| 1. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 3. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 4. |
- Jiao, Xiang, et al.
(författare)
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PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 102769-102782
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Tidskriftsartikel (refereegranskat)abstract
- Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
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| 5. |
- Bien, Stephanie A., et al.
(författare)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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| 6. |
- Brunner, Fabian J., et al.
(författare)
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Application of non-HDL cholesterol for population-based cardiovascular risk stratification : results from the Multinational Cardiovascular Risk Consortium
- 2019
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 394:10215, s. 2173-2183
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Tidskriftsartikel (refereegranskat)abstract
- Background: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment.Methods: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol.Findings: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7–59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0–20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0–1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6–2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0–1·3 to 2·3, 2·0–2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced.Interpretation: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician–patient communication about primary prevention strategies.
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| 7. |
- Chen, Li-Jen, et al.
(författare)
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Electron energization and mixing observed by MMS in the vicinity of an electron diffusion region during magnetopause reconnection
- 2016
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Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 43:12, s. 6036-6043
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Tidskriftsartikel (refereegranskat)abstract
- Measurements from the Magnetospheric Multiscale (MMS) mission are reported to show distinct features of electron energization and mixing in the diffusion region of the terrestrial magnetopause reconnection. At the ion jet and magnetic field reversals, distribution functions exhibiting signatures of accelerated meandering electrons are observed at an electron out-of-plane flow peak. The meandering signatures manifested as triangular and crescent structures are established features of the electron diffusion region (EDR). Effects of meandering electrons on the electric field normal to the reconnection layer are detected. Parallel acceleration and mixing of the inflowing electrons with exhaust electrons shape the exhaust flow pattern. In the EDR vicinity, the measured distribution functions indicate that locally, the electron energization and mixing physics is captured by two-dimensional reconnection, yet to account for the simultaneous four-point measurements, translational invariant in the third dimension must be violated on the ion-skin-depth scale.
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| 8. |
- Couch, Fergus J., et al.
(författare)
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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| 9. |
- Eriksson, Elin, 1989-, et al.
(författare)
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Electron Energization at a Reconnecting Magnetosheath Current Sheet
- 2018
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Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 45:16, s. 8081-8090
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Tidskriftsartikel (refereegranskat)abstract
- We present observations of electron energization within a sub-ion-scale magnetosheath current sheet (CS). A number of signatures indicate ongoing reconnection, including the thickness of the CS (similar to 0.7 ion inertial length), nonzero normal magnetic field, Hall magnetic fields with electrons carrying the Hall currents, and electron heating. We observe localized electron acceleration and heating parallel to the magnetic field at the edges of the CS. Electrostatic waves observed in these regions have low phase velocity and small wave potentials and thus cannot provide the observed acceleration and heating. Instead, we find that the electrons are accelerated by a parallel potential within the separatrix regions. Similar acceleration has been reported based on magnetopause and magnetotail observations. Thus, despite the different plasma conditions in magnetosheath, magnetopause, and magnetotail, the acceleration mechanism and corresponding heating of electrons is similar. Plain Language Summary Magnetic reconnection is an important physical energy conversion process in astrophysical and laboratory plasmas. The easiest place to analyze magnetic reconnection is in near-Earth space. Due to lack of sufficient electron resolution of previous spacecraft missions, there are many unanswered questions regarding electron heating and acceleration processes at small scales. In particular, the regime where thermal pressure dominates over magnetic pressure, the most common state of plasmas in the Universe, is little explored. In this letter we study such a regime using the four-spacecraft Magnetospheric Multiscale mission. We analyze a reconnecting current sheet in the magnetosheath. We show that electrons are energized by a parallel potential, similar to what has been observed in the different plasma regimes the magnetopause and magnetotail. Thus, despite different plasma conditions, a similar acceleration mechanism and corresponding heating of electrons is occurring in all these regions.
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| 10. |
- Gingell, Imogen, et al.
