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BACKGROUND: The main goal of this study was to examine how diabetes, cardiovascular calcification characteristics and other risk factors affect mortality in end-stage renal disease (ESRD) patients in the early stages of hemodialysis. METHODS: A total of 285 ESRD patients in the early stages of hemodialysis were enrolled in this research, including 101 patients with diabetes. Survival time was monitored, and general data, biochemical results, cardiac ultrasound calcification of valvular tissue, and thoracic CT calcification of the coronary artery and thoracic aorta were recorded. Subgroup analysis and logistic regression were applied to investigate the association between diabetes and calcification. Cox regression analysis and survival between calcification, diabetes, and all-cause mortality. Additionally, the nomogram model was used to estimate the probability of survival for these individuals, and its performance was evaluated using risk stratification, receiver operating characteristic, decision, and calibration curves. RESULTS: Cardiovascular calcification was found in 81.2% of diabetic patients (82/101) and 33.7% of nondiabetic patients (62/184). Diabetic patients had lower phosphorus, calcium, calcium-phosphorus product, plasma PTH levels and lower albumin levels (p < 0.001). People with diabetes were more likely to have calcification than people without diabetes (OR 5.66, 95% CI 1.96-16.36; p < 0.001). The overall mortality rate was 14.7% (42/285). The risk of death was notably greater in patients with both diabetes and calcification (29.27%, 24/82). Diabetes and calcification, along with other factors, collectively predict the risk of death in these patients. The nomogram model demonstrated excellent discriminatory power (area under the curve (AUC) = 0.975 at 5 years), outstanding calibration at low to high-risk levels and provided the greatest net benefit across a wide range of clinical decision thresholds. CONCLUSIONS: In patients with ESRD during the early period of haemodialysis, diabetes significantly increases the risk of cardiovascular calcification, particularly multisite calcification, which is correlated with a higher mortality rate. The risk scores and nomograms developed in this study can assist clinicians in predicting the risk of death and providing individualised treatment plans to lower mortality rates in the early stages of hemodialysis.
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Causas de Morte , Falência Renal Crônica , Nomogramas , Diálise Renal , Calcificação Vascular , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Calcificação Vascular/mortalidade , Calcificação Vascular/diagnóstico por imagem , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Diálise Renal/mortalidade , Medição de Risco , Fatores de Tempo , Idoso , Fatores de Risco , Resultado do Tratamento , Diabetes Mellitus/mortalidade , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/sangue , Adulto , Valor Preditivo dos Testes , Nefropatias Diabéticas/mortalidade , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/terapia , Nefropatias Diabéticas/sangue , Técnicas de Apoio para a Decisão , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/terapiaRESUMO
BACKGROUND: Syndrome coronavirus-2 (SARS-CoV-2) has developed various strategies to evade the antiviral impact of type I IFN. Non-structural proteins and auxiliary proteins have been extensively researched on their role in immune escape. Nevertheless, the detailed mechanisms of structural protein-induced immune evasion have not been well elucidated. METHODS: Human alveolar basal epithelial carcinoma cell line (A549) was stimulated with polyinosinic-polycytidylic acid (PIC) and independently transfected with four structural proteins expression plasmids, including nucleocapsid (N), spike (S), membrane (M) and envelope (E) proteins. By RT-qPCR and ELISA, the structural protein with the most pronounced inhibitory effects on IFN-ß induction was screened. RNA-sequencing (RNA-Seq) and two differential analysis strategies were used to obtain differentially expressed genes associated with N protein inhibition of IFN-ß induction. Based on DIANA-LncBase and StarBase databases, the interactive competitive endogenous RNA (ceRNA) network for N protein-associated genes was constructed. By combining single-cell sequencing data (GSE158055), lncRNA-miRNA-mRNA axis was further determined. Finally, RT-qPCR was utilized to illustrate the regulatory functions among components of the ceRNA axis. RESULTS: SARS-CoV-2 N protein inhibited IFN-ß induction in human alveolar epithelial cells most significantly compared with other structural proteins. RNA-Seq data analysis revealed genes related to N protein inhibiting IFNs induction. The obtained 858 differentially expressed genes formed the reliable ceRNA network. The function of LINC01002-miR-4324-FRMD8 axis in the IFN-dominated immune evasion was further demonstrated through integrating single-cell sequencing data. Moreover, we validated that N protein could reverse the effect of PIC on LINC01002, FRMD8 and miR-4324 expression, and subsequently on IFN-ß expression level. And LINC01002 could regulate the production of FRMD8 by inhibiting miR-4324. CONCLUSION: SARS-CoV-2 N protein suppressed the induction of IFN-ß by regulating LINC01002 which was as a ceRNA, sponging miR-4324 and participating in the regulation of FRMD8 mRNA. Our discovery provides new insights into early intervention therapy and drug development on SARS-CoV-2 infection.
