Biomedical subjects

Xin Wang

Publications and source records attributed to Xin Wang.

18 recordsLinked to original sources

PubMed2026

Cross-target and cell-preferential CRISPR-Cas9 inhibition with carbohydrate-tagged oligonucleotides.

Precise control of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) activity is important for limiting off-target effects and chromosomal rearrangements. Existing inhibitors, including anti-CRISPR proteins and spacer-targeting oligonucleotides, can be constrained by immunogenicity, target-sequence dependence, or delivery challenges. Here, we developed single-stranded DNA oligonucleotides that target conserved regions of the Streptococcus pyogenes Cas9 single-guide RNA (sgRNA) scaffold rather than the variable spacer. Screening identified single-stranded DNA 7 (ssDNA7), which targets stem-loop-1 and the adjacent linker and inhibits Cas9 activity across multiple tested spacer sequences and genomic loci without redesigning the inhibitor. Carbohydrate conjugation improved oligonucleotide stability and preferentially enhanced inhibitory activity in selected liver-derived or cancer cell models. Amplicon sequencing confirmed inhibition of endogenous editing in multiple cell models and normal liver-derived organoids, and supported cell-preferential inhibition in matched cell comparisons. These findings establish sgRNA-scaffold targeting as a strategy for cross-target inhibition of Cas9 and show that carbohydrate conjugation can tune its cellular activity.

CRISPR-Cas9↗

PubMed2026

Dynamic Disentanglement Enables Highly Crystalline Fluorinated Polyimide Films Featuring Superior Dielectric Property and Intrinsic Thermal Conductivity.

The advancement of high-frequency communication and miniaturized electronics necessitates dielectric materials that combine high intrinsic thermal conductivity (λ) with low dielectric loss (Df) to mitigate signal delay and thermal accumulation. Conventional strategies, particularly nanocomposite approaches, often struggle to simultaneously achieve high λ and low Df without compromising processability or mechanical integrity. Herein, a semicrystalline polyimide (TAHQ/TFMB) architecture is initially established by circumventing the amorphous nature of fluorinated systems via rigid-rod backbone design and programmed thermal processing. Subsequently, minor dynamically exchangeable siloxane segments (≤ 1 mol%) act as molecular disentanglement switches, triggering topological rearrangement that promotes the formation of widely distributed crystal nuclei and enables the subsequent development of large-scale crystalline domains, ultimately yielding an enhanced crystallinity exceeding 50%. The optimally designed film with merely 0.25 mol% siloxane exhibits an enhanced in-plane λ of 2.33 W·m-1·K-1 and an ultralow Df of 0.00142 at 10 GHz. This synergy facilitates the first realization of a broadband thermoacoustic generator featuring an all-organic substrate and a flexible hairpin bandpass filter with excellent signal transmission performance. Furthermore, the DBPI-0.25 film exhibits excellent thermal stability (Td5% = 478.3°C), superior moisture resistance (water uptake of 0.41%), and good mechanical flexibility, rendering it highly suitable for advanced microelectronics.

crystalline polyimide↗

PubMed2026

Unraveling cadaverine toxicity effect to guide the engineering of robust strain.

End-product inhibition represents a major challenge in the microbial synthesis of various value-added chemicals. Cadaverine, a key monomer for polyamide synthesis, exhibits severe cytotoxicity, limiting its high-titer biosynthesis. Here, transcriptomic analysis and genome-wide library screening were integrated to systematically elucidate the cytotoxic mechanisms of cadaverine in Escherichia coli (E. coli) and identify beneficial genes for enhanced tolerance and overproduction. Transcriptomic analysis revealed that high concentrations of cadaverine disrupted cell membrane integrity and impaired oxidative phosphorylation, leading to redox imbalance and reactive oxygen species (ROS) accumulation. Subsequent genome-wide screening further confirmed these toxicity mechanisms and uncovered crucial cellular defense strategies. Functional validation highlighted the important role of NikR, UbiE, and YcbX in enhancing membrane integrity, restoring respiratory function and ROS homeostasis, or scavenging 6-N-hydroxylaminopurine (6-HAP) to prevent DNA damage. Among these, YcbX emerged as the most effective target for improving production. Consequently, we constructed a robust E. coli strain by implementing a dynamic regulation system for YcbX expression under cadaverine-responsive promoters, which significantly enhanced cadaverine biosynthesis to 87.2 g/L (a 46.8% enhancement). This work provides an in-depth understanding of cadaverine toxicity and tolerance, offering valuable targets and strategies for the rational design of high-performance microbial cell factories for diamines.

