Insights into innate immune cell evasion by Chlamydia trachomatis.

Chlamydia trachomatis, is a kind of obligate intracellular pathogen. The removal of C. trachomatis relies primarily on specific cellular immunity. It is currently considered that CD4+ Th1 cytokine responses are the major protective immunity against C. trachomatis infection and reinfection rather than CD8+ T cells. The non-specific immunity (innate immunity) also plays an important role in the infection process. To survive inside the cells, the first process that C. trachomatis faces is the innate immune response. As the "sentry" of the body, mast cells attempt to engulf and remove C. trachomatis. Dendritic cells present antigen of C. trachomatis to the "commanders" (T cells) through MHC-I and MHC-II. IFN-γ produced by activated T cells and natural killer cells (NK) further activates macrophages. They form the body's "combat troops" and produce immunity against C. trachomatis in the tissues and blood. In addition, the role of eosinophils, basophils, innate lymphoid cells (ILCs), natural killer T (NKT) cells, γδT cells and B-1 cells should not be underestimated in the infection of C. trachomatis. The protective role of innate immunity is insufficient, and sexually transmitted diseases (STDs) caused by C. trachomatis infections tend to be insidious and recalcitrant. As a consequence, C. trachomatis has developed a unique evasion mechanism that triggers inflammatory immunopathology and acts as a bridge to protective to pathological adaptive immunity. This review focuses on the recent advances in how C. trachomatis evades various innate immune cells, which contributes to vaccine development and our understanding of the pathophysiologic consequences of C. trachomatis infection.

The association between statin use and depression in diabetes.

BACKGROUND: Depression is a common mental disorder. Some studies have demonstrated that people with diabetes are more likely to suffer from depression. Statins are an everyday use for diabetes. Trials of statin therapy have had conflicting findings on the potential risk of depression. METHODS: The National Health and Nutrition Examination Survey (NHANES) 2005-2018 was used to collect a representative sample. Weighted multivariate logistic regression models were used to evaluate odds ratios (ORs) and 95 % CIs for having depression symptoms. We performed stratified analyses to compare the effects of statins in subsamples with and without diabetes on depression symptoms. RESULTS: Statin use showed a significant and strong decreasing effect on having depression symptoms in participants with diabetes (aOR (adjusted OR) 0.59, p = 0.014) compared with that in non-diabetics (aOR 0.78, p = 0.128). Diabetic individuals with statin use for >5 years had a lower risk of having depression symptoms (aOR 0.42, p = 0.002) than those with shorter-term statin use (1-5 years, aOR 0.69, p = 0.111; <1 year: aOR 0.83, p = 0.646). Atorvastatin was more effective in decreasing depression symptoms either in diabetes (aOR 0.49, p = 0.018) or in non-diabetes (aOR 0.58, p = 0.033). LIMITATIONS: First, the dosage of statins cannot be obtained from NHANES datasets. Second, after being stratified, the number of participants for several statins was insufficient. Third, recall bias may exist in the survey. CONCLUSIONS: Diabetics with depression symptoms may benefit from long-term statin therapy. Atorvastatin and pravastatin should be recommended for diabetic patients with depression.

Two lncRNA signatures with cuproptosis as a novel prognostic model and clinicopathological value for endometrioid endometrial adenocarcinoma.

