全文获取类型
收费全文 | 6914篇 |
免费 | 508篇 |
国内免费 | 3篇 |
专业分类
7425篇 |
出版年
2023年 | 42篇 |
2022年 | 99篇 |
2021年 | 193篇 |
2020年 | 105篇 |
2019年 | 146篇 |
2018年 | 193篇 |
2017年 | 151篇 |
2016年 | 247篇 |
2015年 | 379篇 |
2014年 | 416篇 |
2013年 | 468篇 |
2012年 | 644篇 |
2011年 | 584篇 |
2010年 | 350篇 |
2009年 | 323篇 |
2008年 | 391篇 |
2007年 | 355篇 |
2006年 | 300篇 |
2005年 | 312篇 |
2004年 | 303篇 |
2003年 | 262篇 |
2002年 | 238篇 |
2001年 | 67篇 |
2000年 | 43篇 |
1999年 | 59篇 |
1998年 | 65篇 |
1997年 | 47篇 |
1996年 | 52篇 |
1995年 | 34篇 |
1994年 | 46篇 |
1993年 | 34篇 |
1992年 | 35篇 |
1991年 | 36篇 |
1990年 | 28篇 |
1989年 | 36篇 |
1988年 | 20篇 |
1987年 | 26篇 |
1986年 | 24篇 |
1985年 | 20篇 |
1984年 | 29篇 |
1983年 | 14篇 |
1982年 | 19篇 |
1981年 | 18篇 |
1980年 | 20篇 |
1979年 | 18篇 |
1978年 | 12篇 |
1977年 | 20篇 |
1976年 | 10篇 |
1975年 | 11篇 |
1973年 | 14篇 |
排序方式: 共有7425条查询结果,搜索用时 9 毫秒
211.
Takamitsu Miyafusa Jose?M. M. Caaveiro Yoshikazu Tanaka Martin?E. Tanner Kouhei Tsumoto 《Bioscience reports》2013,33(3)
Enzymes synthesizing the bacterial CP (capsular polysaccharide) are attractive antimicrobial targets. However, we lack critical information about the structure and mechanism of many of them. In an effort to reduce that gap, we have determined three different crystal structures of the enzyme CapE of the human pathogen Staphylococcus aureus. The structure reveals that CapE is a member of the SDR (short-chain dehydrogenase/reductase) super-family of proteins. CapE assembles in a hexameric complex stabilized by three major contact surfaces between protein subunits. Turnover of substrate and/or coenzyme induces major conformational changes at the contact interface between protein subunits, and a displacement of the substrate-binding domain with respect to the Rossmann domain. A novel dynamic element that we called the latch is essential for remodelling of the protein–protein interface. Structural and primary sequence alignment identifies a group of SDR proteins involved in polysaccharide synthesis that share the two salient features of CapE: the mobile loop (latch) and a distinctive catalytic site (MxxxK). The relevance of these structural elements was evaluated by site-directed mutagenesis. 相似文献
212.
Sheng-Ping Wang Erin Daniels Ying Chen Jose Castro-Perez Haihong Zhou Karen O. Akinsanya Stephen F. Previs Thomas P. Roddy Douglas G. Johns 《Journal of lipid research》2013,54(10):2858-2865
Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol and lowers LDL cholesterol in dyslipidemic patients. We previously demonstrated that ANA increases macrophage-to-feces reverse cholesterol transport and fecal cholesterol excretion in hamsters, and increased preβ HDL-dependent cholesterol efflux via ABCA1 in vitro. However, the effects of ANA on in vivo preβ HDL have not been characterized. In vitro, ANA inhibited the formation of preβ, however in ANA-treated dyslipidemic hamsters, preβ HDL levels (measured by two-dimensional gel electrophoresis) were increased, in contrast to in vitro findings. Because changes in plasma preβ HDL have been proposed to potentially affect markers of cholesterol absorption with other CETP inhibitors, a dual stable isotope method was used to directly measure cholesterol absorption in hamsters. ANA treatment of hamsters (on either dyslipidemic or normal diet) had no effect on cholesterol absorption, while dalcetrapib-treated hamsters displayed an increase in cholesterol absorption. Taken together, these data support the notion that ANA promotes preβ HDL functionality in vivo, with no effects on cholesterol absorption. 相似文献
213.
