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171.
Shuhei Imoto Satoru Kohgo Ryoh Tokuda Hiroki Kumamoto Manabu Aoki Masayuki Amano 《Nucleosides, nucleotides & nucleic acids》2015,34(8):590-602
Exomethylene acycloguanine nucleosides 4, 6 and its monophosphate derivatives 5, 7, and 8 have been synthesized. Mitsunobu-type coupling of 2-N-acetyl-6-O-diphenylcarbamoylguanine (11) with primary alcohols proceeded regioselectively to furnish the desired N9-substituted products in moderate yield. Evaluation of 4-8 for anti-HBV activity in HepG2 cells revealed that the phosphonate derivative 8 was found to exhibit moderated activity (EC50 value of 0.29 μM), but cytotoxicity (CC50 value of 39 μM) against the host cells was also observed. 相似文献
172.
Itoh M Tahimic CG Ide S Otsuki A Sasaoka T Noguchi S Oshimura M Goto Y Kurimasa A 《The Journal of biological chemistry》2012,287(17):13859-13867
Methyl CpG-binding protein 2 gene (MeCP2) mutations are implicated in Rett syndrome (RTT), one of the common causes of female mental retardation. Two MeCP2 isoforms have been reported: MeCP2_e2 (splicing of all four exons) and MeCP2_e1 (alternative splicing of exons 1, 3, and 4). Their relative expression levels vary among tissues, with MeCP2_e1 being more dominant in adult brain, whereas MeCP2_e2 is expressed more abundantly in placenta, liver, and skeletal muscle. In this study, we performed specific disruption of the MeCP2_e2-defining exon 2 using the Cre-loxP system and examined the consequences of selective loss of MeCP2_e2 function in vivo. We performed behavior evaluation, gene expression analysis, using RT-PCR and real-time quantitative PCR, and histological analysis. We demonstrate that selective deletion of MeCP2_e2 does not result in RTT-associated neurological phenotypes but confers a survival disadvantage to embryos carrying a MeCP2_e2 null allele of maternal origin. In addition, we reveal a specific requirement for MeCP2_e2 function in extraembryonic tissue, where selective loss of MeCP2_e2 results in placenta defects and up-regulation of peg-1, as determined by the parental origin of the mutant allele. Taken together, our findings suggest a novel role for MeCP2 in normal placenta development and illustrate how paternal X chromosome inactivation in extraembryonic tissues confers a survival disadvantage for carriers of a mutant maternal MeCP2_e2 allele. Moreover, our findings provide an explanation for the absence of reports on MeCP2_e2-specific exon 2 mutations in RTT. MeCP2_e2 mutations in humans may result in a phenotype that evades a diagnosis of RTT. 相似文献
173.
Kubota T Hamazoe Y Hashiguchi S Ishibashi D Akasaka K Nishida N Katamine S Sakaguchi S Kuroki R Nakashima T Sugimura K 《The Journal of biological chemistry》2012,287(17):14023-14039
We prepared β-sheet-rich recombinant full-length prion protein (β-form PrP) (Jackson, G. S., Hosszu, L. L., Power, A., Hill, A. F., Kenney, J., Saibil, H., Craven, C. J., Waltho, J. P., Clarke, A. R., and Collinge, J. (1999) Science 283, 1935-1937). Using this β-form PrP and a human single chain Fv-displaying phage library, we have established a human IgG1 antibody specific to β-form but not α-form PrP, PRB7 IgG. When prion-infected ScN2a cells were cultured with PRB7 IgG, they generated and accumulated PRB7-binding granules in the cytoplasm with time, consequently becoming apoptotic cells bearing very large PRB7-bound aggregates. The SAF32 antibody recognizing the N-terminal octarepeat region of full-length PrP stained distinct granules in these cells as determined by confocal laser microscopy observation. When the accumulation of proteinase K-resistant PrP was examined in prion-infected ScN2a cells cultured in the presence of PRB7 IgG or SAF32, it was strongly inhibited by SAF32 but not at all by PRB7 IgG. Thus, we demonstrated direct evidence of the generation and accumulation of β-sheet-rich PrP in ScN2a cells de novo. These results suggest first that PRB7-bound PrP is not responsible for the accumulation of β-form PrP aggregates, which are rather an end product resulting in the triggering of apoptotic cell death, and second that SAF32-bound PrP lacking the PRB7-recognizing β-form may represent so-called PrP(Sc) with prion propagation activity. PRB7 is the first human antibody specific to β-form PrP and has become a powerful tool for the characterization of the biochemical nature of prion and its pathology. 相似文献
174.
