全文获取类型
收费全文 | 1529篇 |
免费 | 111篇 |
出版年
2023年 | 3篇 |
2022年 | 19篇 |
2021年 | 34篇 |
2020年 | 24篇 |
2019年 | 26篇 |
2018年 | 40篇 |
2017年 | 33篇 |
2016年 | 47篇 |
2015年 | 81篇 |
2014年 | 87篇 |
2013年 | 131篇 |
2012年 | 130篇 |
2011年 | 115篇 |
2010年 | 92篇 |
2009年 | 70篇 |
2008年 | 121篇 |
2007年 | 86篇 |
2006年 | 90篇 |
2005年 | 84篇 |
2004年 | 59篇 |
2003年 | 67篇 |
2002年 | 52篇 |
2001年 | 9篇 |
2000年 | 7篇 |
1999年 | 12篇 |
1998年 | 12篇 |
1997年 | 11篇 |
1996年 | 9篇 |
1995年 | 9篇 |
1994年 | 3篇 |
1993年 | 6篇 |
1992年 | 7篇 |
1991年 | 8篇 |
1990年 | 5篇 |
1989年 | 3篇 |
1988年 | 8篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 6篇 |
1984年 | 7篇 |
1983年 | 4篇 |
1982年 | 2篇 |
1981年 | 6篇 |
1980年 | 2篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1970年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有1640条查询结果,搜索用时 468 毫秒
941.
Francesco Liguori Simone Carradori Roberto Ronca Sara Rezzola Serena Filiberti Fabrizio Carta Marta Turati Claudiu T. Supuran 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):1857
Among the chemotypes studied for selective inhibition of tumour-associated carbonic anhydrases (CAs), SLC-0111, a ureido-bearing benzenesulfonamide CA IX inhibitor, displayed promising antiproliferative effects in cancer cells in vitro and in vivo, being in Phase Ib/II clinical development. To explore the structural characteristics required for better discrimination of less conserved regions of the enzyme, we investigate the incorporation of the urea linker into an imidazolidin-2-one cycle, a modification already explored previously for obtaining CA inhibitors. This new library of compounds inhibited potently four different hCAs in the nanomolar range with a different isoform selectivity profile compared to the lead SLC-0111. Several representative CA IX inhibitors were tested for their efficacy to inhibit the proliferation of glioblastoma, pancreatic, and breast cancer cells expressing CA IX, in hypoxic conditions. Unlike previous literature data on SLC-149, a structurally related sulphonamide to compounds investigated here, our data reveal that these derivatives possess promising anti-proliferative effects, comparable to those of SLC-0111. 相似文献
942.
Andrea Angeli Marta Ferraroni Fabrizio Carta Ccile Hberli Jennifer Keiser Gabriele Costantino Claudiu T. Supuran 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):1479
The almost empty armamentarium to treat schistosomiasis, a neglected parasitic disorder caused by trematode flatworms of the genus Schistosoma, except Praziquantel (PZQ), urged to find new alternatives to fight this infection. Carbonic Anhydrase from Schistosoma mansoni (SmCA) is a possible new target against this nematode. Here, we propose new PZQ derivatives bearing a primary sulphonamide group in order to obtain hybrid drugs. All compounds were evaluated for their inhibition profiles on both humans and Schistosoma CAs, X-ray crystal data of SmCA and hCA II in adduct with some inhibitors were obtained allowing the understanding of the main structural factors responsible of activity. The compounds showed in vitro inhibition of immature and adult S. mansoni, but further optimisation is required for improved activity. 相似文献
943.
Sir2 blocks extreme life-span extension 总被引:18,自引:0,他引:18
Sir2 is a conserved deacetylase that modulates life span in yeast, worms, and flies and stress response in mammals. In yeast, Sir2 is required for maintaining replicative life span, and increasing Sir2 dosage can delay replicative aging. We address the role of Sir2 in regulating chronological life span in yeast. Lack of Sir2 along with calorie restriction and/or mutations in the yeast AKT homolog, Sch9, or Ras pathways causes a dramatic chronological life-span extension. Inactivation of Sir2 causes uptake and catabolism of ethanol and upregulation of many stress-resistance and sporulation genes. These changes while sufficient to extend chronological life span in wild-type yeast require severe calorie restriction or additional mutations to extend life span of sir2Delta mutants. Our results demonstrate that effects of SIR2 on chronological life span are opposite to replicatve life span and suggest that the relevant activities of Sir2-like deacetylases may also be complex in higher eukaryotes. 相似文献
944.
Tania Fiaschi Elisa Giannoni Maria Letizia Taddei Paolo Cirri Alberto Marini Gianfranco Pintus Cristina Nativi Barbara Richichi Andrea Scozzafava Fabrizio Carta Eugenio Torre Claudiu T. Supuran Paola Chiarugi 《Cell cycle (Georgetown, Tex.)》2013,12(11):1791-1801
Extracellular acidification, a mandatory feature of several malignancies, has been mainly correlated with metabolic reprogramming of tumor cells toward Warburg metabolism, as well as to the expression of carbonic anydrases or proton pumps by malignant tumor cells. We report herein that for aggressive prostate carcinoma, acknowledged to be reprogrammed toward an anabolic phenotype and to upload lactate to drive proliferation, extracellular acidification is mainly mediated by stromal cells engaged in a molecular cross-talk circuitry with cancer cells. Indeed, cancer-associated fibroblasts, upon their activation by cancer delivered soluble factors, rapidly express carbonic anhydrase IX (CA IX). While expression of CAIX in cancer cells has already been correlated with poor prognosis in various human tumors, the novelty of our findings is the upregulation of CAIX in stromal cells upon activation. The de novo expression of CA IX, which is not addicted to hypoxic conditions, is driven by redox-based stabilization of hypoxia-inducible factor-1. Extracellular acidification due to carbonic anhydrase IX is mandatory to elicit activation of stromal fibroblasts delivered metalloprotease-2 and -9, driving in cancer cells the epithelial-mesenchymal transition epigenetic program, a key event associated with increased motility, survival and stemness. Both genetic silencing and pharmacological inhibition of CA IX (with sulfonamide/sulfamides potent inhibitors) or metalloprotease-9 are sufficient to impede epithelial-mesenchymal transition and invasiveness of prostate cancer cells induced by contact with cancer-associated fibroblasts. We also confirmed in vivo the upstream hierarchical role of stromal CA IX to drive successful metastatic spread of prostate carcinoma cells. These data include stromal cells, as cancer-associated fibroblasts as ideal targets for carbonic anhydrase IX-directed anticancer therapies. 相似文献
945.
