ABSTRACT
Homoderus mellyi belongs to the Lucanidae family of Coleoptera. The first complete mitogenome of Homoderus is reported in this paper. The genome is 16,807 bp in length and contains the typical 37 genes with 22 transfer RNA genes, 13 protein coding genes, and 2 ribosomal RNA genes. The gene order is conserved across the lineage. The average base composition of the mitogenome is 36.6% for A, 20.8% for C, 11.6% for G, and 31.1% for T. The percentage of GC is 32.3%. The genome organization, nucleotide composition, and codon usage are similar to other beetles. Phylogenetic analysis shows that Lucanidae is monophyletic, and all subfamilies are monophyletic, respectively. The phylogenetic position of H. mellyi is consistent with other research.
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The Ebola virus (EBOV) has emerged as a significant global health concern, notably during the 2013-2016 outbreak in West Africa. Despite the clinical approval of two EBOV antibody drugs, there is an urgent need for more diverse and effective antiviral drugs, along with comprehensive understanding of viral-host interactions. In this study, we harnessed a biologically contained EBOVΔVP30-EGFP cell culture model which could recapitulate the entire viral life cycle, to conduct a genome-wide CRISPR/Cas9 screen. Through this, we identified PIK3C3 (phosphatidylinositide 3-kinase) and SLC39A9 (zinc transporter) as crucial host factors for EBOV infection. Genetic depletion of SLC39A9 and PIK3C3 lead to reduction of EBOV entry, but not impact viral genome replication, suggesting that SLC39A9 and PIK3C3 act as entry factors, facilitating viral entry into host cells. Moreover, PIK3C3 kinase activity is indispensable for the internalization of EBOV virions, presumably through the regulation of endocytic and autophagic membrane traffic, which has been previously recognized as essential for EBOV internalization. Notably, our study demonstrated that PIK3C3 kinase inhibitor could effectively block EBOV infection, underscoring PIK3C3 as a promising drug target. Furthermore, biochemical analysis showed that recombinant SLC39A9 protein could directly bind viral GP protein, which further promotes the interaction of viral GP protein with cellular receptor NPC1. These findings suggests that SLC39A9 plays dual roles in EBOV entry. Initially, it serves as an attachment factor during the early entry phase by engaging with the viral GP protein. Subsequently, SLC39A9 functions an adaptor protein, facilitating the interaction between virions and the NPC1 receptor during the late entry phase, prior to cathepsin cleavage on the viral GP. In summary, this study offers novel insights into virus-host interactions, contributing valuable information for the development of new therapies against EBOV infection.
Subject(s)
CRISPR-Cas Systems , Ebolavirus , Hemorrhagic Fever, Ebola , Virus Internalization , Ebolavirus/genetics , Ebolavirus/physiology , Ebolavirus/metabolism , Humans , Hemorrhagic Fever, Ebola/virology , Hemorrhagic Fever, Ebola/metabolism , Hemorrhagic Fever, Ebola/genetics , Cation Transport Proteins/metabolism , Cation Transport Proteins/genetics , Class III Phosphatidylinositol 3-Kinases/metabolism , Class III Phosphatidylinositol 3-Kinases/genetics , Virus Replication , Animals , HEK293 CellsABSTRACT
The ZIKA virus (ZIKV) evades the host immune response by degrading STAT2 through its NS5 protein, thereby inhibiting type I interferon (IFN)-mediated antiviral immunity. However, the molecular mechanism underlying this process has remained elusive. In this study, we performed a genome-wide CRISPR/Cas9 screen, revealing that ZSWIM8 as the substrate receptor of Cullin3-RING E3 ligase is required for NS5-mediated STAT2 degradation. Genetic depletion of ZSWIM8 and CUL3 substantially impeded NS5-mediated STAT2 degradation. Biochemical analysis illuminated that NS5 enhances the interaction between STAT2 and the ZSWIM8-CUL3 E3 ligase complex, thereby facilitating STAT2 ubiquitination. Moreover, ZSWIM8 knockout endowed A549 and Huh7 cells with partial resistance to ZIKV infection and protected cells from the cytopathic effects induced by ZIKV, which was attributed to the restoration of STAT2 levels and the activation of IFN signaling. Subsequent studies in a physiologically relevant model, utilizing human neural progenitor cells, demonstrated that ZSWIM8 depletion reduced ZIKV infection, resulting from enhanced IFN signaling attributed to the sustained levels of STAT2. Our findings shed light on the role of ZIKV NS5, serving as the scaffold protein, reprograms the ZSWIM8-CUL3 E3 ligase complex to orchestrate STAT2 proteasome-dependent degradation, thereby facilitating evasion of IFN antiviral signaling. Our study provides unique insights into ZIKV-host interactions and holds promise for the development of antivirals and prophylactic vaccines.
