In the symbiotic interaction between legumes and rhizobia, the induction of peanut super-nodulation by Type II Bradyrhizobium strains represents a relatively unusual phenomenon, yet the underlying regulatory mechanisms remain largely unclear. This study investigated the roles of both nod genes and chromosomal genes of the Type II strain B. guangxiense CCBAU 53363T (II-53363) in regulating peanut nodulation. First, all Type II strains harbor identical plasmid-borne nod genes, which are distinct from their Type I homologs. Knockout and complementation of nodB and nodC genes resulted in the loss and restoration, respectively, of the nodulation phenotype in II-53363. Second, through Tn5 transposon insertion along with targeted gene knockout and complementation, we identified seven chromosomal genes that positively regulate peanut super-nodulation. Disruption of these genes affected the metabolic capacity and EPS production of strain II-53363. Nevertheless, given their absence in some Type II strains and their high sequence similarity to Type I homologs, these chromosomal genes are likely to play an indirect role. This study demonstrates that the plasmid-borne nod genes in Type II bradyrhizobia strains are essential for peanut nodulation, although their specific contribution to super-nodulation remains to be demonstrated. Furthermore, it reveals the indirect roles of multiple chromosomal genes in regulating peanut super-nodulation.
Acute myeloid leukemia (AML) is an aggressive and molecularly heterogeneous hematologic malignancy associated with poor clinical outcomes, particularly in elderly and high-risk patients. Increasing evidence suggests that metabolic reprogramming plays a critical role in leukemia progression, immune dysregulation, and therapeutic resistance. However, the prognostic value of metabolism-associated molecular networks in AML remains insufficiently understood. This study aimed to identify metabolism-related hub genes involved in AML progression and to establish a robust prognostic signature for survival prediction. Integrated transcriptomic analyses were performed using multiple Gene Expression Omnibus datasets and the TCGA-LAML cohort. Weighted gene co-expression network analysis identified AML-associated gene modules, followed by protein-protein interaction and functional enrichment analyses. Metabolic-related hub genes were selected through integration with curated metabolic gene sets. A prognostic model was subsequently developed using univariable and least absolute shrinkage and selection operator (LASSO) Cox regression analyses and validated in independent cohorts. A four-gene metabolic signature consisting of CYP4F3, PFKL, G6PD, and DNMT3A was identified as an independent predictor of overall survival. Patients in the high-risk group showed significantly poorer survival outcomes compared with low-risk patients (p < 0.0001). The prognostic model demonstrated stable and reliable predictive performance across training, testing, and validation cohorts. Functional enrichment analyses revealed that the identified genes are closely associated with metabolic pathways, immune-related signaling, and leukemic microenvironment remodeling. Notably, increased expression of G6PD and PFKL was associated with adverse prognosis, supporting the contribution of altered glycolysis and redox homeostasis to AML pathogenesis. Our findings establish a metabolic-based prognostic signature with strong predictive utility in AML. The identified metabolic hub genes provide insight into the interaction between metabolic dysregulation and immune remodeling in leukemia and may serve as promising biomarkers for risk stratification and potential therapeutic targets.
This study investigates the molecular mechanisms of renal clear cell carcinoma (RCC) induced by Aristolochic acid A (AAA) using machine learning, deep learning, and molecular docking approaches. To identify AAA target genes associated with RCC, differential expression analysis was performed on multiple datasets. Network toxicology, machine learning, deep learning, and molecular docking were used to explore the binding interactions between AAA and target proteins. The top candidate gene was validated using molecular dynamics simulation and in vitro Western blot assays. A total of 74 genes were identified as potential targets in AAA-induced RCC. Subsequent machine learning analysis identified seven core genes as key regulators of RCC. Deep learning classification further highlighted five of these seven genes, including PYGL, ADH1B, PTGS1, EDNRA, and AURKA. Additionally, molecular docking simulations revealed strong binding affinities between AAA and these target proteins. Molecular dynamics simulation demonstrated the binding stability of the AAA-PYGL complex, and in vitro studies highlighted PYGL as a potential target of AAA. Elevated expression of PYGL was observed in both 786-O and AAA-induced HK-2 cells. Moreover, treatment with CP-91149 (a PYGL inhibitor) or PYGL knockdown restored the expression of E-cadherin, an epithelial-mesenchymal transition (EMT) marker, in HK-2 cells. By combining advanced computational methods with in vitro studies, this work elucidates a key toxicity mechanism of AAA in RCC. Our approach provides a feasible and efficient framework for toxicological studies, offering significant value for toxicologists with limited access to clinical specimens.
