全文获取类型
收费全文 | 351篇 |
免费 | 22篇 |
国内免费 | 2篇 |
出版年
2023年 | 3篇 |
2022年 | 7篇 |
2021年 | 16篇 |
2020年 | 11篇 |
2019年 | 12篇 |
2018年 | 16篇 |
2017年 | 9篇 |
2016年 | 21篇 |
2015年 | 35篇 |
2014年 | 22篇 |
2013年 | 23篇 |
2012年 | 26篇 |
2011年 | 21篇 |
2010年 | 9篇 |
2009年 | 10篇 |
2008年 | 18篇 |
2007年 | 13篇 |
2006年 | 21篇 |
2005年 | 20篇 |
2004年 | 7篇 |
2003年 | 6篇 |
2002年 | 6篇 |
2001年 | 3篇 |
2000年 | 4篇 |
1998年 | 1篇 |
1996年 | 1篇 |
1995年 | 3篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1991年 | 1篇 |
1990年 | 5篇 |
1985年 | 2篇 |
1983年 | 1篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1979年 | 4篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1975年 | 3篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1966年 | 1篇 |
1962年 | 1篇 |
1957年 | 1篇 |
排序方式: 共有375条查询结果,搜索用时 171 毫秒
31.
Drug discovery in skin pharmacotherapy is an enormous, continually expanding field. Researchers are developing novel and sensitive
pharmaceutical products and drugs that target specific receptors to elicit concerted and appropriate responses. The pigment-bearing
cells called melanophores have a significant contribution to make in this field. Melanophores, which contain the dark brown
or black pigment melanin, constitute an important class of chromatophores. They are highly specialized in the bidirectional
and coordinated translocation of pigment granules when given an appropriate stimulus. The pigment granules can be stimulated
to undergo rapid dispersion throughout the melanophores, making the cell appear dark, or to aggregate at the center, making
the cell appear light. The major signals involved in pigment transport within the melanophores are dependent on a special
class of cell surface receptors called G-protein-coupled receptors (GPCRs). Many of these receptors of adrenaline, acetylcholine,
histamine, serotonin, endothelin and melatonin have been found on melanophores. They are believed to have clinical relevance
to skin-related ailments and therefore have become targets for high throughput screening projects. The selective screening
of these receptors requires the recognition of particular ligands, agonists and antagonists and the characterization of their
effects on pigment motility within the cells. The mechanism of skin pigmentation is incredibly intricate, but it would be
a considerable step forward to unravel its underlying physiological mechanism. This would provide an experimental basis for
new pharmacotherapies for dermatological anomalies. The discernible stimuli that can trigger a variety of intracellular signals
affecting pigment granule movement primarily include neurotransmitters and hormones. This review focuses on the role of the
hormone and neurotransmitter signals involved in pigment movement in terms of the pharmacology of the specific receptors. 相似文献
32.
Muazzam AG Qureshi S Mansoor A Ali L Iqbal M Siddiqi S Khan KM Mazhar K 《Genetic vaccines and therapy》2011,9(1):14-6
Background
A recently discovered occult HCV entity reported by various investigators seems to be highly controversial. Especially, the clinical significance of these findings remains uncertain. For optimal outcome of antiviral therapy, investigation of occult HCV needs a broad-based probe in order to investigate the results of viral therapy and its host/viral interaction. The current study was aimed at determining the prevalence of occult HCV in peripheral blood lymphocytes of predominantly genotype 3 HCV-infected patients after completion of antiviral therapy and to investigate long term outcomes in the presence or absence of PBMC positivity.Method
A total of 151 chronic, antiHCV and serum RNA-positive patients were enrolled in the study. Patients with a complete virological response at the end of treatment were screened for the presence of viral RNA in their PBMCs and were followed for up to one year for the presence of serum and PBMC viral genomic RNA.Results
Out of 151 patients, 104 (70%) responded to the prescribed interferon treatment and showed viral-clearance from serum. These were screened for the presence of genomic RNA in their PBMCs. Sixteen samples were PBMC-positive for viral RNA at the end of treatment (EOT). All these patients had also cleared the virus from peripheral blood cells after the 6-12 month follow-up study.Conclusion
True occult hepatitis C virus does not exist in our cohort. Residual viremia at the EOT stage merely reflects a difference in viral kinetics in various compartments that remains a target of immune response even after the end of antiviral therapy and is eventually cleared out at the sustained viral response (SVR). 相似文献33.
