全文获取类型
收费全文 | 1758篇 |
免费 | 132篇 |
出版年
2023年 | 5篇 |
2022年 | 12篇 |
2021年 | 27篇 |
2020年 | 23篇 |
2019年 | 24篇 |
2018年 | 23篇 |
2017年 | 29篇 |
2016年 | 36篇 |
2015年 | 86篇 |
2014年 | 72篇 |
2013年 | 140篇 |
2012年 | 178篇 |
2011年 | 147篇 |
2010年 | 97篇 |
2009年 | 81篇 |
2008年 | 107篇 |
2007年 | 114篇 |
2006年 | 108篇 |
2005年 | 101篇 |
2004年 | 89篇 |
2003年 | 81篇 |
2002年 | 79篇 |
2001年 | 7篇 |
2000年 | 10篇 |
1999年 | 18篇 |
1998年 | 24篇 |
1997年 | 19篇 |
1996年 | 14篇 |
1995年 | 17篇 |
1994年 | 12篇 |
1993年 | 15篇 |
1992年 | 12篇 |
1991年 | 9篇 |
1990年 | 10篇 |
1989年 | 5篇 |
1988年 | 8篇 |
1987年 | 4篇 |
1986年 | 5篇 |
1985年 | 8篇 |
1984年 | 5篇 |
1983年 | 4篇 |
1982年 | 2篇 |
1981年 | 7篇 |
1980年 | 3篇 |
1979年 | 5篇 |
1978年 | 2篇 |
1976年 | 2篇 |
1975年 | 3篇 |
1971年 | 1篇 |
排序方式: 共有1890条查询结果,搜索用时 15 毫秒
881.
Sulforaphane increases the efficacy of doxorubicin in mouse fibroblasts characterized by p53 mutations 总被引:1,自引:0,他引:1
Fimognari C Nüsse M Lenzi M Sciuscio D Cantelli-Forti G Hrelia P 《Mutation research》2006,601(1-2):92-101
One novel strategy for increasing cancer chemotherapy efficacy and reversing chemoresistance involves co-administration of natural chemopreventive compounds alongside standard chemotherapeutic protocols. Sulforaphane is a particularly promising chemopreventive agent, which has been shown to exert proapoptotic effects on tumor cells containing p53 mutations. The p53(Ser220) mutation has been implicated in reduced efficacy and drug resistance in the context of osteosarcomas and breast tumors treated with doxorubicin-based protocols. We investigated the effects of a combination of doxorubicin and sulforaphane on cell viability and apoptosis induction in fibroblasts characterized by different p53 status (p53 wild-type, p53 knock-out, and p53(Ser220) mutation), and identified some of the molecular pathways triggered by the drug combination. Very high concentrations of doxorubicin were necessary to decrease the viability of p53(Ser220) and p53 knock-out (but not wild-type) cells. Treatment of p53(Ser220) and p53 knock-out cells with doxorubicin did not induce apoptosis, also at very high concentrations (10muM). Sulforaphane restored chemosensitivity and induced apoptosis in doxorubicin-resistant p53(Ser220) and p53 knock-out cells, irrespective of p53 status. The induction of apoptosis was caspase-3 dependent and caspase-8 independent. Bongkrekic acid, a mitochondrial membrane stabilizer, partially prevented the effects of doxorubicin plus sulforaphane on mitochondrial permeability but was unable to prevent the induction of apoptosis. N-acetyl-cysteine, a glutathione precursor, blocked the induction of apoptosis by doxorubicin plus sulforaphane. Considering the negligible safety profile of sulforaphane, our findings could prompt innovative clinical studies designed to investigate whether its coadministration can enhance the efficacy of doxorubicin-based regimens. 相似文献
882.
