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排序方式: 共有393条查询结果,搜索用时 31 毫秒
71.
Juliana M Sousa-Canavez Flavio C Canavez Kátia RM Leite Luiz H Camara-Lopes 《Genetic vaccines and therapy》2008,6(1):1-7
Background
Electroporation is an established technique for enhancing plasmid delivery to many tissues in vivo, including the skin. We have previously demonstrated efficient delivery of plasmid DNA to the skin utilizing a custom-built four-plate electrode. The experiments described here further evaluate cutaneous plasmid delivery using in vivo electroporation. Plasmid expression levels are compared to those after liposome mediated delivery.Methods
Enhanced electrically-mediated delivery, and less extensively, liposome complexed delivery, of a plasmid encoding the reporter luciferase was tested in rodent skin. Expression kinetics and tissue damage were explored as well as testing in a second rodent model.Results
Experiments confirm that electroporation alone is more effective in enhancing reporter gene expression than plasmid injection alone, plasmid conjugation with liposomes followed by injection, or than the combination of liposomes and electroporation. However, with two time courses of multiple electrically-mediated plasmid deliveries, neither the levels nor duration of transgene expression are significantly increased. Tissue damage may increase following a second treatment, no further damage is observed after a third treatment. When electroporation conditions utilized in a mouse model are tested in thicker rat skin, only higher field strengths or longer pulses were as effective in plasmid delivery.Conclusion
Electroporation enhances reporter plasmid delivery to the skin to a greater extent than the liposome conjugation method tested. Multiple deliveries do not necessarily result in higher or longer term expression. In addition, some impact on tissue integrity with respect to surface damage is observed. Pulsing conditions should be optimized for the model and for the expression profile desired. 相似文献72.
Junqing Guo Andrew Watson James Kempson Marianne Carlsen Joseph Barbosa Karen Stebbins Deborah Lee John Dodd Steven G. Nadler Murray McKinnon Joel Barrish William J. Pitts 《Bioorganic & medicinal chemistry letters》2009,19(7):1935-1938
A series of pyrimidine based inhibitors of PDE7 are discussed. The synthesis, structure–activity relationships (SAR) and selectivity against several other PDE family members as well as activity in T cells are presented. These compounds were found to have effects on T cell proliferation, however it is not clear whether the mechanism is related to PDE7 inhibition. 相似文献
73.
James Kempson Junqing Guo Jagabandhu Das Robert V. Moquin Steven H. Spergel Scott H. Watterson Charles M. Langevine Alaric J. Dyckman Mark Pattoli James R. Burke XiaoXia Yang Kathleen M. Gillooly Kim W. McIntyre Laishun Chen John H. Dodd Murray McKinnon Joel C. Barrish William J. Pitts 《Bioorganic & medicinal chemistry letters》2009,19(10):2646-2649
A new series of tricyclic-based inhibitors of IKK have been derived from an earlier lead compound. The synthesis and structure–activity relationships (SAR) are described. Compound 4k inhibited TNF production in rats stimulated with LPS. 相似文献
74.
Pitts SL Liou GF Mitchenall LA Burgin AB Maxwell A Neuman KC Osheroff N 《Nucleic acids research》2011,39(11):4808-4817
It has long been known that type II topoisomerases require divalent metal ions in order to cleave DNA. Kinetic, mutagenesis and structural studies indicate that the eukaryotic enzymes utilize a novel variant of the canonical two-metal-ion mechanism to promote DNA scission. However, the role of metal ions in the cleavage reaction mediated by bacterial type II enzymes has been controversial. Therefore, to resolve this critical issue, this study characterized the DNA cleavage reaction of Escherichia coli topoisomerase IV. We utilized a series of divalent metal ions with varying thiophilicities in conjunction with oligonucleotides that replaced bridging and non-bridging oxygen atoms at (and near) the scissile bond with sulfur atoms. DNA scission was enhanced when thiophilic metal ions were used with substrates that contained bridging sulfur atoms. In addition, the metal-ion dependence of DNA cleavage was sigmoidal in nature, and rates and levels of DNA cleavage increased when metal ion mixtures were used in reactions. Based on these findings, we propose that topoisomerase IV cleaves DNA using a two-metal-ion mechanism in which one of the metal ions makes a critical interaction with the 3'-bridging atom of the scissile phosphate and facilitates DNA scission by the bacterial type II enzyme. 相似文献
75.
Pitts WJ Guo J Dhar TG Shen Z Gu HH Watterson SH Bednarz MS Chen BC Barrish JC Bassolino D Cheney D Fleener CA Rouleau KA Hollenbaugh DL Iwanowicz EJ 《Bioorganic & medicinal chemistry letters》2002,12(16):2137-2140
A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described. 相似文献
76.
