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PubMed2026

Introgression shapes the genomic conflict landscape of Malus, providing evidence for a reticulate backbone in a woody crop lineage.

Phylogenomic discordance is widespread across plants, but its evolutionary significance is often obscured when conflict is treated primarily as analytical noise rather than as evidence of underlying processes. In woody lineages in particular, incomplete lineage sorting, introgression, and genome duplication can interact over long timescales to produce complex genomic histories that are not adequately summarized by a strictly bifurcating tree. Here, we use Malus as a model woody genus to investigate how these processes structure conflict across a genus-scale, accession-based phylogenomic framework. Using broad taxon sampling, hundreds of nuclear loci, plastid genomes, and genome-wide SNP summaries, we reconstruct a robust nuclear backbone for sampled Malus lineages and evaluate where discordance is concentrated and which processes best explain it. Nuclear analyses resolve eight major clades, whereas conflict is non-random and localized to recurrent hotspots rather than evenly distributed across the tree. Cytonuclear discordance is similarly concentrated, especially around Clade H, represented by sampled accessions of M. tschonoskii, where localized plastid-nuclear disagreement is consistent with candidate plastid capture or organellar introgression. Multiple complementary analyses further indicate that the strongest conflict is not explained by ILS alone, but instead reflects lineage-structured introgression, while polyploid complexes represent additional localized sources of evolutionary complexity. Together, these results provide evidence for a reticulate genomic backbone in Malus and show how integrating nuclear, plastid, and genome-wide conflict analyses can help distinguish background discordance from process-specific signals in woody plant radiations. Several lineage-level reticulation hypotheses identified here should now be tested with broader population-level sampling and curated reference accessions.

Malus↗

PubMed2026

Diverse structures of mcr-10-bearing plasmids and high colistin resistance in Enterobacter cloacae complex clinical isolates from South Korea.

BACKGROUND: The emergence of mcr-mediated colistin resistance in Enterobacter cloacae complex (ECC) poses a significant threat to antimicrobial therapy. Among mcr variants, mcr-10 has been identified in various environments, but its genetic diversity, structural context, and functional role in colistin resistance remain unclear. METHODS: We investigated 183 ECC isolates and identified 60 colistin-resistant strains through minimum inhibitory concentration (MIC) testing. The presence of mcr-10 was screened using reference genomes from NCBI, and whole plasmid sequencing was conducted on mcr-10-positive isolates. The genetic environment of mcr-10 was analyzed via synteny and structural annotation. RESULTS: Whole-plasmid sequencing of eight mcr-10-positive ECC isolates identified three replicon types among the mcr-10-harboring plasmids: IncFIB (n=3), IncFII (n=3), and IncFII/IncFIB (n=2). Although all plasmids shared the xerC-mcr-10 cassette, they lacked a conserved backbone and showed diverse genetic contexts with variable insertion sequences near mcr-10, indicating marked structural heterogeneity. No additional antimicrobial resistance genes were detected on these plasmids. When introduced into E. coli DH5α, the plasmids increased colistin MICs only modestly, whereas representative plasmids transferred into colistin-susceptible E. roggenkampii and E. kobei conferred high-level resistance comparable to that of the parental mcr-10-positive isolates. Consistently, qRT-PCR showed higher mcr-10 expression in ECC transformants than in E. coli under colistin exposure, supporting a hostdependent effect on mcr-10-mediated colistin resistance. CONCLUSION: These findings highlight the diversity of mcr-10-carrying plasmids and suggest that mcr-10-mediated colistin resistance is shaped by the host genetic background. Further studies are needed to clarify the mechanisms underlying mcr-10 expression.

Colistin↗

PubMed2026

Uce-based phylogeny and classification of Megachilini.

