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101.
Yunxiang Zang Alem W. Kahsai Natalia Pakharukova Li-yin Huang Robert J. Lefkowitz 《The Journal of biological chemistry》2021,297(6)
G protein–coupled receptors (GPCRs) convert external stimuli into cellular signals through heterotrimeric guanine nucleotide-binding proteins (G-proteins) and β-arrestins (βarrs). In a βarr-dependent signaling pathway, βarrs link GPCRs to various downstream signaling partners, such as the Raf–mitogen-activated protein kinase extracellular signal–regulated kinase–extracellular signal-regulated kinase cascade. Agonist-stimulated GPCR–βarr complexes have been shown to interact with C-Raf and are thought to initiate the mitogen-activated protein kinase pathway through simple tethering of these signaling partners. However, recent evidence shows that in addition to canonical scaffolding functions, βarrs can allosterically activate downstream targets, such as the nonreceptor tyrosine kinase Src. Here, we demonstrate the direct allosteric activation of C-Raf by GPCR–βarr1 complexes in vitro. Furthermore, we show that βarr1 in complex with a synthetic phosphopeptide mimicking the human V2 vasopressin receptor tail that binds and functionally activates βarrs also allosterically activates C-Raf. We reveal that the interaction between the phosphorylated GPCR C terminus and βarr1 is necessary and sufficient for C-Raf activation. Interestingly, the interaction between βarr1 and C-Raf was considerably reduced in the presence of excess activated H-Ras, a small GTPase known to activate C-Raf, suggesting that H-Ras and βarr1 bind to the same region on C-Raf. Furthermore, we found that βarr1 interacts with the Ras-binding domain of C-Raf. Taken together, these data suggest that in addition to canonical scaffolding functions, GPCR–βarr complexes directly allosterically activate C-Raf by binding to its amino terminus. This work provides novel insights into how βarrs regulate effector molecules to activate downstream signaling pathways. 相似文献
102.
103.
Cristina Molero Isabel Rodríguez‐Escudero Ainel Alemán Rafael Rotger María Molina Víctor J. Cid 《Proteomics》2009,9(14):3652-3665
Through acute enteric infection, Salmonella invades host enterocytes and reproduces intracellularly into specialized vacuolae. This involves changes in host cell signaling elicited by bacterial proteins delivered via type III secretion systems (TTSS). One of the two TTSSs of Salmonella enterica serovar Typhimurium encoded by the Salmonella pathogenicity island‐1, triggers bacterial internalization. Among the effector proteins translocated by this TTSS, the GTPase modulator SopE/E2 and the phosphoinositide phosphatase SigD are known to play key roles in these processes. To better understand their contribution to re‐programming host cell pathways, we used ZeptoMARK reverse‐phase protein array technology, which allows printing 32‐sample lysate arrays that can be analyzed with phospho‐specific antibodies to evaluate the phosphorylation of signaling proteins. Lysates were obtained at different times after infection of HeLa cells with WT, TTSS‐deficient, sopE/E2 and sigD single and double deletants, as well as different sigD Salmonella mutants. Our analysis detected activation of p38, JNK and ERK mitogen‐activated protein kinases, mainly dependent on SopE/E2, as well as SigD‐dependent phosphorylation of PKB/Akt and its targets GSK‐3β and FKHR/FoxO. This is the first time that reverse‐phase protein array technology is used in the cellular microbiology field, demonstrating its value to screen for host signaling events through bacterial infection. 相似文献
104.
Ornella Sosa-Hernández Prathap Parameswaran Gibrán Sidney Alemán-Nava César I. Torres Roberto Parra-Saldívar 《Journal of industrial microbiology & biotechnology》2016,43(9):1195-1204
Anaerobic digestion treatment of brewer’s spent yeast (SY) is a viable option for bioenergy capture. The biochemical methane potential (BMP) assay was performed with three different samples (SY1, SY2, and SY3) and SY1 dilutions (75, 50, and 25 % on a v/v basis). Gompertz-equation parameters denoted slow degradability of SY1 with methane production rates of 14.59–4.63 mL/day and lag phases of 10.72–19.7 days. Performance and kinetic parameters were obtained with the Gompertz equation and the first-order hydrolysis model with SY2 and SY3 diluted 25 % and SY1 50 %. A SY2 25 % gave a 17 % of TCOD conversion to methane as well as shorter lag phase (<1 day). Average estimated hydrolysis constant for SY was 0.0141 (±0.003) day?1, and SY2 25 % was more appropriate for faster methane production. Methane capture and biogas composition were dependent upon the SY source, and co-digestion (or dilution) can be advantageous. 相似文献
105.
Anouk P van Alem Rob H Vrenken Rien de Vos Jan G P Tijssen Rudolph W Koster 《BMJ (Clinical research ed.)》2003,327(7427):1312
Objective To test the hypothesis that the use of an automated external defibrillator by police and fire fighters results in higher discharge rates for out of hospital cardiac arrest.Design Controlled clinical trial with initial random allocation of automated external defibrillators to first responders in four of the eight participating regions; each region switched from control to experimental, and vice versa, every four months.Setting Amsterdam and surroundings, the Netherlands.Participants Patients with witnessed out of hospital cardiac arrests, identified by the emergency medical system between January 2000 and January 2002.Main outcomes measures Survival to hospital discharge; return of spontaneous circulation; admission to hospital.Results 243 patients (65% in ventricular fibrillation) were included in the experimental area and 226 patients (67% in ventricular fibrillation) in the control area. The median time interval between collapse and first shock was 668 seconds in the experimental area and 769 seconds in the control area (P < 0.001). 44 (18%) patients in the experimental area versus 33 (15%) patients in the control area were discharged (odds ratio 1.3 (95% confidence interval 0.8 to 2.2), P = 0.33), 139 (57%) experimental versus 108 (48%) control patients had return of spontaneous circulation (1.5 (1.0 to 2.2), P = 0.05), and 103 (42%) experimental versus 74 (33%) control patients were admitted (1.5 (1.1 to 1.6), P = 0.02). The median delay from receipt of call to dispatch of the ambulance was 120 seconds, and the delay to dispatch of the first responder was 180 seconds.Conclusions Use of automated external defibrillators by first responders did not significantly increase survival to discharge from hospital, although it did improve return of spontaneous circulation and admission to hospital. Improved dispatch procedures should increase the success of programmes of first responders using external defibrillators. 相似文献
106.
