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Genetic analysis of complex traits is crucial for elucidating disease mechanisms and biological inheritance processes. However, traditional Genome-wide Association Study (GWAS) for single trait often fail to capture the synergistic effects of genetic loci on multiple traits. This study proposes a method for analyzing the association between multiple traits and gene regions based on Shannon information entropy. Innovatively, Shannon information entropy is introduced to integrate gene region information as genetic entropy, thereby constructing an Inverse Shannon Entropy-Multi-Trait Association Analysis of Gene Region genetic model (InvSE-MTAGR). Furthermore, a partial regression test is applied to the model to establish the Inverse Partial Shannon Entropy-Multi-Trait Association Analysis of Gene Region method (InvPSE-MTAGR). When performing multi-trait analysis with InvSE-MTAGR, the method achieved statistical significance by accumulating minor effects, thereby enhancing the ability to identify pleiotropic gene regions. The simulation results showed that the proposed multi-trait gene region association analysis method performed well in terms of both Type I error rate control and statistical power. Leveraging tomato and sorghum datasets for validation, the proposed multi-trait gene region association analysis method based on Shannon information entropy accurately pinpointed most of the gene regions harboring candidate genes. The study reveals the advantage of multi-trait method in integrating weak-effect pleiotropic signals and capturing the correlation among traits, which provides an efficient theoretical tool for dynamic analysis of complex multi-trait genetic networks and multi-target collaborative breeding of crops.
Objective: To investigate the prognostic value of CEBPA gene mutations in patients with newly diagnosed acute myeloid leukemia (AML) . Methods: A retrospective cohort analysis was conducted on the clinical data from 237 CEBPA-mutated AML patients who received intensive chemotherapy induction at the First Affiliated Hospital of Soochow University between January 2016 and December 2024. Clinical characteristics, treatment responses, and prognosis were compared among different mutation subgroups. Results: Among 237 patients, 182 (76.8%) harbored bZIP domain in-frame insertion/deletion mutations (bZIP(InDel)), 13 (5.5%) had bZIP domain missense mutations (bZIP(ms)), and 42 (17.7%) carried other mutation types (Other(mut)). Compared with the latter two groups, patients in the bZIP(InDel) group had a younger age at onset (P<0.001), a higher GATA2 mutation rate (P<0.001), and lower mutation rates of NPM1 and DNMT3A (both P<0.05). After two courses of induction therapy, the bZIP(InDel) group achieved significantly higher complete remission (CR) /CR with incomplete hematologic recovery (CRi) rates and measurable residual disease (MRD) -negative rates than the bZIP(ms) and Other(mut) groups (CR/CRi rates: 99.4% vs 75.0% vs 86.8%, P<0.001; MRD-negative rates: 88.6% vs 77.8% vs 66.7%, P=0.008). With a median follow-up of 41 months, the 3-year overall survival (OS) and relapse-free survival (RFS) rates in the bZIP(InDel) group were 90.7% and 72.1%, respectively. Multivariate analysis