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Chitin is the second most abundant polysaccharide in nature, and its degradation by marine microorganisms plays a critical role in the global carbon and nitrogen cycles. This study investigated the marine bacterium Microbulbifer harenosus CGMCC 1.13584T to elucidate its chitin metabolic pathway through genomic and transcriptomic analyses. When cultured with chitin as the carbon source, the strain exhibited an extended lag phase and enhanced extracellular chitinase activity. Genome sequencing revealed the presence of genes involved in both hydrolytic and oxidative chitin degradation pathways. Transcriptomic analysis showed that genes associated with the hydrolytic pathway were significantly upregulated upon chitin induction. In contrast, within the oxidative degradation pathway, only early-stage response genes (such as those encoding LPMOs) were markedly upregulated, while genes involved in subsequent metabolic steps (converting GlcNAc1A to KDG-6-P) did not show significant upregulation. Furthermore, a gene encoding a GH10 domain-containing protein was found to be substantially upregulated during growth on chitin. These findings indicate that Microbulbifer harenosus CGMCC 1.13584T utilizes a coordinated chitin degradation mechanism, where the hydrolytic pathway dominates carbon flux during active growth, while the oxidative pathway (via LPMOs) likely provides critical initial structural disruption.

This study aimed to determine whether fatty acids (FAs) may affect the function of the early porcine placenta. First, the expression of FA transporters (CD36, SLC27A) in conceptuses and placentae of days 10-11, 12-13, 15-16, 18-20, 25, and 30 pregnant gilts (n = 5-8 per group) was examined using Real-time PCR, Western blot, and immunohistochemistry. Then, primary trophoblast (pTr) cells from days 15-16 conceptuses were exposed to n-6 and n-3 polyunsaturated FAs (PUFAs) to study prostaglandin (PG) synthesis and the expression of genes related to FA action, angiogenesis, steroidogenesis, and lipid transport. Furthermore, pTr cell proliferation and adhesion in response to PUFAs were determined colorimetrically. Increased mRNA expression of CD36, SLC27A1, and SLC27A2 was detected in days 18-25 placentae compared with days 10-13 conceptuses. SLC27A4 and SLC27A6 expression was greater in days 10-11 spherical than in days 15-16 elongated conceptuses. SLC27A1, SLC27A4, and SLC27A6 were localized at the placenta-endometrium interface. PUFAs of n-6 series elevated PGE2 and PGI2 synthesis, whereas n-3 PUFAs stimulated PGE2 but inhibited PGI2 output. All PUFAs up-regulated the mRNA expression of CPT1A, a rate-limiting enzyme of FA β-oxidation. Moreover, docosahexaenoic acid (DHA) increased FABP5, SLC27A4, LDLR (lipoprotein receptor), and proangiogenic ANGPT1 and ANGPTL4 mRNA expression. DHA and arachidonic acid stimulated pTr cell proliferation, while linoleic and eicosapentaenoic acids increased cell adhesion. These results are the first demonstrating dynamic changes of FA transporter expression in peri-implantation conceptuses and developing placentae of the pig and indicate FA uptake by the early placenta. Furthermore, PUFAs may support placenta development by modulating gene expression, increasing PGE2 level, and promoting trophoblast cell viability and adhesion.

Host dependency factors (HDF) are essential for viral replication and are promising targets for broad-spectrum antivirals. However, most work has focused on individual viruses or individual data types, limiting our understanding of shared host mechanisms across viruses. We developed a pan-viral framework that integrates multi-omics data-including genome-wide perturbation screens, single-cell transcriptomes and viral interactomes-and combines graph-based learning with classical machine-learning models to prioritize HDF for four RNA viruses (SARS-CoV-2, influenza A virus, dengue virus and Zika virus). Across viruses, the framework achieved high discrimination, with area under the receiver operating characteristic curve (ROC-AUC) greater than 0.90 on benchmark datasets, and identified a conserved signature of 118 genes shared by all four viruses and 427 genes shared by at least three. These genes converge on recurrent host programmes such as clathrin-mediated entry and endomembrane trafficking, nuclear transport, RNA processing and stress granules, and proteostasis and ubiquitin-proteasome signalling. The pan-viral signature generalizes beyond the training set, as genes shared by three or more viruses are strongly enriched among top-ranked Ebola virus candidates. We further provide a prioritized shortlist and an experimental validation roadmap to guide follow-up perturbation studies. Our integrative multi-omics and machine-learning approach outlines a prediction-based, data-driven map of pan-viral host liabilities and highlights tractable opportunities for host-directed therapy against diverse RNA viruses.

