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71.
Soler Artigas M Loth DW Wain LV Gharib SA Obeidat M Tang W Zhai G Zhao JH Smith AV Huffman JE Albrecht E Jackson CM Evans DM Cadby G Fornage M Manichaikul A Lopez LM Johnson T Aldrich MC Aspelund T Barroso I Campbell H Cassano PA Couper DJ Eiriksdottir G Franceschini N Garcia M Gieger C Gislason GK Grkovic I Hammond CJ Hancock DB Harris TB Ramasamy A Heckbert SR Heliövaara M Homuth G Hysi PG James AL Jankovic S Joubert BR Karrasch S Klopp N Koch B Kritchevsky SB Launer LJ Liu Y Loehr LR 《Nature genetics》2011,43(11):1082-1090
Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function. 相似文献
72.
Haiman CA Garcia RR Kolonel LN Henderson BE Wu AH Le Marchand L 《Nature genetics》2008,40(3):259-60; author reply 260-1
73.
Edith Jones Norma Gaytan Iraselia Garcia Alan Herrera Manuel Ramos Divya Agarwala Maahrose Rana Wendy Innis-Whitehouse Erin Schuenzel Robert Gilkerson 《Cellular and molecular life sciences : CMLS》2017,74(7):1347-1363
As an organellar network, mitochondria dynamically regulate their organization via opposing fusion and fission pathways to maintain bioenergetic homeostasis and contribute to key cellular pathways. This dynamic balance is directly linked to bioenergetic function: loss of transmembrane potential across the inner membrane (Δψ m) disrupts mitochondrial fission/fusion balance, causing fragmentation of the network. However, the level of Δψ m required for mitochondrial dynamic balance, as well as the relative contributions of fission and fusion pathways, have remained unclear. To explore this, mitochondrial morphology and Δψ m were examined via confocal imaging and tetramethyl rhodamine ester (TMRE) flow cytometry, respectively, in cultured 143B osteosarcoma cells. When normalized to the TMRE value of untreated 143B cells as 100%, both genetic (mtDNA-depleted ρ0) and pharmacological [carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-treated] cell models below 34% TMRE fluorescence were unable to maintain mitochondrial interconnection, correlating with loss of fusion-active long OPA1 isoforms (L-OPA1). Mechanistically, this threshold is maintained by mechanistic coordination of DRP1-mediated fission and OPA1-mediated fusion: cells lacking either DRP1 or the OMA1 metalloprotease were insensitive to loss of Δψ m, instead maintaining an obligately fused morphology. Collectively, these findings demonstrate a mitochondrial ‘tipping point’ threshold mediated by the interaction of Δψ m with both DRP1 and OMA1; moreover, DRP1 appears to be required for effective OPA1 maintenance and processing, consistent with growing evidence for direct interaction of fission and fusion pathways. These results suggest that Δψ m below threshold coordinately activates both DRP1-mediated fission and OMA1 cleavage of OPA1, collapsing mitochondrial dynamic balance, with major implications for a range of signaling pathways and cellular life/death events. 相似文献
74.
The Euro‐Sting Revisited: The Usefulness of Financial Indicators to Obtain Euro Area GDP Forecasts
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This paper uses an extension of the Euro‐Sting single‐index dynamic factor model to construct short‐term forecasts of quarterly GDP growth for the euro area by accounting for financial variables as leading indicators. From a simulated real‐time exercise, the model is used to investigate the forecasting accuracy across the different phases of the business cycle. Our extension is also used to evaluate the relative forecasting ability of the two most reliable business cycle surveys for the euro area: the PMI and the ESI. We show that the latter produces more accurate GDP forecasts than the former. Finally, the proposed model is also characterized by its great ability to capture the European business cycle, as well as the probabilities of expansion and/or contraction periods. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
75.
