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Sökning: WFRF:(Olivieri Pauline)

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1.
  • Marto, João Pedro, et al. (författare)
  • Safety and Outcome of Revascularization Treatment in Patients With Acute Ischemic Stroke and COVID-19: The Global COVID-19 Stroke Registry.
  • 2023
  • Ingår i: Neurology. - 1526-632X. ; 100:7
  • Tidskriftsartikel (refereegranskat)abstract
    • COVID-19-related inflammation, endothelial dysfunction, and coagulopathy may increase the bleeding risk and lower the efficacy of revascularization treatments in patients with acute ischemic stroke (AIS). We aimed to evaluate the safety and outcomes of revascularization treatments in patients with AIS and COVID-19.This was a retrospective multicenter cohort study of consecutive patients with AIS receiving intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) between March 2020 and June 2021 tested for severe acute respiratory syndrome coronavirus 2 infection. With a doubly robust model combining propensity score weighting and multivariate regression, we studied the association of COVID-19 with intracranial bleeding complications and clinical outcomes. Subgroup analyses were performed according to treatment groups (IVT-only and EVT).Of a total of 15,128 included patients from 105 centers, 853 (5.6%) were diagnosed with COVID-19; of those, 5,848 (38.7%) patients received IVT-only and 9,280 (61.3%) EVT (with or without IVT). Patients with COVID-19 had a higher rate of symptomatic intracerebral hemorrhage (SICH) (adjusted OR 1.53; 95% CI 1.16-2.01), symptomatic subarachnoid hemorrhage (SSAH) (OR 1.80; 95% CI 1.20-2.69), SICH and/or SSAH combined (OR 1.56; 95% CI 1.23-1.99), 24-hour mortality (OR 2.47; 95% CI 1.58-3.86), and 3-month mortality (OR 1.88; 95% CI 1.52-2.33). Patients with COVID-19 also had an unfavorable shift in the distribution of the modified Rankin score at 3 months (OR 1.42; 95% CI 1.26-1.60).Patients with AIS and COVID-19 showed higher rates of intracranial bleeding complications and worse clinical outcomes after revascularization treatments than contemporaneous non-COVID-19 patients receiving treatment. Current available data do not allow direct conclusions to be drawn on the effectiveness of revascularization treatments in patients with COVID-19 or to establish different treatment recommendations in this subgroup of patients with ischemic stroke. Our findings can be taken into consideration for treatment decisions, patient monitoring, and establishing prognosis.The study was registered under ClinicalTrials.gov identifier NCT04895462.
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2.
  • Cruz, Raquel, et al. (författare)
  • Novel genes and sex differences in COVID-19 severity
  • 2022
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
  • Tidskriftsartikel (refereegranskat)abstract
    • Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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3.
  • Barack, Leor, et al. (författare)
  • Black holes, gravitational waves and fundamental physics : a roadmap
  • 2019
  • Ingår i: Classical and quantum gravity. - : IOP Publishing. - 0264-9381 .- 1361-6382. ; 36:14
  • Forskningsöversikt (refereegranskat)abstract
    • The grand challenges of contemporary fundamental physics dark matter, dark energy, vacuum energy, inflation and early universe cosmology, singularities and the hierarchy problem all involve gravity as a key component. And of all gravitational phenomena, black holes stand out in their elegant simplicity, while harbouring some of the most remarkable predictions of General Relativity: event horizons, singularities and ergoregions. The hitherto invisible landscape of the gravitational Universe is being unveiled before our eyes: the historical direct detection of gravitational waves by the LIGO-Virgo collaboration marks the dawn of a new era of scientific exploration. Gravitational-wave astronomy will allow us to test models of black hole formation, growth and evolution, as well as models of gravitational-wave generation and propagation. It will provide evidence for event horizons and ergoregions, test the theory of General Relativity itself, and may reveal the existence of new fundamental fields. The synthesis of these results has the potential to radically reshape our understanding of the cosmos and of the laws of Nature. The purpose of this work is to present a concise, yet comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress. This write-up is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'.
