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81.
Paul R. Clapham Jacqueline D. Reeves Graham Simmons Natalie Dejucq Sam Hibbitts McKnight Aine 《Molecular membrane biology》2013,30(1):49-55
HIV is a persistent virus that survives and replicates despite an onslaught by the host's immune system. A strategy for cell entry, requiring the use of two receptors, has evolved that may help evade neutralizing antibodies. HIV and SIV usually require both CD4 and a seven transmembrane (7TM) coreceptor for infection. At least eleven different 7TM coreceptors have been identified that confer HIV and/ or SIV entry. For HIV-1, the major coreceptors are CCR5 and CXCR4, while the role of other coreceptors for replication and cell tropism in vivo is currently unclear. Polymorphisms in the CCR5 gene that reduce CCR5 expression levels, protect against disease progression, suggesting that drugs targeted to CCR5 could be effective. Such therapies however will not work if HIV simply adapts to use alternative coreceptors. In the light of these themes, this review will discuss the following topics: (i) the coreceptors used by primary HIV-1 and HIV-2 viruses, (ii) the properties and coreceptors of HIV-2 strains that infect cells without CD4, (iii) the role of coreceptors in HIV cell tropism and particularly macrophage infection and (iv) the properties of chemokine receptor ligands that block HIV infection. 相似文献
82.
Anna Drake Christine Rock Sam P. Quinlan David J. Green 《Journal of avian biology》2013,44(4):321-330
We use stable isotope data to investigate the role of winter habitat use in altering the breeding phenology of yellow warblers Setophaga petechia. We first confirm that δ13C and δ15N isotopic signatures vary with winter habitat use in this species. We then examine the relationship between winter habitat use, breeding phenology and productivity within four age‐sex‐classes, since life history theory would predict that carry‐over effects should vary with age and gender. The δ13C signatures of yellow warblers using riparian habitats over winter were more depleted than the signatures of those using agricultural or scrub habitat. Individuals on the Pacific coast of Mexico were also more δ15N enriched than those on the southern Gulf of Mexico. δ13C and δ15N signatures were only correlated with earlier clutch initiation and subsequent higher productivity in first‐breeding‐season females. We estimate that shifts in δ13C equivalent to a shift from scrub to riparian winter habitat would be associated with the production of 0.8 more fledglings by yearling females. Pre‐breeding events that influence the timing of breeding could also influence the reproductive performance of older males and females, but we found little evidence that winter habitat use influenced breeding season phenology in these birds. 相似文献
83.
Dong Song Haonan Wang Catherine Y. Tu Vasilis Z. Marmarelis Robert E. Hampson Sam A. Deadwyler Theodore W. Berger 《Journal of computational neuroscience》2013,35(3):335-357
One key problem in computational neuroscience and neural engineering is the identification and modeling of functional connectivity in the brain using spike train data. To reduce model complexity, alleviate overfitting, and thus facilitate model interpretation, sparse representation and estimation of functional connectivity is needed. Sparsities include global sparsity, which captures the sparse connectivities between neurons, and local sparsity, which reflects the active temporal ranges of the input-output dynamical interactions. In this paper, we formulate a generalized functional additive model (GFAM) and develop the associated penalized likelihood estimation methods for such a modeling problem. A GFAM consists of a set of basis functions convolving the input signals, and a link function generating the firing probability of the output neuron from the summation of the convolutions weighted by the sought model coefficients. Model sparsities are achieved by using various penalized likelihood estimations and basis functions. Specifically, we introduce two variations of the GFAM using a global basis (e.g., Laguerre basis) and group LASSO estimation, and a local basis (e.g., B-spline basis) and group bridge estimation, respectively. We further develop an optimization method based on quadratic approximation of the likelihood function for the estimation of these models. Simulation and experimental results show that both group-LASSO-Laguerre and group-bridge-B-spline can capture faithfully the global sparsities, while the latter can replicate accurately and simultaneously both global and local sparsities. The sparse models outperform the full models estimated with the standard maximum likelihood method in out-of-sample predictions. 相似文献
84.