The generic-level classification of the bee tribe Megachilini (Megachilidae) has remained controversial due to poor phylogenetic resolution at the base of the group, particularly among the brood parasitic genera and the numerous dauber ("Chalicodoma s. l.") lineages. We present a phylogenomic analysis of Megachilini based on ultraconserved elements (UCEs), sampling 52 ingroup taxa with emphasis on the dauber lineages. We also present a combined UCE + six-gene analysis to improve taxon coverage, resulting in a dataset with 127 ingroup taxa. Maximum likelihood, coalescent, and Bayesian analyses of multiple UCE matrices recover largely congruent topologies with substantially improved support relative to previous studies. Our results strongly support the monophyly of Megachilini, the early divergence of Noteriades and Gronoceras, and a single origin of brood parasitism. All remaining non-parasitic Megachilini form a moderately supported clade sister to the brood parasitic lineage. The leafcutter bees are monophyletic and nested within dauber lineages. Several major dauber clades are consistently recovered, including an exclusively Australian clade corresponding to the Hackeriapis group of subgenera, while several recognized subgenera are paraphyletic. The lineage known as Morphella, previously placed in synonymy with the subgenus Callomegachile, was not closely related to that subgenus and is here treated as a valid subgenus. Divergence-time analyses place the crown age of Megachilini in the late Eocene to early Oligocene, with major extant lineages diversifying during the Miocene. Limited morphological diagnosability of several clades indicates that splitting non-parasitic lineages into numerous genera would result in an impractical classification that would widen the gap between taxonomists and non-specialists and exacerbate the taxonomic impediment in bees. We therefore advocate retaining a single genus Megachile for non-parasitic Megachilini (excluding Noteriades and Gronoceras), as the classification best supported by phylogenomic evidence and most robust to future taxon sampling.

Animals↗

PubMed2026

Meningioma methylation profiling as a complement to WHO grading: a single-center experience.

OBJECTIVE: The methylation profile of meningiomas is a promising predictive tool that may improve risk stratification beyond WHO grading. This study aimed to evaluate the clinical relevance and real-world applicability of routine epigenetic testing in meningioma management. METHODS: The authors retrospectively analyzed patients who underwent meningioma resection between January 2021 and December 2023. Histopathological grading (WHO 2021) and methylation profiling (methylation class [MC]) with the MethylationEPIC v1.0 (850k) chip were performed by an independent neuropathologist. RESULTS: A total of 106 patients were included; 81 tumors (76%) were classified as WHO grade 1, 20 (19%) as grade 2, and 5 (5%) as grade 3. Epigenetically, 55 tumors (52%) were classified as benign, 18 (17%) as intermediate, and 2 (2%) as malignant; 31 (29%) could not be classified. Discordances between WHO grading and methylation profiling were observed in 18 of 74 cases. Tumor board decisions were made after a median of 8 days postoperatively, guided by WHO grading; however, the epigenetic report was only available after a median of 23 days. During follow-up, 20 patients experienced tumor progression. Progression was significantly associated with the MC (r = -0.4, p < 0.001) and tumor volume (r = 0.4, p = 0.0005), but not with WHO grading (r = 0.17, p = 0.084). However, the relatively high rate of unclassified tumors and delayed result availability limited the direct impact of MC profiling on immediate clinical decision-making. Interestingly, progression-free survival in MC-unclassified tumors mirrored that of the intermediate group. CONCLUSIONS: Methylation profiling demonstrates superior predictive accuracy for meningioma progression and complements WHO grading, especially in identifying malignant meningiomas. However, its current clinical utility is constrained by technical and logistical limitations. In real-world practice, epigenetic classification should therefore be considered a complementary tool rather than a replacement for established histopathological assessment.

Humans↗

PubMed2026

Metal-organic frameworks nanozyme-integrated portable microneedle patch for visual bacterial monitoring in meat.

Foodborne microbial contamination is a major global health concern, with conventional methods often being time-consuming and complex. Herein, we developed a novel portable biosensor by integrating microneedle patch technology and a metal-organic framework (Fe/Cu-NBDC MOF) nanozyme, enabling rapid, on-site, visual detection of bacteria in meat. The sensing system works by encapsulating aptamer-functionalized MOF nanozymes within a hydrogel patch, where their catalytic sites are initially blocked by the aptamer. In the presence of Staphylococcus aureus (S. aureus) as the target, the specific aptamer's binding to bacteria exposes numerous catalytic sites, further activating the chromogenic reaction of the tetramethylbenzidine‑hydrogen peroxide (TMB-H₂O₂) system, enabling visual detection of S. aureus. The biosensor demonstrates a detection limit of 82 CFU/mL with excellent specificity to successfully apply to commercial mutton. By integrating sampling, enrichment, and visual detection into a single compact device, this platform offers a practical, efficient solution for rapid on-site screening of foodborne pathogens.

Biosensing Techniques↗

PubMed2026

Clinical Outcomes and Genomic Epidemiology of Multidrug-Resistant Methicillin-Resistant Staphylococcus aureus Keratitis.