revealed that CEBPA bZIP(InDel) was an independent favorable prognostic factor for both OS (HR=0.16, 95%CI: 0.06-0.40, P<0.001) and RFS (HR=0.31, 95%CI: 0.17-0.57, P<0.001). Within the bZIP(InDel) group, patients achieving CR/CRi after one course of induction had a superior 3-year OS rate compared with those achieving CR/CRi after two courses (88.3% vs 48.9%, P=0.050). Although allogeneic hematopoietic stem cell transplantation performed during the first CR (CR1) significantly improved the 3-year RFS rate (89.7% vs 57.6%, P<0.001), this benefit did not translate into an OS advantage (P=0.376). Additionally, concurrent KIT mutations were associated with a lower 3-year OS rate (65.6% vs 91.7%, P=0.042), and concurrent CSF3R mutations were associated with a lower 3-year RFS rate (42.9% vs 75.1%, P<0.001) . Conclusion: CEBPA bZIP(InDel) confer a distinct prognostic value. Patients in this subgroup derive substantial benefit from chemotherapy; however, the presence of concurrent KIT or CSF3R mutations is frequently associated with unfavorable outcomes. 目的： 探讨CEBPA基因突变在初诊急性髓系白血病（AML）患者中的预后价值。 方法： 本回顾性队列研究分析2016年1月至2024年12月苏州大学附属第一医院收治的237例接受强化诱导化疗的CEBPA突变阳性AML患者的临床资料，对比不同突变亚组的临床特征、治疗反应及预后。 结果： 237例患者中，bZIP结构域插入缺失突变（bZIP(InDel)）组182例（76.8%），bZIP结构域错义突变（bZIP(ms)）组13例（5.5%），其他类型突变（Other(mut)）组42例（17.7%）。与后两组相比，bZIP(InDel)组患者发病年龄更低（P<0.001），GATA2突变率更高（P<0.001），NPM1与DNMT3A突变率更低（P值均<0.05）。2个疗程诱导治疗后，bZIP(InDel)组完全缓解（CR）/CR伴血细胞不完全恢复（CRi）率及可检测残留病（MRD）阴性率均显著高于bZIP(ms)组和Other(mut)组（CR/CRi率：99.4%对75.0%对86.8%，P<0.001；MRD阴性率：88.6%对77.8%对66.7%，P=0.008）。中位随访41个月，bZIP(InDel)组3年总生存（OS）率及无复发生存（RFS）率分别为90.7%及72.1%。多因素分析显示，CEBPA bZIP(InDel)是OS（HR=0.16，95%CI：0.06~0.40，P<0.001）与RFS（HR=0.31，95%CI：0.17~0.57，P<0.001）的独立良好预后因素。bZIP(InDel)组中，1个疗程达CR/CRi者的3年OS率优于2个疗程达CR/CRi者（88.3%对48.9%，P=0.050）；首次CR（CR1）期行异基因造血干细胞移植虽可显著改善3年RFS率（89.7%对57.6%，P<0.001），但未能转化为OS获益（P=0.376）。此外，合并KIT突变与较低的3年OS率相关（65.6%对91.7%，P=0.042），合并CSF3R突变与较低的3年RFS率相关（42.9%对75.1%，P<0.001）。 结论： CEBPA bZIP(InDel)具有独特的预后价值，该亚组化疗获益显著，但伴随KIT或CSF3R突变者常预后不佳。.
Small cell lung cancer (SCLC) responds exceptionally well to cytotoxic chemotherapy. However, relapse with the emergence of chemoresistant disease is rapid and accompanied by poor treatment outcomes. To understand the genetic basis of chemoresistance in SCLC, we apply in vivo CRISPR deletion screening to patient-derived xenograft (PDX) models. Top screen hits include genes encoding components of the transcriptional co-activator SAGA (Spt-Ada-Gcn5 acetyltransferase) complex. We demonstrate that deletion of the SAGA deubiquitylase USP22 confers cisplatin-etoposide resistance in two chemosensitive PDX models, and that restoring expression in a PDX model harboring homozygous truncating mutation of USP22 re-sensitizes tumors to chemotherapy. USP22 loss increases gene body histone H2AK119 monoubiquitylation at key regulators of neuronal differentiation and suppresses neural and neuroendocrine gene expression including targets of ASCL1. Chemoresistance following USP22 loss reflects attenuated DNA damage-driven phosphorylation events and apoptosis, in conjunction with increased expression of glycolysis and hypoxia-related genes. Glycolysis program upregulation may reflect a targetable vulnerability, as inhibition of GLUT1 re-sensitizes USP22-null tumors to chemotherapy.
