STD NMR study of the interactions between antibody 2G12 and synthetic oligomannosides that mimic selected branches of gp120 glycans

The human immunodeficiency virus type-1 (HIV-1) is able to shield immunogenic peptide epitopes on its envelope spike (a trimer of two glycoproteins, gp120 and gp41) by presenting numerous host-derived N-linked glycans. Nevertheless, broadly neutralizing antibodies against gp120 and gp41 have been isolated from HIV-1-infected patients and provide protection against viral challenge in animal models. Among these, the monoclonal antibody 2G12 binds to clusters of high-mannose-type glycans that are present on the surface of gp120. These types of glycans have thus been envisaged as target structures for the development of synthetic agents capable of eliciting 2G12-like antibodies. High-resolution structural studies of 2G12 and chemically defined glycan-type ligands, including crystallographic data, have been performed to gain an insight into this interaction. Further studies are still required to design a carbohydrate-based vaccine for HIV. Our previous NMR studies highlighted different recognition modes of two branched synthetic oligosaccharides, a penta- and a heptamannoside, by 2G12 in solution. In order to clarify the underlying structural reasons for such different behaviors, we have herein "dissected" the branches into the linear tri- and tetra- oligomannosides by chemical synthesis and studied their interactions with 2G12 in solution by saturation transfer difference (STD) NMR spectroscopy. The results confirm the distinct preferences of 2G12 for the studied branches and afford explanations for the observed differences. This study provides important structural information for further ligand optimizations. Possible effects of structural modifications on the solvent-exposed end of the ligands are also discussed.     

全固态高平均功率宽调谐掺钛蓝宝石激光器

介绍了以激光二极管抽运Nd：YAG晶体的倍频激光器为抽运源，高平均功率准连续运转的全固态宽调谐掺钛蓝宝石(Ti：sapphire)激光器。自由运转时，在抽运光功率为16W，透过率为30％时，获得了最高6．44W的掺钛蓝宝石激光输出，相应光-光转换效率大于40％。为了获得宽波段可调谐激光输出，采用石英布氏棱镜对作腔内色散元件，通过调节输出镜获得了调谐范围740～880nm，线宽约1nm的宽波段输出。在抽运光功率为11．5W时，最高输出功率为2．87W，相应的光-光转换效率为25％。作为对比，又研究了重火石棱镜作为腔内色散元件时，掺钛蓝宝石激光器的调谐输出特性，实验表明输出激光的线宽明显变窄，但输出功率却显著下降。     

Clinical psychology education and training: Commentary on Kenkel et al. and Linden et al.

Despite general acceptance of clinical psychology as a broadly based health-care discipline, many graduate programs in clinical psychology have been slow to change from their continued primary focus on mental health education and training. The two papers in this Special Section (Linden et al., see record 2005-14076-001; Kenkel et al., see record 2005-14076-002) clearly articulate the compelling rationale for clinical psychology's full participation in all aspects of health, and provide a variety of creative ideas and initiatives regarding current and future educational reform. Interestingly, neither paper focused on the considerable research literature that already exists on graduate education reform and hence I have briefly outlined some of this work here. After reading the papers in this Special Section, I found myself agreeing with much of what was said and disagreeing strongly with some ideas. I also found myself sensitized to the notion that as educational reform proceeds, psychologists need to be vigilant to ensure that they maintain their own unique identity without drifting toward adopting key aspects of the identities of other professions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

宽级配粗粒料渗透试验方法探讨

宽级配粗粒料是一种在土石坝中广泛使用的材料.分析了宽级配粗粒料渗透试验方法的研究现状,指出了目前规程规范中存在的问题,归纳了影响宽级配粗粒料渗透试验的几个主要因素,主要包括:试验仪器的尺寸效应、边壁效应以及水中气泡对试验的影响,并有针对性地提出了解决问题的思路.     

