A Novel Metabolic Score for Predicting the Acute Exacerbation in Patients with Chronic Obstructive Pulmonary Disease.

Background: Chronic obstructive pulmonary disease (COPD) has higher mortality when developing to acute exacerbation (AECOPD); hence, the early intervention of COPD is critical for preventing AECOPD. Exploring the serum metabolites associated with acute exacerbation in patients with COPD will contribute to the early intervention of COPD. Methods: In the study, a non-targeted metabolomics strategy combined with multivariate statistical methods was performed to explore the metabolic profiling of COPD developing acute exacerbation, to screen the potential metabolites associated with AECOPD and to analyze the potential value of these metabolites in predicting the development of COPD. Results: Serum lysine, glutamine, 3-hydroxybutyrate, pyruvate and glutamate levels were significantly higher, while 1-methylhistidine, isoleucine, choline, valine, alanine, histidine and leucine levels were significantly lower in AECOPD patients, compared with stable COPD patients after normalization based on the healthy controls. Moreover, eight metabolic pathways were significantly altered (P<0.05) in the serum of AECOPD patients compared with the stable COPD population, including purine metabolism, glutamine and glutamate metabolism, arginine biosynthesis, butyrate metabolism, ketone body synthesis and degradation, and linoleic acid metabolism. In addition, the correlation analysis between metabolites and AECOPD patients demonstrated that an M-score based on a weighted sum of concentrations of four metabolites including pyruvate, isoleucine, 1-methylhistidine and glutamine were significantly associated with the acute exacerbation of pulmonary ventilation function in COPD patients. Conclusion: Altogether, the metabolite score based on a weighted sum of concentrations of four serum metabolites was associated with an increased risk of COPD developing acute exacerbation, which will provide a new insight for the understanding of COPD development.

Upregulation of CDGSH iron sulfur domain 2 attenuates cerebral ischemia/reperfusion injury.

CDGSH iron sulfur domain 2 can inhibit ferroptosis, which has been associated with cerebral ischemia/reperfusion, in individuals with head and neck cancer. Therefore, CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury. To validate this hypothesis in the present study, we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro, respectively. We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells. When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately, mouse neurological dysfunction was greatly improved; the cerebral infarct volume was reduced; the survival rate of HT22 cells was increased; HT22 cell injury was alleviated; the expression of ferroptosis-related glutathione peroxidase 4, cystine-glutamate antiporter, and glutathione was increased; the levels of malondialdehyde, iron ions, and the expression of transferrin receptor 1 were decreased; and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased. Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway. Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury, thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.

Evidence Based Social Science in China Paper 2: The History and Development of Evidence Based Social Work in China.

OBJECTIVES: To present the history and potential for development of evidence-based (EB) social work in China. STUDY DESIGN AND SETTING: The conception and methodology of EB social work is a potential strategy to support high quality development of social work in China. This article documents and analyzes the progress of EB social work in China. We focus on current research, reasons, challenges, and strategies. RESULTS: EB social work started late in China. The number of EB social work literature and systematic reviews has increased since 2004. The development of EB social work has been uneven nationally with few practitioners and decision makers involved. However, more and more social work researchers received training in evidence-based practice through national workshops and conferences. CONCLUSION: EB social work faced various challenges, but there are now more opportunities for EB social work development in China. Researchers, practitioners, managers and decision makers are encouraged to work together to establish a thorough methodological system and use existing evidence as much as possible when carrying out social work programs and services.

MicroRNA panels as disease biomarkers distinguishing hepatitis B virus infection caused hepatitis and liver cirrhosis.

An important unresolved clinical issue is to distinguish hepatitis B virus (HBV) infection caused chronic hepatitis and their corresponding liver cirrhosis (LC). Recent research suggests that circulating microRNAs are useful biomarkers for a wide array of diseases. We analyzed microRNA profiles in the plasmas of a total of 495 chronic hepatitis B (CHB) patients, LC patients and healthy donors and identified 10 miRNAs that were differentially expressed between CHB and LC patients. Our logistic models show that three panels of miRNAs have promising diagnostic performances in discriminating CHB from LC. Blinded tests were subsequently conducted to evaluate the diagnostic performances in clinical practice and a sensitivity of 85% and specificity of 70% have been achieved in separating CHB from LC pateints. The expression levels of some circulating miRNAs were significantly correlated with HBV DNA load and liver function, such as prothrombin activity (PTA) and levels of alanin aminotransferase (ALT), albumin (ALB) and cholinesterase (CHE). Our results provide important information for developing novel diagnostic tools for distinguishing chronic HBV hepatitis and their corresponding cirrhosis.

