| 1. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 2. |
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| 3. |
- Schael, S, et al.
(author)
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Precision electroweak measurements on the Z resonance
- 2006
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In: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 427:5-6, s. 257-454
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Research review (peer-reviewed)abstract
- We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron-positron colliders SLC and LEP. The data consist of 17 million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLID experiment using a polarised beam at SLC. The measurements include cross-sections, forward-backward asymmetries and polarised asymmetries. The mass and width of the Z boson, m(Z) and Gamma(Z), and its couplings to fermions, for example the p parameter and the effective electroweak mixing angle for leptons, are precisely measured: m(Z) = 91.1875 +/- 0.0021 GeV, Gamma(Z) = 2.4952 +/- 0.0023 GeV, rho(l) = 1.0050 +/- 0.0010, sin(2)theta(eff)(lept) = 0.23153 +/- 0.00016. The number of light neutrino species is determined to be 2.9840 +/- 0.0082, in agreement with the three observed generations of fundamental fermions. The results are compared to the predictions of the Standard Model (SM). At the Z-pole, electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward-backward asymmetry in b-quark production shows the largest difference with respect to its SM expectation, at the level of 2.8 standard deviations. Through radiative corrections evaluated in the framework of the Standard Model, the Z-pole data are also used to predict the mass of the top quark, m(t) = 173(+10)(+13) GeV, and the mass of the W boson, m(W) = 80.363 +/- 0.032 GeV. These indirect constraints are compared to the direct measurements, providing a stringent test of the SM. Using in addition the direct measurements of m(t) and m(W), the mass of the as yet unobserved SM Higgs boson is predicted with a relative uncertainty of about 50% and found to be less than 285 GeV at 95% confidence level. (c) 2006 Elsevier B.V. All rights reserved.
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- 2019
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Journal article (peer-reviewed)
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| 15. |
- Beral, V., et al.
(author)
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Ovarian cancer and smoking: individual participant meta-analysis including 28 114 women with ovarian cancer from 51 epidemiological studies
- 2012
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In: The Lancet Oncology. - 1474-5488. ; 13:9, s. 946-956
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Journal article (peer-reviewed)abstract
- Background Smoking has been linked to mucinous ovarian cancer, but its effects on other ovarian cancer subtypes and on overall ovarian cancer risk are unclear, and the findings from most studies with relevant data are unpublished. To assess these associations, we review the published and unpublished evidence. Methods Eligible epidemiological studies were identified by electronic searches, review articles, and discussions with colleagues. Individual participant data for 28 114 women with and 94 942 without ovarian cancer from 51 epidemiological studies were analysed centrally, yielding adjusted relative risks (RRs) of ovarian cancer in smokers compared with never smokers. Findings After exclusion of studies with hospital controls, in which smoking could have affected recruitment, overall ovarian cancer incidence was only slightly increased in current smokers compared with women who had never smoked (RR 1.06, 95% CI 1.01-1.11, p=0.01). Of 17 641 epithelial cancers with specified histology, 2314 (13%) were mucinous, 2360 (13%) endometrioid, 969 (5%) clear-cell, and 9086 (52%) serous. Smoking-related risks varied substantially across these subtypes (p(heterogeneity)<0.0001). For mucinous cancers, incidence was increased in current versus never smokers (1.79, 95% CI 1.60-2.00, p<0.0001), but the increase was mainly in borderline malignant rather than in fully malignant tumours (2.25, 95% CI 1.91-2.65 vs 1.49, 1.28-1.73; p(heterogeneity)=0.01; almost half the mucinous tumours were only borderline malignant). Both endometrioid (0.81, 95% CI 0.72-0.92, p=0.001) and clear-cell ovarian cancer risks (0.80, 95% CI 0.65-0.97, p=0.03) were reduced in current smokers, and there was no significant association for serous ovarian cancers (0.99, 95% CI 0.93-1.06, p=0.8). These associations did not vary significantly by 13 sociodemographic and personal characteristics of women including their body-mass index, parity, and use of alcohol, oral contraceptives, and menopausal hormone therapy. Interpretation The excess of mucinous ovarian cancers in smokers, which is mainly of tumours of borderline malignancy, is roughly counterbalanced by the deficit of endometrioid and clear-cell ovarian cancers. The substantial variation in smoking-related risks by tumour subtype is important for understanding ovarian carcinogenesis.
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| 16. |
- Beral, V., et al.
(author)
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Ovarian Cancer and Body Size : Individual Participant Meta-Analysis Including 25,157 Women with Ovarian Cancer from 47 Epidemiological Studies
- 2012
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In: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 9:4
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Journal article (peer-reviewed)abstract
- Background: Only about half the studies that have collected information on the relevance of women's height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships. Methods and Findings: Individual data on 25,157 women with ovarian cancer and 81,311 women without ovarian cancer from 47 epidemiological studies were collected, checked, and analysed centrally. Adjusted relative risks of ovarian cancer were calculated, by height and by body mass index. Ovarian cancer risk increased significantly with height and with body mass index, except in studies using hospital controls. For other study designs, the relative risk of ovarian cancer per 5 cm increase in height was 1.07 (95% confidence interval [CI], 1.05-1.09; p<0.001); this relationship did not vary significantly by women's age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. For body mass index, there was significant heterogeneity (p<0.001) in the findings between ever-users and never-users of menopausal hormone therapy, but not by the 11 other factors listed above. The relative risk for ovarian cancer per 5 kg/m(2) increase in body mass index was 1.10 (95% CI, 1.07-1.13; p<0.001) in never-users and 0.95 (95% CI, 0.92-0.99; p = 0.02) in ever-users of hormone therapy. Conclusions: Ovarian cancer is associated with height and, among never-users of hormone therapy, with body mass index. In high-income countries, both height and body mass index have been increasing in birth cohorts now developing the disease. If all other relevant factors had remained constant, then these increases in height and weight would be associated with a 3% increase in ovarian cancer incidence per decade.
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| 17. |
- Botvinik-Nezer, Rotem, et al.
(author)
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Variability in the analysis of a single neuroimaging dataset by many teams
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 582, s. 84-88
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Journal article (peer-reviewed)abstract
- Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed. The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.
