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| 2. |
- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 3. |
- Macdonald-Dunlop, Erin, et al.
(författare)
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Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases
- 2021
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
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| 4. |
- Nordebo, Sven, et al.
(författare)
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Electromagnetic dispersion modeling and measurements for HVDC power cables
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This paper provides a general framework for electromagnetic modeling, computation and measurements regarding the wave propagation characteristics of High-Voltage Direct Current (HVDC) power cables. The modeling is focused on very long (10 km or more) HVDC power cables and the relevant frequency range is therefore in the low-frequency regime of about 0-100 kHz. An exact dispersion relation is formulated together with a discussion on practical aspects regarding the computation of the propagation constant and the related characteristic impedance. Experimental time-domain measurement data from an 80 km long HVDC power cable is used to validate the model. It is concluded that a single-mode transmission line model is not adequate to account for the mismatch between the power cable and the instrumentation. A mismatch calibration procedure is therefore devised to account for the connection between the measurement equipment and the cable. A dispersion model is thus obtained that is accurate for early times of pulse arrival. To highlight the potential of accurate electromagnetic modeling, an example of high-resolution length-estimation is discussed and analyzed using statistical methods based on the Cramer-Rao lower bound. The analysis reveals that the estimation accuracy based on the present model (and its related model error) is in the order of 100 m for an 80 km long power cable, and that the potential accuracy using a perfect model based on the given measurement data is in the order of centimeters.
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| 7. |
- Anselm, Jonas, et al.
(författare)
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Bannlys alla politiska beslut som ger mer klimatutsläpp
- 2014
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Ingår i: Dagens Nyheter.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Torftig valdebatt. Dagspolitiken klarar inte att hantera ödesfrågan om klimatet, vilket oroar oss. Vi föreslår därför ett ”utsläppsmoratorium”: inga beslut får tas som ökar utsläppen av växthusgaser. Principen måste kopplas till mål om exempelvis förnybar energi och grön infrastruktur, skriver 23 forskare och debattörer.
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| 8. |
- Bengtsson, Peter, et al.
(författare)
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Energy structure and transition rates in the Ne-like sequence from relativistic CI calculations
- 2012
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Ingår i: Europhysics Conference Abstracts;36C. - : European Physical Society. ; , s. 128-128
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Atomic data are important in astrophysical applications and transition rates can be used in the determination of element abundances and plasma diagnostics. To provide for the extensive data needs a number of general computer codes such as SUPERSTRUCTURE, CIV3, and ATSP2K have been developed. As an alternative to these codes, which all rely on the Breit-Pauli approximation, the fully relativistic GRASP2K code can be used. GRASP2K is based on the multiconfiguration Dirac-Hartree-Fock method and implements a bi-orthogonal transformation method that permits initial and final states in a transition array to be optimized separately, which, in many cases, leads to more accurate values of the resulting rates. The GRASP2K package also contains modules to compute diagonal and off-diagonal hyperfine interaction constants, isotope shifts, Land´e gJ factors, and splittings of magnetic sub-state in intermediate and strong magnetic fields. In this work, GRASP2K has been applied to provide highly accurate spectroscopic data for ions in the Ne-like sequence between Mg III and Kr XXVII. Valence, core-valence, and core-core correlation effects were accounted for through SD-MR expansions to increasing sets of active orbitals. In Mg III, Al IV, Si V, P VI, S VII, and Ar IX, for which experimental energies are known to high accuracy, the mean error in the calculated energies is only 0.011%. For ions with no available experimental energy levels the calculated values should be most valuable in various applications. The high accuracy of the calculated energies makes it possible, in some cases, to to point out experimental values that are in error. Babushkin (length) and Coulomb (velocity) forms of transition rates are computed and agree to within a few percent for the majority of the allowed transitions. Computed lifetimes for states belonging to the 2p33s and 2p53d configurations are in good agreement with values from beam-foil measurements as well as from accurate MCHF Breit-Pauli calculations.
