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排序方式: 共有3813条查询结果,搜索用时 31 毫秒
1.
Steffen Vojacek Lukas Schulig Nathalie Wössner Norman Geist Prof. Dr. Walter Langel Prof. Dr. Manfred Jung Prof. Dr. Dennis Schade Prof. Dr. Andreas Link 《ChemMedChem》2019,14(8):853-864
Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp3 hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC50 value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling. 相似文献
2.
Yachao Dong Christos T. Maravelias Norman F. Jerome 《Optimization and Engineering》2018,19(4):937-976
We study a maritime inventory routing problem, in which shipments between production and consumption nodes are carried out by a fleet of vessels. The vessels have specific capacities and can be chartered under different agreements. The inventory levels of all consumption nodes and some production nodes should be maintained within specified bounds; for the remaining production nodes, orders should be picked up within pre-defined time windows. We propose a discrete-time mixed-integer programming model. In the face of new information and uncertainty, this optimization model has to be re-solved, as the horizon is rolled forward. We discuss how to account for different sources of uncertainty. We present a rolling-horizon reoptimization framework that allows us to study different policies that impact the quality of the implemented solution, so we can identify the optimal set of policies. 相似文献
3.
Neil P. Soice Adrian C. Maladono Doreen Y. Takigawa Arlan D. Norman William B. Krantz Alan R. Greenberg 《应用聚合物科学杂志》2003,90(5):1173-1184
Selected aromatic amides were used to model the chemical reactivity of aromatic polyamides found in thin‐film composite reverse osmosis (RO) membranes. Chlorination and possible amide bond cleavage of aromatic amides upon exposure to aqueous chlorine, which can lead to membrane failure, were investigated. Correlations are made of the available chlorine concentration, pH, and exposure time with chemical changes in the model compounds. From the observed reactivity trends, insights are obtained into the mechanism of RO membrane performance loss upon chlorine exposure. Two chemical pathways for degradation are shown, one at constant pH and another that is pH‐history dependent. An alternative strategy is presented for the design of chlorine‐resistant RO membranes, and an initial performance study of RO membranes incorporating this strategy is reported. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 1173–1184, 2003 相似文献
4.
5.
Myers Nicholas D.; Payment Craig A.; Feltz Deborah L. 《Canadian Metallurgical Quarterly》2004,8(3):182
This study examined reciprocal relationships between collective efficacy and team performance over a season of competition in women's intercollegiate ice hockey within weekends where the opponent was constant for 2 games. Collective efficacy beliefs within 12 teams were assessed prior to both games for at least 7 weekends. Team performance indexes produced an overall measure of performance for each game. The average influence of Saturday collective efficacy on Saturday performance was moderate and positive after controlling for Friday performance. The average influence of Friday performance on Saturday collective efficacy was small and positive after removing the influence of Friday collective efficacy from Friday performance. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
6.
Albrecht Jason E.; O'Brien Edward J.; Mason Robert A.; Myers Jerome L. 《Canadian Metallurgical Quarterly》1995,21(2):364
An implicit assumption of several causal reasoning models is that readers adopt the goals of a narrative's protagonist during text comprehension. In apparent violation of this assumption, readers participating in Experiment 1 of the present study drew inferences relevant to a protagonist's goal even when that goal was already satisfied from the perspective of the protagonist. In Experiments 2 and 3, participants were explicitly asked to view the text situation from the point of view of the protagonist. In this case, the goals of the reader and the protagonist should be the same. In these experiments, participants focused on the goals of the protagonist only when those goals had not been satisfied from the perspective of the protagonist. These results are discussed in terms of reader- and character-based perspectives and in terms of text characteristics that cue perspective taking. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
7.
This paper reviews the current state of industry with regard to the introduction of software metrics. It discusses the benefits that organizations have derived from metrication, it looks at why organizations have sought to introduce metrics programmes, how they have gone about introducing those programmes and the problems that they have encountered during implementation. The review found that, on the whole, only the sanitized aspects of metrics experiences have actually been published. This seems to be especially the case with respect to practitioner resistance. Very few organizations admit to having encountered resistance during the introduction of a metrics programme. The paper also includes the results of a pilot study, conducted by the first author, which examines the attitudes that developers hold towards the introduction of software metrics. The key findings of this pilot study are that positive attitudes to metrics correlate highly with levels of education and to job satisfaction. 相似文献
8.
