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71.
Wilna J. Moree Florence Jovic Timothy Coon Jinghua Yu Bin-Feng Li Fabio C. Tucci Dragan Marinkovic Raymond S. Gross Siobhan Malany Margaret J. Bradbury Lisa M. Hernandez Zhihong O’Brien Jianyun Wen Hua Wang Samuel R.J. Hoare Robert E. Petroski Aida Sacaan Ajay Madan Paul D. Crowe Graham Beaton 《Bioorganic & medicinal chemistry letters》2010,20(7):2316-2320
SAR of lead benzothiophene H1-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H1-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound. 相似文献
72.
The effect of inorganic nutrition on the formation of lateral roots has been studied in Dracaena fragrans Ker-Gawl cultured in vitro. MS macronutrient salts imposed inhibition of lateral root formation in 95% of primary adventitious roots which could be overcome by: 相似文献
73.
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75.
S.N. Khrapunov A.I. Dragan A.F. Protas G.D. Berdyshev 《International journal of biological macromolecules》1984,6(1):26-30
Using the methods of spectrophotometry, spectrofluorimetry, light scattering and gel filtration, it was shown that, at pH 5.6 and 7.4 and various ionic strengths, the histone tetramer (H3-H4)2 may have several structural states with different packing of the polypeptide chains of histones H3 and H4. Two structural changes of the tetramer (H3-H4)2 at pH 7.4 in the ranges 0.1–0.3 m and 0.7–0.9 m NaCl were observed. In the high ionic strength solution, the tetramer (H3-H4)2 had a more compact structure at pH 7.4 than at pH 5.6. At pH 3.0 destruction of the histone tetramer (H3-H4)2 and formation of non-specific aggregates took place. 相似文献
76.
77.
Unexpected role for granzyme K in CD56bright NK cell-mediated immunoregulation of multiple sclerosis
Jiang W Chai NR Maric D Bielekova B 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(2):781-790
Functional NK cell deficiencies are associated with autoimmune diseases, including multiple sclerosis. NK cells can promote or inhibit adaptive immunity via either cytokine production or cytotoxicity toward immature dendritic cells and activated T cells. In humans, this immunoregulatory role resides in the CD56(bright) NK cell subset, which is selectively expanded by daclizumab, a CD25-blocking Ab that suppresses multiple sclerosis-associated inflammation. The objective of this study was to investigate the molecular mechanisms underlying the cytotoxicity of NK cells toward activated T cells. We demonstrated that NK cells induce caspase-independent apoptosis that requires NK cell degranulation and causes mitochondrial dysfunction in activated T cells. Although both granzyme A and granzyme K (GrK) can mediate this form of apoptosis, quantitatively we observed preferential transfer of GrK to target cells. Consequently, gene silencing of GrK in the NK-92 cell line, which retains functional characteristics of CD56(bright) NK cells, profoundly inhibited the ability of NK-92 cells to kill activated syngeneic T cells. Finally, we demonstrated that daclizumab treatment significantly enhanced this newly defined mechanism of cytotoxicity by CD56(bright) NK cells. Our study describes the important physiological role that GrK plays in immunoregulation of adaptive immunity in humans and indicates that therapeutic exploitation of this pathway is beneficial in controlling autoimmunity. 相似文献
78.
Deola S Panelli MC Maric D Selleri S Dmitrieva NI Voss CY Klein H Stroncek D Wang E Marincola FM 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(3):1362-1372
CD8-expressing cytotoxic T cell (CTL) interactions with APCs and helper T cells determine their function and ability to survive. In this study, we describe a novel interaction independent of Ag presentation between activated CTLs and bystander CD19-expressing B lymphocytes. Ag-stimulated CTLs serially engage autologous B lymphocytes through CD27/CD70 contact that promotes their survival and proliferation. Moreover, these interactions induce the release of proinflammatory cytokines that follows two general patterns: 1) an epitope-dependent enhancement of cytokine release, and 2) a previously undiscovered coordinate release of cytokines independent of epitope exposure. The latter includes chemoattractants targeting activated T cells. As a result, activated T cells are attracted to B cells, which exert a "helper" role in lymphatic organs or in areas of inflammation. This observation provides a mechanistic explanation to previously reported experimental observations suggesting that B cells are required for T cell priming in vivo. 相似文献
79.
Rasić-Marković A Krstić D Vujović Z Jakovljevic V Stanojlović O Hrncić D Djurić D Loncar-Stevanović H 《Molecular and cellular biochemistry》2008,308(1-2):111-116
Alcohol intake is associated with numerous degenerative disorders, and the detrimental effects of alcohol may be due to its
influence on plasma membrane and cellular transport systems. The aim of the present study was to compare in vitro and in vivo
effects of ethanol on rabbit erythrocyte ATPase activities and correlate them with ethanol-induced oxidative stress. Age-matched
male rabbits were given 5% ethanol in 2% sucrose solution, for 6 weeks ad libitum; control animals were given tap water. Daily
intake of ethanol was 5 g/kg body weight; this experimental regimen resulted in an average serum ethanol concentration of
16.77 ± 2.00 mM/l. After this period, blood was collected, serum ethanol concentration was determined and erythrocyte membranes
were prepared according to the method of Post et al. Activities of Na+/K+- and Mg2+-ATPases were determined. Thiobarbituric acid-reactive substance (TBARS) assay was used to detect levels of lipid peroxidation,
a major indicator of oxidative stress. In vitro ethanol inhibits both Na+/K+-ATPase and Mg2+-ATPase, but Na+/K+-ATPase is more sensitive to the ethanol-induced inhibition. Increasing concentration of ethanol increased TBARS production,
but significant difference was attained only at 5 and 12.5 mM of ethanol. Chronic ethanol consumption induced significant
increase in Na+/K+- and Mg2+-ATPase activity, and TBARS production. Our results suggest that increased ATPase activity induced by chronic ethanol consumption
is due to oxidative, induced modification of membrane phospholipids and proteins, which are responsible for inhibition of
ATPase activity. Increased production of TBARS induced by in vitro exposure to ethanol is not the only factor that influences
ATPases activity. Further research is needed to elucidate this relationship. 相似文献
80.
Peters BA Kan Z Sebisanovic D Pujara K Wang Z Hong P Chow B Stinson J Carlton VE Pham TQ Stern H Waring P Hillan KJ Eberhard DA de Sauvage F Zheng J Faham M Seshagiri S 《Nature methods》2007,4(9):713-715
The discovery of somatic mutations in cancer tissue is extremely laborious, time-consuming and costly. In an evaluation comparing mismatch repair detection (MRD) against Sanger sequencing for somatic-mutation detection, we found that MRD had a specificity of 96% and a sensitivity of 92%. Our results showed that MRD is a robust and cost-effective alternative to Sanger sequencing for identifying somatic mutations in human tumors. 相似文献