Daniele Capitanio Michele Vasso Chiara Fania Manuela Moriggi Agnese Viganò Patrizia Procacci Valerio Magnaghi Cecilia Gelfi Professor 《Proteomics》2009,9(7):2004-2020
Ageing induces a progressive morphological change and functional decline in muscles and in nerves. Light and electron microscopy, 2‐D DIGE and MS, were applied to profile the qualitative and quantitative differences in the proteome and morphology of rat gastrocnemius muscle and sciatic nerve, in healthy 22‐month‐old rats. At muscle level, morphological changes are associated to fibre atrophy accompanied by myofibrillar loss and degeneration, disappearance of sarcomeres and sarcoplasmic reticulum dilatation, internal migration of nuclei, longitudinal fibre splitting, increment of subsarcolemmal mitochondria aggregates and increment of lipofuscin granules. Sciatic nerve shows myelin abnormalities like enfoldings, invaginations, onion bulbs, breakdowns and side axonal atrophy. Proteomic analysis identified changes correlated to morphological abnormalities in metabolic, contractile and cytoskeletal proteins, deregulation of iron homeostasis, change of Ca2+ balance and stress response proteins, accompanied by a deregulation of myelin membrane adhesion protein and proteins regulating the neuronal caliber. By comparing proteomic results from the two tissues, 16 protein isoforms showed the same up and down regulation trend suggesting that there are changes implying a general process which may act as a signal event of degeneration. Only β enolase and tropomyosin 1α were differentially expressed in the tissues. 相似文献
883.
Serge Arnaudeau Patrizia Arboit Paul Bischof Kasuo Shin‐ya A. Tomida T. Tsuruo Olivier Irion Marie Cohen 《Proteomics》2009,9(23):5316-5327
Although wild‐type p53 protein is overexpressed in first trimester trophoblast, it is inactive towards its target genes Metalloproteinase 2 and 9. This seems to be due to a complex mechanism of inactivation and stabilization of p53 relying on the formation of protein complexes involving the N‐terminus of p53. To detect the proteins associated with this sequence, we incubated biotinylated p53 N‐terminal peptide in cytotrophoblastic cell medium 24 h before lysis of cells. We purified the proteins retained on biotinylated peptide using a neutravidin affinity column. Proteins were then identified by peptide mass finger printing followed or not by peptide fragmentation sequencing. Among these proteins, we identified glucose‐regulated protein 78 (GRP78) and verified its interaction with p53 in trophoblastic cells by immunoprecipitation and Western blot analysis. Moreover, the decreased expression of GRP78 induced by GRP78siRNA or versipelostatin decreased the formation of high molecular weight p53 complexes and p53 monomer and increased trophoblastic invasion. These results suggest that GRP78 is involved in inactivation and stabilization of p53 and in the regulation of trophoblastic invasion. 相似文献
884.
Andrea Tarozzi Fabiana Morroni Adriana Merlicco Silvana Hrelia† Cristina Angeloni† Giorgio Cantelli-Forti Patrizia Hrelia 《Journal of neurochemistry》2009,111(5):1161-1171
The total GSH depletion observed in the substantia nigra (SN) appears to be responsible for subsequent oxidative stress (OS), mitochondrial dysfunction, and dopaminergic cell loss in patients with Parkinson's disease. A strategy to prevent the OS of dopaminergic cells in the SN may be the use of chemopreventive agents as inducers of endogenous GSH, antioxidant and phase 2 enzymes. In this study, we demonstrated that treatment of the dopaminergic-like neuroblastoma SH-SY5Y cell line with sulforaphane (SF), a cruciferous vegetables inducer, resulted in significant increases of total GSH level, NAD(P)H : quinone oxidoreductase-1, GSH-transferase and -reductase, but not GSH-peroxidase, catalase and superoxide dismutase activities. Further, the elevation of GSH levels, GSH-transferase and NAD(P)H:quinone oxidoreductase-1 activities was correlated to an increase of the resistance of SH-SY5Y cells to toxicity induced by H2 O2 or 6-hydroxydopamine (6-OHDA). The pre-treatment of SH-SY5Y cells with SF was also shown to prevent various apoptotic events (mitochondrial depolarization, caspase 9 and 3 activation and DNA fragmentation) and necrosis elicited by 6-OHDA. Further, the impairment of antioxidant capacity and reactive oxygen species formation at intracellular level after exposure to 6-OHDA was effectively counteracted by pre-treatment with SF. Last, both the cytoprotective and antioxidant effects of SF were abolished by the addition of buthionine sulfoximine supporting the main role of GSH in the neuroprotective effects displayed by SF. These findings show that SF may play a role in preventing Parkinson's disease. 相似文献
885.