The loss of chromosome Y (LOY) in leukocytes is the most prevalent form of clonal mosaicism observed in older men. Previous studies provided multiple pieces of evidence for the effect of LOY on the immune system and connected LOY to elevated risk of all major causes of mortality, including cardiovascular diseases and cancer. Despite these associations, the dynamic effects of LOY across the developmental trajectories of immune cell populations remain unclear. We utilized single-cell RNA-sequencing data from the peripheral blood mononuclear cells of 416 male donors (median age = 68) from the OneK1K cohort. LOY was identified in 45,304 cells (8.76%) and exhibited cell type-specific effects on immune cells along the differentiation trajectories. The largest frequency was detected in monocytes (18.6% in classical and 17.1% in nonclassical) with a progressive decrease along the transition trajectory from 22.6% to 15.8% (padj = 2.00 × 10-11), and a gradual reduction in the expression of nonclassical markers LYPD2 and C1QA. LOY is associated with a profibrotic signature in classical monocytes marked by downregulation of IL1B (log FC = -0.22, pfdr = 2.84 × 10-6) and MYC-regulated genes (log FC = -0.25, pfdr = 2.22 × 10-5), consistent with previous observations that LOY-associated macrophages are polarized toward a fibrotic rather than inflammatory phenotype in cardiac and pulmonary injury. Notably, we detected aberrant expression of XIST, the essential X-chromosome-inactivation lncRNA that is not normally expressed in males, and upregulation of genes known to escape X-inactivation, including male-biased cancer-related genes KDM6A, DDX3X, KDM5C, and ZRSR2. Our results indicate associations between LOY and cell type-specific transcriptional changes, including aberrant X-inactivation features.

IL-11, a novel target for drug development, has been associated with several fibroinflammatory diseases including thyroid eye disease (TED), where it plays an important role in signaling to stromal cells activating multiple intracellular pathways. In TED patient tissue, IL-11 is elevated and stimulates multiple effects important in disease progression, including the production of proinflammatory cytokines, hyaluronic acid (HA) and fibrotic markers. LASN01, a potent antibody to IL-11 receptor, inhibits these effects and is a potential therapeutic agent for TED. Teprotumumab, an antibody to IGF-1 receptor, inhibits HA production and adipogenesis and is effective in reduction of proptosis. Activation of the IGF-1 and IL-11 pathways in TED tissue induces the expression of fibroinflammatory genes regulated by LASN01 and lipid biosynthetic genes regulated by Teprotumumab. Clinical studies show that LASN01 is well tolerated and in a placebo-controlled phase II trial in TED, LASN01 resulted in a statistically significant resolution of clinical activity score (CAS) in 88% of treated patients (p = 0.028), but had lesser effects on proptosis. The data supports the importance of IL-11 biology in fibroinflammatory disease and that IL-11 receptor is a pharmacologically active target for drug development.

