Introduction: The escalating global surge in Rifampicin-resistant strains poses a formidable challenge to the worldwide campaign against tuberculosis (TB), particularly in developing countries. The frequent reports of suboptimal treatment outcomes, complications, and the absence of definitive treatment guidelines for Rifampicin-resistant spinal TB (DSTB) contribute significantly to the obstacles in its effective management. Consequently, there is an urgent need for innovative and efficacious drugs to address Rifampicin-resistant spinal tuberculosis, minimizing the duration of therapy sessions. This study aims to investigate potential targets for DSTB through comprehensive proteomic and pharmaco-transcriptomic analyses. Methods: Mass spectrometry-based proteomics analysis was employed to validate potential DSTB-related targets. PPI analysis confirmed by Immunohistochemistry (IHC) and Western blot analysis. Results: The proteomics analysis revealed 373 differentially expressed proteins (DEPs), with 137 upregulated and 236 downregulated proteins. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses delved into the DSTB-related pathways associated with these DEPs. In the context of network pharmacology analysis, five key targets-human leukocyte antigen A chain (HLAA), human leukocyte antigen C chain (HLA-C), HLA Class II Histocompatibility Antigen, DRB1 Beta Chain (HLA-DRB1), metalloproteinase 9 (MMP9), and Phospholipase C-like 1 (PLCL1)-were identified as pivotal players in pathways such as "Antigen processing and presentation" and "Phagosome," which are crucially enriched in DSTB. Moreover, pharmaco-transcriptomic analysis can confirm that 58 drug compounds can regulate the expression of the key targets. Discussion: This research confirms the presence of protein alterations during the Rifampicin-resistant process in DSTB patients, offering novel insights into the molecular mechanisms underpinning DSTB. The findings suggest a promising avenue for the development of targeted drugs to enhance the management of Rifampicin-resistant spinal tuberculosis.
The stone cells in pear fruits cause rough flesh and low juice, seriously affecting the taste. Lignin has been demonstrated as the main component of stone cells. Auxin, one of the most important plant hormone, regulates most physiological processes in plants including lignification. However, the concentration effect and regulators of auxin on pear fruits stone cell formation remains unclear. Here, endogenous indole-3-acetic acid (IAA) and stone cells were found to be co-localized in lignified cells by immunofluorescence localization analysis. The exogenous treatment of different concentrations of IAA demonstrated that the application of 200⯵M IAA significantly reduced stone cell content, while concentrations greater than 500⯵M significantly increased stone cell content. Besides, 31 auxin response factors (ARFs) were identified in pear genome. Putative ARFs were predicted as critical regulators involved in the lignification of pear flesh cells by phylogenetic relationship and expression analysis. Furthermore, the negative regulation of PbARF19 on stone cell formation in pear fruit was demonstrated by overexpression in pear fruitlets and Arabidopsis. These results illustrated that the PbARF19-mediated auxin signal plays a critical role in the lignification of pear stone cell by regulating lignin biosynthetic genes. This study provides theoretical and practical guidance for improving fruit quality in pear production.
INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: Inclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.
OBJECTIVE: The objective of this study was to evaluate the association between hyperthyroidism and the risk of developing erectile dysfunction (ED). METHODS: A comprehensive search of multiple databases, including PubMed, Embase, Cochrane, and Web of Science, was conducted to identify relevant studies investigating the relationship between hyperthyroidism and ED in men. The quality of the included studies was assessed using the NewcastleâOttawa Quality Rating Scale, and a meta-analysis was performed using Stata 16.0 and RevMan 5.3 software. RESULTS: A total of four papers encompassing 25,519 study subjects were included in the analysis. Among these, 6,429 individuals had hyperthyroidism, while 19,090 served as controls. The overall prevalence of ED in patients with hyperthyroidism was determined to be 31.1% (95% CI 0.06-0.56). In patients with uncomplicated hyperthyroidism, the incidence of ED was 21.9% (95% CI 0.05-0.38). The combined odds ratio (OR) for the four studies was 1.73 (OR: 1.73; 95% CI [1.46-2.04]; p < .00001). CONCLUSION: Our findings demonstrate a higher incidence of ED in patients with hyperthyroidism. These results provide valuable information for healthcare professionals and can facilitate discussions surrounding appropriate treatment options for ED in patients with hyperthyroidism.