OBJECTIVE: Cuproptosis may contribute to tumorigenesis. However, the predictive value and therapeutic significance of cuproptosis-related lncRNAs (CRLs) in endometrioid endometrial adenocarcinoma (EEA) remains unknown. METHODS: We obtained RNA-seq data from TCGA database and searched the Literature to identify cuproptosis-related genes. Using machine learning models, we identified prognostic lncRNAs for cuproptosis. Immune properties and drug sensitivity were investigated based on these signatures. Further, a ceRNA network was constructed by bioinformatics and in vitro experiments were performed. RESULTS: We determined two cuproptosis-related signatures to build the prognostic model in EEA. Afterward, the risk scores of two cuproptosis-related signatures were associated with clinicopathological molecular typing and as independent prognostic factors for EEA. In addition, we observed significant differences in immune function, checkpoints, and CD8+ T lymphocyte infiltration between the two risk groups. Furthermore, chemotherapy drugs such as AKT inhibitors exhibited lower IC50 values in the high-risk group. We speculate that ACOXL-AS1 can be served as an endogenous 'sponge' to regulate the expression of MTF1 by miR-421. Through in vitro experiments, we preliminarily validated the ceRNA network relationship in the cellular model. CONCLUSION: In EEAs, this study proposed a broad molecular signature of CRLs are promising biomarkers for predicting clinical outcomes and therapeutic responses.

HPV16 E7 protein antagonizes TNF-α-induced apoptosis of cervical cancer cells via Daxx/JNK pathway.

Human papillomavirus (HPV) E7 protein as an important viral factor was involved in the progression of cervical cancer by mediating the cellular signaling pathways. Daxx (Death domain-associated protein) can interact with a variety of proteins to affect the viral infection process. However, the interaction and its related function between HPV16 E7 and Daxx have not been adequately investigated. Here, it was found that HPV16 E7 can interact with Daxx in HeLa or C33A cells by co-immunoprecipitation. HPV16 E7 protein treatment can up-regulate Daxx protein expression, while the interference in Daxx expression and the agonists for JNK can both reduce the antagonistic effects of HPV16 E7 on TNF-α-induced apoptosis, suggesting that Daxx/JNK pathway may be involved in the anti-apoptotic activity of HPV16 E7.

The association between serum copper and obesity and all-cause mortality: the NHANES 2011-2016.

Excessive serum copper has multiple effects on human health, while the association between copper and obesity remains unclear. The objective of this study is to examine the associations of serum copper concentrations with obesity and adiposity measures, including body fat composition and distribution among adults in the USA. This analysis utilized data from the National Health and Nutrition Examination Survey (NHANES) (2011-2016). A total of 7285 adults aged 18 years or older who had serum copper measures were included in this cross-sectional study. Multi-linear regression and logistic regression were used to estimate the independent risky effect of copper on fat deposition and all-cause mortality. Moreover, these associations were analyzed in stratification analysis by gender, age, and physical activity (PA). Generally, we found that participants who were females, non-Hispanic Black, or with inactive PA tended to have a higher serum level of copper. In addition, we observed positive associations between serum copper and adiposity measurements. Furthermore, a serum copper level higher than 133.9 µg/dL was a risk factor for all-cause mortality, which doubled the odds ratio of all-cause mortality compared to the normal serum copper level. Serum copper was positively associated with fat deposition of whole body and regional parts, and all-cause mortality. Furthermore, the effects of copper on fat distribution were also significant and could be modified by age, gender, and PA.

Identification and validation of transferrin receptor protein 1 for predicting prognosis and immune infiltration in lower grade glioma.