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COVID-19 , MicroRNAs , RNA Longo não Codificante , Humanos , Células A549 , Proteínas do Nucleocapsídeo de Coronavírus/genética , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , COVID-19/virologia , COVID-19/imunologia , Evasão da Resposta Imune , Interferon beta/genética , Interferon beta/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fosfoproteínas , RNA Endógeno Competitivo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
This review offers a comprehensive analysis of the intricate relationship between the gut virome and diabetes, elucidating the mechanisms by which the virome engages with both human cells and the intestinal bacteriome. By examining a decade of scientific literature, we provide a detailed account of the distinct viral variations observed in type 1 diabetes (T1D) and type 2 diabetes (T2D). Our synthesis reveals that the gut virome significantly influences the development of both diabetes types through its interactions, which indirectly modulate immune and inflammatory responses. In T1D, the focus is on eukaryotic viruses that stimulate the host's immune system, whereas T2D is characterized by a broader spectrum of altered phage diversities. Promisingly, in vitro and animal studies suggest fecal virome transplantation as a potential therapeutic strategy to alleviate symptoms of T2D and obesity. This study pioneers a holistic overview of the gut virome's role in T1D and T2D, its interplay with host immunity, and the innovative potential of fecal transplantation therapy in clinical diabetes management.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Viroma , Humanos , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/virologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/virologia , Animais , Bacteriófagos/genética , Bacteriófagos/fisiologia , Vírus/genética , Vírus/classificaçãoRESUMO
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent chronic liver condition. However, the potential therapeutic benefits and underlying mechanism of nicotinate-curcumin (NC) in the treatment of NASH remain uncertain. METHODS: A rat model of NASH induced by a high-fat and high-fructose diet was treated with nicotinate-curcumin (NC, 20, 40 mg·kg- 1), curcumin (Cur, 40 mg·kg- 1) and metformin (Met, 50 mg·kg- 1) for a duration of 4 weeks. The interaction between NASH, Cur and Aldo-Keto reductase family 1 member B10 (AKR1B10) was filter and analyzed using network pharmacology. The interaction of Cur, NC and AKR1B10 was analyzed using molecular docking techniques, and the binding energy of Cur and NC with AKR1B10 was compared. HepG2 cells were induced by Ox-LDL (25 µg·ml- 1, 24 h) in high glucose medium. NC (20µM, 40µM), Cur (40µM) Met (150µM) and epalrestat (Epa, 75µM) were administered individually. The activities of ALT, AST, ALP and the levels of LDL, HDL, TG, TC and FFA in serum were quantified using a chemiluminescence assay. Based on the changes in the above indicators, score according to NAS standards. The activities of Acetyl-CoA and Malonyl-CoA were measured using an ELISA assay. And the expression and cellular localization of AKR1B10 and Acetyl-CoA carboxylase (ACCα) in HepG2 cells were detected by Western blotting and immunofluorescence. RESULTS: The results of the animal experiments demonstrated that NASH rat model induced by a high-fat and high-fructose diet exhibited pronounced dysfunction in liver function and lipid metabolism. Additionally, there was a significant increase in serum levels of FFA and TG, as well as elevated expression of AKR1B10 and ACCα, and heightened activity of Acetyl-CoA and Malonyl-CoA in liver tissue. The administration of NC showed to enhance liver function