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排序方式: 共有125条查询结果,搜索用时 93 毫秒
81.
Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2 总被引:15,自引:0,他引:15
Voltage-gated calcium channels (VGCCs) conduct calcium into cells after membrane depolarization and are vital for diverse biological events. They are regulated by various signalling pathways, which has profound functional consequences. The activity of VGCCs decreases with time in whole-cell and inside-out patch-clamp recordings. This rundown reflects persistent intrinsic modulation of VGCCs in intact cells. Although several mechanisms have been reported to contribute to rundown of L-type channels, the mechanism of rundown of other types of VGCC is poorly understood. Here we show that phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), an essential regulator of ion channels and transporters, is crucial for maintaining the activity of P/Q- and N-type channels. Activation of membrane receptors that stimulate hydrolysis of PtdIns(4,5)P2 causes channel inhibition in oocytes and neurons. PtdIns(4,5)P2 also inhibits P/Q-type channels by altering the voltage dependence of channel activation and making the channels more difficult to open. This inhibition is alleviated by phosphorylation by protein kinase A. The dual actions of PtdIns(4,5)P2 and the crosstalk between PtdIns(4,5)P2 and protein kinase A set up a dynamic mechanism through which the activity of VGCCs can be finely tuned by various neurotransmitters, hormones and trophic factors. 相似文献
82.
HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites 总被引:54,自引:0,他引:54
Kwong PD Doyle ML Casper DJ Cicala C Leavitt SA Majeed S Steenbeke TD Venturi M Chaiken I Fung M Katinger H Parren PW Robinson J Van Ryk D Wang L Burton DR Freire E Wyatt R Sodroski J Hendrickson WA Arthos J 《Nature》2002,420(6916):678-682
The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization. 相似文献
83.
A Bodoky M Heberer J Landmann R Fricker D Behrens J Steinhardt F Harder 《Experientia》1988,44(2):158-161
Postoperative alterations in amino acid exchange across the intestinal tract and in the capacity for protein absorption were investigated in a chronic canine model. Changes in postoperative splanchnic amino acid exchange consisted of a temporary decrease of total splanchnic amino acid release, including a significant reduction in alanine production, and an increase in glutamine consumption. Contrary to results under stable metabolic conditions, branched chain amino acids were also taken up by the intestine in the early postoperative period. The changes in postoperative amino acid exchange were not, however, reflected by a corresponding alteration in protein transport capacity. The absorptive capacity for a protein hydrolysate remained stable during the early postoperative period. 相似文献
84.
85.
Steinhardt PJ 《Nature》2008,452(7183):43-44
86.
Yu X Tsibane T McGraw PA House FS Keefer CJ Hicar MD Tumpey TM Pappas C Perrone LA Martinez O Stevens J Wilson IA Aguilar PV Altschuler EL Basler CF Crowe JE 《Nature》2008,455(7212):532-536
Investigation of the human antibody response to influenza virus infection has been largely limited to serology, with relatively little analysis at the molecular level. The 1918 H1N1 influenza virus pandemic was the most severe of the modern era. Recent work has recovered the gene sequences of this unusual strain, so that the 1918 pandemic virus could be reconstituted to display its unique virulence phenotypes. However, little is known about adaptive immunity to this virus. We took advantage of the 1918 virus sequencing and the resultant production of recombinant 1918 haemagglutinin (HA) protein antigen to characterize at the clonal level neutralizing antibodies induced by natural exposure of survivors to the 1918 pandemic virus. Here we show that of the 32 individuals tested that were born in or before 1915, each showed seroreactivity with the 1918 virus, nearly 90 years after the pandemic. Seven of the eight donor samples tested had circulating B cells that secreted antibodies that bound the 1918 HA. We isolated B cells from subjects and generated five monoclonal antibodies that showed potent neutralizing activity against 1918 virus from three separate donors. These antibodies also cross-reacted with the genetically similar HA of a 1930 swine H1N1 influenza strain, but did not cross-react with HAs of more contemporary human influenza viruses. The antibody genes had an unusually high degree of somatic mutation. The antibodies bound to the 1918 HA protein with high affinity, had exceptional virus-neutralizing potency and protected mice from lethal infection. Isolation of viruses that escaped inhibition suggested that the antibodies recognize classical antigenic sites on the HA surface. Thus, these studies demonstrate that survivors of the 1918 influenza pandemic possess highly functional, virus-neutralizing antibodies to this uniquely virulent virus, and that humans can sustain circulating B memory cells to viruses for many decades after exposure-well into the tenth decade of life. 相似文献
87.
