全文获取类型
收费全文 | 1619篇 |
免费 | 152篇 |
出版年
2024年 | 3篇 |
2023年 | 15篇 |
2022年 | 33篇 |
2021年 | 57篇 |
2020年 | 26篇 |
2019年 | 36篇 |
2018年 | 45篇 |
2017年 | 43篇 |
2016年 | 66篇 |
2015年 | 99篇 |
2014年 | 129篇 |
2013年 | 130篇 |
2012年 | 139篇 |
2011年 | 125篇 |
2010年 | 93篇 |
2009年 | 75篇 |
2008年 | 96篇 |
2007年 | 85篇 |
2006年 | 93篇 |
2005年 | 68篇 |
2004年 | 59篇 |
2003年 | 60篇 |
2002年 | 47篇 |
2001年 | 7篇 |
2000年 | 12篇 |
1999年 | 13篇 |
1998年 | 7篇 |
1997年 | 7篇 |
1996年 | 8篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 8篇 |
1991年 | 2篇 |
1990年 | 3篇 |
1989年 | 13篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1981年 | 2篇 |
1980年 | 6篇 |
1979年 | 6篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1976年 | 4篇 |
1975年 | 2篇 |
1973年 | 3篇 |
排序方式: 共有1771条查询结果,搜索用时 46 毫秒
261.
Functional studies of membrane-bound and purified human Hedgehog receptor Patched expressed in yeast
Olivier Joubert Damien Fleury Michel Bidet Martial Ruat Patrick Mollat Isabelle Mus-Veteau 《生物化学与生物物理学报:生物膜》2009,1788(9):1813-261
The Sonic Hedgehog (Shh) signalling pathway plays an important role both in embryonic development and in adult stem cell function. Inappropriate regulation of this pathway is often due to dysfunction between two membrane receptors Patched (Ptc) and Smoothened (Smo), which lead to birth defects, cancer or neurodegenerative diseases. However, little is known about Ptc, the receptor of the Shh protein, and the way Ptc regulates Smo, the receptor responsible for the transduction of the signal. To develop structure-function studies of these receptors, we expressed human Ptc (hPtc) in the yeast Saccharomyces cerevisiae. We demonstrated that hPtc expressed in a yeast membrane fraction is able to interact with its purified ligand Shh, indicating that hPtc is produced in yeast in its native conformational state. Using Surface Plasmon Resonance technology, we showed that fluorinated surfactants preserve the ability of hPtc to interact with its ligand after purification. This is the first report on the heterologous expression and the purification of a native and stable conformation of the human receptor Ptc. This work will allow the scale-up of hPtc production enabling its biochemical characterization, allowing the development of new therapeutic approaches against diseases induced by Shh signalling dysfunction. 相似文献
262.
Spitsbergen JM Blazer VS Bowser PR Cheng KC Cooper KR Cooper TK Frasca S Groman DB Harper CM Law JM Marty GD Smolowitz RM St Leger J Wolf DC Wolf JC 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2009,149(2):249-257
Utilization of finfish and aquatic invertebrates in biomedical research and as environmental sentinels has grown dramatically in recent decades. Likewise the aquaculture of finfish and invertebrates has expanded rapidly worldwide as populations of some aquatic food species and threatened or endangered aquatic species have plummeted due to overharvesting or habitat degradation. This increasing intensive culture and use of aquatic species has heightened the importance of maintaining a sophisticated understanding of pathology of various organ systems of these diverse species. Yet, except for selected species long cultivated in aquaculture, pathology databases and the workforce of highly trained pathologists lag behind those available for most laboratory animals and domestic mammalian and avian species. Several factors must change to maximize the use, understanding, and protection of important aquatic species: 1) improvements in databases of abnormalities across species; 2) standardization of diagnostic criteria for proliferative and nonproliferative lesions; and 3) more uniform and rigorous training in aquatic morphologic pathology. 相似文献
263.
Raingeard D Bilbao E Sáez-Morquecho C de Cerio OD Orbea A Cancio I Cajaraville MP 《Marine Genomics》2009,2(3-4):201-213
264.
265.
Emilie Sapin Damien Lapray Anne Bérod Romain Goutagny Lucienne Léger Pascal Ravassard Olivier Clément Lucie Hanriot Patrice Fort Pierre-Hervé Luppi 《PloS one》2009,4(1)
Paradoxical sleep (PS) is a state characterized by cortical activation, rapid eye movements and muscle atonia. Fifty years after its discovery, the neuronal network responsible for the genesis of PS has been only partially identified. We recently proposed that GABAergic neurons would have a pivotal role in that network. To localize these GABAergic neurons, we combined immunohistochemical detection of Fos with non-radioactive in situ hybridization of GAD67 mRNA (GABA synthesis enzyme) in control rats, rats deprived of PS for 72 h and rats allowed to recover after such deprivation. Here we show that GABAergic neurons gating PS (PS-off neurons) are principally located in the ventrolateral periaqueductal gray (vlPAG) and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe). Furthermore, iontophoretic application of muscimol for 20 min in this area in head-restrained rats induced a strong and significant increase in PS quantities compared to saline. In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS. Finally, we showed that PS-on neurons triggering PS localized in the SLD are not GABAergic. Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist. From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles. 相似文献
266.
