Bacterial effector restricts liquid-liquid phase separation of ZPR1 to antagonize host UPRER.

How pathogens manipulate host UPRER to mediate immune evasion is largely unknown. Here, we identify the host zinc finger protein ZPR1 as an interacting partner of the enteropathogenic E. coli (EPEC) effector NleE using proximity-enabled protein crosslinking. We show that ZPR1 assembles via liquid-liquid phase separation (LLPS) in vitro and regulates CHOP-mediated UPRER at the transcriptional level. Interestingly, in vitro studies show that the ZPR1 binding ability with K63-ubiquitin chains, which promotes LLPS of ZPR1, is disrupted by NleE. Further analyses indicate that EPEC restricts host UPRER pathways at the transcription level in a NleE-ZPR1 cascade-dependent manner. Together, our study reveals the mechanism by which EPEC interferes with CHOP-UPRER via regulating ZPR1 to help pathogens escape host defense.

Neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and monocyte to lymphocyte ratio in depression: A meta-analysis.

BACKGROUND: The possible associations between depression and neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) have been evaluated in numerous studies. But the results were still controversial. METHODS: The WEB OF SCIENCE, PUBMED, EMBASE, and COCHRANE LIBRARY databases were searched for eligible studies. Standardized mean difference (SMD) and 95% confidence interval (CI) were used to assess the differences in NLR, PLR, and MLR levels between depressed patients and controls. RESULTS: Two thousand five hundred and eighty cases and 2664 controls, 1393 cases and 1370 controls, 744 cases and 765 controls were identified in the meta-analyses for NLR, PLR, and MLR, respectively. The pooled analyses showed that depressed subjects had significantly higher levels of NLR than healthy controls (SMD = 0.33, 95% CI = 0.15-0.15, P < 0.001). Sensitivity analysis and publication bias test confirmed the result. Subgroup analyses suggested that the association between depression and NLR could be affected by country, study design, and antidepressant treatment. While no significant difference of PLR (SMD = 0.13, 95% CI = -0.04-0.31, P = 0.140) and MLR (SMD = 0.02, 95% CI = -0.24-0.28, P = 0.892) values was found between depressed subjects and controls. LIMITATIONS: High heterogeneity was noted across studies. CONCLUSIONS: The present meta-analysis supported the hypothesis that depression is associated with inflammation, and NLR can be used as an indicator of depression. Further large-scale studies are warranted, especially those that evaluate PLR or MLR in depression.

Pan-cancer analysis of FBXW family with potential implications in prognosis and immune infiltration.

Background: The F-box and WD repeat domain containing (FBXW) family of SCF E3 complexes has 10 members that are responsible for ubiquitination and degradation of substrate proteins involved in cell cycle regulation and tumorigenesis. Among them, FBXW1 (also called b-TrCP1/BTRC) and FBXW7 are the central proteins in this category. However, there is still a lack of elaborate exploration of the contribution of FBXW family members, especially FBXW1 and FBXW7, in various tumor types. Methods: In this present study, we preliminarily analyzed the genetic structure characteristics of the FBXW family, and systematically investigated their expression patterns and clinical correlations based on the TCGA pan-cancer data. Survival analysis of FBXWs was also conducted through the Kaplan-Meier method. In addition, we assessed their immune infiltration level through immune-related algorithms like Timer and xCell. Results: There were obvious genetic heterogeneity and different clinical traits in FBXW family members. Moreover, we found that FBXW family genes may be useful in predicting prognosis and therapeutic efficacy using survival analysis. In addition, the immune infiltration of FBXW family was also clearly illustrated in this study. The results showed these genes were closely involved in immune components such as immune score, immune subtypes, tumor-infiltrating lymphocytes and immune checkpoints. Notedly, FBXW1 as an oncogene and FBXW7 as a tumor suppressor gene also show opposite relationships on immune cells. Conclusion: Our results provided valuable strategies to guide the therapeutic orientation concerning the role of FBXW family genes in cancer.

Genetically incorporated crosslinkers reveal NleE attenuates host autophagy dependent on PSMD10.

