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41.
Structural analysis of the initial steps in protein folding is difficult because of the swiftness with which these steps occur. Hence, the link between initial polypeptide chain collapse and formation of secondary and other specific structures remains poorly understood. Here, an equilibrium model has been developed for characterizing the initial steps of folding of the small protein barstar, which lead to the formation of a productive molten globule in the folding pathway. In this model, the high-pH-unfolded form (D form) of barstar, which is shown to be as unstructured as the urea-denatured form, is transformed progressively into a molten globule B form by incremental addition of the salt Na(2)SO(4) at pH 12. At very low concentrations of Na(2)SO(4), the D form collapses into a pre-molten globule (P) form, whose volume exceeds that of the native (N) state by only 20%, and which lacks any specific structure as determined by far- and near-UV circular dichroism. At higher concentrations of Na(2)SO(4), the P form transforms into the molten globule (B) form in a highly noncooperative transition populated by an ensemble of at least two intermediates. The B form is a dry molten globule in which water is excluded from the core, and in which secondary structure develops to 65% and tertiary contacts develop to 40%, relative to that of the native protein. Kinetic refolding experiments carried out at pH 7 and at high Na(2)SO(4) concentrations, in which the rate of folding of the D form to the N state is compared to that of the B form to the N state, indicate conclusively that the B form is a productive intermediate that forms on the direct pathway of folding from the D form to the N state. 相似文献
42.
Darblade B Privat C Caillaud D Rami J Arnal JF 《Journal de la Société de Biologie》2000,194(3-4):151-157
Furchgott et al. demonstrated in 1980 that relaxation of arterial smooth muscle cells in response to acetylcholine is dependent on the integrity of endothelium. They named the factor responsible of this intercellular relationship EDRF (Endothelium Derived Relaxing Factor), which was identified 7 years latter as nitric oxide (NO), a free radical gas. In vessels, NO is generated locally by the endothelial NO synthase and its effect is mainly paracrine (relaxation of the underlying smooth muscle cells, and inhibition of platelet aggregation). The in vivo half-life of NO is short, and the assessment of its production is thus difficult. Invasive and non invasive techniques are now available to explore the variations of arterial diameter or flow. Furchgott's pioneering work anticipated the whole pathophysiology of endothelial-dependent relaxation. Indeed, numerous diseases, in particular atherosclerosis, are accompanied by abnormalities of endothelial-dependent vasodilation ("endothelial dysfunction"). Whereas acetylcholine (or serotonin) infused in a normal artery elicits a vasodilation, in contrast, it promotes a vasoconstriction in an atheromatous artery, as a consequence of a decrease in NO bioavailability. This defect in NO favors arterial spasm, interaction between platelets and arterial wall and thrombosis, and thus probably cardiovascular events. NO cannot be measured directly in humans, except in exhaled NO. In vivo, NO is rapidly oxidized in nitrite (NO2-) and in nitrate (NO3-), the summation being NOx. We shall detail the limitations of this measurement as a biochemical index of NO production from "endothelial" origin. 相似文献
43.
Ghia JE Blennerhassett P El-Sharkawy RT Collins SM 《American journal of physiology. Gastrointestinal and liver physiology》2007,293(4):G711-G718
The vagus nerve inhibits the response to systemic administration of endotoxin, and we have recently extended this observation to show that the vagus attenuates acute experimental colitis in mice. The purpose of the present study was to determine whether there is a tonic counterinflammatory influence of the vagus on colitis maintained over several weeks. We assessed disease activity index, macroscopic and histological damage, myeloperoxidase (MPO) activity, and Th1 and Th2 cytokine profiles in chronic colitis induced by administration of dextran sodium sulfate (DSS) in drinking water for three cycles during 5 days with 11 days of rest between each cycle (DSS 3, 2, 2%) in healthy and vagotomized C57BL/6 mice and in mice deficient in macrophage-colony stimulating factor (M-CSF). A pyloroplasty was performed in vagotomized mice. Vagotomy accelerated the onset and the severity of inflammation during the first and second but not the third cycle. Although macroscopic scores were not significantly changed, histological scores as well as MPO activity and colonic tissue levels of IL-1alpha, TNF-alpha, IFN-gamma, and IL-18 but not IL-4 were significantly increased in vagotomized mice compared with sham-operated mice that received DSS. In control mice (without colitis), vagotomy per se did not affect any inflammatory marker. Vagotomy had no effect on the colitis in M-CSF-derived macrophage-deficient mice. These results indicate that the vagus protects against acute relapses on a background of chronic inflammation. Identification of the molecular mechanisms underlying the protective role of parasympathetic nerves opens a new therapeutic avenue for the treatment of acute relapses of chronic inflammatory bowel disease. 相似文献
44.
Hannoush RN Denisov AY Gehring K Damha MJ 《Nucleosides, nucleotides & nucleic acids》2003,22(5-8):1687-1690
We report on the three dimensional structure of an RNA hairpin containing a 2',5'-linked tetraribonucleotide loop, namely, 5'-rGGAC(UUCG)GUCC-3' (where UUCG = U(2'p5')U(2'p5')C(2'p5')G(2'p5')). We show that the 2',5'-linked RNA loop adopts a conformation that is quite different from that previously observed for the native 3',5'-linked RNA loop. The 2',5'-RNA loop is stabilized by (a) U:G wobble base pairing, with both bases in the anti conformation, (b) extensive base stacking, and (c) sugar-base contacts, all of which contribute to the extra stability of this hairpin structure. 相似文献
45.
