全文获取类型
收费全文 | 632篇 |
免费 | 61篇 |
出版年
2023年 | 7篇 |
2022年 | 1篇 |
2021年 | 17篇 |
2020年 | 12篇 |
2019年 | 13篇 |
2018年 | 14篇 |
2017年 | 19篇 |
2016年 | 25篇 |
2015年 | 44篇 |
2014年 | 38篇 |
2013年 | 57篇 |
2012年 | 65篇 |
2011年 | 62篇 |
2010年 | 41篇 |
2009年 | 32篇 |
2008年 | 46篇 |
2007年 | 42篇 |
2006年 | 33篇 |
2005年 | 24篇 |
2004年 | 32篇 |
2003年 | 25篇 |
2002年 | 10篇 |
2001年 | 3篇 |
2000年 | 3篇 |
1999年 | 2篇 |
1998年 | 4篇 |
1994年 | 2篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1978年 | 1篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1969年 | 1篇 |
1968年 | 2篇 |
1967年 | 2篇 |
1966年 | 1篇 |
排序方式: 共有693条查询结果,搜索用时 140 毫秒
1.
The stress-activated protein kinase Gcn2 regulates protein synthesis by phosphorylation of translation initiation factor eIF2α. Gcn2 is activated in amino acid-deprived cells by binding of uncharged tRNA to the regulatory domain related to histidyl-tRNA synthetase, but the molecular mechanism of activation is unclear. We used a genetic approach to identify a key regulatory surface in Gcn2 that is proximal to the predicted active site of the HisRS domain and likely remodeled by tRNA binding. Mutations leading to amino acid substitutions on this surface were identified that activate Gcn2 at low levels of tRNA binding (Gcd- phenotype), while other substitutions block kinase activation (Gcn- phenotype), in some cases without altering tRNA binding by Gcn2 in vitro. Remarkably, the Gcn- substitutions increase affinity of the HisRS domain for the C-terminal domain (CTD), previously implicated as a kinase autoinhibitory segment, in a manner dampened by HisRS domain Gcd- substitutions and by amino acid starvation in vivo. Moreover, tRNA specifically antagonizes HisRS/CTD association in vitro. These findings support a model wherein HisRS-CTD interaction facilitates the autoinhibitory function of the CTD in nonstarvation conditions, with tRNA binding eliciting kinase activation by weakening HisRS-CTD association with attendant disruption of the autoinhibitory KD-CTD interaction. 相似文献
2.
3.
Mella Adlersberg Kuo-Peing Liu Shu-Chi Hsiung Yigal Ehrlich Hadassah Tamir 《Journal of neurochemistry》1987,49(4):1105-1115
The endogenous phosphorylation of serotonin binding protein (SBP), a soluble protein found in central and peripheral serotonergic neurons, inhibits the binding of 5-hydroxytryptamine (5-HT, serotonin). A protein kinase activity that copurifies with SBP (SBP-kinase) was partially characterized and compared with calcium/calmodulin-dependent protein kinase II (CAM-PK II). SBP itself is not the enzyme since heating destroyed the protein kinase activity without affecting the capacity of the protein to bind [3H]5-HT. SBP-kinase and CAM-PK II kinase shared the following characteristics: (1) size of the subunits; (2) autophosphorylation in a Ca2+-dependent manner; and (3) affinity for Ca2+. In addition, both forms of protein kinase phosphorylated microtubule-associated proteins well and did not phosphorylate myosin, phosphorylase b, and casein. Phorbol esters or diacylglycerol had no effect on either of the protein kinases. However, substantial differences between SBP-kinase and CAM-PK II were observed: (1) CAM enhanced CAM-PK II activity, but had no effect on SBP-kinase; (2) synapsin I was an excellent substrate for CAM-PK II, but not for SBP-kinase; (3) 5-HT inhibited both the autophosphorylation of SBP-kinase and the phosphorylation of SBP, but had no effect on CAM-PK II. These data indicate that SBP-kinase is different from CAM-PK II. Phosphopeptide maps of SBP and SBP-kinase generated by digestion with S. aureus V8 protease are consistent with the conclusion that these proteins are distinct molecular entities. It is suggested that phosphorylation of SBP may regulate the transport of 5-HT within neurons. 相似文献
4.
Jorge J. Casal R. Alejandra Mella Carlos L. Ballaré Sara Maldonado 《Physiologia plantarum》1994,92(4):555-562
Etiolated Vicia faba seedlings were exposed to continuous red light to investigate whether changes in extracellular peroxidase activity were correlated in time and localization with changes in extension growth and/or lignin content in the subapical region of the epicotyl. Continuous red light: (a) increased extracellular peroxidase activity after a lag of ca 0.5 h, followed by a maximum peak after 2.5 h due to slightly acidic isoforms (pI = 6–6.5, according to isoelectrofocusing gels), a minimum after 4 h and a second maximum after 8 h due to acidic isoforms (pI=4–5), (b) increased lignin content and epicotyl resistance to bending after a lag of ca 4 h, i.e. simultaneously with changes in acidic extracellular peroxidase activity, and (c) reduced extension growth to a stable rate after a lag of ca 1 h, not coinciding with the kinetics of any of the extracellular peroxidase isoforms. These effects of continuous red light were at least partially mediated by phytochrome. Tissue printing and anatomical studies revealed red light effects on extracellular peroxidase activity and lignin content mainly in the outer cortical parenchyma. The results are consistent with the involvement of phyto-chrome-mediated effects on extracellular peroxidases (acidic isoforms) in the transduction chain leading to lignin responses to red light. 相似文献
5.