Subject(s)
Cullin Proteins , Interferon Type I , Proteolysis , STAT2 Transcription Factor , Signal Transduction , Ubiquitin-Protein Ligases , Ubiquitination , Viral Nonstructural Proteins , Zika Virus Infection , Zika Virus , Humans , STAT2 Transcription Factor/metabolism , Zika Virus/immunology , Zika Virus/physiology , Zika Virus/metabolism , Viral Nonstructural Proteins/metabolism , Viral Nonstructural Proteins/genetics , Interferon Type I/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Zika Virus Infection/metabolism , Zika Virus Infection/immunology , Zika Virus Infection/virology , Cullin Proteins/metabolism , A549 Cells , HEK293 Cells , CRISPR-Cas SystemsABSTRACT
BACKGROUND: Although intervertebral disc degeneration (IVDD) is a critical factor in many spine-related diseases and has an extremely high prevalence in the aging population, the potential pathogenesis remains to be clarified entirely. Immune cells have been found to perform an essential function during the onset and progression of IVDD in recent years. Therefore, we explored the association between immune cell characteristics and IVDD through Mendelian randomization (MR) analysis and further delved into the mediating role of potential metabolites. METHODS: Based on the MR analysis, the association of 731 immune cell phenotypes and 1400 metabolites on IVDD were assessed. Single nucleotide polymorphisms were closely associated the expression levels of immune cell characteristics and the concentrations of metabolites and have been used as instrumental variables for deducing them as risk factors or protective factors for IVDD. In addition, mediation analyses have been performed to identify potential metabolite mediators between immune cell characteristics and IVDD. RESULTS: MR analysis identified 27 immune cell phenotypes and 79 metabolites significantly associated with IVDD. In addition, mediation analysis was performed by selecting the immune cell phenotype that most significantly increased the risk of IVDD - CD86 on monocytes. A total of 4 metabolite-mediated mediation relationships were revealed (3 b-hydroxy-5-cholenoic acid, X-22509, N-acetyl-L-glutamine, and N2-acetyl, N6, N6-dimethyllysine). CONCLUSIONS: The findings of this analysis identified underlying association between immune cell phenotypes, metabolite, and IVDD that may serve as predictive and prognostic clinical biomarkers and benefit IVDD pathogenesis research.
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Breast cancer is a global public health concern with high mortality rates, necessitating the development of innovative treatment strategies. PARP inhibitors have shown efficacy in certain patient populations, but their application is largely limited to cancers with homologous recombination deficiency. Here, we identified the suppression of FANCI as a therapeutic strategy to enhance the efficacy of PARP inhibitors in breast cancer. Elevated FANCI expression in breast cancer was associated with poor prognosis and increased cell proliferation and migration. FANCI interacted with PARP1, and suppressing FANCI limited the nuclear localization and functionality of PARP1. Importantly, FANCI inhibition sensitized breast cancer cells to the PARP inhibitor talazoparib in the absence of BRCA mutations. Additionally, the CDK4/6 inhibitor palbociclib enhanced the sensitivity of breast cancer cells to talazoparib through FANCI inhibition. These findings highlight the potential of targeting FANCI to enhance the efficacy of PARP inhibitors in treating breast cancer.
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BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9's impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis. METHODS: Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis. RESULTS: The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I2, 39%). However, HMGCR inhibitors are not associated with osteoporosis risk. Additionally, a replication of the analysis was conducted with another exposure-related GWAS dataset, which led to similar conclusions. CONCLUSION: PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.
