Regulatory B cells (Bregs) are a functionally defined yet phenotypically heterogeneous subset of lymphocytes that are essential for maintaining immune homeostasis. Their canonical function is regulated through the secretion of interleukin-10 (IL-10), a potent anti-inflammatory cytokine. However, accumulating evidence indicates that other molecules, such as IL-35 and transforming growth factor-β, and that of contact-dependent pathways, such as Programmed Cell Death Ligand-1(PD-L1) and Programmed Cell Death-1(PD-1), also play indispensable roles in their regulatory arsenal. This review examines the immunoregulatory roles of Bregs across diverse clinical contexts, including infectious diseases, cancers, autoimmune disorders (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and uveitis), and organ transplantation. Crucially, we highlight a fundamental functional dichotomy: although Bregs confer protection against autoimmunity and promote transplant tolerance, they concurrently drive the progression of chronic infections and malignancies by dampening antipathogen and antitumor immune responses. This functional dichotomy highlights the complexity of immune regulation, where Bregs act as critical nodes balancing health and pathology. The immense therapeutic potential by modulating Bregs activity and unresolved questions that will guide the future frontiers of Bregs research are essentially discussed.

Clinically confirmed cohort reveals antioxidant genetic polymorphisms as potential susceptibility factors for long COVID after mild or asymptomatic COVID-19.

Recently, numerous novel phase-space distributions have been proposed by combining the linear canonical transform (LCT) and the Wigner distribution function (WDF), known as the linear canonical Wigner distributions (LCWDs). Among them, the closed-form instantaneous cross-correlation function type of Wigner distribution (CICFWD) has been proven to provide better flexibility for non-stationary signal processing and detection, due to its additional free parameters. Currently, the discrete CICFWD is only defined under a specific LCT parameter constraint and lacks a sampling theorem. This limits its applicability, since in numerical simulations, experiments, and practical optical systems, continuous fields or signals are discretized through digital sampling processes. In this paper, we will develop a general discrete CICFWD formulation without limitations, propose a numerical calculation algorithm, and a corresponding sampling theorem. We will also demonstrate their correctness by comparing the analytical CICFWDs of continuous test signals with their numerically approximated counterparts. Our results will enable more efficient and accurate numerical simulations using CICFWDs, which will be useful in applying them to problems, including optical measurements based on Newton’s rings, numerical optical signal processing, partial coherence, broadband communication and radar systems.

Alternative splicing generates a novel CARD9 isoform.

Adolescence involves pronounced changes in sleep timing and duration that have been linked to executive functioning, impulsivity, and risk behaviors, yet evidence for generalizable sleep - self-regulation associations remains limited. We used regularized canonical correlation analysis to examine multivariate relationships between sleep and self-regulation across two independent cohorts. In the Adolescent Brain Cognitive Development study (n = 11,143), later chronotype and shorter sleep duration were associated with higher impulsivity, particularly urgency and deficits in planning and perseverance (r = 0.21, permutation p < 0.001), with minimal contribution from delay discounting. Social jetlag showed weak loadings. In the National Consortium on Alcohol and Neurodevelopment in Adolescence cohort (n = 831), only one canonical function was statistically significant (r = 0.15, p = 0.011), characterized by later chronotype and greater social jetlag, with minimal contribution from sleep duration and primary loadings on impulsivity-related measures. Applying the ABCD-derived sleep - self-regulation pattern to NCANDA produced a small but nonzero association, driven primarily by social jetlag and delayed sleep timing, with minimal influence of sleep duration. These findings provide multivariate evidence linking delayed sleep timing and circadian misalignment to adolescent self-regulation, though effect sizes attenuate across cohorts. Longitudinal work is needed to clarify predictive pathways and inform sleep-focused interventions during this vulnerable developmental period.

Beyond Oncogenesis: The emerging role of EZH2 in Tumor Microenvironment.

