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111.
Daniel Spinks Emma J. Shanks Laura A. T. Cleghorn Stuart McElroy Deuan Jones Daniel James Alan H. Fairlamb Julie A. Frearson Paul G. Wyatt Ian H. Gilbert 《ChemMedChem》2009,4(12):2060-2069
There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62 000 compound library against T. brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel‐compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed. 相似文献
112.
Maria Albareda-Sambola Elena Fernández Gilbert Laporte 《Computers & Operations Research》2009,36(2):597-611
This article introduces a new problem called the Capacity and Distance Constrained Plant Location Problem. It is an extension of the discrete capacitated plant location problem, where the customers assigned to each plant have to be packed in groups that will be served by one vehicle each. The constraints include two types of capacity. On the one hand plants are capacitated, and the demands of the customers are indivisible. On the other hand, the total distance traveled by each vehicle to serve its assigned customers in round trips plant–customer–plant is also limited. The paper addresses different modeling aspects of the problem. It describes a tabu search algorithm for its solution. Extensive computational tests indicate that the proposed heuristic consistently yields optimal or near-optimal solutions. 相似文献
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The primary parameters of electrophotographic papers are surface charge, and the decay of this charge under both dark and illuminated ambient conditions. The inter-relationship of these parometers is of great practical signiftcance in machine design. It is suggested that the results from conventional static methods for their measurement can be misleading. Special equipment has been constructed for the examination of electrophotographic materials under dynamic conditions. Experimental results are presented together with an indication of their value in assessing the practical performance of electrophotographic papers and their influence in machine design. 相似文献
115.
Purnima Gunness Bernadine M. Flanagan Kinnari Shelat Robert G. Gilbert Michael J. Gidley 《Food chemistry》2012
The kinetics of passage of a model bile salt and complete porcine bile across a dialysis membrane, in the presence and absence of two cereal-derived soluble dietary fibre polysaccharides, were studied as a model for passage across the unstirred water layer that lines the small intestine. A first-order kinetic analysis allowed rate coefficients to be derived which quantified the effectiveness of barley mixed linkage β-glucan and wheat arabinoxylan in retarding the transport of bile. For both, a model bile salt and complete porcine bile, rate coefficients decreased with both concentration and viscosity. A combination of viscosity and molecular interaction effects is suggested to control the effect of the two polysaccharides on the transport of bile. 相似文献
116.
Gilbert R. Hoy 《Journal of Modern Optics》2013,60(16-18):2599-2606
Abstract The purpose of this paper is to describe a method for observing stimulated emission of gamma radiation. Stimulated emission of gamma radiation has never been observed. Stimulated emission of gamma radiation will be essential for developing gamma-ray lasers. The method uses the ‘π phase-shift induced transparency’ of gamma radiation, previously called the ‘gamma echo’. The gamma-echo technique is based on a modification of the time-differential Mössbauer spectroscopic method, i.e. the source is moved ‘instantaneously’ during the lifetime of the excited state. Then a resonant absorber becomes transparent to the resonant gamma radiation. There is a type of ‘self-stimulated’ emission in which the radiation ‘absorbed’, before the phase shift, is stimulated to emit after the phase shift. To observe stimulated emission of the resonant gamma radiation, one performs the same gamma-echo experiment except the resonant absorber is replaced by another source. This secondary source is chosen to be in resonance with the original source. Under these conditions there will be no stimulated emission, in the secondary source, before the π phase shift because the incident radiation is absorbed. However, after the phase shift, the secondary source becomes transparent to the incident radiation. If one uses a matched pair of Co57 sources and the secondary source is 2mCi, there will be about 3 nuclei in the secondary source, in the first excited state of Fe57, that are available to be stimulated during the 97.8ns lifetime of the primary source radiation. 相似文献
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JA Turpin Y Song JK Inman M Huang A Wallqvist A Maynard DG Covell WG Rice E Appella 《Canadian Metallurgical Quarterly》1999,42(1):67-86
Nucleocapsid p7 protein (NCp7) zinc finger domains of the human immunodeficiency virus type 1 (HIV-1) are being developed as antiviral targets due to their key roles in viral replication and their mutationally nonpermissive nature. On the basis of our experience with symmetrical disulfide benzamides (DIBAs; Rice et al. Science 1995, 270, 1194-1197), we synthesized and evaluated variants of these dimers, including sets of 4,4'- and 3,3'-disubstituted diphenyl sulfones and their monomeric benzisothiazolone derivatives (BITA). BITAs generally exhibited diminished antiviral potency when compared to their disulfide precursors. Novel, monomeric structures were created by linking haloalkanoyl groups to the benzamide ring through -NH-C(=O)- (amide) or -S-C(=O)- (thiolester) bridges. Amide-linked compounds generally lacked antiviral activity, while haloalkanoyl thiolesters and non-halogen-bearing analogues frequently exhibited acceptable antiviral potency, thus establishing thiolester benzamides per se as a new anti-HIV chemotype. Pyridinioalkanoyl thiolesters (PATEs) exhibited superior anti-HIV-1 activity with minimal cellular toxicity and appreciable water solubility. PATEs were shown to preferentially target the NCp7 Zn finger when tested against other molecular targets, thus identifying thiolester benzamides, and PATEs in particular, as novel NCp7 Zn finger inhibitors for in vivo studies. 相似文献