Erectile Dysfunction , Hyperthyroidism , Humans , Hyperthyroidism/epidemiology , Hyperthyroidism/complications , Erectile Dysfunction/epidemiology , Erectile Dysfunction/etiology , Male , Prevalence
The synthesis of anode materials plays an important role in determining the production efficiency, cost, and performance of lithium-ion batteries (LIBs). However, a low-cost, high-speed, scalable manufacturing process of the anode with the desired structural feature for practical technology adoption remains elusive. In this study, we propose a novel method called in situ flash shunt-electrothermal shock (SETS) which is controllable, fast, and energy-saving for synthesizing metal oxide-based materials. By using the example of direct electrothermal decomposition of ZIF-67 precursor loaded onto copper foil support, we achieve rapid (0.1-0.3 s) pyrolysis and generate porous hollow cubic structure material consisting of carbon-coated ultrasmall (10-15 nm) subcrystalline CoO/Co nanoparticles with controllable morphology. It was shown that CoO/Co@N-C exhibits prominent electrochemical performance with a high reversible capacity up to 1503.7 mA h g-1 after 150 cycles at 0.2 A g-1and stable capacities up to 434.1 mA h g-1 after 400 cycles at a high current density of 6 A g-1. This fabrication technique integrates the synthesis of active materials and the formation of electrode sheets into one process, thus simplifying the preparation of electrodes. Due to the simplicity and scalability of this process, it can be envisaged to apply it to the synthesis of metal oxide-based materials and to achieve large-scale production in a nanomanufacturing process.
Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI and airway dysbiosis. Thus, a 2 x 2 factorial design, placebo-controlled, double-blinded, pilot and feasibility, clinical trial was proposed to test this hypothesis. Forty adult participants with CF were block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints included 12-week changes in the microbial bacterial communities, gut and airway microbiota richness and diversity before and after the intervention. This pilot study examined whether vitamin D3 with or without prebiotics supplementation was feasible, changed airway and gut microbiota, and reduced dysbiosis, which in turn, may improve health outcomes and quality of life of patients with CF.
The intestinal microbiota is associated with defense against respiratory viral infections. In this issue of Cell Host & Microbe, Ngo and colleagues1 show that intestinal commensal segmented filamentous bacteria reprogram alveolar macrophages with improved influenza-viral-neutralizing and phagocytic functions while maintaining inflammatory anergy to better protect the lung.
Gastrointestinal Microbiome , Orthomyxoviridae , Macrophages, Alveolar , Lung
Escherichia coli K1 is the leading cause of neonatal Gram-negative bacterial meningitis, but the pathogenesis of E. coli K1 meningitis remains unclear. Blood-brain barrier (BBB) penetration is a crucial step in E. coli meningitis development. Here, we uncovered the crucial role of CsiR, a GntR family regulator, in E. coli K1 virulence. During infection, csiR expression was induced due to the derepression by Fur in the blood and human brain microvascular endothelial cells (HBMECs). CsiR positively regulated ilvB expression, which is associated with branched chain amino acid synthesis. Furthermore, we revealed that IlvB activated the FAK/PI3â K pathway of HBMECs to induce actin cytoskeleton rearrangements, thereby promoting the bacterial invasion and penetration of the BBB. Overall, this study reveals a CsiR-mediated virulence regulation pathway in E. coli K1, which may provide a useful target for the prevention or therapy of E. coli meningitis.
The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1-3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor.
Carcinoma, Hepatocellular , Hypoxia-Inducible Factor 1, alpha Subunit , Liver Neoplasms , Phenylurea Compounds , Quinolines , RNA, Small Interfering , RNAi Therapeutics , Salmonella , Animals , Mice , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/therapy , Cell Line, Tumor , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/therapy , Phenylurea Compounds/therapeutic use , Quinolines/therapeutic use , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/therapeutic use , Tumor Microenvironment , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Combined Modality Therapy , RNAi Therapeutics/methods
The rapid development of the economy has led to an increase in the sulfur and nitrogen load in surface water, which has the potential to cause river eutrophication and the emission of malodorous gases. A lab-scale sediment microbial fuel cell coupled with Vallisneria natans (P-SMFC) was designed for surface water remediation. The enhancement of pollutant removal performance of P-SMFC was evaluated in contrast to the SMFC system without plants (SMFC), the open-circuit control system with plants (C-P), and the open-circuit control system without plants (C-S), while illustrating the mechanisms of the sulfur and nitrogen transformation process. The results demonstrated that the effluent and sediment of P-SMFC had lower concentrations of sulfide compared to other systems. Furthermore, P-SMFC exhibited higher removal efficiency for COD (73.1 ± 8.7%), NH4+-N (80.5 ± 19.8%), and NO3--N (88.5 ± 11.8%) compared to other systems. The closed-circuit conditions and growth of Vallisneria natans create a favorable ecological niche for functional microorganisms involved in power generation, sulfur oxidation, and nitrogen transformation. Additionally, metagenomic analysis revealed that multifunctional bacteria possessing both denitrification and sulfur oxidation genes, such as Thiobacillus, Dechloromonas, and Bacillus, may play simultaneous roles in metabolizing sulfur and nitrogen, thus serving as integral factors in maintaining the performance of P-SMFC. In summary, these findings provide a theoretical reference for the concurrent enhancement of sulfur and nitrogen pollutants removal in P-SMFC and will facilitate its practical application in the remediation of contaminated surface water.
