全文获取类型
收费全文 | 2371篇 |
免费 | 160篇 |
国内免费 | 2篇 |
出版年
2023年 | 11篇 |
2022年 | 10篇 |
2021年 | 48篇 |
2020年 | 26篇 |
2019年 | 43篇 |
2018年 | 47篇 |
2017年 | 41篇 |
2016年 | 72篇 |
2015年 | 100篇 |
2014年 | 111篇 |
2013年 | 146篇 |
2012年 | 181篇 |
2011年 | 170篇 |
2010年 | 102篇 |
2009年 | 105篇 |
2008年 | 145篇 |
2007年 | 132篇 |
2006年 | 127篇 |
2005年 | 113篇 |
2004年 | 128篇 |
2003年 | 110篇 |
2002年 | 105篇 |
2001年 | 29篇 |
2000年 | 21篇 |
1999年 | 27篇 |
1998年 | 14篇 |
1997年 | 20篇 |
1996年 | 16篇 |
1995年 | 8篇 |
1994年 | 17篇 |
1993年 | 14篇 |
1992年 | 24篇 |
1991年 | 8篇 |
1990年 | 25篇 |
1989年 | 14篇 |
1988年 | 16篇 |
1987年 | 15篇 |
1986年 | 17篇 |
1984年 | 14篇 |
1983年 | 11篇 |
1982年 | 10篇 |
1981年 | 10篇 |
1980年 | 10篇 |
1979年 | 12篇 |
1978年 | 14篇 |
1977年 | 10篇 |
1975年 | 10篇 |
1974年 | 7篇 |
1972年 | 8篇 |
1971年 | 7篇 |
排序方式: 共有2533条查询结果,搜索用时 328 毫秒
951.
M Santoro R M Melillo F Carlomagno R Visconti G De Vita G Salvatore A Fusco G Vecchio 《Biochimie》1999,81(4):397-402
The RET gene encodes a tyrosine kinase receptor for neurotrophic molecules. RET is a conceptually valuable example of how different mutations of a single gene may cause different diseases. Gene rearrangements activate the oncogenic potential of RET in human thyroid papillary carcinomas. On the other side, different point mutations activate RET in familial multiple endocrine neoplasia syndromes. Finally, inactivating mutations of RET can be present in Hirschsprung's disease patients. The detailed knowledge of the specific RET mutations responsible for human tumors provides relevant tools for the clinical management of these diseases. Moreover, the recent discovery of the growth factors which in vivo stimulate its signaling may shed new light on the role played by RET in the development and differentiation of the central and peripheral nervous system. 相似文献
952.
Salvatore Santamaria Daniel R. Martin Xiangyi Dong Kazuhiro Yamamoto Suneel S. Apte Josefin Ahnstrm 《The Journal of biological chemistry》2021,297(5)
A disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs (ADAMTS)8 is a secreted protease, which was recently implicated in pathogenesis of pulmonary arterial hypertension (PAH). However, the substrate repertoire of ADAMTS8 and regulation of its activity are incompletely understood. Although considered a proteoglycanase because of high sequence similarity and close phylogenetic relationship to the proteoglycan-degrading proteases ADAMTS1, 4, 5, and 15, as well as tight genetic linkage with ADAMTS15 on human chromosome 11, its aggrecanase activity was reportedly weak. Several post-translational factors are known to regulate ADAMTS proteases such as autolysis, inhibition by endogenous inhibitors, and receptor-mediated endocytosis, but their impacts on ADAMTS8 are unknown. Here, we show that ADAMTS8 undergoes autolysis at six different sites within its spacer domain. We also found that in contrast to ADAMTS4 and 5, ADAMTS8 levels were not regulated through low-density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytosis. Additionally, ADAMTS8 lacked significant activity against the proteoglycans aggrecan, versican, and biglycan. Instead, we found that ADAMTS8 cleaved osteopontin, a phosphoprotein whose expression is upregulated in PAH. Multiple ADAMTS8 cleavage sites were identified using liquid chromatography–tandem mass spectrometry. Osteopontin cleavage by ADAMTS8 was efficiently inhibited by TIMP-3, an endogenous inhibitor of ADAMTS1, 4, and 5, as well as by TIMP-2, which has no previously reported inhibitory activity against other ADAMTS proteases. These differences in post-translational regulation and substrate repertoire differentiate ADAMTS8 from other family members and may help to elucidate its role in PAH. 相似文献
953.