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| 9. |
- Bygde, Stefan, 1980-
(författare)
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Static WCET Analysis Based on Abstract Interpretation and Counting of Elements
- 2010
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In a real-time system, it is crucial to ensure that all tasks of the system holdtheir deadlines. A missed deadline in a real-time system means that the systemhas not been able to function correctly. If the system is safety critical, this canlead to disaster. To ensure that all tasks keep their deadlines, the Worst-CaseExecution Time (WCET) of these tasks has to be known. This can be done bymeasuring the execution times of a task, however, this is inflexible, time consumingand in general not safe (i.e., the worst-casemight not be found). Unlessthe task is measured with all possible input combinations and configurations,which is in most cases out of the question, there is no way to guarantee that thelongest measured time actually corresponds to the real worst case.Static analysis analyses a safe model of the hardware together with thesource or object code of a program to derive an estimate of theWCET. This estimateis guaranteed to be equal to or greater than the real WCET. This is doneby making calculations which in all steps make sure that the time is exactlyor conservatively estimated. In many cases, however, the execution time of atask or a program is highly dependent on the given input. Thus, the estimatedworst case may correspond to some input or configuration which is rarely (ornever) used in practice. For such systems, where execution time is highly inputdependent, a more accurate timing analysis which take input into considerationis desired.In this thesis we present a framework based on abstract interpretation andcounting of possible semantic states of a program. This is a general methodof WCET analysis, which is language independent and platform independent.The two main applications of this framework are a loop bound analysis and aparametric analysis. The loop bound analysis can be used to quickly find upperbounds for loops in a program while the parametric framework provides aninput-dependent estimation of theWCET. The input-dependent estimation cangive much more accurate estimates if the input is known at run-time.
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| 10. |
- Córdoba Doña, Juan Antonio, 1962-
(författare)
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Withstanding austerity : economic crisis and health inequalities in Spain
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Along with the austerity measures introduced in many countries, the economic crisis affecting Europe since 2008 seems to have impacted many aspects of the health of the Spanish population and has had a negative effect on the provision health services. An increasing body of knowledge has shown a clear impact of the current crisis on suicidal behaviour and mental health, and a less consistent effect on physical health and access to healthcare. However, little is known about the impact of the crisis on social inequalities in health and healthcare access, an area on which the present study seeks to shed light in the context of Spain, and specifically Andalusia, a region hit very hard by the crisis.Objective: To study the impact of the economic crisis starting in 2008 on health, health inequalities and health service utilisation in Spain and Andalusia and the roles of socio-demographic factors in these associations.Methods: Death rates were analysed to study the annual percent change in overall and cause-specific mortality in Spain between 1999 and 2011, and the Longitudinal Database of the Andalusian Population was used to study educational inequalities in overall mortality from 2002 to 2010 (study 1). To calculate suicide attempt rates, information from 2003 to 2012 on 11,494 men and 12,886 women provided by the Health Emergencies Public Enterprise Information System in Andalusia was utilised. The association between unemployment and suicide attempts was studied through linear regression models (study 2). Two waves of the Andalusian Health Survey (2007 and 2011–12) provided data for the third and fourth studies of this thesis. Educational and employment status inequalities in poor mental health in relation with the crisis were analysed through Poisson regression models (study 3). The change in inequalities (pre-crisis–crisis) in health care utilisation outcomes (general practitioner, specialist, hospitalisation and emergency attendance) was measured by the change in horizontal inequality indices. A decomposition analysis of change in inequality between periods was performed using the Oaxaca approach (study 4).Results: Study 1: Overall mortality in Spain decreased steadily during the period, with annual percent changes of -2.44% in men and -2.20% in women. An increase in educational inequality in mortality was observed in men in Andalusia. In women, the inequalities instead remained stable. Suicide mortality showed a downward trend in both sexes in Spain. Study 2: A sharp increase in suicide attempts in Andalusia was detected after the onset of the crisis in both sexes, with adults aged 35 to 54 years being the most affected. Suicide attempts were associated with unemployment rates only in men. Study 3: Poor mental health increased in working individuals with secondary and primary studies during the crisis compared to the pre-crisis period, while it decreased in the university study group. However, in unemployed individuals poor mental health increased only in the secondary studies group. Financial strain could partly explain the crisis effect on mental health among the unemployed. Study 4: Horizontal inequality in utilisation changed to a greater equality or a more pro-poor inequality in both sexes. In the decomposition analysis, socioeconomic position and health status showed greater contributions to the changes in inequalities.Conclusion: This thesis illustrates the complexity of the influences of the current economic crisis on health inequalities in a Southern European region. Specifically, no noticeable effects of the crisis on overall and suicide mortality were detected; instead, increasing educational inequalities in mortality in men and a large increase in suicide attempts in middle aged men and women were observed. The deterioration in poor mental health was mainly detected in those of intermediate educational level. Economic conditions such as unemployment and financial strain proved to be relevant. Finally, in the light of no increased inequalities in healthcare utilisation, the universal coverage health system seems to buffer the deleterious effect of the crisis and austerity policies in this context.
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