Introduction Pulmonary arterial hypertension (PAH) secondary to congenital left-to-right shunt heart disease (CL-RSHD) is a life-threatening complication with unclear microbial and metabolic mechanisms. This study investigated gut microbiota and plasma metabolic alterations in CL-RSHD-associated PAH to identify biomarkers and mechanistic pathways. Methods This cross-sectional study included 86 participants: healthy controls (HC, n = 13), CL-RSHD ( n = 46), and CL-RSHD + PAH ( n = 27). Gut microbiota was analyzed using 16S rRNA gene sequencing of the V3–V4 region on 41 fecal samples (HC, n = 9; CL-RSHD, n = 15; and CL-RSHD + PAH, n = 17). Untargeted plasma metabolomics was analyzed on all 86 plasma samples. Microbial diversity, differential taxa (DESeq2), metabolic pathways (OPLS-DA, KEGG), and biomarker potential (ROC curves) were assessed. Dynamic correlations linked microbiota-metabolite interactions. Results CL-RSHD + PAH patients showed preserved α/β-diversity but distinct taxonomic shifts: enriched Lachnoclostridium phocaeense (Firmicutes) and reduced SCFA-producing Anaerostipes. Metabolomics revealed dysregulated steroid biosynthesis, cortisol metabolism, and oxidative stress pathways. Key metabolites, including elevated 5-hydroxymethylcytidine (5-hmC) and γ-L-glutamyl-L-cysteine, and reduced histidine intermediate D-E1IG3P, correlated with PAH severity. Strong microbiota-metabolite interactions (e.g., Lactonifactor -D-E1IG3P, r = 0.82, P < 0.01) suggested a disrupted vascular remodeling axis. Metabolites like ADP-glucose (AUC = 0.94) and 3-phenylpropyl glucosinolate (AUC = 0.92) showed high diagnostic accuracy. Conclusion CL-RSHD-associated PAH involves gut microbial restructuring and metabolic reprogramming linked to immune-inflammatory activation and oxidative stress. The Firmicutes-histidine metabolism axis emerges as a therapeutic target. Despite limitations, this study provides foundational insights into microbial-metabolic drivers of PAH, highlighting novel biomarkers for early diagnosis and intervention.

Background POLR3A gene-related syndrome is a complex genetic disorder with diverse clinical manifestations. Understanding its characteristics is crucial for diagnosis and management. Previous studies have reported various aspects of this syndrome, yet a comprehensive analysis of different Variant sites and their associated phenotypes remains necessary. Case report This study presents a case of POLR3A -related syndrome in a pediatric patient. Symptom onset occurred after 2 years of age, initially presenting with gait disturbance. As the disease progressed, gait instability worsened progressively and was accompanied by dysarthria, intellectual developmental impairment, and tremor. Subsequent neuroimaging revealed multiple intracerebral infectious lesions with abscess formation. Whole-genome sequencing identified a homozygous c.1771-6C>G variant in the POLR3A gene. This variant has been previously reported as pathogenic at this locus; however, the complication of multiple intracerebral infections and abscess formation represents a previously unreported manifestation. It is noteworthy that the parents of the proband were consanguineous (first-degree relatives). Conclusion A review of 60 unrelated probands with POLR3A -related syndrome was conducted based on previously published cases. The analysis revealed no significant sex difference in disease occurrence. The median age of onset was approximately 8 years, with common initial symptoms including gait disturbance and cognitive developmental impairment. Neuroimaging findings indicated cerebral atrophy in 31 cases (66.0%) and white matter hypomyelination in 17 cases (34.7%). Among the reported genetic variants, c.1909 + 22G>A was the most prevalent, identified in 19 families (17.8%), followed by c.1771-6C>G in 9 families (6.4%). Furthermore, patients with different variant sites displayed heterogeneity in initial symptoms, clinical presentations, and imaging characteristics. This comprehensive review enhances the understanding of the phenotypic and genotypic spectrum of POLR3A -related syndrome.