Polycomb group (PcG) genes are epigenetic silencers that maintain transcriptional repression of target genes essential for normal development. However, their roles in adult multipotent stem cell lineages remain poorly understood. Here, we show that simultaneous loss of the PRC1 component Psc and its homolog Su(z)2 in intestinal stem cells (ISCs) of the adult Drosophila midgut leads to tumor formation composed of proliferative, undifferentiated cells. Strikingly, these tumor cells do not activate proliferation-associated pathways, including JAK/STAT, Ras/MAPK, and Wnt, nor do they activate Notch or JAK/STAT signaling, which are essential for ISC differentiation. Transcriptomic and chromatin accessibility profiling reveal widespread downregulation of ISC and progenitor cell identity genes and ectopic activation of neural lineage genes. Among these, chinmo is aberrantly upregulated and required for tumor overgrowth. Notably, loss of other PRC1 components does not recapitulate the tumor phenotype, suggesting that the tumor-suppressive role of Psc and Su(z)2 is independent of canonical PRC1 function. Together, our findings uncover a noncanonical, context-specific tumor-suppressive role for Psc and Su(z)2 in preserving ISC identity and restricting lineage deviation.

Hyperglycemia-induced metabolic memory refers to the phenomenon in which cells and tissues retain the persistent damage caused by elevated blood glucose even after glucose levels have returned to normal. Studies have demonstrated that noncoding RNAs, particularly microRNAs (miRNAs), contribute to hyperglycemia-induced metabolic memory through the epigenetic regulation of gene expression. Unlike the canonical function of cytoplasmic miRNAs in gene silencing, nuclear-activating miRNAs (NamiRNAs) have been proposed to interact with enhancers and potentially activate gene transcription, representing an emerging mode of nuclear miRNA function that remains to be validated in diabetic systems. In this review, we summarize the current pathogenic mechanisms of hyperglycemia-induced metabolic memory and highlight both the established and emerging roles of miRNAs in epigenetic regulation within this field.

<SPAN style="font-weight: 400;">The QueC protein family (PF06508) is best known for its role in the biosynthesis of 7‑deazaguanine derivatives, including the tRNA modification queuosine and the DNA base 7‑cyano-7‑deazaguanine (preQ</SPAN><SPAN style="font-weight: 400;">0</SPAN><SPAN style="font-weight: 400;">). Recent discoveries, however, reveal that this ancient scaffold has been repeatedly repurposed for distinct biological functions, including roles in anti‑phage defense. Here, we combine Sequence Similarity Networks (SSN) with genomic neighborhood analyses to map the functional diversification of the PF06508 superfamily. We delineate the canonical QueC cluster and experimentally define a refined catalytic signature, identifying previously unrecognized residues essential for tRNA modification. Beyond the canonical function, we characterize the evolutionary repurposing of the QueC fold in anti-phage systems, distinguishing between the "divergent specialist" QatC, which remodels the active site, and the "minimalist conservationist" Cap9, which retains the ancestral catalytic core. We further uncover the expansion of the superfamily into additional biochemical pathways, including cofactor biosynthesis (e.g., LarE) and purine salvage. Together, these findings provide a comprehensive framework for understanding how the QueC scaffold has been adapted from small‑molecule biosynthesis to roles in protein modification and phage defense.</SPAN>.