Through the GeneMatcher data-sharing database, we identified five affected individuals from four unrelated families with a skeletal dysplasia who have biallelic, putatively deleterious variants in MIMS1 (formerly FAM210A). The common features included chondrodysplasia with short stature, tracheal stenosis, conical teeth and/or early tooth decay, and sparse hair suggestive of ectodermal dysplasia as a component of the phenotype. The radiographic features included platyspondyly, epiphyseal dysplasia of the long bones, short phalanges with delayed carpal ossification, lacy iliac crests, and calcaneal spurs, consistent with a form of spondyloepimetaphyseal dysplasia. Missense variants clustered within the conserved DUF1279 domain of MIMS1, while one family harbored compound heterozygous nonsense variants, collectively supporting a loss-of-function mechanism. According to the dyadic naming convention in the latest Nosology of Genetic Disorders of Bone, we suggest the name of "Spondyloepimetaphyseal dysplasia with tracheal stenosis and ectodermal dysplasia (SEMDTSED), MIMS1-related."
Comprehensive genomic profiling (CGP) tests can identify putative biomarkers for immune checkpoint inhibitors (ICIs), including tumor mutational burden (TMB); however, their clinical utility remains uncertain. In this study, the efficacy and safety of nivolumab treatment based on the CGP results were investigated using a subcohort from the BELIEVE trial (NCCH1901; jRCTs031190104). This trial aims to improve drug accessibility for patients with advanced solid tumors harboring actionable genetic variants through off-label drug administration. Patients for whom off-label nivolumab treatment was proposed based on CGP results were eligible. Nivolumab was administered until disease progression or unacceptable toxicity. The primary endpoint was the best objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Among 60 enrolled patients, 56 patients who received study treatment were included in the analysis. TMB-High was the most frequent biomarker prompting nivolumab treatment (47/56, 83.9%), followed by CD274 (PD-L1) amplification (6/56, 10.7%) and CDK12 inactivating variants (3/56, 5.4%). Among 50 patients with measurable disease, the ORR was 16.0% (95% confidence interval [CI], 7.2-29.1) and the DCR was 40.0% (95% CI, 26.4-54.8). Median PFS and OS were 2.7 months (95% CI, 2.2-4.3) and 7.2 months (95% CI, 4.4-9.0), respectively. Although a subset of patients achieved durable responses, nivolumab treatment guided by CGP results demonstrated limited efficacy. The predictive value of TMB-High may differ across tumor types, and integration with other clinicogenomic factors is warranted to improve its predictive accuracy.
Organic fertilizers significantly influence soil antibiotic resistance genes (ARGs); however, the impact of manure-free organic amendments on ARG dissemination from bulk soil to the rhizosphere remains unclear. This study investigated dissolved organic matter (DOM) composition and ARG profiles in bulk soil and the radish rhizosphere using three manure-free organic fertilizers with varying hydrochar contents (0%BC, 10%BC, and 30%BC). Under non-fertilized conditions, the rhizosphere harbored lower ARG abundances than bulk soil. Organic fertilization significantly elevated rhizospheric ARG enrichment, driven primarily by rhizosphere bacterial community shifts and antibiotic-resistant bacteria (ARB) accumulation rather than direct exogenous ARG inputs. Notably, the 10%BC treatment effectively mitigated this enrichment, maintaining absolute ARG abundances in the rhizosphere that were 69.5% and 72.5% lower than those in the 0%BC and 30%BC treatments, respectively. Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) revealed that 10%BC selectively enriched low-molecular-weight, highly oxidized lignin-like molecules with higher aromaticity. In contrast, 0%BC and 30%BC accumulated higher-molecular-weight, more bioavailable lignins. Network analysis and structural equation modeling (SEM) demonstrated that these chemically distinct lignins exerted contrasting effects: highly oxidized lignins under 10%BC potentially suppressed horizontal gene transfer (HGT) and ARB accumulation, whereas bioavailable lignins under 30%BC promoted them. Overall, fertilizer-derived lignins serve as crucial molecular mediators steering resistome dynamics across the soil-rhizosphere interface, with their oxidation states and molecular weights exhibiting contrasting roles in modulating HGT and ARG dissemination.