Nakamura Y Sugita C Meguro M Miyazaki S Tamaki K Takahashi M Nagai Y Nagayama T Kato M Suemune H Nishi T 《Bioorganic & medicinal chemistry letters》2012,22(14):4561-4566
Introduction of the 2,2-dimethyl-4-phenylpiperazin-5-one scaffold into the P(3)-P(1) portion of the (2S,4S,5S)-5-amino-6-dialkylamino-4-hydroxy-2-isopropylhexanamide backbone dramatically increased the renin inhibitory activity without using the interaction to the S(3)(sp) pocket. Compound 31 exhibited >10,000-fold selectivity over other human proteases, and 18.5% oral bioavailability in monkey. 相似文献
175.
Arai T Ohno M Inoue H Hayashi S Aoki T Hirokawa H Meguro H Koga Y Oshida K Kainoh M Suyama K Kawai H 《Bioorganic & medicinal chemistry letters》2012,22(15):5118-5122
The discovery that pyrazole-benzyl urea derivatives bearing a 2-molpholinopyrimidine moiety are novel p38α inhibitors is described. A comparative view of the binding modes of SB-203580 and BIRB-796 by structural alignment of two X-ray co-crystal structures was utilized to identify this novel series. Modification of the benzyl group led to compound 2b, a highly potent p38α inhibitor. In in vivo studies, 2b inhibited the production of tumor necrosis factor-alpha in lipopolysaccharide-treated mouse in a dose-dependent manner. Furthermore, the results of a 5-day repeated oral dose toxicity study suggest that 2b has low hepatotoxicity. 相似文献
176.
177.
Tsunematsu R Nishiyama M Kotoshiba S Saiga T Kamura T Nakayama KI 《Molecular and cellular biology》2006,26(16):6157-6169
Cullin-based ubiquitin ligases (E3s) constitute one of the largest E3 families. Fbxw8 (also known as Fbw6 or Fbx29) is an F-box protein that is assembled with Cul7 in an SCF-like E3 complex. Here we show that Cul7 forms a heterodimeric complex with Cul1 in a manner dependent on Fbxw8. We generated mice deficient in Fbxw8 and found that Cul7 did not associate with Cul1 in cells of these mice. Two-thirds of Fbxw8-/- embryos die in utero, whereas the remaining one-third are born alive and grow to adulthood. Fbxw8-/- embryos show intrauterine growth retardation and abnormal development of the placenta, characterized by both a reduced thickness of the spongiotrophoblast layer and abnormal vessel structure in the labyrinth layer. Although the placental phenotype of Fbxw8-/- mice resembles that of Cul7-/- mice, other abnormalities of Cul7-/- mice are not apparent in Fbxw8-/- mice. These results suggest that the Cul7-based SCF-like E3 complex has both Fbxw8-dependent and Fbxw8-independent functions. 相似文献
178.