(författare)
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MMS Observations and Hybrid Simulations of Surface Ripples at a Marginally Quasi-Parallel Shock
- 2017
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Ingår i: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 122:11, s. 11003-11017
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Tidskriftsartikel (refereegranskat)abstract
- Simulations and observations of collisionless shocks have shown that deviations of the nominal local shock normal orientation, that is, surface waves or ripples, are expected to propagate in the ramp and overshoot of quasi-perpendicular shocks. Here we identify signatures of a surface ripple propagating during a crossing of Earth's marginally quasi-parallel (theta(Bn) similar to 45 degrees) or quasi-parallel bow shock on 27 November 2015 06: 01: 44 UTC by the Magnetospheric Multiscale (MMS) mission and determine the ripple's properties using multispacecraft methods. Using two-dimensional hybrid simulations, we confirm that surface ripples are a feature of marginally quasi-parallel and quasi-parallel shocks under the observed solar wind conditions. In addition, since these marginally quasi-parallel and quasi-parallel shocks are expected to undergo a cyclic reformation of the shock front, we discuss the impact of multiple sources of nonstationarity on shock structure. Importantly, ripples are shown to be transient phenomena, developing faster than an ion gyroperiod and only during the period of the reformation cycle when a newly developed shock ramp is unaffected by turbulence in the foot. We conclude that the change in properties of the ripple observed by MMS is consistent with the reformation of the shock front over a time scale of an ion gyroperiod.
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| 11. |
- Goodrich, Katherine A., et al.
(författare)
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MMS Multipoint electric field observations of small-scale magnetic holes
- 2016
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Ingår i: Geophysical Research Letters. - : Blackwell Publishing. - 0094-8276 .- 1944-8007. ; 43:12, s. 5953-5959
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Tidskriftsartikel (refereegranskat)abstract
- Small-scale magnetic holes (MHs), local depletions in magnetic field strength, have been observed multiple times in the Earth's magnetosphere in the bursty bulk flow (BBF) braking region. This particular subset of MHs has observed scale sizes perpendicular to the background magnetic field (B) less than the ambient ion Larmor radius (rho(i)). Previous observations by Time History of Events and Macroscale Interactions during Substorms (THEMIS) indicate that this subset of MHs can be supported by a current driven by the E x B drift of electrons. Ions do not participate in the E x B drift due to the small-scale size of the electric field. While in the BBF braking region, during its commissioning phase, the Magnetospheric Multiscale (MMS) spacecraft observed a small-scale MH. The electric field observations taken during this event suggest the presence of electron currents perpendicular to the magnetic field. These observations also suggest that these currents can evolve to smaller spatial scales.
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| 12. |
- Goodrich, Katherine A., et al.
(författare)
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MMS Observations of Electrostatic Waves in an Oblique Shock Crossing
- 2018
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Ingår i: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 123:11, s. 9430-9442
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Tidskriftsartikel (refereegranskat)abstract
- High-resolution particle and wave measurements taken during an oblique bow shock crossing by the Magnetospheric Multiscale (MMS) mission are analyzed. Two regions of differing magnetic behavior are identified within the shock, one with active magnetic fluctuations and one with laminar interplanetary magnetic field topology. A prominent reflected ion population is observed in both regions. The active magnetic region is characterized by large-amplitude (>100 mV/m) electrostatic solitary waves, electron Bernstein waves, and ion acoustic waves, along with intermittent current activity and localized electron heating. In the region of laminar magnetic field, ion acoustic waves are prominently observed. Solar wind ion deceleration is observed in both regions of active and laminar magnetic field. All observations suggest that solar wind deceleration can occur as a result of multiple independent processes, in this case current and ion-ion instabilities.
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| 13. |
- Imamura, Fumiaki, et al.
(författare)
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Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes : A pooled analysis of prospective cohort studies
- 2018
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- Background We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15: 0 and 17: 0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). Methods and findings Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, tri-glycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men ((pinteraction) < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist. Conclusions In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.
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| 14. |
- Johlander, Andreas, 1990-, et al.
(författare)
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Shock ripples observed by the MMS spacecraft : ion reflection and dispersive properties
- 2018
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Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 0741-3335 .- 1361-6587. ; 60
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Tidskriftsartikel (refereegranskat)abstract
- Shock ripples are ion-inertial-scale waves propagating within the front region of magnetized quasi-perpendicular collisionless shocks. The ripples are thought to influence particle dynamics and acceleration at shocks. With the four magnetospheric multiscale (MMS) spacecraft, it is for the first time possible to fully resolve the small scale ripples in space. We use observations of one slow crossing of the Earth's non-stationary bow shock by MMS. From multi-spacecraft measurements we show that the non-stationarity is due to ripples propagating along the shock surface. We find that the ripples are near linearly polarized waves propagating in the coplanarity plane with a phase speed equal to the local Alfvén speed and have a wavelength close to 5 times the upstream ion inertial length. The dispersive properties of the ripples resemble those of Alfvén ion cyclotron waves in linear theory. Taking advantage of the slow crossing by the four MMS spacecraft, we map the shock-reflected ions as a function of ripple phase and distance from the shock. We find that ions are preferentially reflected in regions of the wave with magnetic field stronger than the average overshoot field, while in the regions of lower magnetic field, ions penetrate the shock to the downstream region.