Oilseed rape (Brassica napus L.) is a major oil crop, and both silique and seed size are critical determinants of yield. In Arabidopsis thaliana, mutation of the ABORTED GAMETOPHYTE 1 (AOG1) gene leads to severe defects in gametophyte development and a pronounced reduction in silique length. However, the function of AOG1 homologs in rapeseed remains uncharacterized. In this study, four homologous copies of AOG1 were identified in B. napus: BnaAOG1.A03, BnaAOG1.A10, BnaAOG1.C03, and BnaAOG1.C09. Then a systematic analysis that considered the physiochemical properties, evolution, conserved motifs, gene structure, and cis-regulatory elements of BnaAOG1s family members was conducted. Utilizing the CRISPR/Cas9 system, two of these copies, BnaAOG1.A03 and BnaAOG1.C03, were targeted, and homozygous double mutants were generated. Unlike the Arabidopsis ortholog, the BnaAOG1s were specifically expressed during seed development. Phenotypic evaluation revealed that the double mutants did not exhibit significant changes in silique length, seed number per silique, or thousand-seed weight compared to the wild type. These results indicate that BnaAOG1.A03 and BnaAOG1.C03 are not individually essential for silique and seed development in B. napus. Their functions may be compensated by other homologous copies or have undergone divergence during polyploidization. This investigation provides a valuable case for functional analysis of homologous genes in polyploid crops.
Pulmonary arterial hypertension (PAH) is characterized by high blood pressure in the lungs due to obstruction of small pulmonary arteries. Its exact cause is unknown. We aimed to identify specific genes, signaling pathways, and microRNAs (miRNAs) as novel diagnostic biomarkers for PAH progression. We analyzed differentially expressed genes (DEGs) from PAH and control samples in the GSE144932 and GSE131793 datasets using GEO2R. We performed GO enrichment and KEGG pathway analyses. miRNAs targeting common DEGs were identified using miRDB and TargetScan. MYLK and CLU were upregulated in both datasets, implicating calcium signaling and coagulation pathways, respectively. In silico analysis showed that miR-9-5p, miR-3179, and miR-580-3p potentially target MYLK; miR-369-3p potentially targets CLU; and miR-499a-5p potentially targets both. This study identifies MYLK and CLU, and their associated miRNAs (miR-9-5p, miR-3179, miR-580-3p, miR-499a-5p, and miR-369-3p), as potential noninvasive diagnostic biomarkers for PAH, requiring experimental validation.
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Transcription is an inherently dynamic and stochastic process that often occurs in bursts, governed by gene-gene regulatory interactions and thereby driving cell-to-cell heterogeneity. However, a genome-wide, mechanistic understanding of how regulatory networks globally shape transcriptional bursting dynamics remains lacking. Here, we present BurstLink, an interpretable and tractable statistical-mechanistic framework that simultaneously infers coupled regulatory interactions and transcriptional bursting kinetics at the genome-wide scale from single-cell data. BurstLink introduces reweighted mutual information to quantify regulatory strength as network edge weights, while jointly inferring regulatory directionality and interaction type for each gene pair within a unified mechanistic model of transcriptional bursting. Applied to mouse embryonic fibroblasts data, BurstLink reveals several genome-wide regulatory mechanisms on transcriptional bursting: downstream target genes exhibit higher burst frequency and gene-expression variability than upstream transcription factor genes; stronger transcription factor binding affinity is associated with lower burst frequency and higher burst size of target genes. Notably, positive regulation primarily enhances the burst frequency and gene-expression variability in target genes, in contrast to negative regulation. In summary, BurstLink deciphers multiple general principles of global transcriptional dynamics, providing novel biological insights into cell fate decisions.