PURPOSE: To characterize the clinical features, management, antimicrobial resistance patterns, and genomic epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) keratitis at two North American centers. DESIGN: Retrospective interventional case series combined with laboratory investigation PARTICIPANTS: Seventy eyes of 67 patients presenting laboratory-confirmed MRSA keratitis were included METHODS: We performed a multicenter retrospective case series of patients with culture-proven MRSA keratitis treated between 2005 and 2022. Demographic and clinical data were collected. Antimicrobial susceptibility testing was conducted, and multidrug resistance (MDR) was defined as resistance to ≥3 antibiotic classes. A subset of isolates underwent whole-genome sequencing with core genome multilocus sequence typing. Vancomycin susceptibility, heteroresistance screening, and tolerance testing were performed on available isolates. MAIN OUTCOME MEASURES: Antimicrobial susceptibility and multidrug resistance rates, vancomycin phenotypic profiles, MRSA genotypic distribution, and final best-corrected visual acuity RESULTS: Median age was 63.5 years, and 61.4% were female. Ocular surface disease (67.7%) and prior ocular surgery (65.2%) were common. Only 25.4% had significant healthcare exposure in the preceding year. Most isolates (85.7%) were MDR. Fluoroquinolone susceptibility was low (moxifloxacin 19.7%). All isolates were susceptible to vancomycin (MIC₉₀ 2 µg/mL), and no vancomycin-intermediate, heteroresistant, or tolerant phenotypes were identified. Whole genome sequencing (n = 41) demonstrated predominance of clonal complexes 5 (68.3%) and 8 (29.2%). Visual outcomes were poor, with most patients (85.2%) having a final visual acuity worse than 20/60 among those with follow-up. CONCLUSIONS: MRSA keratitis is associated with high rates of multidrug resistance and poor visual outcomes despite guideline-based therapy. Infections were predominantly caused by CC5 MDR strains despite limited recent healthcare exposure. These findings highlight the persistence of highly resistant MRSA lineages in community-associated corneal infection and underscore the need for ongoing antimicrobial surveillance and optimized treatment strategies.

Humans↗

PubMed2026

Diagnostic utility of high-risk HPV polymerase chain reaction-based testing in head and neck FNA specimens with indeterminate cytomorphology.

BACKGROUND: Fine-needle aspiration (FNA) is critical in the initial diagnosis of many high-risk human papillomavirus (HR-HPV)-associated, metastatic oropharyngeal squamous cell carcinomas. Updated guidelines recommend HR-HPV-specific polymerase chain reaction (PCR) analysis over p16 immunohistochemistry on FNA specimens because p16 performs poorly on cytology material. PCR-based assays on liquid cytology material have demonstrated excellent analytic performance; however, the diagnostic utility of a positive HR-HPV PCR result in specimens with indeterminate cytomorphology remains uncharacterized. METHODS: The authors retrospectively identified 279 head and neck FNA specimens that had paired HR-HPV PCR testing on residual liquid cytology material over a 5-year period. The positive predictive value for histopathologically confirmed squamous cell carcinoma on surgical follow-up was calculated within each cytologic interpretive category. RESULTS: The HR-HPV PCR results were positive in 50.2% of specimens, negative in 40.9%, and indeterminate in 9.0%. The HR-HPV positivity rate ranged from 0% in specimens categorized as negative for malignancy to 57.3% in cytologically positive specimens, with 19.0%, 41.2%, and 50.0% positivity in the atypical, suspicious, and nondiagnostic categories, respectively. Among cytologically indeterminate specimens with positive HR-HPV PCR results (n = 14), the positive predictive value was 100% (95% confidence interval, 78.5%-100.0%). Blinded slide review additionally identified 15 cytologically positive specimens in which the definitive malignant interpretation depended substantially on HR-HPV positivity; all 15 were confirmed as squamous cell carcinoma. CONCLUSIONS: A positive HR-HPV PCR result on liquid cytology material carries a positive predictive value of 100% for malignancy in cytologically indeterminate head and neck FNA specimens. These findings support integrating HR-HPV PCR analysis into routine cytologic interpretation with the potential to upgrade some indeterminate specimens to malignant when HR-HPV is detected, expediting definitive treatment and sparing patients additional, invasive sampling.

Humans↗

PubMed2026

RFC1 Repeat Expansions in Chronic Idiopathic Axonal Polyneuropathy: Prevalence, Phenotype, and Diagnostic Implications.

