| 1. |
- Gao, Hong, et al.
(author)
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The landscape of tolerated genetic variation in humans and primates
- 2023
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6648
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Journal article (peer-reviewed)abstract
- Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.
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| 2. |
- Kuderna, Lukas F. K., et al.
(author)
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A global catalog of whole-genome diversity from 233 primate species
- 2023
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6648, s. 906-913
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Journal article (peer-reviewed)abstract
- The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage wholegenome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human specific. This study will open a wide range of research avenues for future primate genomic research.
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| 3. |
- Kuderna, Lukas F. K., et al.
(author)
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Identification of constrained sequence elements across 239 primate genomes
- 2024
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In: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 625:7996, s. 735-742
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Journal article (peer-reviewed)abstract
- Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.
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| 4. |
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| 5. |
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| 6. |
- Bergman, Ann-Sofie, 1963-, et al.
(author)
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Konflikt och försoning - ett arbetssätt vid familjerättsliga konflikter : En studie av process och effekt
- 2020
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Reports (other academic/artistic)abstract
- Studien är en utvärdering av arbetsmetoden Konflikt och försoning där socialtjänstens familjerättsenhet och tingsrätten i samverkan arbetar för att hjälpa föräldrar att lösa konflikter om gemensamma barns vårdnad, boende och umgänge. Studien bygger på dokumentanalyser av avslutade mål, observationer av muntliga förhandlingar i rätten, samt intervjuer med föräldrar, familjerättssekreterare och rådmän.
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| 7. |
- Ekblom Bak, Elin, 1981-, et al.
(author)
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Accelerometer derived physical activity and subclinical coronary and carotid atherosclerosis : cross-sectional analyses in 22 703 middle-aged men and women in the SCAPIS study
- 2023
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In: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 13:11
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Journal article (peer-reviewed)abstract
- OBJECTIVES: The aim included investigation of the associations between sedentary (SED), low-intensity physical activity (LIPA), moderate-to-vigorous intensity PA (MVPA) and the prevalence of subclinical atherosclerosis in both coronaries and carotids and the estimated difference in prevalence by theoretical reallocation of time in different PA behaviours.DESIGN: Cross-sectional.SETTING: Multisite study at university hospitals.PARTICIPANTS: A total of 22 670 participants without cardiovascular disease (51% women, 57.4 years, SD 4.3) from the population-based Swedish CArdioPulmonary bioImage study were included. SED, LIPA and MVPA were assessed by hip-worn accelerometer.PRIMARY AND SECONDARY OUTCOMES: Any and significant subclinical coronary atherosclerosis (CA), Coronary Artery Calcium Score (CACS) and carotid atherosclerosis (CarA) were derived from imaging data from coronary CT angiography and carotid ultrasound.RESULTS: High daily SED (>70% ≈10.5 hours/day) associated with a higher OR 1.44 (95% CI 1.09 to 1.91), for significant CA, and with lower OR 0.77 (95% CI 0.63 to 0.95), for significant CarA. High LIPA (>55% ≈8 hours/day) associated with lower OR for significant CA 0.70 (95% CI 0.51 to 0.96), and CACS, 0.71 (95% CI 0.51 to 0.97), but with higher OR for CarA 1.41 (95% CI 1.12 to 1.76). MVPA above reference level, >2% ≈20 min/day, associated with lower OR for significant CA (OR range 0.61-0.67), CACS (OR range 0.71-0.75) and CarA (OR range 0.72-0.79). Theoretical replacement of 30 min of SED into an equal amount of MVPA associated with lower OR for significant CA, especially in participants with high SED 0.84 (95% CI 0.76 to 0.96) or low MVPA 0.51 (0.36 to 0.73).CONCLUSIONS: MVPA was associated with a lower risk for significant atherosclerosis in both coronaries and carotids, while the association varied in strength and direction for SED and LIPA, respectively. If causal, clinical implications include avoiding high levels of daily SED and low levels of MVPA to reduce the risk of developing significant subclinical atherosclerosis.
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| 8. |
- Ekblom Bak, Elin, 1981-, et al.