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4.
  • Charpentier Ljungqvist, Fredrik, 1982-, et al. (författare)
  • Regional Patterns of Late Medieval and Early Modern European Building Activity Revealed by Felling Dates
  • 2022
  • Ingår i: Frontiers in Ecology and Evolution. - : Frontiers Media SA. - 2296-701X. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Although variations in building activity are a useful indicator of societal well-being and demographic development, historical datasets for larger regions and longer periods are still rare. Here, we present 54,045 annually precise dendrochronological felling dates from historical construction timber from across most of Europe between 1250 and 1699 CE to infer variations in building activity. We use geostatistical techniques to compare spatiotemporal dynamics in past European building activity against independent demographic, economic, social and climatic data. We show that the felling dates capture major geographical patterns of demographic trends, especially in regions with dense data coverage. A particularly strong negative association is found between grain prices and the number of felling dates. In addition, a significant positive association is found between the number of felling dates and mining activity. These strong associations, with well-known macro-economic indicators from pre-industrial Europe, corroborate the use of felling dates as an independent source for exploring large-scale fluctuations of societal well-being and demographic development. Three prominent examples are the building boom in the Hanseatic League region of northeastern Germany during the 13th century, the onset of the Late Medieval Crisis in much of Europec. 1300, and the cessation of building activity in large parts of central Europe during armed conflicts such as the Thirty Years’ War (1618–1648 CE). Despite new insights gained from our European-wide felling date inventory, further studies are needed to investigate changes in construction activity of high versus low status buildings, and of urban versus rural buildings, and to compare those results with a variety of historical documentary sources and natural proxy archives.
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5.
  • Gao, Hong, et al. (författare)
  • The landscape of tolerated genetic variation in humans and primates
  • 2023
  • Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6648
  • Tidskriftsartikel (refereegranskat)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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6.
  • Kehoe, Laura, et al. (författare)
  • Make EU trade with Brazil sustainable
  • 2019
  • Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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7.
  • Kuderna, Lukas F. K., et al. (författare)
  • A global catalog of whole-genome diversity from 233 primate species
  • 2023
  • Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6648, s. 906-913
  • Tidskriftsartikel (refereegranskat)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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8.
  • Kuderna, Lukas F. K., et al. (författare)
  • Identification of constrained sequence elements across 239 primate genomes
  • 2024
  • Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 625:7996, s. 735-742
  • Tidskriftsartikel (refereegranskat)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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9.
  • Ostaszewski, Marek, et al. (författare)
  • COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms
  • 2021
  • Ingår i: Molecular Systems Biology. - : John Wiley & Sons. - 1744-4292 .- 1744-4292. ; 17:10
  • Tidskriftsartikel (refereegranskat)abstract
    • We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.
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10.
  • Pironi, Loris, et al. (författare)
  • Characteristics of adult patients with chronic intestinal failure due to short bowel syndrome: An international multicenter survey
  • 2021
  • Ingår i: Clinical Nutrition ESPEN. - : Elsevier BV. - 2405-4577. ; 45, s. 433-441
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and aims: The case-mix of patients with intestinal failure due to short bowel syndrome (SBS-IF) can differ among centres and may also be affected by the timeframe of data collection. Therefore, the ESPEN international multicenter cross-sectional survey was analyzed to compare the characteristics of SBS-IF cohorts collected within the same timeframe in different countries. Methods: The study included 1880 adult SBS-IF patients collected in 2015 by 65 centres from 22 countries. The demographic, nutritional, SBS type (end jejunostomy, SBS-J; jejuno-colic anastomosis, SBS-JC; jejunoileal anastomosis with an intact colon and ileocecal valve, SBS-JIC), underlying disease and intravenous supplementation (IVS) characteristics were analyzed. IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorized as <1, 1–2, 2–3 and >3 L/day. Results: In the entire group: 60.7% were females and SBS-J comprised 60% of cases, while mesenteric ischaemia (MI) and Crohn’ disease (CD) were the main underlying diseases. IVS dependency was longer than 3 years in around 50% of cases; IVS was infused ≥5 days/week in 75% and FE in 10% of cases. Within the SBS-IF cohort: CD was twice and thrice more frequent in SBS-J than SBS-JC and SBS-JIC, respectively, while MI was more frequent in SBS-JC and SBS-JIC. Within countries: SBS-J represented 75% or more of patients in UK and Denmark and 50-60% in the other countries, except Poland where SBS-JC prevailed. CD was the main underlying disease in UK, USA, Denmark and The Netherlands, while MI prevailed in France, Italy and Poland. Conclusions: SBS-IF type is primarily determined by the underlying disease, with significant variation between countries. These novel data will be useful for planning and managing both clinical activity and research studies on SBS.
