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51.
Gert Carra Nicole Tegtmeyer Tim Geppert Peter Schröder Norbert Sewald Steffen Backert Silja Wessler 《EMBO reports》2010,11(10):798-804
Mammalian and prokaryotic high‐temperature requirement A (HtrA) proteins are chaperones and serine proteases with important roles in protein quality control. Here, we describe an entirely new function of HtrA and identify it as a new secreted virulence factor from Helicobacter pylori, which cleaves the ectodomain of the cell‐adhesion protein E‐cadherin. E‐cadherin shedding disrupts epithelial barrier functions allowing H. pylori designed to access the intercellular space. We then designed a small‐molecule inhibitor that efficiently blocks HtrA activity, E‐cadherin cleavage and intercellular entry of H. pylori. 相似文献
52.
Emmanuel Ngeufa Happi Alain Tadjong Tcho Jovita Chi Sirri Jean Duplex Wansi Beate Neumann Hans-Georg Stammler Jean Wandji Norbert Sewald 《Phytochemistry letters》2012,5(3):423-426
Two new tirucallane triterpenoids, 21-methoxy-21,23-epoxy-tirucalla-7,24-dien-3α-ol (1) and 21-methoxy-21,23-epoxy-tirucalla-7,24-diene-1α,3α-diol (2), together with thirteen known compounds were isolated from the CH2Cl2 extract of the stem bark of Araliopsis synopsis. The structures of the compounds were determined by comprehensive analyses of their 1D and 2D NMR, mass spectral (EI and ESI) data and comparison with previously known analogs. Compounds 1–10 were tested against bacteria, fungi and plant pathogen oomycetes by the paper disk agar diffusion assay resulting in missing to low activities corresponding with MICs > 1 mg/mL. However, compounds 5–10 exhibited high cytotoxic activity against the human Caucasian prostate adenocarcinoma cell PC-3 line, with IC50 8.5–12.5 μM compared to the standard Doxorubicin with IC50 = 0.9 μM, while compounds 1, 3 and 4 showed low activity. 相似文献
53.
Background
The prediction of the outcomes from multistage breeding schemes is especially important for the introduction of genomic selection in dairy cattle. Decorrelated selection indices can be used for the optimisation of such breeding schemes. However, they decrease the accuracy of estimated breeding values and, therefore, the genetic gain to an unforeseeable extent and have not been applied to breeding schemes with different generation intervals and selection intensities in each selection path.Methods
A grid search was applied in order to identify optimum breeding plans to maximise the genetic gain per year in a multistage, multipath dairy cattle breeding program. In this program, different values of the accuracy of estimated genomic breeding values and of their costs per individual were applied, whereby the total breeding costs were restricted. Both decorrelated indices and optimum selection indices were used together with fast multidimensional integration algorithms to produce results.Results
In comparison to optimum indices, the genetic gain with decorrelated indices was up to 40% less and the proportion of individuals undergoing genomic selection was different. Additionally, the interaction between selection paths was counter-intuitive and difficult to interpret. Independent of using decorrelated or optimum selection indices, genomic selection replaced traditional progeny testing when maximising the genetic gain per year, as long as the accuracy of estimated genomic breeding values was ≥ 0.45. Overall breeding costs were mainly generated in the path "dam-sire". Selecting males was still the main source of genetic gain per year.Conclusion
Decorrelated selection indices should not be used because of misleading results and the availability of accurate and fast algorithms for exact multidimensional integration. Genomic selection is the method of choice when maximising the genetic gain per year but genotyping females may not allow for a reduction in overall breeding costs. Furthermore, the economic justification of genotyping females remains questionable. 相似文献54.
Norbert Schormann Sadanandan E. Velu Srinivasan Murugesan Olga Senkovich Kiera Walker Bala C. Chenna Bidhan Shinkre Amar Desai Debasish Chattopadhyay 《Bioorganic & medicinal chemistry》2010,18(11):4056-4066
Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a potential target for developing drugs to treat Chagas’ disease. We have undertaken a detailed structure–activity study of this enzyme. We report here synthesis and characterization of six potent inhibitors of the parasitic enzyme. Inhibitory activity of each compound was determined against T. cruzi and human DHFR. One of these compounds, ethyl 4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b) was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of T. cruzi and the crystal structure of the ternary enzyme:cofactor:inhibitor complex was determined. Molecular docking was used to analyze the potential interactions of all inhibitors with T. cruzi DHFR and human DHFR. Inhibitory activities of these compounds are discussed in the light of enzyme–ligand interactions. Binding affinities of each inhibitor for the respective enzymes were calculated based on the experimental or docked binding mode. An estimated 60–70% of the total binding energy is contributed by the 2,4-diaminoquinazoline scaffold. 相似文献
55.
