 14 (p < 0.001) versus intact controls. Tenocyte exposure to 500 ng/mL netrin-1 induced transient upregulation of Tnfa (3 h, p = 0.023; 6 h, p = 0.009) and Il6 (3 h–24 h, all p < 0.013), as well as Mmp3 (3–24 h, p < 0.043) and Mmp1 (6 h–24 h, p < 0.024); no induction was observed at 50 ng/mL. In sensory neurons, 50 ng/mL of netrin-1 enhanced neurite extension at day 4 (p = 0.006) but not at 500 ng/mL or at day 14 for either dose. Netrin-1 and its receptors are upregulated in a rat rotator cuff tear model, and netrin-1 elicits distinct pro-inflammatory and matrix-remodeling responses in tenocytes while promoting early neurite growth in sensory neurons. These findings suggest netrin-1 as a key modulator of tendon inflammation, matrix turnover, and peripheral nerve plasticity following injury. Full article

Background/Objectives: The aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic and severe debilitating disease with a complex phenotype, remains elusive. Associations with infectious diseases and autoimmune and neuropsychiatric disorders have been observed, without the identification of mechanisms. Previous studies suggest that genetic predisposition plays a role, but results are difficult to replicate, with Genome-Wide Association Studies of ME/CFS being challenging due to the relative rareness and heterogeneity of the disorder. Methods: We studied a well-defined Australian patient cohort diagnosed via the International Consensus Criteria, recruited by a specialist ME/CFS clinic. The whole-exome sequences of 77 patients were contrasted against genome variation in the 1000 Genome Project’s genome-matched population. Results: Significant associations with ME/CFS were harboured in genes that belong to the Neuroblastoma Breakpoint Family encoding Olduvai (DUF1220) domains, namely NBPF1 (rs3897177, p-value = 3.15 × 10⁻⁸), NBPF10 (rs1553120233, p-value = 9.262 × 10⁻¹³), and NBPF16 (rs200632836, p-value = 1.04 × 10⁻⁶). Other significantly associated variants were detected in the ATR, RSPH10B, ADGRE5-CD97, and NTRK2 genes, among others. Replication of these results was attempted via a GWAS on raw data from a US cohort, which confirmed shared significant associations with variation identified in the PTPRD, CSMD3, RAPGEF5, DCC, ALDH18A1, GALNT16, UNC79, and NCOA3 genes. Conclusions: These genes are involved in cortical neurogenesis, brain evolution, and neuroblastoma, and have been implicated by several studies in schizophrenia and autism. The sharing of these associations by the two cohorts supports their validity and grants the necessity of future studies to evaluate the implications for ME/CFS aetiology. Full article

Background/Objectives: Renal transplantation (RT) remains the gold standard for end-stage renal disease, offering superior outcomes versus dialysis. Despite advances, ureteric complications (leaks/strictures) persist, primarily from ischemic injury, posing substantial graft risks. We review etiology, incidence, and management strategies for post-RT ureteric complications, focusing on surgical reconstruction techniques. Methods: Literature assessment examined ischemic-related ureteric complications. Primary outcomes: incidence, success, complication rates, operative times, and long-term patency. Secondary outcomes: graft/patient survival and reoperation rates. Techniques evaluated included extravesical Lich–Gregoir (L-G) and transvesical Leadbetter–Politano (L-P) ureteroneocystostomy (UNC), Boari flap with psoas hitch, pyelo/ureteroureterostomy, pyelovesicostomy, and ureteroenterostomy. Surgical indications, procedural details, advantages, disadvantages, and quantitative outcomes were systematically analyzed. Results: Ureteric complication incidence ranged from 1 to 15%, with ischemic injury as the primary cause. L-G UNC demonstrated lower complication rates than L-P (6.15% vs. 8.33%) with reduced operative times. Pyelo/ureteroureterostomy achieved excellent salvage outcomes (>90% success, 3.9% reintervention rate). Boari flap provides a suitable option for extensive ureteric defects, consistently preserving graft function without stricture recurrences. Pyelovesicostomy showed 80% long-term success in complex cases. Ureteroenterostomy achieved comparable 5-year graft survival (63%) to standard drainage, despite higher infection rates (65%). Pyelovesicostomy and ureteroenterostomy remain important solutions for specific challenging scenarios. Conclusions: Urinary reconstruction technique selection should be individualized based on anatomical considerations, pathology, and surgical expertise. Comprehensive understanding of reconstruction techniques enables effective management of ureteric complications, preserving graft function and improving outcomes. Full article

