全文获取类型
收费全文 | 1320篇 |
免费 | 62篇 |
出版年
2023年 | 12篇 |
2022年 | 11篇 |
2021年 | 35篇 |
2020年 | 21篇 |
2019年 | 29篇 |
2018年 | 29篇 |
2017年 | 27篇 |
2016年 | 43篇 |
2015年 | 52篇 |
2014年 | 49篇 |
2013年 | 80篇 |
2012年 | 103篇 |
2011年 | 115篇 |
2010年 | 59篇 |
2009年 | 49篇 |
2008年 | 71篇 |
2007年 | 50篇 |
2006年 | 57篇 |
2005年 | 56篇 |
2004年 | 62篇 |
2003年 | 63篇 |
2002年 | 45篇 |
2001年 | 13篇 |
2000年 | 28篇 |
1999年 | 18篇 |
1998年 | 13篇 |
1997年 | 13篇 |
1996年 | 6篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 13篇 |
1991年 | 18篇 |
1990年 | 14篇 |
1989年 | 10篇 |
1988年 | 10篇 |
1987年 | 7篇 |
1986年 | 8篇 |
1985年 | 5篇 |
1984年 | 10篇 |
1983年 | 3篇 |
1982年 | 10篇 |
1981年 | 3篇 |
1980年 | 5篇 |
1979年 | 6篇 |
1978年 | 7篇 |
1977年 | 4篇 |
1974年 | 4篇 |
1973年 | 3篇 |
1970年 | 4篇 |
排序方式: 共有1382条查询结果,搜索用时 46 毫秒
961.
Many bioinformatics problems can be tackled from a fresh angle offered by the network perspective. Directly inspired by metabolic network structural studies, we propose an improved gene clustering approach for inferring gene signaling pathways from gene microarray data. Based on the construction of co-expression networks that consists of both significantly linear and non-linear gene associations together with controlled biological and statistical significance, our approach tends to group functionally related genes into tight clusters despite their expression dissimilarities. We illustrate our approach and compare it to the traditional clustering approaches on a yeast galactose metabolism dataset and a retinal gene expression dataset. Our approach greatly outperforms the traditional approach in rediscovering the relatively well known galactose metabolism pathway in yeast and in clustering genes of the photoreceptor differentiation pathway. AVAILABILITY: The clustering method has been implemented in an R package "GeneNT" that is freely available from: http://www.cran.org. 相似文献
962.
Wiskott-Aldrich Syndrome protein (WASp) is a key regulator of the Arp2/3 complex and the actin cytoskeleton in hematopoietic cells. WASp is capable of forming an auto-inhibited conformation, which can be disrupted by binding of Cdc42 and phosphatidylinositol 4,5-bisphosphate, leading to its activation. Stimulation of the collagen receptor on platelets and crosslinking the B-cell receptor induce tyrosine phosphorylation of WASp. Here we show that the Src family kinase Hck induces phosphorylation of WASp-Tyr(291) independently of Cdc42 and that this causes a shift in the mobility of WASp upon SDS-PAGE. A phospho-mimicking mutant, WASp-Y291E, exhibited an enhanced ability to stimulate actin polymerization in a cell-free system and when microinjected into primary macrophages induced extensive filopodium formation with greater efficiency than wild-type WASp or a Y291F mutant. We propose that phosphorylation of Tyr(291) directly regulates WASp function. 相似文献
963.
964.
