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61.
Schweizer E Hoffmann-Röder A Schärer K Olsen JA Fäh C Seiler P Obst-Sander U Wagner B Kansy M Diederich F 《ChemMedChem》2006,1(6):611-621
A series of 16 tricyclic thrombin inhibitors was prepared by using the 1,3-dipolar cycloaddition of azomethine ylides derived from 3- or 4-hydroxyproline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide as the key step. The terminal pyrrolidine ring of the inhibitors was systematically substituted to explore the potential bioisosteric behavior of C-F, C-OH, and C-OMe residues pointing into the environment of the catalytic center of a serine protease. X-ray crystal structure analyses revealed a distinct puckering preference of this ring. Substitution by F, HO, and MeO has a strong effect on the basicity of the adjacent pyrrolidine nitrogen center which originates from two sigma-inductive pathways between this center and the electronegative O and F atoms. gem-Difluorination decreases the pKa value of this tertiary amine center to <2, making the conjugated ammonium ion a moderately strong acid. Unexpectedly, F substitution next to the nitrogen center reduced the lipophilicity of the ligands, as revealed by measurements of the logarithmic partition coefficient log D. The biological assays showed that all compounds are thrombin inhibitors with activities between Ki=0.08 and 2.17 microM. Bioisosteric behavior of F, HO, and MeO substituents was observed. Their electronegative F and O atoms undergo energetically similar polar interactions with positively polarized centers, such as the N atom of His 57 which is hydrogen bonded to the catalytic Ser 195. However, for energetically similar polar interactions of C-F, C-OH, and C-OMe to occur, sufficient space is necessary for the accommodation of the Me group of the C-OMe residue, and a H-bond acceptor must be present to prevent unfavorable desolvation of the C-OH residue. 相似文献
62.
D Busse FW Busch E Schweizer F Bohnenstengel M Eichelbaum P Fischer K Schumacher WE Aulitzky HK Kroemer 《Canadian Metallurgical Quarterly》1999,43(3):263-268
PURPOSE: The alkylating agent cyclophosphamide (CP) is a prodrug that is metabolized to both cytotoxic and inactive compounds. We have previously shown that following dose escalation from conventional-dose (CD) to high-dose (HD) levels; the fraction of the dose cleared by bioactivation is significantly decreased (66% versus 48.5%) in favor of inactivating elimination pathways when the HD is given as a single 1-h infusion. Based on the concept of bioactivating enzyme saturation with increasing doses, we investigated the influence of fractionated application of HD-CP on dose-dependent changes in metabolism. PATIENTS AND METHODS: Plasma concentrations of CP (measured by high-performance liquid chromatography, HPLC) and urinary concentrations of CP and its major metabolites (quantified by [31P]-nuclear magnetic resonance spectroscopy; [31P]-NMR spectroscopy), were determined in four patients with high-risk primary breast cancer who received adjuvant chemotherapy including both CD-CP (500 mg/ m2 infused over 1 h) and split HD-CP (50 mg/kg infused over 1 h on each of 2 consecutive days (d): d1 and d2. RESULTS: (Data are given as mean values for CD and d1/d2 of HD, respectively). Systemic clearance (CL) of CP was similar during CD and d1 of HD, but significantly increased on d2 of HD (CL: 83 and 78/115 ml/min; P < 0.01 for d1 versus d2). The latter was translated into an increase in formation CL of both active (+ 16.4 ml/min) and inactive metabolites (+ 17.6 ml/ min) and reflects autoinduction of metabolism. As compared with CD-CP, no statistically significant decrease was observed in the relative contribution of bioactivation CL to overall CL during both days of HD (63% versus 57%/53%). Recovery of intact CP in 24-h urine corresponded to 24%, 29%, 22% of the dose (P < 0.05 for d1 versus d2 of HD). CONCLUSIONS: Following dose escalation of CP, dividing the high dose over 2 days instead of one single infusion may favorably impact the metabolism of CP in terms of bioactivation. In addition, on day 2 of a split regimen, renal elimination of CP is decreased, which implies that more drug is available for metabolism. 相似文献
63.
Decisions about reach‐scale river rehabilitation for the purposes of flood protection and ecological enhancement require prediction of the possible consequences of management alternatives. To provide such predictions, an integrative model is necessary that represents the cause–effect relations between rehabilitation options and morphological, hydraulic and ecological consequences. This paper describes the morphological and hydraulic submodel of such an integrative model. This submodel is further subdivided into four modules predicting: (1) channel morphology, (2) flooding (dike overtopping, floodplain flooding and bed moving floods), (3) velocity and depth distribution and (4) riverbed siltation. Model relationships come from results reported in the literature and new data analyses. By using quantities that are all either readily available or easily predictable for changed conditions, the model should be widely applicable, even for data‐limited situations. The overall model is implemented as a probability network to facilitate estimation of uncertainties in model results. An application of the model to a reach of the Thur River in Switzerland demonstrates its utility for predicting morphological and hydraulic consequences of a planned river widening. The full integrative model, including ecological endpoints, will be used together with quantitative assessments of stakeholder preferences to support rehabilitation decisions for a number of Swiss rivers. Copyright © 2007 John Wiley & Sons, Ltd. 相似文献
64.
We study the classic binary search problem, with a delay between query and answer. For all constant delays, we give matching upper and lower bounds on the number of queries. 相似文献
65.
