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181.
182.
McEachern KA Nietupski JB Chuang WL Armentano D Johnson J Hutto E Grabowski GA Cheng SH Marshall J 《The journal of gene medicine》2006,8(6):719-729
BACKGROUND: Gaucher disease is the most common of the lysosomal storage disorders. The primary manifestation is the accumulation of glucosylceramide (GL-1) in the macrophages of liver and spleen (Gaucher cells), due to a deficiency in the lysosomal hydrolase glucocerebrosidase (GC). A Gaucher mouse model (D409V/null) exhibiting reduced GC activity and accumulation of GL-1 was used to evaluate adeno-associated viral (AAV)-mediated gene therapy. METHODS: A recombinant AAV8 serotype vector bearing human GC (hGC) was administered intravenously to the mice. The levels of hGC in blood and tissues were determined, as were the effects of gene transfer on the levels of GL-1. Histopathological evaluation was performed on liver, spleen and lungs. RESULTS: Vector administration to pre-symptomatic Gaucher mice resulted in sustained hepatic secretion of hGC at levels that prevented GL-1 accumulation and the appearance of Gaucher cells in the liver, spleen and lungs. AAV administration to older mice with established disease resulted in normalization of GL-1 levels in the spleen and liver and partially reduced that in the lung. Analysis of the bronchoalveolar lavage fluid (BALF) from treated mice showed significant correction of the abnormal cellularity and cell differentials. No antibodies to the expressed hGC were detected following a challenge with recombinant enzyme suggesting the animals were tolerized to human enzyme. CONCLUSIONS: These data demonstrate the effectiveness of AAV-mediated gene therapy at preventing and correcting the biochemical and pathological abnormalities in a Gaucher mouse model, and thus support the continued consideration of this vector as an alternative approach to treating Gaucher disease. 相似文献
183.
Search for the tumor-related proteins of transition cell carcinoma in Taiwan by proteomic analysis 总被引:3,自引:0,他引:3
To better understand the carcinogenesis of bladder cancer in Taiwan, we utilized the proteomic approach to search for potential biomarkers of transitional cell carcinoma (TCC). Analysis by 2-DE and MS/MS indicated that seven proteins are down-regulated and three proteins up-regulated in grade III samples as compared with those of grade II. Of these deregulated proteins, fatty acid binding proteins, annexin V, heat-shock protein 27, and lactate dehydrogenase have been shown to be associated with bladder cancer. Our studies also found altered expression of a group of proteins that have not been documented previously in bladder cancer, including annexin I, 15-hydroxyprostaglandin dehydrogenase, galectin-1, lysophospholipase and mitochondrial short-chain enoyl-coenzyme A hydratase 1 precursor. These results illustrate a pattern of differential protein expression between low- and high-grade tumors and it may be utilized as the molecular fingerprinting of a subset of bladder cancers. In addition, the present study provides a valuable resource in the study of pathological mechanisms in cancers of urothelial origin. The immunohistochemical staining of grade II and III TCC samples with antiserum to annexin I protein was utilized to confirm that the annexin I protein is up-regulated in grade III TCC. 相似文献
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Michael A. Kiebish Rob Bell Kui Yang Toan Phan Zhongdan Zhao William Ames Thomas N. Seyfried Richard W. Gross Jeffrey H. Chuang Xianlin Han 《Journal of lipid research》2010,51(8):2153-2170
Cardiolipin is a class of mitochondrial specific phospholipid, which is intricately involved in mitochondrial functionality. Differences in cardiolipin species exist in a variety of tissues and diseases. It has been demonstrated that the cardiolipin profile is a key modulator of the functions of many mitochondrial proteins. However, the chemical mechanism(s) leading to normal and/or pathological distribution of cardiolipin species remain elusive. Herein, we describe a novel approach for investigating the molecular mechanism of cardiolipin remodeling through a dynamic simulation. This approach applied data from shotgun lipidomic analyses of the heart, liver, brain, and lung mitochondrial lipidomes to model cardiolipin remodeling, including relative content, regiospecificity, and isomeric composition of cardiolipin species. Generated cardiolipin profiles were nearly identical to those determined by shotgun lipidomics. Importantly, the simulated isomeric compositions of cardiolipin species were further substantiated through product ion analysis. Finally, unique enzymatic activities involved in cardiolipin remodeling were assessed from the parameters used in the dynamic simulation of cardiolipin profiles. Collectively, we described, verified, and demonstrated a novel approach by integrating both lipidomic analysis and dynamic simulation to study cardiolipin biology. We believe this study provides a foundation to investigate cardiolipin metabolism and bioenergetic homeostasis in normal and disease states. 相似文献
186.