(author)
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Accelerometer derived physical activity patterns in 27.890 middle‐aged adults : The SCAPIS cohort study
- 2022
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In: Scandinavian Journal of Medicine and Science in Sports. - : John Wiley & Sons. - 0905-7188 .- 1600-0838. ; 32:5, s. 866-880
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Journal article (peer-reviewed)abstract
- The present study aims to describe accelerometer-assessed physical activity (PA) patterns and fulfillment of PA recommendations in a large sample of middle-aged men and women, and to study differences between subgroups of socio-demographic, socio-economic, and lifestyle-related variables. A total of 27 890 (92.5% of total participants, 52% women, aged 50–64 years) middle-aged men and women with at least four days of valid hip-worn accelerometer data (Actigraph GT3X+, wGT3X+ and wGT3X-BT) from the Swedish CArdioPulmonary bioImage Study, SCAPIS, were included. In total, 54.5% of daily wear time was spent sedentary, 39.1% in low, 5.4% in moderate, and only 0.1% in vigorous PA. Male sex, higher education, low financial strain, born in Sweden, and sedentary/light working situation were related to higher sedentary time, but also higher levels of vigorous PA. High BMI and having multiple chronic diseases associated strongly with higher sedentary time and less time in all three PA intensities. All-year physically active commuters had an overall more active PA pattern. The proportion fulfilling current PA recommendations varied substantially (1.4% to 92.2%) depending on data handling procedures and definition used. Twenty-eight percent was defined as having an “at-risk” behavior, which included both high sedentary time and low vigorous PA. In this large population-based sample, a majority of time was spent sedentary and only a fraction in vigorous PA, with clinically important variations between subgroups. This study provides important reference material and emphasizes the importance of a comprehensive assessment of all aspects of the individual PA pattern in future research and clinical practice.
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| 9. |
- Mohammad, Moman A., et al.
(author)
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On the Natural History of Coronary Artery Disease : A Longitudinal Nationwide Serial Angiography Study
- 2022
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In: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980. ; 11:21
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Journal article (peer-reviewed)abstract
- Background: The long-term course of coronary atherosclerosis has not been studied in large nationwide cohorts. Understanding the natural history of coronary atherosclerosis could help identify patients at risk for future coronary events.Methods and Results: All coronary artery segments with <50% luminal stenosis in patients with a first-time coronary angiogram between 1989 and 2017 were identified (n=2 661 245 coronary artery segments in 248 736 patients) and followed until a clinically indicated angiography within 15 years was performed or until death or end of follow-up (April 2018) using SCAAR (Swedish Coronary Angiography and Angioplasty Registry). The stenosis progression and incidence rates were 2.6% and 1.45 (95% CI, 1.43-1.46) per 1000 segment-years, respectively. The greatest progression rate occurred in the proximal and middle segments of the left anterior descending artery. Male sex and diabetes were associated with a 2-fold increase in risk, and nearly 70% of new stenoses occurred in patients with baseline single-vessel disease (hazard ratio, 3.86 [95% CI, 3.69-4.04]). Coronary artery segments in patients with no baseline risk factors had a progression rate of 0.6% and incidence rate of 0.36 (95% CI, 0.34-0.39), increasing to 8.1% and 4.01 (95% CI, 3.89-4.14) per 1000 segment-years, respectively, in patients with ≥4 risk factors. The prognostic impact of risk factors on stenosis progression was greatest in younger patients and women.Conclusions: Coronary atherosclerosis progressed slowly but more frequently in the left coronary artery in men and in the presence of traditional risk factors. Coronary artery segments in patients without risk factors had little or no risk of stenosis progression, and the relative impact of risk factors appears to be of greater importance in younger patients and women. These findings help in the understanding the long-term course of coronary atherosclerosis.
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| 10. |
- Nilsson, Hans, et al.