Subject(s)
Genome-Wide Association Study , Mendelian Randomization Analysis , Osteoporosis , PCSK9 Inhibitors , Polymorphism, Single Nucleotide , Humans , Osteoporosis/genetics , Osteoporosis/chemically induced , Osteoporosis/epidemiology , Proprotein Convertase 9/genetics , Proprotein Convertase 9/metabolism , Hydroxymethylglutaryl CoA Reductases/geneticsABSTRACT
This study aims to investigate the role and mechanism of Gusong Qianggu Decoction(GSQG) in attenuating bone loss in ovariectomized mice by targeting the endoplasmic reticulum stress(ERS)-induced apoptosis of osteocytes. After the modeling of osteoporosis in mice with bilateral ovary removal(OVX), 60 mice were randomized by the random number method into six groups: sham,model, low-, medium-, and high-dose GSQG(GSQG-L, GSQG-M, and GSQG-H, respectively), and estradiol(E_2), with 10 mice in each group. The mice in each group were administrated with corresponding drugs by gavage one month after surgery and the administration lasted for 3 months. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the serum levels of osteocalcin(OCN), procollagen type â N-terminal propeptide(PINP), carboxy-terminal cross-linked telopeptide of type â collagen(CTX),and anti-tartarte acid phosphatase 5b(TRAcP-5b). Micro-CT was employed to observe the changes in bone microstructure of the distal femur. Hematoxylin-eosin(HE) staining was employed to observe the morphology of the bone tissue. RT-qPCR was conducted to determine the m RNA levels of tibial stem osteogenesis-associated genes [type â collagen(Col-â ), alkaline phosphatase(ALP), Runtrelated transcription factor-2(Runx2), bone sialoprotein(BSP), and OCN] and bone-breaking related genes [tartrate-resistant acid phosphatase(TRAP), nuclear factor-activated T cell 1(NFATc1), and cathepsin K(CATK)]. TUNEL staining and immunohistochemistry were employed to detect the apoptosis of osteoblasts. Western blot was employed to measure the expression of ERS-related proteins glucose-regulated protein 78( Grp78), protein kinase RNA-like endoplasmic reticulum kinase( PERK), phosphorylated PERK(p-PERK),eukaryotic translation initiation factor 2 alpha(eIF2α), phosphorylated e IF2α(p-eIF2α), inositol-requiring enzyme 1 alpha(IRE1α), phosphorylated IRE1α(p-IRE1α), and activating transcription factor 6(ATF6) in the proximal tibial bone tissue. The results showed that GSQG significantly recovered the levels of OCN, PINP, TRAc P-5b, and CTX in the serum of ovariectomized mice, and Micro-CT showed that GSQG improved the bone microstructure of distal femur in a dose-dependent manner. Compared with the model group, GSQG widened and increased the bone trabeculae, restored the reticular structure with neat arrangement and enlarged interstitial gaps, and reduced the number of TUNEL-positive cells(P<0. 05, P<0. 01). Furthermore, GSQG down-regulated the expression levels of cysteine aspartate protease-3( caspase-3) and factor Bcl-2-associated X protein( Bax)(P< 0. 05,P<0. 01) and up-regulated the expression level of Bcl-2(P<0. 05, P<0. 01). The GSQG groups showed up-regulated m RNA levels of Col-â , ALP, Runx2, BSP, and OCN(P< 0. 01) and down-regulated m RNA levels of TRAP, NFATc1, and CATK(P< 0. 05,P<0. 01). In addition, GSQG, especially GSQG-H, down-regulated the protein levels of Grp78, p-PERK, p-eIF2, p-IRE1α, and ATF6(P< 0. 05, P< 0. 01). In conclusion, GSQG can inhibit the apoptosis of osteocytes by inhibiting the Grp78/PERK/e IF2α/IRE1α/ATF6 signaling pathway in the proximal tibia tissue, thus reducing bone loss in ovariectomized mice.
Subject(s)
Apoptosis , Drugs, Chinese Herbal , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress , Osteocytes , Ovariectomy , Animals , Endoplasmic Reticulum Stress/drug effects , Mice , Apoptosis/drug effects , Female , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/administration & dosage , Osteocytes/drug effects , Osteocytes/metabolism , Osteoporosis/drug therapy , Osteoporosis/metabolism , Humans , Osteocalcin/genetics , Osteocalcin/metabolism , Bone Density/drug effectsABSTRACT
Objective: Rheumatoid arthritis (RA) is a systemic disease that attacks the joints and causes a heavy economic burden on humans worldwide. T cells regulate RA progression and are considered crucial targets for therapy. Therefore, we aimed to integrate multiple datasets to explore the mechanisms of RA. Moreover, we established a T cell-related diagnostic model to provide a new method for RA immunotherapy. Methods: scRNA-seq and bulk-seq datasets for RA were obtained from the Gene Expression Omnibus (GEO) database. Various methods were used to analyze and characterize the T cell heterogeneity of RA. Using Mendelian randomization (MR) and expression quantitative trait loci (eQTL), we screened for potential pathogenic T cell marker genes in RA. Subsequently, we selected an optimal machine learning approach by comparing the nine types of machine learning in predicting RA to identify T cell-related diagnostic features to construct a nomogram model. Patients with RA were divided into different T cell-related clusters using the consensus clustering method. Finally, we performed immune cell infiltration and clinical correlation analyses of T cell-related diagnostic features. Results: By analyzing the scRNA-seq dataset, we obtained 10,211 cells that were annotated into 7 different subtypes based on specific marker genes. By integrating the eQTL from blood and RA GWAS, combined with XGB machine learning, we identified a total of 8 T cell-related diagnostic features (MIER1, PPP1CB, ICOS, GADD45A, CD3D, SLFN5, PIP4K2A, and IL6ST). Consensus clustering analysis showed that RA could be classified into two different T-cell patterns (Cluster 1 and Cluster 2), with Cluster 2 having a higher T-cell score than Cluster 1. The two clusters involved different pathways and had different immune cell infiltration states. There was no difference in age or sex between the two different T cell patterns. In addition, ICOS and IL6ST were negatively correlated with age in RA patients. Conclusion: Our findings elucidate the heterogeneity of T cells in RA and the communication role of these cells in an RA immune microenvironment. The construction of T cell-related diagnostic models provides a resource for guiding RA immunotherapeutic strategies.