Binding of receptor-recognized forms of tetrameric human α2-macroglobulin (α2M*) to a macrophage signaling receptor induces cAMP synthesis, increases in inositol 1,4,5-triphosphate (IP3) synthesis, and a concomitant rise in cytosolic free calcium ([Ca2+]i). The α2M* signaling receptor is coupled to a pertussis-toxin insensitive G protein. Binding of α2M* also occurs to the low density lipoprotein receptor-related protein/α2M receptor (LRP/α2MR), but this binding does not induce signal transduction. Rat α1-inhibitor-3 (α1I3) is a monomeric member of the α-macroglobulin/complement superfamily. Like α2M, it can react with proteinases or methylamine which induces a conformational change causing activated α1I3 to bind to LRP/α2MR. We now report that α1I3-methylamine binds to the macrophage α2M* signaling receptor inducing a rapid rise in the synthesis of IP3 with a subsequent 1.5- to 3-fold rise in [Ca2+]i. α1I3-methylamine binding to macrophages also caused a statistically significant elevation in cAMP. Native α1I3, like α2M, was unable to induce signal transduction. α1I3 forms a complex with α1-microglobulin, which has a distinct conformation from α1I3 and is recognized by LRP/α2MR. This complex also induces an increase in [Ca2+]i comparable to the effect of α1I3-methylamine on macrophages. It is concluded that activation of α1I3 by methylamine or binding of α1-microglobulin causes similar conformational changes in the inhibitor, exposing the receptor recognition site for the α2M* signaling receptor, as well as for LRP/α2MR. © 1996 Wiley-Liss, Inc. 相似文献
954.
The direct HPLC enantiomeric separation of five fluorenone-1,4-dihydropyridine-3,5-dicarboxylic diesters has been achieved using a Chiralpak AD stationary phase obtaining simultaneously good enantioselectivities, resolution factors, and elution times. CD spectra of the individual enantiomers for two compounds were measured. Thermodynamic parameters associated with the adsorption equilibria of the enantiomers with the chiral stationary phase were obtained from HPLC runs at various temperatures. The conformational preferences of the synperiplanar fluorenone group and of the cis/cis ester groups were obtained by 1H NMR spectra, including NOE experiments. © 1996 Wiley-Liss, Inc. 相似文献
955.
Giulio Poli Miriana Di Stefano Joan Arias Estevez Filippo Minutolo Carlotta Granchi Antonio Giordano Salvatore Parisi Matteo Mauceri Vincenzo Canzonieri Marco Macchia Isabella Caligiuri Tiziano Tuccinardi Flavio Rizzolio 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):145
PIN1 is considered as a therapeutic target for a wide variety of tumours. However, most of known inhibitors are devoid of cellular activity despite their good enzyme inhibitory profile. Hence, the lack of effective compounds for the clinic makes the identification of novel PIN1 inhibitors a hot topic in the medicinal chemistry field. In this work, we reported a virtual screening study for the identification of new promising PIN1 inhibitors. A receptor-based procedure was applied to screen different chemical databases of commercial compounds. Based on the whole workflow, two compounds were selected and biologically evaluated. Both ligands, compounds VS1 and VS2, showed a good enzyme inhibitory activity and VS2 also demonstrated a promising antitumoral activity in ovarian cancer cells. These results confirmed the reliability of our in silico protocol and provided a structurally novel ligand as a valuable starting point for the development of new PIN1 inhibitors. 相似文献
956.
Andrea Sosa Mariana Diaz Analía Salvatore Alicia Bardon Susana Borkosky Nancy Vera 《Saudi Journal of Biological Sciences》2019,26(5):881-889
Vernonanthura nebularum (Cabrera) H. Rob. (Asteraceae), an endemic species from the north of Argentina, is a rich source of elephantopus-type sesquiterpene lactones. These compounds have proved to be promising antiparasitic agents, but there is no report about their action against pest insects. In this work we studied for the first time the antifeedant and toxic effects of V. nebularum natural products against the fall army warm Spodoptera frugiperda Smith and the oviposition deterrent activity against the fruit fly Ceratitis capitata Wiedemann. As a result, we found that extracts, fractions composed of sesquiterpene lactones and pure sesquiterpene lactones altered larval feeding behavior in the food choice test. Nutritional parameters of S. frugiperda larvae were also affected. Fraction II (300 μg/g of diet.), containing compounds 1, 2 and 3, was the most toxic substance with 80% pupal mortality and wing malformations in adults. In oviposition deterrent experiments against Ceratitis capitata, we observed a moderate effect at 30 μg/cm2 of the test compound. The most active substances were the methanolic extract, dichloromethane subextract and lactone 2. According to our results, V. nebularum natural products could be used for maximizing the effectiveness and specificity in future insecticide design with specific or multiple target sites, while ensuring the economic and ecological sustainability, in addition to combat the increasing resistance rates developed by synthetic pesticides. 相似文献
957.
