全文获取类型
收费全文 | 8264篇 |
免费 | 438篇 |
国内免费 | 5篇 |
出版年
2022年 | 44篇 |
2021年 | 80篇 |
2020年 | 61篇 |
2019年 | 64篇 |
2018年 | 96篇 |
2017年 | 77篇 |
2016年 | 180篇 |
2015年 | 251篇 |
2014年 | 273篇 |
2013年 | 583篇 |
2012年 | 510篇 |
2011年 | 548篇 |
2010年 | 335篇 |
2009年 | 316篇 |
2008年 | 520篇 |
2007年 | 567篇 |
2006年 | 528篇 |
2005年 | 485篇 |
2004年 | 565篇 |
2003年 | 444篇 |
2002年 | 447篇 |
2001年 | 122篇 |
2000年 | 108篇 |
1999年 | 118篇 |
1998年 | 112篇 |
1997年 | 87篇 |
1996年 | 83篇 |
1995年 | 78篇 |
1994年 | 70篇 |
1993年 | 61篇 |
1992年 | 76篇 |
1991年 | 68篇 |
1990年 | 66篇 |
1989年 | 60篇 |
1988年 | 71篇 |
1987年 | 54篇 |
1986年 | 44篇 |
1985年 | 39篇 |
1984年 | 44篇 |
1983年 | 25篇 |
1982年 | 30篇 |
1981年 | 32篇 |
1980年 | 32篇 |
1979年 | 20篇 |
1978年 | 20篇 |
1977年 | 29篇 |
1976年 | 23篇 |
1975年 | 18篇 |
1974年 | 22篇 |
1973年 | 20篇 |
排序方式: 共有8707条查询结果,搜索用时 15 毫秒
941.
A sorting nexin PpAtg24 regulates vacuolar membrane dynamics during pexophagy via binding to phosphatidylinositol-3-phosphate
下载免费PDF全文
![点击此处可从《Molecular biology of the cell》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Ano Y Hattori T Oku M Mukaiyama H Baba M Ohsumi Y Kato N Sakai Y 《Molecular biology of the cell》2005,16(2):446-457
Diverse cellular processes such as autophagic protein degradation require phosphoinositide signaling in eukaryotic cells. In the methylotrophic yeast Pichia pastoris, peroxisomes can be selectively degraded via two types of pexophagic pathways, macropexophagy and micropexophagy. Both involve membrane fusion events at the vacuolar surface that are characterized by internalization of the boundary domain of the fusion complex, indicating that fusion occurs at the vertex. Here, we show that PpAtg24, a molecule with a phosphatidylinositol 3-phosphate-binding module (PX domain) that is indispensable for pexophagy, functions in membrane fusion at the vacuolar surface. CFP-tagged PpAtg24 localized to the vertex and boundary region of the pexophagosome-vacuole fusion complex during macropexophagy. Depletion of PpAtg24 resulted in the blockage of macropexophagy after pexophagosome formation and before the fusion stage. These and other results suggest that PpAtg24 is involved in the spatiotemporal regulation of membrane fusion at the vacuolar surface during pexophagy via binding to phosphatidylinositol 3-phosphate, rather than the previously suggested function in formation of the pexophagosome. 相似文献
942.
943.
Fujita Y Kasuya A Matsushita Y Suga M Kizuka M Iijima Y Ogita T 《Bioorganic & medicinal chemistry letters》2005,15(19):4317-4321
A-74528 (1) is a metabolite of Streptomyces sp. discovered in the screening for 2',5'-oligoadenylate phosphodiesterase inhibitors. The planar structure of 1 was mainly elucidated by NMR techniques including natural abundance INADEQUATE, and the relative configuration and the conformation were elucidated by the analyses of NOEs and assessment of dihedral angles predicted by QUANTA/CHARMm computations and coupling constants. It was proved that 1 is a highly fused polyketide with a side-chain branching site that never appeared before from the nature. 相似文献
944.
Ochi T Sakamoto M Minamida A Suzuki K Ueda T Une T Toda H Matsumoto K Terauchi Y 《Bioorganic & medicinal chemistry letters》2005,15(4):1055-1059
Two major metabolites in humans of blonanserin, 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta-[b]pyridine (code name AD-5423), were synthesized. The first, 7-hydroxylated AD-5423, was synthesized through a four-step process starting from 4-fluorobenzoylacetonitrile (1), and the second, 8-hydroxylated AD-5423, a nine-step process also from 1. The optical resolution, structures, and receptor binding properties of the metabolites were documented. 相似文献
945.
Hashimoto K Tatsuta M Kataoka M Yasoshima K Shogase Y Shimazaki M Yura T Li Y Yamamoto N Gupta JB Urbahns K 《Bioorganic & medicinal chemistry letters》2005,15(3):799-803
A new class of benzimidazole-5-sulfonamides has been identified as nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Initial structure-activity relationships are presented resulting in compounds 19 and 28 with submicromolar dual functional activity on human and rat receptors. 相似文献
946.