Inherited predispositions to lung cancer are increasingly recognized, but the prevalence and distribution of pathogenic germline variants (PGVs) remain incompletely characterized. We performed a systematic literature review of studies reporting the prevalence of pathogenic or likely pathogenic (P/LP) germline variants in lung cancer patients. Random-effects models pooled overall prevalence estimates and gene-specific frequencies for commonly reported genes (EGFR, BRCA1, BRCA2, ATM, CHEK2, TP53). Subgroup analyses were performed according to cohort type and ancestry. Univariable meta-regression evaluated associations of mean age and sequencing panel size with P/LP prevalence. Case reports and series were qualitatively summarized. Twenty-eight studies were included in the meta-analysis. The pooled prevalence of P/LP PGVs was 7.9% (95% CI, 3.8-15.9%) with high heterogeneity (I2=98.8%). Gene-specific prevalence rates were: BRCA2, 0.96%; ATM, 0.67%; TP53, 0.57%; CHEK2, 0.49%; BRCA1, 0.48%; and EGFR, 0.17%. The high-risk enriched cohort had a higher prevalence of P/LP PGVs, while variants in DNA damage repair genes were more frequent in non-Asian populations than in East Asians (p<0.05). Higher PGV prevalence was associated with lower study-level mean age (per-year OR 0.91 for increasing age; p=0.024) and larger sequencing panels (per log increase in tested genes OR, 1.72; p = 0.013). Case reports described over 15 rare PGVs, most frequently involving EGFR, particularly EGFR T790M. Approximately 8% of lung cancer patients harbor P/LP germline variants, with the highest frequencies in DNA damage repair genes. Study-level younger age and non-Asian ancestry are associated with higher prevalence, informing genetic evaluation with established risk factors.
Tomato spotted wilt virus (TSWV) and late leaf spot (LLS) are among the major constraints to peanut production. Cultivated peanut has narrow genetic bases and lacks strong sources of resistance. Wild species, on the other hand, harbor diverse and strong resistances to multiple pathogens. In this study, we evaluated advanced breeding lines carrying introgressions from multiple wild Arachis species (A. stenosperma, A. batizocoi, A. valida, and A. cardenasii) across three contrasting field environments and experimental designs in Georgia, USA using complementary incidence- and severity-based phenotyping. Genotype effects were highly significant for both diseases. Several wild-derived lines -particularly those from A. stenosperma ancestry- showed strong and stable TSWV resistance across environments. Interestingly, some lines lacking detectable wild segments also showed high resistance to TSWV, suggesting cryptic or undetected introgressions. LLS resistance was primarily associated with the characteristic A. cardenasii segments on A02 and A03, and lines stacking these introgressions consistently outperformed both cultivated parents and Georgia-06G, the most popular cultivar in the USA. Correlations between TSWV and LLS responses were weak, confirming genetic independence and emphasizing the need to screen both traits. A small subset of lines combined resistance to both diseases, and many also retained resistance loci to root-knot nematode (RKN), expanding their value as multi-trait donors. These findings demonstrate the power of wild introgression breeding for enhancing disease resistance and provide a foundation for deploying stacked alleles through marker-assisted and multi-environment selection.
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. While the gut microbiota has been shown to influence CRC development, the specific contribution of bacteria to DNA methylation and carcinogenesis remains underexplored. We colonize two groups of GF ApcMin/+ mice with two consortia, one harboring a pks+ E. coli strain with "low-pks" activity (DSMZ) and the second with a clinical isolate exhibiting "high-pks" activity (UM149). These colonized mice are exposed to DSS-induced colitis, and analyzed for tumor burden, DNA methylation, and transcriptional changes. We find that colonization with C13-UM149 leads to more tumors, increased cell proliferation, and higher DNA damage compared to C13-DSMZ (p < 0.05). Methylation analyses show that C13-DSMZ causes extensive promoter hypermethylation and altered gene expression. Differential DNA methylation in mice colonized with either C13-DSMZ or C13-UM149 is associated with changes in pathways controlling tumor suppression, cell proliferation, inflammation, and Wnt signaling. In C13-DSMZ mice, hypermethylation is associated with gene expression involved in tumor suppression in both tumors and normal tissue, whereas hypomethylation is linked to expression of genes promoting Wnt signaling. In C13-UM149 mice, methylation changes were connected to genes involved in epithelial proliferation, extracellular matrix remodeling, and inflammatory responses. These findings demonstrate that intestinal bacteria with distinct pks activities differentially modulate DNA methylation thereby influencing gene expression and tumor development. This highlights bacterial modulation of epigenetic responses as a potential mechanism underlying CRC progression.