The canonical transsulfuration (TSS) pathway enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH) are traditionally recognized for their roles in the sequential conversion of homocysteine to cysteine and in endogenous hydrogen sulfide (H2S) production. Increasing evidence, however, suggests that these enzymes may also exhibit non-canonical ("moonlighting") functions that extend beyond metabolic regulation. In this review, we evaluate the hypothesis that CTH may participate in translational regulation, particularly in the control of hypoxia-inducible factor-1α (HIF-1α) expression in clear cell ovarian carcinoma (CCOC). We first highlight limitations of the prevailing H2S- and cysteine-centric view of the TSS pathway, which may not fully explain emerging context-dependent functions of CTH in cancer biology. Current evidence suggests that CTH enhances HIF-1α protein expression through mechanisms independent of transcription, protein stability, or H2S production, implicating a potential role in translational regulation, although direct mechanistic evidence remains limited. To critically evaluate this emerging hypothesis, we categorize evidence according to its level of experimental support, ranging from direct experimental evidence to indirect mechanistic observations and computational predictions. Within this framework, we examine three non-mutually exclusive models: (1) regulation through PI3K/AKT/mTOR-dependent translational signaling; (2) modulation of translational control through interaction with translation-associated proteins and RNA-binding proteins (RBPs) involved in HIF1A mRNA regulation; and (3) the more speculative possibility of direct interaction between CTH and HIF1A mRNA. Collectively, these observations support a model in which CTH contributes to selective translational regulation beyond its canonical metabolic functions, potentially linking sulfur metabolism to stress-adaptive gene expression in cancer.

Current understanding recognizes that ribosomal proteins (RPs) have regulatory roles beyond their canonical structural functions in translation, raising the question of how their expression is organized across cell types. Given the diversity of neuronal cell types, understanding RP gene expression at the neuronal subtype level is an important and previously inaccessible question. Here, leveraging advances in single-cell transcriptomics, we analyzed single-cell RNA-seq data sets from the mouse cerebral cortex and hippocampus to examine RP mRNA expression across neuronal subtypes. We observed distinct RP mRNA expression profiles between excitatory and inhibitory neurons and found that higher Rps27 transcript levels in inhibitory neurons corresponded to increased RPS27 protein abundance. Beyond excitatory-inhibitory differences, RP mRNA expression further segregated across well-defined neuronal subclasses, with 59 of 84 RP genes differentially expressed, including enrichment of Rpl21 in Lamp5 and Rps27 in Vip interneurons. These patterns were consistent across cortical regions and reproducible across two independent single-cell technologies (Smart-seq2 and 10x Genomics). Analysis of aging- and stress-associated data sets revealed stable RP expression signatures, with limited phenotype-linked changes. Together, we present a comprehensive atlas of ribosomal protein gene expression at neuronal subclass resolution, revealing robust subclass-specific transcriptional signatures, suggesting an underestimated regulatory layer.

Astrocytes exploit a neutrophil extracellular trap - like mechanism for myelin management: A new perspective on myelin-related disorders.

Phosphoglycerate kinase 1 (PGK1), the first ATP-generating enzyme in glycolysis, is frequently overexpressed in a wide range of human malignancies. Beyond its canonical glycolytic function, PGK1 also functions as a protein kinase playing a critical role in tumorigenesis and cancer progression. Here, we report the identification of a novel and highly potent PGK1 inhibitor through structure-based high-throughput virtual screening, exemplified by compound 42 (C67-47). C67-47 binds strongly to PGK1 with a dissociation constant (Kd) of 63 nM and exhibits potent antiproliferative effects in pancreatic cancer cells. In preclinical studies, C67-47 demonstrated excellent oral pharmacokinetics in both mouse and rat models. Strikingly, a single oral dose of C67-47 resulted in up to 80% tumor growth inhibition in pancreatic cancer xenograft models with no observable toxicity. These findings establish C67-47 as a promising lead compound for the development of orally administered, PGK1-targeted therapies for pancreatic cancer.

Transcriptomic alterations upon nuclear XIAP overexpression reveal IGFBP6/Wnt as a regulatory axis in breast cancer cell survival and chemoresistance.

Functions and mechanisms of BRCA1 in early embryonic development.