Subject(s)
Arthritis, Rheumatoid , Mendelian Randomization Analysis , Quantitative Trait Loci , RNA-Seq , Single-Cell Analysis , Humans , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/diagnosis , Single-Cell Analysis/methods , Nomograms , Machine Learning , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Gene Expression Profiling , Single-Cell Gene Expression AnalysisABSTRACT
Gut microbiota-derived extracellular vesicles (mEVs) are reported to regulate inflammatory response by delivering bacterial products into host cells. The complement receptor of the immunoglobulin superfamily macrophages (CRIg+ Mφ) could clear invading bacteria and their derivatives. Here, we investigate the role of CRIg+ Mφ and the mechanism by which mEVs regulate intestinal inflammation. We found that it is exacerbated in IBD patients and colitis mice by mEVs' leakage from disturbed gut microbiota, enriching microbial DNA in the intestinal mucosa. CRIg+ Mφ significantly decrease in IBD patients, allowing the spread of mEVs into the mucosa. The microbial DNA within mEVs is the key trigger for inflammation and barrier function damage. The cGAS/STING pathway is crucial in mEVs-mediated inflammatory injury. Blocking cGAS/STING signaling effectively alleviates inflammation caused by mEVs leakage and CRIg+ Mφ deficiency. Microbial DNA-containing mEVs, along with CRIg+ Mφ deficiency, stimulate inflammation in IBD, with the cGAS/STING pathway playing a crucial role.
Subject(s)
DNA, Bacterial , Extracellular Vesicles , Gastrointestinal Microbiome , Inflammation , Inflammatory Bowel Diseases , Intestinal Mucosa , Macrophages , Membrane Proteins , Nucleotidyltransferases , Extracellular Vesicles/metabolism , Extracellular Vesicles/immunology , Animals , Mice , Macrophages/immunology , Macrophages/microbiology , Macrophages/metabolism , Inflammatory Bowel Diseases/microbiology , Inflammatory Bowel Diseases/pathology , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/immunology , Humans , Membrane Proteins/metabolism , Membrane Proteins/genetics , Nucleotidyltransferases/metabolism , Nucleotidyltransferases/genetics , Intestinal Mucosa/microbiology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Intestinal Mucosa/immunology , Inflammation/microbiology , Inflammation/metabolism , DNA, Bacterial/genetics , Mice, Inbred C57BL , Male , Female , Signal Transduction , Colitis/microbiology , Colitis/pathologyABSTRACT
In tic disorders (TD), tic expression varies across the lifespan and as a function of contextual factors. This study explored connections between tic expression and contextual triggers across life periods in 74 adults (Mage = 23.2) with TDs. The Tic History and Coping Strategies form assessed retrospective self-reports of contextual antecedents, consequences, and tic severity during four life periods (middle school; 9th/10th grade; 11th/12th grade; college/work) and past month. Tics reportedly worsened during and after school in school-aged years and worsened in the evening during college/work years. Stress and anxiety were reported to consistently trigger tics across time. The impact of activities, places, and emotions did not differ across life periods. Attention-based consequences, most prevalent during middle school, were more common than escape- or avoidance-related consequences across all periods. Findings illuminate how contextual factors may influence tics across life periods and underscore the consistent impact of tic-triggering emotions and attention-related consequences.
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BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction activated by microglia. The potential pathological changes of SAE are complex, and the cellular pathophysiological characteristics remains unclear. This study aims to explore the ROS/TXNIP/NLRP3 pathway mediated lipopolysaccharide (LPS)-induced inflammatory response in microglia. METHODS: BV-2 cells were pre-incubated with 10 µM N-acetyl-L-cysteine (NAC) for 2 h, which were then reacted with 1 µg/mL LPS for 24 h. Western blot assay examined the protein levels of IBA1, CD68, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. The contents of inflammatory factor were detected by ELISA assay. The co-immunoprecipitation assay examined the interaction between TXNIP and NLRP3. RESULTS: LPS was confirmed to promote the positive expressions of IBA1 and CD68 in BV-2 cells. The further experiments indicated that LPS enhanced ROS production and NLRP3 inflammasome activation in BV-2 cells. Moreover, we also found that NAC partially reversed the facilitation of LPS on the levels of ROS, IL-1ß, IL-18, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. NAC treatment also notably alleviated the interaction between TXNIP and NLRP3 in BV-2 cells. CONCLUSION: ROS inhibition mediated NLRP3 signaling inactivation by decreasing TXNIP expression.
