全文获取类型
收费全文 | 1228篇 |
免费 | 75篇 |
国内免费 | 1篇 |
出版年
2023年 | 11篇 |
2022年 | 23篇 |
2021年 | 33篇 |
2020年 | 23篇 |
2019年 | 18篇 |
2018年 | 30篇 |
2017年 | 26篇 |
2016年 | 37篇 |
2015年 | 51篇 |
2014年 | 61篇 |
2013年 | 89篇 |
2012年 | 110篇 |
2011年 | 84篇 |
2010年 | 58篇 |
2009年 | 50篇 |
2008年 | 74篇 |
2007年 | 75篇 |
2006年 | 59篇 |
2005年 | 45篇 |
2004年 | 52篇 |
2003年 | 40篇 |
2002年 | 29篇 |
2001年 | 15篇 |
2000年 | 27篇 |
1999年 | 19篇 |
1998年 | 8篇 |
1997年 | 8篇 |
1996年 | 5篇 |
1995年 | 5篇 |
1994年 | 5篇 |
1993年 | 10篇 |
1992年 | 17篇 |
1991年 | 13篇 |
1990年 | 12篇 |
1989年 | 11篇 |
1988年 | 5篇 |
1987年 | 13篇 |
1986年 | 8篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1982年 | 3篇 |
1981年 | 2篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1977年 | 2篇 |
1975年 | 3篇 |
1974年 | 6篇 |
1970年 | 4篇 |
1969年 | 3篇 |
1968年 | 2篇 |
排序方式: 共有1304条查询结果,搜索用时 46 毫秒
921.
Nitric oxide (NO), a mediator of various physiological and pathophysiological processes, is synthesized by three isozymes of nitric oxide synthase (NOS). In developing candidate clinical drugs, it is very important not to inhibit endothelial NOS, because it plays an important role in maintaining normal blood pressure and flow. Here, we describe the design, synthesis and human NOS-inhibitory activities of S-methyl-L-isothiocitrulline-based 3-substituted arginine analogs. The 3R*-methyl compound 4, which has an S-methyl isothiourea moiety, inhibited nNOS and iNOS, but not eNOS (IC(50) > 1 mM). However, the 3R*-methyl compound 7, bearing a 5-iminoethyl moiety, did not inhibit any of the NOS isozymes, although L-N-iminoethylornithine (L-NIO) potently inhibited all three. A computational docking study was carried out to investigate the mechanism of the isozyme selectivity. 相似文献
922.
Yamamoto A Friedlein A Imai Y Takahashi R Kahle PJ Haass C 《The Journal of biological chemistry》2005,280(5):3390-3399
Mutations in the PARKIN gene are the most common cause of hereditary parkinsonism. The parkin protein comprises an N-terminal ubiquitin-like domain, a linker region containing caspase cleavage sites, a unique domain in the central portion, and a special zinc finger configuration termed RING-IBR-RING. Parkin has E3 ubiquitin-protein ligase activity and is believed to mediate proteasomal degradation of aggregation-prone proteins. Whereas the effects of mutations on the structure and function of parkin have been intensely studied, post-translational modifications of parkin and the regulation of its enzymatic activity are poorly understood. Here we report that parkin is phosphorylated both in human embryonic kidney HEK293 cells and human neuroblastoma SH-SY5Y cells. The turnover of parkin phosphorylation was rapid, because inhibition of phosphatases with okadaic acid was necessary to stabilize phosphoparkin. Phosphoamino acid analysis revealed that phosphorylation occurred mainly on serine residues under these conditions. At least five phosphorylation sites were identified, including Ser101, Ser131, and Ser136 (located in the linker region) as well as Ser296 and Ser378 (located in the RING-IBR-RING motif). Casein kinase-1, protein kinase A, and protein kinase C phosphorylated parkin in vitro, and inhibition of casein kinase-1 caused a dramatic reduction of parkin phosphorylation in cell lysates. Induction of protein folding stress in cells reduced parkin phosphorylation, and unphosphorylated parkin had slightly but significantly elevated autoubiquitination activity. Thus, complex regulation of the phosphorylation state of parkin may contribute to the unfolded protein response in stressed cells. 相似文献
923.