De novo designed peptide based super secondary structures are expected to provide scaffolds for the incorporation of functional sites as in proteins. Self-association of peptide helices of similar screw sense, mediated by weak interactions, has been probed by the crystal structure determination of two closely related peptides: Ac-Gly1-Ala2-Delta Phe3-Leu4-Val5-DeltaPhe6-Leu7-Val8-DeltaPhe9-Ala10-Gly11-NH2 (I) and Ac-Gly1-Ala2-DeltaPhe3-Leu4-Ala5-DeltaPhe6-Leu7-Ala8-DeltaPhe9-Ala10-Gly11-NH2 (II). The crystal structures determined to atomic resolution and refined to R factors 8.12 and 4.01%, respectively, reveal right-handed 3(10)-helical conformations for both peptides. CD has also revealed the preferential formation of right-handed 3(10)-helical conformations for both molecules. Our aim was to critically analyze the packing of the helices in the solid state with a view to elicit clues for the design of super secondary structural motifs such as two, three, and four helical bundles based on helix-helix interactions. An important finding is that a packing motif could be identified common to both the structures, in which a given peptide helix is surrounded by six other helices reminiscent of transmembrane seven helical bundles. The outer helices are oriented either parallel or antiparallel to the central helix. The helices interact laterally through a combination of N--H...O, C--H...O, and C--H...pi hydrogen bonds. Layers of interacting leucine residues are seen in both peptide crystal structures. The packing of the peptide helices in the solid state appears to provide valuable leads for the design of super secondary structural modules such as two, three, or four helix bundles by connecting adjacent antiparallel helices through suitable linkers such as tetraglycine segments. 相似文献
965.
Viral RNA is required for the association of APOBEC3G with human immunodeficiency virus type 1 nucleoprotein complexes 总被引:14,自引:12,他引:2 下载免费PDF全文
Khan MA Kao S Miyagi E Takeuchi H Goila-Gaur R Opi S Gipson CL Parslow TG Ly H Strebel K 《Journal of virology》2005,79(9):5870-5874
APOBEC3G (APO3G) is a host cytidine deaminase that is incorporated into human immunodeficiency virus type 1 (HIV-1) particles. We report here that viral RNA promotes stable association of APO3G with HIV-1 nucleoprotein complexes (NPC). A target sequence located within the 5′-untranslated region of the HIV-1 RNA was identified to be necessary and sufficient for efficient APO3G packaging. Fine mapping revealed a sequence normally involved in viral genomic RNA dimerization and Gag binding to be important for APO3G packaging and association with viral NPC. Our data suggest that packaging of APO3G into HIV-1 NPC is enhanced by viral RNA. 相似文献
966.
Functional assessment of glutamate clearance mechanisms in a chronic rat glaucoma model using retinal ganglion cell calcium imaging 总被引:3,自引:0,他引:3
Using optical imaging of retinal ganglion cell (RGC) calcium dynamics in living intact retinal wholemount preparations, we tested whether RGCs in an experimental rat glaucoma model were more sensitive to exogenously applied glutamate as a result of deficient glutamate clearance mechanisms. In contrast to post-natal rat RGCs in purified cultures, in which the calcium influx induced by 200 microm NMDA and 10 microm glutamate was approximately equivalent, application of up to 500 microm glutamate did not affect calcium levels in RGCs in retinal wholemounts, even though the RGCs responded to 200 microm NMDA. Glutamate (500 microm) did elicit a RGC calcium response in retinal wholemounts when glutamate transporters were inhibited pharmacologically with DL-threo-beta-benzyloxyaspartate, confirming the presence of glutamate clearance mechanisms in this intact retina preparation. The effect of glutamate was then assessed on retinas from rats with chronically elevated intraocular pressure in one eye, produced by the injection of hypertonic saline into an episcleral vein. Application of up to 500 microm glutamate had no effect on RGC calcium levels, while millimolar concentrations of glutamate induced a calcium signal in RGCs that was indistinguishable from that in fellow control retinas. Therefore, there was no evidence for a global defect in glutamate uptake in this rat model of experimental glaucoma. Imaging glutamatergic calcium dynamics of RGCs in retinal wholemounts represents a novel methodology to probe glutamate transporter function and dysfunction in an intact CNS tissue system. 相似文献
967.
