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151.
Yoshiari Shimmyo Takeshi Kihara Akinori Akaike Tetsuhiro Niidome Hachiro Sugimoto 《Biochimica et Biophysica Acta (BBA)/General Subjects》2008
Generation and accumulation of the amyloid β peptide (Aβ) following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 (Beta-site APP Cleaving Enzyme-1, β-secretase) and γ-secretase is a main causal factor of Alzheimer's disease (AD). Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Aβ, is an attractive therapeutic approach for the treatment of AD. In this study, we discovered that natural flavonoids act as non-peptidic BACE-1 inhibitors and potently inhibit BACE-1 activity and reduce the level of secreted Aβ in primary cortical neurons. In addition, we demonstrated the calculated docking poses of flavonoids to BACE-1 and revealed the interactions of flavonoids with the BACE-1 catalytic center. We firstly revealed novel pharmacophore features of flavonoids by using cell-free, cell-based and in silico docking studies. These results contribute to the development of new BACE-1 inhibitors for the treatment of AD. 相似文献
152.
Masaki Fujita Tetsuhiro Moriya S. Fujimoto Nobuyuki Hara Kazunobu Amako 《Archives of microbiology》1997,167(4):196-201
The surface array protein (SAP) of Campylobacter fetus strain TK is encoded by seven homologous sapA genes clustered on the chromosomal DNA. The spontaneously arising variant strain TK(SAP–) produces no SAP and carries an approximately 10-kb chromosomal deletion. To elucidate the mechanism underlying the loss
of SAP synthesis, we analyzed the region containing the sapA homologues and the deletion. We constructed a physical map of the sapA cluster region by aligning the clones that contain sapA homologues. These analyses demonstrated that all sapA homologues were located within a limited region of about 50 kb of chromosomal DNA of strain TK. The TK(SAP–) deletion was located within this cluster and was 13.3 kb in size. The deletion occurred between two sapA homologues and resulted in the formation of a chimeric sapA homologue in the variant strain. Sequence analysis of the upstream regions and the conserved regions of all sapA homologues revealed a high degree of similarity. However, only one sapA homologue contained a putative promoter sequence. This promoter sequence was located in the deleted region. Thus, the deletion
of the promoter appears to be responsible for the loss of SAP expression in TK(SAP–).
Received: 17 May 1996 / Accepted: 6 December 1996 相似文献
153.
Tetsuhiro Niidome Yasuaki Goto Masaru Kato Saori Goh Akinori Akaike Hachiro Sugimoto 《Biochemical and biophysical research communications》2009,386(4):734-738
Amyloid-β peptide (Aβ) is thought to be linked to the pathogenesis of Alzheimer’s disease. Recent studies suggest that Aβ has important physiological roles in addition to its pathological roles. We recently demonstrated that Aβ42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between Aβ42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar Aβ42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar Aβ42 on glutamate-induced neurotoxicity. Non-fibrillar Aβ42, but not fibrillar Aβ42, protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar Aβ42 decreased both neurotoxicity and increases in the intracellular Ca2+ concentration induced by N-methyl-d-aspartate (NMDA), but not by α-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar Aβ42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor. 相似文献
154.
Yoshiyuki Ono Akira Kawase Hiroyoshi Watanabe Ayako Shiraishi Satoshi Takeda Yoshinobu Higuchi Katsuhiko Sato Tsuyoshi Yamauchi Tetsuhiro Mikami Masahiro Kato Naoko Tsugawa Toshio Okano Noboru Kubodera 《Bioorganic & medicinal chemistry》1998,6(12):2517-2523
Analogues related to 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71) (2), 26,27-dimethyl ED-71 (3) and 26,27-diethyl ED-71 (4), were synthesized from lithocholic acid (5). In the study of the preventive effects of these analogues and ED-71 (2) on bone mineral loss in ovariectomized rats, 26,27-dimethyl ED-71 (3) showed the most potent activity. 相似文献