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91.
Jeffrey Y. Melamed Amy E. Zartman Nathan R. Kett Anthony L. Gotter Victor N. Uebele Duane R. Reiss Cindra L. Condra Christine Fandozzi Laura S. Lubbers Blake A. Rowe Georgia B. McGaughey Martin Henault Rino Stocco John J. Renger George D. Hartman Mark T. Bilodeau B. Wesley Trotter 《Bioorganic & medicinal chemistry letters》2010,20(15):4700-4703
Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood–brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited 125I-NPS binding in the CNS when administered to rats. 相似文献
92.
ABSTRACT Here we address the personhood of patients in a permanent vegetative state (PVS), who fall outside categories of "alive" or "dead" and "subject" or "object." Drawing on fieldwork in an Israeli hospital, we examine multiple and shifting approaches to PVS patients, which are articulated in the course of caring for and living with them. We argue that, alongside the institutional definition of these patients as being in a PVS, which, as Kaufman showed, evokes irresolvable confusion as to their ontological nature, there appear and disappear other senses of their personhood. Allying with other studies of cognitively impaired patients (e.g., those with dementia and Alzheimer's), we explore this relational person-concept while demonstrating its situational nature. We analyze patients' admission to the hospital, showing how their essentialistic personhood is "emptied" and how and when their fluid, relational personhood appears and disappears, further showing how this personhood is reified by imagined life stories. 相似文献
93.
ITS2 sequences as barcodes for identifying and analyzing spider mites (Acari: Tetranychidae) 总被引:1,自引:0,他引:1
The use of DNA barcodes, short DNA sequences from a standardized region of the genome, has recently been proposed as a tool
to facilitate species identification and discovery. Here we show that second internal transcribed spacer of nuclear ribosomal
DNA (rDNA-ITS2) barcodes effectively discriminate among 16 species of spider mites (Acari: Tetranychidae) from Israel. The
barcode sequences of each species were unambiguously distinguishable from all other species and formed distinct, nonoverlapping
monophyletic groups in the maximum-parsimony tree. Sequence divergences were generally much greater between species than within
them. Using a 0.02 (2%) threshold for species diagnosis in our data set, 14 out of 16 species recognized by morphological
criteria would be accurately identified. The only exceptions involved the low divergence, 0.011–0.015 (1.1–1.5%), between
Tetranychus urticae and Tetranychus turkestani, where speciation may have occurred only recently. Still, these species had fixed alternative rDNA-ITS2 variants, with five
diagnostic nucleotide substitutions. As a result, we tentatively conclude that rDNA-ITS2 sequence barcodes may serve as an
effective tool for the identification of spider mite species and can be applicable as a diagnostic tool for quarantine and
other pest management activities and decision-making. We predict that our work, together with similar efforts, will provide
in the future the platform for a uniform, accurate, practical and easy-to-use method of spider mite species identification. 相似文献
94.
Edry E Koralov SB Rajewsky K Melamed D 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(10):6555-6560
Mature B cells replace the mu constant region of the H chain with a downstream isotype in a process of class switch recombination (CSR). Studies suggest that CSR induction is limited to activated mature B cells in the periphery. Recently, we have shown that CSR spontaneously occur in B lymphopoiesis. However, the mechanism and regulation of it have not been defined. In this study, we show that spontaneous CSR occurs at all stages of B cell development and generates aberrant joining of the switch junctions as revealed by: 1) increased load of somatic mutations around the CSR break points, 2) reduced sequence overlaps at the junctions, and 3) excessive switch region deletion. In addition, we found that incidence of spontaneous CSR is increased in cells carrying VDJ rearrangements. Our results reveal major differences between spontaneous CSR in developing B cells and CSR induced in mature B cells upon activation. These differences can be explained by deregulated expression or function of activation-induced cytidine deaminase early in B cell development. 相似文献
95.
