全文获取类型
收费全文 | 6827篇 |
免费 | 482篇 |
国内免费 | 1篇 |
专业分类
7310篇 |
出版年
2024年 | 6篇 |
2023年 | 40篇 |
2022年 | 115篇 |
2021年 | 181篇 |
2020年 | 138篇 |
2019年 | 163篇 |
2018年 | 209篇 |
2017年 | 160篇 |
2016年 | 281篇 |
2015年 | 449篇 |
2014年 | 438篇 |
2013年 | 571篇 |
2012年 | 650篇 |
2011年 | 623篇 |
2010年 | 340篇 |
2009年 | 310篇 |
2008年 | 389篇 |
2007年 | 369篇 |
2006年 | 333篇 |
2005年 | 301篇 |
2004年 | 257篇 |
2003年 | 211篇 |
2002年 | 234篇 |
2001年 | 41篇 |
2000年 | 28篇 |
1999年 | 40篇 |
1998年 | 53篇 |
1997年 | 28篇 |
1996年 | 34篇 |
1995年 | 23篇 |
1994年 | 28篇 |
1993年 | 22篇 |
1992年 | 27篇 |
1991年 | 16篇 |
1990年 | 15篇 |
1989年 | 14篇 |
1988年 | 12篇 |
1987年 | 13篇 |
1985年 | 9篇 |
1984年 | 13篇 |
1983年 | 6篇 |
1982年 | 11篇 |
1981年 | 8篇 |
1980年 | 13篇 |
1979年 | 9篇 |
1978年 | 6篇 |
1977年 | 11篇 |
1976年 | 5篇 |
1974年 | 6篇 |
1973年 | 14篇 |
排序方式: 共有7310条查询结果,搜索用时 0 毫秒
931.
Vitaly A. Selivanov Marta Cascante Mark Friedman Mark F. Schumaker Massimo Trucco Tatyana V. Votyakova 《PLoS computational biology》2012,8(9)
The mitochondrial electron transport chain transforms energy satisfying cellular demand and generates reactive oxygen species (ROS) that act as metabolic signals or destructive factors. Therefore, knowledge of the possible modes and bifurcations of electron transport that affect ROS signaling provides insight into the interrelationship of mitochondrial respiration with cellular metabolism. Here, a bifurcation analysis of a sequence of the electron transport chain models of increasing complexity was used to analyze the contribution of individual components to the modes of respiratory chain behavior. Our algorithm constructed models as large systems of ordinary differential equations describing the time evolution of the distribution of redox states of the respiratory complexes. The most complete model of the respiratory chain and linked metabolic reactions predicted that condensed mitochondria produce more ROS at low succinate concentration and less ROS at high succinate levels than swelled mitochondria. This prediction was validated by measuring ROS production under various swelling conditions. A numerical bifurcation analysis revealed qualitatively different types of multistationary behavior and sustained oscillations in the parameter space near a region that was previously found to describe the behavior of isolated mitochondria. The oscillations in transmembrane potential and ROS generation, observed in living cells were reproduced in the model that includes interaction of respiratory complexes with the reactions of TCA cycle. Whereas multistationarity is an internal characteristic of the respiratory chain, the functional link of respiration with central metabolism creates oscillations, which can be understood as a means of auto-regulation of cell metabolism. 相似文献
932.
B Dehay M Martinez-Vicente A Ramirez C Perier C Klein M Vila E Bezard 《Autophagy》2012,8(9):1389-1391
Mutations in ATP13A2 (PARK9) cause an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia called Kufor-Rakeb Syndrome (KRS). The ATP13A2 gene encodes a transmembrane lysosomal P5-type ATPase (ATP13A2) whose physiological function in mammalian cells, and hence its potential role in Parkinson disease (PD), remains elusive. In this context, we have recently shown that KRS-linked mutations in ATP13A2 leads to several lysosomal alterations in ATP13A2 KRS patient-derived fibroblasts, including impaired lysosomal acidification, decreased proteolytic processing of lysosomal enzymes, reduced degradation of lysosomal substrates and diminished lysosomal-mediated clearance of autophagosomes (AP). Similar alterations are observed in stable ATP13A2-knockdown dopaminergic cell lines, which are associated with cell death. Restoration of ATP13A2 levels in ATP13A2-mutant/depleted cells is able to restore lysosomal function and attenuate cell death. Relevant to PD, we have determined that ATP13A2 levels are decreased in dopaminergic nigral neurons from sporadic PD patients. Interestingly in these patients, the main signal of ATP13A2 is detected in the Lewy bodies. Our results unravel an instrumental role of ATP13A2 in lysosomal function and in cell viability. Altogether, our results validate ATP13A2 as a likely therapeutic target against PD degeneration. 相似文献
933.
934.
Rolando B Filieri A Chegaev K Lazzarato L Giorgis M De Nardi C Fruttero R Martel S Carrupt PA Gasco A 《Bioorganic & medicinal chemistry》2012,20(2):841-850
A new class of co-drugs were synthesised by joining antioxidant edaravone with a vasodilating substructure containing NO-donor nitrooxy functions, and characterised for their stability in different media, lipophilicity and permeability profile. The products display good stability in water/co-solvent at different pH. Conversely, they are rapidly metabolised into edaravone and NO-donor moieties when incubated in human serum or rat-liver homogenates. In the latter conditions time dependent production of nitrite/nitrate (NO(x)) occurs. The compounds display wide-ranging lipophilicity. PAMPA studies predict good gastrointestinal absorption for a number of these compounds. The title products are potentially useful for treating ROS-related conditions accompanied by decreased NO availability. 相似文献
935.