Preet A Gupta BL Siddiqui MR Yadava PK Baquer NZ 《Molecular and cellular biochemistry》2005,278(1-2):21-31
Vanadium has been reported to have broad pharmacological activity both in vitro and in vivo. Vanadium compound, sodium orthovanadate, Na3VO4, is well known for its hypoglycaemic effects. However, Na3VO4 exerts these effects at relatively high doses (0.6 mg/ml) and exhibit several toxic effects. In the present study lower doses
of Na3VO4 (0.2 mg/ml) are combined with Trigonella foenum graecum seed powder (TSP), another hypoglycaemic agent, to reduce its toxicity without compromising its antidiabetic potential. The
efficacy of the lower doses of Na3VO4 has been investigated in restoring the altered glucose metabolism and histological structure in the sciatic nerves in 21
and 60 days alloxan diabetic rats. A portion of the glucose was found to be channelled from the normal glycolytic route to
polyol pathway, evident by the reduced hexokinase activity and increased polyol pathway enzymes aldose reductase and sorbitol
dehydrogenase activity causing accumulation of sorbitol and fructose in diabetic conditions. Ultrastructural observation of
the sciatic nerve showed extensive demylination and axonal loss after eight weeks of diabetes induction. Blood glucose levels
increased in diabetic rats were normalized with the lower dose of vanadium and Trigonella treatment. The treatment of the diabetic rats with vanadium and Trigonella prevented the activation of the polyol pathway and sugar accumulations. The sciatic nerves were also protected against the
structural abnormalities found in diabetes with Trigonella foenum graecum as well as Na3VO4. Results suggest that lower doses of Na3VO4 may be used in combination with TSP as an efficient antidiabetic agent to effectively control the long-term complications
of diabetes in tissues like peripheral nerve. 相似文献
34.
Siddiqui MR Taha A Moorthy K Hussain ME Basir SF Baquer NZ 《Journal of biosciences》2005,30(4):483-490
Trigonella foenum graecum seed powder (TSP) and sodium orthovanadate (SOV) have been reported to have antidiabetic effects. However, SOV exerts hypoglycemic
effects at relatively high doses with several toxic effects. We used low doses of vanadate in combination with TSP and evaluated
their antidiabetic effects on antioxidant enzymes and membrane-linked functions in diabetic rat brains. In rats, diabetes
was induced by alloxan monohydrate (15 mg/100 g body wt.) and they were treated with 2 IU insulin, 0.6 mg/ml SOV, 5% TSP and
a combination of 0.2 mg/ml SOV with 5% TSP for 21 days. Blood glucose levels, activity of superoxide dismutase (SOD), catalase
(CAT), glutathione peroxidase (GPx), Na+/K+ ATPase, membrane lipid peroxidation and fluidity were determined in different fractions of whole brain after 21 days of treatment.
Diabetic rats showed high blood glucose (P < 0.001), decreased activities of SOD, catalase and Na+/K+ ATPase (P < 0.01,P < 0.001 andP < 0.01), increased levels of GPx and MDA (P < 0.01 andP < 0.001) and decreased membrane fluidity (P < 0.01). Treatment with different antidiabetic compounds restored the above-altered parameters. Combined dose ofTrigonella and vanadate was found to be the most effective treatment in normalizing these alterations. Lower doses of vanadate could
be used in combination with TSP to effectively counter diabetic alterations without any toxic effects. 相似文献
35.
In the present work, the oxidative degradation of gum arabic by colloidal manganese dioxide (MnO2) was carried out. Monitoring the disappearance of the MnO2 spectrophotometrically at 375 nm was used to follow the kinetics. The oxidation obeyed fractional-order kinetics with respect to the [gum arabic]. Effect of various experimental parameters such as the initial colloidal [MnO2], [HClO4], temperature, and complexing agents (P2O7(4-), F-, and Mn2+) for the oxidation of gum arabic was studied. The reaction was acid catalyzed. Addition of P2O(7)4-, F-, and Mn2+ ions enhances the rate of oxidation significantly. Gum arabic adsorbs onto the surface of the colloidal MnO2 through the equatorial -OH groups of the rhamnose moiety, and the complex breaks down into products. The Arrhenius equation was valid for the oxidation kinetics between 40 and 60 degrees C. To explain the observed kinetic results, a suitable mechanism and rate law for the reaction taking place at the surface of the colloidal particle has been proposed. The reducing nature of gum arabic is found be due to the presence of -OH group in the skeleton. 相似文献
36.
Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness 下载免费PDF全文
Riazuddin S Khan SN Ahmed ZM Ghosh M Caution K Nazli S Kabra M Zafar AU Chen K Naz S Antonellis A Pavan WJ Green ED Wilcox ER Friedman PL Morell RJ Riazuddin S Friedman TB 《American journal of human genetics》2006,78(1):137-143
In seven families, six different mutant alleles of TRIOBP on chromosome 22q13 cosegregate with autosomal recessive nonsyndromic deafness. These alleles include four nonsense (Q297X, R788X, R1068X, and R1117X) and two frameshift (D1069fsX1082 and R1078fsX1083) mutations, all located in exon 6 of TRIOBP. There are several alternative splice isoforms of this gene, the longest of which, TRIOBP-6, comprises 23 exons. The linkage interval for the deafness segregating in these families includes DFNB28. Genetic heterogeneity at this locus is suggested by three additional families that show significant evidence of linkage of deafness to markers on chromosome 22q13 but that apparently have no mutations in the TRIOBP gene. 相似文献
37.