in rats with NASH, leading to reductions in ALT, AST and ALP levels, and decrease in blood lipid and significant inhibition of FFA and TG synthesis in the liver. Network pharmacological analysis identified AKR1B10 and ACCα as potential targets for NASH treatment. Molecular docking studies revealed that both Cur and NC are capable of binding to AKR1B10, with NC exhibiting a stronger binding energy to AKR1B10. Western blot analysis demonstrated an upregulation in the expression of AKR1B10 and ACCα in the liver tissue of NASH rats, accompanied by elevated Acetyl-CoA and Malonyl-CoA activity, and increased levels of FFA and TG. The results of the HepG2 cell experiments induced by Ox-LDL suggest that NC significantly inhibited the expression and co-localization of AKR1B10 and ACCα, while also reduced levels of TC and LDL-C and increased level of HDL-C. These effects are accompanied by a decrease in the activities of ACCα and Malonyl-CoA, and levels of FFA and TG. Furthermore, the impact of NC appears to be more pronounced compared to Cur. CONCLUSION: NC could effectively treat NASH and improve liver function and lipid metabolism disorder. The mechanism of NC is related to the inhibition of AKR1B10/ACCα pathway and FFA/TG synthesis of liver.
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Aldo-Ceto Redutases , Curcumina , Hepatopatia Gordurosa não Alcoólica , Triglicerídeos , Curcumina/farmacologia , Curcumina/análogos & derivados , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Humanos , Células Hep G2 , Aldo-Ceto Redutases/metabolismo , Ratos , Masculino , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Acetil-CoA Carboxilase/metabolismo , Aldeído Redutase/metabolismo , Aldeído Redutase/antagonistas & inibidores , Dieta Hiperlipídica/efeitos adversos , Simulação de Acoplamento Molecular , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metformina/farmacologia , Ratos Sprague-Dawley , Modelos Animais de Doenças , Rodanina/análogos & derivados , TiazolidinasRESUMO
BACKGROUND: Nosocomial infections with heavy disease burden are becoming a major threat to the health care system around the world. Through long-term, systematic, continuous data collection and analysis, Nosocomial infection surveillance (NIS) systems are constructed in each hospital; while these data are only used as real-time surveillance but fail to realize the prediction and early warning function. Study is to screen effective predictors from the routine NIS data, through integrating the multiple risk factors and Machine learning (ML) methods, and eventually realize the trend prediction and risk threshold of Incidence of Nosocomial infection (INI). METHODS: We selected two representative hospitals in southern and northern China, and collected NIS data from 2014 to 2021. Thirty-nine factors including hospital operation volume, nosocomial infection, antibacterial drug use and outdoor temperature data, etc. Five ML methods were used to fit the INI prediction model respectively, and to evaluate and compare their performance. RESULTS: Compared with other models, Random Forest showed the best performance (5-fold AUC = 0.983) in both hospitals, followed by Support Vector Machine. Among all the factors, 12 indicators were significantly different between high-risk and low-risk groups for INI (P < 0.05). After screening the effective predictors through importance analysis, prediction model of the time trend was successfully constructed (R2 = 0.473 and 0.780, BIC = -1.537 and -0.731). CONCLUSIONS: The number of surgeries, antibiotics use density, critical disease rate and unreasonable prescription rate and other key indicators could be fitted to be the threshold predictions of INI and quantitative early warning.