During meiosis, chromosomes face a paradox: the machinery that ensures reductional chromosome segregation also destabilizes centromeres by dismantling kinetochores, risking chromosome missegregation. Here we show how cells resolve this crisis through an unexpected activity of the telomere bouquet. We demonstrate that the bouquet transfers heterochromatin components to pericentromeres, which in turn recruit the Aurora B kinase to direct centromere reassembly. The heterochromatin protein Swi6 HP1 relocates from telomeres to centromeres, enabling Haspin kinase-dependent phosphorylation of histone H3 and consequent enrichment of the chromosomal passenger complex, which includes the Aurora B kinase. Aurora B then phosphorylates core centromere proteins, including CenpA and CenpC, to promote kinetochore reassembly. Phosphomimetic mutants of CenpA or CenpC bypass the telomere-heterochromatin-Haspin pathway, demonstrating that Aurora B-mediated phosphorylation is sufficient for reassembly. This function is conserved in mitotically proliferating cells subjected to centromere dismantlement. Our findings establish a safeguarded system that couples meiotic nuclear architecture to centromere identity and reveal a fundamental role for the Aurora B kinase in centromere assembly, beyond its canonical function in correcting kinetochore-spindle attachment errors.

Low-copy-number plasmids often rely on dedicated maintenance mechanisms, such as partitioning systems, to ensure stable inheritance across generations. These partition systems actively segregate sister plasmid copies during cell division and are classified by the NTPase types they encode. While the distribution and organization of partition system types are well characterized in Enterobacteriaceae plasmids, their functions and diversity across broader bacterial taxa remain poorly understood. Here, we analyze a large and diverse plasmid database to examine the distribution of partition system types and find that plasmids encoding multiple partition systems are more common than previously recognized. Notably, many plasmids encode multiple partition systems of the same type, an organization that has not been previously studied. To further investigate, we employ the Streptomyces linear plasmid SCP1, which encodes two type I ATP- and CTP-dependent parABS partition systems, as a model. Sequence analysis shows that both SCP1-encoded ParBs harbor less conserved CTPase domains than their chromosomal counterparts, suggesting they might diverge from canonical ParB functions. However, using chromatin immunoprecipitation with deep sequencing, biochemical assays, and targeted mutagenesis, we demonstrate that both proteins are bona fide ParB CTPase proteins: they recognize distinct parS sites on SCP1, bind and hydrolyze CTP, and slide to accumulate on DNA. Despite both systems being functional, only parABS1, but not parABS2, is crucial for SCP1 maintenance under standard laboratory conditions. Altogether, these findings provide the first functional characterization of dual ParB–CTPase partition systems coexisting on a single plasmid, advancing our understanding of plasmid maintenance in Streptomyces, and reveal new aspects of the diversity and distribution of plasmid partition systems in bacteria.

Heat shock proteins (HSPs) are highly conserved molecular chaperones that play a key role in maintaining protein homeostasis and cellular survival under stress conditions. Clinically relevant human pathogenic fungi include opportunistic fungi, dimorphic fungi, dermatophytes, Mucorales, and other pathogenic groups. HSPs, including Hsp90, Hsp70, Hsp60, Hsp40, and Hsp110, are essential for the correct nascent protein folding, aggregation prevention, and degradation of misfolded polypeptides. Fungal pathogens frequently encounter environmental and host-imposed stresses, including oxidative stress, temperature fluctuations, and antifungal treatments. This review synthesizes and critically analyzes current evidence on the role of HSP families in essential processes linked to fungal virulence, including morphogenetic transitions, biofilm formation, maintenance of cell wall integrity, and interactions with host immune cells. Beyond their canonical chaperone functions, HSPs act as central mediators in pathogenic processes, such as morphogenesis transitions, biofilm formation, cell wall integrity, and interactions with host immune cells. Hsp90 stabilizes key signaling proteins involved in stress responses, morphogenesis, and antifungal resistance, while Hsp60 and Hsp70 contribute to mitochondrial function, cell wall integrity, and immune modulation. Disruption of these chaperones impairs growth, reduces virulence, and increases susceptibility to antifungal agents. The rise of antifungal resistance underscores the urgent need for new therapeutic strategies. Targeting fungal HSPs has emerged as a promising approach due to their essential roles in stress tolerance and pathogenesis. Hsp90 inhibitors, including geldanamycin derivatives and other small molecules, have demonstrated the ability to impair fungal growth, reduce virulence traits, and sensitize resistant strains to conventional antifungal drugs. Combining HSP inhibitors with existing antifungal drugs represents a potential strategy to overcome resistance and improve treatment outcomes. This review summarizes the current knowledge on HSPs in pathogenic fungi, focusing on their roles in stress adaptation, virulence, host-pathogen interaction, antifungal resistance, and their potential as targets for novel antifungal therapies.