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| 15. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 16. |
- Marklund, Matti, et al.
(författare)
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Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality : An Individual-Level Pooled Analysis of 30 Cohort Studies
- 2019
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Ingår i: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 139:21, s. 2422-2436
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Tidskriftsartikel (refereegranskat)abstract
- Background:Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.Methods:We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).Results:In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15198 incident cardiovascular events occurred among 68659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.Conclusions:In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.
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| 17. |
- Mavaddat, Nasim, et al.
(författare)
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Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:5, s. 036-036
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Tidskriftsartikel (refereegranskat)abstract
- Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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| 18. |
- Nakamura, Rumi, et al.
(författare)
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Multiscale Currents Observed by MMS in the Flow Braking Region
- 2018
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Ingår i: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 123:2, s. 1260-1278
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Tidskriftsartikel (refereegranskat)abstract
- We present characteristics of current layers in the off-equatorial near-Earth plasma sheet boundary observed with high time-resolution measurements from the Magnetospheric Multiscale mission during an intense substorm associated with multiple dipolarizations. The four Magnetospheric Multiscale spacecraft, separated by distances of about 50 km, were located in the southern hemisphere in the dusk portion of a substorm current wedge. They observed fast flow disturbances (up to about 500 km/s), most intense in the dawn-dusk direction. Field-aligned currents were observed initially within the expanding plasma sheet, where the flow and field disturbances showed the distinct pattern expected in the braking region of localized flows. Subsequently, intense thin field-aligned current layers were detected at the inner boundary of equatorward moving flux tubes together with Earthward streaming hot ions. Intense Hall current layers were found adjacent to the field-aligned currents. In particular, we found a Hall current structure in the vicinity of the Earthward streaming ion jet that consisted of mixed ion components, that is, hot unmagnetized ions, cold ExB drifting ions, and magnetized electrons. Our observations show that both the near-Earth plasma jet diversion and the thin Hall current layers formed around the reconnection jet boundary are the sites where diversion of the perpendicular currents take place that contribute to the observed field-aligned current pattern as predicted by simulations of reconnection jets. Hence, multiscale structure of flow braking is preserved in the field-aligned currents in the off-equatorial plasma sheet and is also translated to ionosphere to become a part of the substorm field-aligned current system.
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| 19. |
- Nakamura, Rumi, et al.
(författare)
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Near-Earth plasma sheet boundary dynamics during substorm dipolarization
- 2017
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Ingår i: Earth Planets and Space. - : Springer Berlin/Heidelberg. - 1343-8832 .- 1880-5981. ; 69
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Tidskriftsartikel (refereegranskat)abstract
- We report on the large-scale evolution of dipolarization in the near-Earth plasma sheet during an intense (AL similar to -1000 nT) substorm on August 10, 2016, when multiple spacecraft at radial distances between 4 and 15 RE were present in the night-side magnetosphere. This global dipolarization consisted of multiple short-timescale (a couple of minutes) Bz disturbances detected by spacecraft distributed over 9 MLT, consistent with the large-scale substorm current wedge observed by ground-based magnetometers. The four spacecraft of the Magnetospheric Multiscale were located in the southern hemisphere plasma sheet and observed fast flow disturbances associated with this dipolarization. The high-time-resolution measurements from MMS enable us to detect the rapid motion of the field structures and flow disturbances separately. A distinct pattern of the flow and field disturbance near the plasma boundaries was found. We suggest that a vortex motion created around the localized flows resulted in another fieldaligned current system at the off-equatorial side of the BBF-associated R1/R2 systems, as was predicted by the MHD simulation of a localized reconnection jet. The observations by GOES and Geotail, which were located in the opposite hemisphere and local time, support this view. We demonstrate that the processes of both Earthward flow braking and of accumulated magnetic flux evolving tailward also control the dynamics in the boundary region of the near-Earth plasma sheet.
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| 20. |
- Pan, Dong-Xiao, et al.
