全文获取类型
收费全文 | 20592篇 |
免费 | 1946篇 |
国内免费 | 21篇 |
专业分类
22559篇 |
出版年
2023年 | 102篇 |
2022年 | 218篇 |
2021年 | 465篇 |
2020年 | 209篇 |
2019年 | 313篇 |
2018年 | 360篇 |
2017年 | 315篇 |
2016年 | 570篇 |
2015年 | 988篇 |
2014年 | 1083篇 |
2013年 | 1279篇 |
2012年 | 1710篇 |
2011年 | 1667篇 |
2010年 | 1103篇 |
2009年 | 883篇 |
2008年 | 1372篇 |
2007年 | 1344篇 |
2006年 | 1219篇 |
2005年 | 1194篇 |
2004年 | 1155篇 |
2003年 | 1079篇 |
2002年 | 1021篇 |
2001年 | 170篇 |
2000年 | 96篇 |
1999年 | 202篇 |
1998年 | 255篇 |
1997年 | 156篇 |
1996年 | 136篇 |
1995年 | 123篇 |
1994年 | 115篇 |
1993年 | 112篇 |
1992年 | 92篇 |
1991年 | 92篇 |
1990年 | 80篇 |
1989年 | 65篇 |
1988年 | 53篇 |
1987年 | 59篇 |
1986年 | 48篇 |
1985年 | 65篇 |
1984年 | 65篇 |
1983年 | 69篇 |
1982年 | 77篇 |
1981年 | 74篇 |
1980年 | 74篇 |
1979年 | 36篇 |
1978年 | 65篇 |
1977年 | 43篇 |
1976年 | 38篇 |
1975年 | 37篇 |
1973年 | 26篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
M'Barek S Lopez-Gonzalez I Andreotti N di Luccio E Visan V Grissmer S Judge S El Ayeb M Darbon H Rochat H Sampieri F Béraud E Fajloun Z De Waard M Sabatier JM 《The Journal of biological chemistry》2003,278(33):31095-31104
Maurotoxin (MTX) is a 34-residue toxin that has been isolated initially from the venom of the scorpion Scorpio maurus palmatus. It presents a large number of pharmacological targets, including small conductance Ca2+-activated and voltage-gated K+ channels. Contrary to other toxins of the alpha-KTx6 family (Pi1, Pi4, Pi7, and HsTx1), MTX exhibits a unique disulfide bridge organization of the type C1-C5, C2-C6, C3-C4, and C7-C8 (instead of the conventional C1-C5, C2-C6, C3-C7, and C4-C8, herein referred to as Pi1-like) that does not prevent its folding along the classic alpha/beta scaffold of scorpion toxins. Here, we developed an innovative strategy of chemical peptide synthesis to produce an MTX variant (MTXPi1) with a conventional pattern of disulfide bridging without any alteration of the toxin chemical structure. This strategy was used solely to address the impact of half-cystine pairings on MTX structural properties and pharmacology. The data indicate that MTXPi1 displays some marked changes in affinities toward the target K+ channels. Computed docking analyses using molecular models of both MTXPi1 and the various voltage-gated K+ channel subtypes (Shaker B, Kv1.2, and Kv1.3) were found to correlate with MTXPi1 pharmacology. A functional map detailing the interaction between MTXPi1 and Shaker B channel was generated in line with docking experiments. 相似文献
992.
Alpha4beta1 integrin affinity changes govern cell adhesion 总被引:3,自引:0,他引:3
Chigaev A Zwartz G Graves SW Dwyer DC Tsuji H Foutz TD Edwards BS Prossnitz ER Larson RS Sklar LA 《The Journal of biological chemistry》2003,278(40):38174-38182
Integrin alpha4beta1 is a receptor for vascular cell adhesion molecule-1 and fibronectin. It is important in lymphopoiesis, inflammatory recruitment of leukocytes, and other situations that require cell adhesion to the vascular endothelium. The avidity of the cells expressing alpha4beta1 integrin can be rapidly changed by chemokines and chemoattractants. Different mechanisms, including changes in the number of interacting molecules due to the alteration of the receptor topology or changes in the affinity of the individual bonds, have been proposed to explain the nature of these fast changes in avidity. Recently, we described a fluorescent LDV-containing small molecule, which we used to monitor the affinity changes on live cells in real time (Chigaev, A., Blenc, A. M., Braaten, J. V., Kumaraswamy, N., Kepley, C. L., Andrews, R. P., Oliver, J. M., Edwards, B. S., Prossnitz, E. R., Larson, R. S. et al. (2001) J. Biol. Chem. 276, 48670-48678). Here we show that the affinity of the small molecule probe as well as the native ligand vascular cell adhesion molecule-1 varies in parallel when the integrin is modulated with divalent cations and that the affinity modulation leads to the changes in cell avidity. Using formyl peptide receptor-transfected U937 cells, we further show that the time course of avidity changes in response to the receptor activation coincides with the time course of the affinity changes. Taken together, these data are consistent with the idea that affinity regulation is a major factor that governs the avidity of cell adhesion mediated by the alpha4 integrin. 相似文献
993.