6-HAP clearance↗

PubMed2026

Prion-Like Protein LENG8-Mediated Nucleation Drives Stress Granule Assembly.

Stress granules (SGs) are highly dynamic and reversible cytoplasmic biomolecular condensates formed via liquid-liquid phase separation (LLPS) under various stresses. As inherently heterogeneous assemblies, SGs possess distinct stable cores (initial nucleation seeds), substructures, or microphases. However, the mechanisms governing the formation and heterogeneity of SG nucleation seeds, and their dynamic integration, remain largely unclear. Here, we demonstrate that LENG8 is recruited to SGs under multiple stress conditions and is indispensable for SG assembly. Upon stress exposure, nuclear LENG8 granules disassemble, enabling LENG8 to translocate into the cytoplasm and undergo LLPS to form independent initial nucleation foci distinct from canonical G3BP1/TIA1-dependent seeds. Subsequently, these LENG8-initiated foci merge into growing SGs through a direct interaction between the prion-like domain of LENG8 and TIA1, facilitating SG expansion and maturation. Depletion of LENG8 or disruption of the LENG8-TIA1 interaction markedly impairs SG formation. Using conditional Leng8 knockout mice, we further establish that LENG8 deficiency attenuates stress-induced SG assembly and increases cellular apoptosis in germ cells. Collectively, our study identifies LENG8 as a previously unrecognized SG nucleator, revealing the hierarchical assembly and integration mechanism of distinct nucleation modules during early SG biogenesis.

LENG8↗

PubMed2026

Targeting PRMT9 overcomes venetoclax resistance in AML by modulating splicing and inhibiting translation.

Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is required for cancer cell proliferation, but whether PRMTs mediate resistance to therapy remains unclear. Here, we performed loss-of-function screens in venetoclax-resistant (VEN-R) acute myeloid leukemia (AML) patient-derived xenograft cells and found that PRMT9 plays a critical role in promoting VEN resistance. Specifically, VEN-R AML samples exhibited high levels of PRMT9, and PRMT9 inhibition resensitized AML cells to VEN treatment. In preclinical resistant models, genetic ablation of PRMT9 synergized with VEN to eradicate AML cells. Consistently, pharmacologic inhibition of PRMT9 combined with VEN produced similar effects in VEN-R AML mouse models. Mechanistically, PRMT9 ablation disrupted RNA splicing by inducing exon skipping in mRNA encoding ALG13, an uridine diphosphate (UDP)-N-acetylglucosaminyltransferase subunit, thereby downregulating expression of the VEN efflux transporter encoded by the adenosine triphosphate-binding cassette subfamily C member 1 gene. PRMT9 inhibition also suppressed protein synthesis, leading to downregulation of short-lived oncoproteins such as MCL1. These findings establish a connection between PRMT9-mediated arginine methylation and poor VEN responsiveness and demonstrate that targeting PRMT9 may represent a viable strategy to overcome VEN resistance.

Protein-Arginine N-Methyltransferases↗

PubMed2026

Long-read sequencing reveals widespread novel splicing and neojunction-derived neoantigens in nasopharyngeal carcinoma.