BACKGROUND AND AIMS: Chronic idiopathic axonal polyneuropathy (CIAP) accounts for approximately 20%-30% of adult-onset axonal polyneuropathies. Pathogenic RFC1 repeat expansions have emerged as a frequent cause of idiopathic sensory neuropathy, but their recognition in routine clinical practice may be challenging, particularly in the presence of potentially confounding comorbidities. We aimed to determine the prevalence of pathogenic RFC1 repeat expansions in a well-defined CIAP cohort, characterize the associated clinical and electrophysiological phenotype, and evaluate whether coexisting well-controlled diabetes mellitus (DM) or monoclonal gammopathy of undetermined significance (MGUS) may hinder recognition of RFC1-related neuropathy. METHODS: We performed a retrospective observational study of adult patients with CIAP followed at a tertiary neuromuscular unit. All patients underwent RFC1 genetic testing. Clinical and electrophysiological features were compared between RFC1+ and RFC1- patients in the full cohort and after exclusion of patients with DM or MGUS. RESULTS: Ninety patients met CIAP criteria and were analyzed. Twenty-four (27%) carried biallelic pathogenic AAGGG repeat expansions in RFC1, of whom 6 (25%) had coexisting DM or MGUS. Compared with RFC1- patients, RFC1+ individuals more frequently exhibited dysautonomic symptoms, unsteadiness, history of falls, need for walking support, chronic cough, impaired vibration sense in the upper limbs and up to the knees in the lower limbs, brisk upper-limb reflexes, mild cerebellar signs, an abnormal head-impulse test, and a positive Romberg's test. Most of these differences persisted after exclusion of DM or MGUS. Electrophysiological studies in RFC1+ patients showed widespread sensory nerve involvement, including the upper limbs, with relative motor sparing, whereas RFC1- patients exhibited a more typical length-dependent pattern. INTERPRETATION: Biallelic AAGGG repeat expansions in RFC1 were identified in 27% of patients with CIAP. Specific clinical and electrophysiological features may help distinguish RFC1-related disease from other forms of CIAP and identify candidates for genetic testing, even in the presence of potentially confounding comorbidities such as well-controlled DM or MGUS.

Humans↗

PubMed2026

Cross-species variant-to-function analyses implicate MEIS1 in conferring sleep abnormalities and impaired cerebellar development.

Genome-wide association studies (GWAS) have identified numerous loci for insomnia, yet functional validation of effector genes remains limited because most risk variants lie in noncoding regions, and the true causal gene is not known. Here, we use prior human cell-based variant-to-gene mapping to nominate six insomnia effector genes and test them in zebrafish, a tractable diurnal vertebrate model well suited for sleep phenotyping. Our CRISPR-based behavioral screening identifies the MEIS1 ortholog, meis1b, as a regulator of sleep maintenance, with crispants displaying impaired nighttime-specific sleep maintenance and increased sleep latency. Comparative chromatin analyses reveal conserved regulatory architecture spanning the human insomnia-associated locus and selectively implicate meis1b, whereas the duplicated ohnolog meis1a was dispensable. Developmental profiling further shows that meis1b is expressed in cerebellar granule progenitors, paralleling human MEIS1 expression, and that its disruption impairs cerebellar development. Together, these findings establish zebrafish as an efficient vertebrate platform for functional interrogation of GWAS candidates and support an evolutionarily conserved cerebellar role for MEIS1 in sleep maintenance.

Animals↗

PubMed2026

Multi-omics integrative analysis provides insight into potential molecular responses to sustained high water flow in common carp (Cyprinus carpio) cultured in recirculating aquaculture.