Ikeda K Brown JA Yagi T Norrander JM Hirono M Eccleston E Kamiya R Linck RW 《The Journal of biological chemistry》2003,278(9):7725-7734
Ciliary and flagellar axonemes are basically composed of nine outer doublet microtubules and several functional components, e.g. dynein arms, radial spokes, and interdoublet links. Each A-tubule of the doublet contains a specialized "ribbon" of three protofilaments composed of tubulin and other proteins postulated to specify the three-dimensional arrangement of the various axonemal components. The interdoublet links hold the doublet microtubules together and limit their sliding during the flagellar beat. In this study on Chlamydomonas reinhardtii, we cloned a cDNA encoding a 71,985-Da polypeptide with three DM10 repeats, two C-terminal EF-hand motifs, and homologs extending to humans. This polypeptide, designated as Rib72, is a novel component of the ribbon compartment of flagellar microtubules. It remained associated with 9-fold arrays of doublet tubules following extraction under high and low ionic conditions, and anti-Rib72 antibodies revealed an approximately 96-nm periodicity along axonemes, consistent with Rib72 associating with interdoublet links. Following proteolysis- and ATP-dependent disintegration of axonemes, the rate of cleavage of Rib72 correlated closely with the rate of sliding disintegration. These observations identify a ribbon-associated protein that may function in the structural assembly of the axoneme and in the mechanism and regulation of ciliary and flagellar motility. 相似文献
994.
FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines 总被引:15,自引:0,他引:15
995.
Bai F Xi JH Wawrousek EF Fleming TP Andley UP 《The Journal of biological chemistry》2003,278(38):36876-36886
alphaB-Crystallin, a major protein of lens fiber cells, is a stress-induced chaperone expressed at low levels in the lens epithelium and numerous other tissues, and its expression is enhanced in certain pathological conditions. However, the function of alphaB in these tissues is not known. Lenses of alphaB-/- mice develop degeneration of specific skeletal muscles but do not develop cataracts. Recent work in our laboratory indicates that primary cultures of alphaB-/- lens epithelial cells demonstrate genomic instability and undergo hyperproliferation at a frequency 4 orders of magnitude greater than that predicted by spontaneous immortalization of rodent cells. We now demonstrate that the hyperproliferative alphaB-/- lens epithelial cells undergo phenotypic changes that include the appearance of the p53 protein as shown by immunoblot analysis. Sequence analysis showed a lack of mutations in the p53 coding region of hyperproliferative alphaB-/- cells. However, the reentry of hyperproliferative alphaB-/- cells into S phase and mitosis after DNA damage by gamma-irradiation were consistent with impaired p53 checkpoint function in these cells. The results demonstrate that expression of functionally impaired p53 is one of the factors that promote immortalization of lens epithelial cells derived from alphaB-/- mice. Fluorescence in situ hybridization using probes prepared from centromere-specific mouse P1 clones of chromosomes 1 and 9 demonstrated that the hyperproliferative alphaB-/- cells were 30% diploid and 70% tetraploid, whereas wild type cells were 83% diploid. Further evidence of genomic instability was obtained when the hyperproliferative alphaB-/- cells were labeled with anti-beta-tubulin antibodies. Examination of the hyperproliferative alphaB-/- mitotic profiles revealed the presence of cells that failed to round up for mitosis, or arrested in cytokinesis, and binucleated cells in which nuclear division had occurred without cell division. These results suggest that the stress protein and molecular chaperone alphaB-crystallin protects cells from acquiring impaired p53 protein and genomic instability. 相似文献
996.