The widespread transcriptomic diversity driven by alternative splicing (AS) contributes to all hallmarks of cancer and represents a critical source of neoantigens for personalized immunotherapy. However, unlike other major malignancies, the full repertoire of AS in nasopharyngeal carcinoma (NPC) remains underexplored. Here, we employ long-read sequencing (LR-seq) to generate a high-resolution, isoform-level transcriptomic atlas from a cohort of 14 NPC tumor samples and four immortalized nasopharyngeal epithelial cell lines. We identify a substantial number of full-length novel transcripts (22,687; ∼44.38%), which reveal diverse splicing patterns and previously unannotated splicing events. By integrating short-read RNA-seq data to quantify isoform expression, we discover a subset of novel transcripts that are differentially expressed between tumor samples and immortalized nasopharyngeal epithelial cell lines. Furthermore, LR-seq enables precise identification of chimeric readthrough fusion transcripts, such as CLDN15-FIS1 and FOXRED2-TXN2 Finally, we develop a computational framework, tumor-specific splicing neoantigen detection (TS-SNAD), to predict neoantigens originating from novel exon-exon junctions (neojunctions) in tumor-specific novel transcripts. Using this framework, we identify neojunction-derived neoantigens and experimentally validate the immunogenicity of selected HLA-B*40:01-restricted neoantigens. These neojunction-derived peptides constitute a new class of noncanonical neoantigens with significant potential for developing personalized cancer vaccines for NPC.

Humans↗

PubMed2026

Identification of OsCsLF6 Gene Responsible for Rice Seed Submergence Germination Through Genome-Wide Association Analysis.

Flooding stress is a primary environmental barrier that severely limits the widespread adoption of direct-seeded rice systems. Under submerged conditions, rapid coleoptile elongation serves as a vital morphological strategy that facilitates anaerobic germination and successful seedling establishment, yet its underlying molecular mechanisms remain poorly understood. Through a genome-wide association study, we identified a critical locus governing anaerobic coleoptile elongation, in which OsCsLF6, encoding a mixed-linkage glucan (MLG) synthase, was characterized as the causal gene. Genetic and biochemical analyses demonstrated that OsCsLF6 positively regulated coleoptile elongation by directly mediating MLG deposition into the primary cell wall. Mechanistically, we identified OsERF74, an AP2/ERF transcription factor, as an upstream master repressor that directly binds to a conserved core cis-element within the OsCsLF6 promoter. Under submergence, OsERF74 deficiency (oserf74 mutants) completely releases this transcriptional suppression, triggering a substantial upregulation of OsCsLF6 expression and subsequent hyper-accumulation of cell wall MLG. In contrast, constitutive overexpression of OsERF74 persistently blocks MLG biosynthesis. Crucially, a natural single-nucleotide polymorphism located within the OsERF74 binding element in the promoter defines two distinct haplotypes. The elite haplotype (Hap1) effectively disrupts OsERF74 binding affinity, which in turn attenuates transcriptional repression and sustains high OsCsLF6 expression, ultimately driving accelerated MLG synthesis and coleoptile elongation. Our findings establish a condition-specific OsERF74-OsCsLF6 regulatory module that serves as a central biochemical hub orchestrating cell wall remodelling during anaerobic germination. This module thus represents a promising molecular target and elite genetic resource for molecular breeding of flood-tolerant and direct-seeded rice varieties.

OsCsLF6↗

PubMed2026

Genomic Evolution of Myeloproliferative Neoplasms and Therapy-Associated Mutagenesis.

UNLABELLED: Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts, but disease can progress to myelofibrosis or acute myeloid leukemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of hematopoietic colonies revealed age-appropriate polyclonal hematopoiesis in triple-negative essential thrombocythemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C > G mutations following azacitidine and characteristic T > A/T > G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate that progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis. SIGNIFICANCE: Longitudinal whole-genome sequencing shows MPN progression is genomically encoded years before clinical transformation, with distinct evolutionary routes to leukemia and MF. It identifies DNA mutagenesis associated with HC and 5-azacitidine, suggests some triple-negative cases are nonclonal, and supports serial clinical genomic monitoring for improved risk stratification and long-term management. See related commentary by Agarwal and Sankaran, p. 1724.

