全文获取类型
收费全文 | 2118篇 |
免费 | 88篇 |
出版年
2024年 | 6篇 |
2023年 | 7篇 |
2022年 | 35篇 |
2021年 | 59篇 |
2020年 | 34篇 |
2019年 | 37篇 |
2018年 | 45篇 |
2017年 | 51篇 |
2016年 | 70篇 |
2015年 | 78篇 |
2014年 | 123篇 |
2013年 | 159篇 |
2012年 | 199篇 |
2011年 | 185篇 |
2010年 | 103篇 |
2009年 | 92篇 |
2008年 | 120篇 |
2007年 | 119篇 |
2006年 | 132篇 |
2005年 | 83篇 |
2004年 | 85篇 |
2003年 | 90篇 |
2002年 | 82篇 |
2001年 | 12篇 |
2000年 | 8篇 |
1999年 | 10篇 |
1998年 | 26篇 |
1997年 | 12篇 |
1996年 | 5篇 |
1995年 | 14篇 |
1994年 | 6篇 |
1993年 | 9篇 |
1992年 | 11篇 |
1991年 | 13篇 |
1990年 | 4篇 |
1989年 | 7篇 |
1988年 | 8篇 |
1987年 | 8篇 |
1986年 | 3篇 |
1985年 | 6篇 |
1984年 | 12篇 |
1983年 | 4篇 |
1982年 | 8篇 |
1981年 | 4篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1976年 | 2篇 |
1975年 | 1篇 |
1973年 | 4篇 |
1972年 | 3篇 |
排序方式: 共有2206条查询结果,搜索用时 15 毫秒
91.
Unconventional myosin Myo1c promotes membrane fusion in a regulated exocytic pathway 总被引:6,自引:0,他引:6 下载免费PDF全文
Bose A Robida S Furcinitti PS Chawla A Fogarty K Corvera S Czech MP 《Molecular and cellular biology》2004,24(12):5447-5458
Glucose homeostasis is controlled in part by regulation of glucose uptake into muscle and adipose tissue. Intracellular membrane vesicles containing the GLUT4 glucose transporter move towards the cell cortex in response to insulin and then fuse with the plasma membrane. Here we show that the fusion step is retarded by the inhibition of phosphatidylinositol (PI) 3-kinase. Treatment of insulin-stimulated 3T3-L1 adipocytes with the PI 3-kinase inhibitor LY294002 causes the accumulation of GLUT4-containing vesicles just beneath the cell surface. This accumulation of GLUT4-containing vesicles near the plasma membrane prior to fusion requires an intact cytoskeletal network and the unconventional myosin motor Myo1c. Remarkably, enhanced Myo1c expression under these conditions causes extensive membrane ruffling and overrides the block in membrane fusion caused by LY294002, restoring the display of GLUT4 on the cell exterior. Ultrafast microscopic analysis revealed that insulin treatment leads to the mobilization of GLUT4-containing vesicles to these regions of Myo1c-induced membrane ruffles. Thus, localized membrane remodeling driven by the Myo1c motor appears to facilitate the fusion of exocytic GLUT4-containing vesicles with the adipocyte plasma membrane. 相似文献
92.
Adding antioxidant activities to hemoglobin-based oxygen carriers (HBOCs) represents a means of reducing cell-free hemoglobin-mediated oxidative cascades. We have covalently bound nitroxides, a class of antioxidant enzyme mimetics, to HBOCs. The objectives of this study were (1) to evaluate the pharmacokinetic (PK) effects of administering nitroxide covalently bound to HBOCs compared to those of free nitroxide coadministered with HBOCs and (2) to elucidate the effects of differing molecular weight HBOCs on the PK of bound nitroxide in a conscious guinea pig model of 25% blood exchange transfusion. Two HBOC platforms were used, intramolecular cross-linked hemoglobin (XLHb) and dextran polymerized/conjugated XLHb (PolyHb). Polynitroxylation was achieved by reacting 4-(2-bromoacetamido)-2,2,6,6,-tetramethylpiperidine-1-oxyl with XLHb or PolyHb to form polynitroxylated XLHb and polynitroxylated PolyHb, respectively, whereas a physical mixture of XLHb or PolyHb with 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl was prepared to reflect a molar equivalence to HBOC-bound nitroxide. Plasma concentrations of two redox states, nitroxide and hydroxylamine, were determined by electron paramagnetic resonance spectroscopy. Results are presented to illustrate the influence of covalent labeling and HBOC molecular weight on nitroxide PK. The therapeutic potential of polynitroxylation of HBOCs as it relates to observations from the current and previously reported studies is discussed. 相似文献
93.
