全文获取类型
收费全文 | 1724篇 |
免费 | 108篇 |
专业分类
1832篇 |
出版年
2023年 | 11篇 |
2022年 | 23篇 |
2021年 | 48篇 |
2020年 | 20篇 |
2019年 | 52篇 |
2018年 | 50篇 |
2017年 | 41篇 |
2016年 | 46篇 |
2015年 | 81篇 |
2014年 | 116篇 |
2013年 | 139篇 |
2012年 | 154篇 |
2011年 | 125篇 |
2010年 | 70篇 |
2009年 | 69篇 |
2008年 | 97篇 |
2007年 | 81篇 |
2006年 | 84篇 |
2005年 | 72篇 |
2004年 | 66篇 |
2003年 | 47篇 |
2002年 | 37篇 |
2001年 | 33篇 |
2000年 | 20篇 |
1999年 | 24篇 |
1998年 | 15篇 |
1997年 | 14篇 |
1996年 | 17篇 |
1995年 | 5篇 |
1994年 | 9篇 |
1993年 | 8篇 |
1992年 | 14篇 |
1991年 | 13篇 |
1990年 | 10篇 |
1989年 | 7篇 |
1988年 | 5篇 |
1987年 | 10篇 |
1986年 | 8篇 |
1985年 | 7篇 |
1984年 | 4篇 |
1983年 | 12篇 |
1982年 | 4篇 |
1981年 | 5篇 |
1980年 | 4篇 |
1979年 | 10篇 |
1975年 | 8篇 |
1974年 | 6篇 |
1973年 | 5篇 |
1970年 | 4篇 |
1968年 | 6篇 |
排序方式: 共有1832条查询结果,搜索用时 15 毫秒
991.
Colombi M Zoppi N De Petro G Marchina E Gardella R Tavian D Ferraboli S Barlati S 《The Journal of biological chemistry》2003,278(16):14346-14355
Fibronectin (FN) is an extracellular matrix (ECM) protein involved in tumor growth and metastasis. Five human FN cDNA segments encoding for FN fragments, all starting with the II1 repeat and ending with different C-terminal extensions, have been stably expressed in chick embryo fibroblasts (CEF). These FN cDNAs induce the formation of an organized ECM in CEF as long as they retain a sequence coding for a 13-amino acid stretch (FN13), with collagen binding activity, localized between type II2 and I7 repeats. An FN13 synthetic peptide induces in control CEF the assembly of an FN-ECM comparable with that observed in CEF-expressing FN fragments. The activity of FN13 is specific for its amino acid sequence, although the cysteine present in the 6th position can be substituted with a polar serine without affecting the induction of a fibrillar FN-ECM. A less fibrillar matrix is induced by FN13-modified peptides in which the cysteine is methylated or substituted by a non-polar alanine. FN13 induces the assembly of an FN-ECM also in Rous sarcoma virus-transformed CEF lacking the ECM and in hepatoma (SK-Hep1) and fibrosarcoma (HT-1080) human cell lines. FN13 also promotes the adhesion of CEF and Rous sarcoma virus-CEF at levels comparable with those obtained with purified intact FN. Finally, FN13 inhibits the migratory and invasive properties of tumorigenic cells, whereas intact FN favors their migration. All FN13-modified peptides show similar effects, although with reduced efficiency. None of these activities is supported by a scrambled peptide. These data suggest a possible role of FN13 in tumor growth and metastasis inhibition and its possible use as anti-tumorigenic agent. 相似文献
992.
Supramodular structure and synergistic target binding of the N-terminal tandem PDZ domains of PSD-95
Long JF Tochio H Wang P Fan JS Sala C Niethammer M Sheng M Zhang M 《Journal of molecular biology》2003,327(1):203-214
PDZ domain proteins play critical roles in binding, clustering and subcellular targeting of membrane receptors and ion channels. PDZ domains in multi-PDZ proteins often are arranged in groups with highly conserved spacing and intervening sequences; however, the functional significance of such tandem arrangements of PDZs is unclear. We have solved the three-dimensional structure of the first two PDZ domains of postsynaptic density protein-95 (PSD-95 PDZ1 and PDZ2), which are closely linked to each other in the PSD-95 family of scaffold proteins. The two PDZs have limited freedom of rotation and their C-terminal peptide-binding grooves are aligned with each other with an orientation preference for binding to pairs of C termini extending in the same direction. Increasing the spacing between PDZ1 and PDZ2 resulted in decreased binding between PDZ12 and its dimeric targets. The same mutation impaired the functional ability of PSD-95 to cluster Kv1.4 potassium channels in heterologous cells. The data presented provide a molecular basis for preferential binding of PSD-95 to multimeric membrane proteins with appropriate C-terminal sequences. 相似文献
993.