Humans↗

PubMed2026

Paternal exposure to polystyrene nanoplastics induces inter- and transgenerational bronchopulmonary dysplasia-like damage in male offspring by FtMt hypermethylation-mediated ferroptosis.

Bronchopulmonary dysplasia (BPD) is a major cause of chronic lung disease in both preterm infants and adults, but its etiology remains incompletely understood. In this study, F0 generation mice were exposed to polystyrene nanoplastics (PS-NPs), and F1 to F3 generations were obtained by breeding. Multi-omics sequencing including whole genome methylation sequencing, single cell transcriptome sequencing and transcriptome sequencing was performed on the lungs of offspring. The levels of Fe2+, lipid peroxidation products and key gene expression were determined. Male mice exposed to PS-NPs at environmentally relevant doses produced offspring (F1 and F2) that exhibited a typical BPD-like phenotype. Meanwhile, the F0 males showed diminished sperm motility, demonstrating that paternal PS-NPs exposure constituted an etiological factor for BPD in descendants. Mechanistic studies showed that PS-NPs exposure upregulated the expression of DNA methyltransferase Dnmt3a, leading to global hypermethylation of the sperm genome. Importantly, the hypermethylated promoter signature of the mitochondrial ferritin (FtMt) gene partially resisted epigenetic reprogramming and was transmitted to the lungs of offspring, resulting in persistently low FtMt expression in F1 and F2 lungs. This led to increased intracellular Fe2+ levels, subsequently triggered ferroptosis in alveolar epithelial cells, and ultimately impaired alveolarization. Knockdown of FtMt confirmed that FtMt deficiency was sufficient to induce ferroptosis and BPD-like lung injury both in vitro and in vivo. Furthermore, using in vitro fertilization of F0 sperm combined with Dnmt3a siRNA microinjection, we directly demonstrated that Dnmt3a is a key driver for FtMt to escape reprogramming and maintain its hypermethylation. In summary, this study reveals for the first time that paternal PS-NPs exposure causes BPD through a Dnmt3a-FtMt hypermethylation intergenerational and transgenerational axis, providing an epigenetic basis for understanding paternal derived chronic lung disease and potential targets for early intervention.

Animals↗

PubMed2026

RECQL correlates with immune infiltration and serves as a prognostic biomarker and therapeutic predictor in gastric cancer.

BACKGROUND: RecQ-like helicase (RECQL), a member of the RecQ-like DNA helicase family, plays a crucial role in maintaining genomic stability. However, its relevance in gastric cancer (GC) has not been fully investigated. This study aimed to explore the clinical significance, biological functions, and potential role of RECQL in the tumor immune microenvironment of GC through comprehensive bioinformatics analyses and in vitro experiments. METHODS: Weighted gene co-expression network analysis (WGCNA), differential expression analysis, and least absolute shrinkage and selection operator (LASSO) regression were performed using public datasets [The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD), GSE150290] to identify key genes associated with GC progression. Subsequently, key pathways were identified through functional enrichment analysis, while immune infiltration and spatial transcriptomic analyses were conducted to characterize RECQL expression and its association with the tumor immune microenvironment. Finally, the effects of RECQL knockdown on the biological function of GC cells were assessed through Cell Counting Kit-8 (CCK-8), colony formation, scratch, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. RESULTS: RECQL was significantly upregulated in GC tissues and correlated with advanced clinical stage and poor prognosis. Gene set enrichment analysis (GSEA) revealed a strong association between high RECQL expression and DNA repair pathway. Immune infiltration analysis indicated significant enrichment of M2 macrophages in the high-RECQL group, along with upregulation of immune checkpoint molecules including PDCD1, CTLA4, and CD274. Spatial transcriptomics further demonstrated co-localization of RECQL with myeloid cell-enriched regions in tumor parenchymal areas. Furthermore, in vitro experimental results indicated that RECQL was highly expressed in GC cell lines, and its knockdown effectively inhibited the viability, proliferation, and migration capabilities of HGC-27 cells, while enhancing their apoptosis. CONCLUSIONS: RECQL serves as a promising biomarker and potential therapeutic target in GC.

