关于现代病原生物学教学改革的探讨

病原生物学是必不可少的医学基础学科。为适应现代医学发展趋式,病原生物学的教学改革势在必行。本文结合本院实际,通过对病原生物学教学中所存在问题的分析,论述近年来所采取的相应教学改革措施及其所取得的成果。     

巴曲亭对低分子肝素抗凝全髋置换术患者出血量及凝血功能影响的研究

目的 探讨巴曲亭与低分子肝素的相互作用,观察巴曲亭用于骨科低分子肝素抗凝全髋置换术患者的疗效和安全性。方法 采用多中心、随机、双盲对照研究设计,按照1 ∶ 1 比例纳入ASAⅠ～Ⅲ 级单侧全髋置换术患者240 例,试验组（低分子肝素＋巴曲亭组）120 例,对照组（低分子肝素组）120 例,比较两组患者的术中出血量、术后引流量,并检测术前、术中及术后24h 凝血酶原时间（PT）、部分凝血活酶时间（APTT）、纤维蛋白原（FIB）水平变化,两组患者均于术前及术后第3 天行下肢静脉多普勒彩超检查,并记录术后住院时间。结果 最终试验组119 例、对照组120 例纳入数据分析。试验组术中出血量（422.64 ml）明显低于对照组（667.67 ml）（P＜0.01）,两组患者术毕PT、APTT均较给药前有所延长（P＜0.01）,红细胞（RBC）、Hb、红细胞比容积（Hct）、血小板水平均较给药前明显下降（P＜0.01）,组间比较差异无统计学意义（P＞0.05）。术后第3 天下肢多普勒彩超检查均未发现下肢深静脉血栓。两组患者住院期间均无不良事件,且实际住院时间的差异无统计学意义（P＞0.05）。结论 全髋置换术中使用巴曲亭不受低分子肝素的抑制,且安全有效,术前5～10 min静脉注射2 U可明显减少患者出（渗）血量。     

Computational modeling of drug response with applications to neuroscience

The development of novel high-throughput technologies has opened up the opportunity to deeply characterize patient tissues at various molecular levels and has given rise to a paradigm shift in medicine towards personalized therapies. Computational analysis plays a pivotal role in integrating the various genome data and understanding the cellular response to a drug. Based on that data, molecular models can be constructed that incorporate the known downstream effects of drug-targeted receptor molecules and that predict optimal therapy decisions. In this article, we describe the different steps in the conceptual framework of computational modeling. We review resources that hold information on molecular pathways that build the basis for constructing the model interaction maps, highlight network analysis concepts that have been helpful in identifying predictive disease patterns, and introduce the basic concepts of kinetic modeling. Finally, we illustrate this framework with selected studies related to the modeling of important target pathways affected by drugs.     

基于系统药理学探讨草乌改善Ⅱ型糖尿病的分子机制

目的 基于系统药理学、生物信息学、分子对接及体内外实验探讨草乌影响 2 型糖尿病(diabetes mellitus type 2, T2DM)的潜力及对 T2DM 相关症状的潜在机制。方法 利用数据库检索草乌相关化学成分、预测潜在作用靶点以及干预 相关疾病;GEO 数据库检索 T2DM 相对健康人的差异基因,与草乌作用靶点映射后置于 DAVIDavid 数据库进行生物功能 富集,利用单因素方差分析、二元 Logistic 回归分析及 ROC 曲线分析目标基因对于 T2DM 的敏感性。借助分子对接技术 分析草乌化学成分与靶蛋白的结合位置及相互作用力。通过体内外 T2DM 模型验证草乌及其化学成分对目标蛋白表达的 影响。 结果 通过数据库检索与分析得到草乌干预靶点相关疾病 44 种(P value<0.05,FDR<0.05),选取度值最高的 T2DM(Degree=22)进行分析。T2DM 相对健康人差异基因与草乌潜在作用靶点取交集得到 43 个目标基因,进行单因素方 差分析得到有显著性差异的基因共 9 个,二元 Logistic 回归分析得到 5 个有意义基因,ROC 曲线下面积 AUC>0.5 的基因 共 3 个。分子对接得到草乌化学成分(+)-Isoboldine 与蛋白 APEX1、CASP1、CBFB,Napelline 与蛋白 CBX1、EHMT2 结 合通过氢键相互作用、疏水相互作用、可电离性和静电相互作用等不同作用力结合,从而增加配体靶向作用蛋白的能力。 体内模型经草乌水提物治疗 2 周后,草乌可能通过改善周围神经病变进而缓解 T2DM 症状。并且草乌可以影响大鼠肝组织 中 APEX1、CASP1、CBFB、CBX1、EHMT2 的蛋白表达,草乌中(+)-Isoboldine 和 Napelline 化学成分对体外模型的目标蛋 白的影响与体内实验一致。结论 初步揭示草乌可作为改善 T2DM 周围神经病变的潜在治疗药物,为中蒙药研发以及挖掘 治疗 T2DM 新靶标药物奠定理论基础。     

