首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   10248篇
  免费   743篇
  国内免费   1篇
  2023年   78篇
  2022年   153篇
  2021年   255篇
  2020年   235篇
  2019年   245篇
  2018年   314篇
  2017年   287篇
  2016年   410篇
  2015年   599篇
  2014年   602篇
  2013年   735篇
  2012年   842篇
  2011年   798篇
  2010年   550篇
  2009年   465篇
  2008年   563篇
  2007年   558篇
  2006年   552篇
  2005年   453篇
  2004年   432篇
  2003年   371篇
  2002年   356篇
  2001年   110篇
  2000年   103篇
  1999年   108篇
  1998年   77篇
  1997年   68篇
  1996年   54篇
  1995年   56篇
  1994年   47篇
  1993年   48篇
  1992年   33篇
  1991年   37篇
  1990年   36篇
  1989年   25篇
  1988年   24篇
  1987年   24篇
  1986年   22篇
  1985年   23篇
  1984年   29篇
  1983年   29篇
  1982年   24篇
  1981年   22篇
  1980年   13篇
  1979年   13篇
  1977年   17篇
  1976年   12篇
  1975年   13篇
  1974年   16篇
  1973年   13篇
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Agonists for muscle contraction in silkworms were screened by injecting test solutions into the hemolymph of decapitated silkworm larvae. Kainic acid, a glutamate receptor agonist, and D-glutamic acid induced muscle contractions, and D-aspartic acid was partially effective, whereas NMDA and AMPA, representative mammalian glutamate receptor agonists, did not induce contraction. L-Glutamic acid inhibited the kainic acid or D-glutamic acid-induced contraction. Amino acid analysis revealed that 3% of the total glutamic acid in the silkworm hemolymph is D-glutamic acid. These results suggest that d-glutamic acid acts physiologically as an agonist for muscle contraction in silkworms, and that L-glutamic acid functions as an inhibitor.  相似文献   
992.
The loss of glypican-3 induces alterations in Wnt signaling   总被引:9,自引:0,他引:9  
Loss-of-function mutations of the GPC3 gene are the cause of the human Simpson-Golabi-Behmel syndrome. Based on the overgrowth phenotype of the Simpson-Golabi-Behmel syndrome patients and the key role played by the insulin-like growth factor (IGF) signaling system in regulating embryonic growth, it was speculated that GPC3 regulates IGF signaling. In order to test the validity of this hypothesis, we mated GPC3 knockout mice with insulin receptor substrate-1 (IRS-1) nullizygous mice. We found that GPC3 regulates organism growth independent of IRS-1, suggesting that GPC3 does not modulate IGF signaling. Instead, we found that GPC3 knockout mice exhibit alterations in the Wnt signaling pathway, which is also associated with the regulation of cell proliferation. In particular, the loss of GPC3 led to the inhibition of the non-canonical Wnt/JNK signaling pathway, while concomitantly causing the activation of canonical Wnt/beta-catenin signaling. These in vivo findings were confirmed in vitro upon the ectopic overexpression of GPC3 in mesothelioma cells. In these cells, the GPC3-induced increase in JNK activity was associated with an enhanced response to Wnt5a. Most interestingly, the heparan sulfate chains of GPC3 were not required for its stimulatory activity on Wnt5a signaling and for the formation of GPC3-Wnt5a complexes. We propose that at least in some cell types GPC3 serves as a selective regulator of Wnt signaling, by potentiating non-canonical Wnt signaling, while inhibiting the canonical Wnt signaling pathway.  相似文献   
993.
