Domain flexibility in retroviral proteases: structural implications for drug resistant mutations

Rigid body rotation of five domains and movements within their interfacial joints provide a rational context for understanding why HIV protease mutations that arise in drug resistant strains are often spatially removed from the drug or substrate binding sites. Domain motions associated with substrate binding in the retroviral HIV-1 and SIV proteases are identified and characterized. These motions are in addition to closure of the flaps and result from rotations of approximately 6-7 degrees at primarily hydrophobic interfaces. A crystal structure of unliganded SIV protease (incorporating the point mutation Ser 4 His to stabilize the protease against autolysis) was determined to 2.0 A resolution in a new space group, P3221. The structure is in the most "open" conformation of any retroviral protease so far examined, with six residues of the flaps disordered. Comparison of this and unliganded HIV structures, with their respective liganded structures by difference distance matrixes identifies five domains of the protease dimer that move as rigid bodies against one another: one terminal domain encompassing the N- and C-terminal beta sheet of the dimer, two core domains containing the catalytic aspartic acids, and two flap domains. The two core domains rotate toward each other on substrate binding, reshaping the binding pocket. We therefore show that, for enzymes, mutations at interdomain interfaces that favor the unliganded form of the target active site will increase the off-rate of the inhibitor, allowing the substrate greater access for catalysis. This offers a mechanism of resistance to competitive inhibitors, especially when the forward enzymatic reaction rate exceeds the rate of substrate dissociation.     

All that you can be: stereotyping of self and others in a military context

The authors tested the shifting standards model (M. Biernat, M. Manis, & T. E. Nelson, 1991) as it applies to sex- and race-based stereotyping of self and others in the military. U. S. Army officers attending a leadership training course made judgments of their own and their groupmates' leadership competence at 3 time points over a 9-week period. We examined the effects of officer sex and race on both subjective (rating) and objective/common-rule (ranking/Q-sort) evaluations. Stereotyping generally increased with time, and in accordance with the shifting standards model, pro-male judgment bias was more evident in rankings than in ratings, particularly for White targets. Self-judgments were also affected by sex-based shifting standards, particularly in workgroups containing a single ("solo") woman. Differential standard use on the basis of race was less apparent, a finding attributed to the Army's explicit invocation against the use of differential race-based standards.     

Analogues of capsaicin with agonist activity as novel analgesic agents: structure-activity studies. 4. Potent, orally active analgesics

Structural features of three regions of the capsaicin molecule necessary for agonist properties were delineated by a previously reported modular approach. These in vitro agonist effects were shown to correlate with analgesic potency in rodent models. Combination of optimal structural features from each of these regions of the capsaicin molecule have led to highly potent agonists (eg., 1b). Evaluation in vivo established that 1b had analgesic properties but poor oral activity, short duration of action, and excitatory side effects which precluded further development of this compound. Preliminary metabolism studies had shown that the phenol moiety of 1b was rapidly glucuronidated in vivo, providing a possible explanation for the poor pharmacokinetic profile. Subsequent specific modification of the phenol group led to compounds 2a-j, which retained in vitro potency. The in vivo profiles of two representatives of this series, 2a,h, were much improved over the "parent" phenol series, and they are candidates for development as analgesic agents.     

Roald Amundsen--a study of personality

Roald Amundsen is the most famous of the Norwegian polar explorers. His ancestors came from a group of islands south-east of the Oslofjord. From being fishermen and sailors, they progressed to becoming captains and shipowners in the course of two generations. Amundsen's father, Jens, stayed at sea until his ship went down with all the crew. Roald was 14 years of age at the time, the youngest of four competing brothers. Jens had left the close-knit local family community before that, and bought a flat in the capital, Oslo, so that his sons could get a better education. Roald's mother wanted him to study medicine. He did as she wished for a time, but was not at all interested. When his mother died, he abruptly left the university and went to sea, which had been the tradition in his family for decades. As a young boy he was an admirer of Sir John Franklin and his explorers of the Northwest Passage. Fridtjof Nansen became his ideal. The biographies about Roald Amundsen are very diverging--some hold him a hero, others reflect a strongly critical attitude. Here, the author tries to define his personality and places him firmly within the narcissistic domain. His tendency to seek the company of married women, but to take immediate flight when they really became interested reflects an Oedipus complex from before puberty. The tragic death of his father, the sea captain, may have been a supposition; puberty can be seen as a period of coping with ambivalence towards an earlier idealized father. His genius combined ambitious goals with a sharp eye for details as regards the equipment used in his expeditions. In his travels in the Arctic and the Antartic he was driven forward by the energy of the nation. His heroic death, trying to save his earlier "enemy", Nobile, was probably caused by an urge for self-destruction.     