To investigate the potential molecular responses by which water flow intensity affects the growth of common carp (Cyprinus carpio) in a recirculating aquaculture system (RAS), a control group (CG, actual water velocity 0.3 cm/s) and three sustained flow treatment groups were established, including a low-flow group (LF, 1 body length per second, bl/s), a medium-flow group (MF, 2 bl/s), and a high-flow group (HF, 3 bl/s). After 12 weeks of culture in the RAS, growth performance was compared among groups under different flow intensities. The best-performing group and the control group were then selected for the determination of intestinal digestive enzyme activities, as well as transcriptomic and whole-genome bisulfite sequencing analyses of muscle tissue. The results showed that the specific growth rate and feed intake of the HF group were significantly higher than those of the other groups (P < 0.05), whereas no significant difference in feed conversion ratio was observed among groups. Compared with the CG group, lipase activity was significantly higher in the HF group (P < 0.05), while α-amylase and trypsin activities showed increasing trends without significant differences. RNA-seq identified a total of 273 differentially expressed genes, including 72 upregulated genes and 201 downregulated genes in the HF group relative to the CG group. These genes were mainly enriched in glycolysis, pyruvate metabolism, ATP metabolism, the pentose phosphate pathway, the insulin signaling pathway, the PPAR signaling pathway, and the adipocytokine signaling pathway, indicating that sustained high water flow induced a muscle transcriptional response characterized by remodeling of energy metabolism and substrate utilization. Whole-genome bisulfite sequencing analysis showed that DNA methylation in common carp muscle occurred predominantly in the CpG context. Differentially methylated regions between the HF and CG groups were mainly distributed in transcription-related regulatory regions, including promoters, CpG islands, and CpG island shores. In promoter regions, the number of hypermethylated regions in the HF group relative to the CG group was markedly higher than that of hypomethylated regions. Integrated analysis further identified two candidate genes showing both promoter differential methylation and differential expression, namely LOC109094644 and bcorl1, suggesting that adaptation to high water flow may involve IGF-related growth regulation and remodeling of upstream transcriptional programs. The qPCR results were consistent with the transcriptomic data. Taken together, within the tested range, a sustained water flow of 3 bl/s was more conducive to the growth of common carp in the RAS, which may be associated with enhanced lipid digestion and utilization, remodeling of the muscle energy metabolic network, changes in promoter methylation, and the coordinated regulation of key candidate genes. This study provides a theoretical basis for clarifying the exercise adaptation mechanism of common carp in recirculating aquaculture and for optimizing flow velocity parameters.

Animals↗

PubMed2026

Temporal shifts in gyrA mutation types and sublineage replacement in ST11 Salmonella enterica serovar Enteritidis over a decade (2014-2023): A genomic epidemiological study in Guangxi, China.

The overuse or abuse of antibiotics drives the global health threat of antimicrobial resistance. Although bans on certain veterinary antibiotics, such as colistin, have proven effective, the impact of fluoroquinolone stewardship on the evolution of the foodborne pathogen Salmonella enterica serovar Enteritidis (S. Enteritidis) remains unclear. Here, we conducted a decade-long (2014-2023) retrospective longitudinal genomic epidemiological analysis of 441 ST11 S. Enteritidis isolates from Guangxi, China, alongside a global reference dataset of 4297 genomes. Our aim was to elucidate the effect of real-world antibiotic stewardship on the shift of gyrA point mutations and lineage distribution. Surveillance identified three global epidemic clade sublineages (GEC-L2, L3, L4), with the multidrug-resistant GEC-L4 (i.e., GC-c or MMC2), characterized by the gyrA mutation with amino acid substitution D87Y, being domestically dominant (70.07%, 309/441). Following China's 2016 ban on the veterinary use of critical fluoroquinolones, the proportion of the highly resistant GEC-L4 sublineage decreased continuously (from 86.84% in 2017 to 56.00% in 2023), while the less resistant GEC-L3 sublineage (i.e., GC-b or MMC1), mainly characterized by gyrA D87G, increased simultaneously (from 13.16% to 44.00%). This phenomenon might be attributed to the fact that the GEC-L4 sublineage exhibited a higher fitness cost compared with the GEC-L3 sublineage, as confirmed by the competition assay. A Random Forest Model validated that the gyrA mutation with amino acid substitution D87Y was the paramount feature for these sublineages' identification. In contrast, global data showed a continuous increase in gyrA mutations (from 8.63% in 2006 to 68.85% in 2024), primarily D87Y (from 1.44% to 31.15%) and D87N (from 4.32% to 22.95%), correlating with rising average fluoroquinolone consumption. This study provides direct genomic evidence that national-level antibiotic stewardship can drive the replacement of highly resistant sublineages with moderately resistant ones. These findings offer crucial scientific evidence for evaluating the impact of antibiotic management policies and inform strategies for the rational use of antimicrobials.

China↗

PubMed2026

Tracing the evolution and diversity of human parvovirus B19 across human history.