Two pathways of apoptosis are simultaneously induced in the embryonal brains of neural cell-specific HIF-1α-deficient mice 总被引:2,自引:2,他引:0
Ueno M Tomita S Ueki M Iwanaga Y Huang CL Onodera M Maekawa N Gonzalez FJ Sakamoto H 《Histochemistry and cell biology》2006,125(5):535-544
The aim of this study was to clarify the mechanism of apoptosis seen in the cortex of neural cell-specific hypoxia inducible factor-1α (HIF-1α)-deficient embryos. A previous study showed that the neural cells in the cortical area of the mutant embryos underwent apoptosis coincident with vascular regression. Through histological, immunohistochemical, and electron microscopic technique, two kinds of apoptotic cells were detected in the mutant embryonal cortex. Apoptotic cells of one type were clustered in small round structures, 10–20 μm in diameter, whereas the others, present in large numbers, were distributed in a group at the cortical plate located more to the outer side than the round structures. The histochemical and electron microscopic findings indicate that the former represented the appearance of macrophages, in which cellular fragments including vascular cells underwent oxidative stress-related, TNF receptor-mediated, caspase-2-induced apoptosis, while the latter showed c-Myc-related, caspase-3-activated apoptosis of the neural cells. These results suggest that two pathways of apoptosis are induced in neuronal and vascular cells of the cortex in the neural cell-specific HIF-1α-deficient mouse. 相似文献
179.
Naokazu Kumura Hirotaka Furukawa Arnold N. Onyango Minoru Izumi Shuhei Nakajima Hideyuki Ito Tsutomu Hatano Hye-Sook Kim Yusuke Wataya Naomichi Baba 《Chemistry and physics of lipids》2009,160(2):114-120
The reaction of trioxane and tetraoxane endoperoxides with unsaturated phospholipid 1 in the presence of Fe(II) was investigated in the absence of oxygen by means of tandem ESI-MS analysis. The spectral analyses for the reaction mixtures showed that artemisinin 2 with a trioxane structure gave no peak except that for the remaining intact phospholipid 1 (m/z 758.9), indicating that there was no structural change to 1. On other hand, the reaction mixture of 1 with tetraoxanes 3 and 4 afforded a number of new peaks (m/z 620–850) that were presumably assigned to oxidative degradation products originating from phospholipid 1. Since this reaction was completely inhibited by the addition of a phenolic antioxidant, the process was considered to involve some free radical species. The newly discovered marked differences in reactivity between the trioxane and the tetraoxanes possibly reflects their different anti-malarial mechanisms, and this reactivity may contribute to the classification of a number of anti-malarial endoperoxides whose mode of action is based on phospholipid oxidation. 相似文献
180.
Taishi Hashiguchi Shuji Mizumoto Shuhei Yamada Kazuyuki Sugahara 《Glycoconjugate journal》2010,27(1):49-60
The amniotic membrane (AM) is the innermost layer of fetal membranes and possesses various biological activities. Although
the mechanism underlying these biological activities remains unclear, unique components seem to be involved. AM contains various
extracellular matrix components such as type I collagen, laminin, fibronectin, hyaluronan, and proteoglycans bearing chondroitin
sulfate/dermatan sulfate (CS/DS) glycosaminoglycan side chains. Since CS/DS have been implicated in various biological processes,
we hypothesized that CS/DS in AM may play a major role in the biological activities of AM. Therefore, the structure and bioactivity
of the CS/DS chains from porcine fetal membranes (FM-CS/DS) were investigated. A compositional analysis using various chondroitinases
revealed that the characteristic DS domain comprised of iduronic acid-containing disaccharide units is embedded in FM-CS/DS,
along with predominant disaccharide units, GlcA-GalNAc, GlcA-GalNAc(4-O-sulfate), and GlcA-GalNAc(6-O-sulfate), where GlcA and GalNAc represent D-glucuronic acid and N-acetyl-D-galactosamine, respectively. The average molecular mass of FM-CS/DS chains was unusually large and estimated to
be 250 – 300 kDa. The FM-CS/DS chains showed neurite outgrowth-promoting activity, which was eliminated by digestion with
chondroitinase ABC of the CS/DS chains. This activity was suppressed by antibodies against growth factors including pleiotrophin,
midkine, and fibroblast growth factor-2, suggesting the involvement of these growth factors in the neurite outgrowth-promoting
activity. The binding of these growth factors to FM-CS/DS was also demonstrated by surface plasmon resonance spectroscopy. 相似文献