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991.
Tojo T Spears GW Tsuji K Nishimura H Ogino T Seki N Sugiyama A Matsuo M 《Bioorganic & medicinal chemistry letters》2002,12(17):2427-2430
A series of quinoline-3-carbothioamides and their analogues was prepared via four synthetic routes and evaluated for their antinephritic and immunomodulating activities. The optimal compound 9g strongly inhibited the T-cell independent antibody production in mice immunized with TNP-LPS and was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice. 相似文献
992.
Selwood DL Brummell DG Glen RC Goggin MC Reynolds K Tatlock MA Wishart G 《Bioorganic & medicinal chemistry letters》2001,11(8):1089-1092
A lipophilicity constrained library of 5-carboxamido 1-benzyl-3-(3-dimethylaminopropyloxy)-1H-pyrazoles was prepared by solution-phase parallel synthesis with removal of acidic by-products using the strongly basic MP-carbonate resin. Compounds show both activation of soluble guanylate cyclase and inhibition of platelet aggregation. Compound 12 also shows 22% oral bioavailability in rats. 相似文献
993.
Shilpi Arora Ronald L. Korn Elizabeth Lenkiewicz Irene Cherni Thomas G. Beach Galen Hostetter Michael T. Barrett Glen J. Weiss 《PloS one》2012,7(9)
Background
Maxillary sinus carcinoma (MSC) is a rare cancer of the head and neck region. Patients are treated with surgery, radiation therapy, and chemotherapy and the treatment regimen is based on patient’s age, general health condition, disease stage, and its extent of spread. There is very little information available on the genetics of this disease. DNA content based flow sorting of tumor cells followed by array comparative genomic hybridization allows for high definition global assessment of distinct clonal changes within tumor populations.Methods
We applied this technique to primary and metastatic samples collected from a patient with radio- and chemotherapy refractory maxillary sinus carcinoma to gauge the progression of this disease.Results
A clonal KIT amplicon was present in aneuploid populations sorted from the primary tumor and in divergent subclones arising in metastatic foci found in the brain, lung, and jejunum. The evolution of these subclones was associated with distinct genetic aberrations and DNA ploidies.Conclusion
The information presented here paves the path to understanding the development and progression of this disease. 相似文献994.
Winnie S. Liang David W. Craig John Carpten Mitesh J. Borad Michael J. Demeure Glen J. Weiss Tyler Izatt Shripad Sinari Alexis Christoforides Jessica Aldrich Ahmet Kurdoglu Michael Barrett Lori Phillips Hollie Benson Waibhav Tembe Esteban Braggio Jeffrey A. Kiefer Christophe Legendre Richard Posner Galen H. Hostetter Angela Baker Jan B. Egan Haiyong Han Douglas Lake Edward C. Stites Ramesh K. Ramanathan Rafael Fonseca A. Keith Stewart Daniel Von Hoff 《PloS one》2012,7(10)
995.
Coburn GA Fisch DN Moorji SM de Muys JM Murga JD Paul D Provoncha KP Rotshteyn Y Han AQ Qian D Maddon PJ Olson WC 《PloS one》2012,7(4):e35351
Combinations of direct-acting anti-virals offer the potential to improve the efficacy, tolerability and duration of the current treatment regimen for hepatitis C virus (HCV) infection. Viral entry represents a distinct therapeutic target that has been validated clinically for a number of pathogenic viruses. To discover novel inhibitors of HCV entry, we conducted a high throughput screen of a proprietary small-molecule compound library using HCV pseudoviral particle (HCVpp) technology. We independently discovered and optimized a series of 1,3,5-triazine compounds that are potent, selective and non-cytotoxic inhibitors of HCV entry. Representative compounds fully suppress both cell-free virus and cell-to-cell spread of HCV in vitro. We demonstrate, for the first time, that long term treatment of an HCV cell culture with a potent entry inhibitor promotes sustained viral clearance in vitro. We have confirmed that a single amino acid variant, V719G, in the transmembrane domain of E2 is sufficient to confer resistance to multiple compounds from the triazine series. Resistance studies were extended by evaluating both the fusogenic properties and growth kinetics of drug-induced and natural amino acid variants in the HCVpp and HCV cell culture assays. Our results indicate that amino acid variations at position 719 incur a significant fitness penalty. Introduction of I719 into a genotype 1b envelope sequence did not affect HCV entry; however, the overall level of HCV replication was reduced compared to the parental genotype 1b/2a HCV strain. Consistent with these findings, I719 represents a significant fraction of the naturally occurring genotype 1b sequences. Importantly, I719, the most relevant natural polymorphism, did not significantly alter the susceptibility of HCV to the triazine compounds. The preclinical properties of these triazine compounds support further investigation of entry inhibitors as a potential novel therapy for HCV infection. 相似文献
996.