Octavio Aburto-Oropeza Enric Sala Carlos Sánchez-Ortiz 《Environmental Biology of Fishes》2000,57(4):435-442
Feeding behavior and habitat use of the king angelfish, Holacanthus passer, was studied in the southern Sea of Cortés, México. H. passer fed on benthic communities (algae and sessile invertebrates) and in the water column (mainly feces from the damselfish Chromis atrilobata). Although there were not significant differences in feeding rate between sexes, coprophagy was more common in males, while grazing was more common in females. Spatial distribution of size classes followed a pattern of decreasing size with increasing depth. Feeding rate was significantly different among habitats: small females had a higher feeding rate on the bottom, big females and small males had similar feeding rates from the bottom to 3m above the bottom, and big males had higher feeding rates from 5m above the bottom to the surface. Habitat was clearly partitioned, and there was significant habitat overlap only between big females and small males. The abundance of H. passer was partly explained (34% of the total variance) by the abundance of the damselfish C. atrilobata. There was a clear trophic association between C. atrilobata schools and H. passer feeding damselfish feces in the water column. The sex ratio male:female of H. passer populations was >1 at several sites, an unusual pattern for a protogynous fish. The sex ratio on the H. passer water column stock was also biased towards males at most sites. Although there is a positive relationship between C. atrilobata abundance and H. passer, there are factors other than damselfish abundance which cause this dominance of males. 相似文献
994.
995.
Winter Marina Marfil María Jimena La Sala Luciano Francisco Suarez Marcos Maidana Celia Rodriguez Carlos Mesplet María Abate Sergio Rosas Carolina Peña Martinez Jorge Barandiaran Soledad 《EcoHealth》2022,19(2):159-163
Swine coronaviruses affecting pigs have been studied sporadically in wildlife. In Argentina, epidemiological surveillance of TGEV/PRCV is conducted only in domestic pigs. The aim was to assess the prevalence of TGEV/PRCV in wild Suina. Antibodies against these diseases in wild boar and captive collared peccary were surveyed by ELISA. Antibodies against TGEV were found in three collared peccaries (n?=?87). No TGEV/PRCV antibodies were detected in wild boar (n?=?160). Preventive measures should be conducted in contact nodes where the transmission of agents may increase. Epidemiological surveillance in wildlife populations and in captive animals before their reintroduction should be attempted.
相似文献996.
997.
Binding of agonists to nicotinic acetylcholine receptors results in channel opening. Previously, we have shown that several charged residues at three different domains of the alpha7 nicotinic receptor are involved in coupling binding and gating, probably through a network of electrostatic interactions. This network, however, could also be integrated by other residues. To test this hypothesis, non-charged amino acids were mutated and expression levels and electrophysiological responses of mutant receptors were determined. Mutants at positions Asn47 and Gln48 (loop 2), Ile130, Trp134, and Gln140 (loop 7), and Thr264 (M2-M3 linker) showed poor or null functional responses, despite significant membrane expression. By contrast, mutants F137A and S265A exhibited a gain of function effect. In all cases, changes in dose-response relationships were small, EC(50) values being between threefold smaller and fivefold larger, arguing against large modifications of agonist binding. Peak currents decayed at the same rate in all receptors except two, excluding large effects on desensitization. Thus, the observed changes could be mostly caused by alterations of the gating characteristics. Moreover, analysis of double mutants showed an interconnection between some residues in these domains, especially Gln48 with Ile130, suggesting a potential coupling between agonist binding and channel gating through these amino acids. 相似文献
998.
