全文获取类型
收费全文 | 7017篇 |
免费 | 501篇 |
出版年
2023年 | 33篇 |
2022年 | 92篇 |
2021年 | 192篇 |
2020年 | 105篇 |
2019年 | 133篇 |
2018年 | 196篇 |
2017年 | 179篇 |
2016年 | 267篇 |
2015年 | 385篇 |
2014年 | 438篇 |
2013年 | 543篇 |
2012年 | 716篇 |
2011年 | 649篇 |
2010年 | 389篇 |
2009年 | 348篇 |
2008年 | 455篇 |
2007年 | 423篇 |
2006年 | 375篇 |
2005年 | 355篇 |
2004年 | 293篇 |
2003年 | 264篇 |
2002年 | 231篇 |
2001年 | 34篇 |
2000年 | 34篇 |
1999年 | 48篇 |
1998年 | 49篇 |
1997年 | 29篇 |
1996年 | 30篇 |
1995年 | 29篇 |
1994年 | 22篇 |
1993年 | 19篇 |
1992年 | 21篇 |
1991年 | 12篇 |
1990年 | 13篇 |
1989年 | 15篇 |
1988年 | 6篇 |
1987年 | 9篇 |
1986年 | 12篇 |
1985年 | 7篇 |
1984年 | 14篇 |
1983年 | 9篇 |
1982年 | 7篇 |
1981年 | 8篇 |
1980年 | 8篇 |
1979年 | 6篇 |
1978年 | 4篇 |
1977年 | 4篇 |
1974年 | 1篇 |
1973年 | 3篇 |
1972年 | 1篇 |
排序方式: 共有7518条查询结果,搜索用时 46 毫秒
171.
Vasopressin activates Akt/mTOR pathway in smooth muscle cells cultured in high glucose concentration
Daniela K. Montes Marianne Brenet Vanessa C. Muñoz Patricia V. Burgos Carolina I. Villanueva Carlos D. Figueroa Carlos B. González 《Biochemical and biophysical research communications》2013
Mammalian target of rapamycin (mTOR) complex is a key regulator of autophagy, cell growth and proliferation. Here, we studied the effects of arginine vasopressin (AVP) on mTOR activation in vascular smooth muscle cells cultured in high glucose concentration. 相似文献
172.
173.
Simona Maria Monti Giuseppina De Simone Nina A. Dathan Martha Ludwig Daniela Vullo Andrea Scozzafava Clemente Capasso Claudiu T. Supuran 《Bioorganic & medicinal chemistry letters》2013,23(6):1626-1630
Several β-carbonic anhydrases (CAs, EC 4.2.1.1) are present in all land plants examined thus far. Here we report the first detailed biochemical characterization of one such isoform, FbiCA 1, from the C4 plant Flaveria bidentis, which was cloned, purified and characterized as recombinant protein. FbiCA 1 has an interesting CO2 hydrase catalytic activity (kcat of 1.2 × 105 and kcat/Km of 7.5 × 106 M?1 × s?1) and was moderately inhibited by most simple/complex inorganic anions. Potent FbiCA 1 inhibitors were also detected, such as trithiocarbonate, diethyldithiocarbamate, sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid (KIs in the range of 4–60 μM). Such inhibitors may be used as tools to better understand the role of various β-CA isoforms in photosynthesis. 相似文献
174.
Atilla Akdemir Daniela Vullo Viviana De Luca Andrea Scozzafava Vincenzo Carginale Mosè Rossi Claudiu T. Supuran Clemente Capasso 《Bioorganic & medicinal chemistry letters》2013,23(4):1087-1090
The α-carbonic anhydrase (CA, EC 4.2.1.1) from the extremophilic bacterium Sulfurihydrogenibium azorense (SazCA) was recently shown to be the fastest CA known. Here we investigated this enzyme for its activation with a series of amino acids and amines. The best SazCA activators were d-Phe, l-DOPA, l- and d-Trp, dopamine and serotonin, which showed activation constants in the range of 3–23 nM. l- and d-His, l-Phe, l-Tyr, 2-pyridyl-methylamine and L-adrenaline were also effective activators (KAs in the range of 62–90 nM), whereas d-Dopa, d-Tyr and several heterocyclic amines showed activity in the micromolar range. The good thermal stability, robustness, very high catalytic activity and propensity to be activated by simple amino acids and amines, make SazCA a very interesting candidate for biomimetic CO2 capture processes. 相似文献
175.
Ahmed M. Alafeefy Semra Isik Nabila A. Al-Jaber Daniela Vullo Hatem A. Abdel-Aziz Abdelkader E. Ashour Amani S. Awaad Clemente Capasso Claudiu T. Supuran 《Bioorganic & medicinal chemistry letters》2013,23(12):3570-3575
A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogs) were assayed as inhibitors of the β-carbonic anhydrase (CA, EC 4.2.1.1) from Saccharomyces cerevisiae, ScCA. Some of these compounds were low nanomolar or subnanomolar ScCA inhibitors and showed selectivity ratios in the range of 4.91–69.86 for inhibiting the yeast enzyme over the offtarget human (h) isoforms hCA I and of 6.46–13.52 for inhibiting ScCA over hCA II. The model organism S. cerevisiae and this particular enzyme may be useful for detecting antifungals with a novel mechanism of action compared to the classical azole drugs to which significant drug resistance emerged. Indeed, some of these sulfonamides inhibited the growth of the yeast with CC50-s in the range of 0.73–6.54 μM. 相似文献
176.