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Infecção Hospitalar , Aprendizado de Máquina , Humanos , Infecção Hospitalar/epidemiologia , Medição de Risco/métodos , China/epidemiologia , Fatores de Risco , IncidênciaRESUMO
The incidence of papillary thyroid carcinoma (PTC) has increased significantly in recent years, and for patients with metastatic and recurrent PTC, the options for treatment currently available are insufficient. To date, the exact molecular mechanism underlying PTC is still not fully understood. 5-Methylcytosine (m5C) RNA methylation is associated with the prognosis of a variety of tumors. However, the molecular mechanisms and biomarkers associated with m5C in the diagnosis, treatment, and prognosis of this disease have not been fully elucidated. Ten m5C regulators with significantly different expression levels were included in this study. Immune infiltration analysis revealed significant negative correlations between most of these regulators and regulatory T cells. TRDMT1, NSUN5, and NSUN6 had high weights and strong correlations in the protein-protein interaction network. Using gene ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis, 1489 differentially expressed genes were screened from The Cancer Genome Atlas messenger RNA matrix, indicating that these differentially expressed genes were significantly enriched in various pathways and functions related to cancers. Four m5C regulators, NSUN2, NSUN4, NSUN6, and DNMT3B, were screened as prognostic markers by least absolute shrinkage and selection operator regression analysis, and NSUN2 and NSUN6 were identified as risk factors for poor prognosis. We found that the prognostic prediction model constructed using the m5C regulators NSUN2, NSUN4, NSUN6, and DNMT3B showed good prognostic prediction ability and diagnostic ability. This model was applied to predict the survival probability of patients with PTC, the prediction ability of 5-year survival was the best. The multi-factor prognostic prediction model combined with the tumor node metastasis stage and risk score grouping showed better prognostic predictive power.
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Biomarcadores Tumorais , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/mortalidade , Câncer Papilífero da Tireoide/patologia , Prognóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Biomarcadores Tumorais/genética , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica , Metilação , Pessoa de Meia-IdadeRESUMO
Introduction: The incidence of metabolic disorders during pregnancy is increasing year by year, with diseases including hypertension and hyperlipidemia. Statins are the primary drugs for treating hyperlipidemia or atherosclerosis, yet some patients remain unresponsive to them, and pregnant women are prohibited from taking statins. Curculigoside is the major biologically active natural product present in Curculigo orchioides. Methods: In this study, A high-fat mice model was developed to study the lipid-lowering effect of curculigoside. Using intestinal Caco-2 cell monolayer, the curculigoside transport properties at two temperatures and possible transporters were systemically studied. Results: Curculigoside at concentrations used during the experiments have no toxic effect to Caco-2 cells. The curculigoside transfer from the apical to the basolateral side was strongly influenced by temperature. P-glycoprotein, breast cancer resistance protein, and efflux transporters are crucial components of the human intestinal cell line Caco-2. The curculigoside can significantly affect the contents of total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol in mice. Discussion: The transport properties and potential mechanism of curculigoside offer valuable insights for the design of development of hypolipidemic drugs like anti-atherosclerotic drugs and also be helpful to the further study of the pharmacological activity of curculigoside.
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BACKGROUND: Lung squamous cell carcinoma (LUSC) is a subtypes of non-small cell lung cancer (NSCLC). It has been reported that members of the protocadherin γ family can regulate tumor cell growth by inhibiting the Wnt signaling pathway. Protocadherin-gamma subfamily B4 (PCDHGB4) as a family member in LUSC was rarely reported. The aim of this study was to investigate the role and potential prognostic value of PCDHGB4 in the development of LUSC using bioinformatics methods. METHODS: The Cancer Genome Atlas (TCGA), cBioPortal and UALCAN databases were used to analyze the expression, prognosis, clinicopathological features, immune cell infiltration, immune regulatory genes, immune checkpoint inhibitors (ICIs), and methyltransferases of PCDHGB4 in LUSC. At the single cell level, we analyzed the clustering results of cell subtypes and the expression of PCDHGB4 in different immune cell subpopulations. In addition, we compared the promoter methylation levels of PCDHGB4 in LUSC tissues and normal tissues and performed protein-protein interaction and mutation analysis. Finally, enrichment analysis was performed based on the differentially expressed genes. RESULTS: Bioinformatics analysis results showed that the expression level of PCDHGB4 in LUSC tissues was lower than that in normal tissues. Survival analysis showed that increased PCDHGB4 expression was associated with poor prognosis. Single-cell sequencing analysis showed that PCDHGB4 was expressed in T cells, monocytes or macrophages, and dendritic cells. It was further found that PCDHGB4 played an important role in tumor immunity and confirmed that PCDHGB4 was associated with immune checkpoints, immune regulatory genes, and methyltransferases. Besides, enrichment analysis revealed that PCDHGB4 was involved in multiple cancer-related pathways. CONCLUSIONS: The expression of PCDHGB4 was low in LUSC. PCDHGB4 was related to the poor prognosis of patients, and PCDHGB4 was closely related to the infiltration and pathway of tumor immune cells. PCDHGB4 may be a potential prognostic marker and a new target for immunotherapy in LUSC.