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991.
The discovery of potent, selective, and orally bioavailable hNK1 antagonists derived from pyrrolidine 总被引:2,自引:0,他引:2
Lin P Chang L Devita RJ Young JR Eid R Tong X Zheng S Ball RG Tsou NN Chicchi GG Kurtz MM Tsao KL Wheeldon A Carlson EJ Eng W Burns HD Hargreaves RJ Mills SG 《Bioorganic & medicinal chemistry letters》2007,17(18):5191-5198
SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml. 相似文献
992.
The connectivity among marine populations is determined by the dispersal capabilities of adults as well as their eggs and larvae. Dispersal distances and directions have a profound effect on gene flow and genetic differentiation within species. Genetic homogeneity over large areas is a common feature of coral reef fishes and can reflect high dispersal capability resulting in high levels of gene flow. If fish larvae return to their parental reef, gene flow would be restricted and genetic differentiation could occur. Larabicus quadrilineatus (Labridae) is considered as an endemic fish species of the Red Sea and Gulf of Aden. The juveniles of this species are cleaner fish that feed on ectoparasites of other fishes. Here, we investigated the genetic population structure and gene flow in L. quadrilineatus among five locations in the Red Sea to infer connectivity among them. To estimate genetic diversity, we analysed 369 bp of 237 mitochondrial DNA control region sequences. Haplotype and nucleotide diversities were higher in the southern than in the northern Red Sea. Analysis of molecular variance (amova) detected the highest significant genetic variation between northern and central/southern populations (Phi(CT) = 0.01; P < 0.001). Migration analysis revealed a several fold higher northward than southward migration, which could be explained by oceanographic conditions and spawning season. Even though the Phi(ST) value of 0.01 is rather low and implies a long larval dispersal distance, estimates based on the isolation-by-distance model show a very low mean larval dispersal distance (0.44-5.1 km) compared to other studies. In order to enable a sustainable ornamental fishery on the fourline wrasse, the results of this study suggest that populations in the northern and southern Red Sea should be managed separately as two different stocks. The rather low larval dispersal distance of about 5 km needs to be considered in the design of marine protected areas to enable connectivity and self-seeding. 相似文献
993.
Palmer AM Grobbel B Brehm C Zimmermann PJ Buhr W Feth MP Holst HC Simon WA 《Bioorganic & medicinal chemistry》2007,15(24):7647-7660
A series of novel tetrahydroimidazo[2,1-a]isoquinolines was prepared based on a hetero Diels–Alder reaction between an enamine and 1,2,4-triazine as key step. A structure–activity relationship was established focussing on the influence of the substitution pattern in position 3 and 6 of the heterocycle on antisecretory activity, lipophilicity, and pKa value. Potent inhibitors of the gastric acid pump were identified. 相似文献
994.
Ottmann C Marco S Jaspert N Marcon C Schauer N Weyand M Vandermeeren C Duby G Boutry M Wittinghofer A Rigaud JL Oecking C 《Molecular cell》2007,25(3):427-440
Regulatory 14-3-3 proteins activate the plant plasma membrane H(+)-ATPase by binding to its C-terminal autoinhibitory domain. This interaction requires phosphorylation of a C-terminal, mode III, recognition motif as well as an adjacent span of approximately 50 amino acids. Here we report the X-ray crystal structure of 14-3-3 in complex with the entire binding motif, revealing a previously unidentified mode of interaction. A 14-3-3 dimer simultaneously binds two H(+)-ATPase peptides, each of which forms a loop within the typical 14-3-3 binding groove and therefore exits from the center of the dimer. Several H(+)-ATPase mutants support this structure determination. Accordingly, 14-3-3 binding could result in H(+)-ATPase oligomerization. Indeed, by using single-particle electron cryomicroscopy, the 3D reconstruction of the purified H(+)-ATPase/14-3-3 complex demonstrates a hexameric arrangement. Fitting of 14-3-3 and H(+)-ATPase atomic structures into the 3D reconstruction map suggests the spatial arrangement of the holocomplex. 相似文献
995.
CD16 promotes Escherichia coli sepsis through an FcR gamma inhibitory pathway that prevents phagocytosis and facilitates inflammation 总被引:3,自引:0,他引:3
Pinheiro da Silva F Aloulou M Skurnik D Benhamou M Andremont A Velasco IT Chiamolera M Verbeek JS Launay P Monteiro RC 《Nature medicine》2007,13(11):1368-1374
Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here we show that the FcRgamma adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRgamma(-/-) mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The FcRgamma-associated receptor that inhibits E. coli phagocytosis is FcgammaRIII (also called CD16), and its absence protects mice from sepsis. FcgammaRIII binds E. coli, and this interaction induces FcRgamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-alpha production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRgamma on macrophages as the class A scavenger receptor MARCO. E. coli-FcgammaRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcgammaRIII, E. coli triggers an inhibitory FcRgamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-alpha secretion. 相似文献
996.