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11.
  • Steele, Jessica E., et al. (författare)
  • Big Data and the Well-Being of Women and Girls: Applications on the Social Scientific Frontier
  • 2017
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • This work was initiated by Data2X, a collaborative technical and advocacy platform dedicated to improving the quality, availability, and use of gender data in order to make a practical difference in the lives of women and girls worldwide. Data2X works with UN agencies, governments, civil society, academics, and the private sector to close gender data gaps, promote expanded and unbiased gender data collection, and use gender data to improve policies, strategies, and decision-making. Hosted at the United Nations Foundation, Data2X receives funding from the William and Flora Hewlett Foundation and the BillXX1Melinda Gates Foundation.
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12.
  • Abelev, Betty, et al. (författare)
  • Long-range angular correlations on the near and away side in p-Pb collisions at root S-NN=5.02 TeV
  • 2013
  • Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 719:1-3, s. 29-41
  • Tidskriftsartikel (refereegranskat)abstract
    • Angular correlations between charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV for transverse momentum ranges within 0.5 < P-T,P-assoc < P-T,P-trig < 4 GeV/c. The correlations are measured over two units of pseudorapidity and full azimuthal angle in different intervals of event multiplicity, and expressed as associated yield per trigger particle. Two long-range ridge-like structures, one on the near side and one on the away side, are observed when the per-trigger yield obtained in low-multiplicity events is subtracted from the one in high-multiplicity events. The excess on the near-side is qualitatively similar to that recently reported by the CMS Collaboration, while the excess on the away-side is reported for the first time. The two-ridge structure projected onto azimuthal angle is quantified with the second and third Fourier coefficients as well as by near-side and away-side yields and widths. The yields on the near side and on the away side are equal within the uncertainties for all studied event multiplicity and p(T) bins, and the widths show no significant evolution with event multiplicity or p(T). These findings suggest that the near-side ridge is accompanied by an essentially identical away-side ridge. (c) 2013 CERN. Published by Elsevier B.V. All rights reserved.
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13.
  • Abelev, Betty, et al. (författare)
  • Measurement of prompt J/psi and beauty hadron production cross sections at mid-rapidity in pp collisions at root s=7 TeV
  • 2012
  • Ingår i: Journal of High Energy Physics. - 1029-8479. ; :11
  • Tidskriftsartikel (refereegranskat)abstract
    • The ALICE experiment at the LHC has studied J/psi production at mid-rapidity in pp collisions at root s = 7 TeV through its electron pair decay on a data sample corresponding to an integrated luminosity L-int = 5.6 nb(-1). The fraction of J/psi from the decay of long-lived beauty hadrons was determined for J/psi candidates with transverse momentum p(t) > 1,3 GeV/c and rapidity vertical bar y vertical bar < 0.9. The cross section for prompt J/psi mesons, i.e. directly produced J/psi and prompt decays of heavier charmonium states such as the psi(2S) and chi(c) resonances, is sigma(prompt J/psi) (p(t) > 1.3 GeV/c, vertical bar y vertical bar < 0.9) = 8.3 +/- 0.8(stat.) +/- 1.1 (syst.)(-1.4)(+1.5) (syst. pol.) mu b. The cross section for the production of b-hadrons decaying to J/psi with p(t) > 1.3 GeV/c and vertical bar y vertical bar < 0.9 is a sigma(J/psi <- hB) (p(t) > 1.3 GeV/c, vertical bar y vertical bar < 0.9) = 1.46 +/- 0.38 (stat.)(-0.32)(+0.26) (syst.) mu b. The results are compared to QCD model predictions. The shape of the p(t) and y distributions of b-quarks predicted by perturbative QCD model calculations are used to extrapolate the measured cross section to derive the b (b) over bar pair total cross section and d sigma/dy at mid-rapidity.
