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61.
Stephen L. Pinkosky Sergey Filippov Rai Ajit K. Srivastava Jeffrey C. Hanselman Cheryl D. Bradshaw Timothy R. Hurley Clay T. Cramer Mark A. Spahr Ashley F. Brant Jacob L. Houghton Chris Baker Mark Naples Khosrow Adeli Roger S. Newton 《Journal of lipid research》2013,54(1):134-151
ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid β-oxidation. However, the molecular mechanism(s) mediating these activities remained undefined. Studies described here show that ETC-1002 free acid activates AMP-activated protein kinase in a Ca2+/calmodulin-dependent kinase β-independent and liver kinase β 1-dependent manner, without detectable changes in adenylate energy charge. Furthermore, ETC-1002 is shown to rapidly form a CoA thioester in liver, which directly inhibits ATP-citrate lyase. These distinct molecular mechanisms are complementary in their beneficial effects on lipid and carbohydrate metabolism in vitro and in vivo. Consistent with these mechanisms, ETC-1002 treatment reduced circulating proatherogenic lipoproteins, hepatic lipids, and body weight in a hamster model of hyperlipidemia, and it reduced body weight and improved glycemic control in a mouse model of diet-induced obesity. ETC-1002 offers promise as a novel therapeutic approach to improve multiple risk factors associated with metabolic syndrome and benefit patients with cardiovascular disease. 相似文献
62.
Spider silk genes are composed mostly of repetitive sequence that is flanked by non-repetitive terminal regions. Inferences about the evolutionary processes that influenced silk genes have largely been made from analyses using distantly related taxa and ancient silk gene duplicates. These studies have relied on comparisons across the conserved non-repetitive terminal regions to determine orthologous and paralogous relationships, as well as the influence of selection on silk genes. While the repetitive region heavily influences silk fiber mechanical properties, few molecular evolutionary analyses have been conducted on this region due to difficulty in determining homology. Here, we sample internal repetitive and carboxy terminal regions from all extant species of the trapdoor spider genus, Aliatypus. Aliatypus spiders are highly dispersal limited and rely on their silk lined burrow for protection. We determine positional homology across species for the carboxy terminal regions and relative positional homology for the internal repetitive regions. Gene trees based on each of these regions are in good agreement with the Aliatypus species tree, which indicates we sampled single spidroin orthologs in each species. In addition, we find that purifying selection and concerted evolution have acted to conserve Aliatypus spidroin internal repetitive regions. In contrast, selection testing identifies evidence of sites that evolved under positive selection and amino acid replacements that result in radical physicochemical changes in the carboxy terminal region. These findings indicate that comparison of spidroin orthologs across a comprehensive sample of congenerics reveal molecular evolutionary patterns obscured from studies using higher-level sampling of silk encoding genes. 相似文献
63.
Philip J. Robinson Cheryl A. Woolhead 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2013,1833(12):2781-2788
Membrane protein insertion is controlled by proteinaceous factors embedded in the lipid bilayer. Bacterial inner membrane proteins utilise the Sec translocon as the major facilitator of insertion; however some proteins are Sec independent and instead require only YidC. A common feature of YidC substrates is the exposure of a signal anchor sequence when translation is close to completion; this allows minimal time for targeting and favours a post-translational insertion mechanism. Despite this there is little evidence of YidC's post-translational activity. Here we develop an experimental system that uncouples translation and insertion of the endogenous YidC substrate F0c (subunit c of the F0F1 ATP synthase). In this process we (i) develop a novel one step purification method for YidC, including an on column membrane reconstitution, (ii) isolate a soluble form of F0c and (iii) show that incubation of F0c with YidC proteoliposomes results in a high level of membrane integration. Conformational analyses of inserted F0c through Blue Native PAGE and fluorescence quenching reveal a native, oligomerised structure. These data show that YidC can act as a post-translational insertase, a finding which could explain the absence of a ribosome binding domain on YidC. This correlates with the post-translational activity of other YidC family members lacking the ribosome binding domain. 相似文献
64.
This article is part of a Special Issue “Puberty and Adolescence”. 相似文献
65.
66.