(author)
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Upstream solar wind speed at comet 67P : reconstruction method, model comparison, and results
- 2022
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 659
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Journal article (peer-reviewed)abstract
- Context: Rosetta followed comet 67P at heliocentric distances from 1.25 to 3.6 au. The solar wind was observed for much of this time, but was significantly deflected and to some extent slowed down by the interaction with the coma.Aims: We use the different changes in the speed of H+ and He2+ when they interact with the coma to estimate the upstream speed of the solar wind. The different changes in the speed are due to the different mass per charge of the particles, while the electric force per charge due to the interaction is the same. A major assumption is that the speeds of H+ and He2+ were the same in the upstream region. This is investigated.Methods: We derived a method for reconstructing the upstream solar wind from H+ and He2+ observations. The method is based on the assumption that the interaction of the comet with the solar wind can be described by an electric potential that is the same for both H+ and He2+. This is compared to estimates from the Tao model and to OMNI and Mars Express data that we propagated to the observation point.Results: The reconstruction agrees well with the Tao model for most of the observations, in particular for the statistical distribution of the solar wind speed. The electrostatic potential relative to the upstream solar wind is derived and shows values from a few dozen volts at large heliocentric distances to about 1 kV during solar events and close to perihelion. The reconstructed values of the solar wind for periods of high electrostatic potential also agree well with propagated observations and model results.Conclusions: The reconstructed upstream solar wind speed during the Rosetta mission agrees well with the Tao model. The Tao model captures some slowing down of high-speed streams as compared to observations at Earth or Mars. At low solar wind speeds, below 400 km s-1, the agreement is better between our reconstruction and Mars observations than with the Tao model. The magnitude of the reconstructed electrostatic potential is a good measure of the slowing-down of the solar wind at the observation point.
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| 11. |
- Odelstad, Elias, et al.
(author)
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Ion-Ion Cross-Field Instability of Lower Hybrid Waves in the Inner Coma of Comet 67P
- 2022
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In: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 127:9
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Journal article (peer-reviewed)abstract
- We show that an ion-ion cross-field streaming instability between cold newborn cometary ions and heated heavy ions that were picked up upstream is likely a contributing source of observed lower hybrid (LH) waves in the inner coma of comet 67P/Churyumov-Gerasimenko. Electric field oscillations in the LH frequency range are common here, and have previously been attributed mainly to the lower-hybrid drift instability, driven by gradients associated with observed local density fluctuations. However, the observed wave activity is not confined to such gradients, nor is it always strongest there. Thus, other instabilities are likely needed as well to explain the observed wave activity. Several previous works have shown the existence of multiple populations of cometary ions in the inner coma of 67P, distinguished by differences in mass, energy and/or flow direction. We here examine two selected time intervals in October and November 2015, with substantial wave activity in the LH frequency range, where we identify two distinct cometary ion populations: a bulk population of locally produced, predominantly radially outflowing ions, and a more tenuous population picked up further upstream and accelerated back toward the comet by the solar wind electric field. These two populations exhibit strong relative drifts (similar to 20 km/s, or about five times the pickup ion thermal velocity), and we perform an electrostatic dispersion analysis showing that conditions should be favorable for LH wave generation through the ion-ion cross-field instability.
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| 12. |
- Slanina, Tomáš, et al.
