| 1. |
- Gaudet, Mia M., et al.
(författare)
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Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer
- 2010
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
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| 2. |
- Betoule, M., et al.
(författare)
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Improved cosmological constraints from a joint analysis of the SDSS-II and SNLS supernova samples
- 2014
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 568, s. A22-
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We present cosmological constraints from a joint analysis of type la supernova (SN Ia) observations obtained by the SDSS-II and SNLS collaborations. The dataset includes several low-redshift samples (z < 0.1), all three seasons from the SDSS-11 (0.05 < z < 0.4), and three years from SNLS (0.2 < z < 1), and it totals 740 spectroscopically confirmed type la supernovae with high quality light curves. Methods. We followed the methods and assumptions of the SNLS three-year data analysis except for the following important improvements: I) the addition of the full SDSS-II spectroscopically-confirmed SN la sample in both the training of the SALT2 light-curve model and in the Hubble diagram analysis (374 SNe); 2) intercalibration of the SNLS and SDSS surveys and reduced systematic uncertainties in the photometric calibration, performed blindly with respect to the cosmology analysis; and 3) a thorough investigation of systematic errors associated with the SALT2 modeling of SN la light curves. Results. We produce recalibrated SN la light curves and associated distances for the SDSS-II and SNLS samples. The large SOSS-II sample provides an effective, independent, low -z anchor for the Hubble diagram and reduces the systematic error from calibration systematics in the low -z SN sample. For a flat ACDM cosmology, we find Omega(m), = 0.295 0.034 (stat+sys), a value consistent with the most recent cosmic microwave background (CMB) measurement from the Planck and WMAP experiments. Our result is 1.8 sigma (stat+sys) different than the previously published result of SNLS three-year data. The change is due primarily to improvements in the SNLS photometric calibration. When combined with CMB constraints, we measure a constant dark energy equation of state parameter omega = -1.018 +/- 0,057 (sral+sys) for a fiat universe. Adding baryon acoustic oscillation distance measurements gives similar constraints: omega = 59 -1.027 0.055. Our supernova measurements provide the most stringent constraints to date on the nature of dark energy.
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| 3. |
- D'Andrea, S. D., et al.
(författare)
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Understanding global secondary organic aerosol amount and size-resolved condensational behavior
- 2013
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 13:22, s. 11519-11534
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Tidskriftsartikel (refereegranskat)abstract
- Recent research has shown that secondary organic aerosols (SOA) are major contributors to ultrafine particle growth to climatically relevant sizes, increasing global cloud condensation nuclei (CCN) concentrations within the continental boundary layer (BL). However, there are three recent developments regarding the condensation of SOA that lead to uncertainties in the contribution of SOA to particle growth and CCN concentrations: (1) while many global models contain only biogenic sources of SOA (with annual production rates generally 10-30 Tg yr(-1)), recent studies have shown that an additional source of SOA around 100 Tg yr(-1) correlated with anthropogenic carbon monoxide (CO) emissions may be required to match measurements. (2) Many models treat SOA solely as semi-volatile, which leads to condensation of SOA proportional to the aerosol mass distribution; however, recent closure studies with field measurements show nucleation mode growth can be captured only if it is assumed that a significant fraction of SOA condenses proportional to the Fuchs-corrected aerosol surface area. This suggests a very low volatility of the condensing vapors. (3) Other recent studies of particle growth show that SOA con-densation at sizes smaller than 10 nm and that size-dependent growth rate parameterizations (GRP) are needed to match measurements. We explore the significance of these three findings using GEOS-Chem-TOMAS global aerosol microphysics model and observations of aerosol size distributions around the globe. The change in the concentration of particles of size D-p > 40 nm (N40) within the BL assuming surface-area condensation compared to mass-distribution net condensation yielded a global increase of 11% but exceeded 100% in biogenically active regions. The percent change in N40 within the BL with the inclusion of the additional 100 Tg SOAyr(-1) compared to the base simulation solely with biogenic SOA emissions (19 Tg yr-1) both using surface area condensation yielded a global increase of 13.7 %, but exceeded 50% in regions with large CO emissions. The inclusion of two different GRPs in the additional-SOA case both yielded a global increase in N40 of < 1 %, however exceeded 5% in some locations in the most extreme case. All of the model simulations were compared to measured data obtained from diverse locations around the globe and the results confirmed a decrease in the model-measurement bias and improved slope for comparing modeled to measured CCN number concentration when non-volatile SOA was assumed and the extra SOA was included.
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| 4. |
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| 5. |
- D'Andrea, S. D., et al.