Christian Rosenberg Andrea Jahn Tilman Pickartz Ulrich Wahnschaffe Maciej Patrzyk Norbert Hosten 《PloS one》2014,9(12)
Objective
To evaluate the potency of Gd-EOB-DTPA to support hepatic catheter placement in laser ablation procedures by quantifying time-dependent delineation effects for instrumentation and target tumor within liver parenchyma. Monitoring potential influence on online MR thermometry during the ablation procedure is a secondary aim.Materials and Methods
30 cases of MR-guided laser ablation were performed after i.v. bolus injection of gadoxetic acid (0.025 mmol/Kg Gd-EOB-DTPA; Bayer Healthcare, Berlin, Germany). T1-weighted GRE sequences were used for applicator guidance (FLASH 3D) in the catheter placement phase and for therapy monitoring (FLASH 2D) in the therapy phase. SNR and consecutive CNR values were measured for elements of interest plotted over time both for catheter placement and therapy phase and compared with a non-contrast control group of 19 earlier cases. Statistical analysis was realized using the paired Wilcoxon test.Results
Sustainable signal elevation of liver parenchyma in the contrast-enhanced group was sufficient to silhouette both target tumor and applicator against the liver. Differences in time dependent CNR alteration were highly significant between contrast-enhanced and non-contrast interventions for parenchyma and target on the one hand (p = 0.020) and parenchyma and instrument on the other hand (p = 0.002). Effects lasted for the whole procedure (monitoring up to 60 min) and were specific for the contrast-enhanced group. Contrasting maxima were seen after median 30 (applicator) and 38 (tumor) minutes, in the potential core time of a multineedle procedure. Contrast influence on T1 thermometry for real-time monitoring of thermal impact was not significant (p = 0.068–0.715).Conclusion
Results strongly support anticipated promotive effects of Gd-EOB-DTPA for MR-guided percutaneous liver interventions by proving and quantifying the delineating effects for therapy-relevant elements in the procedure. Time benefit, cost effectiveness and oncologic outcome of the described beneficiary effects will have to be part of further investigations. 相似文献56.
SC Joachim OW Gramlich P Laspas H Schmid S Beck HD von Pein HB Dick N Pfeiffer FH Grus 《PloS one》2012,7(7):e40616
Background
Antibodies against retinal and optic nerve antigens are detectable in glaucoma patients. Recent studies using a model of experimental autoimmune glaucoma demonstrated that immunization with certain ocular antigens causes an immun-mediated retinal ganglion cell loss in rats.Methodology/Principal Findings
Rats immunized with a retinal ganglion cell layer homogenate (RGA) had a reduced retinal ganglion cell density on retinal flatmounts (p = 0.007) and a lower number of Brn3+retinal ganglion cells (p = 0.0001) after six weeks. The autoreactive antibody development against retina and optic nerve was examined throughout the study. The levels of autoreactive antibodies continuously increased up to 6 weeks (retina: p = 0.004; optic nerve: p = 0.000003). Additionally, antibody deposits were detected in the retina (p = 0.02). After 6 weeks a reactive gliosis (GFAP density: RGA: 174.7±41.9; CO: 137.6±36.8, p = 0.0006; %GFAP+ area: RGA: 8.5±3.4; CO: 5.9±3.6, p = 0.006) as well as elevated level of Iba1+ microglia cells (p = 0.003) was observed in retinas of RGA animals.Conclusions/Significance
Our findings suggest that these antibodies play a substantial role in mechanisms leading to retinal ganglion cell death. This seems to lead to glia cell activation as well as the invasion of microglia, which might be associated with debris clearance. 相似文献57.