Bioelectric Energy Sources , Microbiota , Nitrogen/metabolism , Geologic Sediments/chemistry , Water/chemistry , Sulfur , Denitrification
The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.
Alzheimer Disease , Humans , Alzheimer Disease/metabolism , Genome-Wide Association Study/methods , Brain/metabolism , Quantitative Trait Loci/genetics , Genetic Variation/genetics , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics
OBJECTIVE: To construct a prognostic model based on MR features and clinical data to evaluate the progression free survival (PFS), overall survival (OS) and objective response rate (ORR) of pancreatic cancer patients with hepatic metastases who received chemoimmunotherapy. METHODS: 105 pancreatic cancer patients with hepatic metastases who received chemoimmunotherapy were assigned to the training set (n = 52), validation set (n = 22), and testing set (n = 31). Multi-lesion volume of interest were delineated, multi-sequence radiomics features were extracted, and the radiomics models for predicting PFS, OS and ORR were constructed, respectively. Clinical variables were extracted, and the clinical models for predicting PFS, OS and ORR were constructed, respectively. The nomogram was jointly constructed by radiomics model and clinical model. RESULT: The ORR exhibits no significant correlation with either PFS or OS. The area under the curve (AUC) of nomogram for predicting 6-month PFS reached 0.847 (0.737-0.957), 0.786 (0.566-1.000) and 0.864 (0.735-0.994) in the training set, validation set and testing set, respectively. The AUC of nomogram for predicting 1-year OS reached 0.770 (0.635-0.906), 0.743 (0.479-1.000) and 0.818 (0.630-1.000), respectively. The AUC of nomogram for predicting ORR reached 0.914 (0.828-1.00), 0.938 (0.840-1.00) and 0.846 (0.689-1.00), respectively. CONCLUSION: The prognostic models based on MR imaging features and clinical data are effective in predicting the PFS, OS and ORR of chemoimmunotherapy in pancreatic cancer patients with hepatic metastasis, and can be used to evaluate the prognosis of patients.
Liver Neoplasms , Pancreatic Neoplasms , Humans , Nomograms , Radiomics , Prognosis , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/drug therapy , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/drug therapy , Retrospective Studies
BACKGROUND: Post-stroke depression (PSD) affects approximately one-third of stroke survivors, leading to adverse outcomes in rehabilitation, reduced quality of life, and increased mortality rates. Despite these implications, the underlying causes of PSD remain unclear, posing challenges for prevention and treatment. Echinacoside (ECH), a natural compound with known neuroprotective and antidepressant properties, holds significant therapeutic potential for PSD. However, the precise mechanism of its action remains unknown. PURPOSE: To unravel the specific mechanism through which ECH alleviates PSD by exploring the intricate interplay between ECH and Nrf2, as well as its impact on the BDNF/TrkB signaling axis. STUDY DESIGN AND METHODS: A rat PSD model was established though middle cerebral artery occlusion coupled with chronic unpredictable mild stress, followed by ECH treatment. The rats' depressive state was evaluated using the sucrose preference test and force swimming test. Brain damage was assessed through TTC staining, Nissl staining, and TUNEL assay. The multifaceted mechanism of ECH in PSD was investigated using immunofluorescence, immunohistochemistry, RT-qPCR, dual-luciferase assay, and western blotting. Additionally, the interaction between ECH and Nrf2 was explored through molecular docking and microscale thermophoresis. RESULTS: Our findings unveiled a novel facet of ECH action, demonstrating its unique ability to upregulate Nrf2 through acetylation within the hippocampus of PSD-affected rats (p < 0.05). Moreover, ECH showcased its distinctive potential by enhancing BDNF transcriptional activity, activating the BDNF/TrkB signaling axis, and orchestrating a comprehensive response against oxidative stress and apoptosis, thereby alleviating PSD symptoms in rats (p < 0.05). CONCLUSIONS: This study not only provides insights into the pivotal role of Nrf2 in mediating the BDNF/TrkB axis activation by ECH but also highlights the novelty of ECH's mechanism in addressing PSD. The elucidation of these unique aspects positions ECH as a groundbreaking candidate for further exploration and development in the realm of PSD intervention.