Gastric cancer (GC) poses a significant health threat, and alterations in Fatty acid β-oxidation (FAO) may influence its progression. However, the precise mechanisms underlying this association remain unclear. FAO-related genes were analyzed using transcriptomic datasets from databases of GEO and TCGA. Totally 160 FAO-associated genes were identified, and a risk scoring model was subsequently established to stratify patients into groups of low- and high-risk. Immune characteristics, drug sensitivities, and hub genes, including IL-6, were assessed. Subsequently, immunoblotting and immunohistochemistry were performed on GC cell lines and tissue samples to evaluate IL-6 expression. Analysis of the TCGA and GEO databases revealed a FAO-related gene signature comprising ACADS, ACO2, CPT2, SLC22A5, AOC3, CD36, CIDEA, G0S2, GABARAPL1, and SERINC1. We also examined gene mutations and constructed a prognostic risk scoring model with validation achieved through a nomogram to predict gastric cancer risk. Immune infiltration analysis and drug sensitivity testing (e.g. AG-014699, Axitinib, BX-795, and Cisplatin) were also conducted. IL-6 emerged as a core gene with significant expression difference across cellular and tissue levels. FAO plays a critical role in the prognosis of GC, and IL-6 may serve as a key biomarker for diagnosis and therapeutic strategies.

Excessive activation of the estrogen receptor (ER) drives proliferation, progression, and the formation of breast cancer stem cells (CSCs) in ER-positive breast cancer. Estrogenic endocrine disrupting compounds (EDCs) found in plastics, water, and food are also able to bind to the ER. Thus, we hypothesized that estrogenic EDCs mimic estrogen (E2) in the pathogenesis of breast cancer by promoting their survival and proliferation. Three estrogenic EDCs routinely found in human biosamples were selected for analysis: bisphenol-A (BPA), diethyl-hexyl phthalate (DEHP), and alpha-zeranol (αZAL). We assessed proliferation, transcriptional reprogramming, and CSC formation in breast cancer cell lines. E2, BPA, and αZAL significantly increased cell proliferation in ER-positive, but not ER-negative cell lines. This was reversed after administration of the ER-antagonist, ICI 182,780. BPA and αZAL upregulated estrogen target genes (PGR, TFF1) and increased levels of cell-cycle protein. RNA sequencing analysis revealed that BPA and αZAL altered expression of genes related to cell division, DNA repair, and estrogen signaling, with a substantial transcriptional overlap between EDCs and estrogen treatments. Additionally, BPA and αZAL increased the proportion of CSCs, defined as the CD24low/CD44high expressing subpopulation. Overall, these data indicate that BPA and αZAL act as functional estrogen mimics in breast cancer cells, activating canonical estrogen signaling pathways and promoting stem-like characteristics. Notably, this study provides the first transcriptomic and stem-associated characterization of αZAL in ER-positive breast cancer cells, revealing a robust estrogenic mode of action. This work provides mechanistic insight into how environmental EDCs may influence ER-positive breast cancer biology.

Executive function is an essential cognitive domain for typical human behavior which is disrupted in neurodevelopmental and neurodegenerative disorders, but little is known about its underlying molecular basis. To address this, we perform genome-wide association studies (GWAS) using three different measures of executive function in UK Biobank (N = 84,238) and NIHR BioResource's Genes and Cognition (N = 9932) study participants, followed by a meta-analysis. The trail-making alphanumeric (TMA) measure is the most heritable phenotype (h²=7-26%), associated with 18 independent loci that exhibit a similar direction of effect in both cohorts. Across these loci, in-silico follow-up implicates 178 genes, of which NT5DC2 and RP11-579E24.2 are independently replicated prior to meta-analysis. TMA is linked to pan-cerebral differences in brain structure, with brain-enriched genes showing a biphasic expression profile from early development through to later life. Our data implicate specific cell types, histone modifications and butyrophilin immunoglobulin family proteins as potential targets for promoting cognitive resilience.

