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301.
Suhre K Shin SY Petersen AK Mohney RP Meredith D Wägele B Altmaier E;CARDIoGRAM Deloukas P Erdmann J Grundberg E Hammond CJ de Angelis MH Kastenmüller G Köttgen A Kronenberg F Mangino M Meisinger C Meitinger T Mewes HW Milburn MV Prehn C Raffler J Ried JS Römisch-Margl W Samani NJ Small KS Wichmann HE Zhai G Illig T Spector TD Adamski J Soranzo N Gieger C 《Nature》2011,477(7362):54-60
Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research. 相似文献
302.
Extended megadroughts in the southwestern United States during Pleistocene interglacials 总被引:1,自引:0,他引:1
Fawcett PJ Werne JP Anderson RS Heikoop JM Brown ET Berke MA Smith SJ Goff F Donohoo-Hurley L Cisneros-Dozal LM Schouten S Sinninghe Damsté JS Huang Y Toney J Fessenden J WoldeGabriel G Atudorei V Geissman JW Allen CD 《Nature》2011,470(7335):518-521
The potential for increased drought frequency and severity linked to anthropogenic climate change in the semi-arid regions of the southwestern United States (US) is a serious concern. Multi-year droughts during the instrumental period and decadal-length droughts of the past two millennia were shorter and climatically different from the future permanent, 'dust-bowl-like' megadrought conditions, lasting decades to a century, that are predicted as a consequence of warming. So far, it has been unclear whether or not such megadroughts occurred in the southwestern US, and, if so, with what regularity and intensity. Here we show that periods of aridity lasting centuries to millennia occurred in the southwestern US during mid-Pleistocene interglacials. Using molecular palaeotemperature proxies to reconstruct the mean annual temperature (MAT) in mid-Pleistocene lacustrine sediment from the Valles Caldera, New Mexico, we found that the driest conditions occurred during the warmest phases of interglacials, when the MAT was comparable to or higher than the modern MAT. A collapse of drought-tolerant C(4) plant communities during these warm, dry intervals indicates a significant reduction in summer precipitation, possibly in response to a poleward migration of the subtropical dry zone. Three MAT cycles ~2?°C in amplitude occurred within Marine Isotope Stage (MIS) 11 and seem to correspond to the muted precessional cycles within this interglacial. In comparison with MIS 11, MIS 13 experienced higher precessional-cycle amplitudes, larger variations in MAT (4-6?°C) and a longer period of extended warmth, suggesting that local insolation variations were important to interglacial climatic variability in the southwestern US. Comparison of the early MIS 11 climate record with the Holocene record shows many similarities and implies that, in the absence of anthropogenic forcing, the region should be entering a cooler and wetter phase. 相似文献
303.
Sicardy B Ortiz JL Assafin M Jehin E Maury A Lellouch E Hutton RG Braga-Ribas F Colas F Hestroffer D Lecacheux J Roques F Santos-Sanz P Widemann T Morales N Duffard R Thirouin A Castro-Tirado AJ Jelínek M Kubánek P Sota A Sánchez-Ramírez R Andrei AH Camargo JI da Silva Neto DN Gomes AR Martins RV Gillon M Manfroid J Tozzi GP Harlingten C Saravia S Behrend R Mottola S Melendo EG Peris V Fabregat J Madiedo JM Cuesta L Eibe MT Ullán A Organero F Pastor S de Los Reyes JA Pedraz S Castro A 《Nature》2011,478(7370):493-496
The dwarf planet Eris is a trans-Neptunian object with an orbital eccentricity of 0.44, an inclination of 44 degrees and a surface composition very similar to that of Pluto. It resides at present at 95.7 astronomical units (1?AU is the Earth-Sun distance) from Earth, near its aphelion and more than three times farther than Pluto. Owing to this great distance, measuring its size or detecting a putative atmosphere is difficult. Here we report the observation of a multi-chord stellar occultation by Eris on 6 November 2010 UT. The event is consistent with a spherical shape for Eris, with radius 1,163?±?6?kilometres, density 2.52?±?0.05 grams per cm(3) and a high visible geometric albedo, Pv = 0.96(+0.09)(-0.04). No nitrogen, argon or methane atmospheres are detected with surface pressure larger than ~1?nanobar, about 10,000 times more tenuous than Pluto's present atmosphere. As Pluto's radius is estimated to be between 1,150 and 1,200 kilometres, Eris appears as a Pluto twin, with a bright surface possibly caused by a collapsed atmosphere, owing to its cold environment. We anticipate that this atmosphere may periodically sublimate as Eris approaches its perihelion, at 37.8 astronomical units from the Sun. 相似文献
304.
