Activation of cyclic GMP-AMP synthase (cGAS) through sensing cytosolic double stranded DNA (dsDNA) plays a pivotal role in innate immunity against exogenous infection as well as cellular regulation ...under stress. Aberrant activation of cGAS induced by self-DNA is related to autoimmune diseases. cGAS accumulates at chromosomes during mitosis or spontaneously in the nucleus. Binding of cGAS to the nucleosome competitively attenuates the dsDNA-mediated cGAS activation, but the molecular mechanism of the attenuation is still poorly understood. Here, we report two cryo-electron microscopy structures of cGAS-nucleosome complexes. The structures reveal that cGAS interacts with the nucleosome as a monomer, forming 1:1 and 2:2 complexes, respectively. cGAS contacts the nucleosomal acidic patch formed by the H2A-H2B heterodimer through the dsDNA-binding site B in both complexes, and could interact with the DNA from the other symmetrically placed nucleosome via the dsDNA-binding site C in the 2:2 complex. The bound nucleosome inhibits the activation of cGAS through blocking the interaction of cGAS with ligand dsDNA and disrupting cGAS dimerization. R236A or R255A mutation of cGAS impairs the binding between cGAS and the nucleosome, and largely relieves the nucleosome-mediated inhibition of cGAS activity. Our study provides structural insights into the inhibition of cGAS activity by the nucleosome, and advances the understanding of the mechanism by which hosts avoid the autoimmune attack caused by cGAS.
STAT3 and STAT5 proteins are oncogenic downstream mediators of the JAK-STAT pathway. Deregulated STAT3 and STAT5 signaling promotes cancer cell proliferation and survival in conjunction with other ...core cancer pathways. Nuclear phosphorylated STAT3 and STAT5 regulate cell-type-specific transcription profiles via binding to promoter elements and exert more complex functions involving interaction with various transcriptional coactivators or corepressors and chromatin remodeling proteins. The JAK-STAT pathway can rapidly reshape the chromatin landscape upon cytokine, hormone, or growth factor stimulation and unphosphorylated STAT proteins also appear to be functional with respect to regulating chromatin accessibility. Notably, cancer genome landscape studies have implicated mutations in various epigenetic modifiers as well as the JAK-STAT pathway as underlying causes of many cancers, particularly acute leukemia and lymphomas. However, it is incompletely understood how mutations within these pathways can interact and synergize to promote cancer. We summarize the current knowledge of oncogenic STAT3 and STAT5 functions downstream of cytokine signaling and provide details on prerequisites for DNA binding and gene transcription. We also discuss key interactions of STAT3 and STAT5 with chromatin remodeling factors such as DNA methyltransferases, histone modifiers, cofactors, corepressors, and other transcription factors.
•The review discusses major advances of JAK/STAT5 signaling in intestinal immunity.•The review discusses STAT5 functions in epithelial cell repair upon injury.•The review highlights gaps in the ...research of intestinal STAT5 function.
Cytokines, growth factors or hormones take action through the JAK/STAT5 signaling pathway, which plays a critical role in regulating the intestinal response to infection and inflammation. However, the way in which STAT5 regulates intestinal epithelial compartment is largely ignored due to the lack of genetic tools for proper exploration and because the two STAT5 transcription factors (STAT5A and STAT5B) have some redundant but also distinct functions. In this review article, by focusing on STAT5 functions in the intestinal undifferentiated and differentiated epithelia, we discuss major advances of the growth factor/cytokine-JAK/STAT5 research in view of intestinal mucosal inflammation and immunity. We highlight the gap in the research of the intestinal STAT5 signaling to anticipate the gastrointestinal explorative insights. Furthermore, we address the critical questions to illuminate how STAT5 signaling influences intestinal epithelial cell differentiation and stem cell regeneration during homeostasis and injury. Overall, our article provides a centric view of the relevance of the relationship between chronic inflammatory diseases and JAK/STAT5 pathway and it also gives an example of how chronic infection and inflammation pirate STAT5 signaling to worsen intestinal injuries. Importantly, our review suggests how to protect a wound healing from gastrointestinal diseases by modulating intestinal STAT5.
The devastating economic and public health consequences caused by the COVID-19 pandemic have prompted outstanding efforts from the scientific community and pharmaceutical companies to develop ...antibody-based therapeutics against SARS-CoV-2. Those efforts are encouraging and fruitful. An unprecedentedly large number of monoclonal antibodies (mAbs) targeting a large spectrum of epitopes on the spike protein has been developed in the last two years. The development of structural biology, especially the cryo-EM technology, provides structural insights into the molecular neutralizing mechanisms of those mAbs. Moreover, neutralizing antibodies are essential in protecting host from infection. Therefore, understanding the antibody neutralizing mechanism is critical for optimizing effective antibody-based therapeutics and developing next-generation pan-coronavirus vaccines. This review summarizes the latest understanding of antibody neutralizing mechanisms against SARS-CoV-2 at the molecular and structural levels.
