SOX4 is a transcriptional activator for CTHRC1 in lung fibroblast activation.

METTL3-mediated m6A modification of circWDR85 drives breast cancer bone metastasis via the CKB/c-Jun axis.

Real-world emergence of nirsevimab resistance in breakthrough infections with respiratory syncytial virus-B: a multicentre observational study in France.

High affinity and selective DNA aptamers for the detection of tobramycin in eye drops.

Postoperative risk stratification using calcitonin doubling rate in medullary thyroid carcinoma with biochemical persistent disease.

Clamp the LAMP: a photoelectrochemical platform for KRAS mutation detection via wild-type blocking.

Promoting keratinocyte psoriasiform changes and IL-17RE expression: Potential role of GLT1D1 in linear psoriasis.

3-n-Propionyl Zaluzanin C from Saussurea involucrata alleviates inflammation and oxidative stress: potential involvement of the NRF2 signaling pathway.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) continue to provide a rich source of structurally diverse and bioactive natural products, yet radical S-adenosylmethionine (rSAM)-catalyzed C-C bond formation remains unexplored in lanthipeptide biosynthesis. Here, we report the discovery of azepinopeptide A, a new class of lanthipeptides featuring an unprecedented tetrahydropyrrolo[1',2':1,2]azepino[3,4-b]indole scaffold formed through rSAM-catalyzed cross-linking of adjacent Trp1 and Pro2 residues. This unusual sp2-sp3 C-C bond formation, which has not been observed in any previously characterized rSAM enzyme-catalyzed RiPP, is mediated by a distinct subclass of lanthipeptide rSAM enzymes. Biochemical reconstitution and mutational analyses demonstrate that these enzymes exclusively recognize the mature, leader-free lanthipeptide substrate and lack both the RiPP recognition element and the auxiliary iron-sulfur cluster that are essential in other RiPP rSAM systems. Computational structural analysis, supported by in vivo co-expression studies, reveals a specialized binding pocket capable of accommodating the lanthipeptide substrate and positioning the catalytic [4Fe-4S] cluster deep within the pocket. This arrangement provides a basis for the observed regioselectivity and strict requirement for leader peptide removal. Azepinopeptides A and B exhibit potent neuroprotective activity at low concentrations comparable to that of the positive control, 3-n-butylphthalide. Bioinformatic analyses further uncover hundreds of related biosynthetic gene clusters, highlighting the prevalence of this biosynthetic strategy. Together, these findings expand the catalytic repertoire of rSAM enzymes and introduce a new platform for the biosynthetic generation of medium-sized ring peptide architectures with therapeutic potential.

Systemic mastocytosis (SM) is a rare clonal myeloproliferative neoplasm typically characterized by cutaneous lesions and mediator-release symptoms. Presentations dominated by visceral organ involvement without skin findings are uncommon and pose a significant diagnostic challenge, often mimicking hematologic malignancies. We report a 50-year-old male presenting with generalized weakness, fatigue, and progressive abdominal distension. Examination revealed significant hepatosplenomegaly with no cutaneous manifestations. Investigations demonstrated severe leukocytosis (peak WBC 112.8 × 103/μL) with a leucoerythroblastic picture, persistently elevated alkaline phosphatase, and anemia. Initial bone marrow morphology suggested chronic myeloid leukemia (CML), showing marked hypercellularity (95-100%) and granulocytic hyperplasia (M:E ratio 32:1). Cytogenetics revealed a normal male karyotype (46, XY), and BCR-ABL1 testing was negative, excluding CML. Comprehensive molecular profiling identified a pathogenic KIT p.D816V mutation, confirming systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). The patient was treated with cladribine (40 mg over five days) followed by maintenance hydroxyurea (300 mg twice daily), with significant clinical improvement at eight-week follow-up. This case underscores that SM-AHN can present with isolated hepatosplenomegaly and profound leukocytosis without cutaneous signs, and highlights the critical role of integrated molecular profiling, including KIT mutation analysis, in the diagnostic workup of atypical hematologic presentations.

YhbO is a DJ-1 family glyoxalase and α-oxoaldehyde hydratase that confers resistance to reactive carbonyl stress (112).