Subject(s)
Carrier Proteins , Caspase 1 , Inflammasomes , Inflammation , Lipopolysaccharides , Microglia , NLR Family, Pyrin Domain-Containing 3 Protein , Reactive Oxygen Species , Signal Transduction , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Microglia/metabolism , Microglia/drug effects , Lipopolysaccharides/pharmacology , Carrier Proteins/metabolism , Animals , Mice , Reactive Oxygen Species/metabolism , Caspase 1/metabolism , Signal Transduction/drug effects , Inflammasomes/metabolism , Inflammation/metabolism , Inflammation/pathology , Cell Line , Acetylcysteine/pharmacology , Calcium-Binding Proteins/metabolism , Interleukin-1beta/metabolism , Interleukin-18/metabolism , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Microfilament Proteins/metabolism , Thioredoxins/metabolism , CARD Signaling Adaptor Proteins/metabolism , Sepsis-Associated Encephalopathy/metabolism , Sepsis-Associated Encephalopathy/pathology , CD68 MoleculeABSTRACT
Redundant carbapenemase-producing (RCP) bacteria, which carry double or multiple carbapenemases, represent a new and concerning phenomenon. The objective of this study is to conduct a comprehensive analysis of the epidemiology and genetic mechanisms of RCP strains to support targeted surveillance and control measures. A retrospective analysis was conducted using surveillance data from 277 articles. Statistical analysis was performed to determine and evaluate species prevalence, proportions of carbapenemases, antibiotic susceptibility profiles, sample information, and patient outcomes. Complete plasmid sequencing data were utilized to investigate potential antimicrobial resistance or virulence advantages that strains may gain from acquiring redundant carbapenemases. RCP bacteria are widely distributed globally, and their prevalence is increasing over time. Several countries, including China, India, Iran, Turkey, and South Korea, have reported more than 100 RCP strains. The most commonly reported RCP species are Klebsiella pneumoniae and Acinetobacter baumannii, which exhibit varying proportions of carbapenemase combinations. Certain species-carbapenemase combinations, such as K. pneumoniae carrying New Delhi metallo-ß-lactamase (NDM) + oxacillinase (OXA) (56.76%) and K. pneumoniae carbapenemase (KPC) + Verona integron-encoded metallo-ß-lactamase (VIM) (50.00%) carbapenemases, are associated with high mortality rates. In patients with RCP strains isolated from the bloodstream and respiratory system, the mortality rates are 58.70% and 69.23%, respectively. Analysis of plasmids from RCP strains suggests that they may acquire additional antibiotic resistance phenotypes and virulence factors. Carbapenem-resistant bacteria carrying redundant carbapenemases pose a significant global health threat. This study provides valuable insights into the epidemiology and genetic mechanisms of these bacteria, supporting the development of effective control and prevention strategies to mitigate their transmission.IMPORTANCEThis study examined the global distribution patterns of 1,780 bacteria with double or multiple carbapenemases from 277 articles and assessed their clinical impact. The presence of multiple carbapenemases increases the chances of co-resistance to other classes of antibiotics and more virulence factors, further complicating the clinical management of infections.
