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41.
Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters 总被引:5,自引:0,他引:5
42.
Chasman DI Schürks M Anttila V de Vries B Schminke U Launer LJ Terwindt GM van den Maagdenberg AM Fendrich K Völzke H Ernst F Griffiths LR Buring JE Kallela M Freilinger T Kubisch C Ridker PM Palotie A Ferrari MD Hoffmann W Zee RY Kurth T 《Nature genetics》2011,43(7):695-698
Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology. 相似文献
43.
Crossan GP van der Weyden L Rosado IV Langevin F Gaillard PH McIntyre RE;Sanger Mouse Genetics Project Gallagher F Kettunen MI Lewis DY Brindle K Arends MJ Adams DJ Patel KJ 《Nature genetics》2011,43(2):147-152
The evolutionarily conserved SLX4 protein, a key regulator of nucleases, is critical for DNA damage response. SLX4 nuclease complexes mediate repair during replication and can also resolve Holliday junctions formed during homologous recombination. Here we describe the phenotype of the Btbd12 knockout mouse, the mouse ortholog of SLX4, which recapitulates many key features of the human genetic illness Fanconi anemia. Btbd12-deficient animals are born at sub-Mendelian ratios, have greatly reduced fertility, are developmentally compromised and are prone to blood cytopenias. Btbd12(-/-) cells prematurely senesce, spontaneously accumulate damaged chromosomes and are particularly sensitive to DNA crosslinking agents. Genetic complementation reveals a crucial requirement for Btbd12 (also known as Slx4) to interact with the structure-specific endonuclease Xpf-Ercc1 to promote crosslink repair. The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway. 相似文献
44.
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
45.
This article discusses the quest for the mechanical advantage of the wedge in the eighteenth century. As a case study, the wedge enlightens our understanding of eighteenth-century mechanics in general and the controversy over “force” or vis viva in particular. In this article, I show that the two different approaches to mechanics, the one that favoured force in terms of velocities and the one that primarily used displacements—known as the ‘Newtonian’ and ‘Leibnizian’ methods, respectively—were not at all on par in their ability to solve the problem of the wedge. In general, only those who used the Leibnizian concept of force or some related notion were able to get to the conventional results. This article thus rebuts the received view that the vis viva controversy was merely a semantic one. Instead, it shows that different understandings of “force” led to real and pragmatic differences in eighteenth-century mechanics. 相似文献
46.
G. M. C. Janssen P. Schwertman T. A. T. Wanga R. S. Jahangir Tafrechi P. J. A. van den Broek A. K. Raap 《Cellular and molecular life sciences : CMLS》2009,66(4):721-730
Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial
oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA
mutation or in mtDNA-less ρ0 cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor
eIF-2α constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2
becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant
cells. Independent of AMPK and mTOR, eIF-2α is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic
reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears
to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive
protein synthesis inhibition through eIF-2α-mediated repression of translation initiation may have pathobiochemical consequences.
Received 29 October 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献
47.
A. Beqqali W. van Eldik C. Mummery R. Passier 《Cellular and molecular life sciences : CMLS》2009,66(5):800-813
Studies on identification, derivation and characterization of human stem cells in the last decade have led to high expectations
in the field of regenerative medicine. Although it is clear that for successful stem cell-based therapy several obstacles
have to be overcome, other opportunities lay ahead for the use of human stem cells. A more immediate application would be
the development of human models for cell-type specific differentiation and disease in vitro. Cardiomyocytes can be generated from stem cells, which have been shown to follow similar molecular events of cardiac development
in vivo. Furthermore, several monogenic cardiovascular diseases have been described, for which in vitro models in stem cells could be generated. Here, we will discuss the potential of human embryonic stem cells, cardiac stem
cells and the recently described induced pluripotent stem cells as models for cardiac differentiation and disease.
Received 07 August 2008; received after revision 26 September 2008; accepted 03 October 2008 相似文献
48.
E. Hubin N. A. J. van Nuland K. Broersen K. Pauwels 《Cellular and molecular life sciences : CMLS》2014,71(18):3507-3521
The aggregation and deposition of the amyloid-β peptide (Aβ) in the brain has been linked with neuronal death, which progresses in the diagnostic and pathological signs of Alzheimer’s disease (AD). The transition of an unstructured monomeric peptide into self-assembled and more structured aggregates is the crucial conversion from what appears to be a harmless polypeptide into a malignant form that causes synaptotoxicity and neuronal cell death. Despite efforts to identify the toxic form of Aβ, the development of effective treatments for AD is still limited by the highly transient and dynamic nature of interconverting forms of Aβ. The variability within the in vivo “pool” of different Aβ peptides is another complicating factor. Here we review the dynamical interplay between various components that influence the heterogeneous Aβ system, from intramolecular Aβ flexibility to intermolecular dynamics between various Aβ alloforms and external factors. The complex dynamics of Aβ contributes to the causative role of Aβ in the pathogenesis of AD. 相似文献
49.
Marij van Strien 《Annals of science》2013,70(3):381-400
During the period 1860–1880, a number of physicists and mathematicians, including Maxwell, Stewart, Cournot and Boussinesq, used theories formulated in terms of physics to argue that the mind, the soul or a vital principle could have an impact on the body. This paper shows that what was primarily at stake for these authors was a concern about the irreducibility of life and the mind to physics, and that their theories can be regarded primarily as reactions to the law of conservation of energy, which was used among others by Helmholtz and Du Bois-Reymond as an argument against the possibility of vital and mental causes in physiology. In light of this development, Maxwell, Stewart, Cournot and Boussinesq showed that it was still possible to argue for the irreducibility of life and the mind to physics, through an appeal to instability or indeterminism in physics: if the body is an unstable or physically indeterministic system, an immaterial principle can act through triggering or directing motions in the body, without violating the laws of physics. 相似文献
50.