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14.
  • Abelev, Betty, et al. (författare)
  • Underlying Event measurements in pp collisions at root s=0.9 and 7 TeV with the ALICE experiment at the LHC
  • 2012
  • Ingår i: Journal of High Energy Physics. - 1029-8479. ; :7
  • Tidskriftsartikel (refereegranskat)abstract
    • We present measurements of Underlying Event observables in pp collisions at root s = 0 : 9 and 7 TeV. The analysis is performed as a function of the highest charged-particle transverse momentum p(T),L-T in the event. Different regions are defined with respect to the azimuthal direction of the leading (highest transverse momentum) track: Toward, Transverse and Away. The Toward and Away regions collect the fragmentation products of the hardest partonic interaction. The Transverse region is expected to be most sensitive to the Underlying Event activity. The study is performed with charged particles above three different p(T) thresholds: 0.15, 0.5 and 1.0 GeV/c. In the Transverse region we observe an increase in the multiplicity of a factor 2-3 between the lower and higher collision energies, depending on the track p(T) threshold considered. Data are compared to PYTHIA 6.4, PYTHIA 8.1 and PHOJET. On average, all models considered underestimate the multiplicity and summed p(T) in the Transverse region by about 10-30%.
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15.
  • Abidine, Yara, et al. (författare)
  • Cellular Chondroitin Sulfate and the Mucin-like Domain of Viral Glycoprotein C Promote Diffusion of Herpes Simplex Virus 1 While Heparan Sulfate Restricts Mobility
  • 2022
  • Ingår i: Viruses. - : MDPI AG. - 1999-4915. ; 14:8
  • Tidskriftsartikel (refereegranskat)abstract
    • The diffusion of viruses at the cell membrane is essential to reach a suitable entry site and initiate subsequent internalization. Although many viruses take advantage of glycosaminoglycans (GAG) to bind to the cell surface, little is known about the dynamics of the virus-GAG interactions. Here, single-particle tracking of the initial interaction of individual herpes simplex virus 1 (HSV-1) virions reveals a heterogeneous diffusive behavior, regulated by cell-surface GAGs with two main diffusion types: confined and normal free. This study reports that different GAGs can have competing influences in mediating diffusion on the cells used here: chondroitin sulfate (CS) enhances free diffusion but hinders virus attachment to cell surfaces, while heparan sulfate (HS) promotes virus confinement and increases entry efficiency. In addition, the role that the viral mucin-like domains (MLD) of the HSV-1 glycoprotein C plays in facilitating the diffusion of the virus and accelerating virus penetration into cells is demonstrated. Together, our results shed new light on the mechanisms of GAG-regulated virus diffusion at the cell surface for optimal internalization. These findings may be extendable to other GAG-binding viruses.
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16.
  • Ademuyiwa, Adesoji O., et al. (författare)
  • Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
  • 2016
  • Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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17.
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18.
  • Altgärde, Noomi, 1983, et al. (författare)
  • Mucin-like region of herpes simplex virus type 1 attachment protein gC modulates the virus-glycosaminoglycan interaction.
