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Chondroitinase ABC promotes functional recovery after spinal cord injury 总被引:82,自引:0,他引:82
Bradbury EJ Moon LD Popat RJ King VR Bennett GS Patel PN Fawcett JW McMahon SB 《Nature》2002,416(6881):636-640
The inability of axons to regenerate after a spinal cord injury in the adult mammalian central nervous system (CNS) can lead to permanent paralysis. At sites of CNS injury, a glial scar develops, containing extracellular matrix molecules including chondroitin sulphate proteoglycans (CSPGs). CSPGs are inhibitory to axon growth in vitro, and regenerating axons stop at CSPG-rich regions in vivo. Removing CSPG glycosaminoglycan (GAG) chains attenuates CSPG inhibitory activity. To test the functional effects of degrading chondroitin sulphate (CS)-GAG after spinal cord injury, we delivered chondroitinase ABC (ChABC) to the lesioned dorsal columns of adult rats. We show that intrathecal treatment with ChABC degraded CS-GAG at the injury site, upregulated a regeneration-associated protein in injured neurons, and promoted regeneration of both ascending sensory projections and descending corticospinal tract axons. ChABC treatment also restored post-synaptic activity below the lesion after electrical stimulation of corticospinal neurons, and promoted functional recovery of locomotor and proprioceptive behaviours. Our results demonstrate that CSPGs are important inhibitory molecules in vivo and suggest that their manipulation will be useful for treatment of human spinal injuries. 相似文献
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Singh R Hoogaars WM Barnett P Grieskamp T Rana MS Buermans H Farin HF Petry M Heallen T Martin JF Moorman AF 't Hoen PA Kispert A Christoffels VM 《Cellular and molecular life sciences : CMLS》2012,69(8):1377-1389
A key step in heart development is the coordinated development of the atrioventricular canal (AVC), the constriction between the atria and ventricles that electrically and physically separates the chambers, and the development of the atrioventricular valves that ensure unidirectional blood flow. Using knock-out and inducible overexpression mouse models, we provide evidence that the developmentally important T-box factors Tbx2 and Tbx3, in a functionally redundant manner, maintain the AVC myocardium phenotype during the process of chamber differentiation. Expression profiling and ChIP-sequencing analysis of Tbx3 revealed that it directly interacts with and represses chamber myocardial genes, and induces the atrioventricular pacemaker-like phenotype by activating relevant genes. Moreover, mutant mice lacking 3 or 4 functional alleles of Tbx2 and Tbx3 failed to form atrioventricular cushions, precursors of the valves and septa. Tbx2 and Tbx3 trigger development of the cushions through a regulatory feed-forward loop with Bmp2, thus providing a mechanism for the co-localization and coordination of these important processes in heart development. 相似文献
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Subbaya Subramanian Reena V. Kartha 《Cellular and molecular life sciences : CMLS》2012,69(21):3571-3585
Sarcomas are a heterogeneous group of tumors with mesenchymal origins. Sarcomas are broadly classified into bone and soft tissue sarcomas with over 50 subtypes. Despite recent advances in sarcoma classification and treatment strategies, the prognosis of some aggressive sarcoma types remains poor due to treatment infectiveness and development of drug resistance. A better understanding of sarcoma pathobiology will significantly increase the potential for the development of therapeutics and treatment strategies. Recently, expressions of microRNAs (miRNA), a class of small non-coding RNAs, have been found to be deregulated in many sarcomas and are implicated in sarcoma pathobiology. Comprehensive understanding of gene regulatory networks mediated by miRNAs in each sarcoma type and the conservation of some shared/conserved miRNA-gene networks could be potentially investigated in the prevention, diagnosis, prognosis and as multi-modal treatment options in these cancers. In this review, we will discuss the current knowledge of miRNA–gene regulatory networks in various sarcoma types and give a perspective of the complex multilayer miRNA-mediated gene regulation in sarcomas. 相似文献
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WF Laurance DC Useche J Rendeiro M Kalka CJ Bradshaw SP Sloan SG Laurance M Campbell K Abernethy P Alvarez V Arroyo-Rodriguez P Ashton J Benítez-Malvido A Blom KS Bobo CH Cannon M Cao R Carroll C Chapman R Coates M Cords F Danielsen B De Dijn E Dinerstein MA Donnelly D Edwards F Edwards N Farwig P Fashing PM Forget M Foster G Gale D Harris R Harrison J Hart S Karpanty WJ Kress J Krishnaswamy W Logsdon J Lovett W Magnusson F Maisels AR Marshall D McClearn D Mudappa MR Nielsen R Pearson N Pitman 《Nature》2012,489(7415):290-294
The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines. 相似文献
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P Dutta G Courties Y Wei F Leuschner R Gorbatov CS Robbins Y Iwamoto B Thompson AL Carlson T Heidt MD Majmudar F Lasitschka M Etzrodt P Waterman MT Waring AT Chicoine AM van der Laan HW Niessen JJ Piek BB Rubin J Butany JR Stone HA Katus SA Murphy DA Morrow MS Sabatine C Vinegoni MA Moskowitz MJ Pittet P Libby CP Lin FK Swirski R Weissleder M Nahrendorf 《Nature》2012,487(7407):325-329
During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression. 相似文献
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