哈特曼装置上粉尘浓度的测量 总被引:1,自引:0,他引:1
粉尘浓度和湍流速度对粉尘爆炸猛烈程度和粉尘云最小着火能的测试有很大影响.针对1.2 L哈特曼装置上的粉尘浓度进行了测量研究,并对测量数据进行了分析讨论,得到了1.2 L哈特曼管上不同位置高度的粉尘浓度随时间的变化曲线.粉尘浓度随哈特曼管高度位置分布很不均匀.对于哈特曼管电极位置高度,当点火延迟时间170 ms、计算浓度为500 g/m3时,其粉尘测量浓度近似等于计算浓度;当计算浓度低于500 g/m3时,其测量浓度高于计算浓度.当计算浓度大于500 g/m3时,测量浓度低于计算浓度.哈特曼管上粉尘浓度随高度分布的获得,为最小着火能在不同装置上的测试比较提供了数据,为粉尘爆炸数学模型的检验提供了... 相似文献
305.
通过与经典全加器的基本模型进行比较后,讨论了一个改进后的量子平面加法器的基本构型.对其原理、组件和算法进行了研究,比较了本加法器两个主要组件与一般量子加法器的不同.作为应用的例,设计了一个n比特量子全加法器的模型,对其具体运算过程和基本功能进行了说明. 相似文献
306.
J. Kim D. C. Han J. M. Kim S. Y. Lee S. J. Kim J. R. Woo J. W. Lee S.-K. Jung K. S. Yoon H. G. Cheon S. S. Kim S. H. Hong B.-M. Kwon 《Cellular and molecular life sciences : CMLS》2009,66(10):1766-1781
Indenone KR-62776 acts as an agonist of PPARγ without inducing obesity in animal models and cells. X-ray crystallography reveals
that the indenone occupies the binding pocket in a different manner than rosiglitazone. 2-Dimensional gel-electrophoresis
showed that the expression of 42 proteins was altered more than 2.0-fold between KR-62776- or rosiglitazone-treated adipocyte
cells and control cells. Rosiglitazone down-regulated the expression of ERK1/2 and suppressed the phosphorylation of ERK1/2
in these cells. However, the expression of ERK1/2 was up-regulated in KR-62776-treated cells. Phosphorylated ERK1/2, activated
by indenone, affects the localization of PPARγ, suggesting a mechanism for indenone-inhibition of adipogenesis in 3T3-L1 preadipocyte
cells. The preadipocyte cells are treated with ERK1/2 inhibitor PD98059, a large amount of the cells are converted to adipocyte
cells. These results support the conclusion that the localization of PPARγ is one of the key factors explaining the biological
responses of the ligands.
Received 04 March 2009; received after revision 13 March 2009; accepted 17 March 2009 相似文献
307.
Functions and pathologies of BiP and its interaction partners 总被引:1,自引:1,他引:0
J. Dudek J. Benedix S. Cappel M. Greiner C. Jalal L. Müller R. Zimmermann 《Cellular and molecular life sciences : CMLS》2009,66(9):1556-1569
The endoplasmic reticulum (ER) is involved in a variety of essential and interconnected processes in human cells, including
protein biogenesis, signal transduction, and calcium homeostasis. The central player in all these processes is the ER-lumenal
polypeptide chain binding protein BiP that acts as a molecular chaperone. BiP belongs to the heat shock protein 70 (Hsp70)
family and crucially depends on a number of interaction partners, including co-chaperones, nucleotide exchange factors, and
signaling molecules. In the course of the last five years, several diseases have been linked to BiP and its interaction partners,
such as a group of infectious diseases that are caused by Shigella toxin producing E. coli. Furthermore, the inherited diseases Marinesco-Sj?gren syndrome, autosomal dominant polycystic liver disease, Wolcott-Rallison
syndrome, and several cancer types can be considered BiP-related diseases. This review summarizes the physiological and pathophysiological
characteristics of BiP and its interaction partners.
Received 20 November 2008; received after revision 09 December 2008; accepted 12 December 2008 相似文献
308.
Large conductance, Ca2+-activated potassium (BK) channels are widely expressed throughout the animal kingdom and play important roles in many physiological
processes, such as muscle contraction, neural transmission and hearing. These physiological roles derive from the ability
of BK channels to be synergistically activated by membrane voltage, intracellular Ca2+ and other ligands. Similar to voltage-gated K+ channels, BK channels possess a pore-gate domain (S5–S6 transmembrane segments) and a voltage-sensor domain (S1–S4). In addition,
BK channels contain a large cytoplasmic C-terminal domain that serves as the primary ligand sensor. The voltage sensor and
the ligand sensor allosterically control K+ flux through the pore-gate domain in response to various stimuli, thereby linking cellular metabolism and membrane excitability.
This review summarizes the current understanding of these structural domains and their mutual interactions in voltage-, Ca2+ - and Mg2+ -dependent activation of the channel.
Received 25 September 2008; received after revision 23 October 2008; accepted 24 October 2008 相似文献
309.
Dynamic protein methylation in chromatin biology 总被引:1,自引:1,他引:0
310.
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