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| 18. |
- McKay, James D., et al.
(author)
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A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium
- 2011
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p <= 5 x 10(-7)). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1 x 10(-8)) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2 x 10(-8)) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 x 10(-8); rs1229984-ADH1B, p = 7 x 10(-9); and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
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| 19. |
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| 21. |
- Bentley, Blair P., et al.
(author)
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Divergent sensory and immune gene evolution in sea turtles with contrasting demographic and life histories
- 2023
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 120:7
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Journal article (peer-reviewed)abstract
- Sea turtles represent an ancient lineage of marine vertebrates that evolved from terrestrial ancestors over 100 Mya. The genomic basis of the unique physiological and ecological traits enabling these species to thrive in diverse marine habitats remains largely unknown. Additionally, many populations have drastically declined due to anthropogenic activities over the past two centuries, and their recovery is a high global conservation priority. We generated and analyzed high-quality reference genomes for the leatherback (Dermochelys coriacea) and green (Chelonia mydas) turtles, representing the two extant sea turtle families. These genomes are highly syntenic and homologous, but localized regions of noncollinearity were associated with higher copy numbers of immune, zinc-finger, and olfactory receptor (OR) genes in green turtles, with ORs related to waterborne odorants greatly expanded in green turtles. Our findings suggest that divergent evolution of these key gene families may underlie immunological and sensory adaptations assisting navigation, occupancy of neritic versus pelagic environments, and diet specialization. Reduced collinearity was especially prevalent in microchromosomes, with greater gene content, heterozygosity, and genetic distances between species, supporting their critical role in vertebrate evolutionary adaptation. Finally, diversity and demographic histories starkly contrasted between species, indicating that leatherback turtles have had a low yet stable effective population size, exhibit extremely low diversity compared with other reptiles, and harbor a higher genetic load compared with green turtles, reinforcing concern over their persistence under future climate scenarios. These genomes provide invaluable resources for advancing our understanding of evolution and conservation best practices in an imperiled vertebrate lineage.
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| 22. |
- Blalock, Zachary N., et al.
(author)
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Circulating cell-free mitochondrial DNA levels and glucocorticoid sensitivity in a cohort of male veterans with and without combat-related PTSD
- 2024
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In: Translational Psychiatry. - 2158-3188. ; 14:1
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Journal article (peer-reviewed)abstract
- Circulating cell-free mitochondrial DNA (ccf-mtDNA) is a biomarker of cellular injury or cellular stress and is a potential novel biomarker of psychological stress and of various brain, somatic, and psychiatric disorders. No studies have yet analyzed ccf-mtDNA levels in post-traumatic stress disorder (PTSD), despite evidence of mitochondrial dysfunction in this condition. In the current study, we compared plasma ccf-mtDNA levels in combat trauma-exposed male veterans with PTSD (n = 111) with those who did not develop PTSD (n = 121) and also investigated the relationship between ccf mt-DNA levels and glucocorticoid sensitivity. In unadjusted analyses, ccf-mtDNA levels did not differ significantly between the PTSD and non-PTSD groups (t = 1.312, p = 0.191, Cohen’s d = 0.172). In a sensitivity analysis excluding participants with diabetes and those using antidepressant medication and controlling for age, the PTSD group had lower ccf-mtDNA levels than did the non-PTSD group (F(1, 179) = 5.971, p = 0.016, partial η 2 = 0.033). Across the entire sample, ccf-mtDNA levels were negatively correlated with post-dexamethasone adrenocorticotropic hormone (ACTH) decline (r = −0.171, p = 0.020) and cortisol decline (r = −0.149, p = 0.034) (viz., greater ACTH and cortisol suppression was associated with lower ccf-mtDNA levels) both with and without controlling for age, antidepressant status and diabetes status. Ccf-mtDNA levels were also significantly positively associated with IC50-DEX (the concentration of dexamethasone at which 50% of lysozyme activity is inhibited), a measure of lymphocyte glucocorticoid sensitivity, after controlling for age, antidepressant status, and diabetes status (β = 0.142, p = 0.038), suggesting that increased lymphocyte glucocorticoid sensitivity is associated with lower ccf-mtDNA levels. Although no overall group differences were found in unadjusted analyses, excluding subjects with diabetes and those taking antidepressants, which may affect ccf-mtDNA levels, as well as controlling for age, revealed decreased ccf-mtDNA levels in PTSD. In both adjusted and unadjusted analyses, low ccf-mtDNA levels were associated with relatively increased glucocorticoid sensitivity, often reported in PTSD, suggesting a link between mitochondrial and glucocorticoid-related abnormalities in PTSD.
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| 23. |
- Caddy, Harrison T., et al.
(author)
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Modelling large scale artery haemodynamics from the heart to the eye in response to simulated microgravity
- 2024
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In: npj Microgravity. - : Nature Research. - 2373-8065. ; 10:1
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Journal article (peer-reviewed)abstract
- We investigated variations in haemodynamics in response to simulated microgravity across a semi-subject-specific three-dimensional (3D) continuous arterial network connecting the heart to the eye using computational fluid dynamics (CFD) simulations. Using this model we simulated pulsatile blood flow in an upright Earth gravity case and a simulated microgravity case. Under simulated microgravity, regional time-averaged wall shear stress (TAWSS) increased and oscillatory shear index (OSI) decreased in upper body arteries, whilst the opposite was observed in the lower body. Between cases, uniform changes in TAWSS and OSI were found in the retina across diameters. This work demonstrates that 3D CFD simulations can be performed across continuously connected networks of small and large arteries. Simulated results exhibited similarities to low dimensional spaceflight simulations and measured data—specifically that blood flow and shear stress decrease towards the lower limbs and increase towards the cerebrovasculature and eyes in response to simulated microgravity, relative to an upright position in Earth gravity.
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| 24. |
- Dean, Kelsey R., et al.
(author)
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Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder
- 2020
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 25:12, s. 3337-3349
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Journal article (peer-reviewed)abstract
- Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.
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| 25. |
- Fischer, Hubertus, et al.