Kim YJ Nakatomi R Akagi T Hashikawa T Takahashi R 《The Journal of biological chemistry》2005,280(22):21515-21521
Formation of misfolded protein aggregates is a remarkable hallmark of various neurodegenerative diseases including Alzheimer disease, Parkinson disease, Huntington disease, prion encephalopathies, and amyotrophic lateral sclerosis (ALS). Superoxide dismutase 1 (SOD1) immunoreactive inclusions have been found in the spinal cord of ALS animal models and patients, implicating the close involvement of SOD1 aggregates in ALS pathogenesis. Here we examined the molecular mechanism of aggregate formation of ALS-related SOD1 mutants in vitro. We found that long-chain unsaturated fatty acids (FAs) promoted aggregate formation of SOD1 mutants in both dose- and time-dependent manners. Metal-deficient SOD1s, wild-type, and mutants were highly oligomerized compared with holo-SOD1s by incubation in the presence of unsaturated FAs. Oligomerization of SOD1 is closely associated with its structural instability. Heat-treated holo-SOD1 mutants were readily oligomerized by the addition of unsaturated FAs, whereas wild-type SOD1 was not. The monounsaturated FA, oleic acid, directly bound to SOD1 and was characterized by a solid-phase FA binding assay using oleate-Sepharose. The FA binding characteristics were closely correlated with the oligomerization propensity of SOD1 proteins, which indicates that FA binding may change SOD1 conformation in a way that favors the formation of aggregates. High molecular mass aggregates of SOD1 induced by FAs have a granular morphology and show significant cytotoxicity. These findings suggest that SOD1 mutants gain FA binding abilities based on their structural instability and form cytotoxic granular aggregates. 相似文献
924.
The Lol system, comprising five Lol proteins, transfers lipoproteins from the inner to the outer membrane of Escherichia coli. Periplasmic LolA accepts lipoproteins from LolCDE in the inner membrane and immediately transfers them to LolB, a receptor anchored to the outer membrane. The unclosed beta-barrel structures of LolA and LolB are very similar to each other and form hydrophobic cavities for lipoproteins. The lipoprotein transfer between these similar structures is unidirectional and very efficient, but requires no energy input. To reveal the mechanisms underlying this lipoprotein transfer, Arg and Phe at positions 43 and 47, respectively, of LolA were systematically mutagenized. The two residues were previously found to affect abilities to accept and transfer lipoproteins. Substitution of Phe-47 with polar residues inhibited the ability to accept lipoproteins from the inner membrane. No derivatives caused periplasmic accumulation of lipoproteins. In contrast, many Arg-43 derivatives caused unusual periplasmic accumulation of lipoproteins to various extents. However, all derivatives, except one having Leu instead of Arg, supported the growth of cells. All Arg-43 derivatives retained the ability to accept lipoproteins from the inner membrane, whereas their abilities to transfer associated lipoproteins to LolB were variously reduced. Assessment of the intensity of the hydrophobic interaction between lipoproteins and Arg-43 derivatives revealed that the LolA-lipoprotein interaction should be weak, otherwise lipoprotein transfer to LolB is inhibited, causing accumulation of lipoproteins in the periplasm. 相似文献
925.
Hashizume A Fudou R Jojima Y Nakai R Hiraishi A Tabuchi A Sen K Shibai H 《Bioscience, biotechnology, and biochemistry》2004,68(1):28-35
Dynamic change in microbial flora was monitored with an oxygen electrode. The 1st phase microorganisms, which first grew well in LB medium, were followed by the 2nd phase microorganisms, which supposedly assimilated microbial cells of the 1st phase and their metabolites. In a similar way, a change in microbial flora was observed from the 1st phase to the 4th phase in 84 hr. Based on this observation, prolonged enrichment culture was done for as long as two months to increase the ratio of existence of rare microorganisms. From these culture liquids, four slow-growing bacteria (provisionally named Shinshu-ah1, -ah2, -ah3, and -ah4), which formed scarcely visible small colonies, were isolated. Sequence analysis of their 16S rDNA showed that Shinshu-ah1 had 97% homology with Bradyrhizobium japonicum and uncultured alpha proteobacterium clone blaii 16, Shinshu-ah2 91% with Rasbo bacterium, Alpha proteobacterium 34619, Bradyrhizobium genosp. P, Afipia felis and an unidentified bacterium, Shinshu-ah3 99% with Methylobacterium mesophilicum, and Shinshu-ah4 95% with Agromyces ramosus DSM 43045. Phylogenetic study indicated that Shinshu-ah2 had a possibility to form a new family, Shinshu-ah1 a new genus, and Shinshu-ah4 a new species. 相似文献
926.
