| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
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| 9. |
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| 10. |
- Fomalont, E. B., et al.
(författare)
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THE 2014 ALMA LONG BASELINE CAMPAIGN: AN OVERVIEW
- 2015
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 808:1
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Tidskriftsartikel (refereegranskat)abstract
- A major goal of the Atacama Large Millimeter/submillimeter Array (ALMA) is to make accurate images with resolutions of tens of milliarcseconds, which at submillimeter (submm) wavelengths requires baselines up to similar to 15 km. To develop and test this capability, a Long Baseline Campaign (LBC) was carried out from 2014 September to late November, culminating in end-to-end observations, calibrations, and imaging of selected Science Verification (SV) targets. This paper presents an overview of the campaign and its main results, including an investigation of the short-term coherence properties and systematic phase errors over the long baselines at the ALMA site, a summary of the SV targets and observations, and recommendations for science observing strategies at long baselines. Deep ALMA images of the quasar 3C 138 at 97 and 241 GHz are also compared to VLA 43 GHz results, demonstrating an agreement at a level of a few percent. As a result of the extensive program of LBC testing, the highly successful SV imaging at long baselines achieved angular resolutions as fine as 19 mas at similar to 350 GHz. Observing with ALMA on baselines of up to 15 km is now possible, and opens up new parameter space for submm astronomy.
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| 11. |
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| 14. |
- Lozano, Rafael, et al.
(författare)
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Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017
- 2018
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Ingår i: The Lancet. - : Elsevier. - 1474-547X .- 0140-6736. ; 392:10159, s. 2091-2138
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Tidskriftsartikel (refereegranskat)abstract
- Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59·4 (IQR 35·4–67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6–14·0) to a high of 84·9 (83·1–86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030.
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| 15. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 16. |
- Cheng, THT, et al.
(författare)
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Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1
- 2015
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5, s. 17369-
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Tidskriftsartikel (refereegranskat)abstract
- High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10−9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10−8), with the alleles showing opposite effects on the risks of the two cancers.
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| 17. |
- Sarwar, Nadeem, et al.
(författare)
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Interleukin-6 receptor pathways in coronary heart disease : a collaborative meta-analysis of 82 studies
- 2012
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Ingår i: The Lancet. - New York, NY, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 379:9822, s. 1205-1213
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Tidskriftsartikel (refereegranskat)abstract
- Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
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| 18. |
- Forabosco, P., et al.
(författare)
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Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus
- 2006
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 7:7, s. 609-614
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Tidskriftsartikel (refereegranskat)abstract
- A genetic contribution to the development of systemic lupus erythematosus (SLE) is well established. Several genome-wide linkage scans have identified a number of putative susceptibility loci for SLE, some of which have been replicated in independent samples. This study aimed to identify the regions showing the most consistent evidence for linkage by applying the genome scan meta-analysis (GSMA) method. The study identified two genome-wide suggestive regions on 6p21.1-q15 and 20p11-q13.13 (P-value=0.0056 and P-value=0.0044, respectively) and a region with P-value<0.01 on 16p13-q12.2.The region on chromosome 6 contains the human leukocyte antigen cluster, and the chromosome 16 and 20 regions have been replicated in several cohorts. The potential importance of the identified genomic regions are also highlighted. These results, in conjunction with data emerging from dense single nucleotide polymorphism typing of specific regions or future genome-wide association studies will help guide efforts to identify the actual predisposing genetic variation contributing to this complex genetic disease.
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| 19. |
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| 20. |
- O'Mara, TA, et al.
(författare)
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Identification of nine new susceptibility loci for endometrial cancer
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 3166-
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
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| 21. |
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| 22. |
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| 23. |
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| 24. |
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Gaziano, Liam, et al.
(författare)
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Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19
- 2021
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Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 27:4
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale Mendelian randomization and colocalization analyses using gene expression and soluble protein data for 1,263 actionable druggable genes, which encode protein targets for approved drugs or drugs in clinical development, identify IFNAR2 and ACE2 as the most promising therapeutic targets for early management of COVID-19. Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 x 10(-6); IFNAR2, P = 9.8 x 10(-11) and IL-10RB, P = 2.3 x 10(-14)) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.
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| 29. |
- Guilding, C., et al.