(author)
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Palaeoclimate constraints on the impact of 2 °C anthropogenic warming and beyond
- 2018
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In: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 11:7, s. 474-485
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Journal article (peer-reviewed)abstract
- Over the past 3.5 million years, there have been several intervals when climate conditions were warmer than during the pre-industrial Holocene. Although past intervals of warming were forced differently than future anthropogenic change, such periods can provide insights into potential future climate impacts and ecosystem feedbacks, especially over centennial-to-millennial timescales that are often not covered by climate model simulations. Our observation-based synthesis of the understanding of past intervals with temperatures within the range of projected future warming suggests that there is a low risk of runaway greenhouse gas feedbacks for global warming of no more than 2 °C. However, substantial regional environmental impacts can occur. A global average warming of 1–2 °C with strong polar amplification has, in the past, been accompanied by significant shifts in climate zones and the spatial distribution of land and ocean ecosystems. Sustained warming at this level has also led to substantial reductions of the Greenland and Antarctic ice sheets, with sea-level increases of at least several metres on millennial timescales. Comparison of palaeo observations with climate model results suggests that, due to the lack of certain feedback processes, model-based climate projections may underestimate long-term warming in response to future radiative forcing by as much as a factor of two, and thus may also underestimate centennial-to-millennial-scale sea-level rise.
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| 26. |
- Mohammed Taha, Hiba, et al.
(author)
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The NORMAN Suspect List Exchange (NORMAN-SLE) : facilitating European and worldwide collaboration on suspect screening in high resolution mass spectrometry
- 2022
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In: Environmental Sciences Europe. - : Springer. - 2190-4707 .- 2190-4715. ; 34:1
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Journal article (peer-reviewed)abstract
- Background: The NORMAN Association (https://www.norman-network.com/) initiated the NORMAN Suspect List Exchange (NORMAN-SLE; https://www.norman-network.com/nds/SLE/) in 2015, following the NORMAN collaborative trial on non-target screening of environmental water samples by mass spectrometry. Since then, this exchange of information on chemicals that are expected to occur in the environment, along with the accompanying expert knowledge and references, has become a valuable knowledge base for “suspect screening” lists. The NORMAN-SLE now serves as a FAIR (Findable, Accessible, Interoperable, Reusable) chemical information resource worldwide.Results: The NORMAN-SLE contains 99 separate suspect list collections (as of May 2022) from over 70 contributors around the world, totalling over 100,000 unique substances. The substance classes include per- and polyfluoroalkyl substances (PFAS), pharmaceuticals, pesticides, natural toxins, high production volume substances covered under the European REACH regulation (EC: 1272/2008), priority contaminants of emerging concern (CECs) and regulatory lists from NORMAN partners. Several lists focus on transformation products (TPs) and complex features detected in the environment with various levels of provenance and structural information. Each list is available for separate download. The merged, curated collection is also available as the NORMAN Substance Database (NORMAN SusDat). Both the NORMAN-SLE and NORMAN SusDat are integrated within the NORMAN Database System (NDS). The individual NORMAN-SLE lists receive digital object identifiers (DOIs) and traceable versioning via a Zenodo community (https://zenodo.org/communities/norman-sle), with a total of > 40,000 unique views, > 50,000 unique downloads and 40 citations (May 2022). NORMAN-SLE content is progressively integrated into large open chemical databases such as PubChem (https://pubchem.ncbi.nlm.nih.gov/) and the US EPA’s CompTox Chemicals Dashboard (https://comptox.epa.gov/dashboard/), enabling further access to these lists, along with the additional functionality and calculated properties these resources offer. PubChem has also integrated significant annotation content from the NORMAN-SLE, including a classification browser (https://pubchem.ncbi.nlm.nih.gov/classification/#hid=101).Conclusions: The NORMAN-SLE offers a specialized service for hosting suspect screening lists of relevance for the environmental community in an open, FAIR manner that allows integration with other major chemical resources. These efforts foster the exchange of information between scientists and regulators, supporting the paradigm shift to the “one substance, one assessment” approach. New submissions are welcome via the contacts provided on the NORMAN-SLE website (https://www.norman-network.com/nds/SLE/).
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| 27. |
- Parker, Louis P., et al.
(author)
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Proximal false lumen thrombosis is associated with low false lumen pressure and fewer complications in type B aortic dissection
- 2022
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In: Journal of Vascular Surgery. - : Elsevier BV. - 0741-5214 .- 1097-6809. ; 75:4, s. 1181-1190.e5
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Journal article (peer-reviewed)abstract
- Background: Improved risk stratification is a key priority for type B aortic dissection (TBAD). Partial false lumen thrombus morphology is an emerging predictor of complications. However, partial thrombosis is poorly defined, and its evaluation in clinical studies has been inconsistent. Thus, we aimed to characterize the hemodynamic pressure in TBAD and determine how the pressure relates to the false lumen thrombus morphology and clinical events. Methods: The retrospective admission computed tomography angiograms of 69 patients with acute TBAD were used to construct three-dimensional computational models for simulation of cyclical blood flow and calculation of pressure. The patients were categorized by the false lumen thrombus morphology as minimal, extensive, proximal or distal thrombosis. Linear regression analysis was used to compare the luminal pressure difference between the true and false lumen for each morphology group. The effect of morphology classification on the incidence of acute complications within 14 days was studied using logistic regression adjusted for clinical parameters. A survival analysis for adverse aortic events at 1 year was also performed using Cox regression. Results: Of the 69 patients, 44 had experienced acute complications and 45 had had an adverse aortic event at 1 year. The mean +/- standard deviation age was 62.6 +/- 12.6 years, and 75.4% were men. Compared with the patients with minimal thrombosis, those with proximal thrombosis had a reduced false lumen pressure by 10.1 mm Hg (95% confidence interval [CI], 4.3-15.9 mm Hg; P = .001). The patients who had not experienced an acute complication had had a reduced relative false lumen pressure (-6.35 mm Hg vs -0.62 mm Hg; P = .03). Proximal thrombosis was associated with fewer acute complications (odds ratio, 0.17; 95% CI, 0.04-0.60; P = .01) and 1-year adverse aortic events (hazard ratio, 0.36; 95% CI, 0.16-0.80; P = .01). Conclusions: We found that proximal false lumen thrombosis was a marker of reduced false lumen pressure. This might explain how proximal false lumen thrombosis appears to be protective of acute complications (eg, refractory hypertension or pain, aortic rupture, visceral or limb malperfusion, acute expansion) and adverse aortic events within the first year.