Michal Meir Yaron Galanty Lior Kashani Michael Blank Rami Khosravi María Jesús Fernández-ávila Andrés Cruz-García Ayelet Star Lea Shochot Yann Thomas Lisa J. Garrett Daniel A. Chamovitz David M. Bodine Thimo Kurz Pablo Huertas Yael Ziv Yosef Shiloh 《Nucleic acids research》2015,43(9):4517-4530
The DNA damage response is vigorously activated by DNA double-strand breaks (DSBs). The chief mobilizer of the DSB response is the ATM protein kinase. We discovered that the COP9 signalosome (CSN) is a crucial player in the DSB response and an ATM target. CSN is a protein complex that regulates the activity of cullin ring ubiquitin ligase (CRL) complexes by removing the ubiquitin-like protein, NEDD8, from their cullin scaffold. We find that the CSN is physically recruited to DSB sites in a neddylation-dependent manner, and is required for timely repair of DSBs, affecting the balance between the two major DSB repair pathways—nonhomologous end-joining and homologous recombination repair (HRR). The CSN is essential for the processivity of deep end-resection—the initial step in HRR. Cullin 4a (CUL4A) is recruited to DSB sites in a CSN- and neddylation-dependent manner, suggesting that CSN partners with CRL4 in this pathway. Furthermore, we found that ATM-mediated phosphorylation of CSN subunit 3 on S410 is critical for proper DSB repair, and that loss of this phosphorylation site alone is sufficient to cause a DDR deficiency phenotype in the mouse. This novel branch of the DSB response thus significantly affects genome stability. 相似文献
46.
Ziad A Audat Mahmoud H. Hajyousef Mohammad D. Fawareh Khaldoon M. Alawneh Mohannad A. Odat Mohammad M. Barbarawi Ali A. Alomari Rami A. Jahmani Mohammad A. Khatatbeh Mohammed A. Assmairan 《Scoliosis》2016,11(1):47
Background
This was a prospective study to evaluate the effect of multilevel vertebral augmentation in addition to conventional therapy in multiple myeloma patients.Methods
We treated 27 patients, whom were recently diagnosed to have multiple myeloma by two ways of treatment. Thirteen patients (group I) were treated with conventional therapy and 14 patients (group II) with adding vertebroplasty and kyphoplasty. Patients were evaluated pre-treatment and at half, one, two and 3-years post-treatment by using Oswestry Disability Index (ODI), the Stanford Score (SS) and the Spinal Instability Neoplastic Score (SINS).Results
Mean values of ODI, SS and SINS were 31.9 (63.8%), 4.3 and 13.8 for group I and 33.2 (66.4%), 4.6 and 12.8 for group II before starting treatment. Group II showed improvement better than group I at all follow-up intervals with best results at first 6 months. P-values at the end of the study were ODI?=?0.047, SS?=?0.180 and SINS?=?0.002. Mortality rates were equal of both groups (four patients of each group).Conclusion
Adding vertebral augmentation to conventional therapy improves multiple myeloma patients’ quality of life, but didn’t affect the mortality rate.47.
48.
Gavva NR Klionsky L Qu Y Shi L Tamir R Edenson S Zhang TJ Viswanadhan VN Toth A Pearce LV Vanderah TW Porreca F Blumberg PM Lile J Sun Y Wild K Louis JC Treanor JJ 《The Journal of biological chemistry》2004,279(19):20283-20295
Vanilloid receptor 1 (TRPV1), a membrane-associated cation channel, is activated by the pungent vanilloid from chili peppers, capsaicin, and the ultra potent vanilloid from Euphorbia resinifera, resiniferatoxin (RTX), as well as by physical stimuli (heat and protons) and proposed endogenous ligands (anandamide, N-arachidonyldopamine, N-oleoyldopamine, and products of lipoxygenase). Only limited information is available in TRPV1 on the residues that contribute to vanilloid activation. Interestingly, rabbits have been suggested to be insensitive to capsaicin and have been shown to lack detectable [(3)H]RTX binding in membranes prepared from their dorsal root ganglia. We have cloned rabbit TRPV1 (oTRPV1) and report that it exhibits high homology to rat and human TRPV1. Like its mammalian orthologs, oTRPV1 is selectively expressed in sensory neurons and is sensitive to protons and heat activation but is 100-fold less sensitive to vanilloid activation than either rat or human. Here we identify key residues (Met(547) and Thr(550)) in transmembrane regions 3 and 4 (TM3/4) of rat and human TRPV1 that confer vanilloid sensitivity, [(3)H]RTX binding and competitive antagonist binding to rabbit TRPV1. We also show that these residues differentially affect ligand recognition as well as the assays of functional response versus ligand binding. Furthermore, these residues account for the reported pharmacological differences of RTX, PPAHV (phorbol 12-phenyl-acetate 13-acetate 20-homovanillate) and capsazepine between human and rat TRPV1. Based on our data we propose a model of the TM3/4 region of TRPV1 bound to capsaicin or RTX that may aid in the development of potent TRPV1 antagonists with utility in the treatment of sensory disorders. 相似文献
49.
Wongi Min Hyun S. Lillehoj Christopher M. Ashwell Curtis P. van Tassell Rami A. Dalloul Lakshmi K. Matukumalli Jae Y. Han Erik P. Lillehoj 《Molecular biotechnology》2005,30(2):143-149
Intraepithelial lymphocytes (IELs) play a critical role in protective immune response to intestinal pathogens such as Eimeria, the etiologic agent of avian coccidiosis. A list of genes expressed by intestinal IELs of Eimeria-infected chickens was compiled using the expressed sequence tag (EST) strategy. The 14,409 ESTs consisted of 1851 clusters
and 7595 singletons, which revealed 9446 unique genes in the data set. Comparison of the sequence data with chicken DNA sequences
in GenBank identified 125 novel clones. This EST library will provide a valuable resource for profiling global gene expression
in normal and pathogen-infected chickens and identifying additional unique immune-related genes. 相似文献