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81.
82.
Duan M Kazmierski WM Chong PY Deanda F Edelstein M Ferris R Peckham J Wheelan P Xiong Z Zhang H Nishizawa R Takaoka Y 《Bioorganic & medicinal chemistry letters》2011,21(21):6470-6475
A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles. 相似文献
83.
Tallant MD Duan M Freeman GA Ferris RG Edelstein MP Kazmierski WM Wheelan PJ 《Bioorganic & medicinal chemistry letters》2011,21(5):1394-1398
We describe the synthesis and potency of a novel series of N-substituted 2-phenyl- and 2-methyl-2-phenyl-1,4-diaminobutane- based CCR5 antagonists. Compounds 7a and 12f were found to be potent in anti-HIV assays and bioavailable in the low-dose rat PK model. 相似文献
84.
The 2011 German E. coli O104:H4 outbreak resulted in thousands of cases of enterohaemorrhagic illness, with approximately 25% of these progressing to develop haemolytic uraemic syndrome (HUS). This high rate of progression to HUS was the first indicator that the bacterial cause of illness was not a typical enterohaemorrhagic E. coli (EHEC) strain. Collaborative bioinformatic analysis while the outbreak was still in progress indicated that the O104:H4 strain was in fact an enteroaggregative E. coli (EAEC) strain which had acquired genes for the production of Shiga - like toxin. 相似文献
85.
Székelyhidi Z Pató J Wáczek F Bánhegyi P Hegymegi-Barakonyi B Erös D Mészáros G Hollósy F Hafenbradl D Obert S Klebl B Kéri G Orfi L 《Bioorganic & medicinal chemistry letters》2005,15(13):3241-3246
SR protein-specific kinase-1 (SRPK-1) has been identified as a validated target for hepatitis B virus (HBV). A series of novel tricyclic quinoxaline derivatives was designed and synthesised as potential kinase inhibitory antiviral agents and was found to be active and selective for SRPK-1 kinase. Most of these novel compounds have drug-like properties according to experimentally determined LogP and LogS values. 相似文献
86.
Furukawa N Ongusaha P Jahng WJ Araki K Choi CS Kim HJ Lee YH Kaibuchi K Kahn BB Masuzaki H Kim JK Lee SW Kim YB 《Cell metabolism》2005,2(2):119-129
Accumulating evidence indicates an important role for serine phosphorylation of IRS-1 in the regulation of insulin action. Recent studies suggest that Rho-kinase (ROK) is a mediator of insulin signaling, via interaction with IRS-1. Here we show that insulin stimulation of glucose transport is impaired when ROK is chemically or biologically inhibited in cultured adipocytes and myotubes and in isolated soleus muscle ex vivo. Inactivation of ROK also reduces insulin-stimulated IRS-1 tyrosine phosphorylation and PI3K activity. Moreover, inhibition of ROK activity in mice causes insulin resistance by reducing insulin-stimulated glucose uptake in skeletal muscle in vivo. Mass spectrometry analysis identifies IRS-1 Ser632/635 as substrates of ROK in vitro, and mutation of these sites inhibits insulin signaling. These results strongly suggest that ROK regulates insulin-stimulated glucose transport in vitro and in vivo. Thus, ROK is an important regulator of insulin signaling and glucose metabolism. 相似文献
87.
We have extended an earlier study, in which we characterized in detail the electrostatic potentials on the inner and outer surfaces of a group of carbon and BxNx model nanotubes, to include several additional ones with smaller diameters plus a new category, C2xBxNx. The statistical features of the surface potentials are presented and analyzed for a total of 19 tubes as well as fullerene and a small model graphene. The potentials on the surfaces of the carbon systems are relatively weak and rather bland; they are much stronger and more variable for the BxNx and C2xBxNx. A qualitative correlation with free energies of solvation indicates that the latter two categories should have considerably greater water solubilities. The inner surfaces are generally more positive than the corresponding outer ones, while both positive and negative potentials are strengthened by increasing curvature. The outsides of BxNx tubes have characteristic patterns of alternating positive and negative regions, while the insides are strongly positive. In the closed C2xBxNx systems, half of the C–C bonds are double-bond-like and have negative potentials above them; the adjacent rows of boron and nitrogens show the usual BxNx pattern. When the C2xBxNx tubes are open, with hydrogens at the ends, the surface potentials are dominated by the B+–H– and N––H+ linkages.Figure Calculated electrostatic potential on the molecular surface of closed (6,0) B48N48; a is an outside view, while b shows the interior. Color ranges, in kcal mol–1: red, greater than 20; yellow, between 20 and 0; green, between 0 and –10; blue, between –10 and –20; purple, more negative than –20 相似文献
88.
T cells from TCR transgenic mice, expressing receptors specific for an allogeneic MHC class I peptide, were used to track T cell activation and migration in normal adoptive recipients that were subsequently transplanted with heterotopic hearts that were syngeneic except for a transgenic MHC class I antigen. T cells rapidly disappeared from the blood into the lymphoid tissues where they were activated within one day after transplantation. T cells initially formed discrete clusters in the spleen and lymph nodes. After proliferating for 2-4 days in lymphoid tissues, T cells reappeared in the blood and migrated to the heart and the intestines. The T cells underwent another round of proliferation in the heart, but not the intestines, and induced cardiac rejection uniformly on 6 day. 相似文献
89.
Michelle Pacholec John E. Bleasdale Boris Chrunyk David Cunningham Declan Flynn Robert S. Garofalo David Griffith Matt Griffor Pat Loulakis Brandon Pabst Xiayang Qiu Brian Stockman Venkataraman Thanabal Alison Varghese Jessica Ward Jane Withka Kay Ahn 《The Journal of biological chemistry》2010,285(11):8340-8351
90.