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| 28. |
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| 29. |
- Wallace, Megan A., et al.
(author)
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The discovery, distribution, and diversity of DNA viruses associated with Drosophila melanogaster in Europe
- 2021
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In: Virus Evolution. - : Oxford University Press (OUP). - 2057-1577. ; 7:1
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Journal article (peer-reviewed)abstract
- Drosophila melanogaster is an important model for antiviral immunity in arthropods, but very few DNA viruses have been described from the family Drosophilidae. This deficiency limits our opportunity to use natural host-pathogen combinations in experimental studies, and may bias our understanding of the Drosophila virome. Here, we report fourteen DNA viruses detected in a metagenomic analysis of 6668 pool-sequenced Drosophila, sampled from forty-seven European locations between 2014 and 2016. These include three new nudiviruses, a new and divergent entomopoxvirus, a virus related to Leptopilina boulardi filamentous virus, and a virus related to Musca domestica salivary gland hypertrophy virus. We also find an endogenous genomic copy of galbut virus, a double-stranded RNA partitivirus, segregating at very low frequency. Remarkably, we find that Drosophila Vesanto virus, a small DNA virus previously described as a bidnavirus, may be composed of up to twelve segments and thus represent a new lineage of segmented DNA viruses. Two of the DNA viruses, Drosophila Kallithea nudivirus and Drosophila Vesanto virus are relatively common, found in 2 per cent or more of wild flies. The others are rare, with many likely to be represented by a single infected fly. We find that virus prevalence in Europe reflects the prevalence seen in publicly available datasets, with Drosophila Kallithea nudivirus and Drosophila Vesanto virus the only ones commonly detectable in public data from wild-caught flies and large population cages, and the other viruses being rare or absent. These analyses suggest that DNA viruses are at lower prevalence than RNA viruses in D.melanogaster, and may be less likely to persist in laboratory cultures. Our findings go some way to redressing an earlier bias toward RNA virus studies in Drosophila, and lay the foundation needed to harness the power of Drosophila as a model system for the study of DNA viruses.
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| 30. |
- Benson, Tyler W, et al.
(author)
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Glycoprotein VI is Critical for the Detection and Progression of Abdominal Aortic Aneurysms.
- 2023
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In: bioRxiv : the preprint server for biology.
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Journal article (peer-reviewed)abstract
- UNLABELLED: A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (J) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.KEY POINTS: Soluble glycoprotein VI, which is a platelet-derived blood biomarker, predicts a diagnosis of AAA, with high sensitivity and specificity in distinguishing patients with fast from slow-growing AAA.Blockade of glycoprotein VI in mice with established aneurysms reduces AAA progression and mortality, indicating therapeutic potential.
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| 31. |
- Benson, Tyler W., et al.
(author)
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Gut Microbiota-Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms
- 2023
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In: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 147:14, s. 1079-1096
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Journal article (peer-reviewed)abstract
- Background:Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention.Methods:TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (Fmo3(-/-)). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA.Results:Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3(-/-) mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells-augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK.Conclusions:These results define a role for gut microbiota-generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress-related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.
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| 32. |
- Brout, Dillon, et al.
(author)
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The Pantheon+ analysis : cosmological constraints
- 2022
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In: Astrophysical Journal. - : Institute of Physics (IOP). - 0004-637X .- 1538-4357. ; 938:2
-
Journal article (peer-reviewed)abstract
- We present constraints on cosmological parameters from the Pantheon+ analysis of 1701 light curves of 1550 distinct Type Ia supernovae (SNe Ia) ranging in redshift from z = 0.001 to 2.26. This work features an increased sample size from the addition of multiple cross-calibrated photometric systems of SNe covering an increased redshift span, and improved treatments of systematic uncertainties in comparison to the original Pantheon analysis, which together result in a factor of 2 improvement in cosmological constraining power. For a flat ΛCDM model, we find ΩM = 0.334 ± 0.018 from SNe Ia alone. For a flat w0CDM model, we measure w0 = −0.90 ± 0.14 from SNe Ia alone, H0 = 73.5 ± 1.1 km s−1 Mpc−1 when including the Cepheid host distances and covariance (SH0ES), and w0 = -0.978-+0.0310.024 when combining the SN likelihood with Planck constraints from the cosmic microwave background (CMB) and baryon acoustic oscillations (BAO); both w0 values are consistent with a cosmological constant. We also present the most precise measurements to date on the evolution of dark energy in a flat w0waCDM universe, and measure wa = -0.1-+2.00.9 from Pantheon+ SNe Ia alone, H0 = 73.3 ± 1.1 km s−1 Mpc−1 when including SH0ES Cepheid distances, and wa = -0.65-+0.320.28 when combining Pantheon+ SNe Ia with CMB and BAO data. Finally, we find that systematic uncertainties in the use of SNe Ia along the distance ladder comprise less than one-third of the total uncertainty in the measurement of H0 and cannot explain the present “Hubble tension” between local measurements and early universe predictions from the cosmological model.
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| 33. |
- Chrysafi, Anna, et al.
(author)
-
Quantifying Earth system interactions for sustainable food production via expert elicitation
- 2022
-
In: Nature Sustainability. - : Springer Science and Business Media LLC. - 2398-9629. ; 5:10, s. 830-842
-
Journal article (peer-reviewed)abstract
- Several safe boundaries of critical Earth system processes have already been crossed due to human perturbations; not accounting for their interactions may further narrow the safe operating space for humanity. Using expert knowledge elicitation, we explored interactions among seven variables representing Earth system processes relevant to food production, identifying many interactions little explored in Earth system literature. We found that green water and land system change affect other Earth system processes strongly, while land, freshwater and ocean components of biosphere integrity are the most impacted by other Earth system processes, most notably blue water and biogeochemical flows. We also mapped a complex network of mechanisms mediating these interactions and created a future research prioritization scheme based on interaction strengths and existing knowledge gaps. Our study improves the understanding of Earth system interactions, with sustainability implications including improved Earth system modelling and more explicit biophysical limits for future food production.