Lymphomatosis cerebri (LC) is a rare variant of primary CNS lymphoma characterized by diffuse fluid-attenuated inversion recovery (FLAIR) hyperintensity on MRI. A 71-year-old woman presented with a 1-month history of nausea. On admission, she showed no focal neurological deficits except dizziness. MRI revealed diffuse FLAIR hyperintensity from the cerebellar vermis to the midbrain involving the right temporal and parietal lobes, accompanied by partial diffusion-weighted imaging (DWI) hyperintensity and no gadolinium enhancement. 18F-fluorodeoxyglucose positron emission tomography demonstrated no abnormal uptake, and CSF analysis demonstrated elevated β2-microglobulin (MG) levels and an MYD88 mutation on cell-free DNA that leaked into the CSF. A targeted biopsy of the DWI-hyperintense region confirmed CD20-positive diffuse large B-cell lymphoma. She underwent therapy with rituximab, methotrexate, procarbazine, and vincristine followed by high-dose cytarabine, achieving temporary remission; however, relapse occurred 1 month after consolidation therapy. Tirabrutinib was initiated, resulting in complete radiological resolution for 5 months. LESSONS Diffuse white matter abnormalities without enhancement should raise suspicion of LC and prompt targeted biopsy, particularly from DWI-hyperintense regions. CSF β2-MG and MYD88 mutation analysis provide valuable diagnostic clues for distinguishing LC from malignant glioma. This case also suggests a potential therapeutic role for tirabrutinib in early-relapsing LC. https://thejns.org/doi/10.3171/CASE26337.

Female gametogenesis in Drosophila melanogaster requires differentiation and mitotic division of germ cells, acquisition of oocyte fate, and entry into meiosis. Each of these processes is well understood individually; however, little is known about the mechanisms that ensure proper temporal integration of germ cell differentiation and meiotic chromosome dynamics. Here, we take advantage of a hypomorphic mutation in mei-P26, a well-characterized gene with multiple diverse functions in germ cell development, to determine the consequences of disrupting the coordination between development and meiosis. While null mutations in mei-P26 lead to tumorous ovaries, the hypomorphic allele mei-P261 allows sufficient germ cell differentiation and fertility to support analysis of meiotic chromosome dynamics. Unlike wildtype germaria, 60% of cysts in mei-P261 germaria co-express the differentiation factor Bag of marbles (Bam) and the oocyte specification factor Orb, suggesting that mitotic division is delayed. In this context, the synaptonemal complex rarely assembles into full length continuous tracks and instead is missing or present only as foci. Despite these phenotypes, meiotic double-strand breaks still form and are repaired as crossovers, but the crossovers are mis-patterned and form in centromere proximal regions rather than chromosome arms. The strength of crossover interference is significantly reduced and the centromere effect is lost, but crossover assurance is intact and the meiosis-specific machinery is used to form crossovers. We suggest a model where the failure to exit mitosis in a timely fashion causes cells to enter meiosis while still receiving mitotic signals, resulting in abnormal meiotic chromosome dynamics and impaired crossover formation.

ABSTRACT Background Thyroid cancer (TC), the most common endocrine malignancy, is closely linked to aging. In this study, we estimated DNA methylation (DNAm) age in TC tissues versus adjacent non-cancerous thyroid tissues using TCGA and GSE97466 datasets. Methods We employed multi-tissue DNAm age estimators, specifically Horvath’s clock and the Bayesian Neural Network (BNN) clock, to quantify epigenetic aging in TC and adjacent normal tissues from the TCGA and GSE97466 cohorts. We further integrated genomic, transcriptomic, and mutational analyses, including assessments of senescence-associated secretory phenotype (SASP), immune cell infiltration, and thyroid differentiation, to elucidate the associations between DNAm age acceleration and various cancer-related features. Results Our results revealed marked DNAm age acceleration in TC tissues relative to controls, with both models yielding significantly higher DNAm age estimates in tumors. Although DNAm age correlated strongly with chronological age in control tissues (R ≈ 0.94), this association was notably diminished in TC tissues (R ≈ 0.62). Moreover, TC tissues with accelerated DNAm age exhibited higher telomerase-associated gene expression score, heightened SASP signaling, and distinct immune profiles characterized by elevated M2 macrophages and reduced activated NK cells. Genomic analysis further showed a higher prevalence of BRAF mutations and lower thyroid differentiation scores (TDS) in the accelerated subgroup. No significant associations were detected between DNAm age and clinicopathological parameters or overall survival. Conclusions Our findings provide valuable insights into the complex interplay between epigenetic regulation, immune dysfunction, and genomic instability in thyroid cancer, highlighting promising avenues for future research and therapeutic intervention.

Beyond acute and chronic poisoning, scientific attention in recent years has shifted toward the negative effects of pesticides on genetic material. Numerous studies demonstrate that these compounds possess both genotoxic and mutagenic potential. Therefore, the aim of this study is to investigate and compare the potential of chlorpyrifos (CPS) and glyphosate (GLY) to induce DNA damage. Human immortalized keratinocytes cell line HaCaT were used as the test organisms in viability (Neutral Red assay) and genotoxicity assays (Comet assay). To test the mutagenicity, S. typhimurium strains TA98 and TA100 assay was used in microplate format. The study demonstrated that CPS exhibits significantly higher toxicity and genotoxicity, compared to GLY. The Ames test showed that CPS possesses mutagenic potential (strain TA98) only after activation with the S9 fraction, remaining inactive against strain TA100. Although GLY did not induce mutations in strain TA98, at the highest concentration (1,000 μM), it caused substitution mutations (strain TA100). Due to the complexity of pesticide biotransformation mechanisms and their diverse impact on genetic material, relying on a single test system is insufficient. To obtain a reliable safety assessment and capture the full spectrum of potential damage, it is necessary to combine bacterial methods, with cytogenetic studies on mammalian cells. Such a complementary approach eliminates errors resulting from the high cytotoxicity of pesticides toward bacteria, and enables the analysis of DNA mutations in non-bacterial models. Further research into the impact of these compounds on the genetic material of living organisms is therefore necessary, but using a greater number of biological models, as well as other methods to resolve this issue.

