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941.
Cancer metastasis is a complex processes, associated with the invasion to tissues with extensive degradation of the surrounding normal components, penetration into vessels, circulation, and then invasion to normal tissues in body. It would be not surprising that tumor cells usurp pathways critical to the developing embryo during metastasis. For the better understanding of tumor metastasis, this review will highlight the recent progress and significance of the signal transduction pathways, relevant to developmental biology. 相似文献
942.
Smurf1, a member of HECT-type E3 ubiquitin ligases, regulates cell polarity and protrusive activity by inducing ubiquitination and subsequent proteasomal degradation of the small GTPase RhoA. We report here that hPEM-2, a guanine nucleotide exchange factor for the small GTPase Cdc42, is a novel target of Smurf1. Pulse-chase labeling and a ubiquitination experiment using MG132, a proteasomal inhibitor, indicate that Smurf1 induces proteasomal degradation of hPEM-2 in cells. GST pull-down assays with heterologously expressed firefly luciferase-fusion proteins that include partial sequences of hPEM-2 reveal that part of the PH domain (residues 318-343) of hPEM-2 is sufficient for binding to Smurf1. In contrast, the hPEM-2 binding domain in Smurf1 was mapped to the C2 domain. Although it has been reported that the binding activities of some C2 domains to target proteins are regulated by Ca2+, Smurf1 interacts with hPEM-2 in a Ca2+-independent manner. Our discovery that hPEM-2 is, in addition to RhoA, a target protein of Smurf1 suggests that Smurf1 plays a crucial role in the spatiotemporal regulation of Rho GTPase family members. 相似文献
943.
Shi D Nakamura T Nakajima M Dai J Qin J Ni H Xu Y Yao C Wei J Liu B Ikegawa S Jiang Q 《Arthritis research & therapy》2008,10(3):R54-6
Introduction
Conflicting findings on the association of single nucleotide polymorphisms (SNPs) in RHOB and TXNDC3 with susceptibility to knee osteoarthritis (OA) have been reported in European Caucasians. To examine the associations of these SNPs with OA in East Asian populations and to evaluate their global significance, we conducted two case-control studies in 955 Chinese and 750 Japanese patients.Methods
We genotyped the previously implicated SNPs rs585017 (in RHOB) and rs4720262 (in TXNDC3) in patients with primary symptomatic knee OA with radiographic confirmation and in matched control individuals, and analyzed their associations. We further conducted a meta-analysis of the study findings together with those of previously reported European studies using the DerSimonian-Laird procedure.Results
A significant association of RHOB with knee OA was observed in male Chinese patients (P = 0.02). No significant associations were found for RHOB in any other comparisons in the East Asian populations. The association of TXNDC3 was replicated in Chinese female (P = 0.04) and Japanese (P = 0.03) patients, although none of these associations persisted after Bonferroni correction. Significant association (P = 0.02 for the allelic frequency) with nonsignificant heterogeneity was found in the East Asian replication study. No significant association was found in any comparison in the meta-analysis for all studies.Conclusion
Our study replicates the association, previously reported in European Caucasians, of TXNDC3 with knee OA susceptibility in an East Asian population. 相似文献944.
ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress 总被引:1,自引:0,他引:1
945.
Honda T Tajima H Kaneko Y Ban M Inaba T Takeno Y Okamoto K Aono H 《Bioorganic & medicinal chemistry letters》2008,18(9):2939-2943
We found 4-pyridylmethylthio derivative 1 to be very effective in using antiangiogenesis activity to prevent proliferation of HUVECs (Human Umbilical Vein Endothelial Cells), which was induced by vascular endothelial growth factor (VEGF). Compound 1 was equally effective in inhibiting VEGF receptor2 tyrosine kinase (KDR, IC50 = 26 nM). We deduced that the inhibition was the result of binding the catalytic domain of VEGF receptor2 tyrosine kinase in a similar fashion to both phthalazine derivative PTK787 2 and anthranylamide derivative AAL993 3. In this report, we will describe the conformational analyses, from ab initio MO calculation and X-ray crystallographic analyses, of compound 1 and the analogs, which include non-active 9, all in comparison with 2 and 3. The conformation–activity relationships suggest that a nonbonded intramolecular interaction between the sulfur and the carbonyl oxygen of 1 was very important in inhibiting KDR. 相似文献
946.