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| 34. |
- Cornwall, L. A., et al.
(author)
-
Authentication and authorization mechanisms for multi-domain grid environments
- 2004
-
In: Journal of Grid Computing. - : Springer Science and Business Media LLC. - 1570-7873 .- 1572-9184. ; 2:4, s. 301-311
-
Journal article (peer-reviewed)abstract
- This article discusses the authentication and the authorization aspects of security in grid environments spanning multiple administrative domains. Achievements in these areas are presented using the EU DataGrid project as an example implementation. It also gives an outlook on future directions of development.
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| 35. |
- Finn, Molly K., et al.
(author)
-
ALMA-LEGUS. I. The Influence of Galaxy Morphology on Molecular Cloud Properties
- 2024
-
In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 964:1
-
Journal article (peer-reviewed)abstract
- We present a comparative study of the molecular gas in two galaxies from the Legacy ExtraGalactic UV Survey (LEGUS) sample: barred spiral NGC 1313 and flocculent spiral NGC 7793. These two galaxies have similar masses, metallicities, and star formation rates, but NGC 1313 is forming significantly more massive star clusters than NGC 7793, especially young massive clusters (<10 Myr, >104M⊙). Using Atacama Large Millimeter/submillimeter Array (ALMA) CO(2–1) observations of the two galaxies with the same sensitivity and resolution (13 pc), we directly compare the molecular gas in these two similar galaxies to determine the physical conditions responsible for their large disparity in cluster formation. By fitting size–line width relations for the clouds in each galaxy, we find that NGC 1313 has a higher intercept than NGC 7793, implying that its clouds have higher kinetic energies at a given size scale. NGC 1313 also has more clouds near virial equilibrium than NGC 7793, which may be connected to its higher rate of massive cluster formation. However, these virially bound clouds do not show a stronger correlation with young clusters than with the general cloud population. We find surprisingly small differences between the distributions of molecular cloud populations in the two galaxies, though the largest of those differences is that NGC 1313 has higher surface densities and lower freefall times.
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| 36. |
- Finn, Molly K., et al.
(author)
-
ALMA-LEGUS. II. The Influence of Subgalactic Environments on Molecular Cloud Properties
- 2024
-
In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 964:1
-
Journal article (peer-reviewed)abstract
- We compare the molecular cloud properties in subgalactic regions of two galaxies, barred spiral NGC 1313, which is forming many massive clusters, and flocculent spiral NGC 7793, which is forming significantly fewer massive clusters despite having a similar star formation rate to NGC 1313. We find that there are larger variations in cloud properties between different regions within each galaxy than there are between the galaxies on a global scale, especially for NGC 1313. There are higher masses, line widths, pressures, and virial parameters in the arms of NGC 1313 and the center of NGC 7793 than in the interarm and outer regions of the galaxies. The massive cluster formation of NGC 1313 may be driven by its greater variation in environment, allowing more clouds with the necessary conditions to emerge, although no one parameter seems primarily responsible for the difference in star formation. Meanwhile NGC 7793 has clouds that are as massive and have as much kinetic energy as the clouds in the arms of NGC 1313, but have densities and pressures more similar to those in the interarm regions and so are less inclined to collapse and form stars. The cloud properties in NGC 1313 and NGC 7793 suggest that spiral arms, bars, interarm regions, and flocculent spirals each represent distinct environments with regard to molecular cloud populations. We see surprisingly little difference in surface density between the regions, suggesting that the differences in surface densities frequently seen between arm and interarm regions in lower-resolution studies are indicative of the sparsity of molecular clouds, rather than differences in their true surface density.
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| 37. |
- Kinkel, Sarah A, et al.
(author)
-
Jarid2 regulates hematopoietic stem cell function by acting with polycomb repressive complex 2.
- 2015
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 125:12, s. 1890-1900
-
Journal article (peer-reviewed)abstract
- Polycomb Repressive Complex 2 (PRC2) plays a key role in hematopoietic stem and progenitor cell (HSPC) function. Analyses of mouse mutants harboring deletions of core components have implicated PRC2 in fine-tuning multiple pathways that instruct HSPC behavior, yet how PRC2 is targeted to specific genomic loci within HSPCs remains unknown. Here we use shRNA-mediated knockdown to survey the function of PRC2 accessory factors that were defined in ES cells, by testing the competitive reconstitution capacity of transduced murine HSPCs. We find that similar to the phenotype observed upon depletion of core subunit Suz12, depleting Jarid2 enhances the competitive transplantation capacity of both fetal and adult mouse HSPCs. Furthermore, we demonstrate that depletion of JARID2 enhances the in vitro expansion and in vivo reconstitution capacity of human HSPCs. Gene expression profiling revealed common Suz12 and Jarid2 target genes that are enriched for the H3K27me3 mark established by PRC2. These data implicate Jarid2 as an important component of PRC2 that has a central role in coordinating HSPC function.
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| 38. |
- Kumarathunge, Dushan P., et al.
(author)
-
Acclimation and adaptation components of the temperature dependence of plant photosynthesis at the global scale
- 2019
-
In: New Phytologist. - : John Wiley & Sons. - 0028-646X .- 1469-8137. ; 222:2, s. 768-784
-
Journal article (peer-reviewed)abstract
- The temperature response of photosynthesis is one of the key factors determining predicted responses to warming in global vegetation models (GVMs). The response may vary geographically, owing to genetic adaptation to climate, and temporally, as a result of acclimation to changes in ambient temperature. Our goal was to develop a robust quantitative global model representing acclimation and adaptation of photosynthetic temperature responses.We quantified and modelled key mechanisms responsible for photosynthetic temperature acclimation and adaptation using a global dataset of photosynthetic CO2 response curves, including data from 141 C3 species from tropical rainforest to Arctic tundra. We separated temperature acclimation and adaptation processes by considering seasonal and common-garden datasets, respectively.The observed global variation in the temperature optimum of photosynthesis was primarily explained by biochemical limitations to photosynthesis, rather than stomatal conductance or respiration. We found acclimation to growth temperature to be a stronger driver of this variation than adaptation to temperature at climate of origin.We developed a summary model to represent photosynthetic temperature responses and showed that it predicted the observed global variation in optimal temperatures with high accuracy. This novel algorithm should enable improved prediction of the function of global ecosystems in a warming climate.