(författare)
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Defining and unpacking the core concepts of pharmacology: A global initiative
- 2024
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Ingår i: British Journal of Pharmacology. - 0007-1188. ; 181:3, s. 375-392
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Tidskriftsartikel (refereegranskat)abstract
- Background and PurposeDevelopment of core concepts in disciplines such as biochemistry, microbiology and physiology have transformed teaching. They provide the foundation for the development of teaching resources for global educators, as well as valid and reliable approaches to assessment. An international research consensus recently identified 25 core concepts of pharmacology. The current study aimed to define and unpack these concepts.Experimental ApproachA two-phase, iterative approach, involving 60 international pharmacology education experts, was used. The first phase involved drafting definitions for core concepts and identifying key sub-concepts via a series of online meetings and asynchronous work. These were refined in the second phase, through a 2-day hybrid workshop followed by a further series of online meetings and asynchronous work.Key ResultsThe project produced consensus definitions for a final list of 24 core concepts and 103 sub-concepts of pharmacology. The iterative, discursive methodology resulted in modification of concepts from the original study, including change of 'drug-receptor interaction' to 'drug-target interaction' and the change of the core concept 'agonists and antagonists' to sub-concepts of drug-target interaction.Conclusions and ImplicationsDefinitions and sub-concepts of 24 core concepts provide an evidence-based foundation for pharmacology curricula development and evaluation. The next steps for this project include the development of a concept inventory to assess acquisition of concepts, as well as the development of case studies and educational resources to support teaching by the global pharmacology community, and student learning of the most critical and fundamental concepts of the discipline.
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| 30. |
- O Gorman, Eamon, 1984, et al.
(författare)
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A search for radio emission from exoplanets around evolved stars
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 612
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Tidskriftsartikel (refereegranskat)abstract
- The majority of searches for radio emission from exoplanets have to date focused on short period planets, i.e., the so-called hot Jupiter type planets. However, these planets are likely to be tidally locked to their host stars and may not generate sufficiently strong magnetic fields to emit electron cyclotron maser emission at the low frequencies used in observations (typically >= 150 MHz). In comparison, the large mass-loss rates of evolved stars could enable exoplanets at larger orbital distances to emit detectable radio emission. Here, we first show that the large ionized mass-loss rates of certain evolved stars relative to the solar value could make them detectable with the LOw Frequency ARray (LOFAR) at 150 MHz (lambda = 2 m), provided they have surface magnetic field strengths >50 G. We then report radio observations of three long period (>1 au) planets that orbit the evolved stars beta Gem, iota Dra, and beta UMi using LOFAR at 150 MHz. We do not detect radio emission from any system but place tight 3 sigma upper limits of 0.98, 0.87, and 0.57 mJy on the flux density at 150 MHz for beta Gem, iota Dra, and beta UMi, respectively. Despite our non-detections these stringent upper limits highlight the potential of LOFAR as a tool to search for exoplanetary radio emission at meter wavelengths.
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| 31. |
- O'Connor, U, et al.
(författare)
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Feasibility study of computational occupational dosimetry : evaluating a proof-of-concept in an endovascular and interventional cardiology setting
- 2022
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Ingår i: Journal of Radiological Protection. - : IOP Publishing. - 1361-6498 .- 0952-4746. ; 42:4
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Tidskriftsartikel (refereegranskat)abstract
- Individual monitoring of radiation workers is essential to ensure compliance with legal dose limits and to ensure that doses are As Low As Reasonably Achievable. However, large uncertainties still exist in personal dosimetry and there are issues with compliance and incorrect wearing of dosimeters. The objective of the PODIUM (Personal Online Dosimetry Using Computational Methods) project was to improve personal dosimetry by an innovative approach: the development of an online dosimetry application based on computer simulations without the use of physical dosimeters. Occupational doses were calculated based on the use of camera tracking devices, flexible individualised phantoms and data from the radiation source. When combined with fast Monte Carlo simulation codes, the aim was to perform personal dosimetry in real-time. A key component of the PODIUM project was to assess and validate the methodology in interventional radiology workplaces where improvements in dosimetry are needed. This paper describes the feasibility of implementing the PODIUM approach in a clinical setting. Validation was carried out using dosimeters worn by Vascular Surgeons and Interventional Cardiologists during patient procedures at a hospital in Ireland. Our preliminary results from this feasibility study show acceptable differences of the order of 40% between calculated and measured staff doses, in terms of the personal dose equivalent quantity Hp(10), however there is a greater deviation for more complex cases and improvements are needed. The challenges of using the system in busy interventional rooms have informed the future needs and applicability of PODIUM. The availability of an online personal dosimetry application has the potential to overcome problems that arise from the use of current dosimeters. In addition, it should increase awareness of radiation protection among staff. Some limitations remain and a second phase of development would be required to bring the PODIUM method into operation in a hospital setting. However, an early prototype system has been tested in a clinical setting and the results from this two-year proof-of-concept PODIUM project are very promising for future development.
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| 32. |
- Olahova, M., et al.
(författare)
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POLRMT mutations impair mitochondrial transcription causing neurological disease
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase gamma, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism. POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.
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| 33. |
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Almanza, A., et al.
(författare)
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Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications
- 2019
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Ingår i: Febs Journal. - : Wiley. - 1742-464X. ; 286:2, s. 241-278
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Tidskriftsartikel (refereegranskat)abstract
- The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.
