生物学最新文献

DNA methylation (DNAm), capturing chronological gestational age (GA) and epigenetic gestational age acceleration (EGAA), can be modified by environmental exposures. The Asthma&Allergy array is a new DNAm array developed with content focused on asthma and allergy loci. The association between content on the Asthma&Allergy array and chronological GA and EGAA has not been evaluated alone or in the context of prenatal/perinatal exposures. We performed an epigenome wide association study (EWAS) chronological GA at single CpG sites and regions in cord blood from 391 newborn children from a Detroit-based birth cohort. We further constructed a multi-CpG site methylation model to predict chronological GA. Also, associations between prenatal/perinatal environmental factors with GA, epigenetic gestational age (EGA), and EGAA were assessed. We identified 2,435 CpG sites associated with chronological GA, and CpGs within the HLA class II locus (HLA-DRB1, HLA-DQB1, HLA-DRB6) were among the most significantly associated with chronological GA. Our multi-CpG site model attained higher predictive accuracy (R² = 0.88) comparable to other published methods. Using genes implicated in region-based analyses (n = 395 regions), the pathways most significantly enriched with chronological GA-associated CpGs included T helper 1(Th1) and 2(Th2) activation, B-cell development, and IL-10 signaling, which were also enriched in at least one of the other published epigenetic GA clocks. In multi-exposure models, infant's first-born status and maternal parity were associated with EGAA. Our findings highlight enrichment for T cell modulated pathways and antigen presentation as biological processes associated with chronological GA, as well as prenatal/perinatal factors that may affect EGAA.

In the tumor microenvironment, tissue-resident macrophages (TRMs) promote malignant tumor progression, yet their tissue-specific heterogeneity and complex functions bring research challenges. This study analyzes the research status and trends of TRMs in oncology. Via VOSviewer, CiteSpace, R software and WoSCC, a visual bibliometric network was built for quantitative analysis, with future research directions explored in depth. The US leads in publications and academic influence, and the University of Washington tops in paper output. Research focuses on TRMs' origin, classification and tumor microenvironment functions; microglia and Kupffer cells are the most studied subsets. Current research centers on pathway exploration, immunotherapy and single-cell sequencing. This study summarizes TRMs' research status, hotspots and trends in oncology, providing valuable insights for relevant collaborators and institutions.

Objectives: Urolithin A (UA) is a natural polyphenolic compound produced by gut bacteria. Vascular remodeling contributes to hypertension, and vascular smooth muscle cells (VSMCs) proliferation and migration are important processes in vascular remodeling.

Methods: VSMCs were obtained from the thoracic aorta of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Intraperitoneal injections of UA (50 mg/kg, every 2 days for 4 weeks) were performed in SHR.

Results: UA attenuated proliferation and migration, reduced mitochondrial reactive oxygen species (mitoROS) levels, and increased SOD2 activity in VSMCs of SHR, which were prevented by SOD2 knockdown. UA promoted mitochondrial short-length SIRT3 (SL-SIRT3) production and SOD2 deacetylation. SIRT3 inhibitor 3-TYP abolished the effects of UA on SOD2 deacetylation, mitoROS levels and VSMCs proliferation and migration. Repeated intraperitoneal injection of UA every 2 days for 4 weeks attenuated vascular remodeling and hypertension, increased SL-SIRT3 levels and SOD2 activity, and reduced SOD2 acetylation and mitoROS levels in aorta and mesenteric arteries of SHR.

Conclusion: UA attenuates VSMCs proliferation and migration in SHR by increasing mitochondrial SL-SIRT3 level, and subsequent SOD2 deacetylation and mitoROS reduction in SHR. Long-term administration of UA attenuates vascular remodeling, hypertension and oxidative stress in SHR.

Thrombomodulin (TM) is a membrane protein with significant roles in coagulation hemostasis and immune response. Its soluble form (sTM) has recently emerged as a key biomarker for severe invasive bacterial infections, including Necrotizing Soft Tissue Infections (NSTI). While various mechanical, chemical, and enzymatic mechanisms have been linked to TM shedding, this study investigates the direct impact of bacterial stimuli on soft tissue cells as primary sources of TM release. We stimulated organotypic models, composed of fibroblast and endothelial cells, with NSTI clinical isolates and found that while Group A Streptococcus and Escherichia coli had minimal effect on TM release, Staphylococcus aureus infection triggered a significant increase of sTM levels. We further assessed whether the secreted proteins of S. aureus led to higher TM levels by increased expression, increased cell toxicity, or direct cleavage of TM from the endothelial cell membrane. To investigate these mechanisms, we performed in vitro stimulations of endothelial monolayers with secreted proteins of two S. aureus isolates differing in their agr-system functionality. Our results indicate that S. aureus agr-regulated proteins induce TM shedding by direct cleavage from the cell membrane, an effect that was inhibited by metalloproteinase inhibitors. Stimulation with the pore-forming protein α-toxin showed similar results, suggesting a potential involvement of ADAM10 in TM cleavage. Additionally, we observed that other agr-regulated proteins can cleave TM directly. Altogether, this study reveals a pathogen-specific mechanism for TM release during S. aureus invasive infection, contributing to its elevated plasma levels and providing deeper insights into the pathophysiology of NSTI.