David G. McLaren Sheng-Ping Wang Steven J. Stout Dan Xie Paul L. Miller Vivienne Mendoza Raymond Rosa Jose Castro-Perez Stephen F. Previs Douglas G. Johns Thomas P. Roddy 《Journal of lipid research》2013,54(1):276-281
Isotopic tracers have been used to examine lipid trafficking for many years, and data from those studies have typically yielded novel insight regarding the pathophysiology of dyslipidemia. Previous experimental designs were suitable for studies in humans because relatively large volumes of plasma could be regularly sampled. We have expanded on the earlier logic by applying high-throughput analytical methods that require reduced sample volumes. Specifically, we have examined the possibility of coupling gel-based separations of lipoproteins (e.g., lipoprint) with LC-MS/MS analyses of complex lipid mixtures as a way to routinely measure the labeling profiles of distinct lipids in discrete lipoprotein subfractions. We demonstrate the ability to measure the incorporation of [U-13C]oleate into triglycerides (TG), PLs (PL), and cholesterol esters (CE) in VLDL, LDL, and HDL particles in mice. Although rodent models of dyslipidemia are inherently different from humans because of alterations in enzyme activities and underlying metabolism, rodent models can be used to screen novel compounds for efficacy in altering a given biochemical pathway and therein enable studies of target engagement in vivo. We expect that it is possible to translate our approach for application in other systems, including studies in humans. 相似文献
214.
Van Anthony M. Villar John Edward Jones Ines Armando Laureano D. Asico Crisanto S. Escano Jr. Hewang Lee Xiaoyan Wang Yu Yang Annabelle M. Pascua-Crusan Cynthia P. Palmes-Saloma Robin A. Felder Pedro A. Jose 《The Journal of biological chemistry》2013,288(1):152-163
The peripheral dopaminergic system plays a crucial role in blood pressure regulation through its actions on renal hemodynamics and epithelial ion transport. The dopamine D5 receptor (D5R) interacts with sorting nexin 1 (SNX1), a protein involved in receptor retrieval from the trans-Golgi network. In this report, we elucidated the spatial, temporal, and functional significance of this interaction in human renal proximal tubule cells and HEK293 cells stably expressing human D5R and in mice. Silencing of SNX1 expression via RNAi resulted in the failure of D5R to internalize and bind GTP, blunting of the agonist-induced increase in cAMP production and decrease in sodium transport, and up-regulation of angiotensin II receptor expression, of which expression was previously shown to be negatively regulated by D5R. Moreover, siRNA-mediated depletion of renal SNX1 in C57BL/6J and BALB/cJ mice resulted in increased blood pressure and blunted natriuretic response to agonist in salt-loaded BALB/cJ mice. These data demonstrate a crucial role for SNX1 in D5R trafficking and that SNX1 depletion results in D5R dysfunction and thus may represent a novel mechanism for the pathogenesis of essential hypertension. 相似文献
215.