Glen Saunders Brian Cooke Ken McColl Richard Shine Tony Peacock 《Biological Control》2010,52(3):288-295
Vertebrate pests cost Australia at least $1 billion annually in lost agricultural production and environmental damage. The spectacular success of myxomatosis in the 1950s and more recently, rabbit hemorrhagic disease, in the biological control of European rabbits has led to ongoing research into similar solutions for other vertebrate pests. There are significant barriers to the successful employment of biological control options including the obvious technological ones, such as host-specificity, as well as the investment required, public concerns and regulatory requirements. The role of biological control in vertebrate pest management and the attempts to develop such strategies in Australia is reviewed with emphasis on species specific case studies for rabbits, cane toads and carp, and the generic approaches of immunocontraception and daughterless genes. 相似文献
997.
Adenovirus core protein pVII is translocated into the nucleus by multiple import receptor pathways 下载免费PDF全文
Wodrich H Cassany A D'Angelo MA Guan T Nemerow G Gerace L 《Journal of virology》2006,80(19):9608-9618
Adenoviruses are nonenveloped viruses with an approximately 36-kb double-stranded DNA genome that replicate in the nucleus. Protein VII, an abundant structural component of the adenovirus core that is strongly associated with adenovirus DNA, is imported into the nucleus contemporaneously with the adenovirus genome shortly after virus infection and may promote DNA import. In this study, we evaluated whether protein VII uses specific receptor-mediated mechanisms for import into the nucleus. We found that it contains potent nuclear localization signal (NLS) activity by transfection of cultured cells with protein VII fusion constructs and by microinjection of cells with recombinant protein VII fusions. We identified three NLS-containing regions in protein VII by deletion mapping and determined important NLS residues by site-specific mutagenesis. We found that recombinant protein VII and its NLS-containing domains strongly and specifically bind to importin alpha, importin beta, importin 7, and transportin, which are among the most abundant cellular nuclear import receptors. Moreover, these receptors can mediate the nuclear import of protein VII fusions in vitro in permeabilized cells. Considered together, these data support the hypothesis that protein VII is a major NLS-containing adaptor for receptor-mediated import of adenovirus DNA and that multiple import pathways are utilized to promote efficient nuclear entry of the viral genome. 相似文献
998.
