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91.
Kermanshahi Sareh Ghanavati Ghazal Abbasi-Mesrabadi Mobina Gholami Mina Ulloa Luis Motaghinejad Majid Safari Sepideh 《Neurochemical research》2020,45(11):2573-2585
Neurochemical Research - Neurodegenerative disorders are characterized by mitochondrial dysfunction and subsequently oxidative stress, inflammation, and apoptosis that contribute to neuronal... 相似文献
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Steven Watterson Maria Luisa Guerriero Mathieu Blanc Alexander Mazein Laurence Loewe Kevin A. Robertson Holly Gibbs Guanghou Shui Markus R. Wenk Jane Hillston Peter Ghazal 《Biochimie》2013
The cholesterol biosynthesis pathway has recently been shown to play an important role in the innate immune response to viral infection with host protection occurring through a coordinate down regulation of the enzymes catalysing each metabolic step. In contrast, statin based drugs, which form the principle pharmaceutical agents for decreasing the activity of this pathway, target a single enzyme. Here, we build an ordinary differential equation model of the cholesterol biosynthesis pathway in order to investigate how the two regulatory strategies impact upon the behaviour of the pathway. We employ a modest set of assumptions: that the pathway operates away from saturation, that each metabolite is involved in multiple cellular interactions and that mRNA levels reflect enzyme concentrations. Using data taken from primary bone marrow derived macrophage cells infected with murine cytomegalovirus or treated with IFNγ, we show that, under these assumptions, coordinate down-regulation of enzyme activity imparts a graduated reduction in flux along the pathway. In contrast, modelling a statin-like treatment that achieves the same degree of down-regulation in cholesterol production, we show that this delivers a step change in flux along the pathway. The graduated reduction mediated by physiological coordinate regulation of multiple enzymes supports a mechanism that allows a greater level of specificity, altering cholesterol levels with less impact upon interactions branching from the pathway, than pharmacological step reductions. We argue that coordinate regulation is likely to show a long-term evolutionary advantage over single enzyme regulation. Finally, the results from our models have implications for future pharmaceutical therapies intended to target cholesterol production with greater specificity and fewer off target effects, suggesting that this can be achieved by mimicking the coordinated down-regulation observed in immunological responses. 相似文献
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Noorchashm H Reed AJ Rostami SY Mozaffari R Zekavat G Koeberlein B Caton AJ Naji A 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(11):7715-7722
Acute allograft rejection requires the activation of alloreactive CD4 T cells. Despite the capacity of B cells to act as potent APCs capable of activating CD4 T cells in vivo, their role in the progression of acute allograft rejection was unclear. To determine the contribution of B cell APC function in alloimmunity, we engineered mice with a targeted deficiency of MHC class II-mediated Ag presentation confined to the B cell compartment. Cardiac allograft survival was markedly prolonged in these mice as compared to control counterparts (median survival time, >70 vs 9.5 days). Mechanistically, deficient B cell-mediated Ag presentation disrupted both alloantibody production and the progression of CD4 T cell activation following heart transplantation. These findings demonstrate that indirect alloantigen presentation by recipients' B cells plays an important role in the efficient progression of acute vascularized allograft rejection. 相似文献
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Taylor CF Field D Sansone SA Aerts J Apweiler R Ashburner M Ball CA Binz PA Bogue M Booth T Brazma A Brinkman RR Michael Clark A Deutsch EW Fiehn O Fostel J Ghazal P Gibson F Gray T Grimes G Hancock JM Hardy NW Hermjakob H Julian RK Kane M Kettner C Kinsinger C Kolker E Kuiper M Le Novère N Leebens-Mack J Lewis SE Lord P Mallon AM Marthandan N Masuya H McNally R Mehrle A Morrison N Orchard S Quackenbush J Reecy JM Robertson DG Rocca-Serra P Rodriguez H Rosenfelder H Santoyo-Lopez J 《Nature biotechnology》2008,26(8):889-896
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