Colitis-associated colorectal carcinoma (CAC) arises in the setting of long-standing inflammatory bowel disease and shows clinicopathological and molecular differences from sporadic colorectal carcinoma. Loss of SATB2 expression is increasingly recognized in a subset of CACs, but its biological significance remains unclear. This study aimed to investigate gene expression profiles of CACs, focusing on differences between SATB2-negative and SATB2-positive tumors. Formalin-fixed, paraffin-embedded CAC samples stratified by SATB2 immunohistochemical expression status underwent bulk RNA sequencing. Differential expression analysis identified 580 genes with significant differences between the two groups. SATB2 expression was markedly reduced in the SATB2-negative group, confirming appropriate stratification. SATB2-negative CACs showed upregulation of lineage-associated and mucin-related genes, including MUC16, CLDN18, and MUC5AC, with MUC16 showing the most prominent increase. MUC16 is a membrane-tethered mucin containing CA125 epitopes. Immunohistochemical validation demonstrated that MUC16 expression was mainly confined to the invasive components of a subset of SATB2-negative CACs, with minimal expression in dysplastic or non-invasive epithelium. These findings suggest that MUC16 expression is more closely related to tumor invasion than to early tumorigenesis. SATB2-negative CACs represent a biologically distinct subset characterized by altered differentiation and upregulation of invasion-associated markers such as MUC16. Loss of SATB2 and gain of MUC16 expression appear to occur within the same tumor lineage, suggesting coordinated phenotypic changes during tumor progression. Overall, these findings support a role for SATB2 loss in colitis-associated tumorigenesis and identify MUC16 as a potential marker of invasive progression in CAC.
Esherishia coli (E. coli) and Salmonella species (spp.) pose serious public health threats because of their ability to contaminate poultry products and spread through farm environments. This study assessed the prevalence, antimicrobial resistance, and virulence gene profiles of E. coli and Salmonella spp. A cross-sectional study was conducted, involving the random collection of 400 samples from broilers, drinker's water, feedstuff, broiler litter, and poultry workers in broiler farms. Furthermore, a structural questionnaire was administered to poultry workers to identify potential risk factors and assess the public health implications associated with pathogen transmission. The antimicrobial and anti-virulence activities of melanin against E. coli and Salmonella enteritidis (S. enteritidis) were also assessed. E. coli and Salmonella spp. were frequently isolated from broiler farms, with a predominance of. E. coli serotype O111:H2 (25.64%) and S. enteritidis strains (30.4%) among the total examined samples. Multivariate analysis revealed that poultry workers, who had symptoms worsened after starting farm work and those did not use of personal protective equipment (PPE) were strongly associated with E. coli positivity. E. coli isolates exhibited full resistance to ampicillin (AMP) and tetracycline (TET), whereas Salmonella spp. isolates showed full resistance to AMP. Most of the examined E. coli isolates (71.8%) and the Salmonella spp. isolates (60.9%) were multidrug resistant (MDR) strains. In addition, 28.2% of E. coli isolates and 30.4% of Salmonella spp. isolates were -XDR. The stx1, stx2, and hylA virulence genes were respectively detected in 69.2%, 69.2%, and 74.4% of the examined E. coli isolates, whereas the sopB and hilA virulence genes were identified in all Salmonella spp. isolates. One-way repeated-measures analysis of variance (ANOVA) showed that natural melanin treatment significantly reduced the expression of virulence genes in both E. coli and S. enteritidis isolates. The predominance of E. coli serotypes O111 and S. enteritidis highlights the need for improved hygiene practices and zoonotic diseases awareness to limit pathogen transmission in poultry farms. The detection of MDR and XDR strains e emphasizes the consequences of antimicrobial misuse and its implications for public health. Melanin has potential antimicrobial and anti-virulence activities against E. coli and S. enteritidis.
Chloroplast genomes are widely used in phylogenetic and evolutionary studies due to their conserved structure and maternal inheritance. However, a comprehensive pan-chloroplast analysis across the genus Hordeum remains lacking. In this study, we assembled and annotated 43 chloroplast genomes representing 12 Hordeum species, together with 18 chloroplast genomes from other Poaceae species, to investigate structural variation, repeat sequences, codon usage, RNA editing, selective pressure, and nucleotide diversity. All chloroplast genomes exhibited the typical quadripartite structure with genome sizes ranging from 136,461 bp to 137,149 bp in Hordeum. The lengths of LSC and IR regions showed strong positive correlations with chloroplast genome size (r = 0.853 and 0.857, respectively). IR boundaries were highly conserved within Hordeum, whereas three distinct boundary types were identified across Poaceae. Pentanucleotide simple sequence repeats (SSRs) were universally present in Hordeum but absent in some other Poaceae species, representing a candidate Hordeum-enriched marker pending broader validation. Based on the newly assembled chloroplast genomes of Hordeum, the phylogenetic relationships were reappraised. A total of 66 protein-coding genes contained RNA editing sites, with ndhB harboring the most edits in Hordeum. All examined protein-coding genes showed Ka/Ks values below 1, while ribosomal subunit genes exhibited the highest interspecific variation in Ka/Ks. Hordeum bulbosum displayed the highest intraspecific nucleotide diversity and haplotype diversity, whereas cultivated Hordeum vulgare showed extremely low diversity. Several hypervariable regions were identified as candidate DNA barcodes. This pan-chloroplast genome study provides new insights into the structural and evolutionary dynamics of Hordeum chloroplast genomes and offers valuable genomic resources for phylogeny, germplasm identification, and adaptive evolution in the genus.
