Molecular dynamics simulations on the dynamics of two-dimensional rounded squares

The collective motion of rounded squares with different comer-roundness ζ is studied by molecular dynamlcs （MD） simulation in this work. Three types of translational collective motion pattern are observed, including＇, gliding, hopping and a mixture of gliding and hopping. Quantitatively, the dynamics of each observed ordered phase is characterized by both mean square displacement and van Hove functions for both translation and rotation. The effect of corner-roundness on the dynamics is further studied by comparing the dynamics of the rhombic crystal phases folmed by different comer-.rounded particles at a same surface fraction. The results show that as ζ increases from 0.286 to 0.667, the translational collective motion of particles changes from a gliding-dominant pattern to a hopping-dominant patte;n, whereas the rotational motion pattern is hopping-like and does not change in its type, but the rotational hopping becomes much more frequent as increases （i.e., as particles become more rounded）. A simple geometrical model is proposed to explain the trend of gliding motion observed in MD simulations.

基于心理健康影响评价的医院室外空间环境分析与优化策略

在当前国内大型综合性医院面临改革的背景下,总结医院室外景观设计的相关理论研究,分析我国城市综合性医院室外空间环境中存在的问题,并基于心理健康影响评价探讨其优化策略。

Identification of human microRNA-disease association via low-rank approximation-based link propagation and multiple kernel learning

Numerous studies have demonstrated that human microRNAs(miRNAs)and diseases are associated and studies on the microRNA-disease association(MDA)have been conducted.We developed a model using a low-rank approximation-based link propagation algorithm with Hilbert–Schmidt independence criterion-based multiple kernel learning(HSIC-MKL)to solve the problem of the large time commitment and cost of traditional biological experiments involving miRNAs and diseases,and improve the model effect.We constructed three kernels in miRNA and disease space and conducted kernel fusion using HSIC-MKL.Link propagation uses matrix factorization and matrix approximation to effectively reduce computation and time costs.The results of the experiment show that the approach we proposed has a good effect,and,in some respects,exceeds what existing models can do.

Cellular gp96 upregulates AFP expression by blocking NR5A2 SUMOylation and ubiquitination in hepatocellular carcinoma

Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, asubstantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlyingmechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, andits stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular dockingshowed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. Thebinding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCCpatients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered anovel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination.These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.

N-糖基化修饰对热休克蛋白gp96免疫学功能的影响

文中旨在以N-糖基化位点突变的重组热休克蛋白gp96为对象,研究N-糖基化修饰对其免疫功能的影响。首先利用昆虫表达系统表达野生型和突变型gp96蛋白,并检测其糖基化水平。进一步通过体外和体内实验,利用流式细胞术和酶联免疫吸附试验(Enzyme linked immunosorbent assay,ELISA)检测小鼠CD8^(+)IFN-γ^(+)T细胞亚群和IFN-γ的分泌,查明糖基化对gp96抗原呈递功能的影响,进一步用ATPase试剂盒检测gp96的ATPase活性。最后通过小鼠免疫实验探究糖基化对gp96疫苗佐剂功能和活化流感疫苗特异性T细胞的影响。结果显示,N-糖基化修饰位点突变后,重组gp96蛋白总含糖量下降了27.8%。与野生型重组蛋白相比,突变gp96的抗原呈递能力减弱,同时ATPase活性明显降低。同时与野生型重组gp96相比,突变gp96佐剂活化流感疫苗特异性T细胞水平也明显减少。这些结果表明,N-糖基化修饰参与调节gp96的ATPase活性和抗原呈递功能,进而影响其疫苗佐剂功能,为开发基于gp96的佐剂疫苗提供了依据。

Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8^+ T Cells in a Mouse Model of Hepatitis B Virus Infection

T cell immunoglobulin- and mucin-domain-containing molecule-3 （Tim-3） has been reported to participate in the pathogenesis of inflammatory diseases. However, whether Tim-3 is involved in hepatitis B virus （HBV） infection remains unknown. Here, we studied the expression and function of Tim-3 in a hydrodynamics-based mouse model of HBV infection. A significant increase of Tim-3 expression on hepatic T lymphocytes, especially on CD8^＋ T cells, was demonstrated in HBV model mice from day 7 to day 18. After Tim-3 knockdown by specific shRNAs, significantly increased IFN-γ production from hepatic CD8^＋ T cells in HBV model mice was observed. Very interestingly, we found Tim-3 expression on CD8^＋ T cells was higher in HBV model mice with higher serum anti-HBs production. Moreover, Tim-3 knockdown influenced anti-HBs production in vivo. Collectively, our data suggested that Tim-3 might act as a potent regulator of antiviral T-cell responses in HBV infection. Cellular ＆ Molecular Immunology.