Moricca Claudia Nigro Lorenzo Masci Lucrezia Pasta Salvatore Cappella Federico Spagnoli Federica Sadori Laura 《Vegetation History and Archaeobotany》2021,30(6):815-829
Vegetation History and Archaeobotany - The present study concerns the Phoenician-Punic site of Motya, a small island set in Western Sicily (Italy), in the Marsala Lagoon (Stagnone di Marsala),... 相似文献
958.
Salvatore Santisi 《Plant biosystems》2013,147(5-6):283-300
Abstract Some ultrastructural features of cells of the marine haptophycean alga, Ochrosphaera neapolitana Schussnig in the palmelloid stage were examined. Chloroplasts which are contained in a compartment isolated from the cytoplasm by ER profiles and nuclear envelope, display trilamellated thylakoids running along the major axis. The stalked pyrenoid with inner bilamellated thylakoids, protrudes in a large membrane-bounded vacuole. Other structures, as the haptonematic and flagellar bases, autophagic vacuoles and mitochondria, are typical of the chrysophycean and haptophycean genera so far investigated. The Golgi apparatus is represented by a single dictyosome composed of stacked cisternae fonctioning in a way that they form organic scales which constitute the main part of the cell covering. The scales, build up of microfibrils disposed parallel each to other, lie in cisternal lumina of the dictyosomal maturing face; scaly cisternae are numerous in the peripheral cytoplasm and are observed merging in the plasma membrane and discharging the content outside the protoplast. Dictyosomal activity is evidenced morphologically by massive vesicle production. Three kinds of membrane-bounded vesicles were identified in the present material: i) inner-granulated vesicles, arising from the maturation face; ii) coated vesicles, scattered in the cytoplasm or at the periphery of the golgi body, and iii) dense-cored vesicles, present in the proximity of the maturation face. The possible functional relationships related to scale production and assembly outside the protoplast, and between the nucleus and dictyosome are discussed. 相似文献
959.
960.
Maurizio Bifulco Chiara Laezza Salvatore M. Aloj Corrado Garbi 《Journal of cellular physiology》1993,155(2):340-348
Blockade of mevalonate synthesis by the 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor mevinolin (lovastatin) causes FRTL-5 thyroid cells to undergo significant morphological changes; these include a transition from a flat, polygonal to a round shape, the development of cytoplasmic arborizations, and the loss of contact between neighboring cells. Immunofluorescence studies of cytoskeletal structures show that, at early times after administering the drug, and before the round phenotype develops, stress fibers disassemble while the peripheral actin filaments, which are adjacent to the cytoplasmic face of the plasma membrane, appear largely unaffected. Subsequently, when this cortical actin network becomes fragmented, cells start to round up and become separated from neighbors. Microtubules become disconnected from the plasma membrane and retract toward the cell center, although they do not appear depolymerized; indeed, at this stage, cytoplasmic elongations contain mostly intact microtubules. After exposure to mevinolin FRTL-5 cells also lose vinculin-related substrate contacts. Treatment of cells with either cycloheximide or colchicine abolishes morphological changes induced by mevinolin, suggesting that ongoing protein synthesis and microtubule integrity are prerequisites for the drug to be effective. Both cytoskeletal and morphological perturbations can be reversed by mevalonate, but not by cholesterol or the non-sterol derivatives of mevalonate such as dolichol, ubiquinone, and isopentenyladenine, individually or in combination. It is suggested that mevalonate deficiency may impair formation of isoprenylated proteins important for cytoskeletal organization and stability. © 1993 Wiley-Liss, Inc. 相似文献