DNA repair↗

PubMed2026

A Common CD36 Variant and the Genetic Landscape of Dilated Cardiomyopathy in Individuals of African Ancestry.

IMPORTANCE: Dilated cardiomyopathy (DCM) is a major cause of heart failure that disproportionately affects individuals of African genetic ancestry (AFR), among whom familial clustering of disease is also more pronounced relative to those of European ancestry (EUR). However, established monogenic DCM genes, identified primarily in EUR populations, explain a smaller proportion of DCM cases in AFR populations. A recent study identified a common AFR-specific nonsense variant in CD36 that accounts for a substantial burden of DCM in AFR. How the risk and population impact of this variant compare with those of established genetic causes of DCM is unknown. OBJECTIVE: To compare the contribution of a CD36 nonsense variant to DCM risk with that of truncating variants in TTN and pathogenic or likely pathogenic (P/LP) variants in other established DCM genes. DESIGN SETTING AND PARTICIPANTS: Multicohort genetic association study including AFR and EUR participants with exome or genome sequence and DCM case status from four datasets: All of Us, Million Veteran Program, Penn Medicine Biobank, and the DCM Precision Medicine Study. EXPOSURE: Carrier status for TTN truncating variants, P/LP variants in 11 high confidence DCM genes, and the CD36 nonsense variant (Y325*; 0, 1, or 2 copies). MAIN OUTCOMES AND MEASURES: Odds of DCM; prevalence of risk-variant carriers among DCM cases; and population attributable fraction (PAF) for DCM. RESULTS: Among 82,623 AFR individuals across four studies, the mean age was 53.4 years and 1,625 had DCM. CD36 Y325* risk-allele homozygotes had 4.8-fold (95% CI, 3.1-7.3) increased odds of DCM, and CD36 Y325* heterozygotes had 1.4-fold (95% CI, 1.2-1.7) increased odds. TTN truncating variants also conferred elevated risk of DCM in AFR participants (OR, 8.46; 95% CI, 5.3-12.3). Among AFR DCM cases, 2.5% were CD36 homozygotes, second only to TTN truncating variants (4.3%) and exceeding all other high-confidence DCM genes combined (1.5%). In population-level analyses incorporating both heterozygous and homozygous CD36 Y325* carriers, the population-attributable fraction for CD36 (9.0%) surpassed that of TTN truncating variants (3.6%). CONCLUSIONS AND RELEVANCE: An ancestry-specific CD36 variant contributes more to DCM burden in AFR ancestry than established DCM genes, including TTN truncating variants, typically considered the most common genetic cause of DCM. These findings reshape the known genetic architecture of DCM in individuals of African ancestry and highlight the importance of representation in genomic research.

Journal Article↗

PubMed2025

Reversing the paradigm: Oxygen-dependent switch of nTiO₂ from promoting to suppressing ARG conjugation.