Mei G Di Venere A Gasperi V Nicolai E Masuda KR Finazzi-Agrò A Cravatt BF Maccarrone M 《The Journal of biological chemistry》2007,282(6):3829-3836
Fatty acid amide hydrolase (FAAH) is a dimeric, membranebound enzyme that degrades neuromodulatory fatty acid amides and esters and is expressed in mammalian brain and peripheral tissues. The cleavage of approximately 30 amino acids from each subunit creates an FAAH variant that is soluble and homogeneous in detergent-containing buffers, opening the avenue to the in vitro mechanistic and structural studies. Here we have studied the stability of FAAH as a function of guanidinium hydrochloride concentration and of hydrostatic pressure. The unfolding transition was observed to be complex and required a fitting procedure based on a three-state process with a monomeric intermediate. The first transition was characterized by dimer dissociation, with a free energy change of approximately 11 kcal/mol that accounted for approximately 80% of the total stabilization energy. This process was also paralleled by a large change in the solvent-accessible surface area, because of the hydration occurring both at the dimeric interface and within the monomers. As a consequence, the isolated subunits were found to be much less stable (DeltaG approximately 3 kcal/mol). The addition of methoxyarachidonyl fluorophosphonate, an irreversible inhibitor of FAAH activity, enhanced the stability of the dimer by approximately 2 kcal/mol, toward denaturant- and pressure-induced unfolding. FAAH inhibition by methoxyarachidonyl fluorophosphonate also reduced the ability of the protein to bind to the membranes. These findings suggest that local conformational changes at the level of the active site might induce a tighter interaction between the subunits of FAAH, affecting the enzymatic activity and the interaction with membranes. 相似文献
999.
Falasca M Hughes WE Dominguez V Sala G Fostira F Fang MQ Cazzolli R Shepherd PR James DE Maffucci T 《The Journal of biological chemistry》2007,282(38):28226-28236
The members of the class II phosphoinositide 3-kinase (PI3K) family can be activated by several stimuli, indicating that these enzymes can regulate many intracellular processes. Nevertheless, to date, there has been no definitive identification of their in vivo product, their mechanism(s) of activation, or their precise intracellular roles. By metabolic labeling, we here identify phosphatidylinositol 3-phosphate as the sole in vivo product of the insulin-dependent activation of PI3K-C2alpha, confirming the emerging role of such a phosphoinositide in signaling. We demonstrate that activation of PI3K-C2alpha involves its recruitment to the plasma membrane and that activation is mediated by the GTPase TC10. This is the first report showing a membrane targeting-mediated mechanism of activation for PI3K-C2alpha and that a small GTP-binding protein can activate a class II PI3K isoform. We also demonstrate that PI3K-C2alpha contributes to maximal insulin-induced translocation of the glucose transporter GLUT4 to the plasma membrane and subsequent glucose uptake, definitely assessing the role of this enzyme in insulin signaling. 相似文献
1000.
Leucci E De Falco G Onnis A Cerino G Cocco M Luzzi A Crupi D Tigli C Bellan C Tosi P Leoncini L Giordano A 《Journal of cellular physiology》2007,212(2):411-415
The Cdk9/Cyclin T1 complex is very important in controlling specific differentiative pathways of several cell types, including muscle cells and neurons. We recently demonstrated the involvement of this complex in B cell activation/differentiation. To check whether the Cdk9/Cyclin T1 complex is also involved in the T cell activation/differentiation process, we isolated different T cell populations by magnetic separation, based on their surface antigens. We observed that the expression level of Cdk9/Cyclin T1 increases in effector T cells (CD27(+)), as well as in activated T cells (CD25(+)) and memory T cells (CD45RA(-)), thus suggesting a specific upregulation of the Cdk9/Cyclin T1 complex following antigen encounter. We have previously demonstrated that in B cells, Cdk9 interacts in vivo with the E2A gene products E12/E47 (members of the basic helix-loop-helix family) which are involved in differentiation. In this article, we show that this interaction also occurs in T cells. This suggests an active role for the Cdk9/Cyclin T1 complex during lymphoid differentiation, through physical binding with E12 and E47. These preliminary results suggest that the Cdk9/Cyclin T1 complex may be important in the activation and differentiation program of lymphoid cells and that its upregulation, which is due to still unknown mechanisms, may contribute to malignant transformation. 相似文献