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| 39. |
- Rijal, Dilli P., et al.
(author)
-
Sedimentary ancient DNA shows terrestrial plant richness continuously increased over the Holocene in northern Fennoscandia
- 2021
-
In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:31
-
Journal article (peer-reviewed)abstract
- The effects of climate change on species richness are debated but can be informed by the past. Here, we generated a sedimentary ancient DNA dataset covering 10 lakes and applied novel methods for data harmonization. We assessed the impact of Holocene climate changes and nutrients on terrestrial plant richness in northern Fennoscandia. We find that richness increased steeply during the rapidly warming Early Holocene. In contrast to findings from most pollen studies, we show that richness continued to increase thereafter, although the climate was stable, with richness and the regional species pool only stabilizing during the past three millennia. Furthermore, overall increases in richness were greater in catchments with higher soil nutrient availability. We suggest that richness will increase with ongoing warming, especially at localities with high nutrient availability and assuming that human activity remains low in the region, although lags of millennia may be expected.
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| 40. |
- Stuart, Kelsey V., et al.
(author)
-
The association of alcohol consumption with glaucoma and related traits : findings from the UK Biobank
- 2023
-
In: Ophthalmology Glaucoma. - : Elsevier. - 2589-4234 .- 2589-4196. ; 6:4, s. 366-379
-
Journal article (peer-reviewed)abstract
- PURPOSE: To examine the associations of alcohol consumption with glaucoma and related traits; to assess whether a genetic predisposition to glaucoma modified these associations; and to perform Mendelian randomization (MR) experiments to probe causal effects.DESIGN: Cross-sectional observational and gene-environment interaction analyses in the UK Biobank. Two-sample MR experiments using summary statistics from large genetic consortia.PARTICIPANTS: UK Biobank participants with data on intraocular pressure (IOP) (n=109 097), OCT derived macular inner retinal layer thickness measures (n=46 236) and glaucoma status (n=173 407).METHODS: Participants were categorized according to self-reported drinking behaviors. Quantitative estimates of alcohol intake were derived from touchscreen questionnaires and food composition tables. We performed a two-step analysis, first comparing categories of alcohol consumption (never, infrequent, regular, and former drinkers), before assessing for a dose-response effect in regular drinkers only. Multivariable linear, logistic and restricted cubic spline (RCS) regression, adjusted for key sociodemographic, medical, anthropometric and lifestyle factors, were used to examine associations. We assessed whether any association was modified by a multi-trait glaucoma polygenic risk score. The inverse-variance weighted method was used for the main MR analyses.MAIN OUTCOME MEASURES: IOP, macular retinal nerve fiber layer (mRNFL) thickness, macular ganglion cell-inner plexiform layer (mGCIPL) thickness, and prevalent glaucoma. RESULTS: Compared to infrequent drinkers, regular drinkers had higher IOP (+0.17mmHg; P<0.001) and thinner mGCIPL (-0.17μm; P=0.049); while former drinkers had a higher prevalence of glaucoma (OR 1.53; P=0.002). In regular drinkers, alcohol intake was adversely associated with all outcomes in a dose-dependent manner (all P<0.001). RCS regression analyses suggested non-linear associations, with apparent threshold effects at approximately 50g (∼6 UK or 4 US alcoholic units)/week, for mRNFL and mGCIPL thickness. Significantly stronger alcohol-IOP associations were observed in participants at higher genetic susceptibility to glaucoma (Pinteraction<0.001). MR analyses provided evidence for a causal association with mGCIPL thickness.CONCLUSIONS: Alcohol intake was consistently and adversely associated with glaucoma and related traits, and at levels below current UK (<112g/week) and US (women: <98g/week; men: <196g/week) guidelines. While we cannot infer causality definitively, these results will be of interest to people with, or at risk of, glaucoma and their advising physicians.
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| 41. |
- Wuestefeld, Anika, et al.
(author)
-
Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories
-
In: Hippocampus. - 1050-9631.
-
Journal article (peer-reviewed)abstract
- The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 μm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 μm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex.
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| 42. |
- Ålund, Murielle, et al.
(author)
-
Academic ecosystems must evolve to support a sustainable postdoc workforce
- 2020
-
In: Nature Ecology and Evolution. - : Springer Science and Business Media LLC. - 2397-334X. ; 4:6, s. 777-781
-
Research review (peer-reviewed)abstract
- The postdoctoral workforce comprises a growing proportion of the science, technology, engineering and mathematics (STEM) community, and plays a vital role in advancing science. Postdoc professional development, however, remains rooted in outdated realities. We propose enhancements to postdoc-centred policies and practices to better align this career stage with contemporary job markets and work life. By facilitating productivity, wellness and career advancement, the proposed changes will benefit all stakeholders in postdoc success—including research teams, institutions, professional societies and the scientific community as a whole. To catalyse reform, we outline recommendations for (1) skills-based training tailored to the current career landscape, and (2) supportive policies and tools outlined in postdoc handbooks. We also invite the ecology and evolution community to lead further progressive reform.
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| 43. |
- Beal, Jacob, et al.
(author)
-
Robust estimation of bacterial cell count from optical density
- 2020
-
In: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
-
Journal article (peer-reviewed)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 44. |
- Calzetti, Daniela, et al.