Brain-Derived Neurotrophic Factor , Depression , Glycosides , NF-E2-Related Factor 2 , Rats, Sprague-Dawley , Signal Transduction , Stroke , Animals , NF-E2-Related Factor 2/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Male , Signal Transduction/drug effects , Depression/drug therapy , Depression/etiology , Stroke/drug therapy , Stroke/complications , Rats , Glycosides/pharmacology , Acetylation , Disease Models, Animal , Neuroprotective Agents/pharmacology , Antidepressive Agents/pharmacology , Molecular Docking Simulation , Hippocampus/drug effects , Hippocampus/metabolism , Infarction, Middle Cerebral Artery/drug therapy
Purpose: We aimed to explore the effects of percutaneous coronary intervention (PCI) on the ophthalmic artery (OA) hemodynamics in patients with acute coronary syndrome (ACS). Methods: A total of 73 participants (Group0: healthy controls, Group1: Patients with ACS underwent PCI < 3 months, Group2: Patients with ACS underwent PCI ≥ 3 months) were enrolled. Computed tomographic angiography images were used to construct three-dimensional models of participants' OAs. Numerical simulations based on computational fluid dynamics were used to acquire hemodynamic parameters. Results: The angle between the OA and internal carotid artery in Group2 was significantly larger compared with Group0 and Group1 (P = 0.003 and P = 0.044). Hemodynamic simulation showed a significantly slower OA blood velocity in Group1 than in the control (P < 0.001) and Group2 (P = 0.033). Lower wall shear stress was found in Group1 than that in control (P = 0.040). Patients after PCI had a higher wall pressure than healthy controls (P = 0.012 and P = 0.004). Mass flow ratios were decreased in Group1 and Group2 (P = 0.021 and P = 0.002). The hemodynamic parameters of OA were correlated with several clinical indicators. Conclusions: The OA blood flow velocity of patients with ACS after PCI initially slowed down, which increased the risk of plaque formation, and then showed an increasing trend. There was a correlation between OA hemodynamic parameters and clinical indexes related to cardiac stress. Ischemia-reperfusion injury and changes in blood flow status after PCI may affect OA morphology and hemodynamics, leading to ocular lesions. Trial registration: ChiCTR2100050428.
This study investigates the nitrogen removal efficacy and microbial community dynamics in seawater aquaculture effluent treatment using three different substrate combinations of microscale laboratory aerated filters (MFs) - MF1 (LECA), MF2 (LECA/Fe-C), and MF3 (LECA/Pyrite). The findings indicated that the COD removal exceeded 95% across all MFs, with higher removal efficiencies in MF2 and MF3. In terms of nitrogen removal performance, MF2 exhibited the highest average nitrogen removal of 93.17%, achieving a 12.35% and 3.56% increase compared to MF1 (80.82%) and MF3 (89.61%), respectively. High-throughput sequencing analysis revealed that the Fe-C substrate significantly enhanced the diversity of the microbial community. Notably, in MF2, the salinophilic denitrifying bacterium Halomonas was significantly enriched, accounting for 42.6% of the total microbial community, which was beneficial for nitrogen removal. Moreover, an in-depth analysis of nitrogen metabolic pathways and microbial enzymes indicated that MF2 and MF3 possessed a high abundance of nitrification and denitrification enzymes, related to the high removal rates of NH4+-N and NO3--N. Therefore, the combination of LECA with iron-based materials significantly enhances the nitrogen removal efficiency from mariculture wastewater.
