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991.
992.
Walsh SP Severino A Zhou C He J Liang GB Tan CP Cao J Eiermann GJ Xu L Salituro G Howard AD Mills SG Yang L 《Bioorganic & medicinal chemistry letters》2011,21(11):3390-3394
The design, synthesis, and structure-activity relationship (SAR) for a series of β-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined for several compounds. Finally, further profiling of compound 7 is presented, including demonstration of enhanced glucose tolerance in an in vivo mouse model. 相似文献
993.
Sander P Hamann H Drögemüller C Kashkevich K Schiebel K Leeb T 《The Journal of biological chemistry》2005,280(45):37408-37414
994.
In order to assess the impact of seasonality versus connectivity on the ecological quality of the Lower Rhine river-floodplain habitats, we studied the seasonal variation in diversity and species assemblages of caddis larvae by monthly sampling of the littoral zone of four water bodies over a lateral connectivity gradient. Seasonal variation in diversity showed a general pattern in these floodplain habitats and could be related to caddisfly life history and habitat preferences. Despite this seasonal variation, caddis larvae species assemblages in the water bodies appeared to be rather stable and could be firmly related to the position of their habitats over the connectivity gradient. The main channel (lotic habitat) was clearly separated from the lentic water bodies, and also the sparsely vegetated water bodies from the well-vegetated water bodies. It is concluded that the impact of connectivity, and related parameters such as stream velocity and vegetation coverage, outweighed the impact of season on the caddis larvae assemblages. 相似文献
995.
996.
Holger Kubas Udo Meyer Mirko Hechenberger Kai-Uwe Klein Patrick Plitt Ronalds Zemribo Harm W. Spexgoor Sander G.A. van Assema Ulrich Abel 《Bioorganic & medicinal chemistry letters》2013,23(23):6370-6376
The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and l-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis’ AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development. 相似文献
997.
Sander G. Basten Erica E. Davis Ad J. M. Gillis Ellen van Rooijen Hans Stoop Nikolina Babala Ive Logister Zachary G. Heath Trudy N. Jonges Nicholas Katsanis Emile E. Voest Freek J. van Eeden Rene H. Medema René F. Ketting Stefan Schulte-Merker Leendert H. J. Looijenga Rachel H. Giles 《PLoS genetics》2013,9(4)
Seminoma is a subclass of human testicular germ cell tumors (TGCT), the most frequently observed cancer in young men with a rising incidence. Here we describe the identification of a novel gene predisposing specifically to seminoma formation in a vertebrate model organism. Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1), associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas. Genotyping of these zebrafish tumors shows loss of heterozygosity (LOH) of the wild-type lrrc50 allele in 44.4% of tumor samples, correlating with tumor progression. In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas. Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation. Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort). Together, our study introduces an animal model for seminoma and suggests LRRC50 to be a novel tumor suppressor implicated in human seminoma pathogenesis. 相似文献
998.
999.
Impairment of sustained attention is assumed to be a core cognitive abnormality in schizophrenia. However, this seems inconsistent with a recent hypothesis that in schizophrenia the implementation of selection (i.e., sustained attention) is intact but the control of selection (i.e., switching the focus of attention) is impaired. Mounting evidence supports this hypothesis, indicating that switching of attention is a bigger problem in schizophrenia than maintaining the focus of attention. To shed more light on this hypothesis, we tested whether schizophrenia patients are impaired relative to controls in sustaining attention, switching attention, or both. Fifteen patients with recent-onset schizophrenia and fifteen healthy volunteers, matched on age and intelligence, performed sustained attention and attention switching tasks, while performance and brain potential measures of selective attention were recorded. In the sustained attention task, patients did not differ from the controls on these measures. In the attention switching task, however, patients showed worse performance than the controls, and early selective attention related brain potentials were absent in the patients while clearly present in the controls. These findings support the hypothesis that schizophrenia is associated with an impairment of the mechanisms that control the direction of attention (attention switching), while the mechanisms that implement a direction of attention (sustained attention) are intact. 相似文献
1000.
Na+/H+ antiporters are pH-dependent membrane transport proteins that maintain the homeostasis of H+ and Na+ in living cells. MjNhaP1 from Methanococcus jannaschii, a hyperthermophilic archaeon that grows optimally at 85 degrees C, was cloned and expressed in Escherichia coli. Two-dimensional crystals were obtained from purified protein at pH 4. Electron cryomicroscopy yielded an 8 A projection map. Like the related E. coli antiporter NhaA, MjNhaP1 is a dimer, but otherwise the structures of the two antiporters differ significantly. The map of MjNhaP1 shows elongated densities in the centre of the dimer and a cluster of density peaks on either side of the dimer core, indicative of a bundle of 4-6 membrane-spanning helices. The effect of pH on the structure of MjNhaP1 was studied in situ. A major change in density distribution within the helix bundle, and an approximately 2 A shift in the position of the helix bundle relative to the dimer core occurred at pH 6 and above. The two conformations at low and high pH most likely represent the closed and open states of the antiporter. 相似文献