Diagnosing skin rejection in vascularized composite allotransplantation: advances and challenges

Refinements in microsurgical techniques coupled with advances in immunosuppressive and immunomodulatory protocols have enabled broader clinical application of vascularized composite allotransplantation (VCA) with encouraging immunological, functional, and esthetic results. However, skin rejection remains a significant obstacle and a serious complication for VCA recipients. Clinical and histopathological features of rejection in VCA have been described in a number of studies, which led to the development of an international consensus on the classification guidelines of rejection in the context of VCA. Nevertheless, currently available diagnostic modalities still have several limitations and shortcomings that can pose a significant diagnostic challenge, particularly when signs of rejection are found to be equivocal. In this review, we provide a critical analysis of these advances and challenges in diagnosing skin rejection. Specifically, we highlight the gaps in understanding of rejection mechanisms, the shortfalls in correlating cellular, molecular, and clinicopathologic markers with rejection grades, deficiencies in defining chronic rejection, and antibody‐mediated rejection after VCA, as well as providing an outlook on novel concepts, such as the utilization of advanced computational analyses and cross‐disciplinary diagnostic approaches.     

Computational Inhibition Studies of the Human Proteasome by Argyrin‐Based Analogues with Subunit Specificity

A computational procedure was developed to study the subunit‐specific interactions of the proteasome inhibitors argyrin A and F, with the aim of indentifying the determinants of subunit selectivity. Three‐dimensional models of humanized proteasome active sites β₁, β₂ and β₅ were developed and subsequently used in molecular docking simulations with the argyrin analogues. The subunit selectivity exhibited by each analogue could be explained based on the site‐specific interactions and a probability‐based specificity parameter derived in this study. A rational approach that involved maximizing site‐specific interactions was followed to guide the design of new argyrin analogues as specific inhibitors of the caspase‐like (β₁ site) activity.     

The Impact of Active Site Mutations of South African HIV PR on Drug Resistance: Insight from Molecular Dynamics Simulations,Binding Free Energy and Per‐Residue Footprints

Molecular dynamics simulations and binding free energy calculations were used to provide an understanding of the impact of active site drug‐resistant mutations of the South African HIV protease subtype C (C‐SA HIV PR), V82A and V82F/I84V on drug resistance. Unique per‐residue interaction energy ‘footprints’ were developed to map the overall drug‐binding profiles for the wild type and mutants. Results confirmed that these mutations altered the overall binding landscape of the amino acid residues not only in the active site region but also in the flaps as well. Four FDA‐approved drugs were investigated in this study; these include ritonavir (RTV), saquinavir (SQV), indinavir (IDV), and nelfinavir (NFV). Computational results compared against experimental findings were found to be complementary. Against the V82F/I84V variant, saquinavir, indinavir, and nelfinavir lose remarkable entropic contributions relative to both wild‐type and V82A C‐SA HIV PRs. The per‐residue energy ‘footprints’ and the analysis of ligand–receptor interactions for the drug complexes with the wild type and mutants have also highlighted the nature of drug interactions. The data presented in this study will prove useful in the design of more potent inhibitors effective against drug‐resistant HIV strains.     

A Re‐examination of the MDM2/p53 Interaction Leads to Revised Design Criteria for Novel Inhibitors

The general model of epitope‐type MDM2 inhibitor was developed based on the structural information on the complexes between MDM2 and various low molecular weight ligands found in the PDB database. Application of this model to our in‐house library has led us to a new scaffold capable of interrupting protein–protein interactions. A synthetic library based on this and related scaffolds resulted in new classes of compounds that possess biochemical and cellular activity and good pharmacokinetic properties. We assume that such general approach to PPI inhibitors design may be useful for the development of inhibitors of various PPI types, including Bcl/XL.