Regulation of T cell proliferation by JMJD6 and PDGF-BB during chronic hepatitis B infection.

T cell functional exhaustion during chronic hepatitis B virus (HBV) infection may contribute to the failed viral clearance; however, the underlying molecular mechanisms remain largely unknown. Here we demonstrate that jumonji domain-containing protein 6 (JMJD6) is a potential regulator of T cell proliferation during chronic HBV infection. The expression of JMJD6 was reduced in T lymphocytes in chronic hepatitis B (CHB) patients, and this reduction in JMJD6 expression was associated with impaired T cell proliferation. Moreover, silencing JMJD6 expression in primary human T cells impaired T cell proliferation. We found that JMJD6 promotes T cell proliferation by suppressing the mRNA expression of CDKN3. Furthermore, we have identified platelet derived growth factor-BB (PDGF-BB) as a regulator of JMJD6 expression. PDGF-BB downregulates JMJD6 expression and inhibits the proliferation of human primary T cells. Importantly, the expression levels of JMJD6 and PDGF-BB in lymphocytes from CHB patients were correlated with the degree of liver damage and the outcome of chronic HBV infection treatment. Our results demonstrate that PDGF-BB and JMJD6 regulate T cell function during chronic HBV infection and may provide insights for the treatment strategies for CHB patients.

A novel antibody humanization method based on epitopes scanning and molecular dynamics simulation.

1-17-2 is a rat anti-human DEC-205 monoclonal antibody that induces internalization and delivers antigen to dendritic cells (DCs). The potentially clinical application of this antibody is limited by its murine origin. Traditional humanization method such as complementarity determining regions (CDRs) graft often leads to a decreased or even lost affinity. Here we have developed a novel antibody humanization method based on computer modeling and bioinformatics analysis. First, we used homology modeling technology to build the precise model of Fab. A novel epitope scanning algorithm was designed to identify antigenic residues in the framework regions (FRs) that need to be mutated to human counterpart in the humanization process. Then virtual mutation and molecular dynamics (MD) simulation were used to assess the conformational impact imposed by all the mutations. By comparing the root-mean-square deviations (RMSDs) of CDRs, we found five key residues whose mutations would destroy the original conformation of CDRs. These residues need to be back-mutated to rescue the antibody binding affinity. Finally we constructed the antibodies in vitro and compared their binding affinity by flow cytometry and surface plasmon resonance (SPR) assay. The binding affinity of the refined humanized antibody was similar to that of the original rat antibody. Our results have established a novel method based on epitopes scanning and MD simulation for antibody humanization.

T lymphocytes from chronic HCV-infected patients are primed for activation-induced apoptosis and express unique pro-apoptotic gene signature.

Although extensive studies have demonstrated the functional impairment of antigen-specific CD4(+) and CD8(+) T-cells during chronic hepatitis C virus (HCV) infection, the functional status of global CD4(+) and CD8(+) T-cells remains unclear. In this report, we recruited 42 long-term (~20 years) treatment-naïve chronic HCV (CHC) patients and 15 healthy donors (HDs) to investigate differences in global CD4(+) and CD8(+) T-cells function. We show that CD4(+) and CD8(+) T-cells from CHC patients underwent increased apoptosis after TCR stimulation. Furthermore, IFN-γ, IL-9 and IP-10 were elevated in CHC patients' plasma and promoted activation-induced T-cells death. Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes. We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures. Importantly, the gene expression patterns of CD4(+) and CD8(+) T-cells from CHC patients differ from those in CD4(+) and CD8(+) T-cells from human immunodeficiency virus type 1 (HIV-1) or hepatitis B virus (HBV) infected individuals. Our results indicate that chronic HCV infection causes a systemic change in cytokine levels that primes T-cells for activation-induced apoptosis. Furthermore, HCV infection programs unique apoptosis-related gene expression profiles in CD4(+) and CD8(+) T-cells, leading to their enhanced activation-induced apoptosis. These results provide novel insights to the pathogenesis of chronic HCV infection.