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| 38. |
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| 39. |
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| 40. |
- Dunnett, Kirsty, et al.
(författare)
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Assessing first-year undergraduate physics students' laboratory practices : seeking to encourage research behaviours
- 2019
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Ingår i: European journal of physics. - : IOP Publishing. - 0143-0807 .- 1361-6404. ; 40:1
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Tidskriftsartikel (refereegranskat)abstract
- Encouraging positive inquiry-focused behaviours within the constraints of a physics teaching laboratory environment can be challenging. Here, we report on an implementation, the 'working grade' ( w-grade), designed to directly assess aspects of students' laboratory practice with the aim of encouraging first-year undergraduate students to look beyond the concept of a correct outcome' to a physics experiment. The w-grade is composed of the five aspects of group work, querying, exploration, attitude and progress which are each marked on a 0, 1, 2, 3 scale. The initial implementation is presented in full as well as a second, simpler variant. The w-grade emphasises and directly rewards inquiry behaviours and students were much more willing to explore the experiments than in previous years.
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| 41. |
- Erdinc, Direnis, et al.
(författare)
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Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability
- 2023
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Ingår i: Embo Molecular Medicine. - 1757-4676. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Topoisomerase 3 alpha (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
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| 42. |
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| 43. |
- Gianfrancesco, MA, et al.
(författare)
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Genetic risk factors for pediatric-onset multiple sclerosis
- 2018
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 24:14, s. 1825-1834
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Tidskriftsartikel (refereegranskat)abstract
- Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10−16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10−16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.
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| 44. |
- Gorman, D. J., et al.
(författare)
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When is spinal pain "neuropathic"?
- 2004
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Ingår i: Orthop Clin North Am. - 0030-5898. ; 35:1, s. 73-84
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Tidskriftsartikel (refereegranskat)abstract
- Although one cannot always determine when a patient's persistent pain is neuropathic, the issues are becoming clearer. Patients with spinal pain need to be examined carefully and the persistence of pain should not necessarily be considered to indicate a continuing search for a nociceptive focus. Similarly, continuing pain following successful surgery may be caused by persistent spinal or central neurologic changes. New methods for characterizing the site of neural changes will develop--functional MRI and PET scanning are now characterizing brain activity and will possibly yield results soon that will be helpful in the clinic. Further work needs to be done to identify which clinical features lead to better responses to agents for the treatment of neuropathic pain. New, more specific agents with actions focused on the specific parts of neural transmission are being developed. These include agents (such as growth factors) that will cure, not just suppress, the pathologic pain generators and pathways in patients with persistent pain.
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| 45. |
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| 46. |
- Khouri, Theo, 1985, et al.
(författare)
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Study of the inner dust envelope and stellar photosphere of the AGB star R Doradus using SPHERE/ZIMPOL
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 591
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Tidskriftsartikel (refereegranskat)abstract
- Context. On the asymptotic giant branch (AGB) low-and intermediate-mass stars eject a large fraction of their envelope, but the mechanism driving these outflows is still poorly understood. For oxygen-rich AGB stars, the wind is thought to be driven by radiation pressure caused by scattering of radiation off dust grains. Aims. We study the photosphere, the warm molecular layer, and the inner wind of the close-by oxygen-rich AGB star R Doradus. We focus on investigating the spatial distribution of the dust grains that scatter light and whether these grains can be responsible for driving the outflow of this star. Methods. We use high-angular-resolution images obtained with SPHERE/ZIMPOL to study R Dor and its inner envelope in a novel way. We present observations in filters V, cntH alpha, and cnt820 and investigate the surface brightness distribution of the star and of the polarised light produced in the inner envelope. Thanks to second-epoch observations in cntH alpha, we are able to see variability on the stellar photosphere. We study the polarised-light data using a continuum-radiative-transfer code that accounts for direction-dependent scattering of photons off dust grains. Results. We find that in the first epoch the surface brightness of R Dor is asymmetric in V and cntH alpha, the filters where molecular opacity is stronger, while in cnt820 the surface brightness is closer to being axisymmetric. The second-epoch observations in cntH alpha show that the morphology of R Dor has changed completely in a timespan of 48 days to a more axisymmetric and compact configuration. This variable morphology is probably linked to changes in the opacity provided by TiO molecules in the extended atmosphere. The observations show polarised light coming from a region around the central star. The inner radius of the region from where polarised light is seen varies only by a small amount with azimuth. The value of the polarised intensity, however, varies by between a factor of 2.3 and 3.7 with azimuth for the different images. We fit the radial profile of the polarised intensity using a spherically symmetric model and a parametric description of the dust density profile, rho(r) = rho(degrees)r(-n). On average, we find exponents of -4.5 +/- 0.5 that correspond to a much steeper density profile than that of a wind expanding at constant velocity. The dust densities we derive imply an upper limit for the dust-to-gas ratio of similar to 2 x 10(-4) at 5.0 R-*. Considering all the uncertainties in observations and models, this value is consistent with the minimum values required by wind-driving models for the onset of a wind, of similar to 3.3 x 10(-4). However, if the steep density profile we find extends to larger distances from the star, the dust-to-gas ratio will quickly become too small for the wind of R Dor to be driven by the grains that produce the scattered light.