Hatakeyama S Matsumoto M Kamura T Murayama M Chui DH Planel E Takahashi R Nakayama KI Takashima A 《Journal of neurochemistry》2004,91(2):299-307
Neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated and ubiquitylated tau, are exhibited at regions where neuronal loss occurs in neurodegenerative diseases; however, the mechanisms of NFT formation remain unknown. Molecular studies of frontotemporal dementia with parkinsonism-17 demonstrated that increasing the ratio of tau with exon 10 insertion induced fibrillar tau accumulation. Here, we show that carboxyl terminus of Hsc70-interacting protein (CHIP), a U-box protein, recognizes the microtubule-binding repeat region of tau and preferentially ubiquitylates four-repeat tau compared with three-repeat tau. Overexpression of CHIP induced the prompt degradation of tau, reduced the formation of detergent-insoluble tau and inhibited proteasome inhibitor-induced cell death. NFT bearing neurons in progressive supranuclear palsy, in which four-repeat tau is a component, showed the accumulation of CHIP. Thus, CHIP is a ubiquitin ligase for four-repeat tau and maintains neuronal survival by regulating the quality control of tau in neurons. 相似文献
927.
Abe N Baba A Takii R Nakayama K Kamaguchi A Shibata Y Abiko Y Okamoto K Kadowaki T Yamamoto K 《Biological chemistry》2004,385(11):1041-1047
Arg- (Rgp) and Lys-gingipains (Kgp) are two individual cysteine proteinases produced by Porphyromonas gingivalis , an oral anaerobic bacterium, and are implicated as major virulence factors in a wide range of pathologies of adult periodontitis. Coaggregation of this bacterium with other oral bacteria is an initial and critical step in infectious processes, yet the factors and mechanisms responsible for this process remain elusive. Here we show that the initial translation products of the rgpA , kgp and hemagglutinin hagA genes are responsible for coaggregation of P. gingivalis and that the proteolytic activity of Rgp and Kgp is indispensable in this process. The rgpA rgpB kgp- and rgpA kgp hagA -deficient triple mutants exhibited no coaggregation activity with Actinomyces viscosus , whereas the kgp -null and rgpA rgpB -deficient double mutants significantly retained this activity. Consistently, the combined action of Rgp- and Kgp-specific inhibitors strongly inhibited the coaggregation activity of the bacterium, although single use of Rgp- or Kgp-specific inhibitor significantly retained this activity. We also demonstrate that the 47- and 43-kDa proteins produced from the translation products of the rgpA , kgp , and hagA genes by proteolytic activity of both Rgp and Kgp are responsible for the coaggregation of P. gingivalis. 相似文献
928.
929.
Murakami A Nakamura Y Ohto Y Yano M Koshiba T Koshimizu K Tokuda H Nishino H Ohigashi H 《BioFactors (Oxford, England)》2000,12(1-4):187-192
Citrus fruit intake is known to be associated with a reduction of cancer incidence. Free radicals, including superoxide (O2-) and nitric oxide (NO), are involved in some epithelial carcinogenesis processes. In the present study, we screened thirty-one citrus fruits for their suppressive activities toward three lines of free radical generating systems: 1) O2- generation by the xanthine (XA)-xanthine oxidase (XOD) system; 2) O2- generation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocytic HL-60 cells; and 3) NO generation in murine macrophage RAW264.7 cells stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma. As a result, the inhibitory activities of peel parts were largely found to be higher than those of the corresponding juice sac parts. In particular, the peel portion of Dancy tangerine (Citrus tangerinia) showed marked anti-oxidative activities in these systems. In addition, nobiletin, a polymethoxyflavonoid isolated from C. nobilis, showed a higher anti-inflammatory activity than indomethacin in a TPA-induced edema formation test in mouse ears. These results indicate that citrus fruits could be notable sources of anti-oxidative, anti-inflammatory, and cancer preventive compounds. 相似文献
930.
We identified a novel structure-specific endonuclease in Pyrococcus furiosus. This nuclease contains two distinct domains, which are similar to the DEAH helicase family at the N-terminal two-third and the XPF endonuclease superfamily at the C-terminal one-third of the protein, respectively. The C-terminal domain has an endonuclease activity cleaving the DNA strand at the 5'-side of nicked or flapped positions in the duplex DNA. The nuclease also incises in the proximity of the 5'-side of a branch point in the template strand for leading synthesis in the fork-structured DNA. The N-terminal helicase may work cooperatively to change the fork structure suitable for cleavage by the C-terminal endonuclease. This protein, designated as Hef (helicase-associated endonuclease for fork-structured DNA), may be a prototypical enzyme for resolving stalled forks during DNA replication, as well as working at nucleotide excision repair. 相似文献