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981.
Søndergaard H Frederiksen KS Thygesen P Galsgaard ED Skak K Kristjansen PE Odum N Kragh M 《Cancer immunology, immunotherapy : CII》2007,56(9):1417-1428
Interleukin (IL)-21 is a recently discovered cytokine in early clinical development, which has shown anti-tumor activity in
various animal models. In the present study, we examine the anti-tumor activity of IL-21 protein therapy in two syngeneic
tumor models and its effect on the density of tumor infiltrating T cells. We treated mice bearing established subcutaneous
B16 melanomas or RenCa renal cell carcinomas with intraperitoneal (i.p.) or subcutaneous (s.c.) IL-21 protein therapy and
subsequently scored the densities of tumor infiltrating CD4+ and CD8+ T cells by immunohistochemistry. Whereas both routes of IL-21 administration significantly inhibited growth of small, established
RenCa and B16 tumors, only s.c. therapy significantly inhibited the growth of large, established tumors. We found a greater
bioavailability and significant drainage of IL-21 to regional lymph nodes following s.c. administration, which could account
for the apparent increase in anti-tumor activity. Specific depletion of CD8+ T cells with monoclonal antibodies completely abrogated the anti-tumor activity, whereas NK1.1+ cell depletion did not affect tumor growth. In accordance, both routes of IL-21 administration significantly increased the
density of tumor infiltrating CD8+ T cells in both B16 and RenCa tumors; and in the RenCa model s.c. administration of IL-21 led to a significantly higher density
of tumor infiltrating CD8+ T cells compared to i.p. administration. The densities of CD4+ T cells were unchanged following IL-21 treatments. Taken together, these data demonstrate that IL-21 protein has anti-tumor
activity in established syngeneic tumors, and we show that IL-21 therapy markedly increases the density of tumor infiltrating
CD8+ T cells. 相似文献
982.
Berger K Stögbauer F Stoll M Wellmann J Huge A Cheng S Kessler C John U Assmann G Ringelstein EB Funke H 《Human genetics》2007,121(2):169-178
983.
Luci S Giemsa B Kluge H Eder K 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,293(1):R70-R77
This study investigated the effect of clofibrate treatment on expression of target genes of peroxisome proliferator-activated receptor (PPAR)-alpha and various genes of the lipid metabolism in liver and adipose tissue of pigs. An experiment with 18 pigs was performed in which pigs were fed either a control diet or the same diet supplemented with 5 g clofibrate/kg for 28 days. Pigs treated with clofibrate had heavier livers, moderately increased mRNA concentrations of various PPAR-alpha target genes in liver and adipose tissue, a higher concentration of 3-hydroxybutyrate, and markedly lower concentrations of triglycerides and cholesterol in plasma and lipoproteins than control pigs (P < 0.05). mRNA concentrations of sterol regulatory element-binding proteins (SREBP)-1 and -2, insulin-induced genes (Insig)-1 and Insig-2, and the SREBP target genes acetyl-CoA carboxylase, 3-methyl-3-hydroxyglutaryl-CoA reductase, and low-density lipoprotein receptor in liver and adipose tissue and mRNA concentrations of apolipoproteins A-I, A-II, and C-III in the liver were not different between both groups of pigs. In conclusion, this study shows that clofibrate treatment activates PPAR-alpha in liver and adipose tissue and has a strong hypotriglyceridemic and hypocholesterolemic effect in pigs. The finding that mRNA concentrations of some proteins responsible for the hypolipidemic action of fibrates in humans were not altered suggests that there were certain differences in the mode of action compared with humans. It is also shown that PPAR-alpha activation by clofibrate does not affect hepatic expression of SREBP target genes involved in synthesis of triglycerides and cholesterol homeostasis in liver and adipose tissue of pigs. 相似文献
984.
Kreier F Buijs RM 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,293(1):R548-9; author reply R550-2, discussion R553-4
985.
Vajdos FF Hoth LR Geoghegan KF Simons SP LeMotte PK Danley DE Ammirati MJ Pandit J 《Protein science : a publication of the Protein Society》2007,16(5):897-905
Lasofoxifene is a new and potent selective estrogen receptor modulator (SERM). The structural basis of its interaction with the estrogen receptor has been investigated by crystallographic analysis of its complex with the ligand-binding domain of estrogen receptor alpha at a resolution of 2.0 A. As with other SERMs, lasofoxifene diverts the receptor from its agonist-bound conformation by displacing the C-terminal AF-2 helix into the site at which the LXXLL motif of coactivator proteins would otherwise be able to bind. Lasofoxifene achieves this effect by occupying the space normally filled by residue Leu 540, as well as by modulating the conformation of residues of helix 11 (His 524, Leu 525). A well-defined salt bridge between lasofoxifene and Asp 351 suggests that charge neutralization in this region of the receptor may explain the some of the antiestrogenic effects of lasofoxifene. The results suggest general features of ERalpha/SERM recognition, and add a new dimension to efforts to rationalize differences between the biological activity profiles exhibited by these important pharmacological agents. 相似文献
986.