Subject(s)
Anti-Bacterial Agents , Bacterial Proteins , beta-Lactamases , beta-Lactamases/genetics , beta-Lactamases/metabolism , Humans , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Virulence/genetics , Anti-Bacterial Agents/pharmacology , Retrospective Studies , Microbial Sensitivity Tests , Drug Resistance, Multiple, Bacterial/genetics , Plasmids/genetics , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/enzymology , Klebsiella pneumoniae/pathogenicity , Klebsiella pneumoniae/isolation & purification , Carbapenems/pharmacology , Clinical RelevanceABSTRACT
Objective: Interleukin-6 (IL-6) is a multiple-effect cell factor implicated in the etiopathogenesis of several rheumatologic disorders. The blockade of the IL-6 pathway via IL6R inhibitors effectively treats these disorders. However, the clinical significance of the IL6R blockade for ankylosing spondylitis (AS) therapy remains controversial. With advances in genomics, increasing evidence has revealed the role of heritability in the etiology of disease, and Mendelian randomization (MR) analyses are being used more broadly to infer causation. Therefore, this MR study aims to evaluate the potential therapeutic utility of IL6R-targeted approaches in AS. Methods: The C-reactive protein (CRP) level was used as an exposure factor, and rheumatoid arthritis (RA) was used as a positive control. As-related genome-wide association study (GWAS) data were used as the primary outcome of drug-targeted MR analyses to test the relation between IL6R blockers and AS. Inverse variance weighting (IVW) is the primary analytical approach. Various sensitivity tests were performed to check the robustness and trustworthiness of the causality estimation, including consistency, heterogeneity, and pleiotropy analyses. In addition, repeated analysis was conducted using different GWAS data related to exposures and outcomes to examine the results for stability. Results: According to the IVW results, IL6R inhibitors significantly reduced the risk of AS in ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.996, P = 5.12 × 10-08) and ukb-a-88 (OR: 0.994, 95% CI 0.993-0.996, P = 6.25 × 10-15). Moreover, repeated analyses were performed using different exposure-related GWAS data, yielding similar results, ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.997, P = 1.25 × 10-06) and ukb-a-88 (OR: 0.995, 95% CI 0.994-0.997, P = 7.81 × 10-09). Heterogeneity analyses and pleiotropy analyses indicated no significant heterogeneity or pleiotropy. Conclusion: This MR analysis result further validates that the IL-6 pathway may contribute to the pathogenesis of AS and that the inhibition of IL6R reduces the risk of AS. These findings may guide future studies and provide more favorable drug treatment options for people at high risk of AS.
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Alphaviruses are mosquito borne RNA viruses that are a reemerging public health threat. Alphaviruses have a broad host range, and can cause diverse disease outcomes like arthritis, and encephalitis. The host ubiquitin proteasome system (UPS) plays critical roles in regulating cellular processes to control the infections with various viruses, including alphaviruses. Previous studies suggest alphaviruses hijack UPS for virus infection, but the molecular mechanisms remain poorly characterized. In addition, whether certain E3 ubiquitin ligases or deubiquitinases act as alphavirus restriction factors remains poorly understood. Here, we employed a cDNA expression screen to identify E3 ubiquitin ligase TRIM32 as a novel intrinsic restriction factor against alphavirus infection, including VEEV-TC83, SINV, and ONNV. Ectopic expression of TRIM32 reduces alphavirus infection, whereas depletion of TRIM32 with CRISPR-Cas9 increases infection. We demonstrate that TRIM32 inhibits alphaviruses through a mechanism that is independent of the TRIM32-STING-IFN axis. Combining reverse genetics and biochemical assays, we found that TRIM32 interferes with genome translation after membrane fusion, prior to replication of the incoming viral genome. Furthermore, our data indicate that the monoubiquitination of TRIM32 is important for its antiviral activity. Notably, we also show two TRIM32 pathogenic mutants R394H and D487N, related to Limb-girdle muscular dystrophy (LGMD), have a loss of antiviral activity against VEEV-TC83. Collectively, these results reveal that TRIM32 acts as a novel intrinsic restriction factor suppressing alphavirus infection and provides insights into the interaction between alphaviruses and the host UPS.
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In this study, we aimed to investigate the involvement of PANoptosis, a form of regulated cell death, in the development of steroid-induced osteonecrosis of the femoral head (SONFH). The underlying pathogenesis of PANoptosis in SONFH remains unclear. To address this, we employed bioinformatics approaches to analyze the key genes associated with PANoptosis. Our analysis was based on the GSE123568 dataset, allowing us to investigate both the expression profiles of PANoptosis-related genes (PRGs) and the immune profiles in SONFHallowing us to investigate the expression profiles of PRGs as well as the immune profiles in SONFH. We conducted cluster classification based on PRGs and assessed immune cell infiltration. Additionally, we used the weighted gene co-expression network analysis (WGCNA) algorithm to identify cluster-specific hub genes. Furthermore, we developed an optimal machine learning model to identify the key predictive genes responsible for SONFH progression. We also constructed a nomogram model with high predictive accuracy for assessing risk factors in SONFH patients, and validated the model using external data (area under the curve; AUC = 1.000). Furthermore, we identified potential drug targets for SONFH through the Coremine medical database. Using the optimal machine learning model, we found that 2 PRGs, CASP1 and MLKL, were significantly correlated with the key predictive genes and exhibited higher expression levels in SONFH. Our analysis revealed the existence of 2 distinct PANoptosis molecular subtypes (C1 and C2) within SONFH. Importantly, we observed significant variations in the distribution of immune cells across these subtypes, with C2 displaying higher levels of immune cell infiltration. Gene set variation analysis indicated that C2 was closely associated with multiple immune responses. In conclusion, our study sheds light on the intricate relationship between PANoptosis and SONFH. We successfully developed a risk predictive model for SONFH patients and different SONFH subtypes. These findings enhance our understanding of the pathogenesis of SONFH and offer potential insights into therapeutic strategies.
