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611.
Wonsuk Chang Jinfa Du Suguna Rachakonda Bruce S. Ross Serge Convers-Reignier Wei T. Yau Jean-Francois Pons Eisuke Murakami Haiying Bao Holly Micolochick Steuer Phillip A. Furman Michael J. Otto Michael J. Sofia 《Bioorganic & medicinal chemistry letters》2010,20(15):4539-4543
Hepatitis C virus afflicts approximately 180 million people worldwide and currently there are no direct acting antiviral agents available to treat this disease. Our first generation nucleoside HCV inhibitor, RG7128 has already established proof-of-concept in the clinic and is currently in phase IIb clinical trials. As part of our continuing efforts to discover novel anti-HCV agents, 3′,4′-oxetane cytidine and adenosine nucleosides were prepared as inhibitors of HCV RNA replication. These nucleosides were shown not to be inhibitors of HCV as determined in a whole cell subgenomic replicon assay. However, 2′-mono/diflouro analogs, 4, 5, and 6 were readily phosphorylated to their monophosphate metabolites by deoxycytidine kinase and their triphosphate derivatives were shown to be inhibitors of HCV NS5B polymerase in vitro. Lack of anti-HCV activity in the replicon assay may be due to the inability of the monophosphates to be converted to their corresponding diphosphates. 相似文献
612.
Co-localization of a glucose transporter and the insulin receptor in microsomes of insulin-treated rat adipocytes 总被引:2,自引:0,他引:2
O Ezaki N Bono H Itakura M Kasahara 《Biochemical and biophysical research communications》1989,159(3):1368-1374
Microsomal vesicles prepared from rat adipocytes were immuno-adsorbed to formaldehyde-fixed Staphylococcus aureus cells (Pansorbin) coated with anti-human-erythrocyte-glucose-transporter IgG. More than 75% of the glucose transporter detected was precipitated. The glucose transporter was about 10-fold enriched by the adsorption procedure. On insulin treatment, the insulin receptor in plasma membranes was internalized and the receptor in the microsome fraction increased 5-fold. Thirty-five % of the insulin receptor in the microsome fraction was recovered with the glucose-transporter-containing vesicles. These observations indicate that on insulin treatment a considerable portion of the microsome vesicles containing the insulin receptor fuses or becomes tightly associated with ones containing the glucose transporter. 相似文献
613.
Takayuki Iida Manabu Itakura Mizue Anda Masayuki Sugawara Tsuyoshi Isawa Takashi Okubo Shusei Sato Kaori Chiba-Kakizaki Kiwamu Minamisawa 《Applied and environmental microbiology》2015,81(12):4143-4154
Extra-slow-growing bradyrhizobia from root nodules of field-grown soybeans harbor abundant insertion sequences (ISs) and are termed highly reiterated sequence-possessing (HRS) strains. We analyzed the genome organization of HRS strains with the focus on IS distribution and symbiosis island structure. Using pulsed-field gel electrophoresis, we consistently detected several plasmids (0.07 to 0.4 Mb) in the HRS strains (NK5, NK6, USDA135, 2281, USDA123, and T2), whereas no plasmids were detected in the non-HRS strain USDA110. The chromosomes of the six HRS strains (9.7 to 10.7 Mb) were larger than that of USDA110 (9.1 Mb). Using MiSeq sequences of 6 HRS and 17 non-HRS strains mapped to the USDA110 genome, we found that the copy numbers of ISRj1, ISRj2, ISFK1, IS1632, ISB27, ISBj8, and IS1631 were markedly higher in HRS strains. Whole-genome sequencing showed that the HRS strain NK6 had four small plasmids (136 to 212 kb) and a large chromosome (9,780 kb). Strong colinearity was found between 7.4-Mb core regions of the NK6 and USDA110 chromosomes. USDA110 symbiosis islands corresponded mainly to five small regions (S1 to S5) within two variable regions, V1 (0.8 Mb) and V2 (1.6 Mb), of the NK6 chromosome. The USDA110 nif gene cluster (nifDKENXSBZHQW-fixBCX) was split into two regions, S2 and S3, where ISRj1-mediated rearrangement occurred between nifS and nifB. ISs were also scattered in NK6 core regions, and ISRj1 insertion often disrupted some genes important for survival and environmental responses. These results suggest that HRS strains of soybean bradyrhizobia were subjected to IS-mediated symbiosis island shuffling and core genome degradation. 相似文献
614.
