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71.
Tatsumi R Seio K Fujio M Katayama J Horikawa T Hashimoto K Tanaka H 《Bioorganic & medicinal chemistry letters》2004,14(14):3781-3784
A series of 3-substituted 1-azabicyclo[2.2.2]octanes was discovered as the alpha7 nicotinic acetylcholine (alpha7) receptor agonists. It was found that (+)-3-[2-(benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]octane (+)-15b has potent agonistic activity for the alpha7 receptor. 相似文献
72.
Saeko?MitoEmail author Yoshiki?Sohrin Kazuhiro?Norisuye Masakazu?Matsui Hiroshi?Hasegawa Masahiro?Maruo Mitsuo?Tsuchiya Munetsugu?Kawashima 《Limnology》2004,5(1):7-16
A comprehensive study on the dynamics of dissolved elements (Mg, Al, Si, P, Ca, V, Cr, Mn, Fe, Ni, Zn, As, Sr, Y, W, and U) in Lake Biwa was carried out using a clean technique. Lake water samples (n = 523) were collected from six stations in the North Basin and three stations in the South Basin. River water samples (n = 178) were collected from 14 major rivers flowing into the North Basin. Rainwater samples (n = 89) were collected at Otsu. The river water was enriched with Mn, Al, Fe, P, and Zn and the rainwater was enriched with Zn, Al, Fe, and Mn compared to North Basin water during winter mixing. The residence times of dissolved species were estimated on the basis of input through the rivers and rain. The residence times for Ca, Mg, and Sr were about 8 years, the same as that for water. Mn, Al, Fe, and Zn showed the shortest residence times (0.05–0.19 year). A budget calculation suggested that more than 60% of the input of dissolved Si, P, V, Cr, Mn, Fe, Ni, and Zn was scavenged and retained in the lake sediments and/or discharged as suspended particles. 相似文献
73.
Yano S Kazuno H Sato T Suzuki N Emura T Wierzba K Yamashita J Tada Y Yamada Y Fukushima M Asao T 《Bioorganic & medicinal chemistry》2004,12(13):3443-3450
A series of novel 6-methylene-bridged uracil derivatives have been optimized for clinical use as the inhibitors of human thymidine phosphorylase (TP). We describe their synthesis and evaluation. Introduction of a guanidino or an amidino group enhanced the in vitro inhibitory activity of TP comparing with formerly reported inhibitor 1. Their selectivity for TP based on uridine phosphorylase inhibitory activity was also evaluated. Compound 2 (TPI) has been selected for clinical evaluation based on its strong TP inhibition and excellent modulation of 2'-deoxy-5-(trifluoromethyl)uridine (F(3)dThd) pharmacokinetics. As a result, TAS-102 (a combination of F(3)dThd and TPI) is currently in phase 1 clinical studies. 相似文献
74.
Arabidopsis thaliana GLN2-encoded glutamine synthetase is dual targeted to leaf mitochondria and chloroplasts
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In higher plants, photorespiratory Gly oxidation in leaf mitochondria yields ammonium in large amounts. Mitochondrial ammonium must somehow be recovered as glutamate in chloroplasts. As the first step in that recovery, we report glutamine synthetase (GS) activity in highly purified Arabidopsis thaliana mitochondria isolated from light-adapted leaf tissue. Leaf mitochondrial GS activity is further induced in response to either physiological CO(2) limitation or transient darkness. Historically, whether mitochondria are fully competent for oxidative phosphorylation in actively photorespiring leaves has remained uncertain. Here, we report that light-adapted, intact, leaf mitochondria supplied with Gly as sole energy source are fully competent for oxidative phosphorylation. Purified intact mitochondria efficiently use Gly oxidation (as sole energy, NH(3), and CO(2) source) to drive conversion of l-Orn to l-citrulline, an ATP-dependent process. An A. thaliana genome-wide search for nuclear gene(s) encoding mitochondrial GS activity yielded a single candidate, GLN2. Stably transgenic A. thaliana ecotype Columbia plants expressing a p35S::GLN2::green fluorescent protein (GFP) chimeric reporter were constructed. When observed by laser scanning confocal microscopy, leaf mesophyll and epidermal tissue of transgenic plants showed punctate GFP fluorescence that colocalized with mitochondria. In immunoblot experiments, a 41-kD chimeric GLN2::GFP protein was present in both leaf mitochondria and chloroplasts of these stably transgenic plants. Therefore, the GLN2 gene product, heretofore labeled plastidic GS-2, functions in both leaf mitochondria and chloroplasts to faciliate ammonium recovery during photorespiration. 相似文献
75.