Human parvovirus B19 (B19V) is an ubiquitously spread, exclusively human pathogen, mainly posing risks to children, as well as pregnant and immunocompromised individuals. Despite evidence of B19V infection of human populations as far back as 7,000 years, the evolutionary history of B19V remains poorly understood. In this study, we present B19V genomic data from the remains of 53 globally distributed individuals spanning more than 8,000 years, including 7 children. Our findings suggest that the most recent common ancestor of all present B19V lineages existed around 12,000 years ago, at the end of the last Ice Age. Additionally, we identified an extinct Eurasian clade that participated in the recombination event that led to the emergence of B19V genotype 2 (GT-2). We date this event to ∼3,200-1,800 BP, potentially in the greater Mediterranean area. Our study shows aspects of how ancient parvovirus variants arose, disseminated, and impacted human health through time.

ancient DNA↗

PubMed2026

In vitro evaluation of sacituzumab govitecan in non-small cell lung cancer with actionable genomic alterations.

PURPOSE: The TROP2-directed antibody-drug conjugate sacituzumab govitecan (SG) has shown substantial therapeutic benefit in several malignancies; however, preclinical evidence supporting its activity in non-small cell lung cancer (NSCLC) is rare. MATERIALS AND METHODS: We evaluated 16 NSCLC cell lines harboring actionable genomic alterations for TROP2 expression and treated them with SG or its unconjugated payload, SN-38, for 3 days to determine cytotoxic effects. Apoptosis and DNA damage signaling were assessed using flow cytometry and western blot. SG internalization and lysosomal trafficking were visualized by confocal microscopy. RESULTS: SG had greater cytotoxic potency than SN-38, across all NSCLC cell lines, independent of genomic subtype or TROP2 expression level. Cell lines that were sensitive to SN-38 showed enhanced vulnerability to SG (P < 0.0001). Higher SLFN11 expression, a recognized determinant of SN-38 responsiveness, correlated with lower SG IC50 values. Both SG and SN-38 triggered apoptotic and DNA damage responses within 6-48 h, with SG inducing stronger activation of these pathways than SN-38. SG was efficiently taken up in CUTO17 and SNU-3173 adenocarcinoma cells, with more than 60% of the conjugate internalized within 3 h and subsequently localized to lysosomes. CONCLUSION: Our study provides in vitro evidence supporting the potential activity of SG in NSCLC with actionable genomic alterations. The efficacy of SG closely paralleled intrinsic sensitivity to the SN-38 payload, suggesting that DNA-damage responses, rather than oncogenic drivers, predominantly contribute to SG activity.

Actionable genomic alterations↗

PubMed2026

A dual-dimensional CRISPR toolkit enables one-step high-efficiency multiplex genome editing in Komagataella phaffii.

Against the backdrop of green biomanufacturing, engineering methanol-utilizing Komagataella phaffii (K. phaffii) represents an effective strategy to expand the one carbon (C1) product profile and speed up the industrialization of C1-based bioeconomy. To address the technical challenges of low efficiency and cumbersome experimental procedures for multiplex gene editing and precise large-fragment integration during the reconstruction of complex metabolic pathways in K. phaffii, this study established a CRISPR toolkit - Efficient Multi-Gene Editing System 3.0 (EMGES 3.0) - which enabled one-step large-fragment integration coupled with multiplex gene knockout. EMGES 3.0 was constructed through the synergistic optimization of a repair-engineered chassis and an episomal CRISPR vector. For chassis engineering, five DNA repair modules: Δlig4 (DNA Ligase IV, non-homologous end joining end ligation), ppMRE11(The endogenous MRE11 gene from Pichia pastoris) overexpression (The Meiotic Recombination 11, DNA double-strand break end resection), Δrad9 (Radiation-Sensitive 9, DNA damage checkpoint regulation), Δmph1 (Mutator Phenotype Helicase 1, improvement of homologous recombinant strand extension), and PapRecT-PaSSB co-expression (stabilization of recombination intermediates) were integrated to generate the highly recombinogenic strain Y09. For vector engineering, cenARS was replaced by panARS and the endogenous promoter PGAP was employed to drive the double hammerhead ribozyme-single guide RNA-hepatitis delta virus ribozyme (double HH-sgRNA-HDV: dHgH)-mediated sgRNA expression, yielding the optimized vector Nov_pGAP_panARS_pLAT1_Cas9. These two features on K. phaffii together enhanced the EMGES 3.0 to a higher standard of transformation rate and editing efficiency. According to our results, EMGES 3.0 achieved dual-functional gene knockout efficiencies between 76.6% and 100%. For insertion of medium-long fragments (>4.5 kb), the efficiency achieved 93.3%. In addition, the one-step integration of ultra-long fragments (>16 kb) achieved 14.8%, which was reported for the first time. Furthermore, the efficiency of simultaneous long-fragment integration at three neutral loci reached 38.4% (>15 kb). We applied the system for one-step production of free fatty acids (FFAs, yield: 5.82 ∼ 7.30 mg/L/OD600) and resveratrol (yield: 1.14 ∼ 1.28 mg/L) using methanol as the sole carbon source. EMGES 3.0 provides a robust technical foundation for complex compounds biosynthesis and high-yield industrial strains, while also advancing K. phaffii as an industrial synthetic biology chassis for efficient C1 utilization.