Preparation of chiral gamma-substituted-gamma-lactones (1) through kinetic resolution is described. (S)-(-)-1-Phenylethylamine (2) in the presence of anhydrous AlCl(3) shows satisfactory levels of enantioselection in reaction with racemic gamma-substituted-gamma-lactones 1, where (R)-1 remains unreacted, while (S)-1 is enantioselectively converted to the ring-opened amide (S,S)-4. The enantiopurity of (R)-(+)- gamma-substituted gamma-lactones recovered ranges from 62-98% ee. 相似文献
94.
Folate, homocysteine, endothelial function and cardiovascular disease 总被引:22,自引:0,他引:22
Moat SJ Lang D McDowell IF Clarke ZL Madhavan AK Lewis MJ Goodfellow J 《The Journal of nutritional biochemistry》2004,15(2):64-79
Evidence reported from numerous clinical studies over the past decade has revealed an association between increased plasma total homocysteine (tHcy) concentrations and cardiovascular disease (CVD). In addition, epidemiological studies have identified an inverse association between blood folate concentrations, folate intake and cardiovascular endpoints, that are independent of homocysteine. Folic acid supplementation can lower plasma tHcy concentrations safely and inexpensively. Furthermore, folic acid can reverse endothelial dysfunction observed in patients with CVD. This reversal in endothelial dysfunction with folic acid has been shown to be independent of plasma tHcy lowering, suggesting that folate has pleiotropic effects on the vasculature other than homocysteine lowering. In vitro evidence demonstrates that 5-methyltetrahydrofolate (5MeTHF) the main circulating metabolite of folate, can increase nitric oxide production and can directly scavenge superoxide radicals. The potential beneficial role of folic acid supplements on vascular disease are currently being tested in randomized placebo controlled studies. 相似文献
95.
The eccentric connectivity index, which has recently been employed successfully for the development of numerous mathematical models for the prediction of biological activities of diverse nature, has been reformed to overcome its limitations caused by degeneracy and insensitivity towards heteroatoms. The reformed eccentric connectivity index, termed the eccentric connectivity topochemical index, overcomes the limitations of the eccentric connectivity index by exhibiting very low degeneracy and displaying sensitivity to both the presence and relative position of heteroatoms without compromizing the discriminating power of the eccentric connectivity index. The relationship of the eccentric connectivity topochemical index, eccentric connectivity index and Wieners index with regard to the anti-HIV activity of 2, 3-diaryl-1, 3-thiazolidin-4-one derivatives was subsequently investigated. The values of the eccentric connectivity topochemical index, the eccentric connectivity index and Wieners index of each of 31 analogues comprizing the data set were computed using in-house computer program. Resultant data was analyzed and suitable models developed after identification of active ranges. Subsequently, each derivative was assigned a biological activity using these models, which was then compared with the reported anti-HIV activity. The accuracy of prediction using these models was found to vary from 81 to 90%. The proposed index offers a vast potential for virtual screening of combinatorial libraries, structure property/activity studies and drug design.Figure Basic structure of 2,3-diaryl-1, 3-thiazoidin-4-ones. 相似文献
96.
The mucoadhesive properties of chitosan microspheres prepared by different method were evaluated by studying the interaction
between mucin and microspheres in aqueous solution. The interaction was determined by the measurement of mucin adsorbed on
the microspheres. A strong interaction between chitosan microspheres and mucin was detected. The intensity of the interaction
was dependent upon the method of preparation of chitosan microspheres and the amount of mucin added. The extent of mucus adsorption
was proportional to the absolute values of the positive zeta potential of chitosan microspheres. The zeta potential in turn
was found to be dependent upon the method of preparation of microspheres. The adsorption of type III mucin (1% sialic acid
content) was interpreted using Freundlich or Langmuir adsorption isotherms. The values ofr
2 were greater for Langmuir isotherm as compared with Freundlich isotherm. The adsorption of a suspension of chitosan microspheres
in the rat small intestine indicated that chitosan microspheres prepared by tripolyphosphate cross-linking and emulsification
ionotropic gelation can be used as an excellent mucoadhesive delivery system. The microspheres prepared by glutaraldehyde
and thermal cross-linking showed good stability in HC1 as compared with microspheres prepared by tripolyphosphate and emulsification
ionotropic gelation. 相似文献
97.
