Analysis of conformational motions and related key residue interactions responsible for a specific function of proteins with elastic network model

Protein collective motions play a critical role in many biochemical processes. How to predict the functional motions and the related key residue interactions in proteins is important for our understanding in the mechanism of the biochemical processes. Normal mode analysis (NMA) of the elastic network model (ENM) is one of the effective approaches to investigate the structure-encoded motions in proteins. However, the motion modes revealed by the conventional NMA approach do not necessarily correspond to a specific function of protein. In the present work, a new analysis method was proposed to identify the motion modes responsible for a specific function of proteins and then predict the key residue interactions involved in the functional motions by using a perturbation approach. In our method, an internal coordinate that accounts for the specific function was introduced, and the Cartesian coordinate space was transformed into the internal/Cartesian space by using linear approximation, where the introduced internal coordinate serves as one of the axes of the coordinate space. NMA of ENM in this internal/Cartesian space was performed and the function-relevant motion modes were identified according to their contributions to the specific function of proteins. Then the key residue interactions important for the functional motions of the protein were predicted as the interactions whose perturbation largely influences the fluctuation along the internal coordinate. Using our proposed methods, the maltose transporter (MalFGK₂) from E. Coli was studied. The functional motions and the key residue interactions that are related to the channel-gating function of this protein were successfully identified.     

Synthesis and biological characterization of new aryloxyindole-4,9-diones as potent trypanosomicidal agents

A new indole-4,9-dione and their phenoxy derivatives were synthesized and evaluated in vitro against the epimastigote form of Trypanosoma cruzi, Y strain. All of these novel compounds were found to be extremely potent and selective that the standard drug nifurtimox. Interestingly, phenoxyindole-4,9-dione 9d displayed excellent nanomolar inhibitory activity, IC₅₀ = 20 nM, and high selectivity index, SI = 625. In silico studies using MOE program were performed to generate a preliminary pharmacophore model.     

Structural similarity and distribution of small cryptic plasmids of Lactobacillus curvatus and L. sake

Plasmid profiles of strains of Lactobacillus curvatus and L. sake isolated from meat or sauerkraut were analysed to investigate plasmid homology and distribution in relation to the ecology of these organisms in fermenting foods. A hybridisation probe was constructed by cloning of pLc2, a cryptic, 2.6-kbp plasmid from L. curvatus LTH683, into the Escherichia coli plasmid pRV50. In Southern hybridisations with the digoxygenine labeled pLc2 probe, pLc2-related small plasmids were frequently detected in meat-borne strains of L. casei subsp. pseudoplantarum, L. curvatus, L. sake, L. alimentarius, L. farciminis and L. halotolerans and in L. curvatus and L. sake isolated from sauerkraut. Among 27 Lactobacillus type strains originally isolated from habitats other than meat this type of homology was detected only with plasmids of L. buchneri and L. mali. Restriction-enzyme mapping of six small cryptic plasmids from L. curvatus and L. sake revealed strong structural homology but no similarity to previously characterized plasmids of lactobacilli. The presence of a variable region in addition to a conserved one and the occurrence of deletions during cloning of pLc2 suggest that vectors derived from these plasmids are likely to be structurally unstable.     

气候变化下中国八种梧桐属树种潜在适生区模拟

中国梧桐属（Firmiana）在世界梧桐属中占比较大，且除梧桐外其余种均为中国特有且分布范围狭窄的植物种，灭绝风险大，研究气候变化对中国梧桐属树种的影响对于维护生物多样性具有重要的意义。结合多时期第六次国际气候耦合模式比较计划（CMIP6）气候变量数据和中国八种梧桐属树种的分布数据，基于R语言kuenm程序包优化的最大熵（Maxent）模型模拟分析中国八种梧桐属树种在多尺度下的潜在适生区，得出梧桐属最适宜的模拟尺度、潜在适生区的面积变化和迁移方向、梧桐属多样性保护关键区域及保护空缺。结果表明：（1）梧桐属最适宜的模拟尺度为亚洲；（2） Maxent模型的接收者操作特征曲线下面积（AUC）值均大于0.9，表明模型对梧桐属潜在适生区预测结果具有较高准确度；（3）气候变化影响下除云南梧桐（Firmiana major）外其它树种的潜在适生区都将在未来有所扩大；（4）中国八种梧桐属树种潜在适生区迁移方向主要为东西向，南北向大跨度迁移较少，纬度变化不大；（5）丹霞梧桐（Firmiana danxiaensis）的稳定潜在适生区最小；（6）中国梧桐属多样性保护关键区域主要分布于广西壮族自治区及云南、广东、海南等省区；（7）中国梧桐属多样性保护空缺区域主要分布于广西壮族自治区中部及海南省北部；（8）梧桐属多样性保护关键区域正在为人造地表所侵蚀。研究分析气候变化对中国八种梧桐属树种的影响及其潜在适生区变化、中国梧桐属多样性保护状态，可为中国梧桐属建立多样性保护廊道提供相关建议，为制定多样性保护规划及相应措施提供参考。     

Effects of amiprilose hydrochloride on the components of human skin equivalents

Summary Amiprilose hydrochloride has been shown to inhibit the proliferation of a number of hyperproliferative cell types including psoriatic skin cells. In the present study, the effects of amiprilose hydrochloride on human tissue equivalents were examined by incubating a) dermal equivalents, b) skin equivalents in the process of epidermalization, and c) mature skin equivalents, with varying concentrations of the drug. In all three models amiprilose hydrochloride concentrations of 0.1% (wt/vol) and lower were not toxic to fibroblasts and keratinocytes and did not interfere with the differentiation of the skin equivalent and the developing skin equivalent. When tested in dermal equivalents, concentrations of amiprilose hydrochloride between 0.1 and 0.5% resulted in changes in fibroblast morphology with development of large intracellular vacuoles, and concentrations greater than 5% were toxic. In mature skin equivalents, in addition to changes in fibroblast morphology, amiprilose hydrochloride in concentrations of 1 to 10% affected the epidermis. When 0.5% amiprilose hydrochloride was present in the developing skin equivalent during differentiation, the epidermal keratinocytes were also affected. Thus the morphology of basal keratinocytes was modified, the differentiation was incomplete, and the dermalepidermal attachment was compromised. These studies suggest the possibility of an extracellular mechanism of action of amiprilose hydrochloride and delineate acceptable dosage ranges for the potential drug. Supported in part by research grant AG01274 from the National Institutes of Health, Bethesda, MD, The R. A. Welch Foundation (B0502), The Texas Advanced Technology and Research Program (Wound Healing and Aging no. 2147), and Greenwich Pharmaceuticals, Inc. R. W. G. is the recipient of a MERIT award from the National Institute on Aging, Bethesda, MD.