Traumatic brain injury (TBI) is a central nervous system disease caused by external trauma, which has complex pathological and physiological mechanisms. The aim of this study was to explore the ...correlation between immune cell infiltration and ferroptosis post-TBI.
This study utilized the GEO database to download TBI data and performed differentially expressed genes (DEGs) and ferroptosis-related differentially expressed genes (FRDEGs) analysis. DEGs were further analyzed for enrichment using the DAVID 6.8. Immunoinfiltration cell analysis was performed using the ssGSEA package and the Timer2.0 tool. The WGCNA analysis was then used to explore the gene modules in the data set associated with differential expression of immune cell infiltration and to identify the hub genes. The tidyverse package and corrplot package were used to calculate the correlations between hub genes and immune cell infiltration and ferroptosis-marker genes. The miRDB and TargetScan databases were used to predict complementary miRNAs for the Hub genes selected from the WGCNA analysis, and the DIANA-LncBasev3 tool was used to identify target lncRNAs for the miRNAs, constructing an mRNA-miRNA-lncRNA regulatory network.
A total of 320 DEGs and 21 FRDEGs were identified in GSE128543. GO and KEGG analyses showed that the DEGs after TBI were primarily associated with inflammation and immune response. Xcell and ssGSEA immune infiltration cell analysis showed significant infiltration of T cell CD4
central memory, T cell CD4
Th2, B cell memory, B cell naive, monocyte, macrophage, and myeloid dendritic cell activated. The WGCNA analysis identified two modules associated with differentially expressed immune cells and identified Lgmn as a hub gene associated with immune infiltrating cells. Lgmn showed significant correlation with immune cells and ferroptosis-marker genes, including Gpx4, Hspb1, Nfe2l2, Ptgs2, Fth1, and Tfrc. Finally, an mRNA-miRNA-lncRNA regulatory network was constructed using Lgmn.
Our results indicate that there is a certain correlation between ferroptosis and immune infiltrating cells in brain tissue after TBI, and that Lgmn plays an important role in this process.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate worldwide. Mounting evidence indicates that mRNA modifications are crucial in RNA metabolism, transcription, ...processing, splicing, degradation, and translation. Studies show that N6-methyladenosine (m6A) is mammalians’ most common epi-transcriptomic modification. It has been demonstrated that m6A is involved in cancer formation, progression, invasion, and metastasis, suggesting it could be a potential biomarker for CRC diagnosis and developing therapeutics. Cytokines, growth factors, and hormones function in JAK/STAT3/5 signaling pathway, and they could regulate the intestinal response to infection, inflammation, and tumorigenesis. Reports show that the JAK/STAT3/5 pathway is involved in CRC development. However, the underlying mechanism is still unclear. Signal Transducer and Activator of Transcription 3/5 (STAT3, STAT5) can act as oncogenes or tumor suppressors in the context of tissue types. Also, epigenetic modifications and mutations could alter the balance between pro-oncogenic and tumor suppressor activities of the STAT3/5 signaling pathway. Thus, exploring the interaction of cytokines-JAKs-STAT3 and/or STAT5 with mRNA m6A is of great interest. This review provides a comprehensive overview of the characteristics and functions of m6A and JAKs-STAT3/5 and their relationship with gastrointestinal (GI) cancers.
Background & Aims Cdc42 is a Rho GTPase that regulates diverse cellular functions, including proliferation, differentiation, migration, and polarity. In the intestinal epithelium, a balance among ...these events maintains homeostasis. We used genetic techniques to investigate the role of Cdc42 in intestinal homeostasis and its mechanisms. Methods We disrupted Cdc42 specifically in intestinal epithelial cells by creating Cdc42flox/flox-villin-Cre+ and Cdc42flox/flox-Rosa26-CreER+ mice. We collected intestinal and other tissues, and analyzed their cellular, molecular, morphologic, and physiologic features, compared with the respective heterozygous mice. Results In all mutant mice studied, the intestinal epithelium had gross hyperplasia, crypt enlargement, microvilli inclusion, and abnormal epithelial permeability. Cdc42 deficiency resulted in defective Paneth cell differentiation and localization without affecting the differentiation of other cell lineages. In mutant intestinal crypts, proliferating stem and progenitor cells increased, compared with control mice, resulting in increased crypt depth. Cdc42 deficiency increased migration of stem and progenitor cells along the villi, caused a mild defect in the apical junction orientation, and impaired intestinal epithelium polarity, which can contribute to the observed defective intestinal permeability. The intestinal epithelium of the Cdc42flox/flox-villin-Cre+ and Cdc42flox/flox-Rosa26-CreER+ mice appeared similar to that of patients with microvillus inclusion disease. In the digestive track, loss of Cdc42 also resulted in crypt hyperplasia in the colon, but not the stomach. Conclusions Cdc42 regulates proliferation, polarity, migration, and differentiation of intestinal epithelial cells in mice and maintains intestine epithelial barrier and homeostasis. Defects in Cdc42 signaling could be associated with microvillus inclusion disease.