The environmental spread of antibiotic resistance genes (ARGs) poses a significant public health threat. While nano-titanium dioxide (nTiO2) is known to promote ARG transfer, its role in prevalent anaerobic environments remains poorly understood. Therefore, we comprehensively evaluated the influence of nTiO2 exposure on the plasmid-mediated ARGs conjugation under aerobic/anaerobic conditions. Under aerobic conditions, nTiO2 significantly promoted the ARGs dissemination through both intra-genus (E. coli to E. coli) and inter-genus (E. coli to P. denitrificans) transfer. Reactive oxygen species (ROS) was determined as the decisive factor driving aerobic conjugation, which increased membrane permeability and downregulated conjugative pathways. Addition of ROS scavenger thiourea effectively abolished the stimulatory effect of nTiO₂ on conjugative transfer. However, nTiO2 treatment significantly inhibited conjugative ARG transfer under anaerobic conditions. The dose-dependent inhibition was confirmed in anaerobic denitrification system. Exogenous H2O2 switched the inhibitory effect of nTiO₂ on anaerobic conjugation. Physical barrier formed by nTiO₂ adsorption might contribute to inhibited conjugative transfer of ARGs. Therefore, this study defines the distinct roles of the inhibitory physical effect caused by the adsorption barrier and promotive chemical effect induced by ROS in the nTiO₂-mediated ARG conjugation, which contributes to a deeper understanding of the environmental propagation mechanisms of ARGs under nanomaterial exposure.

Reactive Oxygen Species↗

PubMed2025

C6ORF120 regulates hepatic lipid metabolism through PPAR signaling pathway in metabolic dysfunction-associated steatotic liver disease.

Background Emerging evidence indicates that C6ORF120 is highly expressed in the liver and may modulate immune responses in various hepatic disorders. However, its role in hepatic lipid metabolism and metabolic dysfunction-associated steatotic liver disease (MASLD) is unexplored. This study aimed to elucidate the effects and potential mechanisms of C6ORF120 on hepatic lipogenesis. Methods C6ORF120 expression in MASLD was assessed using patient serum and the Gene Expression Omnibus (GEO) database. A high-fat diet-induced MASLD model was established in C6orf120-KO rats. Fatty acid-induced lipid accumulation models were generated in primary hepatocytes, HepG2 and Huh7 cells. These models were employed to investigate the effects of C6ORF120 on hepatic lipogenesis and MASLD progression. Results C6ORF120 expression was significantly upregulated in MASLD patients and obese rat models. Genetic deletion of C6ORF120 markedly alleviated high-fat diet-induced steatosis in the liver of rats. In vitro, C6orf120 gene deficiency attenuated lipid accumulation and suppressed key lipogenic genes (such as fatty acid synthase (Fasn), phospho-acetyl coenzyme carboxylase (p-ACC), sterol regulatory element binding protein-1c (Srebp1c)) in primary hepatocytes and HepG2 cells. Conversely, C6ORF120 overexpression increased lipid accumulation in HepG2 cells. RNA sequencing analysis showed that lipid metabolism pathway and peroxisome proliferators activated receptor (PPAR) signaling pathway were significantly altered in the liver of C6orf120-KO rats. We demonstrated that C6ORF120 may regulate lipid metabolism through the hepatic PPARα, which is involved in fatty acid production and lipid oxidation. Further, we found that serum C6ORF120 expression was correlated with clinical indicators in patients with MASLD. Conclusion This study preliminarily revealed a novel function for C6ORF120 in hepatic lipid metabolism via affecting the PPAR pathway. The result identifies C6ORF120 as a novel regulator of hepatic lipid metabolism through PPARα-dependent mechanisms, offering potential therapeutic targets for MASLD.

Lipid Metabolism↗

PubMed2025

Nanoscopy Reveals Heparan Sulfate Clusters as Docking Sites for SARS-CoV-2 Attachment and Entry.

Virus entry is thought to involve binding a unique receptor for cell attachment and cytosolic entry. For SARS-CoV-2 underlying the COVID-19 pandemic, angiotensin-converting enzyme 2 (ACE2) is widely assumed as the receptor. Using advanced light microscopy to resolve individual virions and receptors, we found instead that heparan sulfate (HS), not ACE2, mediates SARS-CoV-2 cell-surface attachment and subsequent endocytosis. ACE2 functions only downstream of HS to enable viral genome expression. Instead of binding single HS molecules that electrostatically interact with viral surface proteins weakly, SARS-CoV-2 binds clusters of ~6-137 HS molecules projecting 60-410 nm above the plasma membrane. These tall, HS-rich clusters, present at about one per 6 μm2, act as docking sites for viral attachment. Blocking HS binding with the clinically used HS-binding agent pixantrone strongly inhibited the clinically relevant SARS-CoV-2 Omicron JN.1 subvariant from attaching to and infecting human airway cells. This work establishes a revised entry paradigm in which HS clusters mediate SARS-CoV-2 attachment and endocytosis, with ACE2 acting downstream, thereby identifying HS interactions as a key anti-COVID-19 strategy. This paradigm and its therapeutic implications may apply broadly beyond COVID-19 because, analogous to SARS-CoV-2, HS binds many other viruses but is only considered an attachment regulator.