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Carcinoma de Células Escamosas/patologia , Prognóstico , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Metiltransferases/metabolismo , Pulmão/patologiaRESUMO
Type 2 diabetes mellitus (T2DM) represents a common complication during pregnancy that affects fetoplacental development. We demonstrated the existence of impaired trophoblast syncytialization under hyperglycemic conditions. However, the exact mechanism remains unknown. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism of mRNA and participates in various biological processes. We described the global m6A modification pattern in T2DM placenta by the combined analysis of methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq). Both the m6A modification and expression of SIK1, which is critical for syncytialization, were significantly decreased in trophoblast exposed to hyperglycemic conditions. In addition, the m6A demethylase fat mass and obesity-associated protein (FTO) affects the expression and mRNA stability of SIK1 by binding to its 3'-untranslated region (UTR) m6A site. This work reveals that the FTO-m6A-SIK1 axis plays critical roles in regulating syncytialization in the placenta.
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BACKGROUND: Temperature is a primary factor that determines the eco-geographical distribution and population development of invasive insects. Temperature stress leads to various negative effects, including excess reactive oxygen species (ROS), and catalase (CAT) is a key enzyme against ROS in the antioxidant pathway. The whitefly Bemisia tabaci MED is a typical invasive pest that causes damage worldwide. Our previous studies have shown that CAT promotes whitefly adaptation to high temperature by eliminating ROS. However, the mechanism underlying the low-temperature adaptation of whiteflies is still unknown. RESULTS: In this study, we investigated the role of CAT in the low-temperature tolerance of B. tabaci MED by analyzing its survival rate, reproduction, and ROS levels at 25 °C (as a control, suitable temperature), 20 °C (moderately decreased temperature), and 4 °C (severely decreased temperature). Silencing of BtCAT1, BtCAT2, or BtCAT3 reduced the viability of whiteflies under a short-term severely decreased temperature (4 °C), which manifested as decreases in survival and fecundity accompanied by significant increases in ROS levels. Moreover, even at a moderately decreased temperature (20 °C), silencing of BtCAT1 led to high ROS levels and low survival rates in adults. CONCLUSION: Silencing of BtCATs significantly increased the sensitivity of B. tabaci MED to low temperatures. BtCAT1 is likely more essential than other BtCATs for low-temperature tolerance in whiteflies. © 2024 Society of Chemical Industry.
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Catalase , Temperatura Baixa , Hemípteros , Espécies Reativas de Oxigênio , Animais , Hemípteros/genética , Hemípteros/fisiologia , Catalase/metabolismo , Catalase/genética , Espécies Reativas de Oxigênio/metabolismo , Inativação Gênica , Feminino , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , MasculinoRESUMO
Lignocellulosic biomass is currently underutilized, but it offers promise as a resource for the generation of commercial end-products, such as biofuels, detergents, and other oleochemicals. Rhodococcus opacus PD630 is an oleaginous, Gram-positive bacterium with an exceptional ability to utilize recalcitrant aromatic lignin breakdown products to produce lipid molecules such as triacylglycerols (TAGs), which are an important biofuel precursor. Lipid carbon storage molecules accumulate only under growth-limiting low nitrogen conditions, representing a significant challenge toward using bacterial biorefineries for fuel precursor production. In this work, we screened overexpression of 27 native transcriptional regulators for their abilities to improve lipid accumulation under nitrogen-rich conditions, resulting in three strains that accumulate increased lipids, unconstrained by nitrogen availability when grown in phenol or glucose. Transcriptomic analyses revealed that the best strain (#13) enhanced FA production via activation of the ß-ketoadipate pathway. Gene deletion experiments confirm that lipid accumulation in nitrogen-replete conditions requires reprogramming of phenylalanine metabolism. By generating mutants decoupling carbon storage from low nitrogen environments, we move closer toward optimizing R. opacus for efficient bioproduction on lignocellulosic biomass.