Aquaculture , Denitrification , Iron , Microbiota , Nitrogen , Waste Disposal, Fluid , Wastewater , Wastewater/chemistry , Wastewater/microbiology , Nitrogen/metabolism , Nitrogen/analysis , Iron/metabolism , Waste Disposal, Fluid/methods , Seawater/microbiology , Filtration/methods , Nitrification , Water Pollutants, Chemical/analysis , Water Pollutants, Chemical/metabolism , Water Purification/methods
BACKGROUND: Pancreatic adenocarcinoma (PC) is an aggressive malignancy with limited treatment options. The poor prognosis primarily stems from late-stage diagnosis and when the disease has become therapeutically challenging. There is an urgent need to identify specific biomarkers for cancer subtyping and early detection to enhance both morbidity and mortality outcomes. The addition of the EGFR tyrosine kinase inhibitor (TKI), erlotinib, to gemcitabine chemotherapy for the first-line treatment of patients with advanced pancreatic cancer slightly improved outcomes. However, restricted clinical benefits may be linked to the absence of well-characterized criteria for stratification and dependable biomarkers for the prediction of treatment effectiveness. METHODS AND RESULTS: We examined the levels of various cancer hallmarks and identified glycolysis as the primary risk factor for overall survival in PC. Subsequently, we developed a glycolysis-related score (GRS) model to accurately distinguish PC patients with high GRS. Through in silico screening of 4398 compounds, we discovered that erlotinib had the strongest therapeutic benefits for high-GRS PC patients. Furthermore, we identified ARNTL2 as a novel prognostic biomarker and a predictive factor for erlotinib treatment responsiveness in patients with PC. Inhibition of ARNTL2 expression reduced the therapeutic efficacy, whereas increased expression of ARNTL2 improved PC cell sensitivity to erlotinib. Validation in vivo using patient-derived xenografts (PDX-PC) with varying ARNTL2 expression levels demonstrated that erlotinib monotherapy effectively halted tumor progression in PDX-PC models with high ARNTL2 expression. In contrast, PDX-PC models lacking ARNTL2 did not respond favorably to erlotinib treatment. Mechanistically, we demonstrated that the ARNTL2/E2F1 axis-mediated cellular glycolysis sensitizes PC cells to erlotinib treatment by activating the PI3K/AKT signaling pathway. CONCLUSIONS: Our investigations have identified ARNTL2 as a novel prognostic biomarker and predictive indicator of sensitivity. These results will help to identify erlotinib-responsive cases of PC and improve treatment outcomes. These findings contribute to the advancement of precision oncology, enabling more accurate and targeted therapeutic interventions.
Adenocarcinoma , Lung Neoplasms , Pancreatic Neoplasms , Humans , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , ARNTL Transcription Factors/metabolism , Biomarkers/metabolism , Cell Line, Tumor , ErbB Receptors/metabolism , Erlotinib Hydrochloride/pharmacology , Lung Neoplasms/pathology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Precision Medicine , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction
Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a common food-borne pathogen that can cause acute diseases. Lysine acetylation is a post-translational modification (PTM) that occurs in various prokaryotes and is regulated by CobB, the only deacetylase found in bacteria. Here, we demonstrated that CobB plays an important role in the virulence of EHEC O157:H7 and that deletion of cobB significantly decreased the intestinal colonization ability of bacteria. Using acetylation proteomic studies, we systematically identified several proteins that could be regulated by CobB in EHEC O157:H7. Among these CobB substrates, we found that acetylation at the K44 site of CesA, a chaperone for the type-III secretion system (T3SS) translocator protein EspA, weakens its binding to EspA, thereby reducing the stability of this virulence factor; this PTM ultimately attenuating the virulence of EHEC O157:H7. Furthermore, we showed that deacetylation of the K44 site, which is deacetylated by CobB, promotes the interaction between CesA and EspA, thereby increasing bacterial virulence in vitro and in animal experiments. In summary, we showed that acetylation influences the virulence of EHEC O157:H7, and uncovered the mechanism by which CobB contributes to bacterial virulence based on the regulation of CesA deacetylation.