(författare)
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Effect of Secondary Organic Aerosol Amount and Condensational Behavior on Global Aerosol Size Distributions
- 2013
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Ingår i: NUCLEATION AND ATMOSPHERIC AEROSOLS. - : American Institute of Physics (AIP). - 9780735411524 ; , s. 667-670
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Konferensbidrag (refereegranskat)abstract
- Recent research has shown that secondary organic aerosols (SOA) are major contributors to ultrafine particle growth to climatically relevant sizes, increasing global cloud condensation nuclei (CCN) concentrations within the continental boundary layer. Many models treat SOA solely as semivolatile, which leads to condensation of SOA proportional to the aerosol mass distribution; however, recent closure studies with field measurements show that a significant fraction of SOA condenses proportional to the aerosol surface area, which suggests a very low volatility. Additionally, while many global models contain only biogenic sources of SOA (with emissions generally 10-30 Tg yr(-1)), recent studies have shown a need for an additional source of SOA around 100 Tg yr(-1) correlated with anthropogenic carbon monoxide (CO) emissions is required to match measurements. Here, we explore the significance of these two findings using the GEOS-Chem-TOMAS global aerosol microphysics model. The percent change in the number of particles of size D-p > 40 nm (N40) within the continental boundary layer between the surface-area-and mass-distribution condensation schemes, both with the base biogenic SOA only, yielded a global increase of 8% but exceeds 100% in biogenically active regions. The percent change in N40 within the continental boundary layer between the base simulation (19 Tg yr(-1)) and the additional SOA (100 Tg yr(-1)) both using the surface area condensation scheme (very low volatility) yielded a global increase of 14%, and a global decrease in the number of particles of size D-p > 10 nm (N10) of 32%. These model simulations were compared to measured data from Hyytiala, Finland and other global locations and confirmed a decrease in the model-measurement bias. Thus, treating SOA as very low volatile as well as including additional SOA correlated with anthropogenic CO emissions causes a significant global increase in the number of climatically relevant sized particles, and therefore we must continue to refine our SOA treatments in aerosol microphysics models.
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| 6. |
- Pierce, J. R., et al.
(författare)
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Weak global sensitivity of cloud condensation nuclei and the aerosol indirect effect to Criegee + SO2 chemistry
- 2013
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7324. ; 13:6, s. 3163-3176
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Tidskriftsartikel (refereegranskat)abstract
- H2SO4 vapor is important for the nucleation of atmospheric aerosols and the growth of ultrafine particles to cloud condensation nuclei (CCN) sizes with important roles in the global aerosol budget and hence planetary radiative forcing. Recent studies have found that reactions of stabilized Criegee intermediates (CIs, formed from the ozonolysis of alkenes) with SO2 may be an important source of H2SO4 that has been missing from atmospheric aerosol models. For the first time in a global model, we investigate the impact of this new source of H2SO4 in the atmosphere. We use the chemical transport model, GEOS-Chem, with the online aerosol microphysics module, TOMAS, to estimate the possible impact of CIs on present-day H2SO4, CCN, and the cloud-albedo aerosol indirect effect (AIE). We extend the standard GEOS-Chem chemistry with CI-forming reactions (ozonolysis of isoprene, methyl vinyl ketone, methacrolein, propene, and monoterpenes) from the Master Chemical Mechanism. Using a fast rate constant for CI+SO2, we find that the addition of this chemistry increases the global production of H2SO4 by 4 %. H2SO4 concentrations increase by over 100% in forested tropical boundary layers and by over 10-25% in forested NH boundary layers (up to 100% in July) due to CI+SO2 chemistry, but the change is generally negligible elsewhere. The predicted changes in CCN were strongly dampened to the CI+ SO2 changes in H2SO4 in some regions: less than 15% in tropical forests and less than 2% in most mid-latitude locations. The global-mean CCN change was less than 1% both in the boundary layer and the free troposphere. The associated cloud-albedo AIE change was less than 0.03 W m(-2). The model global sensitivity of CCN and the AIE to CI+SO2 chemistry is significantly (approximately one order-of-magnitude) smaller than the sensitivity of CCN and AIE to other uncertain model inputs, such as nucleation mechanisms, primary emissions, SOA (secondary organic aerosol) and deposition. Similarly, comparisons to size-distribution measurements show that uncertainties in other model parameters dominate model biases in the model-predicted size distributions. We conclude that improvement in the modeled CI+SO2 chemistry would not likely lead to significant improvements in present-day CCN and AIE predictions.
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| 7. |
- Wray, Selina, et al.
(författare)
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Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
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