Oral cancer (OC) remains a therapeutic challenge due to limited validated targets. Cis-pQTLs from the deCODE cohort (n = 35,559) were harmonized with OC-GWAS (3547 cases and 691,466 controls) meta-data through a two-sample Mendelian randomization (MR) framework. Robust Validation included replication in the UKB-PPP dataset, colocalization analysis, SMR (Summary-based MR), HEIDI (Heterogeneity in Dependent Instruments) tests, and eQTL evidence. Additional analyses encompassed protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes annotation (KEGG)/Gene Ontology (GO) pathway enrichment, mediation, Druggability and side effects analysis. Oral cancer (OC) remains a therapeutic challenge due to limited validated targets. Cis-pQTLs from the deCODE cohort (n = 35,559) were harmonized with OC-GWAS (3547 cases and 691,466 controls) meta-data through a two-sample Mendelian randomization (MR) framework. Robust Validation included replication in the UKB-PPP dataset, colocalization analysis, SMR (Summary-based MR), HEIDI (Heterogeneity in Dependent Instruments) tests, and eQTL evidence. Additional analyses encompassed protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes annotation (KEGG)/Gene Ontology (GO) pathway enrichment, mediation, Druggability and side effects analysis. To experimentally corroborate the MR findings, the quantitative real-time PCR (qRT-PCR) was performed to examine the mRNA expression levels of selected genes in oral squamous cell carcinoma (OSCC) cell lines (SCC-9 and SCC-25) and normal human oral epithelial cells (HOEC). Multi-omics MR identified TNFSF8 (p = 2.49 × 10-8, OR = 1.24) as a Tier 1 target. XXYLT1 (p = 1.41 × 10-4, OR = 1.34) and HSD17B14 (p = 0.04, OR = 2.00) achieved Tier 2. eQTLs-pQTLs Relationship revealed XXYLT1 expression explained 24.65% of risk through elevated plasma protein levels, TNFSF8 eQTLs mediated 72.80% via protein upregulation. Mediation analyses on CD4 on HLA DR+ CD4+ T cells (7.18%) contributed to the risk of OC by upregulating plasma HSD17B14, while daily cigarette consumption (20.63%) and CD8+ T cell percentage leukocytes (12.06%) contributed to the risk of OC by upregulating plasma TNFSF8. Drug safety assessments highlighted systemic TNFSF8 inhibition may elevate skin cancer risk. Multi-omics MR prioritizes TNFSF8 as a therapeutic target for oral cancer. Multi-omics MR identified TNFSF8 (p = 2.49 × 10-8, OR = 1.24) as a Tier 1 target. XXYLT1 (p = 1.41 × 10-4, OR = 1.34) and HSD17B14 (p = 0.04, OR = 2.00) achieved Tier 2. eQTLs-pQTLs Relationship revealed XXYLT1 expression explained 24.65% of risk through elevated plasma protein levels, TNFSF8 eQTLs mediated 72.80% via protein upregulation. Mediation analyses on CD4 on HLA DR+ CD4+ T cells (7.18%) contributed to the risk of OC by upregulating plasma HSD17B14, while daily cigarette consumption (20.63%) and CD8+ T cell percentage leukocytes (12.06%) contributed to the risk of OC by upregulating plasma TNFSF8. Drug safety assessments highlighted systemic TNFSF8 inhibition may elevate skin cancer risk. qRT-PCR confirmed significant upregulation of XXYLT1 and HSD17B14 in both SCC-9 and SCC-25 cell lines (p < 0.001), which is consistent with MR predictions. TNFSF8 was not reliably detected in these cancer cells, aligning with its proposed immune-mediated mechanism. Multi-omics MR prioritizes TNFSF8 as a therapeutic target for oral cancer. qPCR validation confirms the dysregulation of XXYLT1 and HSD17B14, while findings regarding TNFSF8 underscore its immune origin. These findings warrant further functional studies.