Introduction: Transferrin receptor protein 1 (TFRC), an ananda molecule associated with ferroptosis, has been identified as affecting a wide spectrum of pathological processes in various cancers, but the prognostic value correlates with the tumor microenvironment of TFRC in lower-grade glioma (LGG) is still unclear. Materials and methods: Clinical pathological information and gene expression data of patients with LGG come from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), GTEx, Oncomine, UCSC Xena, and GEO databases. We then used various bioinformatics methods and mathematical models to analyze those data, aiming to investigate the clinical significance of TFRC in LGG and illustrate its association with tumor immunity. In addition, the molecular function and mechanisms of TFRC were revealed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). Immunohistochemical experiments and single-cell analysis have been performed. Results: TFRC expression was highly expressed in many tumors and showed a poor prognosis. Including gliomas, it was significantly associated with several poor clinical prognostic variables, tumor immune microenvironment, tumor mutational burden (TMB), m6a modification, and ferroptosis in LGG. TFRC as a key factor was further used to build a prediction nomogram. The C-index, calibration curve, and decision curve analysis showed the nomogram was clinically useful and calibration was accurate. At the same time, we also demonstrated that promoter hypomethylation of DNA upstream of TFRC could lead to high TFRC expression and poor overall survival. There is a significant correlation between TFRC and CD8 + T cell, macrophage cell infiltration, and several immune checkpoints, such as PD-L1(cd274), CTLA4, and PD1, suggesting a novel direction for future clinical application. Functional and molecular mechanism analysis showed an association of TFRC expression with immune-related pathways through GSEA, GO, and KEGG analysis. Finally, immunohistochemical experiments and single-cell analysis confirmed the expression of TFRC in glioma. Conclusion: TFRC may be a potential prognostic biomarker and an immunotherapeutic target for glioma.

Analysis of the Prognostic Value and Gene Expression Mechanism of SHOX2 in Lung Adenocarcinoma.

Background: Detection of SHOX2 methylation has been used to assist in the early diagnosis of lung cancer in many hospitals as SHOX2 may be important in the tumorigenesis of lung cancer. However, there are few studies on the mRNA expression, methylation, and molecular mechanism of SHOX2 in lung cancer. We aimed to explore the role of SHOX2 in lung adenocarcinoma (LUAD). Methods: First, we examined the differential expression of SHOX2 mRNA and methylation in cancerous and normal tissues using databases. Second, we analyzed the relationship between SHOX2 expression and common clinical parameters in LUAD patients. Third, we further explored the methylated level and its specific location of SHOX2 and the mainly factors of SHOX2 gene expression. Finally, we screened the correlatively expressed genes to analyze the pathways from the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes using DAVID. Results: We found that the mRNA expression of SHOX2 was higher in multiple cancers, including LUAD and lung squamous cell carcinoma (LUSC), than in normal tissues. Among LUAD patients, SHOX2 expression was higher in patients of middle-young age, with smoking history, in advanced stages, and with nodal distant metastasis. In addition, our results showed that patients with high expression of SHOX2 are prone to recurrence, poor differentiation, and poor prognosis. Thus, we identified that SHOX2 might be an oncogene for LUAD progression. The main factor influencing the high expression of SHOX2 mRNA may be DNA methylation, followed by copy number variation (CNV), but not by gene mutations in LUAD. Unexpectedly, we found that SHOX2 undergoes hypomethylation in the gene body instead of hypermethylation in the promoter. Additionally, SHOX2 has cross talk in the PI3K-Akt signaling pathway and ECM-receptor interaction. Conclusion: SHOX2 is highly expressed in most cancers. SHOX2 gene expression might be mainly regulated by methylation of its gene body in LUAD, and its high expression or hypomethylation indicates poor differentiation and poor prognosis. SHOX2 could be involved in PI3K-Akt and other important cancer-related signaling pathways to promote tumorigenesis.

Tau internalization: A complex step in tau propagation.

Aggregation of microtubule-associated protein Tau (MAPT) may underlie abnormalities of the intracellular matrix and neuronal death in tauopathies. Tau proteins can be secreted to the extracellular space and internalized into adjacent cells. The internalization of Tau is a complex but critical step in Tau propagation. This review summarizes the internalization pathways of Tau, including macropinocytosis, Clathrin-mediated endocytosis (CME), lipid raft dependent endocytosis, Tunneling nanotubes dependent endocytosis (TNTs) and phagocytosis. The conformation of Tau fibrils and the types of recipient cell determine the internalization pathway. However, the HSPGs-dependent endocytosis seems to be the predominant pathway of Tau internalization. After internalization, Tau fibrils undergo clearance and seeding. Imbalance among Tau secretion, internalization and clearance may result in the propagation of misfolded Tau in the brain, thereby inducing Tauopathies. A better understanding of the internalization of Tau proteins may facilitate the discovery of novel therapeutic strategies to block the propagation of Tau pathology.