CHL1 encodes a component of the low-affinity nitrate uptake system in Arabidopsis and shows cell type-specific expression in roots

The Arabidopsis CHL1 (AtNRT1) gene confers sensitivity to the herbicide chlorate and encodes a nitrate-regulated nitrate transporter. However, how CHL1 participates in nitrate uptake in plants is not yet clear. In this study, we examined the in vivo function of CHL1 with in vivo uptake measurements and in situ hybridization experiments. Under most conditions tested, the amount of nitrate uptake by a chl1 deletion mutant was found to be significantly less than that of the wild type. This uptake deficiency was reversed when a CHL1 cDNA clone driven by the cauliflower mosaic virus 35S promoter was expressed in transgenic chl1 plants. Furthermore, tissue-specific expression patterns showed that near the root tip, CHL1 mRNA is found primarily in the epidermis, but further from the root tip, the mRNA is found in the cortex or endodermis. These results are consistent with the involvement of CHL1 in nitrate uptake at different stages of root cell development. A functional analysis in Xenopus oocytes indicated that CHL1 is a low-affinity nitrate transporter with a K(m) value of approximately 8.5 mM for nitrate. This finding is consistent with the chlorate resistance phenotype of chl1 mutants. However, these results do not fit the current model of a single, constitutive component for the low-affinity uptake system. To reconcile this discrepancy and the complex uptake behavior observed, we propose a "two-gene" model for the low-affinity nitrate uptake system of Arabidopsis.     

MSP430单片机的电桥平衡自调节设计

在应变式火炮膛压测试仪中,直流不平衡电桥测量电路是测量火炮膛压信号的核心环节。由于电阻应变计阻值有一定的偏差,使得电桥在初始时达不到平衡,导致测试仪在没有应变时输出信号有为负值的可能性,致使测试仪所测得的数据无法以计算机数值校正方法实现。对于传统的机械电位器,手动调节的方法无法满足应变式火炮膛压测试仪封闭式、小体积的要求。本文设计的MSP430F2002单片机和MAX5402数字电位器所构成的电桥平衡自调节电路,具有结构简单、占用空间小、功耗低、可靠性高等特性,完全符合火炮膛压测试仪的要求。1电桥平衡自调节原理在火炮膛压测试仪中,考虑到测试仪壳体结构的限制以及低功耗的要求,采用的电桥为1/4直     

Side-effect localization for lazy, purely functional languages via aspects

Many side-effecting programming activities, such as profiling and tracing, can be formulated as crosscutting concerns and be framed as side-effecting aspects in the aspect-oriented programming paradigm. The benefit gained from this separation of concerns is particularly evident in purely functional programming, as adding such aspects using techniques such as monadification will generally lead to crosscutting changes. This paper presents an approach to provide side-effecting aspects for lazy purely functional languages in a user transparent fashion. We propose a simple yet direct state manipulation construct for developing side-effecting aspects and devise a systematic monadification scheme to translate the woven code to monadic style purely functional code. Furthermore, we present a static and dynamic semantics of the aspect programs and reason about the correctness of our monadification scheme with respect to them.     

Grid-based collaborative simulation system for vehicle crashworthiness

Globalization and increasing market competition are forcing the automotive industry to develop technology that will enable more efficient collaboration between carmakers and their suppliers. One of the options that can meet this demand is to adopt grid technology in the collaboration process. For the system to be successfully applied, the trust relationship among Virtual Organization (VO) members becomes a very important factor. Systems lacking in secure mechanisms require all the collaborating members to fully trust each other, and thus make their application quite limited. Based on grid technology, this paper proposes a collaborative simulation system for vehicle crash safety design, and discusses the trust relationship among VO members. The grid middleware VEGA and web services working for the collaboration also contribute to the simulation system. Also, a test bed is set up on the basis of the Local Area Network (LAN). At the end of this paper, a real case involving a carmaker and a door supplier is presented to demonstrate how the grid-based collaborative simulation system works.     

Web-based post-processing visualization system for finite element analysis

In this paper, we propose and implement a website of post-processing system for finite element analysis (WebDFEA). Finite element analysis is a computer-aided engineering tool and is popular for static/dynamic structure analysis. It includes three processing systems where post-processing system is to graphically demonstrate the analysis result of a structure model analyzed by finite element method. WebDFEA performs as a website. It is cross-platform because it can auto-detect a client computer platform and auto-download proper OpenGL API for drawing computer graphics. It can draw precise graphics on webpage which can be free controlled by the mouse as a manner in professional software. A database server is involved to store finite element model data and its analysis result. The graphic user interface (GUI) of WebDFEA is a flexible GUI comprising three parts: the switch buttons designed by HTML, the display board and the color bar both developed in Java. The three components are independent and cooperative with each other. They can be recombined without running errors for different purposes. A ship hull section with half a hatch is chosen as the study case to test WebDFEA website. Its finite element model comprises 11,442 triangle elements (shapes). The timeframe starting when WebDFEA is connected to the end when the model is demonstrated is acceptable.