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941.
Zuber C Knackmuss S Zemora G Reusch U Vlasova E Diehl D Mick V Hoffmann K Nikles D Fröhlich T Arnold GJ Brenig B Wolf E Lahm H Little M Weiss S 《Journal of molecular biology》2008,378(3):530-539
The 37-kDa/67-kDa laminin receptor precursor/laminin receptor (LRP/LR) acting as a receptor for prions and viruses is overexpressed in various cancer cell lines, and their metastatic potential correlates with LRP/LR levels. We analyzed the tumorigenic fibrosarcoma cell line HT1080 regarding 37-kDa/67-kDa LRP/LR levels and its invasive potential. Compared to the less invasive embryonic fibroblast cell line NIH3T3, the tumorigenic HT1080 cells display approximately 1.6-fold higher cell-surface levels of LRP/LR. We show that anti-LRP/LR tools interfere with the invasive potential of HT1080 cells. Anti-LRP/LR single-chain variable fragment antibody (scFv) iS18 generated by chain shuffling from parental scFv S18 and its full-length version immunoglobulin G1-iS18 reduced the invasive potential of HT1080 cells significantly by 37% and 38%, respectively. HT1080 cells transfected with lentiviral plasmids expressing small interfering RNAs directed against LRP mRNA showed reduced LRP levels by approximately 44%, concomitant with a significant decrease in the invasive potential by approximately 37%. The polysulfated glycans HM2602 and pentosan polysulfate (SP-54), both capable of blocking LRP/LR, reduced the invasive potential by 20% and 35%, respectively. Adhesion of HT1080 cells to laminin-1 was significantly impeded by scFv iS18 and immunoglobulin G1-iS18 by 60% and 68%, respectively, and by SP-54 and HM2602 by 80%, suggesting that the reduced invasive capacity achieved by these tools is due to the perturbation of the LRP/LR-laminin interaction on the cell surface. Our in vitro data suggest that reagents directed against LRP/LR or LRP mRNA such as antibodies, polysulfated glycans, or small interfering RNAs, previously shown to encompass an anti-prion activity by blocking or downregulating the prion receptor LRP/LR, might also be potential cancer therapeutics blocking metastasis by interfering with the LRP/LR-laminin interaction in neoplastic tissues. 相似文献
942.
In this study, we have optimized NMR methodology to determine the thermodynamic parameters of basepair opening in DNA and RNA duplexes by characterizing the temperature dependence of imino proton exchange rates of individual basepairs. Contributions of the nuclear Overhauser effect to exchange rates measured with inversion recovery experiments are quantified, and the influence of intrinsic and external catalysis exchange mechanisms on the imino proton exchange rates is analyzed. Basepairs in DNA and RNA have an approximately equal stability, and the enthalpy and entropy values of their basepair dissociation are correlated linearly. Furthermore, the compensation temperature, T(c), which is derived from the slope of the correlation, coincides with the melting temperature, and duplex unfolding occurs at that temperature where all basepairs are equally thermodynamically stable. The impact of protium-deuterium exchange of the imino hydrogen on the free energy of RNA basepair opening is investigated, and it is found that two A·U basepairs show distinct fractionation factors. 相似文献
943.
Merging two arylamidoalkyl substituted phenylpiperazines as prototypical recognition elements for dopamine D(2)-like receptors by oligoethylene glycol linkers led to a series of bivalent ligands. These dimers were investigated in comparison to their monomeric analogues for their dopamine D(2long), D(2short), D(3) and D(4) receptor binding. Radioligand binding experiments revealed strong bivalent effects for some para-substituted benzamide derivatives. For the D(3) subtype, the target compounds 32, 34 and 36 showed an up to 70-fold increase of affinity and a substantial enhancement of subtype selectivity when compared to the monovalent analogue 24. Analysis of the binding curves displayed Hill slopes very close to one indicating that the bivalent ligands displace 1equiv of radioligand. Obviously, the two pharmacophores occupy an orthosteric and an allosteric binding site rather than adopting a receptor-bridging binding mode. 相似文献
944.
Xiaoli Du Cornelia Herrfurth Thomas Gottlieb Steffen Kawelke Kristin Feussner Harald Rühling Ivo Feussner Markus Maniak 《Eukaryotic cell》2014,13(4):517-526
Triacylglycerol (TAG), the common energy storage molecule, is formed from diacylglycerol and a coenzyme A-activated fatty acid by the action of an acyl coenzyme A:diacylglycerol acyltransferase (DGAT). In order to conduct this step, most organisms rely on more than one enzyme. The two main candidates in Dictyostelium discoideum are Dgat1 and Dgat2. We show, by creating single and double knockout mutants, that the endoplasmic reticulum (ER)-localized Dgat1 enzyme provides the predominant activity, whereas the lipid droplet constituent Dgat2 contributes less activity. This situation may be opposite from what is seen in mammalian cells. Dictyostelium Dgat2 is specialized for the synthesis of TAG, as is the mammalian enzyme. In contrast, mammalian DGAT1 is more promiscuous regarding its substrates, producing diacylglycerol, retinyl esters, and waxes in addition to TAG. The Dictyostelium Dgat1, however, produces TAG, wax esters, and, most interestingly, also neutral ether lipids, which represent a significant constituent of lipid droplets. Ether lipids had also been found in mammalian lipid droplets, but the role of DGAT1 in their synthesis was unknown. The ability to form TAG through either Dgat1 or Dgat2 activity is essential for Dictyostelium to grow on bacteria, its natural food substrate. 相似文献
945.