Zaida Araujo Francesca Giampietro María de los Angeles Bochichio Andrea Palacios Jenifer Dinis Jaime Isern Jacobus Henry de Waard Elsa Rada Rafael Borges Carlos Fernández de Larrea Angel Villasmil Magnolia Vanegas Jose Antonio Enciso-Moreno Manuel Alfonso Patarroyo 《Memórias do Instituto Oswaldo Cruz》2013,108(2):131-139
The goal of this study was to demonstrate the usefulness of an enzyme-linked immunosorbent assay (ELISA) for the serodiagnosis of pulmonary tuberculosis (PTB) and extrapulmonary TB (EPTB). This assay used 20 amino acid-long, non-overlapped synthetic peptides that spanned the complete Mycobacterium tuberculosis ESAT-6 and Ag85A sequences. The validation cohort consisted of 1,102 individuals who were grouped into the following five diagnostic groups: 455 patients with PTB, 60 patients with EPTB, 40 individuals with non-EPTB, 33 individuals with leprosy and 514 healthy controls. For the PTB group, two ESAT-6 peptides (12033 and 12034) had the highest sensitivity levels of 96.9% and 96.2%, respectively, and an Ag85A-peptide (29878) was the most specific (97.4%) in the PTB groups. For the EPTB group, two Ag85A peptides (11005 and 11006) were observed to have a sensitivity of 98.3% and an Ag85A-peptide (29878) was also the most specific (96.4%). When combinations of peptides were used, such as 12033 and 12034 or 11005 and 11006, 99.5% and 100% sensitivities in the PTB and EPTB groups were observed, respectively. In conclusion, for a cohort that consists entirely of individuals from Venezuela, a multi-antigen immunoassay using highly sensitive ESAT-6 and Ag85A peptides alone and in combination could be used to more rapidly diagnose PTB and EPTB infection. 相似文献
216.
László Virág Agnieszka Robaszkiewicz Jose Manuel Rodriguez-Vargas Francisco Javier Oliver 《Molecular aspects of medicine》2013
Poly(ADP-ribosyl)ation (PARylation) is a reversible protein modification carried out by the concerted actions of poly(ADP-ribose) polymerase (PARP) enzymes and poly(ADP-ribose) (PAR) decomposing enzymes such as PAR glycohydrolase (PARG) and ADP-ribosyl hydrolase 3 (ARH3). Reversible PARylation is a pleiotropic regulator of various cellular functions but uncontrolled PARP activation may also lead to cell death. The cellular demise pathway mediated by PARylation in oxidatively stressed cells has been described almost thirty years ago. However, the underlying molecular mechanisms have only begun to emerge relatively recently. PARylation has been implicated in necroptosis, autophagic cell death but its role in extrinsic and intrinsic apoptosis appears to be less predominant and depends largely on the cellular model used. Currently, three major pathways have been made responsible for PARP-mediated necroptotic cell death: (1) compromised cellular energetics mainly due to depletion of NAD, the substrate of PARPs; (2) PAR mediated translocation of apoptosis inducing factor (AIF) from mitochondria to nucleus (parthanatos) and (3) a mostly elusive crosstalk between PARylation and cell death/survival kinases and phosphatases. Here we review how these PARP-mediated necroptotic pathways are intertwined, how PARylation may contribute to extrinsic and intrinsic apoptosis and discuss recent developments on the role of PARylation in autophagy and autophagic cell death. 相似文献
217.
218.
219.
220.
Callum F. Ross Richard W. Blob David R. Carrier Monica A. Daley Stephen M. Deban Brigitte Demes Janaya L. Gripper Jose Iriarte‐Diaz Brandon M. Kilbourne Tobias Landberg John D. Polk Nadja Schilling Bieke Vanhooydonck 《Evolution; international journal of organic evolution》2013,67(4):1209-1217
Differences in rhythmicity (relative variance in cycle period) among mammal, fish, and lizard feeding systems have been hypothesized to be associated with differences in their sensorimotor control systems. We tested this hypothesis by examining whether the locomotion of tachymetabolic tetrapods (birds and mammals) is more rhythmic than that of bradymetabolic tetrapods (lizards, alligators, turtles, salamanders). Species averages of intraindividual coefficients of variation in cycle period were compared while controlling for gait and substrate. Variance in locomotor cycle periods is significantly lower in tachymetabolic than in bradymetabolic animals for datasets that include treadmill locomotion, non‐treadmill locomotion, or both. When phylogenetic relationships are taken into account the pooled analyses remain significant, whereas the non‐treadmill and the treadmill analyses become nonsignificant. The co‐occurrence of relatively high rhythmicity in both feeding and locomotor systems of tachymetabolic tetrapods suggests that the anatomical substrate of rhythmicity is in the motor control system, not in the musculoskeletal components. 相似文献