AF-6 controls integrin-mediated cell adhesion by regulating Rap1 activation through the specific recruitment of Rap1GTP and SPA-1 总被引:9,自引:0,他引:9
Su L Hattori M Moriyama M Murata N Harazaki M Kaibuchi K Minato N 《The Journal of biological chemistry》2003,278(17):15232-15238
In the present study, we showed that SPA-1, a Rap1 GTPase-activating protein (GAP), was bound to a cytoskeleton-anchoring protein AF-6. SPA-1 and AF-6 were co-immunoprecipitated in the 293T cells transfected with both cDNAs as well as in normal thymocytes. In vitro binding studies using truncated fragments and their mutants suggested that SPA-1 was bound to the PDZ domain of AF-6 via probable internal PDZ ligand motif within the GAP-related domain. The motif was conserved among Rap1 GAPs, and it was shown that rapGAP I was bound to AF-6 comparably with SPA-1. RapV12 was also bound to AF-6 via the N-terminal domain, and SPA-1 and RapV12 were co-immunoprecipitated only in the presence of AF-6, indicating that they could be brought into close proximity via AF-6 in cells. Immunostaining analysis revealed that SPA-1 and RapV12 were co-localized with AF-6 at the cell attachment sites. In HeLa cells expressing SPA-1 in a tetracycline-regulatory manner, expression of AF-6 inhibited endogenous Rap1GTP and beta(1) integrin-mediated cell adhesion to fibronectin in SPA-1-induced conditions, whereas it affected neither of them in SPA-1-repressed conditions. These results suggested that AF-6 could control integrin-mediated cell adhesion by regulating Rap1 activation through the recruitment of both SPA-1 and Rap1GTP via distinct domains. 相似文献
76.
Heme oxygenase (HO) catalyzes heme degradation by utilizing O(2) and reducing equivalents to produce biliverdin IX alpha, iron, and CO. To avoid product inhibition, the heme[bond]HO complex (heme[bond]HO) is structured to markedly increase its affinity for O(2) while suppressing its affinity for CO. We determined the crystal structures of rat ferrous heme[bond]HO and heme[bond]HO bound to CO, CN(-), and NO at 2.3, 1.8, 2.0, and 1.7 A resolution, respectively. The heme pocket of ferrous heme-HO has the same conformation as that of the previously determined ferric form, but no ligand is visible on the distal side of the ferrous heme. Fe[bond]CO and Fe[bond]CN(-) are tilted, whereas the Fe[bond]NO is bent. The structure of heme[bond]HO bound to NO is identical to that bound to N(3)(-), which is also bent as in the case of O(2). Notably, in the CO- and CN(-)-bound forms, the heme and its ligands shift toward the alpha-meso carbon, and the distal F-helix shifts in the opposite direction. These shifts allow CO or CN(-) to bind in a tilted fashion without a collision between the distal ligand and Gly139 O and cause disruption of one salt bridge between the heme and basic residue. The structural identity of the ferrous and ferric states of heme[bond]HO indicates that these shifts are not produced on reduction of heme iron. Neither such conformational changes nor a heme shift occurs on NO or N(3)(-) binding. Heme[bond]HO therefore recognizes CO and O(2) by their binding geometries. The marked reduction in the ratio of affinities of CO to O(2) for heme[bond]HO achieved by an increase in O(2) affinity [Migita, C. T., Matera, K. M., Ikeda-Saito, M., Olson, J. S., Fujii, H., Yoshimura, T., Zhou, H., and Yoshida, T. (1998) J. Biol. Chem. 273, 945-949] is explained by hydrogen bonding and polar interactions that are favorable for O(2) binding, as well as by characteristic structural changes in the CO-bound form. 相似文献
77.
