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61.
p53 mutant mice that display early ageing-associated phenotypes. 总被引:56,自引:0,他引:56
Stuart D Tyner Sundaresan Venkatachalam Jene Choi Stephen Jones Nader Ghebranious Herbert Igelmann Xiongbin Lu Gabrielle Soron Benjamin Cooper Cory Brayton Sang Hee Park Timothy Thompson Gerard Karsenty Allan Bradley Lawrence A Donehower 《Nature》2002,415(6867):45-53
The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous tumours compared with wild-type (p53+/+) littermates. As p53+/m mice age, they display an early onset of phenotypes associated with ageing. These include reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance. A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes. These data suggest that p53 has a role in regulating organismal ageing. 相似文献
62.
We argue against claims that the classical ? → 0 limit is “singular” in a way that frustrates an eliminative reduction of classical to quantum physics. We show one precise sense in which quantum mechanics and scaling behavior can be used to recover classical mechanics exactly, without making prior reference to the classical theory. To do so, we use the tools of strict deformation quantization, which provides a rigorous way to capture the ? → 0 limit. We then use the tools of category theory to demonstrate one way that this reduction is explanatory: it illustrates a sense in which the structure of quantum mechanics determines that of classical mechanics. 相似文献
63.
Identification of ten loci associated with height highlights new biological pathways in human growth 总被引:1,自引:0,他引:1
Lettre G Jackson AU Gieger C Schumacher FR Berndt SI Sanna S Eyheramendy S Voight BF Butler JL Guiducci C Illig T Hackett R Heid IM Jacobs KB Lyssenko V Uda M;Diabetes Genetics Initiative;FUSION;KORA;Prostate Lung Colorectal Ovarian Cancer Screening Trial;Nurses' Health Study;SardiNIA Boehnke M Chanock SJ Groop LC Hu FB Isomaa B Kraft P Peltonen L Salomaa V Schlessinger D Hunter DJ Hayes RB Abecasis GR Wichmann HE Mohlke KL Hirschhorn JN 《Nature genetics》2008,40(5):584-591
Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet-undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in >10,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for approximately 2% of the population variation in height. Individuals with < or =8 height-increasing alleles and > or =16 height-increasing alleles differ in height by approximately 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait. 相似文献
64.
Weedon MN Lettre G Freathy RM Lindgren CM Voight BF Perry JR Elliott KS Hackett R Guiducci C Shields B Zeggini E Lango H Lyssenko V Timpson NJ Burtt NP Rayner NW Saxena R Ardlie K Tobias JH Ness AR Ring SM Palmer CN Morris AD Peltonen L Salomaa V;Diabetes Genetics Initiative;Wellcome Trust Case Control Consortium Davey Smith G Groop LC Hattersley AT McCarthy MI Hirschhorn JN Frayling TM 《Nature genetics》2007,39(10):1245-1250
Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 x 10(-8)). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 x 10(-11), overall P = 4 x 10(-16), including the genome-wide association data). We also observed the association in children (P = 1 x 10(-6), N = 6,827) and a tall/short case-control study (P = 4 x 10(-6), N = 3,207). We estimate that rs1042725 explains approximately 0.3% of population variation in height (approximately 0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height. 相似文献
65.
Speciation in animals is almost always envisioned as the split of an existing lineage into an ancestral and a derived species. An alternative speciation route is homoploid hybrid speciation in which two ancestral taxa give rise to a third, derived, species by hybridization without a change in chromosome number. Although theoretically possible it has been regarded as rare and hence of little importance in animals. On the basis of molecular and chromosomal evidence, hybridization is the best explanation for the origin of a handful of extant diploid bisexual animal taxa. Here we report the first case in which hybridization between two host-specific animals (tephritid fruitflies) is clearly associated with the shift to a new resource. Such a hybrid host shift presents an ecologically robust scenario for animal hybrid speciation because it offers a potential mechanism for reproductive isolation through differential adaptation to a new ecological niche. The necessary conditions for this mechanism of speciation are common in parasitic animals, which represent much of animal diversity. The frequency of homoploid hybrid speciation in animals may therefore be higher than previously assumed. 相似文献
66.
An important mechanism for ice cloud formation in the Earth's atmosphere is homogeneous nucleation of ice in aqueous droplets, and this process is generally assumed to produce hexagonal ice. However, there are some reports that the metastable crystalline phase of ice, cubic ice, may form in the Earth's atmosphere. Here we present laboratory experiments demonstrating that cubic ice forms when micrometre-sized droplets of pure water and aqueous solutions freeze homogeneously at cooling rates approaching those found in the atmosphere. We find that the formation of cubic ice is dominant when droplets freeze at temperatures below 190 K, which is in the temperature range relevant for polar stratospheric clouds and clouds in the tropical tropopause region. These results, together with heat transfer calculations, suggest that cubic ice will form in the Earth's atmosphere. If there were a significant fraction of cubic ice in some cold clouds this could increase their water vapour pressure, and modify their microphysics and ice particle size distributions. Under specific conditions this may lead to enhanced dehydration of the tropopause region. 相似文献
67.
Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin 总被引:14,自引:0,他引:14
Otto EA Loeys B Khanna H Hellemans J Sudbrak R Fan S Muerb U O'Toole JF Helou J Attanasio M Utsch B Sayer JA Lillo C Jimeno D Coucke P De Paepe A Reinhardt R Klages S Tsuda M Kawakami I Kusakabe T Omran H Imm A Tippens M Raymond PA Hill J Beales P He S Kispert A Margolis B Williams DS Swaroop A Hildebrandt F 《Nature genetics》2005,37(3):282-288
Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of four genes mutated in NPHP subtypes 1-4 (refs. 4-9) has linked the pathogenesis of NPHP to ciliary functions. Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN. 相似文献
68.
69.
Maternal effect of Hsf1 on reproductive success 总被引:17,自引:0,他引:17
70.