全文获取类型
收费全文 | 4665篇 |
免费 | 372篇 |
国内免费 | 99篇 |
专业分类
5136篇 |
出版年
2024年 | 5篇 |
2023年 | 85篇 |
2022年 | 120篇 |
2021年 | 87篇 |
2020年 | 110篇 |
2019年 | 161篇 |
2018年 | 204篇 |
2017年 | 159篇 |
2016年 | 165篇 |
2015年 | 200篇 |
2014年 | 408篇 |
2013年 | 452篇 |
2012年 | 320篇 |
2011年 | 457篇 |
2010年 | 426篇 |
2009年 | 307篇 |
2008年 | 232篇 |
2007年 | 223篇 |
2006年 | 238篇 |
2005年 | 222篇 |
2004年 | 117篇 |
2003年 | 83篇 |
2002年 | 53篇 |
2001年 | 36篇 |
2000年 | 24篇 |
1999年 | 35篇 |
1998年 | 12篇 |
1997年 | 11篇 |
1996年 | 6篇 |
1995年 | 5篇 |
1994年 | 9篇 |
1993年 | 5篇 |
1992年 | 6篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 5篇 |
1987年 | 3篇 |
1985年 | 33篇 |
1984年 | 23篇 |
1983年 | 6篇 |
1982年 | 13篇 |
1981年 | 8篇 |
1980年 | 5篇 |
1979年 | 7篇 |
1978年 | 8篇 |
1977年 | 5篇 |
1976年 | 4篇 |
1975年 | 2篇 |
1974年 | 10篇 |
1973年 | 7篇 |
排序方式: 共有5136条查询结果,搜索用时 15 毫秒
81.
Catherina L. Salanga Douglas P. Dyer Janna G. Kiselar Sayan Gupta Mark R. Chance Tracy M. Handel 《The Journal of biological chemistry》2014,289(21):14896-14912
The interaction of chemokines with glycosaminoglycans (GAGs) facilitates the formation of localized chemokine gradients that provide directional signals for migrating cells. In this study, we set out to understand the structural basis and impact of the differing oligomerization propensities of the chemokines monocyte chemoattractant protein (MCP)-1/CCL2 and MCP-3/CCL7 on their ability to bind GAGs. These chemokines provide a unique comparison set because CCL2 oligomerizes and oligomerization is required for its full in vivo activity, whereas CCL7 functions as a monomer. To identify the GAG-binding determinants of CCL7, an unbiased hydroxyl radical footprinting approach was employed, followed by a focused mutagenesis study. Compared with the size of the previously defined GAG-binding epitope of CCL2, CCL7 has a larger binding site, consisting of multiple epitopes distributed along its surface. Furthermore, surface plasmon resonance (SPR) studies indicate that CCL7 is able to bind GAGs with an affinity similar to CCL2 but higher than the non-oligomerizing variant, CCL2(P8A), suggesting that, in contrast to CCL2, the large cluster of GAG-binding residues in CCL7 renders oligomerization unnecessary for high affinity binding. However, the affinity of CCL7 is more sensitive than CCL2 to the density of heparan sulfate on the SPR surfaces; this is likely due to the inability of CCL7 to oligomerize because CCL2(P8A) also binds significantly less tightly to low than high density heparan sulfate surfaces compared with CCL2. Together, the data suggest that CCL7 and CCL2 are non-redundant chemokines and that GAG chain density may provide a mechanism for regulating the accumulation of chemokines on cell surfaces. 相似文献
82.
Jagjeet S. Mnpotra Zhuanhong Qiao Jian Cai Diane L. Lynch Alan Grossfield Nicholas Leioatts Dow P. Hurst Michael C. Pitman Zhao-Hui Song Patricia H. Reggio 《The Journal of biological chemistry》2014,289(29):20259-20272
In this study, we applied a comprehensive G protein-coupled receptor-Gαi protein chemical cross-linking strategy to map the cannabinoid receptor subtype 2 (CB2)- Gαi interface and then used molecular dynamics simulations to explore the dynamics of complex formation. Three cross-link sites were identified using LC-MS/MS and electrospray ionization-MS/MS as follows: 1) a sulfhydryl cross-link between C3.53(134) in TMH3 and the Gαi C-terminal i-3 residue Cys-351; 2) a lysine cross-link between K6.35(245) in TMH6 and the Gαi C-terminal i-5 residue, Lys-349; and 3) a lysine cross-link between K5.64(215) in TMH5 and the Gαi α4β6 loop residue, Lys-317. To investigate the dynamics and nature of the conformational changes involved in CB2·Gi complex formation, we carried out microsecond-time scale molecular dynamics simulations of the CB2 R*·Gαi1β1γ2 complex embedded in a 1-palmitoyl-2-oleoyl-phosphatidylcholine bilayer, using cross-linking information as validation. Our results show that although molecular dynamics simulations started with the G protein orientation in the β2-AR*·Gαsβ1γ2 complex crystal structure, the Gαi1β1γ2 protein reoriented itself within 300 ns. Two major changes occurred as follows. 1) The Gαi1 α5 helix tilt changed due to the outward movement of TMH5 in CB2 R*. 2) A 25° clockwise rotation of Gαi1β1γ2 underneath CB2 R* occurred, with rotation ceasing when Pro-139 (IC-2 loop) anchors in a hydrophobic pocket on Gαi1 (Val-34, Leu-194, Phe-196, Phe-336, Thr-340, Ile-343, and Ile-344). In this complex, all three experimentally identified cross-links can occur. These findings should be relevant for other class A G protein-coupled receptors that couple to Gi proteins. 相似文献
83.