Journal Article↗

PubMed2025

A whole-brain voxel-based analysis of structural abnormalities in PTSD: An ENIGMA-PGC study.

BACKGROUND: Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group. METHODS: T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9). RESULTS: PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges' g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges' g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (p corrected  = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (p corrected  = .001). CONCLUSIONS: PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.

Humans↗

PubMed2025

The impact of common and rare genetic variants on bradyarrhythmia development.

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (rg = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.

Humans↗

PubMed2025

Differential methylation of a retrotransposon upstream of a MYB gene causes variegation of lettuce leaves, which is abolished by the presence of an (AT)5 repeat in the promoter.

Variegation, a common phenomenon in plants, can be the result of several genetic, developmental, and physiological factors. Leaves of some lettuce cultivars exhibit dramatic red variegation; however, the genetic mechanisms underlying this variegation remain unknown. In this study, we cloned the causal gene for variegation on lettuce leaves and elucidated the underlying molecular mechanisms. Genetic analysis revealed that the polymorphism of variegated versus uniformly red leaves is caused by an "AT" repeat in the promoter of the RLL2A gene encoding a MYB transcription factor. Complementation tests demonstrated that the RLL2A allele (RLL2AV) with (AT)n repeat numbers other than five led to variegated leaves. RLL2AV was expressed in the red spots but not in neighboring green regions. This expression pattern was in concert with a relatively low level of methylation in a retrotransposon inserted in -761 bp of the gene in the red spots compared to high methylation of the retrotransposon in the green region. The presence of (AT)5 in the promoter region, however, stabilized the expression of RLL2A, resulting in uniformly red leaves. In summary, we identified a novel promoter mechanism controlling variegation through inconsistent levels of methylation and showed that the presence of a simple sequence repeat of specific size could stabilize gene expression.

Promoter Regions, Genetic↗

PubMed2025

Integrated genomic, transcriptomic, and metabolomic analyses of Chrysanthemum aromaticum provide insights into the volatile terpene biosynthesis.

Chrysanthemum aromaticum is renowned for its uniformly emitted strong and attractive scent, primarily attributed to volatile terpenes. Despite its commercial and horticultural significance, the molecular mechanisms underlying volatile terpene production in C. aromaticum remain largely unexplored. Here, we present the haplotype-resolved genome assembly of C. aromaticum, with a total size of 3.10 Gb, comprising nine anchored chromosomes with a contig N50 of 30.66 Mb and a scaffold N50 of 350.58 Mb. Phylogenetic analyses revealed a distant relationship between C. aromaticum and C. indicum, suggesting that C. aromaticum likely represents a distinct species rather than a variety of C. indicum. Through integrated genomic, transcriptomic, metabolomic, and biochemical analyses, we identified seven TPS involved in monoterpene biosynthesis and six TPS for sesquiterpene biosynthesis. Notably, comparative genomic analysis revealed a gene cluster for α-bisabolol biosynthesis in C. aromaticum, which has specifically expanded in Chrysanthemum species through tandem gene duplications, contributing to the elevated accumulation of α-bisabolol in the leaves of C. aromaticum. Our study provides important insights into the biosynthesis of volatile terpenes, highlighting the genetic basis for C. aromaticum's unique aromatic profile.

Chrysanthemum↗