Abstract
This study was to develop a computer vision evaluation method to automatically measure the degree of scoliosis based on the machine learning algorithm. For the X-ray images of 204 patients ...with idiopathic scoliosis who underwent full-spine radiography, histogram equalization of original image was performed before a flipping method was used to magnify asymmetric elements, search for the global maximum pixel value in each line, and scan local maximal pixel value, with the intersection set of two point sets being regarded as candidate anchor points. All fine anchors were fitted with cubic spline algorithm to obtain the approximate curve of the spine, and the degree of scoliosis was measured by the standardized integral area. All measured data were analyzed. In manual measurement, the Cobb angle was 11.70–25.00 (20.15 ± 3.60), 25.20–44.70 (33.89 ± 5.41), and 45.10–49.40 (46.98 ± 1.25) in the mild, moderate and severe scoliosis group, respectively, whereas the value for the standardized integral area algorithm was 0.072–0.298 (0.185 ± 0.040), 0.100–0.399 (0.245 ± 0.050), and 0.246–0.901 (0.349 ± 0.181) in the mild, moderate and severe scoliosis group, respectively. Correlation analysis between the manual measurement of the Cobb angle and the evaluation of the standardized integral area algorithm demonstrated the Spearman correlation coefficient r = 0.643 (
P
< 0.001). There was a positive correlation between the manual measurement of the Cobb angle and the measurement of the standardized integral area value. Two methods had good consistency in evaluating the degree of scoliosis. ROC curve analysis of the standardized integral area algorithm to measure the degree of scoliosis showed he cutoff value of the standardized integral area algorithm was 0.20 for the moderate scoliosis with an AUC of 0.865, sensitivity 0.907, specificity 0.635, accuracy 0.779, positive prediction value 0.737 and negative prediction value 0.859, and the cutoff value of the standardized integral area algorithm was 0.40 for the severe scoliosis with an AUC of 0.873, sensitivity 0.188, specificity 1.00, accuracy 0.936, positive prediction value 1 and a negative prediction value 0.935. Using the standardized integral area as an independent variable and the Cobb angle as a dependent variable, a linear regression equation was established as Cobb angle = 13.36 + 70.54 × Standardized area, the model has statistical significance. In conclusion,
t
he integrated area algorithm method of machine learning can quickly and efficiently assess the degree of scoliosis and is suitable for screening the degree of scoliosis in a large dataset as a useful supplement to the fine measurement of scoliosis Cobb angle.
Circadian control of nutrient availability is critical to efficiently meet the energetic demands of an organism. Production of bile acids (BAs), which facilitate digestion and absorption of ...nutrients, is a major regulator of this process. Here we identify a KLF15-Fgf15 signalling axis that regulates circadian BA production. Systemic Klf15 deficiency disrupted circadian expression of key BA synthetic enzymes, tissue BA levels and triglyceride/cholesterol absorption. Studies in liver-specific Klf15-knockout mice suggested a non-hepatic basis for regulation of BA production. Ileal Fgf15 is a potent inhibitor of BA synthesis. Using a combination of biochemical, molecular and functional assays (including ileectomy and bile duct catheterization), we identify KLF15 as the first endogenous negative regulator of circadian Fgf15 expression. Elucidation of this novel pathway controlling circadian BA production has important implications for physiologic control of nutrient availability and metabolic homeostasis.
Intestinal L cells regulate a wide range of metabolic processes, and L-cell dysfunction has been implicated in the pathogenesis of obesity and diabetes. However, it is incompletely understood how ...luminal signals are integrated to control the development of L cells. Here we show that food availability and gut microbiota-produced short-chain fatty acids control the posttranslational modification on intracellular proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) in intestinal epithelial cells. Via FOXO1 O-GlcNAcylation, O-GlcNAc transferase (OGT) suppresses expression of the lineage-specifying transcription factor Neurogenin 3 and, thus, L cell differentiation from enteroendocrine progenitors. Intestinal epithelial ablation of OGT in mice not only causes L cell hyperplasia and increased secretion of glucagon-like peptide 1 (GLP-1) but also disrupts gut microbial compositions, which notably contributes to decreased weight gain and improved glycemic control. Our results identify intestinal epithelial O-GlcNAc signaling as a brake on L cell development and function in response to nutritional and microbial cues.
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•O-GlcNAcylation in intestinal epithelial cells suppresses L cell differentiation•FOXO1 O-GlcNAcylation inhibits Ngn3 transcription•SCFA-dependent O-GlcNAc is required for microbial regulation of L cell function•Microbial dysbiosis in OGT-deficient mice contributes to improved metabolism
Zhao et al. identify OGT in intestinal epithelial cells as a “molecular brake” on L cell development and function in response to nutritional and microbial cues. OGT inhibits Ngn3 gene transcription and enteroendocrine differentiation via FOXO1 O-GlcNAcylation. Microbiota-derived SCFAs drive epithelial O-GlcNAcylation, which further influences gut microbiota to control systemic metabolism.
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