1,3-dithia-2-stannacyclopentane derivatives with dialkyldithiocarbamates of the types SCH(2)CH(2)SSn[S(2)CNR(2)]Cl (I) and SCH(2)CH(2)SSn[S(2)CNR(2)](2) (II) (where R = CH(3), C(2)H(5) and -CH(2)-CH(2)-) have been synthesized by the reaction of 2,2-dichloro-1,3-dithia-2-stannacyclopentane and sodium/ammonium salts of dialkyldithiocarbamates in 1:1 and 1:2 molar ratios, respectively, in anhydrous benzene. These newly synthesized derivatives have been characterized by elemental analyses (C, H, N, S and Sn), thermal [thermogravimetry (TG) and differential thermal analyses (DTA)] as well as spectral [UV, IR and multinuclear NMR ((1)H, (13)C and (119)Sn)] studies. The monodentate behaviour of the dialkyldithiocarbamate ligands was confirmed by IR and (119)Sn NMR spectral data and distorted tetrahedral structures have been suggested for both type (I) and (II) compounds. The free ligands and their tin complexes have also been screened for their antibacterial and antifungal activities. These results made it desirable to delineate a comparison between free ligands and their tin complexes. These exhibit higher antibacterial effect than some of the previously investigated antibiotics. 相似文献
968.
Trinucleotide repeats are involved in a number of debilitating diseases such as myotonic dystrophy. Twelve to seventy-five base-long (CTG)n oligodeoxynucleotides were analysed using a combination of biophysical [UV-absorbance, circular dichroism and differential scanning calorimetry (DSC)] and biochemical methods (non-denaturing gel electrophoresis and enzymatic footprinting). All oligomers formed stable intramolecular structures under near physiological conditions with a melting temperature that was only weakly dependent on oligomer length. Thermodynamic analysis of the denaturation process by UV-melting and calorimetric experiments revealed an unprecedented length-dependent discrepancy between the enthalpy values deduced from model-dependent (UV-melting) and model-independent (calorimetry) experiments. Evidence for non-zero molar heat capacity changes was also derived from the analysis of the Arrhenius plots and DSC profiles. Such behaviour is analysed in the framework of an intramolecular ‘branched-hairpin’ model, in which long CTG oligomers do not fold into a simple long hairpin–stem intramolecular structure, but allow the formation of several independent folding units of unequal stability. We demonstrate that, for sequences ranging from 12 to 25 CTG repeats, an intramolecular structure with two loops is formed which we will call ‘bis-hairpin’. Similar results were also found for CAG oligomers, suggesting that this observation may be extended to various trinucleotide repeats-containing sequences. 相似文献
969.
We have identified theDrosophila homologue of the non-motor accessory subunit of kinesin-II motor complex. It is homologous to the SpKAP115 of the sea urchin,
KAP3A and KAP3B of the mouse, and SMAP protein in humans.In situ hybridization using a DmKAP specific cRNA probe has revealed a dynamic pattern of expression in the developing nervous system.
The staining first appears in a subset of cells in the embryonic central nervous system at stage 13 and continues till the
first instar larva stage. At the third instar larva stage the staining gets restricted to a few cells in the optic lobe and
in the ventral ganglion region. It has also stained a subset of sensory neurons from late stage 13 and till the first instar
larva stage. The DmKAP expression pattern in the nervous system corresponds well with that of Klp64D and Klp68D as reported
earlier. In addition, we have found that the DmKAP gene is constitutively expressed in the germline cells and in follicle
cells during oogenesis. These cells are also stained using an antibody to KLP68D protein, but mRNAin situ hybridization using KLP64D specific probe has not stained these cells. Together these results proved a basis for further
analysis of tissue specific function of DmKAP in future. 相似文献
970.
Latifu?A?Sanni Catherine?EM?Allsopp Lieke?Reubsaet Ambaliou?Sanni Chris?Newbold Virander?S?Chauhan Jean?LanghorneEmail author 《Malaria journal》2002,1(1):7