84.
The anti-Fusarium oxysporum f. sp cicer (FOC) and anti-Alternaria porri (A. porri) effects were evaluated for 75 different essential oils. The most active essential oils found were those of lemongrass, clove,
cinnamon bark, cinnamon leaf, cassia, fennel, basil and evening primrose. However, the effectiveness of these essential oils
with both the tested fungi showed different responses. The level of inhibition was compared with Hexaconazole. GC–MS analysis
for five oils amongst the 75 essential oils tested was performed. The potential of these essential oils as an ecofriendly
and economic approach as a fungicide for FOC and A. porri is discussed. 相似文献
85.
Direct analysis of the extracellular proteome from two strains of Helicobacter pylori 总被引:1,自引:0,他引:1
Helicobacter pylori extracellular proteins are of interest because of possible roles in pathogenesis, host recognition, and vaccine development. We utilized a unique approach by growing two strains (including one nonsequenced strain) in a defined serum-free medium and directly analyzing the proteins present in the culture supernatants by LC-MS/MS. Over 125 proteins were identified in the extracellular proteomes of two H. pylori strains. Forty-five of these proteins were enriched in the extracellular fraction when compared to soluble cell-associated protein samples. Our analysis confirmed and expanded on the previously reported H. pylori extracellular proteome. Extracellular proteins of interest identified here included cag pathogenicity island protein Cag24 (CagD); proteases HP0657 and HP1012; a polysaccharide deacetylase, HP0310, possibly involved in the hydrolysis of acetyl groups from host N-acetylglucosamine residues or from residues on the cell surface; and HP0953, an uncharacterized protein that appears to be restricted to Helicobacter species that colonize the gastric mucosa. In addition, our analysis found eight previously unidentified outer membrane proteins and two lipoproteins that could be important cell surface proteins. 相似文献
86.
Venkata Sai Prakash Chaturvedula John F. Clos Joshua Rhea Dennis Milanowski Ulla Mocek Grant E. DuBois Indra Prakash 《Phytochemistry letters》2011,4(3):209-212
From the commercial extract of the leaves of Stevia rebaudiana, three new diterpenoid glycosides were isolated besides eight known steviol glycosides including stevioside, rebaudiosides A–F and dulcoside A. The structures of the three compounds were identified as 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-kaur-16-en-18-oic acid-(6-O-β-d-xylopyranosyl-β-d-glucopyranosyl) ester (1), 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-17-hydroxy-kaur-15-en-18-oic acid β-d-glucopyranosyl ester (2), and 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-17-oxo-kaur-15-en-18-oic acid β-d-glucopyranosyl ester (3) on the basis of extensive NMR and MS spectral studies. Another known diterpenoid glycoside, 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-kaur-15-en-18-oic acid β-d-glucopyranosyl ester (4) was also isolated and its complete NMR spectral assignments were made on the basis of COSY, HSQC and HMBC spectral data. 相似文献
87.