Hyun‐Joo Lee MinSeok Chang Jong‐Mook Kim HyeJin Hong KiEun Maeng Jane Koo ShinJae Chang Myung‐Sam Cho 《Biotechnology progress》2013,29(2):432-440
Host cell lines developed by genetic engineering sometimes show instabilities in maintaining their genetically acquired phenotypes. Previously, a hybrid host cell line, designated as hybrid of kidney and B cells (HKB), capable of retaining selected phenotypes originally existing in the parental cells was developed via fusion of 293 cells and HH514‐16 cells. Although HKB did indeed successfully preserve several favorable phenotypes, the expression of Epstein‐Barr virus (EBV) specific nuclear antigen 1 (EBNA1), which should be constitutively expressed for host cells to utilize oriP expression vector in transient production of therapeutic proteins, was observed to be unstable. Here, in an attempt to obtain stable expression of EBNA1, a cell type that contains an integrated EBV genome, rather than HH514‐16 cells, which harbor an episomal EBV genome, was applied for fusion with 293 cells. Fusion of 293 cells with Namalwa cells led to the creation of a new type of hybrid, F2N, which was able to stably express EBNA1 while not producing EBV particles. One of the F2N clones, F2N78, was observed to maintain EBNA1 expression for more than 1 year under serum‐free suspension culture conditions along with human specific glycosyl phenotypes observed previously in HKB. In addition, F2N78 was demonstrated to be an appropriate host cell line for both the transient and stable production of recombinant therapeutics with the features of safety expected of production cell lines for human use. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29: 432–440, 2013 相似文献
85.
Roxanne Dutia Andrea J. Kim Matthew Modes Robert Rothlein Jane M. Shen Ye Edward Tian Jumana Ihbais Sam F. Victory Carmen Valcarce Sharon L. Wardlaw 《PloS one》2013,8(6)
Activation of brain melanocortin-4 receptors (MC4-R) by α-melanocyte-stimulating hormone (MSH) or inhibition by agouti-related protein (AgRP) regulates food intake and energy expenditure and can modulate neuroendocrine responses to changes in energy balance. To examine the effects of AgRP inhibition on energy balance, a small molecule, non-peptide compound, TTP2515, developed by TransTech Pharma, Inc., was studied in vitro and in rodent models in vivo. TTP2515 prevented AgRP from antagonizing α-MSH-induced increases in cAMP in HEK 293 cells overexpressing the human MC4-R. When administered to rats by oral gavage TTP2515 blocked icv AgRP-induced increases in food intake, weight gain and adiposity and suppression of T4 levels. In both diet-induced obese (DIO) and leptin-deficient mice, TTP2515 decreased food intake, weight gain, adiposity and respiratory quotient. TTP2515 potently suppressed food intake and weight gain in lean mice immediately after initiation of a high fat diet (HFD) but had no effect on these parameters in lean chow-fed mice. However, when tested in AgRP KO mice, TTP2515 also suppressed food intake and weight gain during HFD feeding. In several studies TTP2515 increased T4 but not T3 levels, however this was also observed in AgRP KO mice. TTP2515 also attenuated refeeding and weight gain after fasting, an effect not evident in AgRP KO mice when administered at moderate doses. This study shows that TTP2515 exerts many effects consistent with AgRP inhibition however experiments in AgRP KO mice indicate some off-target effects of this drug. TTP2515 was particularly effective during fasting and in mice with leptin deficiency, conditions in which AgRP is elevated, as well as during acute and chronic HFD feeding. Thus the usefulness of this drug in treating obesity deserves further exploration, to define the AgRP dependent and independent mechanisms by which TTP2515 exerts its effects on energy balance. 相似文献
86.
Mindy I. Davis Atsuo T. Sasaki Min Shen Brooke M. Emerling Natasha Thorne Sam Michael Rajan Pragani Matthew Boxer Kazutaka Sumita Koh Takeuchi Douglas S. Auld Zhuyin Li Lewis C. Cantley Anton Simeonov 《PloS one》2013,8(1)
Phosphoinositide kinases regulate diverse cellular functions and are important targets for therapeutic development for diseases, such as diabetes and cancer. Preparation of the lipid substrate is crucial for the development of a robust and miniaturizable lipid kinase assay. Enzymatic assays for phosphoinositide kinases often use lipid substrates prepared from lyophilized lipid preparations by sonication, which result in variability in the liposome size from preparation to preparation. Herein, we report a homogeneous 1536-well luciferase-coupled bioluminescence assay for PI5P4Kα. The substrate preparation is novel and allows the rapid production of a DMSO-containing substrate solution without the need for lengthy liposome preparation protocols, thus enabling the scale-up of this traditionally difficult type of assay. The Z’-factor value was greater than 0.7 for the PI5P4Kα assay, indicating its suitability for high-throughput screening applications. Tyrphostin AG-82 had been identified as an inhibitor of PI5P4Kα by assessing the degree of phospho transfer of γ-32P-ATP to PI5P; its inhibitory activity against PI5P4Kα was confirmed in the present miniaturized assay. From a pilot screen of a library of bioactive compounds, another tyrphostin, I-OMe tyrphostin AG-538 (I-OMe-AG-538), was identified as an ATP-competitive inhibitor of PI5P4Kα with an IC50 of 1 µM, affirming the suitability of the assay for inhibitor discovery campaigns. This homogeneous assay may apply to other lipid kinases and should help in the identification of leads for this class of enzymes by enabling high-throughput screening efforts. 相似文献
87.
