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181.
M Okaniwa T Imada T Ohashi T Miyazaki T Arita M Yabuki A Sumita S Tsutsumi K Higashikawa T Takagi T Kawamoto Y Inui S Yoshida T Ishikawa 《Bioorganic & medicinal chemistry》2012,20(15):4680-4692
As an alternative to the previously reported solid dispersion formulation for enhancing the oral absorption of thiazolo[5,4-b]pyridine 1, we investigated novel N-acyl imide prodrugs of 1 as RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. Introducing N-acyl promoieties at the benzanilide position gave chemically stable imides. N-tert-Butoxycarbonyl (Boc) introduced imide 6 was a promising prodrug, which was converted to the active compound 1 after its oral administration in mice. Cocrystals of 6 with AcOH (6b) possessed good physicochemical properties with moderate thermodynamic solubility (19μg/mL). This crystalline prodrug 6b was rapidly and enzymatically converted into 1 after its oral absorption in mice, rats, dogs, and monkeys. Prodrug 6b showed in vivo antitumor regressive efficacy (T/C=-6.4%) in an A375 melanoma xenograft model in rats. Hence, we selected 6b as a promising candidate and are performing further studies. Herein, we report the design, synthesis, and characterization of novel imide-type prodrugs. 相似文献
182.
Xu Y Nakajima Y Ito K Zheng H Oyama H Heiser U Hoffmann T Gärtner UT Demuth HU Yoshimoto T 《Journal of molecular biology》2008,375(3):708-719
A new inhibitor, H-Ala-Ile-pyrrolidin-2-yl boronic acid, was developed as an inhibitor against prolyl tripeptidyl aminopeptidase with a Ki value of 88.1 nM. The structure of the prolyl tripeptidyl aminopeptidase complexed with the inhibitor (enzyme-inhibitor complex) was determined at 2.2 Å resolution. The inhibitor was bound to the active site through a covalent bond between Ser603 and the boron atom of the inhibitor. This structure should closely mimic the structure of the reaction intermediate between the enzyme and substrate. We previously proposed that two glutamate residues, Glu205 and Glu636, are involved in the recognition of substrates. In order to clarify the function of these glutamate residues in substrate recognition, three mutant enzymes, E205A, E205Q, and E636A were generated by site-directed mutagenesis. The E205A mutant was expressed as an inclusion body. The E205Q mutant was expressed in soluble form, but no activity was detected. Here, the structures of the E636A mutant and its complex with the inhibitor were determined. The inhibitor was located at almost the same position as in the wild-type enzyme-inhibitor complex. The amino group of the inhibitor interacted with Glu205 and the main-chain carbonyl group of Gln203. In addition, a water molecule in the place of Glu636 of the wild-type enzyme interacted with the amino group of the inhibitor. This water molecule was located near the position of Glu636 in the wild-type and formed a hydrogen bond with Gln203. The kcat/KM values of the E636A mutant toward the two substrates used were smaller than those of the wild-type by two orders of magnitude. The Ki value of our inhibitor for the E636A mutant was 48.8 μM, which was 554-fold higher than that against the wild-type enzyme. Consequently, it was concluded that Glu205 and Glu636 are significant residues for the N-terminal recognition of a substrate. 相似文献
183.
Some animals, such as Melittobia wasps and surface-living mites, have extremely female-biased sex ratios that cannot be explained by the existing local mate competition (LMC) theories. The restricted production of sons may entail cooperation among mothers, enabling the production of more daughters and avoiding severe competition among sons for insemination access. These unusual examples are characterized by the long-term cohabitation of egg-layers (foundresses) on resource patches and possible contact with oviposited eggs. By applying the logic of mutual policing, we develop a novel game theoretical model for the evolution of cooperation in sex-ratio traits. This is the first attempt to model the evolution of sex ratios based on iterated games. We assumed that foundresses have two abilities to enable mutual policing: they can monitor the sex ratio in the resource patch, and they can punish defectors that produce an overabundance of males. Numerical analysis and evolutionary simulations demonstrate that cooperative low sex ratios can evolve when the number of foundresses per patch is sufficiently small. Our model predicts a slight, but steady increase in oviposition sex ratios with an increase in the number of foundresses, which mimics the phenomenon observed in several animals with extremely female-biased sex ratios. We also discuss the relationship between our model and other models of sex-ratio evolution. 相似文献
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186.