Reinhard Hilbig Harald Rösner Gertraude Merz Kordula Segler-Stahl Hinrich Rahmann 《Development genes and evolution》1982,191(4):281-284
Summary Developmental profiles of 11 gangliosides, concentration of lipid- and glycoprotein-bound sialic acid, and activity of AChE of the rat and mouse cerebral cortex were followed from the 7th day of gestation to the 21st postnatal day.There are three main changes in ganglioside concentration, which are similar in both species. The first occurs from gestation day 10 until birth: parallel to decreased proliferation, cell migration, and neuroblast differentiation, GM3 and GD3 in mouse cortex and GD3 in the rat's decreases in favor of GQ1b, GT1b, and GD1a.The second occurs from birth until the first postnatal week: Parallel to increased growth and arborization of dendrites and axons as well as synaptogenesis in rats and mice, there is a two-fold rise of GD1a, whereas GQ1b and GT1b remain on a nearly constant level. Concomitantly, GM3 and GD3 decreases. The third period of ganglioside changes starts in the second postnatal week, parallel to onset of myelination, and is characterized by an increase of GM1 in parallel with a decrease of the polysialogangliosides GT1b and GQ1b. 相似文献
946.
Understanding the impact of anthropogenic threats, such as light pollution, on biodiversity is necessary to establish effective guidelines to protect diminishing wildlife. In this study, we examined the effect of artificial light at night (ALAN) on the roosting behaviour of Chimney Swifts Chaetura pelagica, a highly threatened migratory bird species that lives commensally with humans, where it often breeds and roosts in artificial structures such as chimneys. Although Chimney Swifts are known to use time of sunset in combination with temperature, wind and season to coordinate roost entry, we predicted that high ALAN exposure would override these natural cues and lead to a delayed entry compared with sites with less light pollution. To test this, we examined the effects of ALAN on the start and end times of entry to 21 roosting sites located along a light pollution gradient in New Jersey and the New York Metropolitan area. We found that ALAN was a significant predictor of roosting entry time, with birds entering later in sites with more light pollution. While Chimney Swifts initiated roosting earlier in the summer months compared with the autumn, this effect was absent in areas with high light pollution. These findings highlight the need to determine the causes and consequences of light pollution effects. 相似文献
947.
Protective and therapeutic capacity of human single-chain Fv-Fc fusion proteins against West Nile virus 总被引:5,自引:0,他引:5 下载免费PDF全文
Gould LH Sui J Foellmer H Oliphant T Wang T Ledizet M Murakami A Noonan K Lambeth C Kar K Anderson JF de Silva AM Diamond MS Koski RA Marasco WA Fikrig E 《Journal of virology》2005,79(23):14606-14613
West Nile virus has spread rapidly across the United States, and there is currently no approved human vaccine or therapy to prevent or treat disease. Passive immunization with antibodies against the envelope protein represents a promising means to provide short-term prophylaxis and treatment for West Nile virus infection. In this study, we identified a panel of 11 unique human single-chain variable region antibody fragments (scFvs) that bind the envelope protein of West Nile virus. Selected scFvs were converted to Fc fusion proteins (scFv-Fcs) and were tested in mice for their ability to prevent lethal West Nile virus infection. Five of these scFv-Fcs, 11, 15, 71, 85, and 95, protected 100% of mice from death when given prior to infection with virus. Two of them, 11 and 15, protected 80% of mice when given at days 1 and 4 after infection. In addition, four of the scFv-Fcs cross-neutralized dengue virus, serotype 2. Binding assays using yeast surface display demonstrated that all of our scFvs bind to sites within domains I and II of West Nile virus envelope protein. These recombinant human scFvs are potential candidates for immunoprophylaxis and therapy of flavivirus infections. 相似文献
948.
Heat shock protein 90 regulates stabilization rather than activation of soluble guanylate cyclase 总被引:1,自引:0,他引:1
Endothelium-derived nitric oxide (NO) activates the heterodimeric heme protein soluble guanylate cyclase (sGC) to form cGMP. In different disease states, sGC levels and activity are diminished possibly involving the sGC binding chaperone, heat shock protein 90 (hsp90). Here we show that prolonged hsp90 inhibition in different cell types reduces protein levels of both sGC subunits by about half, an effect that was prevented by the proteasome inhibitor MG132. Conversely, acute hsp90 inhibition affected neither basal nor NO-stimulated sGC activity. Thus, hsp90 is a molecular stabilizer for sGC tonically preventing proteasomal degradation rather than having a role in short-term activity regulation. 相似文献
949.
950.
The clonal structure of the pancreas was analysed in neonatal and adult mouse chimeras in which one partner displayed cell
patches expressing green fluorescent protein (eGFP). Coherent growth during pancreatic histogenesis was suggested by the presence
of large eGFP-labelled acinar clusters rather than a scattered distribution of individual labelled acinar cells. The adult
chimeric pancreas contained monophenotypic acini, whereas surprisingly 5% of acini in neonates were polyclonal. Monophenotypic
acini presumably arose by coherent expansion leading to large 3D patches and may not be monoclonal. Islets of Langerhans were
oligoclonal at both ages investigated. The proportion of eGFP positive cells within islets did not correlate with that of
the surrounding acinar tissue indicating clonal independence of islets from their neighbourhood. The patterns observed argue
against a secondary contribution of blood-borne progenitor/stem cells to the acinar compartment during tissue turnover. The
different clonal origins of acini and islets are integrated into a model of pancreatic histogenesis. 相似文献