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111.
Tamara Hirsch Didier Decaudin Santos A. Susin Philippe Marchetti Nathanael Larochette Michèle Resche-Rigon Guido Kroemer 《Experimental cell research》1998,241(2):426
One critical step of the apoptotic process is the opening of the mitochondrial permeability transition (PT) pore leading to the disruption of mitochondrial membrane integrity and to the dissipation of the inner transmembrane proton gradient (ΔΨm). The mitochondrial PT pore is a polyprotein structure which is inhibited by the apoptosis-inhibitory oncoprotein Bcl-2 and which is closely associated with the mitochondrial benzodiazepine receptor (mBzR). Here we show that PK11195, a prototypic ligand of the 18-kDa mBzR, facilitates the induction of ΔΨmdisruption and subsequent apoptosis by a number of different agents,including agonists of the glucocorticoid receptor,chemotherapeutic agents (etoposide, doxorubicin),gamma irradiation, and the proapoptotic second messenger ceramide. Whereas PK11195 itself has no cytotoxic effect, it enhances apoptosis induction by these agents. This effect is not observed for benzodiazepine diazepam, whose binding site in the mBzR differs from PK11195. PK11195 partially reverses Bcl-2 mediated inhibition of apoptosis in two different cell lines. Thus, transfection-enforced Bcl-2 overexpression confers protection against glucocorticoids and chemotherapeutic agents, and this protection is largely reversed by the addition of PK11195. This effect is observed at the level of ΔΨmdissipation as well as at the level of nuclear apoptosis. To gain insights into the site of action of PK11195, we performed experiments on isolated organelles. PK11195 reverses the Bcl-2-mediated mitochondrial retention of apoptogenic factors which cause isolated nuclei to undergo apoptosis in a cell-free system. Mitochondria from control cells, but not mitochondria from Bcl-2-overexpressing cells, readily release such apoptogenic factors in response to atractyloside, a ligand of the adenine nucleotide translocator. However, control and Bcl-2-overexpressing mitochondria respond equally well to a combination of atractyloside and PK11195. Altogether, these findings indicate that PK11195 abolishes apoptosis inhibition by Bcl-2 via a direct effect on mitochondria. Moreover, they suggest a novel strategy for enhancing the susceptibility of cells to apoptosis induction and, concomitantly, for reversing Bcl-2-mediated cytoprotection. 相似文献
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113.
Mehmet Haluk Morgul Katrin Splith Christoph Leonhardt Nathanael Raschzok Anja Reutzel-Selke Rosa Bianca Schmuck 《Biomarkers》2018,23(1):25-32
Context: Non-invasive markers for diagnosis of acute rejection (AR) following liver transplantation have not been developed, yet.Objective: We analyzed the correlation of plasma microparticle levels (MP) with AR.Materials and Methods: MP (CD4, CD8, CD25, CD31, MHC) of 11?AR patients and 11 controls were analyzed within the first week after transplantation.Results: CD4, CD8 and CD31 positive MP were higher in the AR, whereas overall MP count, CD25 and MHCI positive MP proportions did not differ between both groups.Discussion and Conclusion: MP dynamics within the first period of transplantation could help to clarify on-going mechanisms of immunomodulation. 相似文献
114.
Mariscal Carlos Barahona Ana Aubert-Kato Nathanael Aydinoglu Arsev Umur Bartlett Stuart Cárdenas María Luz Chandru Kuhan Cleland Carol Cocanougher Benjamin T. Comfort Nathaniel Cornish-Bowden Athel Deacon Terrence Froese Tom Giovannelli Donato Hernlund John Hut Piet Kimura Jun Maurel Marie-Christine Merino Nancy Moreno Alvaro Nakagawa Mayuko Peretó Juli Virgo Nathaniel Witkowski Olaf James Cleaves H. 《Origins of life and evolution of the biosphere》2019,49(3):111-145
Origins of Life and Evolution of Biospheres - In this review, we describe some of the central philosophical issues facing origins-of-life research and provide a targeted history of the developments... 相似文献
115.
How can we harness quantitative genetic variation in crop root systems for agricultural improvement?