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Norovirus (NV) infection causes acute gastroenteritis in children and adults. Upon infection with NV, specific CD8+ T cells, which play an important role in anti-infective immunity, are activated in the host. Owing to the NV's wide genotypic variability, it is challenging to develop vaccines with cross-protective abilities against infection. To aid effective vaccine development, we examined specific CD8+ T-cell responses towards viral-structural protein (VP) epitopes, which enable binding to host susceptibility receptors. We isolated peripheral blood mononuclear cells from 196 participants to screen and identify predominant core peptides towards NV main and small envelope proteins using ex vivo and in vitro intracellular cytokine staining assays. Human leukocyte antigen (HLA) restriction characteristics were detected using next-generation sequencing. Three conservative immunodominant VP-derived CD8+ T-cell epitopes, VP294-102 (TDAARGAIN), VP2153-161 (RGPSNKSSN), and VP1141-148 (FPHIIVDV), were identified and restrictively presented by HLA-Cw * 0102, HLA-Cw * 0702, and HLA-A *1101 alleles, separately. Our findings provide useful insights into the development of future vaccines and treatments for NV infection.
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Linfócitos T CD8-Positivos , Infecções por Caliciviridae , Proteínas do Capsídeo , Epitopos de Linfócito T , Gastroenterite , Norovirus , Humanos , Linfócitos T CD8-Positivos/imunologia , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Infecções por Caliciviridae/imunologia , Infecções por Caliciviridae/virologia , Norovirus/imunologia , Norovirus/genética , Adulto , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Masculino , Gastroenterite/virologia , Gastroenterite/imunologia , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Criança , Adolescente , Leucócitos Mononucleares/imunologia , Epitopos Imunodominantes/imunologia , Pré-Escolar , IdosoRESUMO
Gastrointestinal colonization by Clostridioides difficile is common in healthcare settings and ranges in clinical presentation from asymptomatic carriage to lethal C. difficile infection (CDI). We used a systems biology approach to investigate why patients colonized with C. difficile have a range of outcomes. Microbiota-humanization of germ-free mice with fecal samples from toxigenic C. difficile carriers revealed a spectrum of virulence among clade 1 lineages and identified commensal Blautia associated with markers of non-pathogenic colonization. Using gnotobiotic mice engrafted with defined human microbiota, we observed strain-specific CDI severity across clade 1 strains. Yet, mice engrafted with a higher diversity community were protected from severe disease across all strains without suppression of C. difficile colonization. These results indicate that when colonization resistance has been breached without overt infection, commensals can attenuate a diversity of virulent strains without inhibiting pathogen colonization, providing insight into determinants of stable C. difficile carriage.
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Maintaining protein balance within a cell is essential for proper cellular function, and disruptions in the ubiquitin-proteasome pathway, which is responsible for degrading and recycling unnecessary or damaged proteins, can lead to various diseases. Deubiquitinating enzymes play a vital role in regulating protein homeostasis by removing ubiquitin chains from substrate proteins, thereby controlling important cellular processes, such as apoptosis and DNA repair. Among these enzymes, ubiquitin-specific protease 7 (USP7) is of particular interest. USP7 is a cysteine protease consisting of a TRAF region, catalytic region, and C-terminal ubiquitin-like (UBL) region, and it interacts with tumor suppressors, transcription factors, and other key proteins involved in cell cycle regulation and epigenetic control. Moreover, USP7 has been implicated in the pathogenesis and progression of various diseases, including cancer, inflammation, neurodegenerative conditions, and viral infections. Overall, characterizing the functions of USP7 is crucial for understanding the pathophysiology of diverse diseases and devising innovative therapeutic strategies. This article reviews the structure and function of USP7 and its complexes, its association with diseases, and its known inhibitors and thus represents a valuable resource for advancing USP7 inhibitor development and promoting potential future treatment options for a wide range of diseases.