Jack H. Westwood Lucy Mccann Matthew Naish Heather Dixon Alex M. Murphy Matthew A. Stancombe Mark H. Bennett Glen Powell Alex A. R. Webb John P. Carr 《Molecular Plant Pathology》2013,14(2):158-170
Cucumber mosaic virus (CMV) encodes the 2b protein, which plays a role in local and systemic virus movement, symptom induction and suppression of RNA silencing. It also disrupts signalling regulated by salicylic acid and jasmonic acid. CMV induced an increase in tolerance to drought in Arabidopsis thaliana. This was caused by the 2b protein, as transgenic plants expressing this viral factor showed increased drought tolerance, but plants infected with CMVΔ2b, a viral mutant lacking the 2b gene, did not. The silencing effector ARGONAUTE1 (AGO1) controls a microRNA‐mediated drought tolerance mechanism and, in this study, we noted that plants (dcl2/3/4 triple mutants) lacking functional short‐interfering RNA‐mediated silencing were also drought tolerant. However, drought tolerance engendered by CMV may be independent of the silencing suppressor activity of the 2b protein. Although CMV infection did not alter the accumulation of the drought response hormone abscisic acid (ABA), 2b‐transgenic and ago1‐mutant seeds were hypersensitive to ABA‐mediated inhibition of germination. However, the induction of ABA‐regulated genes in 2b‐transgenic and CMV‐infected plants was inhibited more strongly than in ago1‐mutant plants. The virus engenders drought tolerance by altering the characteristics of the roots and not of the aerial tissues as, compared with the leaves of silencing mutants, leaves excised from CMV‐infected or 2b‐transgenic plants showed greater stomatal permeability and lost water more rapidly. This further indicates that CMV‐induced drought tolerance is not mediated via a change in the silencing‐regulated drought response mechanism. Under natural conditions, virus‐induced drought tolerance may serve viruses by aiding susceptible hosts to survive periods of environmental stress. 相似文献
999.
Impaired calcium pump function does not slow relaxation in human skeletal muscle after prolonged exercise 总被引:2,自引:0,他引:2
Booth John; McKenna Michael J.; Ruell Patricia A.; Gwinn Tom H.; Davis Glen M.; Thompson Martin W.; Harmer Alison R.; Hunter Sandra K.; Sutton John R. 《Journal of applied physiology》1997,83(2):511-521
Booth, John, Michael J. McKenna, Patricia A. Ruell, Tom H. Gwinn, Glen M. Davis, Martin W. Thompson, Alison R. Harmer, Sandra K. Hunter, and John R. Sutton. Impaired calcium pump function doesnot slow relaxation in human skeletal muscle after prolonged exercise.J. Appl. Physiol. 83(2): 511-521, 1997.This study examined the effects of prolonged exercise on humanquadriceps muscle contractile function and homogenate sarcoplasmicreticulum Ca2+ uptake andCa2+-adenosinetriphosphataseactivity. Ten untrained men cycled at 75 ± 2% (SE) peak oxygenconsumption until exhaustion. Biopsies were taken from theright vastus lateralis muscle at rest, exhaustion, and 20 and 60 minpostexercise. Peak tension and half relaxation time of the leftquadriceps muscle were measured during electrically evoked twitch andtetanic contractions and a maximal voluntary isometric contraction atrest, exhaustion, and 10, 20, and 60 min postexercise. At exhaustion,homogenate Ca2+ uptake andCa2+ adenosinetriphosphataseactivity were reduced by 17 ± 4 and 21 ± 5%, respectively, andremained depressed after 60 min recovery (P 0.01). Muscle ATP, creatinephosphate, and glycogen were all depressed at exhaustion(P 0.01). Peak tension during a maximal voluntary contraction, a twitch, and a 10-Hz stimulation werereduced after exercise by 28 ± 3, 45 ± 6, 65 ± 5%,respectively (P 0.01), but noslowing of half relaxation times were found. Thus fatigue induced byprolonged exercise reduced muscleCa2+ uptake, but this did notcause a slower relaxation of evoked contractions. 相似文献
1000.
We propose a new approach to fitting marginal models to clustered data when cluster size is informative. This approach uses a generalized estimating equation (GEE) that is weighted inversely with the cluster size. We show that our approach is asymptotically equivalent to within-cluster resampling (Hoffman, Sen, and Weinberg, 2001, Biometrika 73, 13-22), a computationally intensive approach in which replicate data sets containing a randomly selected observation from each cluster are analyzed, and the resulting estimates averaged. Using simulated data and an example involving dental health, we show the superior performance of our approach compared to unweighted GEE, the equivalence of our approach with WCR for large sample sizes, and the superior performance of our approach compared with WCR when sample sizes are small. 相似文献