Cédric Montigny Paulette Decottignies Pierre Le Maréchal Pierre Capy Maike Bublitz Claus Olesen Jesper Vuust M?ller Poul Nissen Marc le Maire 《The Journal of biological chemistry》2014,289(49):33850-33861
Sarcolipin (SLN) is a regulatory peptide present in sarcoplasmic reticulum (SR) from skeletal muscle of animals. We find that native rabbit SLN is modified by a fatty acid anchor on Cys-9 with a palmitic acid in about 60% and, surprisingly, an oleic acid in the remaining 40%. SLN used for co-crystallization with SERCA1a (Winther, A. M., Bublitz, M., Karlsen, J. L., Moller, J. V., Hansen, J. B., Nissen, P., and Buch-Pedersen, M. J. (2013) Nature 495, 265–2691; Ref. 1) is also palmitoylated/oleoylated, but is not visible in crystal structures, probably due to disorder. Treatment with 1 m hydroxylamine for 1 h removes the fatty acids from a majority of the SLN pool. This treatment did not modify the SERCA1a affinity for Ca2+ but increased the Ca2+-dependent ATPase activity of SR membranes indicating that the S-acylation of SLN or of other proteins is required for this effect on SERCA1a. Pig SLN is also fully palmitoylated/oleoylated on its Cys-9 residue, but in a reverse ratio of about 40/60. An alignment of 67 SLN sequences from the protein databases shows that 19 of them contain a cysteine and the rest a phenylalanine at position 9. Based on a cladogram, we postulate that the mutation from phenylalanine to cysteine in some species is the result of an evolutionary convergence. We suggest that, besides phosphorylation, S-acylation/deacylation also regulates SLN activity. 相似文献
88.
ANDREA GHIRARDO WERNER HELLER MATTHIAS FLADUNG JÖRG‐PETER SCHNITZLER HILKE SCHROEDER 《Plant, cell & environment》2012,35(12):2192-2207
The indirect defences of plants are comprised of herbivore‐induced plant volatiles (HIPVs) that among other things attract the natural enemies of insects. However, the actual extent of the benefits of HIPV emissions in complex co‐evolved plant‐herbivore systems is only poorly understood. The observation that a few Quercus robur L. trees constantly tolerated (T‐oaks) infestation by a major pest of oaks (Tortrix viridana L.), compared with heavily defoliated trees (susceptible: S‐oaks), lead us to a combined biochemical and behavioural study. We used these evidently different phenotypes to analyse whether the resistance of T‐oaks to the herbivore was dependent on the amount and scent of HIPVs and/or differences in non‐volatile polyphenolic leaf constituents (as quercetin‐, kaempferol‐ and flavonol glycosides). In addition to non‐volatile metabolic differences, typically defensive HIPV emissions differed between S‐oaks and T‐oaks. Female moths were attracted by the blend of HIPVs from S‐oaks, showing significantly higher amounts of (E)‐4,8‐dimethyl‐1,3,7‐nonatriene (DMNT) and (E)‐β‐ocimene and avoid T‐oaks with relative high fraction of the sesquiterpenes α‐farnesene and germacrene D. Hence, the strategy of T‐oaks exhibiting directly herbivore‐repellent HIPV emissions instead of high emissions of predator‐attracting HIPVs of the S‐oaks appears to be the better mechanism for avoiding defoliation. 相似文献
89.
Pär Jonsson Hans Stenlund Thomas Moritz Johan Trygg Michael Sjöström Elwin R. Verheij Johan Lindberg Ina Schuppe-Koistinen Henrik Antti 《Metabolomics : Official journal of the Metabolomic Society》2006,2(3):135-143
A multivariate strategy for studying the metabolic response over time in urinary GC/MS data is presented and exemplified by a study of drug-induced liver toxicity in the rat. The strategy includes the generation of representative data through hierarchical multivariate curve resolution (H-MCR), highlighting the importance of obtaining resolved metabolite profiles for quantification and identification of exogenous (drug related) and endogenous compounds (potential biomarkers) and for allowing reliable comparisons of multiple samples through multivariate projections. Batch modelling was used to monitor and characterize the normal (control) metabolic variation over time as well as to map the dynamic response of the drug treated animals in relation to the control. In this way treatment related metabolic responses over time could be detected and classified as being drug related or being potential biomarkers. In summary the proposed strategy uses the relatively high sensitivity and reproducibility of GC/MS in combination with efficient multivariate curve resolution and data analysis to discover individual markers of drug metabolism and drug toxicity. The presented results imply that the strategy can be of great value in drug toxicity studies for classifying metabolic markers in relation to their dynamic responses as well as for biomarker identification. 相似文献
90.
Effendy Corrado Di Nicola Claudio Pettinari Brian W. Skelton 《Inorganica chimica acta》2005,358(3):735-747
Syntheses, spectroscopic (IR, NMR and ESI MS) and single crystal X-ray structural characterizations are reported for a wide variety of adducts of Ag(oxyanion):dpem(:S) (1:1(:n))2 (oxyanion = ClO4, F3CCO2 (tfa) F3CSO3 (tfs); dpem = Ph2E(CH2)EPh2) stoichiometry among which the basic Ag(Ph2E(CH2)EPh2)2Ag core is diversely perturbed by interactions with anions and solvent molecules. ESI MS and 31P NMR spectroscopy indicated that dinuclear species also exist in solution. 相似文献