Root systems are a black box obscuring a comprehensive understanding of plant function,from the ecosystem scale down to the individual. In particular,a lack of knowledge about the genetic mechanisms and environmental effects that condition root system growth hinders our ability to develop the next generation of crop plants for improved agricultural productivity and sustainability. We discuss how the methods and metrics we use to quantify root systems can affect our ability to understand them,how we can bridge knowledge gaps and accelerate the derivation of structurefunction relationships for roots,and why a detailed mechanistic understanding of root growth and function will be important for future agricultural gains. 相似文献
116.
Boya P González-Polo RA Casares N Perfettini JL Dessen P Larochette N Métivier D Meley D Souquere S Yoshimori T Pierron G Codogno P Kroemer G 《Molecular and cellular biology》2005,25(3):1025-1040
Mammalian cells were observed to die under conditions in which nutrients were depleted and, simultaneously, macroautophagy was inhibited either genetically (by a small interfering RNA targeting Atg5, Atg6/Beclin 1-1, Atg10, or Atg12) or pharmacologically (by 3-methyladenine, hydroxychloroquine, bafilomycin A1, or monensin). Cell death occurred through apoptosis (type 1 cell death), since it was reduced by stabilization of mitochondrial membranes (with Bcl-2 or vMIA, a cytomegalovirus-derived gene) or by caspase inhibition. Under conditions in which the fusion between lysosomes and autophagosomes was inhibited, the formation of autophagic vacuoles was enhanced at a preapoptotic stage, as indicated by accumulation of LC3-II protein, ultrastructural studies, and an increase in the acidic vacuolar compartment. Cells exhibiting a morphology reminiscent of (autophagic) type 2 cell death, however, recovered, and only cells with a disrupted mitochondrial transmembrane potential were beyond the point of no return and inexorably died even under optimal culture conditions. All together, these data indicate that autophagy may be cytoprotective, at least under conditions of nutrient depletion, and point to an important cross talk between type 1 and type 2 cell death pathways. 相似文献
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S1P receptors (S1PR1-5) are a group of GPCRs activated by a high affinity binding with S1P that have important roles in the regulation of the immune system. A potent S1PR agonist FTY720 is an immunomodulator used to treat multiple sclerosis and several ‘second generation’ drugs are under clinical development. Subtype-selective agonists have been reported for each S1PR isotype, some of which are used as pharmacological tools for functional studies. Here we report the discovery and initial characterization of compound 5c, a benzo[b]thiophene amino carboxylate which exhibits potent and selective agonist activity for S1PR4. Compound 5c has an EC50 = 200 nM as an agonist in GTPγ35S binding assay for S1PR4 and exhibits no activity against S1PR1,2,3,5. We confirmed its potent activity and decent S1PR subtype selectivity using biochemical and cellular assays. 相似文献
119.
Xianming Deng Advait Nagle Tao Wu Tomoyo Sakata Kerstin Henson Zhong Chen Kelli Kuhen David Plouffe Elizabeth Winzeler Francisco Adrian Tove Tuntland Jonathan Chang Susan Simerson Steven Howard Jared Ek John Isbell David C. Tully Arnab K. Chatterjee Nathanael S. Gray 《Bioorganic & medicinal chemistry letters》2010,20(14):4027-4031
A novel family of 1H-imidazol-2-yl-pyrimidine-4,6-diamines has been identified with potent activity against the erythrocyte-stage of Plasmodium falciparum (Pf), the most common causative agent of malaria. A systematic SAR study resulted in the identification of compound 40 which exhibits good potency against both wild-type and drug resistant parasites and exhibits good in vivo pharmacokinetic properties. 相似文献
120.
Targeting the epidermal growth factor receptor kinase (EGFR) with ATP-competitive kinase inhibitors results in dramatic but short-lived responses in patients with EGFR mutant non small cell lung cancer. A series of novel covalent EGFR kinase inhibitors with selectivity for the clinically relevant T790M ‘gatekeeper’ resistance mutation relative to wild-type EGFR were discovered by library screening. A representative compound 3i was obtained through a systematic SAR study guided by mutant EGFR-dependent cellular proliferation assays. 相似文献