Grobler JA Markel EJ Fay JF Graham DJ Simcoe AL Ludmerer SW Murray EM Migliaccio G Flores OA 《The Journal of biological chemistry》2003,278(19):16741-16746
Efficient replication of hepatitis C virus (HCV) replicons in cell culture is associated with specific sequences not generally observed in vivo. These cell culture adaptive mutations dramatically increase the frequency with which replication is established in vitro. However, replicons derived from HCV isolates that have been shown to replicate in chimpanzees do not replicate in cell culture even when these adaptive mutations are introduced. To better understand this apparent paradox, we performed a gain-of-function screen to identify sequences that could confer cell culture replication competence to replicons derived from chimpanzee infectious HCV isolates. We found that residue 470 in domain II of the NS3 helicase is a critical determinant in cell culture adaptation. Substitutions in residue 470 when combined with the NS5A-S232I adaptive mutation are both necessary and sufficient to confer cell culture replication to otherwise inactive replicons, including those derived from genotype 1b HCV-BK and genotype 1a HCV-H77 isolates. The specific substitution at residue 470 required for replication is context-dependent, with R470M and P470L being optimal for the activity of HCV-BK and HCV-H77 replicons, respectively. Together these data indicate that mutations in the NS3 helicase domain II act in concert with previously identified adaptive mutations and predict that introduction of compatible residues at these positions can confer cell culture replication activity to diverse HCV isolates. 相似文献
997.
998.
999.
We conducted laboratory experiments to examine the effects of single versus double exposures of spruce budworm, Choristoneura fumiferana (Lepidoptera: Tortricidae) female larvae to various concentrations of a Bacillus thuringiensis variety kurstaki (Btk) commercial formulation (Foray 48B). Our main objective was to document the vulnerability to Btk and the sublethal responses of fifth-instar larvae that survived from a first ingestion of Btk during their fourth stadium and to compare them with insects treated either during their fifth or fourth stadium only. As reported in the literature, fifth-instar larvae were more vulnerable than fourth-instar larvae, but only at low and medium concentrations. Fifth-instar larvae that had survived Btk ingestion during their fourth stadium were more vulnerable to a high concentration of Btk and had a shorter feeding inhibition period than those that had not been exposed during their fourth stadium. Compared with a single treatment at the fourth stadium, a double exposure to Btk further reduced the population by 20-30%, depending on the concentration applied. The second treatment also induced another feeding inhibition period and increased larval development time by 14%. The impact of the different treatments on pupal weight depended on whether treated insects exhibited supernumerary instars. In the absence of developmental polymorphism, a higher concentration, a late, or a double exposure to Btk significantly reduced pupal weight. 相似文献
1000.
Synergistic interactions between volicitin,jasmonic acid and ethylene mediate insect-induced volatile emission in Zea mays 总被引:11,自引:0,他引:11
Plants display differential responses following mechanical damage and insect herbivory. Both caterpillar attack and the application of caterpillar oral secretions (OS) to wounded leaves stimulates volatile emission above mechanical damage alone. Volicitin ( N- 17-hydroxylinolenoyl- l -glutamine), present in beet armyworm (BAW, Spodoptera exigua ) OS, is a powerful elicitor of volatiles in excised maize seedlings ( Zea mays cv. Delprim). We consider some of the mechanistic differences between wounding and insect herbivory in maize by examining the activity of volicitin, changes in jasmonic acid (JA) levels, and volatile emission from both intact plant and excised leaf bioassays. Compared to mechanical damage alone, volicitin stimulated increases in both JA levels and sesquiterpene volatiles when applied to intact plants. In a bioassay comparison, excised leaves were more sensitive and produced far greater volatile responses than intact plants following applications of both volicitin and JA. In the excised leaf bioassay, volicitin applications (10–500 pmol) to wounded leaves resulted in dose dependent JA increases and a direct positive relationship between JA and sesquiterpene volatile emission. Interestingly, volicitin-induced JA levels did not differ between intact and excised bioassays, suggesting a possible interaction of JA with other regulatory signals in excised plants. In addition to JA, insect herbivory is known to stimulate the production of ethylene. Significant increases in ethylene were induced only by BAW herbivory and not by either wounding or volicitin treatments. Using intact plant bioassays, ethylene (at 1 µl l−1 or less) greatly promoted volatile emission induced by volicitin and JA but not mechanical damage alone. For intact plants, wounding, elicitor-induced JA and insect-induced ethylene appear to be important interacting components in the stimulation of insect-induced volatile emission. 相似文献