Familial Danish dementia is an early onset autosomal dominant neurodegenerative disorder linked to a genetic defect in the BRI2 gene and clinically characterized by dementia and ataxia. Cerebral amyloid and preamyloid deposits of two unrelated molecules (Danish amyloid (ADan) and beta-amyloid (Abeta)), the absence of compact plaques, and neurofibrillary degeneration indistinguishable from that observed in Alzheimer disease (AD) are the main neuropathological features of the disease. Biochemical analysis of extracted amyloid and preamyloid species indicates that as the solubility of the deposits decreases, the heterogeneity and complexity of the extracted peptides exponentially increase. Nonfibrillar deposits were mainly composed of intact ADan-(1-34) and its N-terminally modified (pyroglutamate) counterpart together with Abeta-(1-42) and Abeta-(4-42) in approximately 1:1 mixture. The post-translational modification, glutamate to pyroglutamate, was not present in soluble circulating ADan. In the amyloid fractions, ADan was heavily oligomerized and highly heterogeneous at the N and C terminus, and, when intact, its N terminus was post-translationally modified (pyroglutamate), whereas Abeta was mainly Abeta-(4-42). In all cases, the presence of Abeta-(X-40) was negligible, a surprising finding in view of the prevalence of Abeta40 in vascular deposits observed in sporadic and familial AD, Down syndrome, and normal aging. Whether the presence of the two amyloid subunits is imperative for the disease phenotype or just reflects a conformational mimicry remains to be elucidated; nonetheless, a specific interaction between ADan oligomers and Abeta molecules was demonstrated in vitro by ligand blot analysis using synthetic peptides. The absence of compact plaques in the presence of extensive neuro fibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia.  相似文献   
994.
Transmembrane proteins BRI2 and amyloid precursor protein (APP) co-localize with amyloid beta (Abeta) lesions in sporadic Alzheimer disease and mutations in both precursor proteins are linked to early-onset familial cases of cerebral amyloidosis associated with dementia and/or cerebral hemorrhage. A specific interaction between BRI2 and APP was unveiled by immunoprecipitation experiments using transfected and non-transfected cells. The use of deletion mutants further revealed that stretches 648-719 of APP751 and 46-106 of BRI2, both inclusive of the full transmembrane domains, are sufficient for the interaction. Removal of most of the APP and BRI2 extracellular domains without affecting the interaction implies that both proteins interact when are expressed on the same cell membrane (cis) rather than on adjacent cells (trans). The presence of BRI2 had a modulatory effect on APP processing, specifically increasing the levels of cellular APP as well as beta-secretase-generated COOH-terminal fragments while decreasing the levels of alpha-secretase-generated COOH-terminal fragments as well as the secretion of total APP and Abeta peptides. Determining the precise molecular pathways affected by the specific binding between APP and BRI2 could result in the identification of common therapeutic targets for these sporadic and familial neurodegenerative disorders.  相似文献   
995.
Carbon monoxide (CO), one of the end products of heme oxygenase activity, inhibits smooth muscle proliferation by decreasing ERK1/2 phosphorylation and cyclin D1 expression, a signaling pathway that is known to be modulated by reactive oxygen species (ROS) in airway smooth muscle cells (ASMCs). Two important sources of ROS involved in cell signaling are the membrane NAD(P)H oxidase and the mitochondrial respiratory chain. Thus, that CO could modulate redox signaling in ASMCs by interacting with the heme moiety of NAD(P)H oxidase and/or the respiratory chain is a plausible hypothesis. Here we show that a recently identified carbon monoxide-releasing molecule, [Ru(CO)3Cl2]2 (or CORM-2) 1) inhibits NAD(P)H oxidase cytochrome b558 activity, 2) increases oxidant production by the mitochondria, and 3) inhibits ASMC proliferation and phosphorylation of the ERK1/2 mitogen-activated protein kinase and expression of cyclin D1, two critical pathways involved in muscle proliferation. No such effects were observed with the negative control (Ru(Me2SO)4Cl2), which does not contain CO groups. Because both diphenylene iodinium or apocynin (inhibitors of NAD(P)H oxidase) and rotenone (a molecule that increases mitochondrial ROS production by blocking the respiratory chain) mimicked the effect of CORM-2 on cyclin D1 expression and ASMC proliferation, the antiproliferative effect of CORM-2 is probably related to inhibition of cytochromes on both NAD(P)H oxidase and the respiratory chain. The involvement of increased mitochondria-derived oxidants is substantiated by the findings showing that the antioxidant N-acetylcysteine partially inhibited the effects of CORM-2. This study provides a new mechanism to explain redox signaling by CO.  相似文献   
996.