Rivieccio MA Suh HS Zhao Y Zhao ML Chin KC Lee SC Brosnan CF 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(7):4735-4741
TLR3 functions as a viral nucleic acid sentinel activated by dsRNA viruses and virus replication intermediates within intracellular vesicles. To explore the spectrum of genes induced in human astrocytes by TLR3, we used a microarray approach and the analog polyriboinosinic polyribocytidylic acid (pIC) as ligand. As expected for TLR activation, pIC induced a wide array of cytokines and chemokines known for their role in inflammatory responses, as well as up-regulation of the receptor itself. The data also showed activation of a broad spectrum of antiviral response genes. To determine whether pIC induced an antiviral state in astrocytes, a pseudotyped HIV viral particle, vesicular stomatitis virus g-env-HIV-1, was used. pIC significantly abrogated HIV-1 replication, whereas IL-1, which also potently activates astrocytes, did not. One of the most highly up-regulated genes on microarray was the protein viperin/cig5. We found that viperin/cig5 expression was dependent on IFN regulatory factor 3 and NF-kappaB signaling, and that repetitive stimulation with pIC, but not IL-1, further increased expression. Viperin induction could also be substantially inhibited by neutralizing Abs to IFN-beta, as could HIV-1 replication. To explore a role for viperin in IFN-beta-mediated inhibition of HIV-1, we used an RNA interference (RNAi) approach. RNAi directed against viperin, but not a scrambled RNAi, significantly inhibited viperin expression, and also significantly reversed pIC-induced inhibition of HIV-1 replication. We conclude that viperin contributes to the antiviral state induced by TLR3 ligation in astrocytes, supporting a role for astrocytes as part of the innate immune response against infection in the CNS. 相似文献
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Syndecan-2 was found to detach from RACK1 and associate with caveolin-2 and Ras in cells transformed with oncogenic ras. Most of syndecan-2 from transformed cells was revealed with negligible phosphorylations at tyrosine residues. We experimented with HeLa cells transfected with plasmids encoding syndecan-2 and its mutants (syndecan-2(Y180F), syndecan-2(Y192F), and syndecan-2(Y180,192F)) to provide evidences that PY180 of syndecan-2 is a binding site for RACK1 and is deprived in cells transfected with oncogenic ras. However, in HeLa cells transfected with syndecan-2(Y180F), RACK1 was found to sustain its reactions with syndecan-2 independent of phosphorylation. The finding of syndecan-2 reactive with caveolin-2/Ras suggests the molecular complex most likely to obstruct RACK1 for functional attachment at syndecan-2, as revealed in cells transfected with oncogenic ras. We provided evidences to reinforce the view that molecular rearrangements upon transformation are specific and interesting. 相似文献
189.
Hedgehog (Hh) is a secreted signaling protein that regulates the development of many organ systems. It can travel from its site of synthesis, a process that involves covalent attachment of cholesterol to its carboxyl terminus, proteins with putative sterol sensing domains in both sending and receiving cells, and glycosaminoglycans. Understanding how the movement of Hh is controlled and propelled will be key to understanding how it carries out its essential roles. 相似文献
190.
Resistin and endothelin-1 (ET-1) are upregulated in people with type II diabetes mellitus, central obesity, and hypertension. ET-1 signaling is involved in Ca(2+)-contraction coupling and related to blood pressure regulation. The aim of this study is to investigate the role of resistin on ET-1-increased blood pressure and Ca(2+) signaling. The blood pressure and cytosolic Ca(2+) of vascular smooth muscle cells (VSMCs) of Sprague-Dawley rats were detected. The data demonstrated that resistin accelerated and prolonged ET-1-induced increases in blood pressure and had significant effects on ET-1-increased Ca(2+) reactions. Resistin-enhanced ET-1-increased Ca(2+) reactions were reversed by blockers of store-operated Ca(2+) entry (SOCE) and extracellular-signal-regulated kinase (ERK). The endogenous expression of Orai and stromal interaction molecular (STIM) were characterized in the VSMCs. Furthermore, resistin-enhanced ET-1 Ca(2+) reactions and the resistin-dependent activation of SOCE were abolished under STIM1-siRNA treatment, indicating that STIM1 plays an important role in resistin-enhanced ET-1 Ca(2+) reactions in VSMCs. Resistin appears to exert effects on ET-1-induced Ca(2+) increases by enhancing the activity of ERK-dependent SOCE (STIM1-partcipated), and may accelerate and prolong ET-1-increased blood pressure via the same pathway. 相似文献