CRISPR-Cas Systems↗

PubMed2026

Exercise-associated epigenetic remodeling and TCR repertoire dynamics in Lynch syndrome carriers.

Lynch syndrome (LS) carriers are at elevated cancer risk. Emerging evidence suggests that exercise may serve as a non-pharmacologic preventive strategy, yet the epigenetic and immunological mechanisms underlying its protective effects in this population remain unclear. Here, we perform integrative multi-omics profiling of DNA methylation, gene expression, and the T cell receptor (TCR) repertoire in LS carriers undergoing a 52-week aerobic cycling intervention. We identify compartment-specific DNA methylation changes, including innate immune activation in cfDNA and oncogenic pathway repression in tissue. Integrative transcriptomic analysis highlights ISL1 as a key exercise-repressed, epigenetically regulated gene, and identifies FLCN as a colorectal cancer (CRC)-associated methylation target. TCR analysis reveals an exercise-associated increase in systemic repertoire diversity and tissue-specific clonal convergence, thus suggesting antigen-driven recruitment. Collectively, these findings uncover epigenetic and immune remodeling as potential mechanisms of exercise-mediated protection in LS.

Lynch syndrome↗

PubMed2026

Recurrent myocardial infarction identified by centralized troponin review: Insights from the MINT trial.

BACKGROUND: The utility of routine troponin testing to identify recurrent myocardial infarction (MI) after an incident MI is unclear. We assessed the incidence and prognosis of recurrent MIs identified from centralized troponin review in patients from the Myocardial Ischemia and Transfusion (MINT) trial. METHODS: The MINT trial randomized patients with acute MI and anemia to a liberal vs restrictive red blood cell transfusion strategy. Suspected recurrent MIs were identified through both site-report and centralized review of troponin levels collected for 3 days following randomization. Differences in cardiac, noncardiac, and all-cause death at 30 and 180 days were compared across patients with any site-reported MI, only centrally identified MI, and no recurrent MI. RESULTS: Among 3,504 patients, 275 (7.8%) had a recurrent MI within 30 days; 119 (43.3%) by site-report, and 156 (56.7%) by central troponin review only. Rates of cardiac and all-cause death at 30 and 180 days were highest for patients with site-reported MI, intermediate for centrally identified MI, and lowest for no recurrent MI; rates of noncardiac death did not vary. Patients with only centrally identified recurrent MI had an increased risk of cardiac death at 30 days (RR 1.9, 95% CI 1.0-3.4) and 180 days (RR 1.7, 95% CI 1.1-2.7) compared to those without recurrent MI. CONCLUSIONS: In patients with acute MI and anemia, centralized troponin review identified more than half of all recurrent MI events. Patients with centrally identified MI had a higher risk of cardiac death than those with no recurrent MI. TRIAL REGISTRATION: ClinicalTrials.gov NCT02981407 https://clinicaltrials.gov/study/NCT02619136.

Humans↗

PubMed2026

Smoke-Free Home Intervention in Permanent Supportive Housing: A Cluster Randomized Clinical Trial.