Analyses of levels of thyroid hormones and its receptor expression in puerperants and newborns from an e-waste dismantling site

In this study,the serum levels,including thyr-oid hormones free triiodothyronine(FT3),free thyroxine(FT4),thyroid stimulating hormone(TSH)among the sub-jects from the exposed group(n 548)and the control group(n 545)were detected by immuno radiometric assay(IRMA).The expression levels of TRa1,TRb1,TSHR mRNA in placentas and umbilical cords were detected by fluorescent quantitative real-time PCR(FQ-PCR).The correlations between the thyroid hormone levels in maternal serum and umbilical serum,and between the expression levels of its receptors mRNA in placentas and umbilical cords were determined.We found that the FT4 levels of both maternal serum and umbilical cord serum in the exposed group were lower than those in the control(P<0.05).However,the increased TSH levels in the exposed group had statistically significance com-pared to those in the control group(P<0.05).The TRa1 and TRb1 mRNA levels both in placentas and umbilical cords in the exposed group were lower than those in the control group(P<0.05 and 0.01).How-ever,the TSHR mRNA levels in the exposed group were significantly different compared to those in the control group(P<0.01).The serum FT4 and TSH levels of par-turient women were positively correlated with those of the newborns in both groups(P<0.05 and 0.01).The mRNA levels of TRa1,TRb1 and TSHR in the placentas were positively correlated with those in umbilical cords in both groups(P<0.01).The findings suggest that some envir-onmental pollutants existing in the electronic waste(e-waste)dismantling region may affect the health of local parturient women and newborns,representing changes both in serum levels of thyroid hormones and in mRNA expression of its receptors.

MHC Class I Assembly Function and Intracellular Transport Routes for Hepatitis B Virus Antigen Cross-presentation by Heat Shock Protein gp96

Background:During hepatitis B virus(HBV)infection,virus-infected hepatocytes directly cross-present viral antigens and regulate T cell response within the liver microenvironment.However,little is known regarding the regulatory pathways involved in viral antigen presentation in HBV-infected hepatocytes.This study investigated the underlying mechanism of antigen assembly and the HBV antigen-presenting function of major histocompatibility complex(MHC)class I molecules using heat shock protein gp96.Methods:First,western blotting,flow cytometry,co-immuno precipitation,GST pull-down,and confocal microscopic assays were performed to determine whether endogenous gp96 affects MHC-I levels via an antigen presentation pathway.Second,the B3Z assay and an AAV/HBV-infected hepatocyte-specific gp96-deficient mouse model were used to determine whether gp96 knockout functionally impaired peptide cross-presentation and produced a weakened antiviral cytotoxic T cell(CTL)response both in vivo and in vitro.Finally,confocal microscopic analysis and the B3Z assay were employed to show that exogenous gp96-associated peptide was present in MHC-I molecules via the endoplasmic reticulum(ER)-Golgi secretory pathway.Results:Compared with the control,gp96 knockdown significantly reduced the cell surface levels of MHC-I by approximately 75%(P<0.01).Endogenous gp96 interacts with MHC-I and is involved in antigen presentation.Moreover,a weakened antiviral CTL response(34%compared to control mice)has been observed in hepatocyte-specific gp96-deficient mice following HBV infection.gp96 directed exogenous antigen to the ER,and the exogenous gp96-chaperoned peptide was endosome-and proteasome-dependent but not transporter associated with antigen processing dependent.Conclusions:Cellular gp96 promotes the assembly and antigen presentation of MHC class I molecules.In addition,extracellular gp96 served as a natural adjuvant to induce a CTL response in a concerted and regulated manner within different cellular compartments.Our results elucidate the mechanism of assembly of MHC class I molecules by gp96,which may be beneficial for the design of immunotherapy and vaccines.