The activity of the housekeeping ATP:co(I)rrinoid adenosyltransferase (CobA) enzyme of Salmonella enterica sv. Typhimurium is required to adenosylate de novo biosynthetic intermediates of adenosylcobalamin and to salvage incomplete and complete corrinoids from the environment of this bacterium. In vitro, reduced flavodoxin (FldA) provides an electron to generate the co(I)rrinoid substrate in the CobA active site. To understand how CobA and FldA interact, a computer model of a CobA.FldA complex was generated. This model was used to guide the introduction of mutations into CobA using site-directed mutagenesis and the synthesis of a peptide mimic of FldA. Residues Arg-9 and Arg-165 of CobA were critical for FldA-dependent adenosylation but were catalytically as competent as the wild-type protein when cob(I)alamin was provided as substrate. These results indicate that Arg-9 and Arg-165 are important for CobA.FldA docking but not to catalysis. A truncation of the 9-amino acid N-terminal helix of CobA reduced its FldA-dependent cobalamin adenosyltransferase activity by 97.4%. The same protein, however, had a 4-fold higher specific activity than the native enzyme when cob(I)alamin was generated chemically in situ.  相似文献   
997.
HF/6-31G** and molecular dynamics (MD) simulations were used to evaluate the performance of different atomic charge basis sets (i.e., Mulliken, Lowdin, and Electrostatic Potential Derived Charges--ESP) in heparin simulations. HF/3-21 G calculations were also used to study the NMR conformation of the IdoA residue. The results thus obtained indicated that ESP and Lowdin charges gave the better results in heparin simulations, followed by Mulliken charges, and that the minimum-energy conformation of IdoA can be different from that observed by NMR spectroscopy by less than 1 Angstrom. However, it was found that this small conformational modification is capable of inducing a change of almost 200 kJ/mol in the interactions of heparin with the surrounding environment, which is a meaningful amount of energy in the context of ligand-receptor interactions. This information can be potentially of great relevance in the design of heparin-derived antithrombotic compounds.  相似文献   
998.
This review article evaluates various techniques that have been used to determine in vivo loads in the human knee. Two main techniques that have been used are telemetry, which is an experimental approach, and mathematical modeling, which is a theoretical approach. Telemetric analyses have previously been used to determine the in vivo loading of the human hip and more recently evaluated in the determination of in vivo knee loads. Mathematical modeling approaches can be categorized two ways; those that use optimization techniques to solve an indeterminate system and those that utilize a reduction method that minimizes the number of unknowns, keeping the system solvable as the number of equations of motion are equal to the number of unknown quantities. More recently, we have developed an approach that relies fully on the use of in vivo data from fluoroscopy, CT scanning, magnetic resonant imaging and a revised motion analysis technique that involves only two markers on each rigid body. A review of all techniques revealed a wide range of forces at the human knee, ranging from 1.9 to 7.2 times body weight during level walking.  相似文献   
999.
Child mortality (the mortality of children less than five years old) declined considerably in the developing world in the 1990s, but infant mortality declined less. The reductions in neonatal mortality were not impressive and, as a consequence, there is an increasing percentage of infant deaths in the neonatal period. Any further reduction in child mortality, therefore, requires an understanding of the determinants of neonatal mortality. 209,628 birth and 2581 neonatal death records for the 1998 birth cohort from the city of S?o Paulo, Brazil, were probabilistically matched. Data were from SINASC and SIM, Information Systems on Live Births and Deaths of Brazil. Logistic regression was used to find the association between neonatal mortality and the following risk factors: birth weight, gestational age, Apgar scores at 1 and 5 minutes, delivery mode, plurality, sex, maternal education, maternal age, number of prior losses, prenatal care, race, parity and community development. Infants of older mothers were less likely to die in the neonatal period. Caesarean delivery was not found to be associated with neonatal mortality. Low birth weight, pre-term birth and low Apgar scores were associated with neonatal death. Having a mother who lives in the highest developed community decreased the odds of neonatal death, suggesting that factors not measured in this study are behind such association. This result may also indicate that other factors over and above biological and more proximate factors could affect neonatal death.  相似文献   
1000.
Yeast population used in industrial production of fuel-ethanol may vary according to the plant process condition and to the environmental stresses imposed to yeast cells. Therefore, yeast strains isolated from a particular industrial process may be adapted to such conditions and should be used as starter strain instead of less adapted commercial strains. This work reports the use of PCR-fingerprinting method based on microsatellite primer (GTG)5 to characterize the yeast population dynamics along the fermentation period in six distilleries. The results show that indigenous fermenting strains present in the crude substrate can be more adapted to the industrial process than commercial strains. We also identified new strains that dominate the yeast population and were more present either in molasses or sugar cane fermenting distilleries. Those strains were proposed to be used as starters in those industrial processes. This is the first report on the use of molecular markers to discriminate Saccharomyces cerevisiae strains from fuel-ethanol producing process.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号