Eisuke Kato Kazuhiro Kawakami Jun Kawabata 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):106-109
Dipeptidyl peptidase 4 (DPP-4) inhibitors are used for the treatment of type-2 diabetes mellitus. Various synthetic inhibitors have been developed to date, and plants containing natural DPP-4 inhibitors have also been identified. Here, 13 plant samples were tested for their DPP-4 inhibitory activity. Macrocarpals A–C were isolated from Eucalyptus globulus through activity-guided fractionation and shown to be DPP-4 inhibitors. Of these, macrocarpal C showed the highest inhibitory activity, demonstrating an inhibition curve characterised by a pronounced increase in activity within a narrow concentration range. Evaluation of macrocarpal C solution by turbidity, nuclear magnetic resonance spectroscopy and mass spectrometry indicated its aggregation, which may explain the characteristics of the inhibition curve. These findings will be valuable for further study of potential small molecule DPP-4 inhibitors. 相似文献
615.
Shoji-Kasai Y Morishima M Kuwahara R Kondo S Itakura M Takahashi M 《Biochimica et biophysica acta》2001,1499(3):180-190
Clonal rat pheochromocytoma (PC12) cells have been widely used to study the molecular mechanism of exocytosis. We have isolated variant PC12 subclones with deficiencies in stimulation-secretion coupling, by a single cell recloning, and investigated the defects. PC12-1G2 hardly released dopamine following high-K(+)-induced depolarization, but normal release was evoked by the Ca(2+)-ionophore, ionomycin. Fura-2 fluorometry indicated that a nicardipine-sensitive component of Ca(2+) influx was missing, suggesting that PC12-1G2 has defects in L-type Ca(2+) channel function. PC12-2B3 was not responsive to high-K(+)-induced depolarization and ionomycin, and voltage-dependent Ca(2+) entry was identical to that of the normal clone. Electron microscopy revealed that the number of vesicles adjacent or directly attached to the plasma membrane was decreased in PC12-2B3. The expression of presynaptic proteins was analyzed by immunoblotting using a panel of antibodies. Syntaxin 1, VAMP-2, SNAP-25, Munc18, Rab3C and Sec-6 were decreased compared to the control clone and that of synaptophysin was extremely low. PC12-D60 synthesized and released dopamine normally, but had almost lost its catecholamine-uptake activity. These results show that multiple PC12 cells variants are spontaneously generated, and that recloning can select PC12 subclones useful for the study of the molecular mechanisms of neurotransmitter release. 相似文献
616.
Tomoko Kanno Eisuke F. Sato Shikibu Muranaka Hirofumi Fujita Takuzo Fujiwara Toshihiko Utsumi 《Free radical research》2013,47(1):27-35
Recent studies demonstrated that the generation of intracellular reactive oxygen species (ROS) was enhanced prior to the onset of mitochondrial membrane permeability transition (MPT), a critical step for the induction of DNA fragmentation and apoptosis. Although Ca2+ induces typical MPT that involves depolarization and swelling of mitochondria and finally releases cytochrome c into cytosol, the mechanism by which ROS induce MPT remains unclear. In the presence of inorganic phosphate, Ca2+ increased the oxygen consumption and ROS production by isolated mitochondria as determined by a chemiluminescence (CHL) method using L-012. Ca2+ increased the generation of H2O2 by some mechanism that was inhibited by cyclosporin A but not by superoxide dismutase (SOD) and trifluoperazine. Ca2+ decreased the content of free thiols in adenine nucleotide translocase (ANT) in mitochondrial membranes with concomitant increase in ROS generation. The presence of cyclosporin A, trifluoperazine, or SOD inhibited the Ca2+-induced increase of L-012 CHL and decrease in the free thiols of ANT. These results indicate that Ca2+ increases the generation of ROS which oxidize the free thiol groups in mitochondrial ANT, thereby inducing MPT to release cytochrome c. 相似文献
617.
618.
IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1-42) by rat primary type 2 microglia 总被引:1,自引:0,他引:1
Shimizu E Kawahara K Kajizono M Sawada M Nakayama H 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(9):6503-6513
A hallmark of immunopathology associated with Alzheimer's disease is the presence of activated microglia (MG) surrounding senile plaque deposition of beta-amyloid (Abeta) peptides. Abeta peptides are believed to be potent activators of MG, which leads to Alzheimer's disease pathology, but the role of MG subtypes in Abeta clearance still remains unclear. In this study, we found that IL-4 treatment of rat primary-type 2 MG enhanced uptake and degradation of oligomeric Abeta(1-42) (o-Abeta(1-42)). IL-4 treatment induced significant expression of the scavenger receptor CD36 and the Abeta-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) but reduced expression of certain other scavenger receptors. Of cytokines and stimulants tested, the anti-inflammatory cytokines IL-4 and IL-13 effectively enhanced CD36, NEP, and IDE. We demonstrated the CD36 contribution to IL-4-induced Abeta clearance: Chinese hamster ovary cells overexpressing CD36 exhibited marked, dose-dependent degradation of (125)I-labeled o-Abeta(1-42) compared with controls, the degradation being blocked by anti-CD36 Ab. Also, we found IL-4-induced clearance of o-Abeta(1-42) in type 2 MG from CD36-expressing WKY/NCrj rats but not in cells from SHR/NCrj rats with dysfunctional CD36 expression. NEP and IDE also contributed to IL-4-induced degradation of Abeta(1-42), because their inhibitors, thiorphan and insulin, respectively, significantly suppressed this activity. IL-4-stimulated uptake and degradation of o-Abeta(1-42) were selectively enhanced in type 2, but not type 1 MG that express CD40, which suggests that the two MG types may play different neuroimmunomodulating roles in the Abeta-overproducing brain. Thus, selective o-Abeta(1-42) clearance, which is induced by IL-4, may provide an additional focus for developing strategies to prevent and treat Alzheimer's disease. 相似文献
619.
Zhu X Sato EF Wang Y Nakamura H Yodoi J Inoue M 《Archives of biochemistry and biophysics》2008,478(2):154-160
To elucidate the mechanism by which l-carnitine and related metabolites inhibited mitochondria-dependent apoptosis, we used conditional TRX2-knockout DT40 cells (TRX2−/−) and compared the properties of signaling pathways leading to apoptosis in the wild and TRX2−/− cells. Caspase-3 and 9, but not caspase-8, were strongly activated in TRX2−/− cells but not in wild cells. TRX2−/− cells generated large amounts of reactive oxygen species that markedly decreased cellular glutathione levels both in cytosol and mitochondria. We found that the critical thiol groups of adenine nucleotide translocator (ANT) were oxidized more easily in TRX2−/− cells than in wild cells and that the reduced form, but not oxidized form, of ANT selectively bound to TRX2. Cytochrome c and SOD1 were released from mitochondria more easily in TRX2−/− cells than in wild cells. All these phenomena observed with TRX2−/− cells were effectively inhibited by acetyl-l-carntine but not l-carnitine. Thus, acetyl-l-carnitine effectively suppressed the oxidative stress in and around mitochondria thereby preventing mitochondrial signaling pathway leading to apoptosis. 相似文献
620.
The impacts of mining activities on aquatic biota have been documented in many stream ecosystems. In mining streams, point‐source heavy metal pollution often appears in the stream. We hypothesize that this pollution is toxic to macroinvertebrates owing to high concentrations of metals and therefore affects macroinvertebrate community structure. We investigated macroinvertebrate community structure in mountain streams, including heavy metal‐polluted sites and neutral‐pH streams, to determine the relationship between community structure and environmental factors such as low pH and heavy metal concentrations. Based on multidimensional scaling ordination, the macroinvertebrate community at heavy metal pollution sites was remarkably different from that at the other sites. Inductively coupled plasma mass spectrometry revealed high concentrations of aluminum and iron in surface water at the polluted sites. Macroinvertebrate community structure at the metal pollution sites was significantly different from that at other sites in the same stream and in neutral‐pH streams. Thus, point‐source metal pollution may reduce the density and diversity of in situ macroinvertebrates. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim) 相似文献