Flanagan K Stevens R Pocock M Lee P Wipat A 《Comparative and Functional Genomics》2004,5(6-7):537-544
We present an ontology for describing genomes, genome comparisons, their evolution and biological function. This ontology will support the development of novel genome comparison algorithms and aid the community in discussing genomic evolution. It provides a framework for communication about comparative genomics, and a basis upon which further automated analysis can be built. The nomenclature defined by the ontology will foster clearer communication between biologists, and also standardize terms used by data publishers in the results of analysis programs. The overriding aim of this ontology is the facilitation of consistent annotation of genomes through computational methods, rather than human annotators. To this end, the ontology includes definitions that support computer analysis and automated transfer of annotations between genomes, rather than relying upon human mediation. 相似文献
98.
Stable transformation of petunia plastids 总被引:11,自引:0,他引:11
Plastid transformation results in stably expressed foreign genes, which for most Angiosperms are largely excluded from sperm cells, thereby greatly reducing the risk of foreign gene spread through pollen. Prior to this work, fertile plastid transformants were restricted to tobacco, tomato and Lesquerella . Application of plastid engineering in the important floriculture industry requires the development of stable plastid transformation in a major ornamental plant species such as Petunia hybrida. Here we describe the successful isolation of fertile and stable plastid transformants in a commercial cultivar of P. hybrida (var. Pink Wave). Plastid targeting regions from tobacco were used to integrate aad A and gusA between the acc D and rbc L genes of P. hybrida plastid DNA following particle bombardment of leaves. For three spectinomycin and streptomycin resistant lines, DNA blot analysis confirmed transgene integration into plastid DNA and homoplasmy. Maternal inheritance and homoplasmy resulted in 100 transmission of spectinomycin resistance to progeny after selfing. Plastid transformants expressed the gusA gene uniformly within leaves and to comparable levels in all three lines. Insertion of trait genes in place of gusA coding sequences enables immediate applications of our plastid transformation vector. Establishment of plastid transformation in P. hybrida facilitates a safe and reliable use of this important ornamental plant for research and plant biotechnology.These two authors contributed equally to this work. 相似文献
99.
Synthesis and in vitro testing of J591 antibody-dendrimer conjugates for targeted prostate cancer therapy 总被引:5,自引:0,他引:5
Targeted therapeutics using antibodies are an attractive option over conventional cancer chemotherapeutics due to their potential to deliver a therapeutic specifically to cancer tissue without damaging normal tissue. However, there are known problems with immunoconjugates such as decreased immunoreactivity and poor solubility. Using dendrimers as carriers for these agents has the potential to resolve these issues. We synthesized J591 anti-PSMA (prostate specific membrane antigen) antibody dendrimer conjugates containing fluorophores on the dendrimer. The in vitro studies of these conjugates show that they specifically bind to cells expressing PSMA. Confocal microscopy experiments document the binding and internalization of these conjugates. This research encourages the further study of antibody-dendrimer-drug conjugates for use in targeted therapeutics. 相似文献
100.
Saxena AK Ram S Saxena M Singh N Prathipati P Jain PC Singh HK Anand N 《Bioorganic & medicinal chemistry》2003,11(9):2085-2090
A series of nineteen substituted 1,2,3,4,6,7,12,12a-octahydropyrazino[2',1':6,1]pyrido[3, 4-b]indoles analogues of neuroleptic drug, Centbutindole have been studied using quantitative structure-activity relationship analysis. The derived models display good fits to the experimental data (r>or=0.75) having good predictive power (r(cv)>or=0.688). The best model describes a high correlation between predicted and experimental activity data (r=0.967). Statistical analysis of the equation populations indicates that hydrophobicity (as measured by pi(R), logP(o/w) and SlogP_VSA8), dipole y and structural parameters in terms of indicator variable, (In(1)) and globularity are important variables in describing the variation in the neuroleptic activity in the series. 相似文献