Niessen F Schaffner F Furlan-Freguia C Pawlinski R Bhattacharjee G Chun J Derian CK Andrade-Gordon P Rosen H Ruf W 《Nature》2008,452(7187):654-658
Defining critical points of modulation across heterogeneous clinical syndromes may provide insight into new therapeutic approaches. Coagulation initiated by the cytokine-receptor family member known as tissue factor is a hallmark of systemic inflammatory response syndromes in bacterial sepsis and viral haemorrhagic fevers, and anticoagulants can be effective in severe sepsis with disseminated intravascular coagulation. The precise mechanism coupling coagulation and inflammation remains unresolved. Here we show that protease-activated receptor 1 (PAR1) signalling sustains a lethal inflammatory response that can be interrupted by inhibition of either thrombin or PAR1 signalling. The sphingosine 1-phosphate (S1P) axis is a downstream component of PAR1 signalling, and by combining chemical and genetic probes for S1P receptor 3 (S1P3) we show a critical role for dendritic cell PAR1-S1P3 cross-talk in regulating amplification of inflammation in sepsis syndrome. Conversely, dendritic cells sustain escalated systemic coagulation and are the primary hub at which coagulation and inflammation intersect within the lymphatic compartment. Loss of dendritic cell PAR1-S1P3 signalling sequesters dendritic cells and inflammation into draining lymph nodes, and attenuates dissemination of interleukin-1beta to the lungs. Thus, activation of dendritic cells by coagulation in the lymphatics emerges as a previously unknown mechanism that promotes systemic inflammation and lethality in decompensated innate immune responses. 相似文献
88.
Claudia Compagnucci Monica Nizzardo Stefania Corti Ginevra Zanni Enrico Bertini 《Cellular and molecular life sciences : CMLS》2014,71(9):1623-1639
Neurogenesis is the developmental process regulating cell proliferation of neural stem cells, determining their differentiation into glial and neuronal cells, and orchestrating their organization into finely regulated functional networks. Can this complex process be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology? Can neurodevelopmental and neurodegenerative diseases be modeled using iPSCs? What is the potential of iPSC technology in neurobiology? What are the recent advances in the field of neurological diseases? Since the applications of iPSCs in neurobiology are based on the capacity to regulate in vitro differentiation of human iPSCs into different neuronal subtypes and glial cells, and the possibility of obtaining iPSC-derived neurons and glial cells is based on and hindered by our poor understanding of human embryonic development, we reviewed current knowledge on in vitro neural differentiation from a developmental and cellular biology perspective. We highlight the importance to further advance our understanding on the mechanisms controlling in vivo neurogenesis in order to efficiently guide neurogenesis in vitro for cell modeling and therapeutical applications of iPSCs technology. 相似文献
89.
Niko P. Bretz Alexei V. Salnikov Claudia Perne Sascha Keller Xiaoli Wang Claudia T. Mierke Mina Fogel Natalie Erbe-Hofmann Thomas Schlange Gerhard Moldenhauer Peter Altevogt 《Cellular and molecular life sciences : CMLS》2012,69(22):3863-3879
CD24 is a glycosyl-phosphatidylinositol-anchored membrane protein that is frequently over-expressed in a variety of human carcinomas and is correlated with poor prognosis. In cancer cell lines, changes of CD24 expression can alter several cellular properties in vitro and tumor growth in vivo. However, little is known about how CD24 mediates these effects. Here we have analyzed the functional consequences of CD24 knock-down or over-expression in human cancer cell lines. Depletion of CD24 reduced cell proliferation and adhesion, enhanced apoptosis, and regulated the expression of various genes some of which were identified as STAT3 target genes. Loss of CD24 reduced STAT3 and FAK phosphorylation. Diminished STAT3 activity was confirmed by specific reporter assays. We found that reduced STAT3 activity after CD24 knock-down was accompanied by altered Src phosphorylation. Silencing of Src, similar to CD24, targeted the expression of prototype STAT3-regulated genes. Likewise, the over-expression of CD24 augmented Src-Y416 phosphorylation, the recruitment of Src into lipid rafts and the expression of STAT3-dependent target genes. An antibody to CD24 was effective in reducing tumor growth of A549 lung cancer and BxPC3 pancreatic cancer xenografts in mice. Antibody treatment affected the level of Src-phosphorylation in the tumor and altered the expression of STAT3 target genes. Our results provide evidence that CD24 regulates STAT3 and FAK activity and suggest an important role of Src in this process. Finally, the targeting of CD24 by antibodies could represent a novel route for tumor therapy. 相似文献
90.
Bocchinfuso G Bobone S Mazzuca C Palleschi A Stella L 《Cellular and molecular life sciences : CMLS》2011,68(13):2281-2301
Since their initial discovery, 30 years ago, antimicrobial peptides (AMPs) have been intensely investigated as a possible
solution to the increasing problem of drug-resistant bacteria. The interaction of antimicrobial peptides with the cellular
membrane of bacteria is the key step of their mechanism of action. Fluorescence spectroscopy can provide several structural
details on peptide–membrane systems, such as partition free energy, aggregation state, peptide position and orientation in
the bilayer, and the effects of the peptides on the membrane order. However, these “low-resolution” structural data are hardly
sufficient to define the structural requirements for the pore formation process. Molecular dynamics simulations, on the other
hand, provide atomic-level information on the structure and dynamics of the peptide–membrane system, but they need to be validated
experimentally. In this review we summarize the information that can be obtained by both approaches, highlighting their versatility
and complementarity, suggesting that their synergistic application could lead to a new level of insight into the mechanism
of membrane destabilization by AMPs. 相似文献