  • 2015
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 290:35, s. 21473-21485
  • Tidskriftsartikel (refereegranskat)abstract
    • Glycoprotein C (gC) mediates the attachment of herpes simplex virus type 1 (HSV-1) to susceptible host cells by interacting with glycosaminoglycans (GAGs) on the cell surface. gC contains a mucin-like region located near the GAG-binding site, which may affect the binding activity. Here, we address this issue by studying an HSV-1 mutant lacking the mucin- like domain in gC and the corresponding purified mutant protein (gCΔmuc), in cell culture and GAG-binding assays, respectively. The mutant virus exhibited two functional alterations as compared to native HSV-1, i.e. decreased sensitivity to GAG-based inhibitors of virus attachment to cells, and reduced release of viral particles from the surface of infected cells. Kinetic and equilibrium binding characteristics of purified gC were assessed using surface plasmon resonance-based sensing together with a surface platform consisting of end-on immobilized GAGs. Both native gC and gCΔmuc bound via the expected binding region to chondroitin sulfate and sulfated hyaluronan but not to the non-sulfated hyaluronan, confirming binding specificity. In contrast to native gC, gCΔmuc exhibited a decreased affinity for GAGs and a slower dissociation, indicating that once formed, the gCΔmuc-GAG complex is more stable. It was also found that a larger number of gCΔmuc bound to a single GAG chain, compared to native gC. Taken together, our data suggest that the mucin-like region of HSV-1 gC is involved in the modulation of the GAG-binding activity, a feature of importance both for unrestricted virus entry into the cells and release of newly produced viral particles from infected cells.
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19.
  • Bausch, Birke, et al. (författare)
  • Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1.
  • 2007
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:7, s. 2784-92
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma.MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed.RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype.CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.
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20.
  • Beal, Jacob, et al. (författare)
  • Robust estimation of bacterial cell count from optical density
  • 2020
  • Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
  • Tidskriftsartikel (refereegranskat)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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21.
  • Biffi, Alessandro, et al. (författare)
  • Variants at APOE Influence Risk of Deep and Lobar Intracerebral Hemorrhage
  • 2010
  • Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 68:6, s. 934-943
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Prior studies investigating the association between APOE alleles epsilon 2/epsilon 4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods: We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for epsilon 2 and epsilon 4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results: Alleles epsilon 2 and epsilon 4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 x 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 x 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele epsilon 4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 x 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation: APOE epsilon 2 and epsilon 4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE epsilon 4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010;68:934-943
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22.
  • Canudas, Silvia, et al. (författare)
  • Mediterranean Diet and Telomere Length : A Systematic Review and Meta-Analysis
  • 2020
  • Ingår i: Advances in Nutrition. - : Elsevier BV. - 2161-8313. ; 11:6, s. 1544-1554
  • Forskningsöversikt (refereegranskat)abstract
    • Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered to be 1 of the most recognized diets for disease prevention and healthy aging, partially due to its demonstrated anti-inflammatory and antioxidative properties which may impact on telomere length (TL). The aim of this meta-analysis was to determine the associations between MedDiet adherence and TL maintenance. MEDLINE-PubMed and Cochrane databases were searched up to December 2018 for studies evaluating the association between MedDiet adherence and TL in blood cells. Two reviewers, working independently, screened all titles and abstracts to identify studies that met the inclusion criteria [cross-sectional, case-control, and prospective cohort studies and randomized clinical trials (RCTs) published in English and excluded nonoriginal articles]. Data were pooled by the generic inverse variance method using the random effects model and expressed as standardized mean difference (SMD). Heterogeneity was identified using the Cochran Q test and quantified by the I2 statistic. A total of 8 original cross-sectional studies were included for the quantitative meta-analysis, comprising a total of 13,733 participants from 5 countries. A positive association between adherence to the MedDiet and TL was observed in all meta-analyses, with the exception of those conducted only in men: SMD (95% CI) of 0.130 (0.029; 0.231) for all subjects, 0.078 (0.005; 0.152) for women, and 0.095 (-0.005; 0.195) for men. Only 1 prospective cohort study and 1 RCT were identified, therefore, we could not undertake a meta-analysis for these study designs. The present meta-analysis of cross-sectional studies demonstrates that higher MedDiet adherence is associated with longer TL. At the same time, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.