(author)
-
Dust-buried Compact Sources in the Dwarf Galaxy NGC 4449
- 2023
-
In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 946:1
-
Journal article (peer-reviewed)abstract
- Multiwavelength images from the Hubble Space Telescope covering the wavelength range 0.27–1.6 μm show that the central area of the nearby dwarf galaxy NGC 4449 contains several tens of compact sources that are emitting in the hydrogen recombination line Paβ (1.2818 μm) but are only marginally detected in Hα (0.6563 μm) and undetected at wavelengths λ ≤ 0.55 μm. An analysis of the spectral energy distributions (SEDs) of these sources indicates that they are likely relatively young stellar clusters heavily attenuated by dust. The selection function used to identify the sources prevents meaningful statistical analyses of their age, mass, and dust extinction distributions. However, these cluster candidates have ages ∼5–6 Myr and AV > 6 mag, according to their SED fits, and are extremely compact, with typical deconvolved radii of 1 pc. The dusty clusters are located at the periphery of the dark clouds within the galaxy and appear to be partially embedded. Density and pressure considerations indicate that the H ii regions surrounding these clusters may be stalled, and that pre-supernova (pre-SN) feedback has not been able to clear the clusters of their natal cocoons. These findings are in potential tension with existing models that regulate star formation with pre-SN feedback, since pre-SN feedback acts on short timescales, ≲4 Myr, for a standard stellar initial mass function. The existence of a population of dusty stellar clusters with ages >4 Myr, if confirmed by future observations, paints a more complex picture for the role of stellar feedback in controlling star formation.
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| 45. |
- Chan, Elizabeth S. M., et al.
(author)
-
Triarchic traits as risk versus protective factors for ADHD symptomatology : A prospective longitudinal investigation
- 2024
-
In: Development and psychopathology (Print). - : Cambridge University Press. - 0954-5794 .- 1469-2198. ; , s. 1-12
-
Journal article (peer-reviewed)abstract
- Attention-deficit/hyperactivity disorder (ADHD) symptoms are associated with myriad adverse outcomes, including interpersonal difficulties, but factors that moderate the developmental course and functional impact of ADHD over time are not well understood. The present study evaluated developmental contributions of the triarchic neurobehavioral traits (boldness, meanness, and disinhibition) to ADHD symptomatology and its subdimensions from adolescence to young adulthood. Participants were twins and triplets assessed at ages 14, 17, and 19 (initial N = 1,185, 51.2% female). Path analyses using negative binomial regression revealed that boldness at age 14 was associated with more ADHD symptoms cross-sectionally (especially hyperactivity/impulsivity), but fewer symptoms (especially inattention) at age 19 in the prospective analysis. Notably, inclusion of interpersonal problems at ages 14 and 17 as covariates reduced the latter effect to nonsignificant. Disinhibition concurrently and prospectively predicted higher levels of ADHD symptoms, including both subdimensions, and the prospective effects were partially mediated by greater social impairment at age 17. Meanness prospectively (but not concurrently) predicted higher levels of hyperactivity/impulsivity symptoms. Sex moderated certain associations of meanness and disinhibition with ADHD symptoms. These findings highlight how fundamental neurobehavioral traits shape both psychopathology and adaptive outcomes in the developmental course of ADHD.
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| 46. |
- Christiansen, Colette, et al.
(author)
-
Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers
- 2022
-
In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 14:1
-
Journal article (peer-reviewed)abstract
- Background: There is considerable evidence for the importance of the DNA methylome in metabolic health, for example, a robust methylation signature has been associated with body mass index (BMI). However, visceral fat (VF) mass accumulation is a greater risk factor for metabolic disease than BMI alone. In this study, we dissect the subcutaneous adipose tissue (SAT) methylome signature relevant to metabolic health by focusing on VF as the major risk factor of metabolic disease. We integrate results with genetic, blood methylation, SAT gene expression, blood metabolomic, dietary intake and metabolic phenotype data to assess and quantify genetic and environmental drivers of the identified signals, as well as their potential functional roles. Methods: Epigenome-wide association analyses were carried out to determine visceral fat mass-associated differentially methylated positions (VF-DMPs) in SAT samples from 538 TwinsUK participants. Validation and replication were performed in 333 individuals from 3 independent cohorts. To assess functional impacts of the VF-DMPs, the association between VF and gene expression was determined at the genes annotated to the VF-DMPs and an association analysis was carried out to determine whether methylation at the VF-DMPs is associated with gene expression. Further epigenetic analyses were carried out to compare methylation levels at the VF-DMPs as the response variables and a range of different metabolic health phenotypes including android:gynoid fat ratio (AGR), lipids, blood metabolomic profiles, insulin resistance, T2D and dietary intake variables. The results from all analyses were integrated to identify signals that exhibit altered SAT function and have strong relevance to metabolic health. Results: We identified 1181 CpG positions in 788 genes to be differentially methylated with VF (VF-DMPs) with significant enrichment in the insulin signalling pathway. Follow-up cross-omic analysis of VF-DMPs integrating genetics, gene expression, metabolomics, diet, and metabolic traits highlighted VF-DMPs located in 9 genes with strong relevance to metabolic disease mechanisms, with replication of signals in FASN, SREBF1, TAGLN2, PC and CFAP410. PC methylation showed evidence for mediating effects of diet on VF. FASN DNA methylation exhibited putative causal effects on VF that were also strongly associated with insulin resistance and methylation levels in FASN better classified insulin resistance (AUC=0.91) than BMI or VF alone. Conclusions: Our findings help characterise the adiposity-associated methylation signature of SAT, with insights for metabolic disease risk.
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| 47. |
- Douglas, Pamela S, et al.
(author)
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Comparison of an Initial Risk-Based Testing Strategy vs Usual Testing in Stable Symptomatic Patients With Suspected Coronary Artery Disease: The PRECISE Randomized Clinical Trial.
- 2023
-
In: JAMA cardiology. - 2380-6591.