Sheep ovarian tissue is a valuable model for studying folliculogenesis, cellular interactions, and fertility preservation strategies. The impact of culture duration, culture conditions, and cryopreservation techniques on the transcriptome of ovarian tissue remains incompletely understood. Ovarian fragments were subjected to conventional or bioreactor culture for up to 12 weeks, with or without prior cryopreservation by slow freezing or vitrification. RNA was extracted at multiple time points and analyzed using RNA sequencing to identify differentially expressed genes and enriched pathways. Prolonged conventional culture induced metabolic reprogramming, increased glycolytic and biosynthetic activity, and triggered stress, inflammatory, and even apoptosis pathways, whereas bioreactor culture limited stress responses and better-preserved cell proliferation and development. Ovarian tissue culture in bioreactor allowed for extended in vitro culture periods of up to 12 weeks, whereas conventional culture did not allow survival of the samples. Cryopreservation had minor effects on gene expression, with slow freezing and vitrification yielding largely similar transcriptomic profiles. Folliculogenesis-related genes showed a trend towards downregulation. Bioreactor culture seems to provide a more physiologically relevant environment for maintaining ovarian tissue viability and function, and cryopreservation seems to have limited impact on the transcriptome compared to culture conditions. These findings offer valuable insights for optimizing fertility preservation and translational approaches in reproductive medicine.
The Culex pipiens complex includes major mosquito vectors involved in the transmission of West Nile virus and filarial nematodes. In Türkiye, particularly in the Black Sea region, members of this complex are widely distributed, yet mitogenome-scale data from local populations remain limited. Here, we sequenced, assembled, and annotated the complete mitochondrial genomes of five Culex pipiens form pipiens isolates collected from different provinces along the Turkish Black Sea coast. Following the current taxonomic interpretation, subspecies-level names were avoided, Cx. pallens was treated as a species, and molestus was treated as a form of Cx. pipiens. The newly generated mitogenomes were highly conserved, ranging from 15,602 to 15,604 bp, and each contained the typical set of 37 mitochondrial genes with a strong A + T bias (~78.2%). Comparative analyses showed a conserved gene order and a characteristic culicid mitogenome architecture. Expanded comparisons across the broader Cx. pipiens complex dataset showed that mitochondrial diversity was concentrated in selected loci, particularly COX1, ND2, COX3, CYTB, ND5, and 12S rRNA, as well as in terminal regions associated with the A + T-rich control region. Phylogenetic analyses based on the concatenated sequences of 13 mitochondrial protein-coding genes and two rRNA genes showed that the Turkish isolates do not form a single exclusive mitochondrial lineage, but are distributed across different parts of the ingroup together with other members of the Cx. pipiens complex, including Cx. pipiens form molestus, Cx. pallens, and Cx. quinquefasciatus. These findings support the view that mitochondrial genomes in this complex primarily reflect maternal lineage history and may be influenced by introgression and incomplete lineage sorting rather than sharply discrete taxonomic or form-level boundaries. Overall, the mitogenomic resources generated in this study provide a useful regional reference for future comparative and evolutionary studies of the Cx. pipiens complex.
In heterotrophic plants, the loss of photosynthesis is often associated with plastid genome (ptDNA) reduction, although the extent of genome decay varies widely among lineages and may culminate in complete genome loss. Of the multiple transitions to heterotrophy among angiosperms, the ptDNA status remains poorly defined in lineages such as the endoparasitic Mitrastemonaceae (Ericales). Adopting a panplastome perspective, we characterized genomic variation across Mitrastemon yamamotoi individuals, assembling two complete circular ptDNAs and re-evaluating all available genomic resources for the species. Our results reveal a highly minimized ptDNA (18-26 kb) with elevated AT content (>77%) and loss of the typical quadripartite architecture. The M. yamamotoi panplastome exhibits remarkable structural stability and collinearity among individuals. The reduced plastid gene set comprises 26 genes, including accD, infA, clpP, ycf1, ycf2, and the essential tetrapyrrole precursor trnE-UUC. Root-to-tip substitution-rate analyses of 13 conserved protein-coding genes revealed elevated synonymous and nonsynonymous substitution rates in M. yamamotoi relative to photosynthetic angiosperms. However, dN/dS analyses showed that the retained protein-coding genes evolve under purifying selection (ω < 1), indicating persistent functional constraint. Furthermore, transcriptomic analysis identified a nearly complete set of nuclear-encoded plastid-targeted DNA-RRR factors, with the notable exception of the MUTS2 surveillance system and two photolyases. The convergent loss of MUTS2 homologs in M. yamamotoi and holoparasitic Balanophoraceae may be linked to shared plastome features (genome compaction, accelerated substitution rates, and severe AT bias). In contrast, the shared loss of the photolyases CRY3 and UVR3 likely results from relaxed selection pressure associated with an underground lifestyle. Deciphering the M. yamamotoi panplastome provides a definitive genomic framework for understanding plastid evolution within the endoparasitic Mitrastemonaceae.