Damien Guillaumot Stéphanie Guillon Pierre Morsomme Henri Batoko 《Plant signaling & behavior》2009,4(11):1087-1090
We have shown that, unexpectedly, AtTSPO (Arabidopsis thaliana TSPO-related protein) is an endoplasmic reticulum and Golgi-localized membrane protein in plant cells.1 This localization contrasts with that of mammalian 18-kDa translocator protein (at least for the mostly studied isoform, 18-kDa TSPO), a mitochondrial outer membrane protein (reviewed in ref. 2). Whereas the potential functions of 18-kDa TSPO are well documented, involved mainly in mitochondrial physiology,2 and its interest as a drug target is being explored,3 the roles of TSPO-related proteins in plant growth and development are yet to be specified. AtTSPO is expressed in dry seeds and can be induced in vegetative tissues by osmotic and salt stress or abscisic acid (ABA) treatment. Moreover, it was shown that the ABA-dependent induction is transient, and that boosting tetrapyrroles biosynthesis through 5-aminolevulinic acid (ALA) feeding enhanced downregulation of AtTSPO, suggesting an inherent post-translational regulation mechanism also involving ABA and likely porphyrins. We present additional evidence that ABA can help stabilize constitutively expressed AtTSPO and that ALA feeding to knockout mutant seeds, induces substantial germination delay. Here we discuss the possible link between ABA and tetrapyrroles in AtTSPO expression and posttranslational regulation.Key words: plant TSPO, subcellular localization, regulation, abscisic acid, porphyrins 相似文献
267.
268.
269.
Crane L Anastassiadou M El Hage S Stigliani JL Baziard-Mouysset G Payard M Leger JM Bizot-Espiard JG Ktorza A Caignard DH Renard P 《Bioorganic & medicinal chemistry》2006,14(22):7419-7433
Imidazoline derivatives have been reported to show antihyperglycemic activity in vivo. In the present study, we first showed that there was no correlation between the in vivo antidiabetic activity and the in vitro affinities for the I1/I2 binding sites for several substituted aryl imidazolines. Among these compounds, 2-(alpha-cyclohexyl-benzyl)-4,5-dihydro-1H-imidazole 2 exhibited potent antihyperglycemic properties. It was then chosen as lead compound. Thirty-six new derivatives were synthesized by replacing the cyclohexyl/benzyl group by various cyclic systems or the imidazoline ring by isosteric heterocycles. These compounds were evaluated in vivo for their antihyperglycemic activity using an oral glucose tolerance test (OGTT) in a rat model of type-2 diabetes obtained by giving a single intravenous (iv) injection of a low dose of streptozotocin to rats (STZ rats) and in normal rats. Nine compounds with an imidazoline moiety, possibly substituted by a methyl group, had a potent effect on the glucose tolerance in normal or STZ-diabetic rats, after an oral (po) administration of the test compound at a dose of 30 or 10 mg kg(-1), without any hypoglycemia. Replacement of the imidazoline ring by isosteric heterocycles resulted in a total loss of activity. 相似文献
270.
Cossy J Belotti D Brisson M Skoko JJ Wipf P Lazo JS 《Bioorganic & medicinal chemistry》2006,14(18):6283-6287
Cdc25B protein phosphatase represents an attractive potential therapeutic target for small molecule intervention because of its central role in positively regulating cyclin dependent kinases and thus cell proliferation, as well as its elevated levels observed in many human tumors. Among the most potent previously identified Cdc25 inhibitors have been quinoline quinones, which have a rich legacy as therapeutic agents but have also been associated with nonspecific interactions. In this study, we have interrogated the structure-activity relationship of a focused series of C2-, C3-, or C4-modified quinoline-5,8-quinones on Cdc25B inhibition in vitro. Substitution at the C3-position in this small chemical series were slightly superior to substitutions at the C3-position. For all compounds, recombinant human Cdc25B was approximately 5-fold more sensitive compared to recombinant human PTP1B. Two compounds inhibited HeLa cell growth with IC50 values of approximately 2 microM. Consistent with other para-quinones, some members of this series generated intracellular reactive oxygen species and the in vitro enzyme inhibition was mitigated by addition of reductants or catalase. These results indicate that chemical modifications on the pyridine core are tolerated, providing additional sites for future structural modification of this biologically active pharmacophore. 相似文献