Dougherty GW Adler HJ Rzadzinska A Gimona M Tomita Y Lattig MC Merritt RC Kachar B 《Cell motility and the cytoskeleton》2005,62(3):141-156
Microtubules (MTs) are polymers of alpha and beta tubulin dimers that mediate many cellular functions, including the establishment and maintenance of cell shape. The dynamic properties of MTs may be influenced by tubulin isotype, posttranslational modifications of tubulin, and interaction with microtubule-associated proteins (MAPs). End-binding (EB) family proteins affect MT dynamics by stabilizing MTs, and are the only MAPs reported that bind MTs via a calponin-homology (CH) domain (J Biol Chem 278 (2003) 49721-49731; J Cell Biol 149 (2000) 761-766). Here, we describe a novel 27 kDa protein identified from an inner ear organ of Corti library. Structural homology modeling demonstrates a CH domain in this protein similar to EB proteins. Northern and Western blottings confirmed expression of this gene in other tissues, including brain, lung, and testis. In the organ of Corti, this protein localized throughout distinctively large and well-ordered MT bundles that support the elongated body of mechanically stiff pillar cells of the auditory sensory epithelium. When ectopically expressed in Cos-7 cells, this protein localized along cytoplasmic MTs, promoted MT bundling, and efficiently stabilized MTs against depolymerization in response to high concentration of nocodazole and cold temperature. We propose that this protein, designated CLAMP, is a novel MAP and represents a new member of the CH domain protein family. 相似文献
947.
Usui I Imamura T Babendure JL Satoh H Lu JC Hupfeld CJ Olefsky JM 《Molecular endocrinology (Baltimore, Md.)》2005,19(11):2760-2768
G protein-coupled receptor kinases (GRKs) regulate seven-transmembrane receptors (7TMRs) by phosphorylating agonist-activated 7TMRs. Recently, we have reported that GRK2 can function as a negative regulator of insulin action by interfering with G protein-q/11 alpha-subunit (Galphaq/11) signaling, causing decreased glucose transporter 4 (GLUT4) translocation. We have also reported that chronic endothelin-1 (ET-1) treatment leads to heterologous desensitization of insulin signaling with decreased tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and Galphaq/11, and decreased insulin-stimulated glucose transport in 3T3-L1 adipocytes. In the current study, we have investigated the role of GRK2 in chronic ET-1-induced insulin resistance. Insulin-induced GLUT4 translocation was inhibited by pretreatment with ET-1 for 24 h, and we found that this inhibitory effect was rescued by microinjection of anti-GRK2 antibody or GRK2 short interfering RNA. We further found that GRK2 mediates the inhibitory effects of ET-1 by two distinct mechanisms. Firstly, adenovirus-mediated overexpression of either wild-type (WT)- or kinase-deficient (KD)-GRK2 inhibited Galphaq/11 signaling, including tyrosine phosphorylation of Galphaq/11 and cdc42-associated phosphatidylinositol 3-kinase activity. Secondly, ET-1 treatment caused Ser/Thr phosphorylation of IRS-1 and IRS-1 protein degradation. Overexpression of KD-GRK2, but not WT-GRK2, inhibited ET-1-induced serine 612 phosphorylation of IRS-1 and restored activation of this pathway. Taken together, these results suggest that GRK2 mediates ET-1-induced insulin resistance by 1) inhibition of Galphaq/11 activation, and this effect is independent of GRK2 kinase activity, and 2) GRK2 kinase activity-mediated IRS-1 serine phosphorylation and degradation. 相似文献
948.
OCA4: evidence for a founder effect for the p.D157N mutation of the MATP gene in Japanese and Korean
Inagaki K Suzuki T Ito S Suzuki N Fukai K Horiuchi T Tanaka T Manabe E Tomita Y 《Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society》2005,18(5):385-388
Oculocutaneous albinism type 4 (OCA4) was identified as a rare form of human OCA among a group of autosomal recessive hypopigmentary disorders. Little is known about the prevailing distribution of patients of OCA4 with mutations of the MATP gene, although one Turkish, five German, one Korean, and 18 Japanese patients have been reported so far. The p.D157N mutation was previously reported to be the most frequent (0.389; 14/36) in Japanese patients and was also found in a Korean patient. On the other hand, this mutation has not been found in Turkish and German patients. We therefore investigated haplotypes of the patients who have the p.D157N mutation. The results showed that OCA4 is prevalent in East Asia including Japan and Korea likely as a result of a founder effect for the p.D157N mutation. Furthermore, it is suspected that the p.D157N mutation might have occurred on an ancestral chromosome after the divergence of Orientals and Caucasians. 相似文献
949.
Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice 总被引:10,自引:0,他引:10
Sakurai T Nagata R Yamanaka A Kawamura H Tsujino N Muraki Y Kageyama H Kunita S Takahashi S Goto K Koyama Y Shioda S Yanagisawa M 《Neuron》2005,46(2):297-308
The finding of orexin/hypocretin deficiency in narcolepsy patients suggests that this hypothalamic neuropeptide plays a crucial role in regulating sleep/wakefulness states. However, very little is known about the synaptic input of orexin/hypocretin-producing neurons (orexin neurons). We applied a transgenic method to map upstream neuronal populations that have synaptic connections to orexin neurons and revealed that orexin neurons receive input from several brain areas. These include the amygdala, basal forebrain cholinergic neurons, GABAergic neurons in the preoptic area, and serotonergic neurons in the median/paramedian raphe nuclei. Monoamine-containing groups that are innervated by orexin neurons do not receive reciprocal connections, while cholinergic neurons in the basal forebrain have reciprocal connections, which might be important for consolidating wakefulness. Electrophysiological study showed that carbachol excites almost one-third of orexin neurons and inhibits a small population of orexin neurons. These neuroanatomical findings provide important insights into the neural pathways that regulate sleep/wakefulness states. 相似文献
950.