排序方式: 共有12条查询结果,搜索用时 9 毫秒
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Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm 总被引:2,自引:0,他引:2
ME Lindsay D Schepers NA Bolar JJ Doyle E Gallo J Fert-Bober MJ Kempers EK Fishman Y Chen L Myers D Bjeda G Oswald AF Elias HP Levy BM Anderlid MH Yang EM Bongers J Timmermans AC Braverman N Canham GR Mortier HG Brunner PH Byers J Van Eyk L Van Laer HC Dietz BL Loeys 《Nature genetics》2012,44(8):922-927
Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies. 相似文献
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Schulz KG Zondervan I Gerringa LJ Timmermans KR Veldhuis MJ Riebesell U 《Nature》2004,430(7000):673-676
The deposition of atmospheric dust into the ocean has varied considerably over geological time. Because some of the trace metals contained in dust are essential plant nutrients which can limit phytoplankton growth in parts of the ocean, it has been suggested that variations in dust supply to the surface ocean might influence primary production. Whereas the role of trace metal availability in photosynthetic carbon fixation has received considerable attention, its effect on biogenic calcification is virtually unknown. The production of both particulate organic carbon and calcium carbonate (CaCO3) drives the ocean's biological carbon pump. The ratio of particulate organic carbon to CaCO3 export, the so-called rain ratio, is one of the factors determining CO2 sequestration in the deep ocean. Here we investigate the influence of the essential trace metals iron and zinc on the prominent CaCO3-producing microalga Emiliania huxleyi. We show that whereas at low iron concentrations growth and calcification are equally reduced, low zinc concentrations result in a de-coupling of the two processes. Despite the reduced growth rate of zinc-limited cells, CaCO3 production rates per cell remain unaffected, thus leading to highly calcified cells. These results suggest that changes in dust deposition can affect biogenic calcification in oceanic regions characterized by trace metal limitation, with possible consequences for CO2 partitioning between the atmosphere and the ocean. 相似文献
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van de Laar IM Oldenburg RA Pals G Roos-Hesselink JW de Graaf BM Verhagen JM Hoedemaekers YM Willemsen R Severijnen LA Venselaar H Vriend G Pattynama PM Collée M Majoor-Krakauer D Poldermans D Frohn-Mulder IM Micha D Timmermans J Hilhorst-Hofstee Y Bierma-Zeinstra SM Willems PJ Kros JM Oei EH Oostra BA Wessels MW Bertoli-Avella AM 《Nature genetics》2011,43(2):121-126
Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis. 相似文献
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Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy 总被引:6,自引:0,他引:6
Jordanova A Irobi J Thomas FP Van Dijck P Meerschaert K Dewil M Dierick I Jacobs A De Vriendt E Guergueltcheva V Rao CV Tournev I Gondim FA D'Hooghe M Van Gerwen V Callaerts P Van Den Bosch L Timmermans JP Robberecht W Gettemans J Thevelein JM De Jonghe P Kremensky I Timmerman V 《Nature genetics》2006,38(2):197-202
Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration. 相似文献
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Target mimics modulate miRNAs 总被引:4,自引:0,他引:4
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网络表示和网络优化长期以来被用于解决很多工程和科学上的问题.这种应用最早可以追溯到哥尼斯堡七桥问题,然后延伸到各种各样的经典的P类问题和Np-难题,比如最小生成树、最短路及旅行商问题等.为了表述各种子系统之间的关联,在过去几十年里,不同层次的网络扩展被提出来,并对交通和经济这样的复杂系统进行了建模.这些网络扩展被称为超网络,它们可以用统一的方式来描述不同网络上不同选择维度.近年来,多状态的超网络被认为是一种很有潜力的方法来研究基于活动建模领域里的活动和出行行为.本文综述了这方面的研究进展,从最开始的经典交通网络到至今最高层次的一种超网络.这种最高层次的超网络能支持对出行路径和模式选择、活动和停车位置选择、ICT的使用,以及共同出行扣活动的建模. 相似文献
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