Expression of BAG1 is associated with prognosis in kidney renal clear cell carcinoma based on bioinformatics.

BACKGROUND: BCL2 associated Athano-Gene 1 (BAG1) has been described to be involved in the development and progression of cancer. But the role of BAG1 in kidney renal clear cell carcinoma (KIRC) has remained largely unknown. METHODS: We performed bioinformatic analysis of data from TCGA and GEO dataset. The role of BAG1 in KIRC was explored by Logistic and Cox regression model. The molecular mechanisms of BAG1 was revealed by GSEA. RESULTS: The current study found that the KIRC tumor samples have a low level of BAG1 mRNA expression compared to the matched normal tissues based on TCGA data and GEO databases. Low expression of BAG1 in KIRC was significantly associated with Sex, clinical pathological stage, tumor-node-metastasis (TNM) stage, hemoglobin levels, cancer status and history of neoadjuvant treatment. Kaplan-Meier survival analysis indicated that KIRC patients with BAG1 high expression have a longer survival time than those with BAG1 low expression (p < 0.000). Cox regression analysis showed that BAG1 remained independently associated with overall survival, with a hazard ratio (HR) of 1.75(CI:1.05-2.90; p = 0.029). GSEA indicated that the signaling pathways including fatty acid metabolism and oxidative phosphorylation were differentially enriched in high BAG1 expression phenotype. CONCLUSIONS: These findings suggested that BAG1 expression may act as a potential favorable prognostic marker and challenging therapeutic target.

Multifunctional roles of zinc in Alzheimer's disease.

Zinc is the second abundant trace element in the human central nervous system (CNS). Zinc homeostasis is impaired in the elderly population and Alzheimer's disease (AD) patients. Due to the failures of ß-amyloid (Aß)- and microtubule-associated protein tau (MAP-tau, tau)-targeting drugs, many researchers consider AD as a multifactorial disease. Emerging evidence demonstrates that zinc is also widely associated with the development of AD. Zinc dyshomeostasis hypothesis of AD has been proposed. In this review, we summarize the role of zinc in Aß production, protein quality control, redox homeostasis, tau phosphorylation, and BDNF signaling. Due to the multifunctional roles of zinc, when zinc dyshomeostasis occurs, it may influence these different biological activities. Zinc dyshomeostasis could be a therapeutic target for AD treatment. However, there is no consensus on the zinc concentration alteration and the effect of zinc overload or zinc deficiency in AD patients, mouse models and cell lines. Given these significant differences across reported studies, it still needs a long time for clinical application in the treatment of AD.

GRASP55: A Multifunctional Protein.

GRASP55 was first found as Golgi cisternae stacking protein. Due to the crucial role of Golgi in vesicular trafficking and protein modification, GRASP55 was found to function in these two aspects. Further investigation revealed that GRASP55 also participates in the unconventional secretory pathway under stress. Moreover, GRASP55 is involved in autophagy initiation and autophagosome maturation, as well as cell activity.

Disruption of the Golgi apparatus mediates zinc deficiency-induced impairment of cognitive function in mice.

Zinc deficiency is reported to be a global problem that affects cognitive function. The mechanism underlying zinc deficiency-induced impairment of cognitive function is still obscure. In this study, we treated KM mice (Kun Ming mice) with zinc chelator TPEN (N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine) by i.p. injection. NOR (New Object Recognition) tests demonstrated that TPEN can impair the cognitive function of KM mice. Disruption of the GRASP55/Golgin45 complex, and even the Golgi apparatus, was also observed in hippocampus cells by TPEN treatment. Further investigation by IHF showed that enrichment of Aß peptides occurs in neurons of the cerebral tissue of mice, suggesting that amyloidosis may mediate TPEN-induced impairment of cognitive function. This research not only clarifies that zinc plays an important role in Golgi organization in vivo, but also gives us a possible novel pathway underlying AD development.