Kevin Anderson Yi Chen Zhi Chen Romyr Dominique Kelli Glenn Yang He Cheryl Janson Kin-Chun Luk Christine Lukacs Ann Polonskaia Qi Qiao Aruna Railkar Pamela Rossman Hongmao Sun Qing Xiang Masha Vilenchik Peter Wovkulich Xiaolei Zhang 《Bioorganic & medicinal chemistry letters》2013,23(24):6610-6615
DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented. 相似文献
67.
68.
Background
Environmental exposure to respiratory syncytial virus (RSV) is a leading cause of respiratory infections in infants, but it remains unknown whether this infection is transmitted transplacentally from the lungs of infected mothers to the offspring. We sought to test the hypothesis that RSV travels from the respiratory tract during pregnancy, crosses the placenta to the fetus, persists in the lung tissues of the offspring, and modulates pre- and postnatal expression of growth factors, thereby predisposing to airway hyperreactivity.Methodology
Pregnant rats were inoculated intratracheally at midterm using recombinant RSV expressing red fluorescent protein (RFP). Viral RNA was amplified by RT-PCR and confirmed by sequencing. RFP expression was analyzed by flow cytometry and viral culture. Developmental and pathophysiologic implications of prenatal infection were determined by analyzing the expression of genes encoding critical growth factors, particularly neurotrophic factors and receptors. We also measured the expression of key neurotransmitters and postnatal bronchial reactivity in vertically infected lungs, and assessed their dependence on neurotrophic signaling using selective biological or chemical inhibition.Principal Findings
RSV genome was found in 30% of fetuses, as well as in the lungs of 40% of newborns and 25% of adults. RFP expression was also shown by flow cytometry and replicating virus was cultured from exposed fetuses. Nerve growth factor and its TrkA receptor were upregulated in RSV- infected fetal lungs and co-localized with increased cholinergic innervation. Acetylcholine expression and smooth muscle response to cholinergic stimulation increased in lungs exposed to RSV in utero and reinfected after birth, and blocking TrkA signaling inhibited both effects.Conclusions/Significance
Our data show transplacental transmission of RSV from mother to offspring and persistence of vertically transmitted virus in lungs after birth. Exposure to RSV in utero is followed by dysregulation of neurotrophic pathways predisposing to postnatal airway hyperreactivity upon reinfection with the virus. 相似文献69.
Brian J. Burke William T. Peterson Brian R. Beckman Cheryl Morgan Elizabeth A. Daly Marisa Litz 《PloS one》2013,8(1)
Most modeling and statistical approaches encourage simplicity, yet ecological processes are often complex, as they are influenced by numerous dynamic environmental and biological factors. Pacific salmon abundance has been highly variable over the last few decades and most forecasting models have proven inadequate, primarily because of a lack of understanding of the processes affecting variability in survival. Better methods and data for predicting the abundance of returning adults are therefore required to effectively manage the species. We combined 31 distinct indicators of the marine environment collected over an 11-year period into a multivariate analysis to summarize and predict adult spring Chinook salmon returns to the Columbia River in 2012. In addition to forecasts, this tool quantifies the strength of the relationship between various ecological indicators and salmon returns, allowing interpretation of ecosystem processes. The relative importance of indicators varied, but a few trends emerged. Adult returns of spring Chinook salmon were best described using indicators of bottom-up ecological processes such as composition and abundance of zooplankton and fish prey as well as measures of individual fish, such as growth and condition. Local indicators of temperature or coastal upwelling did not contribute as much as large-scale indicators of temperature variability, matching the spatial scale over which salmon spend the majority of their ocean residence. Results suggest that effective management of Pacific salmon requires multiple types of data and that no single indicator can represent the complex early-ocean ecology of salmon. 相似文献
70.
Joseph E. Donnelly Jeffery J. Honas Bryan K. Smith Matthew S. Mayo Cheryl A. Gibson Debra K. Sullivan Jaehoon Lee Stephen D. Herrmann Kate Lambourne Rik A. Washburn 《Obesity (Silver Spring, Md.)》2013,21(3):E219-E228
Exercise is recommended by public health agencies for weight management; however, the role of exercise is generally considered secondary to energy restriction. Few studies exist that have verified completion of exercise, measured the energy expenditure of exercise, and prescribed exercise with equivalent energy expenditure across individuals and genders.