Mucinous cystadenocarcinoma of the breast is rare and has been recently classified as a distinct entity in the fifth edition of the WHO Classification of Tumors. Here, we present a 47-year-old woman with a history of NST carcinoma in her right breast who subsequently developed a lump in the right chest wall close to the breast implant. Immunohistochemical analysis showed negativity for keratin 20 and CDX2, and positivity for mammaglobin, GCDFP15 and TRPS1 with a triple-negative phenotype. The diagnosis of primary mucinous cystadenocarcinoma of the breast was finally established. Next-generation sequencing identified likely pathogenetic mutations specifically in AKT1, EGFR, FANCA, BCL10, CTCF and RUNX1 and RP1-34H18.1::NAV3 gene fusion, making this as the first reported example in the literature harboring an RP1-34H18.1::NAV3 gene fusion identified within a comprehensive RNA-based molecular analysis, representing the 49th reported patient worldwide.
The growing global population and rising food demand have intensified reliance on chemical fertilizers, leading to soil degradation, environmental pollution, and heavy metal accumulation. As a sustainable alternative, Trichoderma spp. have gained prominence as bioinoculants due to their diverse plant growth-promoting abilities. However, emerging evidence highlights strain-specific variability and regulatory complexity in their beneficial traits, aspects that remain insufficiently addressed in current literature. This review explores the molecular basis of three key mechanisms: (i) indole-3-acetic acid (IAA) biosynthesis through indole-3-pyruvic acid (IPA), indole-3-acetamide (IAM), and tryptophan-independent pathways; (ii) phosphate solubilization mediated by phytase, phosphatase, and organic acid production; and (iii) iron (Fe) acquisition through siderophore production, primarily synthesized by nonribosomal peptide synthetases (NRPSs). Not all Trichoderma species exhibit the full spectrum of plant growth-promoting traits; while some are efficient in phosphate solubilization, others may primarily contribute through IAA production or siderophore production. Genomic and bioinformatic studies have revealed that T. atroviride, T. asperellum, T. virens, T. harzianum, T. citrinoviride, T. reesei, T. longibrachiatum, and T. koningiopsis harbor putative genes encoding proteins homologous to enzymes associated with IAA production, such as flavin monooxygenase and indoleamine-2,3-dioxygenase, as well as genes involved in siderophore production, including sidA, sidF, sidL, sidC, sidD, and sidG. However, the genetic and regulatory mechanisms underlying IAA production and phosphate solubilization in Trichoderma remain poorly characterized, with limited genomic information available on genes encoding auxin-related enzymes, phytases, acid phosphatases, and those involved in organic acid biosynthesis. These findings highlight the importance of targeted molecular research to support the development of strain-specific bioformulations that enhance nutrient use efficiency, reduce chemical inputs, and advance sustainable agricultural practices.
Xenotransplantation holds promise for addressing the organ shortage crisis. Multi-genetic modification of pigs, such as knockout of three carbohydrate antigen-related genes and expression of immunoprotective proteins, can significantly improve xenograft survival. However, existing multi-gene modification strategies face challenges: transposon-based transgenic technology may lead to unstable expression, while exogenous promoters used in site-specific integration strategies are susceptible to epigenetic silencing, making it difficult to maintain long-term, stable expression levels. Therefore, developing a donor pig model capable of achieving stable and long-lasting multi-gene expression is a critical need in the field. CRISPR-Cas9 technology was used to knockout three major glycan antigen genes (GGTA1, CMAH, β4GalNT2) to eliminate hyperacute rejection. Subsequently, four human protective genes (hCD55, hCD46, hTHBD, hEPCR) were site-specifically integrated into the porcine Rosa26 safe-harbor locus. Their expression was driven by the porcine endogenous Rosa26 promoter and the THBD core promoter, respectively, to ensure long-term stable and tissue-specific expression. Furthermore, the selection marker gene was efficiently removed using the Cre/loxP system. The three glycan antigens were completely absent at both cellular and tissue levels in BM7G genetically modified pigs. What's more, four protective proteins were stably expressed in vascular endothelial cells and major organs such as the heart, liver, and kidneys. Among them, hCD55 and hCD46 were widely expressed, while hTHBD and hEPCR were specifically expressed in the vascular region. In-vitro functional assays confirmed that BM7G porcine vascular endothelial cells significantly reduced the binding of human antibodies, effectively inhibited complement-dependent cytotoxicity, and decreased the formation of thrombin-antithrombin (TAT) complexes. In summary, by combining the knockout of xenoantigens with the use of endogenous promoters to drive the expression of multiple human protective genes, we successfully constructed a seven-gene modified pig model with low immunogenicity and synergistic protective functions. This provides an important donor resource for preclinical research in xenotransplantation.
