Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance

The discovery of human immunodeficiency virus (HIV) protease inhibitors (PIs) and their utilization in highly active antiretroviral therapy (HAART) have been a major turning point in the management of HIV/acquired immune-deficiency syndrome (AIDS). However, despite the successes in disease management and the decrease of HIV/AIDS-related mortality, several drawbacks continue to hamper first-generation protease inhibitor therapies. The rapid emergence of drug resistance has become the most urgent concern because it renders current treatments ineffective and therefore compels the scientific community to continue efforts in the design of inhibitors that can efficiently combat drug resistance. The present line of research focuses on the presumption that an inhibitor that can maximize interactions in the HIV-1 protease active site, particularly with the enzyme backbone atoms, will likely retain these interactions with mutant enzymes. Our structure-based design of HIV PIs specifically targeting the protein backbone has led to exceedingly potent inhibitors with superb resistance profiles. We initially introduced new structural templates, particulary nonpeptidic conformationally constrained P 2 ligands that would efficiently mimic peptide binding in the S 2 subsite of the protease and provide enhanced bioavailability to the inhibitor. Cyclic ether derived ligands appeared as privileged structural features and allowed us to obtain a series of potent PIs. Following our structure-based design approach, we developed a high-affinity 3( R),3a( R),6a( R)-bis-tetrahydrofuranylurethane (bis-THF) ligand that maximizes hydrogen bonding and hyrophobic interactions in the protease S 2 subsite. Combination of this ligand with a range of different isosteres led to a series of exceedingly potent inhibitors. Darunavir, initially TMC-114, which combines the bis-THF ligand with a sulfonamide isostere, directly resulted from this line of research. This inhibitor displayed unprecedented enzyme inhibitory potency ( K i = 16 pM) and antiviral activity (IC 90 = 4.1 nM). Most importantly, it consistently retained is potency against highly drug-resistant HIV strains. Darunavir's IC 50 remained in the low nanomolar range against highly mutated HIV strains that displayed resistance to most available PIs. Our detailed crystal structure analyses of darunavir-bound protease complexes clearly demonstrated extensive hydrogen bonding between the inhibitor and the protease backbone. Most strikingly, these analyses provided ample evidence of the unique contribution of the bis-THF as a P 2-ligand. With numerous hydrogen bonds, bis-THF was shown to closely and tightly bind to the backbone atoms of the S 2 subsite of the protease. Such tight interactions were consistently observed with mutant proteases and might therefore account for the unusually high resistance profile of darunavir. Optimization attempts of the backbone binding in other subsites of the enzyme, through rational modifications of the isostere or tailor made P 2 ligands, led to equally impressive inhibitors with excellent resistance profiles. The concept of targeting the protein backbone in current structure-based drug design may offer a reliable strategy for combating drug resistance.     

螺旋分级机和旋流器分级费用的比较

本文对在矿物处理过程中使用最普遍的分级设备－水力旋流器和螺旋分级机的应用与费用进行了比较。虽然螺旋分级机在采矿工业中已经应用了数十年，但由于旋流器的发展，分级机已经失去了它的重要地位。然而，这种趋势正在被扭转回来，近几年，人们对螺旋分级机的兴趣日益增长，原因是螺旋分级机比旋流器更有优势。诸如：能获得含固体浓度更高的物料；分路少；生产成本低。本文探讨了这些设备的安装，使用和维修等方面的费用，对有关费     

Real-time and full-field detection of near-wall salinity using surface plasmon resonance reflectance

An idea of real-time and full-field detection of near-wall salinity is presented to use the surface plasmon resonance (SPR) reflectance that changes with refractive index variations of the tested saline fluid. The laboratory-designed SPR system, based on the Kretschmann's configuration, uses a 47.5 nm thick gold layer as the SPR resonator, coated on a BK7 prism (n=1.515), and requires a one-time system calibration to establish a correlation of the specified saline mass concentration levels to the corresponding CCD (charge-coupled device) pixel gray levels. As a gravity-falling saline drop in water reaches the bottom and diffuses thereafter, the SPR system quantitatively maps the evolution of the salinity distributions in the near-wall region (less than 1 microm). An elaborate uncertainty analysis shows that the overall measurement uncertainties critically depend on the uniformity of the metal film thickness and the accuracy of its dielectric constant.     