Rad26, a yeast homologue of mammalian Cockayne syndrome protein B (CSB), plays an essential role in transcription-coupled nucleotide excision repair (TC-NER). Rad26/CSB binds RNA polymerase II stalled at DNA lesions and recruits DNA repair factors, functioning as a molecular scaffold. In addition, Rad26/CSB possesses nucleosome-remodeling activity that may help restore transcription after DNA repair. Here we determine the cryo-electron microscopy structure of the Rad26/CSB-nucleosome complex. Rad26/CSB binds near the nucleosomal entry/exit region (superhelical location ±6) through a unique mechanism in which its ATPase domains, Lobe 1 and Lobe 2, engage nucleosomal DNA in a reverse orientation compared with other remodelers such as Snf2 and Ino80. Mutational, biochemical, and crosslinking mass-spectrometric analyses demonstrate the requirement of the KR loop for nucleosome binding and remodeling. Furthermore, we show that N-terminal auto-inhibition involves long-range contacts between the disordered N-terminus and the Lobe 2 region, and is relieved by mutations of Leu8 and Leu11. These findings reveal the structural basis of Rad26/CSB-mediated nucleosome remodeling in TC-NER.

A YafK family protein from Legionella pneumophila exhibits serine-dependent β-lactam hydrolysis activity.

Genome-wide SNP-based Profiling of Loss of Heterozygosity Reveals Distinct Molecular Subgroup-specific Patterns in Gastrointestinal Stromal Tumors (GIST).

To identify the mutational landscape of oral cancers of unknown etiology by leveraging publicly available datasets. Oral cancer mutation data in TCGA were accessed to identify never-smoking and never-alcohol-drinking subjects with genomic, epigenomic, and transcriptomic data. Habit-free participants within published individual whole-exome sequencing studies of oral cancer were examined as the replication dataset. Somatic mutation analysis of 42 habit-free TCGA oral cancer subjects revealed MUC16 and MUC5B as recurrent mutational targets in 30% of all habit-free oral cancers; the highest after previously reported oral cancer genes such as TP53, CASP8, CDKN2A, NOTCH1. Comparison against other habit-free oral cancers not only confirmed these observations but also identified additional mucin genes as frequent mutational targets, supporting their potential causal role. Gene expression and immune fraction analysis of bulk transcriptomic data showed that habit-free oral cancers were enriched for the expression of mesenchymal genes and in T-regulatory cells. Together, these data suggest that mucin genes, specifically MUC16 and MUC5B, are important for oral carcinogenesis in the absence of tobacco and alcohol. These results are relevant given the increasing clinical utility of mucins as druggable targets in cancer, particularly MUC16.

Hepatitis B virus (HBV), a major human pathogen, replicates its DNA genome by protein-primed reverse transcription of a pregenomic RNA (pgRNA). This process is directed by the pgRNA-borne epsilon (ε) element, which provides the origin for minus-strand DNA synthesis and mediates coencapsidation of pgRNA with the viral polymerase (P protein) into nucleocapsids. ε adopts a thermodynamically stable hairpin structure that is remodeled upon formation of functional ε-P complexes, but the nature of the rearranged RNA structure and its implication for pgRNA encapsidation has remained elusive. Guided by in silico analyses of ε-like elements from distantly related nackednaviruses, we identify a distinct conformation of HBVε whose defining feature is a cryptic stem-loop (cSL), masked within the upper stem of ε. The P-dependent cSL conformation reorganizes key sequences into a compact structural unit that enables initiation of DNA synthesis and packaging of the viral pgRNA-P complex. RNAs engineered to favor cSL formation exhibit increased P protein affinity and strongly enhanced priming activity in vitro while maintaining replication competence in cells. Mutational analyses identify the cSL and its immediate vicinity, but not the remaining upper stem sequence, as the dominant determinants of ε function. Genetic variation in cSL-forming potential across hepadnaviruses links in vitro priming competence to the energetic accessibility of this alternative fold. Together, our findings reveal ε as a P protein-dependent RNA switch that tightly couples pregenome encapsidation to reverse transcription competence. This regulatory mechanism advances our understanding of HBV replication and could be exploited for antiviral intervention.