DNA methylation is important to maintain genome stability, but alterations in genome-wide methylation patterns can produce widespread genomic effects, with the potential to facilitate rapid adaptation. Here we investigate DNA methylation evolution in Arabidopsis thaliana during its colonization of the drought-prone Cape Verde Islands (CVI). We identified three high-impact changes in genes linking histone modification to DNA methylation that underlie variation in DNA methylation within CVI. We show that gene body methylation is reduced in CVI relative to the Moroccan outgroup due to a 2.7-kb deletion between two VARIANT IN METHYLATIONgenes (VIM2and VIM4), causing aberrant expression of the VIM2/4 homologues. Disruptions of CHROMOMETHYLASE 2 (CMT2) and a newly identified DNA methylation modulator, F-BOX PROTEIN 5 (FBX5), which we validated using CRISPR mutant analysis, contribute to DNA methylation of transposable elements within CVI. Overall, our results reveal rapid methylome evolution driven largely by high-impact variants in three genes.
This study analyzed SARS-CoV-2 surveillance results in the urban wastewater of Zhengzhou, central China, to explore its association with community COVID-19 incidence and evaluate its early warning performance across different SARS-CoV-2 variant epidemic phases. Weekly monitoring was conducted at five representative wastewater treatment plants from May 2024 to July 2025, yielding 325 samples. Viral loads of the ORF1ab and N genes were quantified using RT-qPCR, with statistical analyses performed included Spearman correlation, ANOVA, and cross-correlation function. The two target genes showed high consistency and significant positive correlation with 14-day cumulative COVID-19 incidence. However, significant variant and marked heterogeneity was observed across variant periods and gene targets, with the N gene outperforming ORF1ab in stability. Wastewater viral signals preceded clinical cases by one week. These findings supported the application value of wastewater-based epidemiology in post-pandemic COVID-19 surveillance, indicate its potential early warning capacity, and reveal notable heterogeneity in surveillance performance across viral variants and target genes.
Chemotherapy-related toxicities remain a major barrier to optimal outcomes in pediatric cancer care in low-resource settings. Genetic variation in drug-metabolizing and transport pathways contributes to interindividual differences in toxicity risk; however, pharmacogenomic data from African pediatric populations are limited. This study assessed the distribution of selected pharmacogenomic variants and chemotherapy-related toxicities profiles in Tanzanian children with cancer. A cross-sectional study was conducted among 155 pediatric patients with cancer (1-17 years) receiving chemotherapy at Bugando Medical Centre, Tanzania. Clinical data, clinician-reported toxicities, and patient-reported outcomes were collected. Eleven pharmacogenomic variants in genes involved in drug metabolism, transport, and detoxification pathways (CYP3A5, SLC19A1, TPMT, NUDT15, GSTP1, NCF4, CYBA, and CEP72), selected based on prior evidence of functional relevance and reported associations with chemotherapy response, were genotyped using the Agena MassARRAY® platform. Toxicities were graded using CTCAE version 5.0. Hematologic toxicities, including anemia (50.3%) and leukopenia (37.4%), and mucocutaneous toxicities such as alopecia (38.1%) and oral ulcers (24.5%) were common. Reduced muscle strength was observed in 78.1% of patients. Reduced-function CYP3A5 variants were frequent (CYP3A5*6: 38.1%; CYP3A5*3: 27.7%). Variants in GSTP1 rs1695 (MAF 0.46), CYBA rs4673 (MAF 0.44), and SLC19A1 rs1051296 (MAF 0.49) demonstrated substantial variability, indicating potential interindividual differences in drug metabolism and transport. However, no genotype-toxicity associations were assessed in this study. This study provides baseline data on pharmacogenomic variability among Tanzanian pediatric patients with cancer. The observed genetic diversity in pharmacogenes involved in drug metabolism and transport may be relevant to variability in chemotherapy-related toxicities, as reported in previous studies. These findings highlight the need for further research to evaluate genotype-toxicity relationships and to inform the future integration of pharmacogenomics into pediatric oncology care in resource-limited settings.