K Rickels E Schweizer F Garcia Espa?a G Case N DeMartinis D Greenblatt 《Canadian Metallurgical Quarterly》1999,141(1):1-5
Dithiocarbamate compounds are widely used agricultural fungicides that display low acute toxicity in mammals and that may become neurotoxic after prolonged exposure. Mancozeb, among other dithiocarbamates tested, proved to be the most potent (Ki= 0.27 microM) at noncompetitively inhibiting the in vitro ATP-dependent uptake of [3H]glutamate in rat cortical vesicles. Furthermore, mancozeb partially (20%) inhibited the ATP-dependent uptake of [14C]methylamine, used as an index for the vesicular transmembrane proton gradient (DeltapH), and evoked its efflux from organelles previously incubated with the 3H-labeled marker. Meanwhile, the vesicular uptake of 36chloride- anions whose concentrations regulate the transmembrane potential gradient (DeltapsiSV) was not impaired. The dithiocarbamate effects on the vesicular transport of [3H]glutamate thus appeared to involve mainly the DeltapH gradient rather than the potential gradient. Dithiocarbamate metabolites, the potent neurotoxin carbon disulfide included, did not affect the uptake process, thus implying the relevance for inhibition of the persistence, if any, of parent compounds in the brain. The present novel and potent in vitro interferences of selected dithiocarbamate pesticides with the vesicular transport of glutamate, if representative of in vivo alterations, may play some role in the probably complex origin of dithiocarbamate neurotoxicity. 相似文献
66.
We present a novel transient gain-spectra measurement method based on the traditional variable pump-stripe technique. Using the pump-stripe technique with ultra-short optical pulse excitation, time-resolved amplified spontaneous emission spectroscopy of an InGaAs-InGaAsP multiquantum-well (MQW) laser structure was measured, and time-development of the transient optical net gain spectra was obtained accordingly. By fitting the measured gain spectra with a model for band-to-band transitions including momentum conservation and an energy- and density-dependent lifetime broadening, dynamics of band filling, carrier density, carrier temperature and bandgap renormalization have been obtained. This opens the possibility to study simultaneously the influence of transient-carrier density and, in particular, transient-carrier temperature on the transient optical gain. Strong gain compression in the whole gain-spectra region due to transient high carrier temperature after ultra-short pulse injection is clearly demonstrated for the first time 相似文献
67.
Paul Schweizer 《Minds and Machines》1998,8(2):263-272
The paper examines the nature of the behavioral evidence underlying attributions of intelligence in the case of human beings, and how this might be extended to other kinds of cognitive system, in the spirit of the original Turing Test (TT). I consider Harnad's Total Turing Test (TTT), which involves successful performance of both linguistic and robotic behavior, and which is often thought to incorporate the very same range of empirical data that is available in the human case. However, I argue that the TTT is still too weak, because it only tests the capabilities of particular tokens within a preexisting context of intelligent behavior. What is needed is a test of the cognitive type, as manifested through a number of exemplary tokens, in order to confirm that the cognitive type is able to produce the context of intelligent behavior presupposed by tests such as the TT and TTT. 相似文献
68.
Dr. Karin Schweizer Dr. Manuela Paechter Prof. Dr. Bernd Weidenmann 《Journal of Computer-Mediated Communication》2001,6(2):0-0
It is clear that the Internet has the capacity to change how individuals interact with others as well as increase access to information. Whether either one of these factors affects the social landscape has yet to be determined. This fact has not kept many from anticipating the effects of the technology on society. In this paper, we contextualize some of the main issues of discussion regarding the Internet, describing these positions in terms of utopian and dystopian perspectives. By resurrecting William Ogburn's theory of the cultural lag (1964), we present a framework for understanding the extreme responses to the technology. The lag suggests that the effects of a technology will not be apparent to social actors for some time after it is introduced to a society. As such, much of the discourse concerning the Internet is ideologically charged, filled as much with the hopes and fears of individual authors as with the reality of the medium's effects. 相似文献
69.
Using NMR techniques on two single crystals of H2, we have determined the crystalline field V
c that splits the rotational ground state of isolated ortho-H2 molecules in para-H2. From the temperature-dependent splitting of the NMR doublet peak, we obtain an average % MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4baFfea0dXde9vqpa0lb9% cq0dXdb9IqFHe9FjuP0-iq0dXdbba9pe0lb9hs0dXda91qaq-xfr-x% fj-hmeGabaqaciGacaGaaeqabaWaaeaaeaaakeaacaGG8bacbaGab8% NvayaaraWaaSbaaSqaaiaa-ngaaeqaaOGaaiiFaiaac+cacaWFRbWa% aSbaaSqaaiaa-jeaaeqaaOGaeyypa0JaaGimaiaac6cacaaIWaGaaG% imaiaaiIdacaaIZaGaeyySaeRaaGimaiaac6cacaaIWaGaaGimaiaa% ikdacaqGGaGaa83saaaa!4563!\[|\bar V_c |/k_B = 0.0083 \pm 0.002{\rm{ }}K\] independent of ortho concentration X over the range between x= 0.1% and 1.5%. The experimental spectra, as a function of both T and the applied field orientation, can be fitted by a model where V
c has a Gaussian distribution about its average value with a standard deviation V
c289-03. This distribution might be caused by strains in the sample. The values of V
c are compared with those from previous experiments.Research supported by a grant from the National Science Foundation. 相似文献
70.
Schreiner R. Schweizer H. 《IEEE journal of selected topics in quantum electronics》2003,9(5):1179-1182
Laterally coupled distributed feedback lasers with self-aligned ohmic contacts show the advantage of a considerably simplified fabrication process. These lasers exhibit superior spectral properties with full benefit from the gain coupling mechanism. Side-mode suppression ratios up to 55- and 3-dB bandwidths beyond 15 GHz were obtained for these devices. 相似文献