(författare)
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Rippled Electron-Scale Structure of a Dipolarization Front
- 2018
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Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 45:22, s. 12116-12124
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Tidskriftsartikel (refereegranskat)abstract
- We use the Magnetospheric Multiscale mission to investigate electron-scale structures at a dipolarization front. The four spacecraft are separated by electron scales and observe large differences in plasma and field parameters within the dipolarization front, indicating strong deviation from typically assumed plane or slightly curved front surface. We attribute this to ripples generated by the lower hybrid drift instability (LHDI) with wave number of k(rho e)similar or equal to 0.4 and maximum wave potential of similar to 1 kV similar to k(B)T(e). Power law-like spectra of E-perpendicular to with slope of -3 indicates the turbulent cascade of LHDI. LHDI is observed together with bursty high-frequency parallel electric fields, suggesting coupling of LHDI to higher-frequency electrostatic waves. Plain Language Summary Dipolarization fronts (DFs) are narrow boundaries with sharp enhancement of magnetic field, located at the leading part of fast plasma jets observed in Earth's magnetotail. DFs are typically assumed to be smooth boundaries at scales comparable to the ion gyroradius and below. In this study, we use the four Magnetospheric Multiscale spacecraft separated by several electron gyroradii to investigate fine structure of a DF. Surprisingly, we observe significant differences in the fields and plasma measurements between the spacecraft despite their small separation. We attribute these signatures to electron-scale disturbances propagating along the DF surface, and thus the DF surface is not smooth as expected but rather rippled. The ripples develop as a result of a plasma instability driven by the strong inhomogeneities present at the DF. The fact that the ripples have such small scales means that they can effectively interact with plasma electrons.
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| 21. |
- Peedu, Elisabet, 1985-
(författare)
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Metapopulations dynamics and sex-specific resource allocation in Silene dioica
- 2018
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rising archipelagos provide unique settings for the study of the temporal and spatial dynamics of their biota. This offers the possibility to study the ecology and genetics of early successional processes; both between islands that differ in age and within islands when already established organisms have to keep pace with the changing environment. I have worked in the Skeppsvik Archipelago housing about 100 islands that due to land uplift vary in age, thus representing various stages of primary succession. I have utilized a naturally created metapopulation of Silene dioica, which in this archipelago is a dominant plant of the deciduous border, offering the possibility to study subpopulations on islands of different ages and in different phases of primary succession. Many plant species exist as metapopulations, which consists of many local populations which may differ in size and degree of connectivity. Metapopulations are further characterized by recurrent colorizations and extinctions of local populations, meaning that a species continually must disperse and relocate to allow for persistence in this system. For a dioecious plant species, gene flow is in the shape of seeds and pollen and to allow for the persistence of populations, it is necessary that levels of seed dispersal and pollen gene flow are enough to ensure both colonisation, establishment and subsequent population growth. Levels of seed dispersal and pollen gene flow is in turn influenced by how the two sexes partition resources between reproduction, growth and survival.In paper I, I combined a field survey, a common garden experiment and a nine-year demographic study to assess the demographic consequences of sex-specific resource allocation and to investigate if differential costs of reproduction may be a driver in the evolution of sexual dimorphism in dioecious Silene dioica. Significant somatic intersexual dimorphism was found with females being the larger sex, both in terms of above – and belowground biomass. Furthermore, the reproductive effort of females exceeds that of males across a growing season which largely confirms what has been observed earlier in dioecious, herbaceous plant species. According to the cost of reproduction hypothesis, high reproductive investment should result in trade-offs with somatic and/or life-history traits. Somatic trade-offs were not observed, and instead I found strong, positive associations between reproductive investment and vegetative growth in both males and females. Compensation mechanisms were found in both sexes although females are generally more efficient at compensating their reproductive costs. At the end of a flowering season, after having paid the current costs of reproduction, females are better than males at provisioning perennial roots and rosettes potentially influencing the ability to set future flower buds and winter survival. Trade-offs were found between current and future reproduction and survival, but this is condition dependent and compensation through frequency of flowering plays an important role. The cost of reproduction hypothesis appears to play some role in driving the somatic and demographic sexual dimorphisms observed in this system but sexual selection acting on males will be a fruitful avenue for future research.In paper II, I investigated the population genetic consequences of metapopulation dynamics in Silene dioica. The occurrence of islands in different phases of primary succession together with successional gradients across islands, makes it possible to investigate the genetic dynamics occurring in an age-structured metapopulation across several hierarchical levels. Genetic diversity and differentiation were estimated