Thermo-optical parameters and dispersion of pure and Yb(3+)-doped KY(WO4)2 laser crystals

Dispersion of the principal refractive indices of pure and Yb(3+) (20 at.%)-doped KY(WO(4))(2) crystal is obtained in the visible range of the spectrum. A comparatively strong increase of the refractive indices (0.005-0.007) was observed for the doped crystal. Temperature dependence of the principal refractive indices is measured in the temperature region of 290-690 K. Thermo-optical coefficients (TOCs) of the first dn/dt and the second (1/2)(d(2)n/dT(2)) order are determined. It is found that TOCs are negative for n(p) and n(g) and positive for n(m) in both crystals. Doping increases dn(p)/dT almost two times more in comparison to that of the pure crystal, while for the other two indices TOC changes are insignificant.     

Identification of inhibitors of the Leishmania cdc2-related protein kinase CRK3

New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of ~3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3-CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2.     

Development of a dynamic model for estimating the food web transfer of chemicals in small aquatic ecosystems

A dynamic combined fate and food web model was developed to estimate the food web transfer of chemicals in small aquatic ecosystems (i.e. ponds). A novel feature of the modeling approach is that aquatic macrophytes (submerged aquatic vegetation) were included in the fate model and were also a food item in the food web model. The paper aims to investigate whether macrophytes are effective at mitigating chemical exposure and to compare the modeling approach developed here with previous modeling approaches recommended in the European Union (EU) guideline for risk assessment of pesticides. The model was used to estimate bioaccumulation of three hypothetical chemicals of varying hydrophobicity in a pond food web comprising 11 species. Three different macrophyte biomass densities were simulated in the model experiments to determine the influence of macrophytes on fate and bioaccumulation. Macrophytes were shown to have a significant effect on the fate and food web transfer of highly hydrophobic compounds with log K_OW > = 5. Modeled peak concentrations in biota were highest for the scenarios with the lowest macrophyte biomass density. The distribution and food web transfer of the hypothetical compound with the lowest hydrophobicity (log K_OW = 3) was not affected by the inclusion of aquatic macrophytes in the pond environment. For the three different hypothetical chemicals and at all macrophyte biomass densities, the maximum predicted concentrations in the top predator in the food web model were at least one order of magnitude lower than the values estimated using methods suggested in EU guidelines. The EU guideline thus provides a highly conservative estimate of risk. In our opinion, and subject to further model evaluation, a realistic assessment of dynamic food web transfer and risk can be obtained using the model presented here.     

Dispersal and attenuation of trace contaminants downstream of the Ajka bauxite residue (red mud) depository failure, Hungary

This paper identifies the spatial extent of bauxite processing residue (red mud)-derived contaminants and modes of transport within the Marcal and Ra?ba river systems after the dike failure at Ajka, western Hungary. The geochemical signature of the red mud is apparent throughout the 3076 km2 Marcal system principally with elevated Al, V, As, and Mo. Elevated concentrations of Cr, Ga, and Ni are also observed within 2 km of the source areas in aqueous and particulate phases where hyperalkalinity (pH < 13.1) is apparent. Although the concentrations of some trace elements exceed aquatic life standards in waters (e.g., V, As) and fluvial sediments (As, Cr, Ni, V), the spatial extent of these is limited to the Torna Creek and part of the upper Marcal. Source samples show a bimodal particle size distribution (peaks at 0.7 and 1.3 μm) which lends the material to ready fluvial transport. Where elevated concentrations are found in fluvial sediments, sequential extraction suggests the bulk of the As, Cr, Ni, and V are associated with residual (aqua-regia/HF digest) phases and unlikely to be mobile in the environment. However, at some depositional hotspots, association of As, Cr, and V with weak acid-extractable phases is observed.     

惠普将推“革命性”操作系统:Linux++

正据Technology Review报道,日前惠普宣布将于明年在一款新奇的计算机上发布一款"革命性"系统,这有望重振它的计算机业务并撼动整个行业。该公司的研究部门正在打造一款名为The Machine的计算机,它将比现在市面上的计算机更加节能省电,同时拥有更强的性能。惠普计划用一种新型的计算机内存来代替当前计算机上使用的两种类型内存。当前的内存读取方式起源于上世纪40年代,由于数据需要在两种类型的内存之间来回穿梭,因此限制了计算机的性能。"这种计算方式从一开始就已经反映出问题,它阻碍了我们的发展。"The     

以众包+O2O的方式筑就快递行业的未来之路

不能确定这些互联网尝试能否“重构”或者“超越”现有的业务形态，但有一点可以肯定的是，互联网一定会大幅度地促进快递行业的效率提升，深刻地改变快递服务的形式     

元心实为芬兰货“国产”自主操作系统又被打脸

自主芯片也好，自主操作系统也好，都离不开市场。只有尊重市场需求，一步步脚踏实地，慢慢积累，自主核心技术才会水到渠成