Exome sequencing is widely used for genetic studies; however, accurate detection of copy number variants (CNV) in paralogous genes is challenging due to short-read mapping ambiguity and extensive copy-number variation. The human genome contains several hundred paralogous genes, many of which are known to harbor disease-associated CNVs. Existing exome CNV callers are primarily designed for rare CNV detection in uniquely mappable regions and are not well-suited for paralogous genes. We describe a computational method (EdgeCopy) for copy number profiling of paralogous genes using whole-exome sequence data. EdgeCopy aggregates reads mapped to all copies of paralogous genes and relates observed read depth to copy number for multiple exome samples using an approximate composite likelihood function. The likelihood function is optimized using numerical optimization to obtain gene-level fractional copy number estimates that are discretized and refined using a Hidden Markov Model to obtain exon-level copy number estimates. Benchmarking of Edgecopy using experimental copy number data showed high concordance (mean = 0.973) for six disease-associated paralogous genes. We evaluated performance using whole-exome data from approximately 2400 samples across five continental populations from the 1000 Genomes Project. EdgeCopy shows robust concordance with whole-genome sequencing based estimates (0.974-0.982) across populations and 130 paralogous genes spanning a wide range of copy-number variation. In comparison, copy number analysis using a state-of-the-art exome CNV caller failed to estimate copy number for paralogous genes with very high mapping ambiguity and showed much lower concordance (0.565) for CNV events compared to EdgeCopy (0.908). EdgeCopy is freely available at https://github.com/vibansal-lab/edgecopy.
Proteus mirabilis (P. mirabilis) is a leading cause of urinary tract infections (UTIs) in both community and healthcare settings, especially in catheterized patients. Proteus species express various types of fimbriae that can serve as colonization-related virulence factors. The severity of infection escalates when these virulent strains acquire antibiotic resistance. The aim of this study was to investigate the prevalence, antimicrobial susceptibility, and genetic determinants of fluoroquinolone resistance in P. mirabilis isolates. Further, to screen for the presence of virulence genes encoding fimbriae and integrons. A total of 103 P. mirabilis isolates were recovered from urine samples collected from catheterized and non-catheterized UTI patients at Minia University Hospitals, Egypt. Antimicrobial susceptibility of fluoroquinolone-resistant (FQR) isolates was evaluated using the disc diffusion method. Phenotypic detection of extended-spectrum β-lactamase (ESBL) production was then performed, followed by molecular analysis for ESBL and plasmid-mediated quinolone resistance (PMQR) genes within the FQR isolates. All P. mirabilis isolates were screened by PCR for four virulence genes encoding fimbriae. Additionally, class 1, 2, and 3 integrons were investigated. Among the 103 P. mirabilis isolates, 47 (45.6%) were non-susceptible to ciprofloxacin, of which 22 exhibited intermediate non-susceptibility and 25 were resistant. Multidrug resistance (MDR) was found in 70.2% (33/47) of FQR isolates, with significantly higher resistance to amoxicillin-clavulanic