JE Myers T Mieczkowski J Perel D Abbondanza TB Cooper JJ Mann 《Canadian Metallurgical Quarterly》1994,35(2):112-120
Serotonergic responsivity was assessed in 20 psychiatric patients by the prolactin response to a fenfluramine challenge test. During the fenfluramine challenge 6 of 20 patients (30%) spontaneously reported psychopathologic reactions that included: increased anxiety/agitation, psychotic symptoms, illusions, mood elevation, and anergia. The time of peak behavioral symptoms (2.5 +/- 0.8 hrs) corresponded closely to the time of peak increase in prolactin levels (3.0 +/- 1.1 hr). Abnormal behavioral responders had statistically significant greater increases in prolactin 1 to 4 hr after fenfluramine when compared to normal responders. Patients who developed an abnormal psychopathologic response to fenfluramine were characterized by higher levels of anxiety and agitation at the time of admission to the hospital but otherwise were not distinguishable on the basis of severity of other psychiatric symptoms. This study suggests that increased serotonergic transmission may trigger anxiety, psychosis, and mood elevation in specific vulnerable individuals, whereas other patients with similar psychiatric illnesses are not affected. 相似文献
9.
AM De Mattos MA Head J Everett J Hosenpud R Hershberger A Cobanoglu G Ott R Ratkovec DJ Norman 《Canadian Metallurgical Quarterly》1994,57(4):626-630
To determine if cardiac allograft outcome is improved among patients with fewer HLA-DR mismatches with their donors, we studied 132 recipients of a primary cardiac allograft who were transplanted between December 1985 and December 1991. These recipients and their donors all had high-confidence-level serological HLA-DR typing, previously shown to correlate highly with DNA DR typing. Patients were divided in two groups based on the HLA-DR mismatch with their donors. Group I consisted of 78 patients with 1 or zero DR mismatch and group II of 54 patients with 2 DR mismatches. Allograft outcome measurements included incidence of moderate rejection, incidence of allograft vasculopathy at 12 months, cardiac function measured as left ventricular ejection fraction (LVEF) and cardiac index (CI), and actuarial graft survival up to 7 years. Groups I and group II were not different with regard to recipient age, donor age, ischemia time, pulmonary vascular resistance, sex, or PRA greater than 0%. Group II had a higher incidence of moderate rejection on the first-week biopsy (47% vs. 25%, P = 0.019), and during the first month (84% vs. 58%, P = 0.006), but no difference was found in frequency of rejection from months 2 to 12. LVEF was not different in the groups at any point. CI was better in group I at 12 months (2.76 vs. 2.5, P = 0.03). No statistically significant difference was found in incidence of allograft vasculopathy (17% vs. 26%, P = 0.204). Actual graft survival at 1 year was better for group I (91% vs. 74%, P = 0.008), and actuarial graft survival at 6 years also favored group I (76% vs. 56%, P = 0.04). Using high-confidence-level serological HLA-DR typing assignments we demonstrated that HLA-DR mismatching correlates highly with cardiac allograft outcome. Implications are that heart transplant survival could be improved if prospective matching were feasible and prioritized or if immunosuppression were tailored to the HLA-DR match. 相似文献
10.
Myers Jerome L.; O'Brien Edward J.; Albrecht Jason E.; Mason Robert A. 《Canadian Metallurgical Quarterly》1994,20(4):876
Previous research demonstrated a contradiction effect: Although text currently being processed was locally coherent, readers were aware of inconsistencies between a protagonist's actions and characteristics of the protagonists that were described earlier in the text and subsequently backgrounded. In the present experiments, not only the critical characteristics but also the protagonist were backgrounded. When the protagonist was reintroduced into the narrative in the context of carrying out an inconsistent action, the contradiction effect again occurred. In Exps 1–3, we examined the effects of several variables on the onset of the effect. In Exp 4, we presented probes at various points in the passage with results that supported the conclusion that the critical characteristics had been backgrounded before the sentence that contradicted them. Results are discussed in terms of several recent models in which currently active representational elements serve as retrieval cues for other inactive, but highly related, elements. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献