Subject(s)
Computational Biology , Femur Head Necrosis , Humans , Femur Head Necrosis/genetics , Femur Head Necrosis/chemically induced , Computational Biology/methods , Machine Learning , Steroids/adverse effects , Caspase 1/genetics , Nomograms , Gene Expression Profiling/methods , Protein Kinases/geneticsABSTRACT
BACKGROUND: The Premonitory Urge for Tics Scale (PUTS) is a common self-report measure of premonitory urges for patients with tic disorders. This study aims to evaluate the Chinese version of the PUTS (PUTS-C) and to explore its association with psychiatric symptoms in Chinese children diagnosed with tic disorders. METHODS: The psychometric evaluation involved 204 outpatients with tic disorders, aged 7-16 years, who were divided into two age groups: (7-10 years, n = 103; 11-16 years, n = 95). RESULTS: The PUTS-C demonstrated good internal consistency (McDonald'sω = 0.84) and two-week test-retest reliability (0.76). We observed a statistically significant correlation between the total PUTS-C score and various Yale Global Tic Severity Scale (YGTSS) subscales and total tic severity scores. The PUTS-C score also showed significant correlations with the Children Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Screening Child Anxiety-Related Emotional Disorders (SCARED), and Children's Depression Inventory (CDI). Notably, premonitory urges independently predicted tic severity, beyond the influence of comorbid symptoms. A two-factor structure of the PUTS-C was identified in the total sample through factor analysis. CONCLUSIONS: The PUTS-C possesses acceptable validity and good reliability. It appears that premonitory urges in Chinese patients with tic disorders are associated with obsessive-compulsive symptoms, anxiety, and depression, but can independently predict tic severity. Specific PUTS-C factors possibly related to motor and vocal tics. Future research should continue to investigate age-related differences and the association with tics and other sensory symptoms.
Subject(s)
Psychometrics , Tic Disorders , Humans , Child , Tic Disorders/diagnosis , Tic Disorders/psychology , Male , Adolescent , Female , Reproducibility of Results , China , Psychiatric Status Rating Scales , Severity of Illness Index , Self ReportABSTRACT
Previous studies through targeted mutagenesis of K-D-K-E motif have demonstrated that 2'-O-MTase activity is essential for efficient viral replication and immune evasion. However, the K-D-K-E catalytic motif of 2'-O-MTase is highly conserved across numerous viruses, including flaviviruses, vaccinia viruses, coronaviruses, and extends even to mammals. Here, we observed a stronger 2'-O-MTase activity in SARS-CoV-2 compared to SARS-CoV, despite the presence of a consistently active catalytic center. We further identified critical residues (Leu-36, Asn-138 and Ile-153) which served as determinants of discrepancy in 2'-O-MTase activity between SARS-CoV-2 and SARS-CoV. These residues significantly enhanced the RNA binding affinity of 2'-O-MTase and boosted its versatility toward RNA substrates. Of interest, a triple substitution (Leu36 â Ile36, Asn138 â His138, Ile153 â Leu153, from SARS-CoV-2 to SARS-CoV) within nsp16 resulted in a proportional reduction in viral 2'-O-methylation and impaired viral replication. Furthermore, it led to a significant upregulation of type I interferon (IFN-I) and proinflammatory cytokines both in vitro and vivo, relying on the cooperative sensing of melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2). In conclusion, our findings demonstrated that alterations in residues other than K-D-K-E of 2'-O-MTase may affect viral replication and subsequently influence pathogenesis. Monitoring changes in nsp16 residues is crucial as it may aid in identifying and assessing future alteration in viral pathogenicity resulting from natural mutations occurring in nsp16.