Susanne Siebentritt Enrico Avancini Marcus Br Jakob Bombsch Emilie Bourgeois Stephan Buecheler Romain Carron Celia Castro Sebastien Duguay Roberto Flix Evelyn Handick Dimitrios Hariskos Ville Havu Philip Jackson Hannu‐Pekka Komsa Thomas Kunze Maria Malitckaya Roberto Menozzi Milos Nesladek Nicoleta Nicoara Martti Puska Mohit Raghuwanshi Philippe Pareige Sascha Sadewasser Giovanna Sozzi Ayodhya Nath Tiwari Shigenori Ueda Arantxa Vilalta‐Clemente Thomas Paul Weiss Florian Werner Regan G. Wilks Wolfram Witte Max Hilaire Wolter 《Liver Transplantation》2020,10(8)
6.
Koffler Christoph Amor Ben Carbajales-Dale Michael Cascio Joseph Conroy Alison Fava James A. Gaudreault Caroline Gloria Thomas Hensler Connie Horvath Arpad Humbert Sebastien Manzardo Alessandro Margni Manuele Osset Philippe Sinistore Julie Vigon Bruce Wallace Michele L Wang Michael Prox Martina 《The International Journal of Life Cycle Assessment》2020,25(3):478-482
The International Journal of Life Cycle Assessment - 相似文献
7.
Yukiko Hori Yuji Nagai Koki Mimura Tetsuya Suhara Makoto Higuchi Sebastien Bouret Takafumi Minamimoto 《PLoS biology》2021,19(7)
It has been widely accepted that dopamine (DA) plays a major role in motivation, yet the specific contribution of DA signaling at D1-like receptor (D1R) and D2-like receptor (D2R) to cost–benefit trade-off remains unclear. Here, by combining pharmacological manipulation of DA receptors (DARs) and positron emission tomography (PET) imaging, we assessed the relationship between the degree of D1R/D2R blockade and changes in benefit- and cost-based motivation for goal-directed behavior of macaque monkeys. We found that the degree of blockade of either D1R or D2R was associated with a reduction of the positive impact of reward amount and increasing delay discounting. Workload discounting was selectively increased by D2R antagonism. In addition, blocking both D1R and D2R had a synergistic effect on delay discounting but an antagonist effect on workload discounting. These results provide fundamental insight into the distinct mechanisms of DA action in the regulation of the benefit- and cost-based motivation, which have important implications for motivational alterations in both neurological and psychiatric disorders.Using quantitatively controlled pharmacological manipulations, this study teases apart the role of D1- and D2-like dopamine receptors in motivation and goal-directed behavior in monkeys, revealing complementary roles of two dopamine receptor subtypes in the computation of the cost/benefit trade-off to guide action. 相似文献
8.
Abdala Hiam David Sebastien Bekesi George Fellous Arlette Jorge Kalil Patrice Le Pape 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):305-312
A new family of antimicrotubule drugs named (3-haloacetamidobenzoyl) ureas and ethyl 3-haloacetamidobenzoates were found to be cytotoxic to the Leishmania parasite protozoa. While the benzoylureas were shown to strongly inhibit in vitro mammalian brain microtubule assembly, the ethyl ester derivatives were characterized as very poor inhibitors of this process. Ethyl 3-chloroacetamidobenzoate, MF29, was found to be the most efficient drug on the promastigote stage of three Leishmania species (IC50: 0.3–1.8 μM). MF29 maintained its activity against the clinical relevant intracellular stage of L. mexicana with IC50 value of 0.33 μM. It was the only compound that exhibits a high activity on all the Leishmania species tested. This compound appeared to alter parasite microtubule organisation as demonstrated by using antibodies directed against microtubule components and more precisely the class of microtubule decorated by the MAP2-like protein. It is interesting to notice that this MAP2-like protein was identified for the first time in a Leishmania parasite 相似文献
9.
Inke Wallrodt Lotte Jelsbak Lotte Thorndahl Line E. Thomsen Sebastien Lemire John E. Olsen 《PloS one》2013,8(8)
The phage-shock protein PspE and GlpE of the glycerol 3-phosphate regulon of Salmonella enterica serovar Typhimurium are predicted to belong to the class of thiosulfate sulfurtransferases, enzymes that traffic sulfur between molecules. In the present study we demonstrated that the two genes contribute to S. Typhimurium virulence, as a glpE and pspE double deletion strain showed significantly decreased virulence in a mouse model of systemic infection. However, challenge of cultured epithelial cells and macrophages did not reveal any virulence-associated phenotypes. We hypothesized that their contribution to virulence could be in sulfur metabolism or by contributing to resistance to nitric oxide, oxidative stress, or cyanide detoxification. In vitro studies demonstrated that glpE but not pspE was important for resistance to H2O2. Since the double mutant, which was the one affected in virulence, was not affected in this assay, we concluded that resistance to oxidative stress and the virulence phenotype was most likely not linked. The two genes did not contribute to nitric oxid stress, to synthesis of essential sulfur containing amino acids, nor to detoxification of cyanide. Currently, the precise mechanism by which they contribute to virulence remains elusive. 相似文献
10.