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991.
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
992.
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
993.
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
994.
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
995.
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
996.
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
997.
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
998.
999.
Loftin M Sothern M Koss C Tuuri G Vanvrancken C Kontos A Bonis M 《Journal of strength and conditioning research / National Strength & Conditioning Association》2007,21(4):1188-1191
This study examined energy expenditure and physiologic determinants for marathon performance in recreational runners. Twenty recreational marathon runners participated (10 males aged 41 +/- 11.3 years, 10 females aged 42.7 +/- 11.7 years). Each subject completed a V(.-)O2max and a 1-hour treadmill run at recent marathon pace, and body composition was indirectly determined via dual energy X-ray absorptiometry. The male runners exhibited higher V(.-)O2max (ml x kg(-1) x min(-1)) values (52.6 +/- 5.5) than their female counterparts (41.9 +/- 6.6), although ventilatory threshold (T-vent) values were similar between groups (males: 76.2 +/- 6.1 % of V(.-)O2max, females: 75.1 +/- 5.1%). The male runners expended more energy (2,792 +/- 235 kcal) for their most recent marathon as calculated from the 1-hour treadmill run at marathon pace than the female runners (2,436 +/- 297 kcal). Body composition parameters correlated moderately to highly (r ranging from 0.50 to 0.87) with marathon run time. Also, V(.-)O2max (r = -0.73) and ventilatory threshold (r = -0.73) moderately correlated with marathon run time. As a group, the participants ran near their ventilatory threshold for their most recent marathon (r = 0.74). These results indicate the influence of body size on marathon run performance. In general, the larger male and female runners ran slower and expended more kilocalories than smaller runners. Regardless of marathon finishing time, the runners maintained a pace near their T-vent, and as T-vent or V(.-)O2max increased, marathon performance time decreased. 相似文献
1000.
Gregarines are early diverging apicomplexans that appear to be closely related to Cryptosporidium. Most apicomplexans, including Plasmodium, Toxoplasma, and Eimeria, possess both plastids and corresponding plastid genomes. Cryptosporidium lacks both the organelle and the genome. To investigate the evolutionary history of plastids in the Apicomplexa, we tried to determine whether gregarines possess a plastid and/or its genome. We used PCR and dot-blot hybridization to determine whether the gregarine Gregarina niphandrodes possesses a plastid genome. We used an inhibitor of plastid function for any reduction in gregarine infection, and transmission electron microscopy to search for plastid ultrastructure. Despite an extensive search, an organelle of the appropriate ultrastructure in transmission electron microscopy, was not observed. Triclosan, an inhibitor of the plastid-specific enoyl-acyl carrier reductase enzyme, did not reduce host infection by G. niphandrodes. Plastid-specific primers produced amplicons with the DNA of Babesia equi, Plasmodium falciparum, and Toxoplasma gondii as templates, but not with G. niphandrodes DNA. Plastid-specific DNA probes, which hybridized to Babesia equi, failed to hybridize to G. niphandrodes DNA. This evidence indicates that G. niphandrodes is not likely to possess either a plastid organelle or its genome. This raises the possibility that the plastid was lost in the Apicomplexan following the divergence of gregarines and Cryptosporidium. 相似文献