Introduction The killer-cell immunoglobulin-like receptor ( KIR ) gene cluster exhibits complicated diversity in haplotype content, copy-number variation (CNV), and allelic polymorphism. To date, 2,286 distinct KIR alleles have been released in the IPD-KIR Database. However, little is known about the impact of high-resolution-level KIR allelic polymorphisms on leukemia. Our previous study showed that the KIR AA genotype carrying more inhibitory genes conferred differential protection against leukemia in the Chinese Southern Han population. Herein, we hypothesized the impact of KIR alleles in the KIR A haplotype and cognate human leukocyte antigen (HLA) ligand on leukemia. Methods The study cohort included 318 ALL patients, 336 AML patients, and 306 unrelated healthy controls. All the study samples were subject to HLA-A , - B , and - C sequencing-based genotyping (PCR-SBT) and high-resolution KIR genotyping for all the seven functional KIR genes ( KIR2DL1 , KIR2DL3 , KIR2DL4 , KIR3DL1 , KIR3DL2 , KIR3DL3 , and KIR2DS4 ) on the KIR A haplotype. HLA and KIR genotypes were assigned using Assign 4.7.1 software. Results In the present study, our high-resolution genetic analysis revealed protective KIR – HLA interactions in individuals with the KIR AA genotype. The strong inhibitory KIR2DL1*00201 + C2 interaction reduced ALL risk ( p = 0.01), while KIR2DL1*00302 + C2 ( p = 0.008), KIR2DL3*00201 + C1 ( p = 0.03), and KIR3DL1*00501 + Bw4 80I ( p = 0.008) interactions protected against AML ( p < 0.05). However, the functionally weaker inhibitory KIR2DL1*004 + C2 interaction conferred ALL risk ( p = 0.01) in individuals with the KIR Bx genotype. Notably, we found that the allelic polymorphisms of the structure gene KIR3DL3 were associated with the occurrence of leukemia. KIR3DL3*001 tends to confer protection against AML (8.4% vs. 1.3%, p = 0.004, Pc = 0.06), whereas KIR3DL3*009 conferred susceptibility to AML (29.3% vs. 47.1%, p = 0.001, Pc = 0.016). KIR3DL3*001 differs from KIR3DL3*009 by an amino acid substitution of non-charged asparagine (N) to charged histidine (H) in its transmembrane domain, suggesting that this functional variant site KIR3DL3_N300H may play a critical role in the occurrence of leukemia in the Chinese population. Conclusion These data suggest that KIR AA individuals possess strong inhibitory interactions of KIR alleles and HLA , arming KIR AA + NK cells to meditate stronger alloreactivity and cytotoxicity against leukemia cells with lowered HLA expression. Our findings may provide valuable insights into leukemia pathogenesis and better understanding of the immune mechanisms.

Background Maternal nutrition during gestation plays a critical role in fetal muscle development and long-term metabolic programming; however, its persistent molecular effects on offspring skeletal muscle remain unclear. Therefore, the main objective of this study was to investigate the influence of prenatal nutrition on long-term differential gene expression (DGE), differential mRNA transcript expression (DTE), and differential transcript usage (DTU) in skeletal muscle of beef cattle. Methods A total of 126 pregnant Nellore cows were assigned to three dietary treatments: mineral supplementation only (NP), protein-energy supplementation during late gestation (PP), and protein-energy supplementation throughout gestation (FP). At 676 ± 28 days of age, muscle samples were collected from offspring for RNA sequencing. The DGE and DTE analyses were performed using the edgeR package, while DTU was evaluated with the IsoformSwitchAnalyzeR package. Over-representation analysis was conducted using g:Profiler. Results A total of 27,412 genes and 111,185 transcripts, including novel loci and isoforms were identified. Gene-level differences were modest (16 genes), whereas transcript-level analyses revealed stronger effects, with a higher number of significant expression and usage changes across conditions. The FP × NP comparison exhibited the greatest impact on gene expression, with 14 DTEs and 87 DTUs, compared with 12 and 30 in PP × NP, and 10 and three in FP × PP, respectively. Isoform switching was observed in key genes including SLC7A8 , SLC25A30 , SORBS3 , and CDH13 genes, influencing coding potential, functional domains, and mRNA stability, with potential consequences for amino acid transport, cytoskeletal organization, and muscle regeneration. Functional enrichment analyses highlighted significant metabolic pathways related to amino acid and biotin metabolism, intracellular trafficking, and immune regulation. Conclusion Overall, prenatal nutrition, particularly protein-energy supplementation throughout gestation in comparison to mineral supplementation, modulates offspring muscle mainly through transcript usage and splicing, suggesting long-term adaptive mechanisms beyond gene-level regulation.

Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is traditionally recognized as a risk factor for drug- or infection-induced hemolytic anemia. Emerging evidence implicates potential roles of G6PD in neurodevelopment, yet its association with rare neurological disorders remains underexplored in population-based genetic studies, especially within the Chinese population. Methods We conducted a retrospective case-control study utilizing whole-exome sequencing (WES) data from a Chinese cohort. Six most prevalent pathogenic G6PD variants in China were screended in children with rare neurological disorders (n = 211) and in controls without neurological involvement (n = 202). Genotype and carrier frequency comparisons were performed. Stratified analyses were performed based on diagnostic certainty and the presence of de novo mutations. Multivariable logistic regression was employed to calculate sex-adjusted odds ratios (ORs) to control for potential sex-related confounding. Results After adjusting for sex, the overall carrier rate of pathogenic G6PD variants was significantly higher in patients with neurological disorders than in controls (adjusted OR = 2.44, 95% CI: 1.18–5.06, p = 0.014). Further comparisons across specific groups revealed distinct patterns: affected male patients had a higher carrier rate than their own unaffected fathers (OR = 2.30, 95% CI: 1.08–4.91, p = 0.043), and mothers of case patients showed a higher carrier rate than mothers of controls (OR = 2.03, 95% CI: 1.09–3.78, p = 0.030). The variants NM_001042351.3: c.1376G>T (G6PD Canton) and NM_001042351.3:c.1388G>A (G6PD Kaiping) were the most prevalent across all groups. Conclusion This population-based genetic analysis provides preliminary evidence that G6PD deficiency may be a underrecognized genetic risk factor for rare neurological disorders in Chinese children. The findings suggest a potential maternal genetic contribution and indicate that the phenotypic spectrum of G6PD deficiency may extend beyond hematological manifestations to include neurodevelopmental vulnerability. Important limitations include the lack of functional validation and the use of a clinical control group. Further prospective studies incorporating G6PD enzyme activity assessment and functional investigations are warranted to elucidate the underlying mechanisms.