Sheep have evolved remarkable phenotypic diversity through artificial and natural selection, with reproductive traits being pivotal for breeding economics. As a unique genetic resource, Pishan red sheep exhibit exceptional advantages, including perennial estrus, high fecundity, and stable hereditary characteristics, establishing them as an optimal model for investigating reproductive genetics. In this study, we performed whole-genome resequencing of Pishan red sheep, generating 9084.81 Gb of raw data and identifying 53,968,686 high-quality single-nucleotide polymorphisms (SNPs). Through selective sweep analysis, 92 genomic regions under selection were detected, containing 90 positional candidate genes significantly associated with growth, reproduction, and immune functions. Notably, we revealed BMPRIB, UNC5C, PDLIM5, GRID2, and HPGDS as core positional candidate genes influencing litter size, operating through the TGF-beta and Thyroid hormone signaling pathways. A genome-wide association study (GWAS) further identified 59 trait-related SNPs, including 39 loci linked to growth traits (affecting positional candidate genes such as PROM1, TAPT1, LDB2, and KIF16B) and 20 loci of positional candidate genes associated with reproductive traits (involving ASPA, RAP1GAP2, PHIP, and WDR82).These findings not only elucidate the molecular basis of superior reproductive performance in Pishan red sheep, but also provide functional markers for precision breeding. Full article

Acrylamide (ACR), utilized as a precursor for producing polyacrylamide for water purification, has demonstrated neurotoxic properties. However, the mechanisms underlying its neurotoxicity remain inadequately understood. In this investigation, Caenorhabditis elegans were exposed to ACR at concentrations ranging from 250 to 1000 μg/mL and then their locomotor behavior, neuronal development, neurotransmitter concentrations, and gene expression profiles were assessed. Exposure to 250–1000 μg/mL ACR resulted in observable behaviors such as head swiveling and body bending, accompanied by a significant reduction in body size. Furthermore, ACR exposure caused damage to serotonergic, cholinergic, dopaminergic, and glutamatergic neuronal structures. In this context, elevated levels of serotonin, dopamine, acetylcholine, and glutamate were detected, along with notable upregulation of the expression of genes associated with neurotransmitters, including tph-1, cat-4, mod-1, mod-5, cat-1, ser-1, dat-1, dop-1, dop-3, unc-17, cho-1, eat-4, and glr-2. Moreover, ACR exposure elevated reactive oxygen species (ROS), O₂, and H₂O₂ levels while concurrently depleting glutathione (GSH), thereby compromising the antioxidant defense system. This led to a significant upsurge in the expression of genes involved in the nematode ACR detoxification pathway, specifically daf-16, skn-1, mlt-1, sod-3, gst-4, gcs-1, hsf-1, and hsp-16.2. Additionally, Spearman correlation analysis revealed a significant inverse relationship between certain neurotransmitter and antioxidant genes and locomotor activities, highlighting the role of these genes in mediating ACR-induced neurotoxicity in C. elegans. Collectively, this research enhances the understanding of the mechanisms related to ACR neurotoxicity. Full article