IMPORTANCE: Chronic diseases related to tobacco use and secondhand smoke exposure are the leading causes of death among formerly homeless adults living in permanent supportive housing (PSH) in the US. OBJECTIVE: To evaluate the efficacy of a brief, smoke-free home intervention in promoting voluntary smoke-free home adoption among PSH residents. DESIGN, SETTING, AND PARTICIPANTS: In this cluster randomized clinical trial, data collection occurred from January 11, 2022, to March 31, 2025. Participants were residents aged 18 years or older who smoked cigarettes at home in 40 multiunit PSH sites in the San Francisco Bay area, randomized to intervention or waiting list control clusters, and housing staff who worked at the study sites. INTERVENTION: Residents in intervention sites received one-on-one in-person coaching from research staff on adopting a smoke-free home; waiting list control site residents received no interventions during the study but were offered the intervention once the intervention group completed follow-up. Staff in both intervention and control sites received training on providing brief tobacco cessation coaching. MAIN OUTCOMES AND MEASURES: Primary outcomes were smoke-free home adoption for at least 90 days and 7-day carbon monoxide-verified point prevalence abstinence (PPA; expired carbon monoxide level ≤5 ppm) at 6 months. Secondary outcomes were any adoption (≥1 day) of a smoke-free home in the past 90 days among residents and changes in Smoking Knowledge, Attitudes, and Practices (S-KAP) scores among staff. RESULTS: The trial enrolled 400 residents (mean [SD] age, 54.5 [10.7] years; 251 [63.1%] male), 191 in the intervention and 209 in the control cluster. At 6 months, 13 residents (6.8%) in the intervention and 10 (4.8%) in the control group adopted a smoke-free home for at least 90 days (odds ratio [OR], 1.45; 95% CI, 0.69-3.07). Few residents achieved 7-day PPA, though more intervention residents (12 [6.3%]) achieved it compared with controls (2 [1.0%]) (OR, 6.94; 95% CI, 1.69-28.45). Intervention residents had greater odds than control residents of any smoke-free home adoption of at least 1 day (121 [63.4%] vs 77 [36.8%]; adjusted OR, 3.83 [95% CI, 2.63-5.57]). Among staff, mean (SD) S-KAP scores increased at 6 months vs baseline for beliefs (by 0.21 [0.55] points) and practices (by 0.24 [0.61] points) pertaining to providing cessation treatment. CONCLUSIONS AND RELEVANCE: In this cluster randomized clinical trial, the brief intervention did not result in a significant increase in smoke-free home adoption for at least 90 days, though more residents in the intervention than the control group attempted adoption for at least 1 day. These findings support the scalability of this approach to reduce smoking in PSH, but more intensive interventions may be needed to sustain intervention effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04855357.

Humans↗

PubMed2026

Adaptive proteomic remodeling and eNOS upregulation in luminal endothelium and perivascular adipose tissue of patent saphenous vein grafts after CABG.

OBJECTIVE: Long-term patency of saphenous vein grafts (SVGs) remains a significant challenge in coronary artery bypass grafting (CABG). The biological factors underlying successful human grafts are poorly understood. We aimed to characterize the structural and molecular features associated with successful graft function. METHODS: Patent and occluded SVG and internal thoracic artery (ITA) grafts were obtained from explanted hearts of CABG patients undergoing heart transplantation for end-stage heart failure not attributable to graft failure, along with freshly harvested ITA and SVG controls. Samples underwent histomorphological analysis, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics. RESULTS: Patent ITA (ITA-P) showed minimal intimal hyperplasia with medial reinforcement, whereas patent SVGs (SVG-P) had organized, α-smooth muscle actin (αSMA)-positive myofibroblast-rich neointima. Endothelial nitric oxide synthase (eNOS) was markedly upregulated in patent grafts at two sites-the luminal endothelium and adventitial microvessels within perivascular adipose tissue (PVAT)-and lost at both sites in occluded SVG (SVG-O). Adventitial CD31-positive microvessels were significantly increased in patent grafts. Proteomically, ITA-P and SVG-P shared a largely common adaptive proteome enriched in translation, RNA processing, and extracellular matrix (ECM) organization, with shared upstream activation of NR4A3, EGFR, and STAT1, and conduit-specific signatures (IGF-1/RUNX2 in ITA-P; RETN/SRC/PTGES in SVG-P). PTGES was strongly expressed in the adventitia of SVG-P. CONCLUSIONS: Patent arterial and venous bypass grafts exhibited a shared adaptive phenotype characterized by dual-site upregulation of eNOS in both the luminal endothelium and the perivascular microvessels/PVAT. In SVG-P, PTGES was co-upregulated alongside eNOS, indicating a mechanistic link between the proteomic and IHC findings. These findings highlight the perivascular compartment as a site of adaptive, eNOS-associated changes in patent vein grafts.

Humans↗