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23.
  • del Río, Miren, et al. (författare)
  • Emerging stability of forest productivity by mixing two species buffers temperature destabilizing effect
  • 2022
  • Ingår i: Journal of Applied Ecology. - : John Wiley & Sons. - 0021-8901 .- 1365-2664. ; 59:11, s. 2730-2741
  • Tidskriftsartikel (refereegranskat)abstract
    • The increasing disturbances in monocultures around the world are testimony to their instability under global change. Many studies have claimed that temporal stability of productivity increases with species richness, although the ecological fundamentals have mainly been investigated through diversity experiments. To adequately manage forest ecosystems, it is necessary to have a comprehensive understanding of the effect of mixing species on the temporal stability of productivity and the way in which it is influenced by climate conditions across large geographical areas. Here, we used a unique dataset of 261 stands combining pure and two-species mixtures of four relevant tree species over a wide range of climate conditions in Europe to examine the effect of species mixing on the level and temporal stability of productivity. Structural equation modelling was employed to further explore the direct and indirect influence of climate, overyielding, species asynchrony and additive effect (i.e. temporal stability expected from the species growth in monospecific stands) on temporal stability in mixed forests. We showed that by adding only one tree species to monocultures, the level (overyielding: +6%) and stability (temporal stability: +12%) of stand growth increased significantly. We identified the key effect of temperature on destabilizing stand growth, which may be mitigated by mixing species. We further confirmed asynchrony as the main driver of temporal stability in mixed stands, through both the additive effect and species interactions, which modify between-species asynchrony in mixtures in comparison to monocultures. Synthesis and applications. This study highlights the emergent properties associated with mixing two species, which result in resource efficient and temporally stable production systems. We reveal the negative impact of mean temperature on temporal stability of forest productivity and how the stabilizing effect of mixing two species can counterbalance this impact. The overyielding and temporal stability of growth addressed in this paper are essential for ecosystem services closely linked with the level and rhythm of forest growth. Our results underline that mixing two species can be a realistic and effective nature-based climate solution, which could contribute towards meeting EU climate target policies.
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24.
  • Delguste, Martin, et al. (författare)
  • Regulatory Mechanisms of the Mucin-Like Region on Herpes Simplex Virus during Cellular Attachment
  • 2019
  • Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8937 .- 1554-8929. ; 14:3, s. 534-542
  • Tidskriftsartikel (refereegranskat)abstract
    • Mucin-like regions, characterized by a local high density of O-linked glycosylation, are found on the viral envelope glycoproteins of many viruses. Herpes simplex virus type 1 (HSV-1), for example, exhibits a mucin-like region on its glycoprotein gC, a viral protein involved in initial recruitment of the virus to the cell surface via interaction with sulfated glycosaminoglycans. So far, this mucin-like region has been proposed to play a key role in modulating the interactions with cellular glycosaminoglycans, and in particular to promote release of HSV-1 virions from infected cells. However, the molecular mechanisms and the role as a pathogenicity factor remains unclear. Using single virus particle tracking, we show that the mobility of chondroitin sulfate-bound HSV-1 virions is decreased in absence of the mucin-like region. This decrease in mobility correlates with an increase in HSV-1-chondroitin sulfate binding forces as observed using atomic force microscopy-based force spectroscopy. Our data suggest that the mucin-like region modulates virus-glycosaminoglycan interactions by regulating the affinity, type, and number of glycoproteins involved in the virus-glycosaminoglycan interaction. This study therefore presents new evidence for a role of the mucin-like region in balancing the interaction of HSV-1 with glycosaminoglycans and provides further insights into the molecular mechanisms used by the virus to ensure both successful cell entry and release from the infected cell.
