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41.
Irie O Kosaka T Kishida M Sakaki J Masuya K Konishi K Yokokawa F Ehara T Iwasaki A Iwaki Y Hitomi Y Toyao A Gunji H Teno N Iwasaki G Hirao H Kanazawa T Tanabe K Hiestand PC Malcangio M Fox AJ Bevan SJ Yaqoob M Culshaw AJ Hart TW Hallett A 《Bioorganic & medicinal chemistry letters》2008,18(19):5280-5284
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain. 相似文献
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T Nikai N Mori M Kishida Y Kato C Takenaka T Murakami S Shigezane H Sugihara 《Biochimica et biophysica acta》1985,838(1):122-131
Hemorrhagic factors a and b were isolated from Trimeresurus mucrosquamatus venom by Sephadex G-100, CM-Sephadex C-50 and DEAE-Sephacel column chromatographies. The hemorrhagic factors were homogeneous, as established by a single band on acrylamide gel electrophoresis, isoelectric focusing and sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. Molecular weights of 15 000 and 27 000 were found for hemorrhagic factors a and b, respectively. Factor a possesses proteolytic activity hydrolyzing the His(10)-Leu(11), Tyr(16)-Leu(17) and Arg(22)-Gly(23) bonds of oxidized insulin B chain, whereas, factor b hydrolyzed only the Ala(14)-Leu(15) bond. Hemorrhagic activity of these hemorrhagic factors was inhibited by ethylenediaminetetraacetic acid, 1,10-phenanthroline or p-chloromercuribenzoate, but not by soybean trypsin inhibitor or diisopropyl fluorophosphate. The hemorrhagic factors were injected into the skin of the back of albino rabbits, and the minimum hemorrhagic dose of factors a and b was 1.7 and 2.3 micrograms, respectively. These purified hemorrhagic factors were not lethal at 15 micrograms/g in mice. Factor a hydrolyzed the B beta chain of fibrinogen, while factor b hydrolyzed the A alpha chain. Hemorrhagic factor a was shown to differ immunologically from factor b. Factors a and b produced systemic hemorrhage in internal organs such as the heart and stomach of mice. Moreover, factor b produced hemorrhage in the liver. 相似文献
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Yasuhiro Morisawa Yukichi Kishida Katsumi Tanabe 《Bioscience, biotechnology, and biochemistry》2013,77(11):788-800
3β-Acetoxy-B-nor-5β-cholestan-6-one (Ia) afforded only one isolatable oxime (IIa), while oximation of 3β, 17β-diacetoxy-B-nor-5β-androstan-6-one (Ib) yielded two isomeric oximes (IIb and IIIb). 7-Aza-5β-cholestan-3β-ol (VIa), 7-aza-5β-androstane-3β, 17β-diol (VIc), and 6-aza-5β-androstane-3β, 17β-diol (VIIc) were synthesized by Beckmann rearrangement of these oximes, followed by reduction with lithium aluminium hydride. The structure of the aza-steroids were established by conversion of the intermediate lactams (IVa, b) into the lactones (IXa, b), prepared from the 3β-acetoxy-B-nor-6-oxo-5β-steroids (Ia, b) by Baeyer Villiger reaction. 相似文献
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The proteinase (Prot. II) from Scopulariopsis brevicaulis has rather a broader specificity in its action on oxidized A- and B-chain of bovine insulin, than that of trypsin or chymotrypsin.The cleavage in the above peptides occurred rapidly at such bonds, where leucine, valine or glutamic acid is linked by its respective carboxyl group, and slowly at the carboxyl side of cysteic acid or alanine. 相似文献
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Naomi Sakashita Motohiro Takeya Takeshi Kishida Thomas M. Stackhouse Berton Zbar Kiyoshi Takahashi 《The Histochemical journal》1999,31(2):133-144
To examine the localization of von Hippel–Lindau (VHL) protein in human tissues, we produced four novel monoclonal antibodies against human VHL protein. Western blot analysis revealed that two of these antibodies recognized the epitope in amino acid sequence 60–89 of the VHL protein and the others recognized sequences 54–60 and 189–213. In a wild-type VHL gene-transfected cell line, immunocytochemistry and immunoelectron microscopy demonstrated the intracytoplasmic localization of VHL protein, particularly in mitotic cells. In normal human tissues, VHL protein was detected immunohistochemically in epithelial cells covering the body surface and the alimentary, respiratory, and genitourinary tracts; in secretory epithelial cells of exocrine and endocrine organs; in parenchymal cells of visceral organs; in cardiomyocytes; in neurons in nervous tissue; in lymphocytes in lymphoid tissue; and in macrophages. In pathological specimens, VHL protein was expressed in VHL-related tumor, as well as in endothelial cells, fibroblasts, and pericytes, all of which are involved in active angiogenesis. These findings suggest that these monoclonal antibodies can be useful for various immunological assays and that the VHL protein plays fundamental roles in physiological and pathological situations, especially in neovascularization. 相似文献
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H Okuda S Hirai Y Takaki M Kamada M Baba N Sakai T Kishida S Kaneko M Yao S Ohno T Shuin 《Biochemical and biophysical research communications》1999,263(2):491-497
VHL tumor suppressor protein contains two domains, alpha and beta. The alpha-domain is involved in the formation of a large protein complex suggested to be involved in ubiquitin-mediated protein degradation. However, the role of the beta-domain, which may recognize the target proteins for protein degradation, remains unknown. Here we report that the beta-domain interacts directly with atypical PKC isotypes, PKCzeta and PKClambda. Further, the regulatory domain of aPKC is sufficient for this direct protein-protein interaction. Since aPKC isotypes have been implicated in the regulation of cell growth and apoptosis, these results suggest that aPKC isotypes are potential direct target of the VHL beta-domain. 相似文献