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A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2 总被引:18,自引:0,他引:18
Loeys BL Chen J Neptune ER Judge DP Podowski M Holm T Meyers J Leitch CC Katsanis N Sharifi N Xu FL Myers LA Spevak PJ Cameron DE De Backer J Hellemans J Chen Y Davis EC Webb CL Kress W Coucke P Rifkin DB De Paepe AM Dietz HC 《Nature genetics》2005,37(3):275-281
We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor beta receptor in ten families with a newly described human phenotype that includes widespread perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGFbeta signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFbeta signaling. These data definitively implicate perturbation of TGFbeta signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events. 相似文献
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RNAi-mediated gene silencing in non-human primates 总被引:2,自引:0,他引:2
Zimmermann TS Lee AC Akinc A Bramlage B Bumcrot D Fedoruk MN Harborth J Heyes JA Jeffs LB John M Judge AD Lam K McClintock K Nechev LV Palmer LR Racie T Röhl I Seiffert S Shanmugam S Sood V Soutschek J Toudjarska I Wheat AJ Yaworski E Zedalis W Koteliansky V Manoharan M Vornlocher HP MacLachlan I 《Nature》2006,441(7089):111-114
The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs. 相似文献
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S. E. Judge G. A. Kerkut R. J. Walker 《Cellular and molecular life sciences : CMLS》1976,32(5):596-597
Summary An interneurone, making excitatory synaptic connections with a second neurone has been identified in the brain ofHelix pomatia. The results suggest that the connection is monosynaptic.We thank the M.R.C. for a Training Grant to S.E.J. 相似文献
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Wu J Feng Y Xie D Li X Xiao W Tao D Qin J Hu J Gardner K Judge SI Li QQ Gong J 《Cellular and molecular life sciences : CMLS》2006,63(21):2538-2545
Cyclin-dependent kinase 1 (CDK1) is a major component of the cell cycle progression engine. Recently, several investigations
provided evidence demonstrating that unscheduled CDK1 activation may also be involved in apoptosis in cancerous cells. In
this article, we demonstrate that X-ray irradiation induced G1 arrest in MOLT-4 lymphocytic leukemia cells, the arrest being
accompanied by reduction in the activity of CDK2, but increased CDK1 activity and cell apoptosis in the G1 phase. Interestingly,
this increase in CDK1 and apoptosis by ionizing radiation was prevented by pretreatment with the CDK1 inhibitor, roscovitine,
suggesting that CDK1 kinase activity is required for radiation-induced apoptotic cell death in this model system. Furthermore,
cyclin B1 and CDK1 were detected co-localizing and associating in G1 phase MOLT-4 cells, with the cellular lysates from these
cells revealing a genotoxic stress-induced increase in CDK1 phosphorylation (Thr-161) and dephosphorylation (Tyr-15), as analyzed
by postsorting immunoprecipitation and immunoblotting. Finally, X-irradiation was found to increase Bcl-2 phosphorylation
in G1 phase cells. Taken together, these novel findings suggest that CDK1 is activated by unscheduled accumulation of cyclin
B1 in G1 phase cells exposed to X-ray, and that CDK1 activation, at the wrong time and in the wrong phase, may directly or
indirectly trigger a Bcl-2-dependent signaling pathway leading to apoptotic cell death in MOLT-4 cells.
Received 30 March 2006; received after revision 23 June 2006; accepted 24 August 2006
J. Wu and Y. Feng contributed equally to this work. 相似文献
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An interneurone, making excitatory synaptic connections with a second neurone has been identified in the brain of Helix pomatia. The results suggest that the connection is monosynaptic. 相似文献
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Myofibrillar protein degradation after eccentric exercise 总被引:3,自引:0,他引:3
A. C. Snyder D. R. Lamb C. P. Salm M. D. Judge E. D. Aberle E. W. Mills 《Cellular and molecular life sciences : CMLS》1984,40(1):69-70
Summary Male rats were run downhill for 90 minutes (nonexhaustive). Following the exercise, muscle protein degradation was increased, as determined by urinary 3-methylhistidine. However, minimal changes were observed in the relative percentage of the minor myofibrillar proteins and in the protease calcium activated factor in the long head of the triceps brachii muscle (eccentrically exercised) following the exercise bout. 相似文献
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Myofibrillar protein degradation after eccentric exercise 总被引:2,自引:0,他引:2
Male rats were run downhill for 90 minutes (nonexhaustive). Following the exercise, muscle protein degradation was increased, as determined by urinary 3-methylhistidine. However, minimal changes were observed in the relative percentage of the minor myofibrillar proteins and in the protease calcium activated factor in the long head of the triceps brachii muscle (eccentrically exercised) following the exercise bout. 相似文献
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Consensus supertrees: The synthesis of rooted trees containing overlapping sets of labeled leaves 总被引:2,自引:2,他引:0
AD Gordon 《Journal of Classification》1986,3(2):335-348
Given two dendrograms (rooted tree diagrams) which have some but not all of their base points in common, a supertree is a dendrogram from which each of the original trees can be regarded as samples The distinction is made between inconsistent and consistent sample trees, defined by whether or not the samples provide contradictory information about the supertree An algorithm for obtaining the strict consensus supertree of two consistent sample trees is presented, as are procedures for merging two inconsistent sample trees Some suggestions for future work are made 相似文献
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