acid, sulfamethoxazole-trimethoprim, gentamicin, and amikacin compared to fluoroquinolone susceptible isolates. The virulence genes pmfA and mrpA were detected in 86.4% (89/103) and 78.6% (81/103) of isolates, respectively, while both atfA and ucaA were present in 70.9%. Isolates from catheterized patients showed significantly higher prevalence of virulence genes compared to those from non-catheterized individuals. PMQR genes were detected in 91.5% (43/47) of FQR isolates. The most prevalent were qnrS (74.5%), aac(6')-Ib-cr and qnrA (66% each), followed by qnrC (42.6%), qnrB (31.9%), and qepA (8.5%). Co-carriage of multiple PMQR genes was significantly more frequent in isolates with ciprofloxacin resistance than in those with intermediate non-susceptible (p = 0.0001). ESBL genes were detected in 36.8% of ESBL-producing FQR isolates, with blaTEM being the most prevalent (26.3%), followed by blaCTX-M-9 (21.1%), while blaSHV was not detected. Among the 103 P. mirabilis isolates, 99 (96.1%) carried class 1 and/or class 2 integrons, while none harbored class 3 integrons. Our findings reveal a significantly high prevalence of fimbriae-associated virulence genes in P. mirabilis isolates from catheterized UTI inpatients, alongside notable dissemination of PMQR genes and class 1 integrons. The coexistence of these virulence and resistance determinants, particularly in hospital-derived strains, is concerning, as it may enhance horizontal gene transfer. This combination contributes significantly to MDR strain persistence and dissemination in the clinical settings.
To identify causal links between gut microbes and tumorigenesis, we colonized germ-free, colon tumor-susceptible mice (ApcMin/+;Il10-/-) with 19 cultured human fecal microbiotas from healthy individuals and patients with inflammatory bowel disease or colorectal cancer. Colonic tumor counts vary by donor microbiota but not by donor health status. In vitro screens of host cell proliferation, genotoxicity, and inflammation in bacteria-mammalian cell co-cultures reveal that genotoxicity best predicts tumorigenic microbes in vivo, with genotoxic microbes present in all tested individuals. The genotoxic subset of strains from each donor induces more tumors than the complete community-even when the complete community is not tumorigenic. Combining genotoxic microbes from multiple sources increases tumor number and decreases time to tumor onset. Together, these results suggest that most individuals harbor genotoxic bacterial strains and that the balance of genotoxic to protective strains determines the timing and severity of tumorigenesis in vivo.
Bedaquiline's (BDQ) incorporation into the recommended treatment for drug-resistant tuberculosis (DR-TB) has ushered in a new era of highly effective, shorter course, all-oral regimens. Unfortunately, as the uptake of BDQ-based regimens has increased, so has the emergence of BDQ resistance. In a recent ASM Case Reports article, M. Richard-Greenblatt, R. Bagga, C. Duncan, M. J. Billick, et al. (ASM Case Rep 2:e00126-25, 2025, https://doi.org/10.1128/asmcr.00126-25) reported on a patient with treatment-emergent extensively drug-resistant (XDR) TB, whose isolate harbored a novel loss-of-function pepQ mutation, with resulting BDQ resistance. This commentary briefly highlights the benefits of BDQ-based DR-TB therapy, while also reviewing data related to the growing challenge posed by BDQ resistance.