Tertiary lymphoid structures (TLSs) are key components of the tumor immune microenvironment and show prognostic relevance in many cancers. However, their genetic association with lung adenocarcinoma (LUAD) is still lacking. This study aims to construct a TLS-related prognostic model through an integrated multi-omics strategy and to elucidate relevant immunogenetic mechanisms. TLS-related genes (TRGs) showing genetically supported associations with LUAD were identified using Mendelian randomization (MR). A TRG-based model was established using machine learning (ML), with its accuracy assessed through a nomogram. Downstream analyses were performed, including immune microenvironment, tumor mutational burden (TMB), pathway enrichment, drug sensitivity profiling, and single-cell RNA sequencing (scRNA-seq). The expression of TRGs was confirmed using reverse transcription quantitative polymerase chain reaction (RT-qPCR). The prognostic model we built using the best algorithm showed strong prognostic value (1-, 3-, and 5-year AUCs >&#x2009;0.75). Individuals classified in the high-risk (H-R) cohort exhibited markedly poorer outcomes (p&#x2009;<&#x2009;0.001). Incorporation of the risk model into the nomogram improved its predictive accuracy compared with the model without this variable (AUC&#x2009;=&#x2009;0.769 for risk score). TMB analysis suggested a higher TMB in the H-R group, which may predict a worse prognosis. Drugs targeting the PI3K-AKT-mTOR and cell cycle pathways showed higher efficacy in the H-R group. According to enrichment results, TRGs were mainly involved in immune activation and cell cycle regulation, suggesting that these genes may regulate LUAD prognosis through PI3K-AKT-mTOR and cell cycle pathways. The scRNA-seq analysis showed that the 10 TRGs were predominantly localized within T/NK and myeloid cell clusters, indicating their potential involvement in modulating local immune responses. The differential expression patterns of these genes across multiple cell lines were validated using RT-qPCR. In summary, this comprehensive model highlights the significance of TRGs in LUAD, providing a new paradigm for immunogenetic risk evaluation and personalized therapy.

The human lipidome comprises numerous complex lipids, dysregulation of which can contribute to the pathogenesis of a wide range of diseases. Despite the high heritability of parts of the lipidome, the genetic architecture of many circulating lipid species and their structure remains mostly unknown. Thus, we perform genome-wide association studies on 970 lipid species and 267 fatty acid composite measures using samples from the population-based Rhineland Study (n&#x2009;=&#x2009;6096). We validate our findings using corresponding data from two other independent cohorts, including FinnGen (n&#x2009;=&#x2009;7266) and EPIC-Potsdam (n&#x2009;=&#x2009;1188). Out of 217 lead genomic loci, we find 136 to be novel, such as FDFT1. Using mendelian randomization and individual-level gene expression data, we identify 43 possible causal associations between candidate genes and corresponding lipid species, including FDFT1 - diacylglycerol (16:0/18:0). Our findings provide new insights into the intricate genetic underpinnings of lipid metabolism, which may facilitate risk stratification and discovery of new therapeutic targets.

Lactate, an energy source and metabolic by-product, has been implicated in cancer progression, but its role in colorectal cancer (CRC) remains incompletely understood. This study investigated the clinical significance, biological effects, and transcriptomic responses of CRC cells to lactate. In human CRC specimens, lactate levels were positively associated with advanced clinical stage and poorer disease-free survival. Functional assays showed that lactate promoted malignant cellular behaviors in both SW480 and HCT116 cells, while pH-control experiments suggested that these effects were not merely due to extracellular acidification alone. RNA sequencing in SW480 cells identified 1,418 differentially expressed genes after lactate treatment. GO and KEGG analyses revealed alterations in multiple metabolic and signaling pathways. qRT-PCR validated the alterations of representative genes, including HK2, VEGFA, JUNB, CCNB1, MAPK4, and COX2. In addition, flow cytometry showed activation of NF-&#x3ba;B and HIF-1&#x3b1; signaling following lactate treatment, and pharmacological inhibition of either pathway significantly attenuated the lactate-induced malignant phenotypes. Together, these findings provide transcriptomic and functional evidence that lactate promotes malignant phenotypes in CRC cells and offer exploratory mechanistic insights into the involvement of NF-&#x3ba;B and HIF-1&#x3b1; signaling.