Fibrosis, which is characterized by excessive extracellular matrix deposition and tissue stiffening, impairs organ function and particularly affects the heart, lungs, liver, and kidneys. The persistent activation of fibrosis-driving cells, such as myofibroblasts, lung epithelial cells, hepatic stellate cells and tubular epithelial cells, by various transcriptional cues and posttranslational modifications (PTMs) rewires cellular substrate metabolism, most notably glucose, amino acid and lipid flux, thereby recapitulating the Warburg effect originally described in cancer cells. Although the organ-specific mechanisms of fibrosis remain incompletely elucidated, different forms of fibrosis share common features of metabolic reprogramming. In this review, we first introduce the core metabolic pathways involved in fibrotic disorders including glycolysis, glutaminolysis and lipid metabolism. Next, we focus on organ-specific metabolic alterations and their regulatory mechanisms in fibrosis-related diseases, including those of the heart, lungs, liver, kidneys, skin, peritoneum and glands, and discuss their underlying mechanisms: altered enzyme expression, subcellular localization and PTMs, within each organ-specific context. In addition to their canonical catalytic functions, enzymes that participate in glucose and lipid metabolism influence fibrosis through nonenzymatic activities mediated by PTMs, including phosphorylation, acetylation, ubiquitination, and the newly recognized lactylation. We further summarize mechanistic insights across organs and metabolic crosstalk in fibrosis. Finally, we discuss the current clinical translation and applications of these pathways. This review provides a reference for further research on metabolic reprogramming, highlights the role of aberrant metabolism and its underlying mechanisms in fibrosis across organs, and identifies emerging therapeutic strategies targeting glycolysis and lipid metabolism.

Triple-negative breast cancer (TNBC) is a clinically aggressive subtype lacking targeted therapies, often characterized by hyperactivation of the Wnt/β-catenin signaling pathway and an enriched population of cancer stem cells (CSCs). Here, we identify the DEAD-box RNA helicase DP103 as a novel modulator of Wnt/β-catenin signaling in TNBC, acting independently of its canonical helicase function. DP103 expression correlates with increased phosphorylation of LRP6 and nuclear β-catenin accumulation, enhancing Wnt transcriptional activity. Mechanistically, DP103 physically interacts with GSK3β to facilitate post-translational modifications essential for Wnt activation. Notably, DP103 itself is a Wnt target, forming a feedforward loop that sustains oncogenic signaling. Functional studies reveal that DP103 promotes CSC-like traits in TNBC cells, including self-renewal and expression of stemness markers (Nanog, Oct4, Sox2), linking its role in Wnt activation to breast cancer stemness and metastasis. In vivo studies using Drosophila models confirmed the evolutionarily conserved role of Gemin3/DP103 in epithelial transformation, though context-dependent differences were observed. Importantly, we demonstrate that RX-5902, a Wnt pathway inhibitor currently in clinical trials, suppresses DP103 expression and Wnt/β-catenin signaling, reducing TNBC cell viability and mammosphere formation without affecting normal epithelial cells. RX-5902 efficacy was abrogated by DP103 depletion, underscoring DP103's critical role in mediating drug response. In xenograft models, RX-5902 treatment significantly reduced tumor burden and prolonged survival. Collectively, our findings establish DP103 as a key regulator of Wnt-driven oncogenesis in TNBC and highlight its dual role in promoting CSC traits and therapeutic resistance. These insights position DP103 as a potential biomarker and therapeutic target to disrupt sustained Wnt signaling in TNBC, offering new avenues for precision intervention in this challenging breast cancer subtype.