Leaf spots caused by Curvularia lunata infection pose a significant threat to global maize production. Although resistance gene breeding faces challenges due to pathogen evolution, the plant microbiome has emerged as a key modulator of disease resistance. However, the mechanisms via which plant genes regulate phyllosphere metabolites to recruit beneficial microbes remain poorly understood. Here, we combined gene mapping, metabolomics, microbiome analyses, cytological analysis, and in vitro and in vivo experiments to investigate the disease resistance mechanism of ZmHPATR1. We first identified that the loss-of-function mutation in ZmHPATR1 significantly increased the levels of fumaric acid, folic acid, and tetrahydrofolic acid in the leaves, leading to the enrichment of the genus Sphingomonas. We further demonstrated that the extracellular polysaccharide, welan gum, biosynthesized by Sphingomonas, effectively inhibited C. lunata growth and disrupted its cell structure. These results enable us to comprehensively understand the complicated mechanisms of plant resistance to disease through a four-level regulatory network that links plant genes, metabolites, microbes, and pathogens. Our findings provide new strategies for targeted microbiome-based disease-resistant breeding and the development of novel biopesticides for maize.
In vertebrate adaptive immune systems, somatically diversified antigen receptors assume a central role in self/nonself discrimination. Attesting to the presence of a unique but unknown selective environment at early stages of vertebrate evolution, this facility emerged twice, in the ancestors of jawless and jawed vertebrates. Thus, the molecular structure of incomplete antigen receptor genes and their mode of assembly into functional genes are different in the two sister groups of vertebrates. It appears that adaptive immunity evolved in steps, trading immunologically favorable diversity of antigen receptor repertoires against the inherent risks of potentially destructive self recognition. Initially, the associated quality control mechanisms were largely cell-autonomous and grounded in the evolutionarily selected sequence composition of individual components available for assembly. At later stages, diversity increased in lock-step with emerging cell-nonautonomous quality control strategies: primary lymphoid organs spatially and temporally coupled repertoire development and assessment for self reactivity; regulatory cell types emerged to keep self reactive clones in check in the periphery. In this review, we discuss how comparative studies of vertebrate species situated at key positions in the phylogenetic tree have revealed traces of the evolutionary past of adaptive immune systems.
Deep learning models based on both distant protein sequence homology and genetic neighbourhood context searches predicted that 1.5% of bacterial genes or 30 genes per E. coli genome represent anti-phage systems (APS); many are colocalized on defence islands or are found on mobile DNA elements. Thousands of APS thus remain to be defined molecularly. Selected recent examples highlighting an astonishing molecular diversity of these defence systems are described in this editorial. The mechanisms include allosterically regulated dGTPase responding to competing nucleotide signals (Clover); bacterial defence systems activated by phage anti-defence manoeuvres (Panoptes); a prophage encoded tRNA nuclease activated by a phage tail tip protein (HepS); a helicase-nuclease complex that scans for ssDNA 3' overhangs created by phage DNA transaction (Hachiman); and systems that cleave free ends of linear DNA (Shedu). Systems were described that synthesize template-free poly-dA chains which are degraded by a phage exonuclease thereby activating an ion channel (Hailong). Several systems interfere with phage DNA injection into the cell, for example, a cell membrane associated protein complex inhibiting injection (KIWA); or destroying phage DNA at injection (SNIPE); or a complex membrane motor system that senses phage DNA injection and activates nuclease effectors (Zorya). Other systems consist of a single pore building protein that combines sensor and effector functions (Rip1) or degrade NAD+ (Cat1). Defence-associated reverse transcriptase (DRT) preceded by non-coding RNA (ncRNA) come in different forms: in DRT2 a rolling circle reverse transcription leads to an endless protein inducing cell dormancy; in DRT3 a mixed templated and untemplated repeat DNA synthesis becomes cytotoxic in presence of a phage protein; DRT9 synthesizes a polyA strand that might sequester a phage protein needed for DNA replication. Striking are bacterial APS that resemble innate immune reaction directed against viruses in animals (gasdermin, Argonaute, RAZR, Schlafen, Thoeris 2, ubiquitin-like proteins) pointing to an ancient origin.