in eight young, recently colonised populations and in ten populations of an intermediate successional stage. Young populations were less genetically diverse compared to older populations, indicating that bottlenecks, created by small founding groups derived from a limited number of source populations, reduce the genetic diversity within newly founded populations. The observation of strong genetic structure both between islands and between patches with islands, indicates that gene flow is restricted across several spatial levels in this system. However, the lack of statistically significant differences in genetic differentiation between young and intermediate populations, indicates that levels of gene flow may not be high enough to reduce the genetic differentiation that arise from the initial founder event.The patterns of sexual dimorphism and the roles of males and females in Silene dioica have evolved to allow persistence in an ecological and population context of this species. The nature of this habitat, where islands rise up from the sea creating new environments for colonisation while at the same time, autogenic primary succession processes eventually leads to extinction, means that S. dioica continuously must relocate within successional phases for its persistence. The obvious success of this dioecious plant is apparent as it is one of the few dominant species in the deciduous border. This suggests that levels of seed dispersal and gene flow are sufficient enough to allow for establishment and persistence of island populations and that the sexual dimorphisms that have evolved in this metapopulation system act to increase levels of gene flow. The "live hard – die young" strategy, with extensive flowering bouts, which we find in the males may have evolved as a way of maintaining sufficient levels of genetic diversity in the metapopulation but will only be a possible strategy if there are continuous opportunities for re-establishments. Thus, the continuous land uplift that is occurring in the northern part of the Gulf of Bothnia may very well be a prerequisite for the long-term persistence of this dioecious, perennial plant species.
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| 22. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 23. |
- Schwartz, Steven J., et al.
(författare)
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Ion Kinetics in a Hot Flow Anomaly : MMS Observations
- 2018
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Ingår i: Geophysical Research Letters. - : Blackwell Publishing. - 0094-8276 .- 1944-8007. ; 45:21, s. 11520-11529
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Tidskriftsartikel (refereegranskat)abstract
- Hot Flow Anomalies (HFAs) are transients observed at planetary bow shocks, formed by the shock interaction with a convected interplanetary current sheet. The primary interpretation relies on reflected ions channeled upstream along the current sheet. The short duration of HFAs has made direct observations of this process difficult. We employ high resolution measurements by NASA's Magnetospheric Multiscale Mission to probe the ion microphysics within a HFA. Magnetospheric Multiscale Mission data reveal a smoothly varying internal density and pressure, which increase toward the trailing edge of the HFA, sweeping up particles trapped within the current sheet. We find remnants of reflected or other backstreaming ions traveling along the current sheet, but most of these are not fast enough to out-run the incident current sheet convection. Despite the high level of internal turbulence, incident and backstreaming ions appear to couple gyro-kinetically in a coherent manner. Plain Language Summary Shock waves in space are responsible for energizing particles and diverting supersonic flows around planets and other obstacles. Explosive events known as Hot Flow Anomalies (HFAs) arise when a rapid change in the interplanetary magnetic field arrives at the bow shock formed by, for example, the supersonic solar wind plasma flow from the Sun impinging on the Earth's magnetic environment. HFAs are known to produce impacts all the way to ground level, but the physics responsible for their formation occur too rapidly to be resolved by previous satellite missions. This paper employs NASA's fleet of four Magnetospheric Multiscale satellites to reveal for the first time clear, discreet populations of ions that interact coherently to produce the extreme heating and deflection.
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| 24. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 25. |
- Sorriso-Valvo, Luca, et al.
(författare)
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Sign Singularity of the Local Energy Transfer in Space Plasma Turbulence
- 2019
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Ingår i: Frontiers in Physics. - : FRONTIERS MEDIA SA. - 2296-424X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- In weakly collisional space plasmas, the turbulent cascade provides most of the energy that is dissipated at small scales by various kinetic processes. Understanding the characteristics of such dissipative mechanisms requires the accurate knowledge of the fluctuations that make energy available for conversion at small scales, as different dissipation processes are triggered by fluctuations of a different nature. The scaling properties of different energy channels are estimated here using a proxy of the local energy transfer, based on the third-order moment scaling law for magnetohydrodynamic turbulence. In particular, the sign-singularity analysis was used to explore the scaling properties of the alternating positive-negative energy fluxes, thus providing information on the structure and topology of such fluxes for each of the different type of fluctuations. The results show the highly complex geometrical nature of the flux, and that the local contributions associated with energy and cross-helicity non-linear transfer have similar scaling properties. Consequently, the fractal properties of current and vorticity structures are similar to those of the Alfvenic fluctuations.