Proteus mirabilis is an opportunistic pathogen associated with urinary tract infections, wound infections, and bacteremia. We analyzed 17 clinical isolates collected from hospitals in Narathiwat Province, southern Thailand, to characterize their antimicrobial resistance (AMR), virulence potential, plasmid replicon content, and genomic relatedness. Most isolates were phenotypically susceptible to all tested antibiotics. Resistance was limited to two strains: KS160 (ceftriaxone, ciprofloxacin, levofloxacin) and KS044 (ciprofloxacin, levofloxacin). Whole-genome analysis, however, identified 50 unique AMR genes, including determinants associated with aminoglycoside, chloramphenicol, trimethoprim, sulfonamide, and quinolone resistance. PlasmidFinder identified IncQ1- and Col3M-replicon-associated contigs. The quinolone resistance gene qnrD1 was detected on highly similar Col3M-associated contigs in two isolates, indicating the occurrence of related putative mobile genetic elements among the clinical isolates. Virulence gene profiling showed a conserved core associated with motility, chemotaxis, LPS/capsule biosynthesis, and stress adaptation. KS155 exhibited the most distinct virulence-gene detection profile, with several motility- and stress response-associated genes not detected above the predefined threshold. Phylogenomic, ANI, and dDDH analyses confirmed that all isolates belonged to P. mirabilis. Although KS155 exhibited the lowest ANI values (96-97%) relative to the other isolates, it represented the greatest genomic divergence among the isolates analyzed. Our findings provide evidence that P. mirabilis circulating in southern Thailand exhibits genetic diversity, maintains a stable core of intrinsic virulence traits, and harbors additional, variably distributed AMR determinants associated with putative mobile genetic elements, emphasizing the importance of continued genomic surveillance in this region.
Citrus is a pivotal economic crop in southern China, while citrus canker caused by Xanthomonas citri subsp. citri (Xcc) is a devastating quarantine disease that severely threatens the sustainability of the citrus industry. Endophytic bacteria represent a promising sustainable alternative for disease management, yet systematic exploration of their potential against Xcc in citrus leaves remains limited. To address this, we characterized the leaf endophytic microbiome from major citrus-growing regions in southern China via high-throughput sequencing, revealing significant differences in the endophytic bacterial community structure between symptomatic and asymptomatic citrus leaves, with a significantly elevated relative abundance of Proteobacteria and prominent enrichment of the genera Xanthomonas, Enterobacter, and Pseudomonas in symptomatic tissues. Furthermore, symptomatic leaves harbored significantly higher endophytic bacterial diversity than asymptomatic leaves from the same production region, and the Xanthomonas abundance in the samples was highly consistent with the actual field disease severity. From 519 bacterial isolates, four strains-A1 (Bacillus altitudinis), A3 (Bacillus velezensis), A6 (Pseudomonas parafulva), and A7 (Delftia tsuruhatensis) demonstrated strong in vitro and detached-leaf antagonism against Xcc. Strain-specific fermentation parameters were optimized, and all four strains were successfully formulated into wettable powders. In a field trial, these formulations achieved control efficacies ranging from 25.8% to 53.5%, with strain A1 showing the highest and most sustained activity. Strains A3, A6, and A7 also exhibited broad-spectrum antibacterial activity against several other phytopathogenic bacteria. This study not only elucidates shifts in the endophytic microbiome associated with citrus canker but also provides novel, efficacious biocontrol resources and a practical development pipeline for sustainable disease management.
Long-term persistent measles virus (MeV) infection of the central nervous system (CNS) can result in subacute sclerosing panencephalitis (SSPE), an invariably fatal late neurological complication of measles. Analogous SSPE-like chronic diseases have also been reported in adult dogs, cetaceans, and more recently harbor seals following infection by canine distemper virus (CDV), dolphin morbillivirus (DMV), and phocine distemper virus (PDV), respectively. Here, we characterize different animal morbilliviruses (CDVlynx, PDV2001, PDV2014, and DMV232-18) that persisted in the CNS of their respective host species for several years after the initial infections. The CDVlynx and DMV232-18 strains encode nonfunctional matrix proteins and hyperfusogenic fusion proteins which are hallmark features of SSPE MeV strains. The complex mutational profile apparent in the PDV2001 strain also has parallels with MeV strains from SSPE cases. In contrast, the PDV2014 strain encodes for a nonfunctional matrix protein but an unmodified F protein supporting the evolutionary precedence of M protein changes in facilitating long-term morbillivirus infections of the CNS. Consequently, our findings show that similar evolutionary pathways across different animal species drive morbilliviruses to evolve analogous mechanisms favoring virus persistence in the CNS and the development of chronic neurological disease. Such naturally occurring chronic animal morbillivirus infections of the CNS provide natural analogues for studying the evolutionary trajectory and molecular basis of the pathogenesis of SSPE in humans. This may pave the way for developing early diagnostics and intervention strategies.