96.
p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway 总被引:1,自引:0,他引:1
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Sachs BD Baillie GS McCall JR Passino MA Schachtrup C Wallace DA Dunlop AJ MacKenzie KF Klussmann E Lynch MJ Sikorski SL Nuriel T Tsigelny I Zhang J Houslay MD Chao MV Akassoglou K 《The Journal of cell biology》2007,177(6):1119-1132
Clearance of fibrin through proteolytic degradation is a critical step of matrix remodeling that contributes to tissue repair in a variety of pathological conditions, such as stroke, atherosclerosis, and pulmonary disease. However, the molecular mechanisms that regulate fibrin deposition are not known. Here, we report that the p75 neurotrophin receptor (p75NTR), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and up-regulating plasminogen activator inhibitor-1 (PAI-1). We have discovered a new mechanism in which phosphodiesterase PDE4A4/5 interacts with p75NTR to enhance cAMP degradation. The p75NTR-dependent down-regulation of cAMP results in a decrease in extracellular proteolytic activity. This mechanism is supported in vivo in p75NTR-deficient mice, which show increased proteolysis after sciatic nerve injury and lung fibrosis. Our results reveal a novel pathogenic mechanism by which p75NTR regulates degradation of cAMP and perpetuates scar formation after injury. 相似文献
97.
Immune synapse formation requires ZAP-70 recruitment by ezrin and CD43 removal by moesin 总被引:1,自引:0,他引:1
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Immunological synapse (IS) formation involves receptor–ligand pair clustering and intracellular signaling molecule recruitment with a coincident removal of other membrane proteins away from the IS. As microfilament–membrane linkage is critical to this process, we investigated the involvement of ezrin and moesin, the two ezrin/radixin/moesin proteins expressed in T cells. We demonstrate that ezrin and moesin, which are generally believed to be functionally redundant, are differentially localized and have important and complementary functions in IS formation. Specifically, we find that ezrin directly interacts with and recruits the signaling kinase ZAP-70 to the IS. Furthermore, the activation of ezrin by phosphorylation is essential for this process. In contrast, moesin dephosphorylation and removal, along with CD43, are necessary to prepare a region of the cell cortex for IS. Thus, ezrin and moesin have distinct and critical functions in the T cell cortex during IS formation. 相似文献
98.
99.
Egbertson MS Moritz HM Melamed JY Han W Perlow DS Kuo MS Embrey M Vacca JP Zrada MM Cortes AR Wallace A Leonard Y Hazuda DJ Miller MD Felock PJ Stillmock KA Witmer MV Schleif W Gabryelski LJ Moyer G Ellis JD Jin L Xu W Braun MP Kassahun K Tsou NN Young SD 《Bioorganic & medicinal chemistry letters》2007,17(5):1392-1398
A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme. 相似文献
100.
Colmenero-Flores JM Martínez G Gamba G Vázquez N Iglesias DJ Brumós J Talón M 《The Plant journal : for cell and molecular biology》2007,50(2):278-292
Chloride (Cl(-)) is an essential nutrient and one of the most abundant inorganic anions in plant tissues. We have cloned an Arabidopsis thaliana cDNA encoding for a member of the cation-Cl(-) cotransporter (CCC) family. Deduced plant CCC proteins are highly conserved, and phylogenetic analyses revealed their relationships to the sub-family of animal K(+):Cl(-) cotransporters. In Xenopus laevis oocytes, the A. thaliana CCC protein (At CCC) catalysed the co-ordinated symport of K(+), Na(+) and Cl(-), and this transport activity was inhibited by the 'loop' diuretic bumetanide, a specific inhibitor of vertebrate Na(+):K(+):Cl(-) cotransporters, indicating that At CCC encodes for a bona fide Na(+):K(+):Cl(-) cotransporter. Analysis of At CCC promoter-beta-glucuronidase transgenic Arabidopsis plants revealed preferential expression in the root and shoot vasculature at the xylem/symplast boundary, root tips, trichomes, leaf hydathodes, leaf stipules and anthers. Plants homozygous for two independent T-DNA insertions in the CCC gene exhibited shorter organs such as inflorescence stems, roots, leaves and siliques. The elongation zone of the inflorescence stem of ccc plants often necrosed during bolt emergence, while seed production was strongly impaired. In addition, ccc plants exhibited defective Cl(-) homeostasis under high salinity, as they accumulated higher and lower Cl(-) amounts in shoots and roots, respectively, than the treated wild type, suggesting At CCC involvement in long-distance Cl(-) transport. Compelling evidence is provided on the occurrence of cation-chloride cotransporters in the plant kingdom and their significant role in major plant developmental processes and Cl(-) homeostasis. 相似文献