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| 26. |
- Sorriso-Valvo, Luca, et al.
(författare)
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Turbulence-Driven Ion Beams in the Magnetospheric Kelvin-Helmholtz Instability
- 2019
-
Ingår i: Physical Review Letters. - : AMER PHYSICAL SOC. - 0031-9007 .- 1079-7114. ; 122:3
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Tidskriftsartikel (refereegranskat)abstract
- The description of the local turbulent energy transfer and the high-resolution ion distributions measured by the Magnetospheric Multiscale mission together provide a formidable tool to explore the cross-scale connection between the fluid-scale energy cascade and plasma processes at subion scales. When the small-scale energy transfer is dominated by Alfvenic, correlated velocity, and magnetic field fluctuations, beams of accelerated particles are more likely observed. Here, for the first time, we report observations suggesting the nonlinear wave-particle interaction as one possible mechanism for the energy dissipation in space plasmas.
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| 27. |
- Toledo-Redondo, Sergio, et al.
(författare)
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Cold ion demagnetization near the X-line of magnetic reconnection
- 2016
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Ingår i: Geophysical Research Letters. - : Blackwell Publishing. - 0094-8276 .- 1944-8007. ; 43:13, s. 6759-6767
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Tidskriftsartikel (refereegranskat)abstract
- Although the effects of magnetic reconnection in magnetospheres can be observed at planetary scales, reconnection is initiated at electron scales in a plasma. Surrounding the electron diffusion region, there is an Ion-Decoupling Region (IDR) of the size of the ion length scales (inertial length and gyroradius). Reconnection at the Earth's magnetopause often includes cold magnetospheric (few tens of eV), hot magnetospheric (10keV), and magnetosheath (1keV) ions, with different gyroradius length scales. We report observations of a subregion inside the IDR of the size of the cold ion population gyroradius (approximate to 15km) where the cold ions are demagnetized and accelerated parallel to the Hall electric field. Outside the subregion, cold ions follow the E x B motion together with electrons, while hot ions are demagnetized. We observe a sharp cold ion density gradient separating the two regions, which we identify as the cold and hot IDRs.
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| 28. |
- Toledo-Redondo, Sergio, et al.
(författare)
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Energy budget and mechanisms of cold ion heating in asymmetric magnetic reconnection
- 2017
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Ingår i: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 122:9, s. 9396-9413
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Tidskriftsartikel (refereegranskat)abstract
- Cold ions (few tens of eV) of ionospheric origin are commonly observed on the magnetospheric side of the Earth's dayside magnetopause. As a result, they can participate in magnetic reconnection, changing locally the reconnection rate and being accelerated and heated. We present four events where cold ion heating was observed by the Magnetospheric Multiscale mission, associated with the magnetospheric Hall E field region of magnetic reconnection. For two of the events the cold ion density was small compared to the magnetosheath density, and the cold ions were heated roughly to the same temperature as magnetosheath ions inside the exhaust. On the other hand, for the other two events the cold ion density was comparable to the magnetosheath density and the cold ion heating observed was significantly smaller. Magnetic reconnection converts magnetic energy into particle energy, and ion heating is known to dominate the energy partition. We find that at least 10-25% of the energy spent by reconnection into ion heating went into magnetospheric cold ion heating. The total energy budget for cold ions may be even higher when properly accounting for the heavier species, namely helium and oxygen. Large E field fluctuations are observed in this cold ion heating region, i.e., gradients and waves, that are likely the source of particle energization. Plain Language Summary The magnetic field of Earth creates a natural shield that isolates and protects us from the particles and fields coming from our star, the Sun. This natural shield is called the magnetosphere and is filled by plasma. The particles coming from the Sun form another plasma called the solar wind and are usually deviated around the magnetosphere. However, under certain circumstances these two plasmas can reconnect (magnetic reconnection), and part of the energy and mass of the two plasmas is interchanged. Magnetic reconnection is the driver of storms and substorms inside the magnetosphere. In this work, we investigate what occurs to particles of very low energy (cold ions) of ionospheric origin when they reach the reconnecting boundary of the magnetosphere. It is found that they are energized and take an important part of the energy spent in reconnecting the plasmas. The plasma boundary develops spatial structures and emits waves that are able to heat the cold ions. Once heated, these cold ions irreversibly will escape the Earth's magnetosphere to never come back to Earth.