Werner Scheuer Markus Thomas Petra Hanke Johannes Sam Franz Osl Diana Weininger 《MABS-AUSTIN》2016,8(3):562-573
Vascular endothelial growth factor (VEGF)-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) is a key regulator of blood vessel remodeling and maturation. In tumors, Ang-2 is up-regulated and an unfavorable prognostic factor. Recent data demonstrated that Ang-2 inhibition mediates anti-tumoral effects. We generated a tetravalent bispecific antibody (Ang-2-VEGF-TAvi6) targeting VEGF-A with 2 arms based on bevacizumab (Avastin®), and targeting Ang-2 with 2 arms based on a novel anti-Ang-2 antibody (LC06). The two Ang-2-targeting single-chain variable fragments are disulfide-stabilized and fused to the C-terminus of the heavy chain of bevacizumab. Treatment with Ang-2-VEGF-A-TAvi6 led to a complete abrogation of angiogenesis in the cornea micropocket assay. Metastatic spread and tumor growth of subcutaneous, orthotopic and anti-VEGF-A resistant tumors were also efficiently inhibited. These data further establish Ang-2-VEGF bispecific antibodies as a promising anti-angiogenic, anti-metastatic and anti-tumor agent for the treatment of cancer. 相似文献
88.
89.
Midpoint attractors and species richness: Modelling the interaction between environmental drivers and geometric constraints 下载免费PDF全文
Robert K. Colwell Nicholas J. Gotelli Louise A. Ashton Jan Beck Gunnar Brehm Tom M. Fayle Konrad Fiedler Matthew L. Forister Michael Kessler Roger L. Kitching Petr Klimes Jürgen Kluge John T. Longino Sarah C. Maunsell Christy M. McCain Jimmy Moses Sarah Noben Katerina Sam Legi Sam Arthur M. Shapiro Xiangping Wang Vojtech Novotny 《Ecology letters》2016,19(9):1009-1022
We introduce a novel framework for conceptualising, quantifying and unifying discordant patterns of species richness along geographical gradients. While not itself explicitly mechanistic, this approach offers a path towards understanding mechanisms. In this study, we focused on the diverse patterns of species richness on mountainsides. We conjectured that elevational range midpoints of species may be drawn towards a single midpoint attractor – a unimodal gradient of environmental favourability. The midpoint attractor interacts with geometric constraints imposed by sea level and the mountaintop to produce taxon‐specific patterns of species richness. We developed a Bayesian simulation model to estimate the location and strength of the midpoint attractor from species occurrence data sampled along mountainsides. We also constructed midpoint predictor models to test whether environmental variables could directly account for the observed patterns of species range midpoints. We challenged these models with 16 elevational data sets, comprising 4500 species of insects, vertebrates and plants. The midpoint predictor models generally failed to predict the pattern of species midpoints. In contrast, the midpoint attractor model closely reproduced empirical spatial patterns of species richness and range midpoints. Gradients of environmental favourability, subject to geometric constraints, may parsimoniously account for elevational and other patterns of species richness. 相似文献
90.
Kyu‐Won Kwak Hong‐Soo Choi Sung‐Hee Nam Myung‐Sae Han Eunsun Kim Kwanho Park Heui‐Sam Lee 《Entomological Research》2019,49(12):534-538
This report reveals the structure of a virus extracted from the Korean horn beetle Allomyrina dichotoma. The purified virus particle was 100% identical to Allomyrina virus lef‐8 sequence registered as KM_233709.1. The structure of this virus was confirmed to be closely related to that of the Nudiviridae family, and it was rod shaped and enveloped, and observed to be of approximately the mean length of a single viral nucleocapsid of 200–210 nm and mean diameter of 100–110 nm. These results provide an insight into the structural characteristics of the Nudiviridae family that can be used for nudiviral identification. 相似文献