全文获取类型
收费全文 | 1135篇 |
免费 | 71篇 |
国内免费 | 2篇 |
出版年
2022年 | 8篇 |
2021年 | 9篇 |
2018年 | 16篇 |
2017年 | 7篇 |
2016年 | 21篇 |
2015年 | 19篇 |
2014年 | 21篇 |
2013年 | 44篇 |
2012年 | 47篇 |
2011年 | 48篇 |
2010年 | 36篇 |
2009年 | 33篇 |
2008年 | 51篇 |
2007年 | 50篇 |
2006年 | 52篇 |
2005年 | 44篇 |
2004年 | 43篇 |
2003年 | 41篇 |
2002年 | 31篇 |
2001年 | 43篇 |
2000年 | 34篇 |
1999年 | 31篇 |
1998年 | 23篇 |
1997年 | 7篇 |
1996年 | 13篇 |
1995年 | 11篇 |
1994年 | 16篇 |
1993年 | 9篇 |
1992年 | 20篇 |
1991年 | 19篇 |
1990年 | 14篇 |
1989年 | 24篇 |
1988年 | 27篇 |
1987年 | 14篇 |
1986年 | 32篇 |
1985年 | 21篇 |
1984年 | 21篇 |
1983年 | 16篇 |
1982年 | 11篇 |
1981年 | 8篇 |
1980年 | 10篇 |
1979年 | 25篇 |
1978年 | 18篇 |
1977年 | 9篇 |
1976年 | 12篇 |
1975年 | 21篇 |
1974年 | 15篇 |
1973年 | 11篇 |
1972年 | 7篇 |
1971年 | 6篇 |
排序方式: 共有1208条查询结果,搜索用时 15 毫秒
191.
P.J. Niziolek S. Murthy S.N. Ellis K.B. Sukhija T.A. Hornberger C.H. Turner A.G. Robling 《Journal of cellular physiology》2009,221(3):579-585
The osteo‐anabolic effects of intermittent parathyroid hormone (PTH) treatment require insulin‐like growth factor (IGF) signaling through the IGF‐I receptor. A major downstream target of the IGF‐I receptor (via Akt) is the mammalian target of rapamycin (mTOR), a kinase involved in protein synthesis. We investigated whether the bone‐building effects of intermittent PTH require functional mTOR signaling. Mice were treated with daily PTH 1–34 (0, 10, 30, or 90 µg/kg) for 6 weeks in the presence or absence of rapamycin, a selective inhibitor of mTOR. We found that all PTH doses were effective in enhancing bone mass, whether rapamycin was present or not. Rapamycin had little to no effect on the anabolic response at low (10 µg) PTH doses, small effects in a minority of anabolic measures at moderate doses (30 µg), but the anabolic effects of high‐dose PTH (90 µg) were consistently and significantly suppressed by rapamycin (~4–36% reduction). Serum levels of Trap5b, a marker of resorption, were significantly enhanced by rapamycin, but these effects were observed whether PTH was absent or present. Our data suggest that intermittent PTH, particularly at lower doses, is effective in building bone mass in the presence of rapamycin. However, the full anabolic effects of higher doses of PTH are significantly suppressed by rapamycin, suggesting that PTH might normally activate additional pathways (including mTOR) for its enhanced high‐dose anabolic effects. Clinical doses of intermittent PTH could be an effective treatment for maintaining or increasing bone mass among patients taking rapamycin analogs for unrelated health issues. J. Cell. Physiol. 221: 579–585, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
192.
Marie-Line Peyot Joshua P. Gray Julien Lamontagne Peter J. S. Smith George G. Holz S. R. Murthy Madiraju Marc Prentki Emma Heart 《PloS one》2009,4(7)
Background
Glucagon like peptide-1 (GLP-1) and its analogue exendin-4 (Ex-4) enhance glucose stimulated insulin secretion (GSIS) and activate various signaling pathways in pancreatic β-cells, in particular cAMP, Ca2+ and protein kinase-B (PKB/Akt). In many cells these signals activate intermediary metabolism. However, it is not clear whether the acute amplification of GSIS by GLP-1 involves in part metabolic alterations and the production of metabolic coupling factors.Methodology/Prinicipal Findings
GLP-1 or Ex-4 at high glucose caused release (∼20%) of the total rat islet insulin content over 1 h. While both GLP-1 and Ex-4 markedly potentiated GSIS in isolated rat and mouse islets, neither had an effect on β-cell fuel and energy metabolism over a 5 min to 3 h time period. GLP-1 activated PKB without changing glucose usage and oxidation, fatty acid oxidation, lipolysis or esterification into various lipids in rat islets. Ex-4 caused a rise in [Ca2+]i and cAMP but did not enhance energy utilization, as neither oxygen consumption nor mitochondrial ATP levels were altered.Conclusions/Significance
The results indicate that GLP-1 barely affects β-cell intermediary metabolism and that metabolic signaling does not significantly contribute to GLP-1 potentiation of GSIS. The data also indicate that insulin secretion is a minor energy consuming process in the β-cell, and that the β-cell is different from most cell types in that its metabolic activation appears to be primarily governed by a “push” (fuel substrate driven) process, rather than a “pull” mechanism secondary to enhanced insulin release as well as to Ca2+, cAMP and PKB signaling. 相似文献193.