Gastroesophageal reflux disease (GERD) exhibits significant epidemiological comorbidity with psychiatric disorders, yet their shared genetic architecture remains poorly characterized in East Asian populations. Leveraging ancestry-specific genome-wide association study (GWAS) summary statistics from East Asian cohorts, we employed linkage disequilibrium score regression and conditional false discovery rate (condFDR) approaches to investigate cross-trait genetic enrichment between GERD and major psychiatric disorders, including major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BIP). We identified significant genetic correlations between GERD and both MDD (r g = 0.49, P = 0.03) and SCZ (r g = 0.25, P = 0.02), but not with BIP. Through condFDR analysis, two novel loci were discovered: rs3980178 near MEIS1 (associated with GERD-MDD pleiotropy) and rs9844126 near ZBTB20 (associated with GERD-SCZ pleiotropy). These loci are implicated in neurodevelopment, autonomic regulation, and neural circuit formation, providing mechanistic insights into the gut-brain axis. Our findings demonstrate that cross-trait genetic enrichment significantly enhances locus discovery for GERD in underpowered East Asian GWAS and reveal ancestry-specific genetic links between gastrointestinal and psychiatric phenotypes.

Background Global efforts to control and eventually eliminate malaria have been less effective for Plasmodium vivax relative to Plasmodium falciparum due to its unique biology, including dormant liver stages that cause later relapse, and earlier commitment to transmission stages. After the nationwide distribution of long-lasting insecticide treated nets (LLIN) in Papua New Guinea (PNG), P. vivax initially reduced to low prevalence, but again resurged to levels similar to those before LLIN distributions. Method To explore changes in P. vivax population structure and identify sources of resurgence over this period, we applied a previously validated genome-wide SNP barcode to genotype 336 P. vivax isolates obtained from serial cross-sectional surveys conducted over a decade in East Sepik (2005, 2012, 2016) and Madang Province (2006, 2010, 2014). Results Population genetic analyses of the resulting parasite genotypes revealed contrasting spatiotemporal patterns between the two provinces. In Madang, the complexity of infection, genetic diversity, and population structure varied with prevalence, with a possible population bottleneck and early clonal expansion at low transmission, and rapid recovery of the population with resurgence. In East Sepik, there was a less dramatic impact on the parasite population after prevalence decline, and ongoing transmission of multiple residual lineages throughout the study period. P. vivax decline was also accompanied by an increase in genetic differentiation between the two areas, which reduced with resurgence suggesting changes in parasite migration between areas associated with prevalence. Conclusion The earlier implementation of LLIN in East Sepik, smaller rebound, heterogeneity in transmission and relative isolation, compared to Madang may have contributed to these differing patterns. The results demonstrate that long term sustained control efforts are essential to make a lasting impact on the P. vivax population, and that SNP barcodes can provide valuable insights into parasite transmission dynamics as a result of control efforts.

Accurate identification of 5-methylcytosine (5 mC) sites in promoter regions is crucial for understanding epigenetic regulation, but experimental methods remain costly and time-consuming, highlighting the need for reliable computational prediction tools. While existing deep learning approaches, such as BiLSTM-based, Transformer-based, and pretrained language models, have advanced the field, opportunities remain for further improvements in capturing long-range dependencies and handling imbalanced genomic data. Here, we present TCN-5mC, a deep learning model that integrates Temporal Convolutional Networks (TCN) inspired block with Bidirectional Gated Recurrent Units (BiGRU) and employs hybrid One-Hot and Nucleotide Chemical Property feature encoding. This architecture is designed to more effectively model both extended sequence contexts and local patterns. The model achieves high predictive performance on imbalanced datasets from lung cancer cell lines, with AUC values of 0.967 and 0.989 on two independent test sets, outperforming existing methods in specificity, accuracy, MCC, and AUC. The model thus provides a robust, high-throughput computational tool for 5 mC site prediction, with promising potential for epigenetic research and biomarker discovery.