Molecular dynamics simulation of dimeric and monomeric forms of human prion protein: insight into dynamics and properties 总被引:1,自引:0,他引:1
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A central theme in prion protein research is the detection of the process that underlies the conformational transition from the normal cellular prion form (PrP(C)) to its pathogenic isoform (PrP(Sc)). Although the three-dimensional structures of monomeric and dimeric human prion protein (HuPrP) have been revealed by NMR spectroscopy and x-ray crystallography, the process underlying the conformational change from PrP(C) to PrP(Sc) and the dynamics and functions of PrP(C) remain unknown. The dimeric form is thought to play an important role in the conformational transition. In this study, we performed molecular dynamics (MD) simulations on monomeric and dimeric HuPrP at 300 K and 500 K for 10 ns to investigate the differences in the properties of the monomer and the dimer from the perspective of dynamic and structural behaviors. Simulations were also undertaken with Asp178Asn and acidic pH, which is known as a disease-associated factor. Our results indicate that the dynamics of the dimer and monomer were similar (e.g., denaturation of helices and elongation of the beta-sheet). However, additional secondary structure elements formed in the dimer might result in showing the differences in dynamics and properties between the monomer and dimer (e.g., the greater retention of dimeric than monomeric tertiary structure). 相似文献
78.
Hoxa-11 and Hoxa-13 are involved in repression of MyoD during limb muscle development 总被引:1,自引:0,他引:1
Under the influence of the limb mesenchyme, Hoxa-11 is expressed in migrating and proliferating premyoblasts in the limb field and Hoxa-13 is induced in subdomains of congregated limb muscle masses. To evaluate the roles of Hoxa-11 and Hoxa-13 in myogenesis of the limb, we performed electroporation in ovo to force expression of these Hox genes in limb muscle precursors. In the presence of ectopic Hoxa-11, expression of MyoD was blocked transiently. In C2C12 myoblasts, transfection of Hoxa-11 also repressed the expression of endogenous MyoD. Forced expression of Hoxa-13 resulted in more pronounced repression of MyoD in both limb and C2C12 myoblasts. In contrast, targeted disruption of Hoxa-13 gave rise to enhanced expression of MyoD in the flexor carpi radialis muscle, a forearm muscle that normally expressed Hoxa-13. These results suggest that Hoxa-11 and Hoxa-13 are involved in the negative regulation of MyoD expression in limb muscle precursors. 相似文献
79.
Kobayashi A Tanaka Y Shimada M 《Evolution; international journal of organic evolution》2003,57(11):2659-2664
The genetic variation of sex ratio and sex allocation were examined in a series of half-sib analyses on the sex ratio of braconid parasitoid wasp Heterospilus prosopidis populations collected in Hawaii and Arizona. The mean threshold value and the range of the threshold for change in the sex of offspring in response to resource quality (host size) were determined. Estimates of the narrow-sense heritability (h2) of sex ratio at a specific host size ranged from 0.185 to 0.315, and those of the sex changing point (threshold value) ranged from 0.220 to 0.342. The coefficient of variation (CV(A)) of sex ratio was significantly larger than CV(A) of body weight. We discuss factors that maintained the significant additive genetic variation of sex ratio. 相似文献
80.
CD98 is a multifunctional protein involved in amino acid transport and regulation of integrin-mediated cell adhesion. Herein, we demonstrated that CD98 stimulation by anti-CD98 antibodies induced CEA-CAM-1-mediated cell adhesion in BaF3 cells expressing CEA-CAM-1, and suggest that this might be responsible for compact clumping of F9 embryonic carcinoma cells by CD98 stimulation. CEA-CAM-1 was co-immunoprecipitated by anti-CD98 antibody. CD98 stimulation induced the translocation of cytoplasmic protein kinase Cdelta (PKCdelta) to the cell adhesion sites, and rottlerin that inhibited the PKCdelta translocation abolished the cell aggregation without affecting integrin activation. The results suggested that CD98 stimulation could activate CEA-CAM-1-mediated cell adhesion independently of integrins. 相似文献