Mariana A Antunes Soraia C Abreu Fernanda F Cruz Ana Clara Teixeira Miquéias Lopes-Pacheco Elga Bandeira Priscilla C Olsen Bruno L Diaz Christina M Takyia Isalira PRG Freitas Nazareth N Rocha Vera L Capelozzi Débora G Xisto Daniel J Weiss Marcelo M Morales Patricia RM Rocco 《Respiratory research》2014,15(1)
We sought to assess whether the effects of mesenchymal stromal cells (MSC) on lung inflammation and remodeling in experimental emphysema would differ according to MSC source and administration route. Emphysema was induced in C57BL/6 mice by intratracheal (IT) administration of porcine pancreatic elastase (0.1 UI) weekly for 1 month. After the last elastase instillation, saline or MSCs (1×105), isolated from either mouse bone marrow (BM), adipose tissue (AD) or lung tissue (L), were administered intravenously (IV) or IT. After 1 week, mice were euthanized. Regardless of administration route, MSCs from each source yielded: 1) decreased mean linear intercept, neutrophil infiltration, and cell apoptosis; 2) increased elastic fiber content; 3) reduced alveolar epithelial and endothelial cell damage; and 4) decreased keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8) and transforming growth factor-β levels in lung tissue. In contrast with IV, IT MSC administration further reduced alveolar hyperinflation (BM-MSC) and collagen fiber content (BM-MSC and L-MSC). Intravenous administration of BM- and AD-MSCs reduced the number of M1 macrophages and pulmonary hypertension on echocardiography, while increasing vascular endothelial growth factor. Only BM-MSCs (IV > IT) increased the number of M2 macrophages. In conclusion, different MSC sources and administration routes variably reduced elastase-induced lung damage, but IV administration of BM-MSCs resulted in better cardiovascular function and change of the macrophage phenotype from M1 to M2. 相似文献
77.
78.
The x-ray structure of the PTX:NADPH:L22F human mutant DHFR ternary complex was used as a structural template to generate structural models for the following wild type DHFR complexes: PTX:DHFR:NADPH, TMP:DHFR:NADPH, EPM:DHFR:NADPH, and TMQ:DHFR:NADPH. Each of these complexes were subsequently modeled in a 60 Å cube of explicit water and minimized to a rms gradient of from 1.0-3.0·10-5 kcal·Å-1. For each complex, interaction energies were calculated for the antifolate interaction with each of the following: the DHFR binding site residues, the entire DHFR protein, the solvated complex (containing DHFR, NADPH, and solvent water), water alone, and NADPH. Additionally, each antifolate was subdivided into distinct substructural regions and interaction energy calculations were performed in order to evaluate their contributions to overall antifolate interaction. Each antifolate showed its most stable interaction with the solvated complex. Substructural regions which consisted of a nitrogen containing aromatic ring system contributed most to the stability of the antifolate interactions, while the hydrocarbon aromatic rings, methoxy, and ethoxy groups showed much less stable interaction energies. Since the different substructural regions of nonclassical antifolates differ in their contributions to overall antifolate binding, those substructural regions which exhibit relatively unfavorable interaction energies may constitute important targets in the design of improved DHFR inhibitors. 相似文献
79.
In the present study, effects of d-amphetamine on sensitivity to reinforcement amount under concurrent schedules were examined using a rapid-acquisition procedure. Four pigeons key pecked under single concurrent variable-interval 30-s schedules of grain presentation. Two different reinforcer-amount ratios (7:1 and 1:7) changed across sessions according to a 31-step pseudo-random binary sequence (PRBS). After at least four times through the PRBS, response ratios generally tracked the session-to-session changes in amount ratios; estimates of sensitivity ranged from 0.26 to 0.31 across the four pigeons. Effects of a range of doses of d-amphetamine (0.3-5.6 mg/kg) then were determined. For 3 of 4 pigeons, at least one dose, which did not dramatically alter overall response output or bias, decreased sensitivity to reinforcement amount. These results suggest that reducing sensitivity of responding to reinforcement amount may be one behavioral mechanism of stimulants, which may have implications for interpreting drug effects on self-control. 相似文献
80.
It is desired to understand the effect of alginic acid sodium salt from brown algae (alginate) as a viscosity modifier on the behavior of blood in vitro using a micro-particle image velocimetry (µPIV) system. The effect of alginate on the shape of the velocity profile, the flow rate and the maximum velocity achieved in rectangular microchannels channels are measured. The channels were constructed of polydimethylsiloxane (PDMS), a biocompatible silicone. Porcine blood cells suspended in saline was used as the working fluid at twenty percent hematocrit (H = 20). While alginate was only found to have minimal effect on the maximum velocity and the flow rate achieved, it was found to significantly affect the shear rate at the wall by between eight to a hundred percent. 相似文献