Structure-based high-throughput epitope analysis of hexon proteins in B and C species human adenoviruses (HAdVs).

Human adenoviruses (HAdVs) are the etiologic agent of many human infectious diseases. The existence of at least 54 different serotypes of HAdVs has resulted in difficulties in clinical diagnosis. Acute respiratory tract disease (ARD) caused by some serotypes from B and C species is particularly serious. Hexon, the main coat protein of HAdV, contains the major serotype-specific B cell epitopes; however, few studies have addressed epitope mapping in most HAdV serotypes. In this study, we utilized a novel and rapid method for the modeling of homologous proteins based on the phylogenetic tree of protein families and built three-dimensional (3D) models of hexon proteins in B and C species HAdVs. Based on refined hexon structures, we used reverse evolutionary trace (RET) bioinformatics analysis combined with a specially designed hexon epitope screening algorithm to achieve high-throughput epitope mapping of all 13 hexon proteins in B and C species HAdVs. This study has demonstrated that all of the epitopes from the 13 hexon proteins are located in the proteins' tower regions; however, the exact number, location, and size of the epitopes differ among the HAdV serotypes.

Downregulation of the AU-rich RNA-binding protein ZFP36 in chronic HBV patients: implications for anti-inflammatory therapy.

Inflammation caused by chronic hepatitis B virus (HBV) infection is associated with the development of cirrhosis and hepatocellular carcinoma; however, the mechanisms by which HBV infection induces inflammation and inflammatory cytokine production remain largely unknown. We analyzed the gene expression patterns of lymphocytes from chronic HBV-infected patients and found that the expression of ZFP36, an AU-rich element (ARE)-binding protein, was dramatically reduced in CD4(+) and CD8(+) T lymphocytes from chronic HBV patients. ZFP36 expression was also reduced in CD14(+) monocytes and in total PBMCs from chronic HBV patients. To investigate the functional consequences of reduced ZFP36 expression, we knocked down ZFP36 in PBMCs from healthy donors using siRNA. siRNA-mediated silencing of ZFP36 resulted in dramatically increased expression of multiple inflammatory cytokines, most of which were also increased in the plasma of chronic HBV patients. Furthermore, we found that IL-8 and RANTES induced ZFP36 downregulation, and this effect was mediated through protein kinase C. Importantly, we found that HBsAg stimulated PBMCs to express IL-8 and RANTES, resulting in decreased ZFP36 expression. Our results suggest that an inflammatory feedback loop involving HBsAg, ZFP36, and inflammatory cytokines may play a critical role in the pathogenesis of chronic HBV and further indicate that ZFP36 may be an important target for anti-inflammatory therapy during chronic HBV infection.

[Effect of different mixing and curing methods on the mechanical properties of denture base resin].

OBJECTIVE: To investigate the differences between the mechanical properties of denture base processed by traditional mixing and malaxation method, and by traditional hot water polymerization and electrical heat-polymerization. METHODS: Samples used in this investigation were commercial acrylic denture base resin made by using two different mixing methods, and by using two different curing methods. The samples were assigned to 4 test groups. Group 1: traditional mixing + hot water polymerization. Group 2: malaxation + hot water polymerization. Group 3: traditional mixing + electrical heat-polymerization. Group 4: malaxation + electrical heat-polymerization. Surface hardness, flexural strength, flexural modulus, and impact strength were tested of each sample. RESULTS: The mean of the four groups' surface hardness was 19.4, 21.2, 22.3, 23.2 N/mm2, and of flexural strength was 58.58, 63.32, 66.73, 63.76 MPa, and of impact strength was 1.42, 1.53, 1.77, 1.78 KJ/m2, and of flexural modulus was 2311.38, 2417.82, 2566.36, 2400.37 MPa. CONCLUSIONS: Surface hardness and impact strength of malaxation method + electrical heat-polymerization group are higher than those of traditional mixing + hot water polymerization group.