Fustero S Sánchez-Roselló M Báez C Del Pozo C García Ruano JL Alemán J Marzo L Parra A 《Amino acids》2011,41(3):559-573
In this work, we describe the asymmetric synthesis of a series of fluorinated and non-fluorinated quaternary α-amino acid
derivatives. This methodology involves the diastereoselective addition of chiral 2-p-tolylsulfinyl benzylcarbanions to either imines containing a 2-furyl moiety or trifluoromethyl α-imino esters. Synthetic
practicality of this method is demonstrated by short (two-steps) and convenient preparation of 2-(trifluoromethyl)indoline-2-carboxylates. 相似文献
107.
Maximilien Lopes-Rodrigues David Zanuy Carlos Alemán Catherine Michaux Eric A. Perpète 《Journal of biomolecular structure & dynamics》2013,31(15):3923-3935
AbstractBrucella melitensis is a pathogenic bacterium responsible for brucellosis in mammals and humans. Its outer membrane proteins (Omp) control the diffusion of solutes through the membrane, and they consequently have a crucial role in the design of diagnostics and vaccines. Moreover, such proteins have recently revealed their potential for protein-based biomaterials. In the present contribution, the structure of the B. melitensis porin Omp2a is built using the RaptorX threading method. This is a 16-stranded β-barrel with an α-helix on the third loop folding inside the barrel and forming the constriction zone of the channel, a typical feature of general porins such as PhoE and OmpF. The preferential diffusion of cations over anions experimentally observed in anterior studies is evidenced by the presence of distinct clusters of charges in the extracellular loops and in the inner pore. Docking studies support the previously reported hypothesis of Omp2a ability to aid maltotetraose diffusion. The monomer model is then assembled into a homotrimer, stabilized by the L2 loop involved in most of the interface interactions. The stability of the trimer is evaluated in three bilayers: pure 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), pure 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and a mixture of 1:1 of POPC/POPE. All-atom molecular dynamics simulations demonstrate the β-barrel-structural stability over time even though a breathing-like motion is observed. Compared to the pure bilayers, the POPC/POPE better preserves the integrity of the protein and its channel. Overall, this work demonstrates the relevancy of the Omp2a model and will help to design new therapeutic agents and bioinspired nanomaterials. 相似文献
108.
Adiponectin synthesis and secretion by subcutaneous adipose tissue is impaired during obesity by endoplasmic reticulum stress
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Ivan Torre‐Villalvazo Ana E. Bunt Gabriela Alemán Claudia C. Marquez‐Mota Andrea Diaz‐Villaseñor Lilia G. Noriega Isabela Estrada Elizabeth Figueroa‐Juárez Claudia Tovar‐Palacio Leonardo A. Rodriguez‐López Patricia López‐Romero Nimbe Torres Armando R. Tovar 《Journal of cellular biochemistry》2018,119(7):5970-5984
109.
Jordi Triguero Alejandra Flores‐Ortega David Zanuy Carlos Alemán 《Journal of peptide science》2018,24(1)
The RPAR peptide, a prototype C‐end Rule (CendR) sequence that binds to neuropilin‐1 (NRP‐1), has potential therapeutic uses as internalization trigger in anticancer nanodevices. Recently, the functionalization of gold nanoparticles with CendR peptides has been proved to be a successful strategy to target the NRP‐1 receptor in prostate cancer cells. In this work, we investigate the influence of two gold surface facets, (100) and (111), on the conformational preferences of RPAR using molecular dynamics simulations. Both clustering and conformational analyses revealed that the peptide backbone becomes very rigid upon adsorption onto gold, which is a very fast and favored process, the only flexibility being attributed to the side chains of the two Arg residues. Thus, the different components of RPAR tend to adopt an elongated shape, which is characterized by the pseudo‐extended conformation of both the backbone and the Arg side chains. This conformation is very different from the already known bioactive conformation, indicating that RPAR is drastically affected by the substrate. Interestingly, the preferred conformations of the peptide adsorbed onto gold facets are not stabilized by salt bridges and/or specific intramolecular hydrogen bonds, which represent an important difference with respect to the conformations found in other environments (e.g. the peptide in solution and interacting with NRP‐1 receptor). However, the conformational changes induced by the substrate are not detrimental for the use of gold nanoparticles as appropriate vehicles for the transport and targeted delivery of the RPAR. Thus, once their high affinity for the NRP‐1 receptor induces the targeted delivery of the elongated peptide molecules from the gold nanoparticles, the lack of intramolecular interactions facilitates their evolution towards the bioactive conformation, increasing the therapeutic efficacy of the peptide. 相似文献
110.
Muluken Melese Degu Jerene Genetu Alem Jemal Seid Feleke Belachew Yewulsew Kassie Dereje Habte Solomon Negash Gonfa Ayana Belaineh Girma Yared K. Haile Nebiyu Hiruy Pedro G. Suarez 《PloS one》2016,11(3)