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25.
  • Domínguez Del Campo, Marta, et al. (författare)
  • Cross-cultural adaptation and psychometric properties of the Spanish Quality in Psychiatric Care Forensic Inpatient Staff (QPC-FIPS) instrument
  • 2022
  • Ingår i: Scientific Reports. - : Nature portfolio. - 2045-2322. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Quality in Psychiatric Care-Forensic Inpatient Staff (QPC-FIPS) is an instrument of Swedish origin validated to measure the perception of the quality of mental health care provided by forensic psychiatry professionals. The aim of this study was to cross-culturally adapt the QPC-FIPS instrument and to evaluate the psychometric properties of the Spanish version of the instrument. A psychometric study was carried out. For validity, content validity, convergent validity and construct validity were included. For reliability, the analysis of internal consistency and temporal stability was included. The sample consisted of 153 mental health professionals from four Forensic Psychiatry units. The adapted Spanish version of the QPC-FIPS scale was configured with the same number of items and dimensions as the original. The psychometric properties, in terms of temporal stability and internal consistency, were adequate and the factor structure, such as the homogeneity of the dimensions of the Spanish version of the QPC-FIPS, was equivalent to the original Swedish version. We found that the QPC_FIPS-Spanish is a valid, reliable and easy-to-apply instrument for assessing the self-perception of professionals regarding the care they provide.
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26.
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27.
  • Erttmann, Saskia F., et al. (författare)
  • Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity
  • 2016
  • Ingår i: Immunity. - : Elsevier BV. - 1074-7613 .- 1097-4180. ; 45:1, s. 106-118
  • Tidskriftsartikel (refereegranskat)abstract
    • The ATM kinase is a central component of the DNA damage repair machinery and redox balance. ATM dysfunction results in the multisystem disease ataxia-telangiectasia (AT). A major cause of mortality in AT is respiratory bacterial infections. Whether ATM deficiency causes innate immune defects that might contribute to bacterial infections is not known. Here we have shown that loss of ATM impairs inflammasome- dependent anti-bacterial innate immunity. Cells from AT patients or Atm(-/-) mice exhibited diminished interleukin-1 beta (IL-1 beta) production in response to bacteria. In vivo, Atm(-/-) mice were more susceptible to pulmonary S. pneumoniae infection in a manner consistent with inflammasome defects. Our data indicate that such defects were due to oxidative inhibition of inflammasome complex assembly. This study reveals an unanticipated function of reactive oxygen species (ROS) in negative regulation of inflammasomes and proposes a theory for the notable susceptibility of AT patients to pulmonary bacterial infection.
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28.
  • García-Revilla, Juan, et al. (författare)
  • Galectin-3 shapes toxic alpha-synuclein strains in Parkinson’s disease
  • 2023
  • Ingår i: Acta Neuropathologica. - 0001-6322. ; 146:1, s. 51-75
  • Tidskriftsartikel (refereegranskat)abstract
    • Parkinson’s Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which triggers neuronal degeneration in a mouse model of PD.
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29.
  • Gillett, Alan, et al. (författare)
  • TNF production in macrophages is genetically determined and regulates inflammatory disease in rats.