-
Journal article (peer-reviewed)abstract
- Trials showing equivalent or better outcomes with initial evaluation using coronary computed tomography angiography (cCTA) compared with stress testing in patients with stable chest pain have informed guidelines but raise questions about overtesting and excess catheterization.To test a modified initial cCTA strategy designed to improve clinical efficiency vs usual testing (UT).This was a pragmatic randomized clinical trial enrolling participants from December 3, 2018, to May 18, 2021, with a median of 11.8 months of follow-up. Patients from 65 North American and European sites with stable symptoms of suspected coronary artery disease (CAD) and no prior testing were randomly assigned 1:1 to precision strategy (PS) or UT.PS incorporated the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) minimal risk score to quantitatively select minimal-risk participants for deferred testing, assigning all others to cCTA with selective CT-derived fractional flow reserve (FFR-CT). UT included site-selected stress testing or catheterization. Site clinicians determined subsequent care.Outcomes were clinical efficiency (invasive catheterization without obstructive CAD) and safety (death or nonfatal myocardial infarction [MI]) combined into a composite primary end point. Secondary end points included safety components of the primary outcome and medication use.A total of 2103 participants (mean [SD] age, 58.4 [11.5] years; 1056 male [50.2%]) were included in the study, and 422 [20.1%] were classified as minimal risk. The primary end point occurred in 44 of 1057 participants (4.2%) in the PS group and in 118 of 1046 participants (11.3%) in the UT group (hazard ratio [HR], 0.35; 95% CI, 0.25-0.50). Clinical efficiency was higher with PS, with lower rates of catheterization without obstructive disease (27 [2.6%]) vs UT participants (107 [10.2%]; HR, 0.24; 95% CI, 0.16-0.36). The safety composite of death/MI was similar (HR, 1.52; 95% CI, 0.73-3.15). Death occurred in 5 individuals (0.5%) in the PS group vs 7 (0.7%) in the UT group (HR, 0.71; 95% CI, 0.23-2.23), and nonfatal MI occurred in 13 individuals (1.2%) in the PS group vs 5 (0.5%) in the UT group (HR, 2.65; 95% CI, 0.96-7.36). Use of lipid-lowering (450 of 900 [50.0%] vs 365 of 873 [41.8%]) and antiplatelet (321 of 900 [35.7%] vs 237 of 873 [27.1%]) medications at 1 year was higher in the PS group compared with the UT group (both P < .001).An initial diagnostic approach to stable chest pain starting with quantitative risk stratification and deferred testing for minimal-risk patients and cCTA with selective FFR-CT in all others increased clinical efficiency relative to UT at 1 year. Additional randomized clinical trials are needed to verify these findings, including safety.ClinicalTrials.gov Identifier: NCT03702244.
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| 48. |
- Eglit, Yana, et al.
(author)
-
Meteora sporadica, a protist with incredible cell architecture, is related to Hemimastigophora
- 2024
-
In: Current Biology. - : Elsevier. - 0960-9822 .- 1879-0445.
-
Journal article (peer-reviewed)abstract
- “Kingdom-level” branches are being added to the tree of eukaryotes at a rate approaching one per year, with no signs of slowing down.1,2,3,4 Some are completely new discoveries, whereas others are morphologically unusual protists that were previously described but lacked molecular data. For example, Hemimastigophora are predatory protists with two rows of flagella that were known since the 19th century but proved to represent a new deep-branching eukaryote lineage when phylogenomic analyses were conducted.2 Meteora sporadica5 is a protist with a unique morphology; cells glide over substrates along a long axis of anterior and posterior projections while a pair of lateral “arms” swing back and forth, a motility system without any obvious parallels. Originally, Meteora was described by light microscopy only, from a short-term enrichment of deep-sea sediment. A small subunit ribosomal RNA (SSU rRNA) sequence was reported recently, but the phylogenetic placement of Meteora remained unresolved.6 Here, we investigated two cultivated Meteora sporadica isolates in detail. Transmission electron microscopy showed that both the anterior-posterior projections and the arms are supported by microtubules originating from a cluster of subnuclear microtubule organizing centers (MTOCs). Neither have a flagellar axoneme-like structure. Sequencing the mitochondrial genome showed this to be among the most gene-rich known, outside jakobids. Remarkably, phylogenomic analyses of 254 nuclear protein-coding genes robustly support a close relationship with Hemimastigophora. Our study suggests that Meteora and Hemimastigophora together represent a morphologically diverse “supergroup” and thus are important for resolving the tree of eukaryote life and early eukaryote evolution.
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| 49. |
- Elmegreen, Debra Meloy, et al.
(author)
-
HIERARCHICAL STAR FORMATION IN NEARBY LEGUS GALAXIES
- 2014
-
In: Astrophysical Journal Letters. - 2041-8205. ; 787:1, s. L15-
-
Journal article (peer-reviewed)abstract
- Hierarchical structure in ultraviolet images of 12 late-type LEGUS galaxies is studied by determining the numbers and fluxes of nested regions as a function of size from similar to 1 to similar to 200 pc, and the number as a function of flux. Two starburst dwarfs, NGC 1705 and NGC 5253, have steeper number-size and flux-size distributions than the others, indicating high fractions of the projected areas filled with star formation. Nine subregions in seven galaxies have similarly steep number-size slopes, even when the whole galaxies have shallower slopes. The results suggest that hierarchically structured star-forming regions several hundred parsecs or larger represent common unit structures. Small galaxies dominated by only a few of these units tend to be starbursts. The self-similarity of young stellar structures down to parsec scales suggests that star clusters form in the densest parts of a turbulent medium that also forms loose stellar groupings on larger scales. The presence of super star clusters in two of our starburst dwarfs would follow from the observed structure if cloud and stellar subregions more readily coalesce when self-gravity in the unit cell contributes more to the total gravitational potential.
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| 50. |
- Fischer, Debra A., et al.
(author)
-
M2K. II. A Triple-Planet System Orbiting Hip 57274
- 2012
-
In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 745:1, s. 21-
-
Journal article (peer-reviewed)abstract
- Doppler observations from Keck Observatory have revealed a triple-planet system orbiting the nearby K4V star, HIP 57274. The inner planet, HIP 57274b, is a super-Earth with M sin i = 11.6 M-circle plus (0.036 M-Jup), an orbital period of 8.135 +/- 0.004 days, and slightly eccentric orbit e = 0.19 +/- 0.1. We calculate a transit probability of 6.5% for the inner planet. The second planet has M sin i = 0.4 M-Jup with an orbital period of 32.0 +/- 0.02 days in a nearly circular orbit (e = 0.05 +/- 0.03). The third planet has M sin i = 0.53 M-Jup with an orbital period of 432 +/- 8 days (1.18 years) and an eccentricity e = 0.23 +/- 0.03. This discovery adds to the number of super-Earth mass planets with M sin i < 12 M-circle plus that have been detected with Doppler surveys. We find that 56% +/- 18% of super-Earths are members of multi-planet systems. This is certainly a lower limit because of observational detectability limits, yet significantly higher than the fraction of Jupiter mass exoplanets, 20% +/- 8%, that are members of Doppler-detected, multi-planet systems.
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