Autophagy acts as a pivotal innate immune response against infection. Some virulence effectors subvert the host autophagic machinery to escape the surveillance of autophagy. The mechanism by which pathogens interact with host autophagy remains mostly unclear. However, traditional strategies often have difficulty identifying host proteins that interact with effectors due to the weak, dynamic, and transient nature of these interactions. Here, we found that Enteropathogenic Escherichia coli (EPEC) regulates autophagosome formation in host cells dependent on effector NleE. The 26S Proteasome Regulatory Subunit 10 (PSMD10) was identified as a direct interaction partner of NleE in living cells by employing genetically incorporated crosslinkers. Pairwise chemical crosslinking revealed that NleE interacts with the N-terminus of PSMD10. We demonstrated that PSMD10 homodimerization is necessary for its interaction with ATG7 and promotion of autophagy, but not necessary for PSMD10 interaction with ATG12. Therefore, NleE-mediated PSMD10 in monomeric state attenuates host autophagosome formation. Our study reveals the mechanism through which EPEC attenuates host autophagy activity.

Plasma lipoprotein(a) levels are associated with the severity of coronaryheart disease in Han Chinese people.

BACKGROUND/AIM: The aim of this study was to investigate the association of lipoprotein(a) [Lp(a)] with the severity of coronary heart disease (CHD) in Han Chinese people. MATERIALS AND METHODS: Six hundred and seventy-nine patients with angiographically defined CHD were enrolled in this cross-sectional study. Fasting lipids were measured, and the severity of CHD was quantitatively assessed for each patient according to the number of stenotic coronary branches and the Gensini scoring system. RESULTS: The levels of Lp(a), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and apolipoprotein (apo) B100 increased, while high-density lipoprotein cholesterol (HDL-C) and apoAI decreased significantly with the number of stenotic vessels. The levels of Lp(a) increased and HDL-C and apoAI decreased significantly with the Gensini scores. The logistic regression analyses showed that Lp(a) and HDL-C were independently associated with the number of stenotic coronary vessels after adjusting for age, weight, body mass index, sex, smoking, alcohol consumption, hypertension, diabetes, triglycerides, TC, LDL-C, VLDL-C, apoAI, and apoB100. However, only Lp(a) was independently associated with the Gensini scores after adjustment. CONCLUSION: Our data indicate that Lp(a) might be a useful marker in predicting the severity of coronary heart disease.

Lipoprotein ratios are better than conventional lipid parameters in predicting coronary heart disease in Chinese Han people.

BACKGROUND AND AIM: Dyslipidaemia is the main risk factor for coronary heart disease (CHD). Plasma lipid levels are conven-tionally used to predict coronary risk globally, but further studies are required to investigate whether the lipoprotein ratios are superior to conventional lipid parameters as predictors for CHD. METHODS: A hospital-based case-control study consisting of 738 CHD patients and 157 control subjects was conducted in a Chinese Han population. Demographic characteristics and plasma lipid or apolipoprotein data were collected. Univariate and multivariate logistic regression analyses were carried out to examine the relationship between the lipoprotein ratios and CHD risk. RESULTS: The CHD group had significantly higher age, non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein (a) [Lp(a)], triglyceride (TG)/HDL-C, total cholesterol (TC)/HDL-C, low-density lipoprotein cholesterol (LDL-C)/HDL-C, non-HDL-C/HDL-C, very low-density lipoprotein cholesterol (VLDL-C)/HDL-C, and apolipoprotein B100/apolipoprotein AI (apoB100/apoAI) than the control group (p < 0.05 for all). Moreover, the prevalence of male sex, smoking, and hypertension in the CHD group was significantly higher than in the control group. The results from univariate logistic regression analysis showed that the ratios of TC/HDL-C (OR 1.135, 95% CI 1.019-1.265), LDL-C/HDL-C (OR 1.216, 95% CI 1.033-1.431), non-HDL-C/HDL-C (OR 1.135, 95% CI 1.019-1.265), and apoB100/apoAI (OR 1.966, 95% CI 1.013-3.817) significantly increased the risk for CHD. By multivariate logistic regression analysis, the results were not materially altered and each of the four ratios was independently associated with CHD after adjustment for non-lipid coronary risk factors. ApoB100/apoAI showed the strongest association with CHD in both the univariate and multivariate logistic regression analyses. CONCLUSIONS: Our data indicate that the lipoprotein ratios are superior to conventional lipid parameters as predictors for CHD. Of the ratios, apoB100/apoAI is the best to predict CHD risk.