One of the proposed functions of human smiling is to advertise cooperative dispositions and thereby increase the likelihood that a social partner would invest resources in a relationship. In particular, smiles involving an emotional component would be honest signals of altruistic dispositions because they are not easy to produce voluntarily. In this study, 60 people were covertly filmed while interacting with a friend in two conditions: control and sharing. Smiles were classified into Duchenne (spontaneous) and non-Duchenne smiles. Participants also completed a series of questionnaires, including the Altruism Scale and a self-report questionnaire of emotional state. Interestingly, Duchenne smiles were displayed at higher rates in the sharing situation as opposed to the control situation, whereas non-Duchenne smiles were unaffected by the type of interaction. Furthermore, Duchenne smiles in the sharing interaction were positively affected by a measure of altruism. Self-reported emotional states did not vary between conditions and were poorly related to smiling. This study shows that the Duchenne smile is relevant to situations that involve the sharing of material resources because it would reliably advertise altruistic intentions. The Duchenne smile could therefore be an important signal in the formation and maintenance of cooperative relationships. 相似文献
997.
Orchard S Salwinski L Kerrien S Montecchi-Palazzi L Oesterheld M Stümpflen V Ceol A Chatr-aryamontri A Armstrong J Woollard P Salama JJ Moore S Wojcik J Bader GD Vidal M Cusick ME Gerstein M Gavin AC Superti-Furga G Greenblatt J Bader J Uetz P Tyers M Legrain P Fields S Mulder N Gilson M Niepmann M Burgoon L De Las Rivas J Prieto C Perreau VM Hogue C Mewes HW Apweiler R Xenarios I Eisenberg D Cesareni G Hermjakob H 《Nature biotechnology》2007,25(8):894-898
A wealth of molecular interaction data is available in the literature, ranging from large-scale datasets to a single interaction confirmed by several different techniques. These data are all too often reported either as free text or in tables of variable format, and are often missing key pieces of information essential for a full understanding of the experiment. Here we propose MIMIx, the minimum information required for reporting a molecular interaction experiment. Adherence to these reporting guidelines will result in publications of increased clarity and usefulness to the scientific community and will support the rapid, systematic capture of molecular interaction data in public databases, thereby improving access to valuable interaction data. 相似文献
998.
Chen J Lake MR Sabet RS Niforatos W Pratt SD Cassar SC Xu J Gopalakrishnan S Pereda-Lopez A Gopalakrishnan M Holzman TF Moreland RB Walter KA Faltynek CR Warrior U Scott VE 《Journal of biomolecular screening》2007,12(1):61-69
Despite increasing use of cell-based assays in high-throughput screening (HTS) and lead optimization, one challenge is the adequate supply of high-quality cells expressing the target of interest. To this end, cell lines stably expressing targets are often established, maintained, and scaled up by cell culture. These steps require large investments of time and resources. Moreover, significant variability invariably occurs in cell yield, viability, expression levels, and target activities. In particular, stable expression of targets such as transient receptor potential A1 (TRPA1) causes toxicity, cell line degeneration, and loss of functional activity. Therefore, in an effort to identify TRPA1 antagonists, the authors used large-scale transiently transfected (LSTT) cells, enabling rapid establishment of assays suitable for HTS. LSTT cells, which could- be stored frozen for a long period of time (e.g., at least 42 weeks), retained TRPA1 protein expression and could be easily revived to produce robust and consistent signals in calcium influx and electrophysiological assays. Using cells from a single transfection, a chemical library of 700,000 compounds was screened, and TRPA1 antagonists were identified. The use of LSTT circumvented issues associated with stable TRPA1 expression, increased flexibility and consistency, and greatly reduced labor and cost. This approach will also be applicable to other pharmaceutical targets. 相似文献
999.
Jacobs M Togbe D Fremond C Samarina A Allie N Botha T Carlos D Parida SK Grivennikov S Nedospasov S Monteiro A Le Bert M Quesniaux V Ryffel B 《Microbes and infection / Institut Pasteur》2007,9(5):623-628
Tumor necrosis factor (TNF) is critical and non-redundant to control Mycobacterium tuberculosis infection and cannot be replaced by other proinflammatory cytokines. Overproduction of TNF may cause immunopathology, while TNF neutralization reactivates latent and chronic, controlled infection, which is relevant for the use of neutralizing TNF therapies in patients with rheumatoid arthritis. 相似文献
1000.