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| 47. |
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| 48. |
- Nicholls, Thomas J., et al.
(författare)
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Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA
- 2018
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 69:1
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Tidskriftsartikel (refereegranskat)abstract
- How mtDNA replication is terminated and the newly formed genomes are separated remain unknown. We here demonstrate that the mitochondrial isoform of topoisomerase 3α (Top3α) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLM-Top3α-RMI1-RMI2 (BTR) complex. Our data indicate that mtDNA replication termination occurs via a hemicatenane formed at the origin of H-strand replication and that Top3α is essential for resolving this structure. Decatenation is a prerequisite for separation of the segregating unit of mtDNA, the nucleoid, within the mitochondrial network. The importance of this process is highlighted in a patient with mitochondrial disease caused by biallelic pathogenic variants in TOP3A, characterized by muscle-restricted mtDNA deletions and chronic progressive external ophthalmoplegia (CPEO) plus syndrome. Our work establishes Top3α as an essential component of the mtDNA replication machinery and as the first component of the mtDNA separation machinery. Nicholls et al. identify a role for topoisomerase 3α in the separation of mtDNA following replication. Loss of Top3α activity impairs mtDNA segregation and, consequently, segregation of the mtDNA nucleoid within the mitochondrial network. Mutations in TOP3A cause human mitochondrial disease associated with mtDNA deletions and impaired mtDNA separation. © 2017 Elsevier Inc.
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| 49. |
- O Gorman, Eamon, 1984, et al.
(författare)
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ALMA Observations of Anisotropic Dust Mass Loss around VY CMa
- 2015
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Ingår i: 4th ALMA Science Conference on Revolution in Astronomy with ALMA: The Third Year, Tokyo, Japan, 8-11 December. - 9781583818831 ; 499, s. 335-336
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Konferensbidrag (refereegranskat)abstract
- We present high resolution ALMA Science Verification data of the continuum emission around the highly evolved oxygen-rich red supergiant VY CMa. These data enable us to study the dust in its inner circumstellar environment at a spatial resolution of 129 mas at 321 GHz and 59 mas at 658 GHz, thus allowing us to trace dust on spatial scales down to 11 R-star (71 AU). Two prominent dust components are detected and resolved. We find that at least 17% of the dust mass around VY CMa is located in clumps ejected within a more quiescent roughly spherical stellar wind, with a quiescent dust mass loss rate of 5 x 10(-6) M-circle dot yr(-1). The anisotropic morphology of the dust indicates a continuous, directed mass loss over a few decades, suggesting that this mass loss cannot be driven by large convection cells alone.
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| 50. |
- O Gorman, Eamon, 1984, et al.
(författare)
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ALMA observations of anisotropic dust mass loss in the inner circumstellar environment of the red supergiant VY Canis Majoris
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 573, s. Article no. L1-
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Tidskriftsartikel (refereegranskat)abstract
- The processes leading to dust formation and the subsequent role it plays in driving mass loss in cool evolved stars is an area of intense study. Here we present high resolution ALMA Science Verification data of the continuum emission around the highly evolved oxygen-rich red supergiant VY CMa. These data enable us to study the dust in its inner circumstellar environment at a spatial resolution of 129 mas at 321 GHz and 59 mas at 658 GHz, thus allowing us to trace dust on spatial scales down to 11 R-star (71 AU). Two prominent dust components are detected and resolved. The brightest dust component. C, is located 334 mas (61 R-star) southeast of the star and has a dust mass of at least 2.5 x 10(-4) M-circle dot. It has a dust emissivity spectral index of beta = -0.1 at its peak, implying that it is optically thick at these frequencies with a cool core of T-d less than or similar to 100 K. Interestingly, not a single molecule in the ALMA data has emission close to the peak of this massive dust clump. The other main dust component. VY, is located at the position of the star and contains a total dust mass of 4.0 x 10(-)5 M-circle dot. It also contains a weaker dust feature extending over 60 R-star to the north with the total component having a typical dust emissivity spectral index of beta = 0.7. We find that at least 17% of the dust mass around VY CMa is located in clumps ejected within a more quiescent roughly spherical stellar wind, with a quiescent dust mass loss rate of 5 x 10(-6) M-circle dot yr(-1). The anisotropic morphology of the dust indicates a continuous, directed mass loss over a few decades, suggesting that this mass loss cannot be driven by large convection cells alone.
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