Tom D. Bunney Diego Esposito Corine Mas-Droux Ekatarina Lamber Rhona W. Baxendale Marta Martins Ambrose Cole Dmitri Svergun Paul C. Driscoll Matilda Katan 《Structure (London, England : 1993)》2012,20(12):2062-2075
Highlights? Domains from PLCγ regulatory region show structural and functional integration ? Only cSH2 domain interacts with the PLC-core forming a high affinity surface ? Activation involves removal of autoinhibition and dissociation from the receptor ? Disease-linked mutations map to the autoinhibitory interface 相似文献
936.
Piernicola Pedicini Rocchina Caivano Barbara A Jereczek-Fossa Lidia Strigari Barbara Vischioni Daniela Alterio Marta Cremonesi Francesca Botta Antonio Nappi Giuseppina Improta Giovanni Storto Alba Fiorentino Marcello Benassi Roberto Orecchia Vincenzo Fusco 《Theoretical biology & medical modelling》2012,9(1):1-1
937.
938.
Sara Benedetti Pia Bernasconi Enrico Bertini Elena Biagini Giuseppe Boriani Cristina Capanni Nicola Carboni Giovanna Cenacchi Marta Columbaro Monica D’Adamo Adele D’Amico Maria Rosaria D’Apice Marianna Fontana Alessandra Gambineri Giovanna Lattanzi Rocco Liguori Nadir M Maraldi Laura Mazzanti Eugenio Mercuri Tiziana Mongini Lucia O Morandi Iria Neri Giovanni Nigro Giuseppe Novelli Michela Ortolani Renato Pasquali Antonella Pini Stefania Petrini Luisa Politano Stefano Previtali Lisa Pucci Claudio Rapezzi Giulia Ricci Carmelo Rodolico Paolo Sbraccia Emanuela Scarano Gabriele Siciliano Stefano Squarzoni Antonio Toscano Liliana Vercelli Matteo Ziacchi 《Orphanet journal of rare diseases》2012,7(1):1-3
The need for a collaborative approach to complex inherited diseases collectively referred to as laminopathies, encouraged Italian researchers, geneticists, physicians and patients to join in the Italian Network for Laminopathies, in 2009. Here, we highlight the advantages and added value of such a multidisciplinary effort to understand pathogenesis, clinical aspects and try to find a cure for Emery-Dreifuss muscular dystrophy, Mandibuloacral dysplasia, Hutchinson-Gilford Progeria and forms of lamin-linked cardiomyopathy, neuropathy and lipodystrophy. 相似文献
939.
Ana Belen Sanz Maria Dolores Sanchez-Ni?o Susana Carrasco Felix Manzarbeitia Olga Ruiz-Andres Rafael Selgas Marta Ruiz-Ortega Carmen Gonzalez-Enguita Jesus Egido Alberto Ortiz 《PloS one》2012,7(10)
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK, TNFSF12) is a member of the tumor necrosis factor superfamily. TWEAK activates the Fn14 receptor, and may regulate cell death, survival and proliferation in tumor cells. However, there is little information on the function and regulation of this system in prostate cancer. Fn14 expression and TWEAK actions were studied in two human prostate cancer cell lines, the androgen-independent PC-3 cell line and androgen-sensitive LNCaP cells. Additionally, the expression of Fn14 was analyzed in human biopsies of prostate cancer. Fn14 expression is increased in histological sections of human prostate adenocarcinoma. Both prostate cancer cell lines express constitutively Fn14, but, the androgen-independent cell line PC-3 showed higher levels of Fn14 that the LNCaP cells. Fn14 expression was up-regulated in PC-3 human prostate cancer cells in presence of inflammatory cytokines (TNFα/IFNγ) as well as in presence of bovine fetal serum. TWEAK induced apoptotic cell death in PC-3 cells, but not in LNCaP cells. Moreover, in PC-3 cells, co-stimulation with TNFα/IFNγ/TWEAK induced a higher rate of apoptosis. However, TWEAK or TWEAK/TNFα/IFNγ did not induce apoptosis in presence of bovine fetal serum. TWEAK induced cell death through activation of the Fn14 receptor. Apoptosis was associated with activation of caspase-3, release of mitochondrial cytochrome C and an increased Bax/BclxL ratio. TWEAK/Fn14 pathway activation promotes apoptosis in androgen-independent PC-3 cells under certain culture conditions. Further characterization of the therapeutic target potential of TWEAK/Fn14 for human prostate cancer is warranted. 相似文献
940.
Jo Nelissen Koen Nuyts Marta De Zotti Rob Lavigne Chris Lamberigts Wim M. De Borggraeve 《PloS one》2012,7(12)
The total synthesis is reported of the peptaibol Septocylindrin B which is related to the well documented channel forming peptaibol antibiotic Alamethicin. Several analogues were synthesized with a modified C-terminus, to investigate the SAR of the terminal residue Phaol. All these peptides were tested for their membrane perturbation properties by fluorescent dye leakage assay and for their antibacterial activity. 相似文献