Probing van der Waals interactions at two-dimensional heterointerfaces.

Two-dimensional (2D) heterostructures assembled via van der Waals (vdW) interactions have sparked immense interest in fields from physics1,2 to electronics3,4. Understanding the vdW interaction at these heterointerfaces is critical for the sophisticated construction and manipulation of these 2D heterostructures. However, previous experimental research has mainly focused on the interlayer interactions in homogeneous graphite crystals5,6 and the interactions between graphene and substrates7. Theoretically, although a variety of vdW methods have been incorporated in density functional theory to probe the interactions of homogeneous vdW crystals, the reliability of these vdW methods in 2D heterostructures remains to be verified. Here, we show, by contact-splitting transfer of graphite from hexagonal boron nitride (BN) to molybdenum disulfide (MoS2), that graphite experiences a stronger vdW interaction with MoS2 than with boron nitride. Quantitative measurements using a graphite-wrapped atomic force microscope tip show that the critical adhesion pressures between BN and graphite and MoS2 and graphite are respectively 0.953 and 1.028 times that between graphite and graphite. The results are consistent with the prediction based on Lifshitz theory, implying an important role of material dielectric function in the vdW interactions at heterointerfaces. These findings offer us more freedom in the construction of 2D heterostructures, and a technique to disassemble 2D heterostructures is demonstrated.

Ultrathin Molybdenum Dioxide Nanosheets as Uniform and Reusable Surface-Enhanced Raman Spectroscopy Substrates with High Sensitivity.

Metal oxides have advantages over the traditional noble metals to be used as substrate materials for surface-enhanced Raman spectroscopy (SERS) with low cost, versatility, and biocompatibility, but their enhancement factors are generally quite low with a poor limit of detection. Here, ultrathin molybdenum dioxide (MoO2 ) nanosheets synthesized by chemical vapor deposition demonstrated in large area are used as SERS substrates with superior signal uniformity in the whole area with a limit of detectable concentration down to 4 × 10-8 m and enhancement factor up to 2.1 × 105 , exceeding that of 2D materials and comparable to that of noble metal films. More practically important, the planar MoO2 substrate is more robust than noble metals and shows excellent reusability and uniformity, which is usually prohibited for nanostructured or nanoparticle-based metal oxide substrates. The enhancement is mainly attributed to the surface plasmon resonance effect as evidenced by the first principle calculations and UV-vis absorption spectroscopy characterization, which can be further increased by decreasing the thickness of the MoO2 nanosheets. The overall superior performance makes the MoO2 nanosheets an ideal substrate for practical SERS applications.

Decreased expression of TFAP2B in endometrial cancer predicts poor prognosis: A study based on TCGA data.

BACKGROUND: Transcription factor activator protein-2ß (TFAP-2ß) was previously reported to constituted promoter activity in endometrial carcinoma (EC). We evaluated the role of TFAP2B in ECs using publicly available data from The Cancer Genome Atlas (TCGA). METHODS: The relationship between clinical pathologic features and TFAP2B were analyzed with the Wilcoxon signed-rank test and logistic regression. Clinicopathologic characteristics associated with overall survival in TCGA patients using Cox regression and the Kaplan-Meier method. Gene Set Enrichment Analysis (GSEA) was performed using TCGA data set. RESULTS: Reduced TFAP2B expression in EC was significantly associated with high grade (OR=2.2 for well, moderate vs. poor), stage (OR=2.5 for I vs. IV), histology (OR=1.8 for serous vs. endometrioid), distant metastasis (OR=2.4 for positive vs. negative) (all p-values<0.05). Kaplan-Meier survival analysis showed that EC with TFAP2B-low had a worse prognosis than that with TFAP2B-high (p=0.013). The univariate analysis revealed that TFAP2B-low correlated significantly with a poor overall survival (OS) (HR: 2.35; 95% confidence interval [CI]: 1.17-4.73; p=0.016). The multivariate analysis revealed that TFAP2B remained independently associated with overall survival, with a HR of 4.42 (CI: 1.25-12.64; p=0.021). GSEA show that p53/hypoxia pathway, androgen response, notch signaling, fatty acid metabolism, glycolysis and estrogen response late are differentially enriched in TFAP2B high expression phenotype. CONCLUSIONS: TFAP2B expression may be a potential prognostic molecular marker of poor survival in endometrial cancer, Moreover, the p53/hypoxia, androgen response and notch signaling pathway may be the key pathway regulated by TFAP2B in EC.