Subject(s)
COVID-19 , Methyltransferases , SARS-CoV-2 , Virus Replication , Humans , SARS-CoV-2/genetics , SARS-CoV-2/enzymology , SARS-CoV-2/pathogenicity , COVID-19/virology , COVID-19/genetics , Methyltransferases/genetics , Methyltransferases/metabolism , Methyltransferases/chemistry , Virus Replication/genetics , RNA, Viral/genetics , RNA, Viral/metabolism , RNA, Viral/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Severe acute respiratory syndrome-related coronavirus/genetics , Severe acute respiratory syndrome-related coronavirus/enzymology , Severe acute respiratory syndrome-related coronavirus/pathogenicity , Animals , Interferon-Induced Helicase, IFIH1/genetics , Interferon-Induced Helicase, IFIH1/metabolismABSTRACT
Minimally invasive thermal therapy is a successful alternative treatment to surgery in solid tumors with high complete ablation rates, however, tumor recurrence remains a concern. Central memory CD8+ T cells (TCM) play important roles in protection from chronic infection and cancer. Here we find, by single-cell RNA analysis of human breast cancer samples, that although the memory phenotype of peripheral CD8+ T cells increases slightly after microwave ablation (MWA), the metabolism of peripheral CD8+ T cells remains unfavorable for memory phenotype. In mouse models, glycolysis inhibition by 2-deoxy-D-glucose (2DG) in combination with MWA results in long-term anti-tumor effect via enhancing differentiation of tumor-specific CD44hiCD62L+CD8+ TCM cells. Enhancement of CD8+ TCM cell differentiation determined by Stat-1, is dependent on the tumor-draining lymph nodes (TDLN) but takes place in peripheral blood, with metabolic remodeling of CD8+ T cells lasting the entire course of the the combination therapy. Importantly, in-vitro glycolysis inhibition in peripheral CD8+ T cells of patients with breast or liver tumors having been treated with MWA thrice leads to their differentiation into CD8+ TCM cells. Our work thus offers a potential strategy to avoid tumor recurrence following MWA therapy and lays down the proof-of-principle for future clinical trials.
Subject(s)
Breast Neoplasms , CD8-Positive T-Lymphocytes , Cell Differentiation , Glycolysis , Immunologic Memory , Microwaves , Glycolysis/drug effects , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Humans , Cell Differentiation/drug effects , Mice , Female , Breast Neoplasms/immunology , Breast Neoplasms/therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Microwaves/therapeutic use , Deoxyglucose/pharmacology , Deoxyglucose/therapeutic use , Cell Line, Tumor , Liver Neoplasms/immunology , Liver Neoplasms/therapy , Memory T Cells/immunology , Memory T Cells/metabolismABSTRACT
Langya virus (LayV) was recently detected in patients with acute pneumonic diseases in China. Genome alignment indicated that LayV is a type of zoonotic henipavirus (HNV) that might also infect domestic animals. Previous studies revealed that HNVs mainly use ephrin-B1, ephrin-B2, or ephrin-B3 as cell receptors and the attachment glycoprotein (G) is the host cell receptor-binding protein. However, the LayV receptor remains unknown. Here, we present the 2.77 Å crystal structure of the LayV G C-terminal domain (CTD). We show that the LayV G protein CTD possesses a similar architecture as the Mojiang virus (MojV) G protein but is markedly different from the Nipah virus (NiV), Hendra virus (HeV), and Cedar virus (CedV) G proteins. Surface plasmon resonance (SPR) experiments indicate that LayV G does not bind ephrin-B proteins. Steric hindrance may prevent interactions between LayV G and ephrin-B. Our data might facilitate drug development targeting LayV.
Subject(s)
Models, Molecular , Protein Binding , Viral Envelope Proteins , Crystallography, X-Ray , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/metabolism , Henipavirus/metabolism , Henipavirus/chemistry , Humans , Binding Sites , Amino Acid Sequence , Protein Domains , Protein Conformation, beta-Strand , Animals , Protein Conformation, alpha-HelicalABSTRACT
OBJECTIVE: Increasing evidence has shown that dietary behaviors are closely correlated with the carcinogenesis and progression of many types of cancer. However, few studies have assessed the global diet-related burden of cancer. This study aimed to estimate the pooled burdens and trends of five types of cancers attributable to dietary behaviors. METHODS: Data regarding cancer attributable to dietary behaviors were extracted from the Global Burden of Disease study 2019, including the death cases and age-standardized death rates, and disability-adjusted life years (DALYs) estimated according to diseases, age, sex, the socio-demographic index (SDI) and location. RESULTS: According to the Global Burden of Disease study 2019, five types of cancer were affected by dietary behaviors: colon and rectum cancer; tracheal, bronchus and lung cancer; stomach cancer; esophageal cancer and breast cancer. Unhealthy dietary behaviors for cancer caused a total of 605.4 thousand deaths and 13951.3 thousand DALYs globally. The burden of cancer attributable to dietary risks was higher for men than for women. The highest age-standardized death rates in 2019 were observed in southern Latin America, and the lowest rates were observed in North Africa and the Middle East. The greatest increases in the age-standardized death rates, from 1990 to 2019, were found in Western Sub-Saharan Africa, with the greatest decreases in Central Asia. The highest attributable proportions of death or DALYs were colon and rectum cancer. The greatest diet-related cancer burden was observed in regions with a high-middle SDI. CONCLUSION: Global age-standardized deaths and DALYs rates attributable to diet-related cancer are considerable and cause a substantial burden. Successful population-wide initiatives targeting unhealthy dietary behaviors would reduce this burden.