Estrada K Styrkarsdottir U Evangelou E Hsu YH Duncan EL Ntzani EE Oei L Albagha OM Amin N Kemp JP Koller DL Li G Liu CT Minster RL Moayyeri A Vandenput L Willner D Xiao SM Yerges-Armstrong LM Zheng HF Alonso N Eriksson J Kammerer CM Kaptoge SK Leo PJ Thorleifsson G Wilson SG Wilson JF Aalto V Alen M Aragaki AK Aspelund T Center JR Dailiana Z Duggan DJ Garcia M Garcia-Giralt N Giroux S Hallmans G Hocking LJ Husted LB Jameson KA Khusainova R Kim GS Kooperberg C Koromila T Kruk M Laaksonen M 《Nature genetics》2012,44(5):491-501
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. 相似文献
76.
Modelling conservation in the Amazon basin 总被引:4,自引:0,他引:4
Soares-Filho BS Nepstad DC Curran LM Cerqueira GC Garcia RA Ramos CA Voll E McDonald A Lefebvre P Schlesinger P 《Nature》2006,440(7083):520-523
Expansion of the cattle and soy industries in the Amazon basin has increased deforestation rates and will soon push all-weather highways into the region's core. In the face of this growing pressure, a comprehensive conservation strategy for the Amazon basin should protect its watersheds, the full range of species and ecosystem diversity, and the stability of regional climates. Here we report that protected areas in the Amazon basin--the central feature of prevailing conservation approaches--are an important but insufficient component of this strategy, based on policy-sensitive simulations of future deforestation. By 2050, current trends in agricultural expansion will eliminate a total of 40% of Amazon forests, including at least two-thirds of the forest cover of six major watersheds and 12 ecoregions, releasing 32 +/- 8 Pg of carbon to the atmosphere. One-quarter of the 382 mammalian species examined will lose more than 40% of the forest within their Amazon ranges. Although an expanded and enforced network of protected areas could avoid as much as one-third of this projected forest loss, conservation on private lands is also essential. Expanding market pressures for sound land management and prevention of forest clearing on lands unsuitable for agriculture are critical ingredients of a strategy for comprehensive conservation. 相似文献
77.
78.
A decline in the T-cell population usually marks the onset of progressive immunological disease in individuals infected with the human immunodeficiency virus (HIV). Because CD4+ cells help to coordinate efficient immune responses, some of the defects in the immune function in advanced cases of AIDS may be explained by the disappearance of these cells. Therefore, an understanding of the mechanisms used by HIV to induce the reduction of CD4+ cells is important. Here we use a Moloney murine leukaemia virus-based retroviral vector in order to express the nef gene of HIV-1 in three lymphocytic cell lines expressing CD4. In all cases we find that cell-surface CD4 expression is inversely related to nef expression. However, nef does not alter steady-state levels of CD4 RNA or CD4 protein. Also, nef can downregulate a CD4 triple mutant (Ser----Ala) that is neither phosphorylated nor down-regulated by phorbol esters, indicating that nef is acting by a different mechanism. 相似文献
79.
Sequential chromatographic fractionation of Rhodnius prolixus midgut homogenate yielded only one endopeptidase, but revealed the presence of carboxypeptidase-A and B-like enzyme, di- and tripeptidases, as well as aminopeptidase activities. 相似文献
80.
Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9 总被引:21,自引:0,他引:21
The low-density lipoprotein receptor (LDLR) prevents hypercholesterolemia and atherosclerosis by removing low-density lipoprotein (LDL) from circulation. Mutations in the genes encoding either LDLR or its ligand (APOB) cause severe hypercholesterolemia. Missense mutations in PCSK9, encoding a serine protease in the secretory pathway, also cause hypercholesterolemia. These mutations are probably gain-of-function mutations, as overexpression of PCSK9 in the liver of mice produces hypercholesterolemia by reducing LDLR number. To test whether loss-of-function mutations in PCSK9 have the opposite effect, we sequenced the coding region of PCSK9 in 128 subjects (50% African American) with low plasma levels of LDL and found two nonsense mutations (Y142X and C679X). These mutations were common in African Americans (combined frequency, 2%) but rare in European Americans (<0.1%) and were associated with a 40% reduction in plasma levels of LDL cholesterol. These data indicate that common sequence variations have large effects on plasma cholesterol levels in selected populations. 相似文献