Vallabhaneni S. Murthy Yasinalli Tamboli Vagolu Siva Krishna Dharmarajan Sriram Siddique Akber Ansari Abdullah A. Alarfaj Abdurahman H. Hirad Vijayaparthasarathi Vijayakumar 《Journal of enzyme inhibition and medicinal chemistry》2021,36(1):1751
Molecular hybridisation of four bioactive fragments piperazine, substituted-benzofuran, amino acids, and 2,4-dinitrobenzenesulfonamide as single molecular architecture was designed. A series of new hybrids were synthesised and subjected to evaluation for their inhibitory activity against Mycobacterium tuberculosis (Mtb) H37Rv. 4d–f and 4o found to exhibit MIC as 1.56 µg/mL, equally active as ethambutol whereas 4a, 4c, 4j displayed MIC 0.78 µg/mL were superior to ethambutol. Tested compounds demonstrated an excellent safety profile with very low toxicity, good selectivity index, and antioxidant properties. All the newly synthesised compounds were thoroughly characterised by analytical methods. The result was further supported by molecular modelling studies on the crystal structure of Mycobacterium tuberculosis enoyl reductase. 相似文献
194.
To improve large-scale in vitro production of Oplopanax elatus Nakai, we cultured somatic embryo-derived plantlets under a heterotrophic condition (semi-solid culture with sucrose), photoautotrophic
condition (semi-solid culture without sucrose), or modified photoautotrophic condition (liquid culture with forced ventilation).
The plantlets grown under the modified photoautotrophic condition had more leaves as well as higher chlorophyll content, and
higher net photosynthetic rate than those grown under the conventional conditions. Further, the photoautotrophically grown
plantlets acclimatized better and sooner upon ex vitro transplantation than did the conventionally cultured plantlets. Consequently, a photoautotrophic culture method with forced
ventilation is effective for enhancing the growth and acclimatization of O. elatus. 相似文献
195.
196.
197.
198.
Ancy D. Nalli Divya P. Kumar Othman Al-Shboul Sunila Mahavadi John F. Kuemmerle John R. Grider Karnam S. Murthy 《Cell biochemistry and biophysics》2014,70(2):867-880
In gastrointestinal smooth muscle, agonists that bind to Gi-coupled receptors activate preferentially PLC-β3 via Gβγ to stimulate phosphoinositide (PI) hydrolysis and generate inositol 1,4,5-trisphosphate (IP3) leading to IP3-dependent Ca2+ release and muscle contraction. In the present study, we identified the mechanism of inhibition of PLC-β3-dependent PI hydrolysis by cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG). Cyclopentyl adenosine (CPA), an adenosine A1 receptor agonist, caused an increase in PI hydrolysis in a concentration-dependent fashion; stimulation was blocked by expression of the carboxyl-terminal sequence of GRK2(495–689), a Gβγ-scavenging peptide, or Gαi minigene but not Gαq minigene. Isoproterenol and S-nitrosoglutathione (GSNO) induced phosphorylation of PLC-β3 and inhibited CPA-induced PI hydrolysis, Ca2+ release, and muscle contraction. The effect of isoproterenol on all three responses was inhibited by PKA inhibitor, myristoylated PKI, or AKAP inhibitor, Ht-31, whereas the effect of GSNO was selectively inhibited by PKG inhibitor, Rp-cGMPS. GSNO, but not isoproterenol, also phosphorylated Gαi-GTPase-activating protein, RGS2, and enhanced association of Gαi3-GTP and RGS2. The effect of GSNO on PI hydrolysis was partly reversed in cells (i) expressing constitutively active GTPase-resistant Gαi mutant (Q204L), (ii) phosphorylation-site-deficient RGS2 mutant (S46A/S64A), or (iii) siRNA for RGS2. We conclude that PKA and PKG inhibit Gβγi-dependent PLC-β3 activity by direct phosphorylation of PLC-β3. PKG, but not PKA, also inhibits PI hydrolysis indirectly by a mechanism involving phosphorylation of RGS2 and its association with Gαi-GTP. This allows RGS2 to accelerate Gαi-GTPase activity, enhance Gαβγi trimer formation, and inhibit Gβγi-dependent PLC-β3 activity. 相似文献
199.
Jennifer L. Larson-Casey Shubha Murthy Alan J. Ryan A. Brent Carter 《The Journal of biological chemistry》2014,289(52):36204-36219
Protein kinase B (Akt) is a key effector of multiple cellular processes, including cell survival. Akt, a serine/threonine kinase, is known to increase cell survival by regulation of the intrinsic pathway for apoptosis. In this study, we found that Akt modulated the mevalonate pathway, which is also linked to cell survival, by increasing Rho GTPase activation. Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. This phosphorylation in macrophages increased activation of Rac1, which enhanced macrophage survival because mutation of MDD (MDDS96A) induced apoptosis. Akt-mediated activation in macrophages was specific for Rac1 because Akt did not increase activity of other Rho GTP-binding proteins. The relationship between Akt and Rac1 was biologically relevant because Akt+/− mice had significantly less active Rac1 in alveolar macrophages, and macrophages from Akt+/− mice had an increase in active caspase-9 and -3. More importantly, Akt+/− mice were significantly protected from the development of pulmonary fibrosis, suggesting that macrophage survival is associated with the fibrotic phenotype. These observations for the first time suggest that Akt plays a critical role in the development and progression of pulmonary fibrosis by enhancing macrophage survival via modulation of the mevalonate pathway. 相似文献
200.
Effect of UV-B (1.9 W m-2) alone or in combination with supplemental "white light". WL (20 W m-2) exposure was studied on the energy transfer process of intact phycobilisomes isolated from Spirulina platensis. Exposure of UV-B or supplemental irradiation induced a decrease in room temperature fluorescence intensity and caused a shift towards shorter wavelengths. The low temperature fluorescence measurements showed that UV-B impairs energy transfer from phycocyanin to allophycocyanin B and the extent of damage may be reduced by the exposure to supplemental WL. 相似文献