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| 29. |
- Toledo-Redondo, Sergio, et al.
(författare)
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Perpendicular Current Reduction Caused by Cold Ions of Ionospheric Origin in Magnetic Reconnection at the Magnetopause : Particle-in-Cell Simulations and Spacecraft Observations
- 2018
-
Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 45:19, s. 10033-10042
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Tidskriftsartikel (refereegranskat)abstract
- Cold ions of ionospheric origin are present throughout the Earth's magnetosphere, including the dayside magnetopause, where they modify the properties of magnetic reconnection, a major coupling mechanism at work between the magnetosheath and the magnetosphere. We present Magnetospheric MultiScale (MMS) spacecraft observations of the reconnecting magnetopause with different amounts of cold ions and show that their presence reduces the Hall term in the Ohm's law. Then, we compare two particle-in-cell simulations, with and without cold ions on the magnetospheric side. The cold ions remain magnetized inside the magnetospheric separatrix region, leading to the reduction of the perpendicular currents associated with the Hall effect. Moreover, this reduction is proportional to the relative number density of cold ions. And finally, the Hall electric field peak is reduced along the magnetospheric separatrix owing to cold ions. This should have an effect on energy conversion by reconnection from electromagnetic fields to kinetic energy of the particles. Plain Language Summary The magnetic field of Earth creates a natural boundary that isolates and protects us from the particles and fields coming from the Sun, typically known as the solar wind. This natural shield is called the magnetosphere and is filled by plasma. The particles are coming from the solar wind and are usually deviated around the magnetosphere. However, various mechanisms are capable of interconnecting these two regions of plasma, permitting the exchange of mass and energy. Magnetic reconnection is a primary coupling mechanism and the driver of storms and substorms inside the magnetosphere. In this work, we investigate what occurs when particles of very low energy (cold ions) of ionospheric origin reach the reconnecting boundary between the solar wind and the magnetosphere. We use both spacecraft observations and numerical simulations, and we find that they modify the way reconnection operates, by reducing the currents carried by electrons. The electric fields associated with energization of particles are reduced as well under the presence of cold ions coming from the ionosphere.
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| 30. |
- Wang, Rongsheng, et al.
(författare)
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An Electron-Scale Current Sheet Without Bursty Reconnection Signatures Observed in the Near-Earth Tail
- 2018
-
Ingår i: Geophysical Research Letters. - : AMER GEOPHYSICAL UNION. - 0094-8276 .- 1944-8007. ; 45:10, s. 4542-4549
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Tidskriftsartikel (refereegranskat)abstract
- Observations of a current sheet as thin as the electron scale are extremely rare in the near-Earth magnetotail. By measurement from the novel Magnetospheric Multiscale mission in the near-Earth magnetotail, we identified such an electron-scale current sheet and determined its detailed properties. The electron current sheet was bifurcated, with a half-thickness of nine electron inertial lengths, and was sandwiched between the Hall field. Because of the strong Hall electric field, the super-Alfvenic electron bulk flows were created mainly by the electric field drift, leading to the generation of the strong electron current. Inevitably, a bifurcated current sheet was formed since the Hall electric field was close to zero at the center of the current sheet. Inside the electron current sheet, the electrons were significantly heated while the ion temperature showed no change. The ions kept moving at a low speed, which was not affected by this electron current sheet. The energy dissipation was negligible inside the current sheet. The observations indicate that a thin current sheet, even as thin as electron scale, is not the sufficient condition for triggering bursty reconnection.
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| 31. |
- Wang, Rongsheng, et al.