Background: Colonic diverticulosis is a common condition, particularly in the elderly population. While dietary habits, obesity, smoking, and physical inactivity contribute to its pathogenesis, emerging evidence highlights a genetic predisposition affecting extracellular matrix (ECM) remodeling, inflammation, and connective tissue integrity. The aim of this systematic review was to summarize genetic determinants of colonic diverticulosis. Methods: The PubMed^® database was searched for original studies in humans. The inclusion criteria were named genetic factor and confirmed diverticulosis. Patients with diverticulitis and diverticular diseases were excluded from this review. Results: Out of 137 publications, 10 articles met the inclusion criteria: six large association studies (GWAS) and four cross-sectional studies. The genes regulating ECM turnover, including TIMP1, MMP3, and MMP9, are involved in diverticulosis development. The TIMP1 (rs4898) T allele has been associated with increased susceptibility, potentially due to its role in ECM remodeling. Similarly, MMP3 (rs3025058) and MMP9 (rs3918242) polymorphisms contribute to altered collagen degradation. The COL3A1 (rs3134646) variant coding modified collagen type III may promote diverticular formation. Other genes, such as ARHGAP15 (rs4662344, rs6736741), affect cytoskeletal dynamics. Identified in GWAS studies, gene candidates may be grouped into blood group and immune system-related genes (ABO, HLA-DQA1, HLA-H, OAS1, TNFSF13, FADD), extracellular matrix and connective tissue genes (COL6A1, COLQ, EFEMP1, ELN, HAS2, TIMP2), signaling and cell communication (BMPR1B, WNT4, RHOU, PHGR1, PCSK5), nervous system and neurodevelopment (BDNF, CACNB2, GPR158, SIRT1, SCAPER, TRPS1), metabolism and transporters (SLC25A28, SLC35F3, RBKS, PPP1R14A, PPP1R16B), lipids and cholesterol (LDAH, LYPLAL1, STARD13), transcription and gene regulation (ZBTB4, UBTF, TNRC6B), apoptosis (FADD, PIAS1), and poorly characterized genes (C1TNF7, ENSG00000224849, ENSG00000251283, LINC01082, DISP2, SNX24, THEM4, UBL4B, UNC50, WDR70, SREK1IP1). Conclusions: There are a number of gene variants that probably predispose to colonic diverticulosis. Detailed characterization of the multigene background of diverticulosis will enable appropriate therapeutic or preventive interventions in the future. Full article

The tomato leafminer, Tuta absoluta, is an invasive pest that poses a significant threat to Solanaceae crops, including tomatoes, potatoes, and eggplants. Its ability to adapt to various environmental conditions, especially cold stress, allows it to survive in regions with fluctuating temperatures. In this study, the molecular response of T. absoluta adults to rapid cold hardening (RCH) under gradually decreasing non-lethal temperatures was investigated. Using RNA-seq, 197 upregulated genes and 626 downregulated genes were identified in response to cold hardening. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that upregulated genes were primarily associated with the cell cycle and cell division, including key genes such as CDC25A, BUB1, ORC2, and PlK1, as well as metal ion transporters like unc-93. Downregulated genes were found to be involved in metabolism and oxidative phosphorylation, including COX4, ATPase_I, and ATP-synt_ab. Weighted gene coexpression network analysis (WGCNA) indicated a positive correlation between cell cycle-related genes and RCH, while metabolic processes, including fatty acid metabolism, were negatively correlated with cold hardening. These findings provide new insights into the transcriptional mechanisms of insect responses to cold stress, and highlight potential targets for environmentally sustainable pest management strategies. Full article

Cellular metabolism must adapt rapidly to environmental alterations and adjust nutrient uptake. Low glucose availability activates the AMP-dependent kinase (AMPK) pathway. We demonstrate that activation of AMPK or the downstream Unc-51-like autophagy-activating kinase (ULK1) inhibits receptor-mediated endocytosis. Beyond limiting dextran uptake, this activation prevents endocytic uptake of human pathogenic enveloped and non-enveloped, positive- and negative-stranded RNA viruses, such as yellow fever, dengue, tick-borne encephalitis, chikungunya, polio, rubella, rabies lyssavirus, and SARS-CoV-2, not only in mammalian and insect cells but also in precision-cut lung slices and neuronal organoids. ULK1 activation inhibited enveloped viruses but not EV71. However, receptor presentation at the cytoplasmic membrane remained unaffected, indicating that receptor binding was unchanged, while later stages of endocytosis were targeted via two distinct pathways. Drug-induced activation of the AMPK pathway reduced early endocytic factor TXNIP by suppressing translation. In contrast, the amounts of Rab5 and the late endosomal marker Rab7 decreased due to translation inactivation and ULK1-dependent proteasome activation within minutes. Furthermore, activation of AMPK hindered the late replication steps of SARS-CoV-2 by reducing viral RNAs and proteins and the endo-lysosomal markers LAMP1 and GRP78, suggesting a reduction in early and late endosomes and lysosomes. Inhibition of the PI3K and mTORC2 pathways, which sense amino acid and growth factor availability, promotes AMPK activity and blocks viral entry. Our results indicate that AMPK and ULK1 emerge as restriction factors of cellular endocytosis, impeding the receptor-mediated endocytic entry of enveloped and non-enveloped RNA viruses. Full article