Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many ...genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).
To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample.
We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/-10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations.
The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV(1) or FEV(1)/FVC traits using a carefully defined significance threshold of 1.3×10(-5). The most significant loci associated with FEV(1) include SNPs tagging MACROD2 (P = 6.81×10(-5)), CNTN5 (P = 4.37×10(-4)), and TRPV4 (P = 1.58×10(-3)). Among ever-smokers, SERPINA1 showed the most significant association with FEV(1) (P = 8.41×10(-5)), followed by PDE4D (P = 1.22×10(-4)). The strongest association with FEV(1)/FVC ratio was observed with ABCC1 (P = 4.38×10(-4)), and ESR1 (P = 5.42×10(-4)) among ever-smokers.
Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV(1) among smokers in the general population.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To check the accuracy of column-average dry air CO2 mole fractions (XCO2) retrieved from Orbiting Carbon Observatory (OCO-2) data, a similar quantity has been measured from the Multi-functional Fiber ...Laser Lidar (MFLL) aboard aircraft flying underneath OCO-2 as part of the Atmospheric Carbon and Transport (ACT) – America flight campaigns. Here we do a lagged correlation analysis of these MFLL–OCO-2 column CO2 differences and find that their correlation spectrum falls off rapidly at along-track separation distances under 10 km, with a correlation length scale of about 10 km, and less rapidly at longer separation distances, with a correlation length scale of about 20 km.The OCO-2 satellite takes many CO2 measurements with small (∼3 km2) fields of view (FOVs) in a thin (<10 km wide) swath running parallel to its orbit: up to 24 separate FOVs may be obtained per second (across a ∼6.75 km distance on the ground), though clouds, aerosols, and other factors cause considerable data dropout. Errors in the CO2 retrieval method have long been thought to be correlated at these fine scales, and methods to account for these when assimilating these data into top-down atmospheric CO2 flux inversions have been developed. A common approach has been to average the data at coarser scales (e.g., in 10 s long bins) along-track, then assign an uncertainty to the averaged value that accounts for the error correlations. Here we outline the methods used up to now for computing these 10 s averages and their uncertainties, including the constant-correlation-with-distance error model that was used to summarize the OCO-2 version 9 XCO2 retrievals as part of the OCO-2 flux inversion model intercomparison project. We then derive a new one-dimensional error model using correlations that decay exponentially with separation distance, apply this model to the OCO-2 data using the correlation length scales derived from the MFLL–OCO-2 differences, and compare the results (for both the average and its uncertainty) to those given by the current constant correlation error model. To implement this new model, the data are averaged first across 2 s spans to collapse the cross-track distribution of the real data onto the 1-D path assumed by the new model. Considering correlated errors can cause the average value to fall outside the range of the values averaged; two strategies for preventing this are presented. The correlation lengths over the ocean, which the land-based MFLL data do not clarify, are assumed to be twice those over the land.The new correlation model gives 10 s XCO2 averages that are only a few tenths of 1 ppm different from the constant correlation model. Over land, the uncertainties in the mean are also similar, suggesting that the +0.3 constant correlation coefficient currently used in the model there is accurate. Over the oceans, the twice-the-land correlation lengths that we assume here result in a significantly lower uncertainty on the mean than the +0.6 constant correlation currently gives – measurements similar to the MFLL ones are needed over the oceans to do better. Finally, we show how our 1-D exponential error correlation model may be used to account for correlations in inversion methods that choose to assimilate each XCO2 retrieval individually and also to account for correlations between separate 10 s averages when these are assimilated instead.
In the 21st century, intangible resources such as knowledge and social capital have become as necessary to the modern economy as coal, diamonds, and oil were to the past. This shift from ...product-focused to service-focused economies necessitates a drastic re-thinking of the ways in which we support the mission and business of economic development on a global, regional, and national scale. In order to effect and sustain a positive change, innovation and knowledge networks need to be connected to every aspect of life, from the private and domestic, to the corporate and the global. This book integrates a wide variety of perspectives and treatises on mutually adaptive and complementary processes of knowledge generation, diffusion, and transfer within organizations and industry, addressing both the what and how to questions of knowledge management in a conceptual as well as an applied manner. It should be of strong interest to science and technology policy makers, research and development managers, business decision makers, and students of innovation and knowledge dynamics alike.
The receptor subunit gp130 transduces multiple cell type-specific activities of the leukemia inhibitory factor (LIF)/interleukin (IL)-6 family of cytokines through the signal transducer and activator ...of transcription (STAT) and src homology 2 domain-bearing protein tyrosine phosphatase (SHP)-2/ras/Erk pathways. To define STAT-dependent physiological responses, we generated mice with a COOH-terminal gp130(DeltaSTAT) "knock-in" mutation which deleted all STAT-binding sites. gp130(DeltaSTAT) mice phenocopyed mice deficient for IL-6 (impaired humoral and mucosal immune and hepatic acute phase responses) and LIF (failure of blastocyst implantation). However, unlike mice with null mutations in any of the components in the gp130 signaling pathway, gp130(DeltaSTAT) mice also displayed gastrointestinal ulceration and a severe joint disease with features of chronic synovitis, cartilaginous metaplasia, and degradation of the articular cartilage. Mitogenic hyperresponsiveness of synovial cells to the LIF/IL-6 family of cyto-kines was caused by sustained gp130-mediated SHP-2/ras/Erk activation due to impaired STAT-mediated induction of suppressor of cytokine signaling (SOCS) proteins which normally limits gp130 signaling. Therefore, the joint pathology in gp130(DeltaSTAT) mice is likely to arise from the disturbance of the otherwise balanced activation of the SHP-2/ras/Erk and STAT signaling cascades emanating from gp130.
Marine mammals can play important ecological roles in aquatic ecosystems, and their presence can be key to community structure and function. Consequently, marine mammals are often considered ...indicators of ecosystem health and flagship species. Yet, historical population declines caused by exploitation, and additional current threats, such as climate change, fisheries bycatch, pollution and maritime development, continue to impact many marine mammal species, and at least 25% are classified as threatened (Critically Endangered, Endangered or Vulnerable) on the IUCN Red List. Conversely, some species have experienced population increases/recoveries in recent decades, reflecting management interventions, and are heralded as conservation successes. To continue these successes and reverse the downward trajectories of at-risk species, it is necessary to evaluate the threats faced by marine mammals and the conservation mechanisms available to address them. Additionally, there is a need to identify evidence-based priorities of both research and conservation needs across a range of settings and taxa. To that effect we: (1) outline the key threats to marine mammals and their impacts, identify the associated knowledge gaps and recommend actions needed; (2) discuss the merits and downfalls of established and emerging conservation mechanisms; (3) outline the application of research and monitoring techniques; and (4) highlight particular taxa/populations that are in urgent need of focus.
We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma ...risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 × 10−15). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.
Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the ...contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability (Formula: see text) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability (Formula: see text, 0.18-0.34). In the African ancestry samples, Formula: see text was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.
Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European ...and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.
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