Kusche-Gullberg M Nybakken K Perrimon N Lindahl U 《The Journal of biological chemistry》2012,287(26):21950-21956
Heparan sulfate (HS) proteoglycans play critical roles in a wide variety of biological processes such as growth factor signaling, cell adhesion, wound healing, and tumor metastasis. Functionally important interactions between HS and a variety of proteins depend on specific structural features within the HS chains. The fruit fly (Drosophila melanogaster) is frequently applied as a model organism to study HS function in development. Previous structural studies of Drosophila HS have been restricted to disaccharide composition, without regard to the arrangement of saccharide domains typically found in vertebrate HS. Here, we biochemically characterized Drosophila HS by selective depolymerization with nitrous acid. Analysis of the generated saccharide products revealed a novel HS design, involving a peripheral, extended, presumably single, N-sulfated domain linked to an N-acetylated sequence contiguous with the linkage to core protein. The N-sulfated domain may be envisaged as a heparin structure of unusually low O-sulfate content. 相似文献
58.
Phylogeography of the Lacerta viridis complex: mitochondrial and nuclear markers provide taxonomic insights 下载免费PDF全文
Ellen Marzahn Ulrich Joger Çetin Ilgaz Daniel Jablonski Carolin Kindler Yusuf Kumlutaş Annamaria Nistri Norbert Schneeweiss Melita Vamberger Anamarija Žagar Uwe Fritz 《Journal of Zoological Systematics and Evolutionary Research》2016,54(2):85-105
Based on broad, nearly rangewide sampling, we reanalysed the phylogeography of the Lacerta viridis complex using the mitochondrial cytochrome b gene and the intron 7 of the nuclear β‐fibrinogen gene. Using the mitochondrial marker, we identified in phylogenetic analyses 10 terminal clades clustering in four deeply divergent main lineages whose relationships are weakly resolved. These lineages correspond to Lacerta bilineata, L. viridis, the previously identified Adriatic or West Balkan lineage and a newly discovered fourth lineage from the Anatolian Black Sea coast and the south‐eastern Balkan Peninsula. Except for the latter lineage, there is considerable phylogeographic structuring in each lineage, with higher diversity in the south of the distribution ranges. This pattern indicates the existence of two distinct microrefugia in the Italian Peninsula and Sicily and of up to seven microrefugia in the Balkan Peninsula, but of only one refugium along the Black Sea coast of Anatolia. We identified secondary contact zones of the main lineages and of terminal clades within these lineages. However, most of the formerly described putative contact zone of L. bilineata and L. viridis turned out to be a contact zone between the Adriatic lineage and L. viridis, but L. bilineata seems to be involved only marginally. Our nuclear marker could not unambiguously resolve whether there is gene flow in contact zones. Thus, further research is necessary to decide whether the four main lineages are conspecific or whether they represent distinct biological species. We restrict the name L. v. meridionalis to the newly identified genetic lineage from Turkey and south‐eastern Europe, synonymize some previously recognized taxa and suggest a tentative nomenclature for the L. viridis complex. 相似文献
59.
Roldan M de Guia Adam J Rose Anke Sommerfeld Oksana Seibert Daniela Strzoda Annika Zota Yvonne Feuchter Anja Krones‐Herzig Tjeerd Sijmonsma Milen Kirilov Carsten Sticht Norbert Gretz Geesje Dallinga‐Thie Sven Diederichs Nora Klöting Matthias Blüher Mauricio Berriel Diaz Stephan Herzig 《The EMBO journal》2015,34(3):344-360
In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)‐379/410 genomic cluster as a key component of GC/GR‐driven metabolic dysfunction. Particularly, miR‐379 was up‐regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR‐dependent manner. Hepatocyte‐specific silencing of miR‐379 substantially reduced circulating very‐low‐density lipoprotein (VLDL)‐associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR‐379 effects on key receptors in hepatic TG re‐uptake. As hepatic miR‐379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR‐controlled miRNA cluster not only defines a novel layer of hormone‐dependent metabolic control but also paves the way to alternative miRNA‐based therapeutic approaches in metabolic dysfunction. 相似文献
60.
René H?hn Ulrike Kottler Tunde Peto Maria Blettner Thomas Münzel Stefan Blankenberg Karl J. Lackner Manfred Beutel Philipp S. Wild Norbert Pfeiffer 《PloS one》2015,10(3)