We used gel electrophoresis and mass spectrometry to investigate differences in protein expression in ovarian tissues from Babesia bovis-infected and uninfected southern cattle tick, Rhipicephalus (Boophilus) microplus. Soluble and membrane proteins were extracted from ovaries of adult female ticks, and analyzed by isoelectric focusing (IEF) and one-dimensional or two-dimensional (2-D) gel electrophoresis. Protein patterns were analyzed for differences in expression between infected and uninfected ticks. 2-D separation of proteins revealed a number of proteins that appeared to be up- or down-regulated in response to infection with Babesia, in particular membrane/membrane-associated proteins and proteins in a low molecular mass range between 6 and 36 kDa. A selection of differentially expressed proteins was subjected to analysis by capillary-HPLC-electrospray tandem mass spectrometry (HPLC-ESI-MS/MS). Among the ovarian proteins that were up-regulated in infected ticks were calreticulin, two myosin subunits, an endoplasmic reticulum protein, a peptidyl-prolyl cis–trans isomerase (PPIase), a cytochrome c oxidase subunit, a glutamine synthetase, and a family of Kunitz-type serine protease inhibitors. Among the down-regulated ovarian proteins were another PPIase, a hemoglobin subunit, and a lysozyme. This study is part of an ongoing effort to establish a proteome database that can be utilized to investigate specific proteins involved in successful pathogen transmission. 相似文献
987.
Urbahns K Härter M Albers M Schmidt D Stelte-Ludwig B Brüggemeier U Vaupel A Keldenich J Lustig K Tsujishita H Gerdes C 《Bioorganic & medicinal chemistry letters》2007,17(22):6151-6154
Vitronectin receptor (alpha(V)beta(3)) antagonists have been implicated as a possible new treatment of restenosis following balloon angioplasty. In this work we investigate a series of novel arginine mimetic scaffolds leading to new insight of the alpha(V)beta(3)/ligand interaction. Squaric acid amide 10 is a subnanomolar alpha(V)beta(3) antagonist with improved potency on human smooth muscle cell migration. 相似文献
988.
Lang PA Schenck M Nicolay JP Becker JU Kempe DS Lupescu A Koka S Eisele K Klarl BA Rübben H Schmid KW Mann K Hildenbrand S Hefter H Huber SM Wieder T Erhardt A Häussinger D Gulbins E Lang F 《Nature medicine》2007,13(2):164-170
Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease. 相似文献
989.
Wilgenbus K Hill R Warrander A Kakkar S Steiness E Wessel R 《Nature biotechnology》2007,25(9):967-969
990.
Rainer Seitz Friedger von Auer Johannes Blümel Reinhard Burger Anne Buschmann Klaus Dietz Margarethe Heiden Walter E Hitzler Horst Klamm Thomas Kreil Hans Kretzschmar Micha Nübling Ruth Offergeld Georg Pauli Volkmar Schottstedt Peter Volkers Inga Zerr 《Biologicals》2007,35(2):79-97
Variant Creutzfeldt-Jakob disease (vCJD) is an at present inevitably lethal neurodegenerative disease which can only be diagnosed definitely post mortem. The majority of the approximately 200 victims to date have resided in the UK where most contaminated beef materials entered the food chain. Three cases in the UK demonstrated that vCJD can be transmitted by blood transfusion. Since BSE and vCJD have spread to several countries outside the UK, it appears advisable that specific risk assessments be carried out in different countries and geographic areas. This review explains the approach adopted by Germany in assessing the risk and considering precautionary measures. A fundamental premise is that the feeding chain of cattle and the food chain have been successfully and permanently cleared from contaminated material. This raises the question of whether transmissions via blood transfusions could have the potential to perpetuate vCJD in mankind. A model calculation based on actual population data showed, however, that this would not be the case. Moreover, an exclusion of transfusion recipients from blood donation would add very little to the safety of blood transfusions, but would have a considerable impact on blood supply. Therefore, an exclusion of transfusion recipients was not recommended in Germany. 相似文献