Priorities and standards in pharmacogenetic research

The current enthusiasm for pharmacogenetics draws much of its inspiration from the relatively few examples of polymorphisms that have marked and seemingly clinically relevant effects on drug response. In this regard, pharmacogenetic research has paralleled the study of human disease, which has enjoyed success in identifying mutations underlying mendelian conditions. Progress in deciphering the genetics of complex diseases, involving the interaction of multiple genes with each other and with the environment has been considerably less successful. In most instances, drug responses will probably also prove to be complex, influenced by both the environment and multiple genetic factors. For pharmacogenetics to deliver on its potential, this complexity will need to be recognized and accommodated, both in basic research and in clinical application of pharmacogenetics. As the attention of researchers begins to shift toward more systematic pharmacogenetic investigations, we suggest some priorities and standards for pharmacogenetic research.     

The N-terminal groups of glutamic aspartic transaminase

Riassunto Su una preparazione altamente purificata di glutammico aspartico transaminasi del cuore di porco sono stati determinati i gruppi N-terminali con il metodo diSanger. È stata dimostrata la presenza di una mole di alanina N-terminale per 58 000 g di proteina, cioè per una mole di coenzima. La transaminasi risulterebbe pertanto costituita da due catene polipeptidiche.     

Synthetic homeostatic materials with chemo-mechano-chemical self-regulation

Living organisms have unique homeostatic abilities, maintaining tight control of their local environment through interconversions of chemical and mechanical energy and self-regulating feedback loops organized hierarchically across many length scales. In contrast, most synthetic materials are incapable of continuous self-monitoring and self-regulating behaviour owing to their limited single-directional chemomechanical or mechanochemical modes. Applying the concept of homeostasis to the design of autonomous materials would have substantial impacts in areas ranging from medical implants that help stabilize bodily functions to 'smart' materials that regulate energy usage. Here we present a versatile strategy for creating self-regulating, self-powered, homeostatic materials capable of precisely tailored chemo-mechano-chemical feedback loops on the nano- or microscale. We design a bilayer system with hydrogel-supported, catalyst-bearing microstructures, which are separated from a reactant-containing 'nutrient' layer. Reconfiguration of the gel in response to a stimulus induces the reversible actuation of the microstructures into and out of the nutrient layer, and serves as a highly precise 'on/off' switch for chemical reactions. We apply this design to trigger organic, inorganic and biochemical reactions that undergo reversible, repeatable cycles synchronized with the motion of the microstructures and the driving external chemical stimulus. By exploiting a continuous feedback loop between various exothermic catalytic reactions in the nutrient layer and the mechanical action of the temperature-responsive gel, we then create exemplary autonomous, self-sustained homeostatic systems that maintain a user-defined parameter--temperature--in a narrow range. The experimental results are validated using computational modelling that qualitatively captures the essential features of the self-regulating behaviour and provides additional criteria for the optimization of the homeostatic function, subsequently confirmed experimentally. This design is highly customizable owing to the broad choice of chemistries, tunable mechanics and its physical simplicity, and may lead to a variety of applications in autonomous systems with chemo-mechano-chemical transduction at their core.     

RNA translocation and unwinding mechanism of HCV NS3 helicase and its coordination by ATP

Helicases are a ubiquitous class of enzymes involved in nearly all aspects of DNA and RNA metabolism. Despite recent progress in understanding their mechanism of action, limited resolution has left inaccessible the detailed mechanisms by which these enzymes couple the rearrangement of nucleic acid structures to the binding and hydrolysis of ATP. Observing individual mechanistic cycles of these motor proteins is central to understanding their cellular functions. Here we follow in real time, at a resolution of two base pairs and 20 ms, the RNA translocation and unwinding cycles of a hepatitis C virus helicase (NS3) monomer. NS3 is a representative superfamily-2 helicase essential for viral replication, and therefore a potentially important drug target. We show that the cyclic movement of NS3 is coordinated by ATP in discrete steps of 11 +/- 3 base pairs, and that actual unwinding occurs in rapid smaller substeps of 3.6 +/- 1.3 base pairs, also triggered by ATP binding, indicating that NS3 might move like an inchworm. This ATP-coupling mechanism is likely to be applicable to other non-hexameric helicases involved in many essential cellular functions. The assay developed here should be useful in investigating a broad range of nucleic acid translocation motors.     

Magma-maintained rift segmentation at continental rupture in the 2005 Afar dyking episode

Seafloor spreading centres show a regular along-axis segmentation thought to be produced by a segmented magma supply in the passively upwelling mantle. On the other hand, continental rifts are segmented by large offset normal faults, and many lack magmatism. It is unclear how, when and where the ubiquitous segmented melt zones are emplaced during the continental rupture process. Between 14 September and 4 October 2005, 163 earthquakes (magnitudes greater than 3.9) and a volcanic eruption occurred within the approximately 60-km-long Dabbahu magmatic segment of the Afar rift, a nascent seafloor spreading centre in stretched continental lithosphere. Here we present a three-dimensional deformation field for the Dabbahu rifting episode derived from satellite radar data, which shows that the entire segment ruptured, making it the largest to have occurred on land in the era of satellite geodesy. Simple elastic modelling shows that the magmatic segment opened by up to 8 m, yet seismic rupture can account for only 8 per cent of the observed deformation. Magma was injected along a dyke between depths of 2 and 9 km, corresponding to a total intrusion volume of approximately 2.5 km3. Much of the magma appears to have originated from shallow chambers beneath Dabbahu and Gabho volcanoes at the northern end of the segment, where an explosive fissural eruption occurred on 26 September 2005. Although comparable in magnitude to the ten year (1975-84) Krafla events in Iceland, seismic data suggest that most of the Dabbahu dyke intrusion occurred in less than a week. Thus, magma intrusion via dyking, rather than segmented normal faulting, maintains and probably initiated the along-axis segmentation along this sector of the Nubia-Arabia plate boundary.     

基于收益管理的班轮联盟舱位互换与分配优化

运用收益管理原理方法,研究了联盟条件下班轮公司舱位互换与分配问题,构建了综合考虑班轮联盟多条航线、不同种类和不同尺寸的集装箱等因素的舱位互换与分配随机优化共赢模型,运用机会约束方法加以求解,算例分析验证了模型和算法的适用性和有效性,结果表明舱位互换与分配优化可以明显地提高班轮联盟的总收益,联盟内舱位互换与分配数量及其总收益与合同客户需求量呈负相关、与现货市场需求量呈正相关,从而可为班轮公司制定舱位互换与分配策略提供科学的决策参考.