Recent reports have highlighted the increasing frequency of influenza A virus (IAV) spillover events from other species to dogs and cats. IAV, particularly the H3 subtype, exhibits a broad host range and a propensity for interspecies transmission, as exemplified by the sustained circulation of H3N2 and H3N8 canine influenza viruses in dog populations. This raises concerns about the potential role of companion animals as intermediate hosts in influenza virus transmission. To evaluate the susceptibility of dogs and cats to the prevalent H3 subtype influenza viruses, we experimentally inoculated groups of both species with three prevalent influenza viruses: H3N2 avian influenza virus (AIV), H3N8 avian influenza virus, and H3N2 swine influenza virus (SIV). Results showed that while all inoculated dogs exhibited seroconversion to all three viruses at 7, 14, and 21 days post-inoculation (dpi), they displayed no clinical signs, viral shedding, or evidence of viral replication in their organ tissues. In contrast, despite the cats did not exhibit apparent clinical signs, all inoculated cats exhibited seroconversion to all viruses at 7, 14 and 21 dpi, sustained nasal viral shedding for approximately one week, and demonstrated viral replication in their lungs, trachea, and nasal turbinate. Our findings underscore the higher susceptibility of cats compared to dogs to H3 subtype influenza viruses. These results emphasize the critical need for enhanced surveillance of cats within the influenza virus transmission network.

Malassezia globosa plays a crucial role as part of the human skin's mycobiome. However, this yeast has been detected in other niches, such as the gut. Despite being commensal, the pathogenic link in several dermatological conditions, but recently, chronic diseases such as cancer, Crohn's disease, and Parkinson's disease, among others, have been explored. Lipids can be involved in fungal pathogenesis, and this yeast is characterized by a significant lipid metabolic versatility, with a lack of the complex fatty acid synthase (FAS) required for the de novo synthesis of fatty acids, as it relies on lipase-releasing enzymes. Here, we assess lipid dynamics (lipids consumed vs. lipids secreted) using lipidomic analysis in the supernatant of mDixon media during two growth phases. 87 lipids within 17 classes of lipids were identified in three different lipid uptake-secretion patterns. Some lipids were characteristic, including the presence of glycochenodeoxycholic acid, glycerophospholipids (such as phosphocholine), cardiolipins, and sphingolipids (such as Cer-PI). Interestingly, sterols, bile acids, cholic acid and its derivates, some phosphocholines, fatty acyls, and cardiolipins were lipids consumed over time. The dynamic consumption of these lipids could presume an intriguing role in the metabolism of lipid processes in this yeast that could determine the interaction process and its pathogenic role.

Drosophila melanogaster Nora virus (DmNV), a positive-sense single stranded RNA virus related to picornaviruses. Given its genetic and structural similarity to neurotropic picornaviruses, such as poliovirus, we sought to determine whether DmNV could be found within the head and brain of D. melanogaster. RNA was extracted from heads of chronically DmNV-infected stocks, as well as from uninfected controls, and assayed using reverse transcription-polymerase chain reaction (RT-PCR) for DmNV open reading frame 1 (ORF1). The results showed that DmNV genomic material can be isolated from the heads of DmNV-infected D. melanogaster, which suggests that the virus reaches the head during the course of infection. To determine whether DmNV infects the brain tissue itself, small-molecule RNA fluorescence in situ hybridization (smRNA FISH) experiments on whole brains dissected from DmNV-infected and uninfected D. melanogaster were done. The smRNA FISH detection method was validated by identifying DmNV RNA in gut tissue, but there was no evidence of DmNV localization in any brain specimens examined. These findings suggest an alternative explanation for why DmNV may be present in dissected head specimens. Additionally, we highlight the effectiveness of smRNA FISH as a highly specific and accessible method for detecting RNA viruses in Drosophila, offering an alternative to antibody-based or transgenic fluorescence approaches. Together, our results refine the understanding of DmNV tissue tropism and provide methodological insights for future studies using insect RNA viruses.

Non-coding RNAs (ncRNAs) modulate protein-protein interactions (PPIs) by shaping the structural context in which binding occurs, rather than acting as direct inhibitors or enhancers. Using an integrative framework combining catRAPID RNA-protein interaction prediction and AlphaFold3-based structural modelling, we analysed RNA-dependent modulation of interaction states across physiological and oncogenic protein complexes. At the network level, physiological PPIs exhibit high shared ncRNA buffering capacity, whereas oncogenic interactions are characterized by reduced or absent RNA overlap. AlphaFold3 modelling of mutant IDH1/2 complexes illustrates how loss of RNA buffering permits excessive stabilization of enzyme-associated interfaces, reflected by directional changes in buried surface area (ΔBSA) and contact heterogeneity.

In response to stress, cells undergo gene expression reprogramming to cope with external stimuli. Cells utilize a conserved stress response mechanism called global downregulation of translation, leading to the storage of translationally repressed mRNAs in RNA granules. During oxidative stress induced by H2O2, genes responsible for combating oxidative stress, such as catalases, are strongly induced. However, the post-transcriptional regulatory events affecting these genes during H2O2 stress are not well-explored. Scd6, an RGG-motif-containing protein in yeast, acts as a translational repressor through its interaction with eIF4G1. This study identifies the role of Scd6 in oxidative stress response by regulating cytoplasmic catalase T1 (CTT1). We observe that peroxide stress induces the assembly of Scd6 puncta, which do not colocalize with P-bodies or stress granules. Scd6 overexpression increased sensitivity, while deletion enhanced tolerance to H2O2 treatment. Increased ROS accumulation and decreased Ctt1 protein levels were observed upon Scd6 overexpression due to translation repression of CTT1 mRNA. CTT1 mRNA interacts with Scd6. smFISH analysis and RNA immunoprecipitation studies reveal that localization of Scd6 to puncta upon peroxide stress reduces its interaction with CTT1 mRNA, allowing derepression. The role of Scd6 in peroxide stress response is conserved since the human homolog LSm14A also localizes to puncta upon H2O2 stress, and its overexpression reduces survival in response to peroxide stress. Overall, this study identifies a unique example of translation regulation whereby stress-induced localization of the translation repressor protein to puncta leads to derepression of the target mRNA.