(författare)
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Interaction of Magnetic Flux Ropes Via Magnetic Reconnection Observed at the Magnetopause
- 2017
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Ingår i: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 122:10, s. 10436-10447
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Tidskriftsartikel (refereegranskat)abstract
- Using the high-resolution field and plasma data obtained from the Magnetospheric Multiscale mission at the magnetopause, a series of three flux transfer events was observed one after another inside southward ion flows, without time gap between any two successive flux ropes. Using the plasma measurements, the current densities within the flux ropes were studied in detail. The currents within the first two flux ropes, dubbed Fr1 and Fr2, were composed of a series of well-separated filamentary currents. The thickness of the filamentary currents and the gap between them were sub ion scale, occasionally dropped down to electron scale. In the third flux rope Fr3 which was closest to the expected reconnection X line, the current displayed a singular compact current layer, was ion scale in width and concentrated on its center. Considering the location of the flux ropes relative to the reconnection X line, we suggested that the current density could be a singular structure when the flux rope was just created and then fragmented into a series of filamentary currents as time. By examining the interregions between Fr1 and Fr2, and between Fr2 and Fr3, reconnection was only confirmed to occur between Fr2 and Fr3 and no reconnection signature was found between Fr1 and Fr2. It seems that magnetic field compression resulted from collision of two neighboring flux ropes is one necessary condition for the occurrence of the coalescence.
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| 32. |
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| 33. |
- Watts, Eleanor L., et al.
(författare)
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Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:12
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin.Methods: Statistical analyses of individual participant data from 12,330 male controls aged 25–85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates.Results: Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones.Conclusion: Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption.
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| 34. |
- Watts, Eleanor L., et al.
(författare)
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Low Free Testosterone and Prostate Cancer Risk : A Collaborative Analysis of 20 Prospective Studies
- 2018
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Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 74:5, s. 585-594
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Tidskriftsartikel (refereegranskat)abstract
- Background: Experimental and clinical evidence implicates testosterone in the aetiology of prostate cancer. Variation across the normal range of circulating free testosterone concentrations may not lead to changes in prostate biology, unless circulating concentrations are low. This may also apply to prostate cancer risk, but this has not been investigated in an epidemiological setting. Objective: To examine whether men with low concentrations of circulating free testosterone have a reduced risk of prostate cancer. Design, setting, and participants: Analysis of individual participant data from 20 prospective studies including 6933 prostate cancer cases, diagnosed on average 6.8 yr after blood collection, and 12 088 controls in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group. Outcome measurements and statistical analysis: Odds ratios (ORs) of incident overall prostate cancer and subtypes by stage and grade, using conditional logistic regression, based on study-specific tenths of calculated free testosterone concentration. Results and limitations: Men in the lowest tenth of free testosterone concentration had a lower risk of overall prostate cancer (OR = 0.77, 95% confidence interval [CI] 0.69-0.86; p < 0.001) compared with men with higher concentrations (2nd-10th tenths of the distribution). Heterogeneity was present by tumour grade (p(het) = 0.01), with a lower risk of low-grade disease (OR = 0.76, 95% CI 0.67-0.88) and a nonsignificantly higher risk of high-grade disease (OR = 1.56, 95% CI 0.95-2.57). There was no evidence of heterogeneity by tumour stage. The observational design is a limitation. Conclusions: Men with low circulating free testosterone may have a lower risk of overall prostate cancer; this may be due to a direct biological effect, or detection bias. Further research is needed to explore the apparent differential association by tumour grade. Patient summary: In this study, we looked at circulating testosterone levels and risk of developing prostate cancer, finding that men with low testosterone had a lower risk of prostate cancer. (c) 2018 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.
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| 35. |
- Webb, Robert, et al.
(författare)
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Sustainable urban systems : Co-design and framing for transformation
- 2018
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Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 47:1, s. 57-77
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Tidskriftsartikel (refereegranskat)abstract
- Rapid urbanisation generates risks and opportunities for sustainable development. Urban policy and decision makers are challenged by the complexity of cities as social-ecological-technical systems. Consequently there is an increasing need for collaborative knowledge development that supports a whole-of-system view, and transformational change at multiple scales. Such holistic urban approaches are rare in practice. A co-design process involving researchers, practitioners and other stakeholders, has progressed such an approach in the Australian context, aiming to also contribute to international knowledge development and sharing. This process has generated three outputs: (1) a shared framework to support more systematic knowledge development and use, (2) identification of barriers that create a gap between stated urban goals and actual practice, and (3) identification of strategic focal areas to address this gap. Developing integrated strategies at broader urban scales is seen as the most pressing need. The knowledge framework adopts a systems perspective that incorporates the many urban trade-offs and synergies revealed by a systems view. Broader implications are drawn for policy and decision makers, for researchers and for a shared forward agenda.
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- Zeng, Chenjie, et al.
(författare)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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