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51.
Han MH Hwang SI Roy DB Lundgren DH Price JV Ousman SS Fernald GH Gerlitz B Robinson WH Baranzini SE Grinnell BW Raine CS Sobel RA Han DK Steinman L 《Nature》2008,451(7182):1076-1081
Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade. 相似文献
52.
In Young Hwang Hui Ling Lee James Guoxian Huang Yvonne Yijuan Lim Wen Shan Yew Yung Seng Lee Matthew Wook Chang 《Cellular and molecular life sciences : CMLS》2018,75(15):2719-2733
Lack of pathogen specificity in antimicrobial therapy causes non-discriminant microbial cell killing that disrupts the microflora present. As a result, potentially helpful microbial cells are killed along with the pathogen, altering the biodiversity and dynamic interactions within the population. Moreover, the unwarranted exposure of antibiotics to microbes increases the likelihood of developing resistance and perpetuates the emergence of multidrug resistance. Synthetic biology offers an alternative solution where specificity can be conferred to reduce the non-specific, non-targeted activity of currently available antibiotics, and instead provides targeted therapy against specific pathogens and minimising collateral damage to the host’s inherent microbiota. With a greater understanding of the microbiome and the available genetic engineering tools for microbial cells, it is possible to devise antimicrobial strategies for novel antimicrobial therapy that are able to precisely and selectively remove infectious pathogens. Herein, we review the strategies developed by unlocking some of the natural mechanisms used by the microbes and how these may be utilised in targeted antimicrobial therapy, with the promise of reducing the current global bane of multidrug antimicrobial resistance. 相似文献
53.
Differential use of an in-frame translation initiation codon regulates human mu opioid receptor (OPRM1) 总被引:1,自引:1,他引:0
Kyu Young Song Hack Sun Choi Cheol Kyu Hwang Chun Sung Kim Ping-Yee Law Li-Na Wei Horace H. Loh 《Cellular and molecular life sciences : CMLS》2009,66(17):2933-2942
The pharmacological effects of morphine and morphine-like drugs are mediated primarily through the μ opioid receptor. Here
we show that differential use of an in-frame translational start codon in the 5′-untranslated region of the OPRM1 generates
different translational products in vivo and in vitro. The 5′-end of the OPRM1 gene is necessary for initiating the alternate
form and for subsequent degradation of the protein. Initiation of OPRM1 at the upstream site decreases the initiation at the
main AUG site. However, alternative initiation of the long form of OPRM1 produces a protein with a short half-life, resulting
from degradation mediated by the ubiquitin–proteasome pathway. Reporter and degradation assays showed that mutations of this
long form at the second and third lysines reduce ubiquitin-dependent proteasome degradation, stabilizing the protein. The
data suggest that MOP expression is controlled in part by initiation of the long form of MOP at the alternate site. 相似文献
54.
Eun Seong Hwang Gyesoon Yoon Hyun Tae Kang 《Cellular and molecular life sciences : CMLS》2009,66(15):2503-2524
Various intracellular organelles, such as lysosomes, mitochondria, nuclei, and cytoskeletons, change during replicative senescence,
but the utility of these changes as general markers of senescence and their significance with respect to functional alterations
have not been comprehensively reviewed. Furthermore, the relevance of these alterations to cellular and functional changes
in aging animals is poorly understood. In this paper, we review the studies that report these senescence-associated changes
in various aging cells and their underlying mechanisms. Changes associated with lysosomes and mitochondria are found not only
in cells undergoing replicative or induced senescence but also in postmitotic cells isolated from aged organisms. In contrast,
other changes occur mainly in cells undergoing in vitro senescence. Comparison of age-related changes and their underlying
mechanisms in in vitro senescent cells and aged postmitotic cells would reveal the relevance of replicative senescence to
the physiological processes occurring in postmitotic cells as individuals age. 相似文献
55.
A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2.
S E Holmes E O'Hearn A Rosenblatt C Callahan H S Hwang R G Ingersoll-Ashworth A Fleisher G Stevanin A Brice N T Potter C A Ross R L Margolis 《Nature genetics》2001,29(4):377-378
We recently described a disorder termed Huntington disease-like 2 (HDL2) that completely segregates with an unidentified CAG/CTG expansion in a large pedigree (W). We now report the cloning of this expansion and its localization to a variably spliced exon of JPH3 (encoding junctophilin-3), a gene involved in the formation of junctional membrane structures. 相似文献
56.
Roell W Lewalter T Sasse P Tallini YN Choi BR Breitbach M Doran R Becher UM Hwang SM Bostani T von Maltzahn J Hofmann A Reining S Eiberger B Gabris B Pfeifer A Welz A Willecke K Salama G Schrickel JW Kotlikoff MI Fleischmann BK 《Nature》2007,450(7171):819-824
Ventricular tachyarrhythmias are the main cause of sudden death in patients after myocardial infarction. Here we show that transplantation of embryonic cardiomyocytes (eCMs) in myocardial infarcts protects against the induction of ventricular tachycardia (VT) in mice. Engraftment of eCMs, but not skeletal myoblasts (SMs), bone marrow cells or cardiac myofibroblasts, markedly decreased the incidence of VT induced by in vivo pacing. eCM engraftment results in improved electrical coupling between the surrounding myocardium and the infarct region, and Ca2+ signals from engrafted eCMs expressing a genetically encoded Ca2+ indicator could be entrained during sinoatrial cardiac activation in vivo. eCM grafts also increased conduction velocity and decreased the incidence of conduction block within the infarct. VT protection is critically dependent on expression of the gap-junction protein connexin 43 (Cx43; also known as Gja1): SMs genetically engineered to express Cx43 conferred a similar protection to that of eCMs against induced VT. Thus, engraftment of Cx43-expressing myocytes has the potential to reduce life-threatening post-infarct arrhythmias through the augmentation of intercellular coupling, suggesting autologous strategies for cardiac cell-based therapy. 相似文献
57.
Bankruptcy prediction methods based on a semiparametric logit model are proposed for simple random (prospective) and case–control (choice‐based; retrospective) data. The unknown parameters and prediction probabilities in the model are estimated by the local likelihood approach, and the resulting estimators are analyzed through their asymptotic biases and variances. The semiparametric bankruptcy prediction methods using these two types of data are shown to be essentially equivalent. Thus our proposed prediction model can be directly applied to data sampled from the two important designs. One real data example and simulations confirm that our prediction method is more powerful than alternatives, in the sense of yielding smaller out‐of‐sample error rates. Copyright © 2007 John Wiley & Sons, Ltd. 相似文献
58.
结合伸缩坐标法和多重尺度法, 对一类一阶常微分方程组的奇异摄动问题构造了一致有效的渐近展开式, 并以Duffing方程为例, 用本文的方法求得其一阶有效的渐近展开式. 结果表明, 所给方法与其他方法所得结果相符. 相似文献
59.
60.
Résumé Par l'injection d'iodoacétate dans l'uf de poule, on peut, par l'analyse histochimique et l'usage du microscope électronique, démontrer la présence d'une augmentation de l'activité du succinodéhydrogénase pendant la période embryonnaire.
Supported by Grant No. G-362 of the National Council to Combat Blindness, Inc., N.Y. 相似文献
Supported by Grant No. G-362 of the National Council to Combat Blindness, Inc., N.Y. 相似文献