Long non-coding RNA Gas5 regulates proliferation and apoptosis in HCS-2/8 cells and growth plate chondrocytes by controlling FGF1 expression via miR-21 regulation.

BACKGROUND: LncRNA Gas5 is known to be a key control element during growth, differentiation and development in mammalian species. However, the role and function of Gas5 in growth plate chondrocytes has not been determined. METHODS: The overexpression and knockdown models of Gas5 and miR-21 in cells and animals were constructed. Cell survival was determined by MTT assay and flow cytometry. Animal biochemical indices were measured by enzyme-linked immunosorbent assay, hematoxylin/eosin staining, immunohistochemistry or in situ hybridisation. Dual luciferase reporter gene assay was carried out to study targeting. RESULTS: First, we found the expression levels of fibroblast growth factor 1(FGF1) were up-regulated and miR-21 were down-regulated in Gas5 overexpressing model cells. Meanwhile, the expression levels of FGF1 and Gas5 were up-regulated in miR-21 knockdown model cells. Furthermore, cell proliferation was significantly promoted after Gas5 knockdown or miR-21 overexpression. Subsequently, Gas5 promoted apoptosis, while miR-21 suppressed apoptosis. Animal assays demonstrated that both Gas5 and dexamethasone suppressed proliferation and promoted apoptosis of growth plate chondrocytes, up-regulated FGF1 expression but reduced miR-21 expression. Finally, there was a binding relationship between Gas5, miR-21 and FGF1. CONCLUSION: We concluded that Gas5 regulated proliferation and apoptosis in growth plate by controlling FGF1 expression via miR-21 regulation.

Tunable Electrical Performance of Few-Layered Black Phosphorus by Strain.

Strain engineering shows promising applications in low-dimensional materials. It is demonstrated that the bandgap of few-layered black phosphorus can be effectively reduced by out-of-plane compressive strain, resulting in a significant modulation of the vertical electrical performance of black phosphorus and even inducing a nonlinear current-voltage curve to linear current-voltage curve transition.

Fast and large-area growth of uniform MoS2 monolayers on molybdenum foils.

A controllable synthesis of two-dimensional crystal monolayers in a large area is a prerequisite for potential applications, but the growth of transition metal dichalcogenide monolayers in a large area with spatial homogeneity remains a great challenge. Here we report a novel and efficient method to fabricate large-scale MoS2 monolayers by direct sulfurization of pre-annealed molybdenum foil surfaces with large grain boundaries of more than 50 µm in size at elevated temperatures. Continuous MoS2 monolayers can be formed uniformly by sulfurizing the Mo foils in sulfur vapor at 600 °C within 1 min. At a lower temperature even down to 500 °C, uniform MoS2 monolayers can still be obtained but in a much longer sulfurizing duration. It is demonstrated that the formed monolayers can be nondestructively transferred onto arbitrary substrates by removing the Mo foil using diluted ferric chloride solution and can be successfully fabricated into photodetectors. The results show a novel avenue to efficiently fabricate two-dimensional crystals in a large area in a highly controllable way and should have great potential for the development of large-scale applications of two-dimensional crystals in electrophotonic systems.