Escherichia coli Infections , Escherichia coli O157 , Escherichia coli Proteins , Gastrointestinal Microbiome , Animals , Escherichia coli O157/metabolism , Virulence , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Proteomics , Escherichia coli Infections/microbiology
Objective: To investigate the impact of CYP2C19 gene polymorphism on clopidogrel reactivity and its association with long-term clinical outcome in patients with coronary heart disease (CHD) undergoing percutaneous coronary intervention (PCI). Methods: In total, 675 patients were enrolled. Based on the platelet inhibition rate, patients were categorized into two groups: clopidogrel low responsiveness (CLR) and normal clopidogrel responsiveness (NCR). The CLR group was divided into ticagrelor and clopidogrel group based on the antiplatelet drugs used in the follow-up treatment. Patients were classified into three groups (normal metabolizer, intermediate metabolizer, and poor metabolizer) based on the CYP2C19 genotype. We aimed to evaluate the impact of CYP2C19 gene polymorphism on clopidogrel reactivity. The cumulative rates of 12-month all-cause deaths, major adverse cardiovascular events (MACCEs), and bleeding events were calculated. Results: CLR was observed in 44.4% of the overall population. Significant differences were observed in the platelet inhibition rate of clopidogrel among the three metabolic genotypes (P < 0.05). At the 12-month follow-up, 13 patients (1.9%) died and 96 patients (14.2%) experienced MACCEs. Patients with CLR (9.6% vs. 11.7% vs. 22.1%, P < 0.05) or poor metabolizer (10.7% vs. 16.4% vs. 22.6%, P = 0.026) experienced a higher rate of MACCEs. A MACCEs risk score between zero and two was calculated. The highest incidence of MACCEs significantly increased with the 2-positive results, and the area under the curve (AUC) was 0.712 (95% CI: 0.650-0.774, P < 0.05). There was no significant difference between the group with a score of one and the occurrence of MACCEs (P > 0.05). Conclusions: Low response to clopidogrel in CHD patients is correlated with CYP2C19 gene polymorphism. CYP2C19 genotyping combined with platelet reactivity is an independent predictor of 12-months MACCEs in patients with clopidogrel treatment after PCI, which is better than either test alone.
Background: Thyroid Dysfunction (TD) is a common immune-related adverse events (irAEs) in the treatment of advanced lung cancer with programmed cell death protein 1 (PD-1) and programmed death 1 ligand (PD-L1) inhibitors, with incidence accounting for 6-8% of all irAEs. The incidence of TD is receiving increasing attention from clinicians, given its potential impact on clinical efficacy. However, the molecular mechanisms, biomarkers, and clinical impact of TD resulting from PD-1/PD-L1 inhibitor treatment in advanced lung cancer are unclear. Objective: To present a comprehensive review of current advancements in research about the molecular mechanisms, influential factors, and clinical manifestations in the treatment of advanced lung cancer with PD-1 and PD-L1 inhibitors, as well as the correlation between TD and the efficacy of PD-1 and PD-L1 inhibitors. Methods: A systematic search was conducted using PubMed, Web of Science, Cochrane Library, Embase and Google Scholar databases, with the keywords including thyroid dysfunction, efficacy, mechanisms, immune checkpoint inhibitors, PD-1/PD-L1 inhibitors, and advanced lung cancer. Results: PD-1/PD-L1 inhibitors can induce T cell-mediated destructive thyroiditis, thyroid autoantibody-mediated autoimmunity, and a decrease in the number of immunosuppressive monocytes (circulating cluster of differentiation (CD)14+ human leukocyte antigen (HLA)-DRlow/negatives monocytes, CD14+ HLA-DR + lo/neg), leading to TD. Several factors, including peripheral blood inflammatory markers, body mass index (BMI), baseline thyroid-stimulating hormone (TSH) level, gender, smoking history, hypertension, and previous opioid use, may also contribute to the development of TD. However, there is currently a lack of reliable predictive biomarkers for TD, although anti-thyroid antibodies, TSH levels, and peripheral blood inflammatory markers are expected to be predictive.Interestingly, some studies suggested a positive correlation between TD and clinical efficacy, i.e., patients experiencing TD showed better outcomes in objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), compared with those without TD. However, most of these studies were single-center and had small sample sizes, so more multi-center studies are needed to provide further data support. Conclusion: TD resulting from PD-1/PD-L1 inhibitor treatment in advanced lung cancer may be associated with good clinical outcomes. The clarification of the molecular mechanisms underlying TD and the identification of reliable predictive biomarkers will guide clinicians in managing TD in this patient population.
Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI dysbiosis and improving intestinal functions. Thus, a 2 × 2 factorial design, placebo-controlled, double-blind, clinical trial was proposed to test this hypothesis. Forty adult participants with CF will be block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints will include 12-week changes in the reduced relative abundance of gammaproteobacteria, and gut microbiota richness and diversity before and after the intervention. This clinical study will examine whether vitamin D3 with or without prebiotics will improve intestinal health and reduce GI dysbiosis, which in turn, should improve health outcomes and quality of life of patients with CF.