Broadly Antiviral Activities of TAP1 through Activating the TBK1-IRF3-Mediated Type I Interferon Production

Deeply understanding the virus-host interaction is a prerequisite for developing effective anti-viral strategies. Traditionally, the transporter associated with antigen processing type 1 (TAP1) is critical for antigen presentation to regulate adaptive immunity. However, its role in controlling viral infections through modulating innate immune signaling is not yet fully understood. In the present study, we reported that TAP1, as a product of interferon-stimulated genes (ISGs), had broadly antiviral activity against various viruses such as herpes simplex virus 1 (HSV-1), adenoviruses (AdV), vesicular stomatitis virus (VSV), dengue virus (DENV), Zika virus (ZIKV), and influenza virus (PR8) etc. This antiviral activity by TAP1 was further confirmed by series of loss-of-function and gain-of-function experiments. Our further investigation revealed that TAP1 significantly promoted the interferon (IFN)-β production through activating the TANK binding kinase-1 (TBK1) and the interferon regulatory factor 3 (IRF3) signaling transduction. Our work highlighted the broadly anti-viral function of TAP1 by modulating innate immunity, which is independent of its well-known function of antigen presentation. This study will provide insights into developing novel vaccination and immunotherapy strategies against emerging infectious diseases.     

宽级配砾质土三轴渗透试验研究

为研究宽级配砾质土的渗透特性,对不同砾石含量的宽级配砾质土进行了一系列的三轴渗透试验。试验结果表明随砾石含量的增加,宽级配砾质土的结构分别为悬浮-密实、密实-骨架、骨架-空隙3种形式;随砾石含量的增大,渗透系数呈现出先略微减小然后逐渐增大、最后迅速增大的变化规律;含水率、干密度均对宽级配砾质土的渗透系数有较大的影响;在最优含水率左右,渗透系数有明显的差异,施工中应注意对含水率控制。     

多级配砾石土反滤设计方法试验研究

多级配砾石土反滤层工作机理及设计方法的研究，国内外均刚开始。本文通过试验研究，主要阐明以下几个问题：①反滤层研究的主要内容是确定极限反滤的等效粒径值。多级配土极限等效粒径的确定原则是在反滤进口能形成自滤的反滤层，从而保证土的渗透稳定性。②多级配砾石土是不均匀系数大于１００的土，具有较多无粘性土的渗透稳定性质，因此可以直接采用无粘性土反滤设计的一般数学模型。③控制粒径出现的机率不再是常数，它随土的渗透稳定性质而变化，文中给出了控制粒径确定的方法。④给出反滤层的设计准则     

宽调谐室温Co:MgF2激光器

用双折射滤光片不同干涉级次和多组谐振腔镜连续调谐室温Co:MgF2激光器,波长调谐范围达到1700～2550nm,在2090 nm峰值波长的输出能量及效率分别为115 mJ和16%.     

Functional Delineation of a Protein–Membrane Interaction Hotspot Site on the HIV-1 Neutralizing Antibody 10E8

Antibody engagement with the membrane-proximal external region (MPER) of the envelope glycoprotein (Env) of HIV-1 constitutes a distinctive molecular recognition phenomenon, the full appreciation of which is crucial for understanding the mechanisms that underlie the broad neutralization of the virus. Recognition of the HIV-1 Env antigen seems to depend on two specific features developed by antibodies with MPER specificity: (i) a large cavity at the antigen-binding site that holds the epitope amphipathic helix; and (ii) a membrane-accommodating Fab surface that engages with viral phospholipids. Thus, besides the main Fab–peptide interaction, molecular recognition of MPER depends on semi-specific (electrostatic and hydrophobic) interactions with membranes and, reportedly, on specific binding to the phospholipid head groups. Here, based on available cryo-EM structures of Fab–Env complexes of the anti-MPER antibody 10E8, we sought to delineate the functional antibody–membrane interface using as the defining criterion the neutralization potency and binding affinity improvements induced by Arg substitutions. This rational, Arg-based mutagenesis strategy revealed the position-dependent contribution of electrostatic interactions upon inclusion of Arg-s at the CDR1, CDR2 or FR3 of the Fab light chain. Moreover, the contribution of the most effective Arg-s increased the potency enhancement induced by inclusion of a hydrophobic-at-interface Phe at position 100c of the heavy chain CDR3. In combination, the potency and affinity improvements by Arg residues delineated a protein–membrane interaction site, whose surface and position support a possible mechanism of action for 10E8-induced neutralization. Functional delineation of membrane-interacting patches could open new lines of research to optimize antibodies of therapeutic interest that target integral membrane epitopes.