(author)
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Impact of Excited-State Antiaromaticity Relief in a Fundamental Benzene Photoreaction Leading to Substituted Bicyclo[3.1.0]hexenes
- 2020
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In: Journal of the American Chemical Society. - : American Chemical Society. - 0002-7863 .- 1520-5126. ; 142:25, s. 10942-10954
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Journal article (peer-reviewed)abstract
- Benzene exhibits a rich photochemistry which can provide access to complex molecular scaffolds that are difficult to access with reactions in the electronic ground state. While benzene is aromatic in its ground state, it is antiaromatic in its lowest ππ∗ excited states. Herein, we clarify to what extent relief of excited-state antiaromaticity (ESAA) triggers a fundamental benzene photoreaction: the photoinitiated nucleophilic addition of solvent to benzene in acidic media leading to substituted bicyclo[3.1.0]hex-2-enes. The reaction scope was probed experimentally, and it was found that silyl-substituted benzenes provide the most rapid access to bicyclo[3.1.0]hexene derivatives, formed as single isomers with three stereogenic centers in yields up to 75% in one step. Two major mechanism hypotheses, both involving ESAA relief, were explored through quantum chemical calculations and experiments. The first mechanism involves protonation of excited-state benzene and subsequent rearrangement to bicyclo[3.1.0]hexenium cation, trapped by a nucleophile, while the second involves photorearrangement of benzene to benzvalene followed by protonation and nucleophilic addition. Our studies reveal that the second mechanism is operative. We also clarify that similar ESAA relief leads to puckering of S1-state silabenzene and pyridinium ion, where the photorearrangement of the latter is of established synthetic utility. Finally, we identified causes for the limitations of the reaction, information that should be valuable in explorations of similar photoreactions. Taken together, we reveal how the ESAA in benzene and 6π-electron heterocycles trigger photochemical distortions that provide access to complex three-dimensional molecular scaffolds from simple reactants.
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| 13. |
- Sobiech, Cilli, et al.
(author)
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Safety Case for Autonomous Trucks (SCAT)
- 2023
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Reports (other academic/artistic)abstract
- To aim for market introduction and sustainability of automated vehicles requires technology innovation towards safe products and policy innovation to enable testing on open roads and type approvals. Further, it needs an enabling infrastructure to provide reliable connectivity, business models and increased public acceptance of this new technology. The project SCAT – Safety Case for Autonomous Trucks contributed to this transmission by looking at new policy strategies and system tests to prove how to handle vehicles when introducing this new technology safely. Main objective of the project was to investigate more systematically – from a legal and technical perspective – how to safely operate remote controlled vehicles in mixed traffic and with higher velocity. A safety case for the selected traffic environment has been described and explorative tests have been performed at the AstaZero test site in Sweden. This allowed us to investigate limiting parameters and stress testing the system's boundaries under real conditions with higher velocity – before the actual demo will be run. With regards to policy, we addressed which obligations drivers and road users have according to today's regulations and which of those may need to be handled through technological development, but also through adaptation of legislation in terms of new roles, tasks, and liability when a vehicle is driven automatically. We looked also at if and how these issues are treated in national and international legislation, in Sweden, France and the USA. What we learned from exploring the safety case contributes to practical improvement, theory building and recommendations on how to safely operate the vehicles. Together the partners have developed an approach to advanced argumentation for safety. In our approach, we combined policy lab methodology and an investigation of the technical safety aspects that helped to identify gaps and tests for improved safety. The approach provides step-by-step guidance before future trials. The project was running from October 2020 until September 2022. The consortium consisted of the partners AstaZero, Einride, Ericsson, RISE (coordinator), Telia as well as reference partners in France and the USA.
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| 14. |
- Yan, Jiajie, et al.
(author)
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Photochemistry Driven by Excited-State Aromaticity Gain or Antiaromaticity Relief
- 2023
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In: Chemistry - A European Journal. - : Wiley-VCH Verlagsgesellschaft. - 0947-6539 .- 1521-3765. ; 29:19
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Research review (peer-reviewed)abstract
- Gain of aromaticity or relief of antiaromaticity along a reaction path are important factors to consider in mechanism studies. Analysis of such changes along potential energy surfaces has historically focused on reactions in the electronic ground state (S-0), but can also be used for excited states. In the lowest pi pi* states, the electron counts for aromaticity and antiaromaticity follow Baird's rule where 4n pi-electrons indicate aromaticity and 4n+2 pi-electrons antiaromaticity. Yet, there are also cases where Huckel's rule plays a role in the excited state. The electron count reversals of Baird's rule compared to Huckel's rule explain many altered physicochemical properties upon excitation of (hetero)annulene derivatives. Here we illustrate how the gain of excited-state aromaticity (ESA) and relief of excited-state antiaromaticity (ESAA) have an impact on photoreactivity and photostability. Emphasis is placed on recent findings supported by the results of quantum chemical calculations, and photoreactions in a wide variety of areas are covered.
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