Hozawa A Okamura T Oki I Murakami Y Kadowaki T Nakamura K Miyamatsu N Hayakawa T Kita Y Nakamura Y Nakamura Y Abbott RD Okayama A Ueshima H;NIPPON DATA Study Group 《Obesity (Silver Spring, Md.)》2008,16(7):1714-1717
As body composition in Asian populations is largely different from Western populations, a healthy BMI could also differ between the two populations. Thus, further study is needed to determine whether a healthy BMI in Asians should be lower than Western populations, as recommended by the World Health Organization (WHO). We investigated the relationship between BMI and mortality in a sample of 8,924 Japanese men and women without stroke or heart disease. During 19 years of follow-up, 1,718 deaths were observed. We found a U-shaped relationship between BMI and fatal events. Risk of total mortality was highest in participants with BMI <18.5 kg/m(2) and lowest in participants with BMI 23.0-24.9 kg/m(2). These findings persisted even after excluding the first 5 years of follow-up with a focus on healthy participants who never smoked, were aged <70 years, and had total cholesterol (TC) levels >or=4.1 mmol/l (N=3712). For both the full sample and healthy participants, all-cause mortality risk did not differ between BMI ranges 21.0-22.9 and 23.0-24.9 kg/m(2). Our findings do not support the recent WHO implications that BMIs <23.0 kg/m(2) is healthy for Asians. Therefore, further studies are needed to identify an optimal BMI range for Asia. 相似文献
187.
Background
Adult neurogenesis occurs in specific regions of the mammalian brain such as the dentate gyrus of the hippocampus. In the neurogenic region, neural progenitor cells continuously divide and give birth to new neurons. Although biological properties of neurons and glia in the hippocampus have been demonstrated to fluctuate depending on specific times of the day, it is unclear if neural progenitors and neurogenesis in the adult brain are temporally controlled within the day.Methodology/Principal Findings
Here we demonstrate that in the dentate gyrus of the adult mouse hippocampus, the number of M-phase cells shows a day/night variation throughout the day, with a significant increase during the nighttime. The M-phase cell number is constant throughout the day in the subventricular zone of the forebrain, another site of adult neurogenesis, indicating the daily rhythm of progenitor mitosis is region-specific. Importantly, the nighttime enhancement of hippocampal progenitor mitosis is accompanied by a nighttime increase of newborn neurons.Conclusions/Significance
These results indicate that neurogenesis in the adult hippocampus occurs in a time-of-day-dependent fashion, which may dictate daily modifications of dentate gyrus physiology. 相似文献188.
Tanimoto A Murata Y Wang KY Tsutsui M Kohno K Sasaguri Y 《The Journal of biological chemistry》2008,283(8):4643-4651
189.
Adachi O Ano Y Akakabe Y Shinagawa E Matsushita K 《Applied microbiology and biotechnology》2008,81(1):143-151
Chlorogenate hydrolase (EC 3.1.1.42, CHase) was highly induced in mycelia of Aspergillus sojae AKU 3312 grown in Czapek medium containing either instant coffee powder or coffee pulp as inducer. No CHase formation was
observed in the mycelia when cultivated without the inducer. CHase was purified readily from CHase-induced mycelia to high
homogeneity, and the purified CHase revealed the molecular weight of 180,000 consisting of two identical subunits of 88 kDa.
Equimolar quinate (QA) and caffeate (CA) were confirmed on hydrolysis of chlorogenate (CGA). The purified CHase was only useful
for a laboratory scale hydrolysis of CGA. For practical QA and CA production using scaled up hydrolysis of vegetable extracts
of natural CGA resources, the enzyme activity of purified CHase decreased and denatured irreversibly. Preparation of coffee
pulp koji and its application to QA and CA production were proposed instead of purified CHase. When coffee pulp koji was heated at
60°C for 30 min, CHase survived without any appreciable loss of enzyme activity while vegetative mycelial growth and spore
germination were terminated. The heated coffee pulp koji thus prepared was effective itself as stable immobilized catalyst
of CHase for QA and CA production from vegetable CGA resources such as coffee powders, coffee pulp, and others. 相似文献
190.
Manser C Stevenson A Banner S Davies J Tudor EL Ono Y Leigh PN McLoughlin DM Shaw CE Miller CC 《FEBS letters》2008,582(15):2303-2308
Neurofilaments are synthesised in neuronal cell bodies and then transported through axons. Damage to neurofilament transport is seen in amyotrophic lateral sclerosis (ALS). Here, we show that PKN1, a neurofilament head-rod domain kinase is cleaved and activated in SOD1G93A transgenic mice that are a model of ALS. Moreover, we demonstrate that glutamate, a proposed toxic mechanism in ALS leads to caspase cleavage and disruption of PKN1 in neurons. Finally, we demonstrate that a cleaved form of PKN1 but not wild-type PKN1 disrupts neurofilament organisation and axonal transport. Thus, deregulation of PKN1 may contribute to the pathogenic process in ALS. 相似文献