Maria Teresa Tebano Alberto Martire Valentina Chiodi Rita Pepponi Antonella Ferrante Maria Rosaria Domenici Claudio Frank Jiang-Fan Chen† Catherine Ledent‡ Patrizia Popoli 《Journal of neurochemistry》2009,110(6):1921-1930
Adenosine A2A , cannabinoid CB1 and metabotropic glutamate 5 (mGlu5 ) receptors are all highly expressed in the striatum. The aim of the present work was to investigate whether, and by which mechanisms, the above receptors interact in the regulation of striatal synaptic transmission. By extracellular field potentials (FPs) recordings in corticostriatal slices, we demonstrated that the ability of the selective type 1 cannabinoid receptor (CB1 R) agonist WIN55,212-2 to depress synaptic transmission was prevented by the pharmacological blockade or the genetic inactivation of A2A Rs. Such a permissive effect of A2A Rs towards CB1 Rs does not seem to occur pre-synaptically as the ability of WIN55,212-2 to increase the R2/R1 ratio under a protocol of paired-pulse stimulation was not modified by ZM241385. Furthermore, the effects of WIN55,212-2 were reduced in slices from mice lacking post-synaptic striatal A2A Rs. The selective mGlu5 R agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) potentiated the synaptic effects of WIN55,212-2, and such a potentiation was abolished by A2A R blockade. Unlike the synaptic effects, the ability of WIN55,212-2 to prevent NMDA-induced toxicity was not influenced by ZM241385. Altogether, these results show that the state of activation of A2A Rs regulates the synaptic effects of CB1 Rs and that A2A Rs may control CB1 effects also indirectly, namely through mGlu5 Rs. 相似文献
886.
887.
888.
Patrizia Adamczyk Claudia Zenkert Prakash G. Balasubramanian Shuhei Yamada Saori Murakoshi Kazuyuki Sugahara Jung Shan Hwang Takashi Gojobori Thomas W. Holstein Suat ?zbek 《The Journal of biological chemistry》2010,285(33):25613-25623
Membrane tubulation is generally associated with rearrangements of the cytoskeleton and other cytoplasmic factors. Little is known about the contribution of extracellular matrix components to this process. Here, we demonstrate an essential role of proteoglycans in the tubulation of the cnidarian nematocyst vesicle. The morphogenesis of this extrusive organelle takes place inside a giant post-Golgi vesicle, which topologically represents extracellular space. This process includes the formation of a complex collagenous capsule structure that elongates into a long tubule, which invaginates after its completion. We show that a non-sulfated chondroitin appears as a scaffold in early morphogenesis of all nematocyst types in Hydra and Nematostella. It accompanies the tubulation of the vesicle membrane forming a provisional tubule structure, which after invagination matures by collagen incorporation. Inhibition of chondroitin synthesis by β-xylosides arrests nematocyst morphogenesis at different stages of tubule outgrowth resulting in retention of tubule material and a depletion of mature capsules in the tentacles of hydra. Our data suggest a conserved role of proteoglycans in the stabilization of a membrane protrusion as an essential step in organelle morphogenesis. 相似文献
889.
890.
Lenaers G Amati-Bonneau P Delettre C Chevrollier A Verny C Miléa D Procaccio V Bonneau D Hamel C Reynier P 《Médecine sciences : M/S》2010,26(10):836-841
Ten years ago, OPA1 was identified as the major gene responsible for hereditary optic nerve degeneration, evidencing the first defect in mitochondrial network dynamics as the princeps pathophysiological mechanism in a mitochondriopathy. Later, alterations in other genes involved in mitochondrial fusion or fission, such as MFN2, DRP1 and GDAP1, were also associated with inherited neurological diseases, mainly affecting peripheral nerves. More recently, altered mitochondrial plasticity was also demonstrated in common age-related neurodegenerative disorders, as Alzheimer and Parkinson diseases, thus substantiating the critical role of mitochondrial dynamics in neurons as a key element governing the efficiency of oxidative respiration and its distribution along the axons. 相似文献