Takada T Shitara H Matsuoka K Kojima E Ishii R Kikkawa Y Taya C Karasuyama H Kohno K Yonekawa H 《Transgenic research》2008,17(6):1155-1162
Current mouse models for atopic dermatitis (AD) have a serious drawback, being the existence of dense hair on the body. Thus,
a hairless animal model on an AD-prone genetic background will be a powerful tool to investigate the basis of and therapy
for this complex disease. We applied the Toxin Receptor-mediated Cell Knockout (TRECK) method to generate a hairless transgenic
(Tg) mice on the NC/Nga background, an AD-prone inbred strain. A minigene with the mouse Keratin71 (Krt71) promoter and human diphtheria toxin receptor, which intrinsically functions as the heparin-binding EGF-like growth factor,
was introduced into the pronucleus of NC/Nga oocytes. Unexpectedly NCN24, one NC/Nga Tg line, showed a dominant hairless phenotype
without diphtheria toxin administration. Furthermore, the atopic dermatitis-like predisposition and IgE elevation was observed
in both NCN24 and the NC/Nga wildtype strain. NCN24 mice, which we have newly developed, will be useful to assess drugs for
AD therapy, being able to monitor skin inflammation without shaving.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
947.
Yokoyama K Ishikawa N Igarashi S Kawano N Hattori K Miyazaki T Ogino S Matsumoto Y Takeuchi M Ohta M 《Bioorganic & medicinal chemistry》2008,16(14):7021-7032
A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure-activity relationships and led the identification of 2-(1,4'-bipiperidine-1'-yl)-N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine 14a, which showed potent inhibition in the [(35)S]GTPgammaS-binding assay (IC(50)=18nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC(50)=140nM, 39nM). 相似文献
948.
Tashiro T Hongo N Nakagawa R Seino K Watarai H Ishii Y Taniguchi M Mori K 《Bioorganic & medicinal chemistry》2008,16(19):8896-8906
RCAI-17, 22, 24-26, 29, 31, 34-36, 38-40, and 88, the analogs of KRN7000 with a sulfonamide linkage instead of an amide bond, were synthesized to examine their bioactivity for mouse natural killer (NK) T cells. RCAI-17, 22, 24-26, 29, 31, 34-36, and 88 are the aromatic sulfonamide analogs, while RCAI-39 and 40 are the aliphatic ones. RCAI-38 is a C-galactoside analog of RCAI-26, which is the p-toluenesulfonamide analog of KRN7000. According to their bioassay, these sulfonamide analogs were shown to be the stimulants of mouse NKT cells to induce the production of Th2-biased cytokines in vitro, while RCAI-38 did not induce any cytokine production. 相似文献
949.
Kondo T Nekado T Sugimoto I Ochi K Takai S Kinoshita A Hatayama A Yamamoto S Kishikawa K Nakai H Toda M 《Bioorganic & medicinal chemistry》2008,16(4):1613-1631
A series of (4beta-substituted)-L-prolylpyrrolidine analogs lacking the electrophilic nitrile function were synthesized and their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and duration of ex vivo activity were evaluated. Structural optimization of a N-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine analog 8, which was found by high-speed analog synthesis, was carried out to improve the potency and duration of action. A representative compound 26 was evaluated to assess its effect on the plasma glucose level after the oGTT (oral glucose tolerance test) in normal rats. Structure-activity relationships (SAR) are also presented. 相似文献
950.
Just noticeable differences in component concentrations modify the odor quality of a blending mixture 总被引:1,自引:0,他引:1
Le Berre E Béno N Ishii A Chabanet C Etiévant P Thomas-Danguin T 《Chemical senses》2008,33(4):389-395
The odors we perceive are mainly the result of mixtures of odorants that, however, are commonly perceived as single undivided entities; nevertheless, the processes involved remain poorly explored. It has been recently reported that perceptual blending based on configural olfactory processing can cause odorant mixtures to give rise to an emergent odor not present in the components. The present study examined whether specific component proportions are required to elicit an emergent odor. Starting from the composition of a ternary target mixture in which an emergent pineapple odor was perceived, 4 concentration levels of each component were chosen to elicit just noticeable differences (JNDs). Each combination of levels was used to design sample mixtures. Fifteen subjects evaluated the intensity, typicality, and pleasantness of each sample mixture against the target mixture in a paired-comparison protocol. Statistical modeling showed that a variation of less than 1 JND in one of the components was sufficient to induce a significant decrease in pineapple odor typicality in the ternary mixture. This finding confirms previous findings on perceptual blending in simple odorant mixtures and underscores the human ability to discriminate between odor percepts induced by mixtures including very similar odorant proportions. 相似文献