Riazuddin S Ahmed ZM Fanning AS Lagziel A Kitajiri S Ramzan K Khan SN Chattaraj P Friedman PL Anderson JM Belyantseva IA Forge A Riazuddin S Friedman TB 《American journal of human genetics》2006,79(6):1040-1051
The inner ear has fluid-filled compartments of different ionic compositions, including the endolymphatic and perilymphatic spaces of the organ of Corti; the separation from one another by epithelial barriers is required for normal hearing. TRIC encodes tricellulin, a recently discovered tight-junction (TJ) protein that contributes to the structure and function of tricellular contacts of neighboring cells in many epithelial tissues. We show that, in humans, four different recessive mutations of TRIC cause nonsyndromic deafness (DFNB49), a surprisingly limited phenotype, given the widespread tissue distribution of tricellulin in epithelial cells. In the inner ear, tricellulin is concentrated at the tricellular TJs in cochlear and vestibular epithelia, including the structurally complex and extensive junctions between supporting and hair cells. We also demonstrate that there are multiple alternatively spliced isoforms of TRIC in various tissues and that mutations of TRIC associated with hearing loss remove all or most of a conserved region in the cytosolic domain that binds to the cytosolic scaffolding protein ZO-1. A wild-type isoform of tricellulin, which lacks this conserved region, is unaffected by the mutant alleles and is hypothesized to be sufficient for structural and functional integrity of epithelial barriers outside the inner ear. 相似文献
38.
The nicotinic acetylcholine receptor Dalpha7 is required for an escape behavior in Drosophila 下载免费PDF全文
Acetylcholine is the major excitatory neurotransmitter in the central nervous system of insects. Mutant analysis of the Dalpha7 nicotinic acetylcholine receptor (nAChR) of Drosophila shows that it is required for the giant fiber-mediated escape behavior. The Dalpha7 protein is enriched in the dendrites of the giant fiber, and electrophysiological analysis of the giant fiber circuit showed that sensory input to the giant fiber is disrupted, as is transmission at an identified cholinergic synapse between the peripherally synapsing interneuron and the dorsal lateral muscle motor neuron. Moreover, we found that gfA1, a mutation identified in a screen for giant fiber defects more than twenty years ago, is an allele of Dalpha7. Therefore, a combination of behavioral, electrophysiological, anatomical, and genetic data indicate an essential role for the Dalpha7 nAChR in giant fiber-mediated escape in Drosophila. 相似文献
39.
Nathan J. Baird Syed S. Zaheer Tao Pan Tobin R. Sosnick 《Journal of molecular biology》2010,397(5):1298-242
RNA folding occurs via a series of transitions between metastable intermediate states for Mg2+ concentrations below those needed to fold the native structure. In general, these folding intermediates are considerably less compact than their respective native states. Our previous work demonstrates that the major equilibrium intermediate of the 154-residue specificity domain (S-domain) of the Bacillus subtilis RNase P RNA is more extended than its native structure. We now investigate two models with falsifiable predictions regarding the origins of the extended intermediate structures in the S-domains of the B. subtilis and the Escherichia coli RNase P RNA that belong to different classes of P RNA and have distinct native structures. The first model explores the contribution of electrostatic repulsion, while the second model probes specific interactions in the core of the folding intermediate. Using small-angle X-ray scattering and Langevin dynamics simulations, we show that electrostatics plays only a minor role, whereas specific interactions largely account for the extended nature of the intermediate. Structural contacts in the core, including a nonnative base pair, help to stabilize the intermediate conformation. We conclude that RNA folding intermediates adopt extended conformations due to short-range, nonnative interactions rather than generic electrostatic repulsion of helical domains. These principles apply to other ribozymes and riboswitches that undergo functionally relevant conformational changes. 相似文献
40.
GMF-Knockout Mice are Unable to Induce Brain-Derived Neurotrophic Factor after Exercise 总被引:2,自引:0,他引:2
We earlier reported that overexpression of glia maturation factor (GMF) in cultured astrocytes enhances the production of brain-derived neurotrophic factor (BDNF). The current study was conducted to find out whether BDNF production is impaired in animals devoid of GMF. To this end GMF-knockout (KO) mice were subjected to exercise and the neurotrophin mRNAs were determined by real-time RT-PCR. Compared to wild-type (WT) mice, there is a decrease in exercise-induced BDNF in the KO mice. The observation was correlated with the finding that, in WT mice, exercise increases GMF expression. The results are consistent with the hypothesis that GMF is necessary for exercise-induction of BDNF, and that GMF may promote neuroprotection through BDNF production. 相似文献