946.
Francesca Grassi Marina Bouch Salvatore Aguanno Mario Molinaro Fabrizio Eusebi 《Experimental cell research》1987,171(2):498-502
Acetylcholine receptor (AChR) was found to be present on the cell surface of the human rhabdomyoblast (RD) cell line. Two classes of ACh-activated channels have been observed, one with a large conductance and long duration and the other with smaller conductance and short duration, similar to those of human myotubes. RD membrane exhibited a specific binding to the alpha-bungarotoxin indicating the presence of nicotinic AChRs. These results support the hypothesis that rhabdomyosarcomas derive from myogenic precursors. 相似文献
947.
Julia Winkelmann Giulia Calloni Benedetta Mannini Fabrizio Chiti 《Journal of molecular biology》2010,398(4):600-613
Aggregation of peptides and proteins into insoluble amyloid fibrils or related intracellular inclusions is the hallmark of many degenerative diseases, including Alzheimer's disease, Parkinson's disease, and various forms of amyloidosis. In spite of the considerable progress carried out in vitro in elucidating the molecular determinants of the conversion of purified and isolated proteins into amyloid fibrils, very little is known on factors governing this process in the complex environment of living organisms. Taking advantage of increasing evidence that bacterial inclusion bodies consist of amyloid-like aggregates, we have expressed in Escherichia coli both wild type and 21 single-point mutants of the N-terminal domain of the E. coli protein HypF. All variants were expressed as folding-incompetent units in a controlled manner, at low and comparable levels. Their solubilities were measured by quantifying the protein amount contained in the soluble and insoluble fractions by Western blot analysis. A significant negative correlation was found between the solubility of the variants in E. coli and their intrinsic propensity to form amyloid fibrils, predicted using an algorithm previously validated experimentally in vitro on a number of unfolded peptides and proteins, and considering hydrophobicity, β-sheet propensity, and charge as major sequence determinants of the aggregation process. These findings show that the physicochemical parameters previously recognized to govern amyloid formation by fully or partially unfolded proteins are largely applicable in vivo and pave the way for the molecular exploration of a process as complex as protein aggregation in living organisms. 相似文献
948.
Two species belonging to the recently revised Pristaulacus comptipennis species-group, P. manuelae Turrisi and Madl, sp. n. from Laos and P. iosephi Turrisi and Madl, sp. n. from Thailand, are described, illustrated and compared with most related species. The former species most resembles P. watanabei Turrisi and Smith, 2011, from Thailand, but is readily recognizable, mainly by the shape of the head, which is elongated, with a well-developed temple. The latter species resembles two other species, P. nobilei Turrisi and Smith, 2011, from south China, and P. emarginaticeps Turner, 1922, from Vietnam, but it is easily recognizable mainly by the shape of the medial occipital groove, which is shallow and V-shaped, as well as the shape of the mesosoma, with anterior lobe of mesoscutum, anterior to notauli, strongly elevated dorsally and anteriorly and distinctly overhanging pronotum. 相似文献
949.
950.
Annalisa Monaco Ruggero Cattaneo Luca Mesin Irma Ciarrocchi Fabrizio Sgolastra Davide Pietropaoli 《PloS one》2012,7(9)
The role of the autonomic nervous system (ANS) was recently investigated in Temporomandibular disorders (TMD). Several authors argue that in subjects with TMD there is a dysregulation of ANS. Recent literature support that Pupillometry is a simple non-invasive tool to study ANS. The aim of this study was to investigate the relationship between TMD and ANS activity using pupillometry recording in Infrared light at rest Mandible Position (RP); Infrared light at Forced Habitual Occlusion (FHO); Yellow-green light at RP; Yellow-green light at FHO. Forty female subjects were enrolled: 20 case patients showed TMD based on the Research Diagnostic Criteria for TMD, and 20 control patients, aged matched, had no signs or symptoms of TMD. Statistical analysis was performed on average pupil size. Ratio between pupil size in FHO and RP (FHO/RP ratio) and yellow-green and infrared (light/darkness ratio) lighting were carried out. Within group differences of pupil size and of “ratio” were analyzed using a paired t test, while differences of pupil size between groups were tested using an unpaired t test. Statistical comparisons between groups showed no significant differences of absolute values of pupil dimension in RP and FHO, both in yellow-green and in infrared lighting. In addition, there were no significant differences within groups comparing RP and FHO in yellow-green light. In within group comparison of pupil size, differences between RP and FHO were significant in infrared conditions. Control subjects increased, whereas TMD patients decreased pupil size at FHO in infrared lightening. FHO/RP ratio in darkness and light/darkness ratio in RP were significantly different between groups. Taken together, these data suggest that TMD subjects have an impairment of the sympathetic-adrenergic component of the ANS to be activated under stress. The present study provides preliminary pupillometric data confirming that adrenergic function is dysregulated in patients with TMD. 相似文献