Sonia Del Prete Daniela Vullo Viviana De Luca Vincenzo Carginale Andrea Scozzafava Claudiu T. Supuran Clemente Capasso 《Bioorganic & medicinal chemistry letters》2013,23(14):4067-4071
Carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the γ-class are present in archaea, bacteria and plants but, except the Methanosarcina thermophila enzymes CAM and CAMH, they were poorly characterized so far. Here we report a new such enzyme (PgiCA), the γ-CA from the oral cavity pathogenic bacterium Porphyromonas gingivalis, the main causative agent of periodontitis. PgiCA showed a good catalytic activity for the CO2 hydration reaction, comparable to that of the human (h) isoform hCA I. Inorganic anions such as thiocyanate, cyanide, azide, hydrogen sulfide, sulfamate and trithiocarbonate were effective PgiCA inhibitors with inhibition constants in the range of 41–97 μM. Other effective inhibitors were diethyldithiocarbamate, sulfamide, and phenylboronic acid, with KIs of 4.0–9.8 μM. The role of this enzyme as a possible virulence factor of P. gingivalis is poorly understood at the moment but its good catalytic activity and the possibility to be inhibited by a large number of compounds may lead to interesting developments in the field. 相似文献
177.
Thomas Troxler Paulette Greenidge Kaspar Zimmermann Sandrine Desrayaud Peter Drückes Tatjana Schweizer Daniela Stauffer Giorgio Rovelli Derya R. Shimshek 《Bioorganic & medicinal chemistry letters》2013,23(14):4085-4090
Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common genetic cause of Parkinson’s disease (PD). The most frequent kinase-enhancing mutation is the G2019S residing in the kinase activation domain. This opens up a promising therapeutic avenue for drug discovery targeting the kinase activity of LRRK2 in PD. Several LRRK2 inhibitors have been reported to date. Here, we report a selective, brain penetrant LRRK2 inhibitor and demonstrate by a competition pulldown assay in vivo target engagement in mice. 相似文献
178.
179.
Daniela Volcan Almeida Camila de Martinez Gaspar Martins M��rcio de Azevedo Figueiredo Carlos Frederico Ceccon Lanes Adalto Bianchini Luis Fernando Marins 《Transgenic research》2013,22(1):75-88
Growth hormone (GH) transgenic fish are at a critical step for possible approval for commercialization. Since this hormone is related to salinity tolerance in fish, our main goal was to verify whether the osmoregulatory capacity of the stenohaline zebrafish (Danio rerio) would be modified by GH-transgenesis. For this, we transferred GH-transgenic zebrafish (T) from freshwater to 11 ppt salinity and analyzed survival as well as relative changes in gene expression. Results show an increased mortality in T versus non-transgenic (NT) fish, suggesting an impaired mechanism of osmotic acclimation in T. The salinity effect on expression of genes related to osmoregulation, the somatotropic axis and energy metabolism was evaluated in gills and liver of T and NT. Genes coding for Na+, K+-ATPase, H+-ATPase, plasma carbonic anhydrase and cytosolic carbonic anhydrase were up-regulated in gills of transgenics in freshwater. The growth hormone receptor gene was down-regulated in gills and liver of both NT and T exposed to 11 ppt salinity, while insulin-like growth factor-1 was down-regulated in liver of NT and in gills of T exposed to 11 ppt salinity. In transgenics, all osmoregulation-related genes and the citrate synthase gene were down-regulated in gills of fish exposed to 11 ppt salinity, while lactate dehydrogenase expression was up-regulated in liver. Na+, K+-ATPase activity was higher in gills of T exposed to 11 ppt salinity as well as the whole body content of Na+. Increased ATP content was observed in gills of both NT and T exposed to 11 ppt salinity, being statistically higher in T than NT. Taking altogether, these findings support the hypothesis that GH-transgenesis increases Na+ import capacity and energetic demand, promoting an unfavorable osmotic and energetic physiological status and making this transgenic fish intolerant of hyperosmotic environments. 相似文献
180.
Mariangela Ceruso Daniela Vullo Andrea Scozzafava Claudiu T. Supuran 《Bioorganic & medicinal chemistry》2013,21(22):6929-6936
Reaction of cyanuryl fluoride with sulfanilamide or 4-aminoethylbenzenesulfonamide afforded triazinyl-substituted benzenesulfonamides incorporating fluorine, which were further derivatized by reaction with amines, amino alcohols, amino acids or amino acid esters. Inhibition studies of all the human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, hCA I–XIV with these compounds revealed that they show moderate-weak inhibition of hCA III, IV, VA and XIII, rather moderate inhibition against hCA I, VI, and IX, and excellent inhibition of the physiologically relevant hCA II, VII and XII. The inhibition profile of these fluorine containing triazinyl sulfonamides is thus very different from the corresponding analogs incorporating chlorine, which were previously investigated as inhibitors of some of these enzymes. 相似文献