  • 2010
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 185:1, s. 442-50
  • Tidskriftsartikel (refereegranskat)abstract
    • Dysregulation of TNF is an important pathophysiological phenotype for many diseases. Recently, certain genetically regulated loci have been identified to regulate several inflammatory diseases. We hypothesized that a region on rat chromosome 4 known to regulate experimental autoimmune encephalomyelitis, experimental arthritis and experimental autoimmune neuritis harbors a gene regulating central inflammatory molecules, such as TNF. We therefore mapped TNF production using linkage analysis in the 12th generation of an advanced intercross line between DA and PVG.AV1 rats, which differ in susceptibility to several inflammatory conditions. A single TNF-regulating quantitative trait locus with a logarithm of odds score of 6.2 was identified and its biological effect was confirmed in a congenic rat strain. The profound TNF regulation mapped in congenic strains to the macrophage population. Several TLR signaling cascades led to the same reduced proinflammatory phenotype in congenic macrophages, indicating control of a convergence point for innate inflammatory activity. The decreased TNF potential and reduced proinflammatory macrophage phenotype in congenic rats was also associated with reduced clinical severity in experimental autoimmune encephalomyelitis, pristane-induced arthritis and sepsis experimental models. Determination of genes and mechanisms involved in this genetically determined TNF regulation will be valuable in understanding disease pathogenesis and aid treatment development.
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30.
  • Gyllensten, Ulf B., et al. (författare)
  • Next Generation Plasma Proteomics Identifies High-Precision Biomarker Candidates for Ovarian Cancer
  • 2022
  • Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple Summary Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. The aim of our study was to broadly measure protein biomarkers to find tests for the early detection of ovarian cancer. We found that combinations of 4-7 protein biomarkers can provide highly accurate detection of early- and late-stage ovarian cancer compared to benign conditions. The performance of the tests was then validated in a second independent cohort. Background: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. Methods: We employed the Explore PEA technology for high-precision analysis of 1463 plasma proteins and conducted a discovery and replication study using two clinical cohorts of previously untreated patients with benign or malignant ovarian tumours (N = 111 and N = 37). Results: The discovery analysis identified 32 proteins that had significantly higher levels in malignant cases as compared to benign diagnoses, and for 28 of these, the association was replicated in the second cohort. Multivariate modelling identified three highly accurate models based on 4 to 7 proteins each for separating benign tumours from early-stage and/or late-stage ovarian cancers, all with AUCs above 0.96 in the replication cohort. We also developed a model for separating the early-stage from the late-stage achieving an AUC of 0.81 in the replication cohort. These models were based on eleven proteins in total (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2), notably without MUCIN-16. The majority of the associated proteins have been connected to ovarian cancer but not identified as potential biomarkers. Conclusions: The results show the ability of using high-precision proteomics for the identification of novel plasma protein biomarker candidates for the early detection of ovarian cancer.
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31.
  • Huberle, Alexander, et al. (författare)
  • Advanced Intercross Line Mapping Suggests That Ncf1 (Ean6) Regulates Severity in an Animal Model of Guillain-Barre Syndrome
  • 2009
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 182:7, s. 4432-4438
  • Tidskriftsartikel (refereegranskat)abstract
    • We here present the first genetic fine mapping of experimental autoimmune neuritis (EAN), the animal model of Guillain-Barre syndrome, in a rat advanced intercross line. We identified and refined a total of five quantitative trait loci on rat chromosomes 4, 10, and 12 (RNO4, RNO10, RNO12), showing linkage to splenic IFN-gamma secretion and disease severity. All quantitative trait loci were shared with other models of complex inflammatory diseases. The quantitative trait locus showing strongest linkage to clinical disease was Ean6 and spans 4.3 Mb on RNO12, harboring the neutrophil cytosolic factor 1 (Ncf1) among other genes. Polymorphisms in Ncf1, a member of the NADPH oxidase complex, have been associated with disease regulation in experimental arthritis and encephalomyelitis. We therefore tested the Ncf1 pathway by treating rats with a NADPH oxidase complex activator and ameliorated EAN compared the oil-treated control group. By proving the therapeutic effect of stimulating the NADPH oxidase complex, our data strongly suggest the first identification of a gene regulating peripheral nervous system inflammation. Taken together with previous reports, our findings suggest a general role of Ncf1 and oxidative burst in pathogenesis of experimental autoimmune animal models. The Journal of Immunology, 2009, 182: 4432-4438.
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32.
  • Kattge, Jens, et al. (författare)
  • TRY plant trait database - enhanced coverage and open access
  • 2020
  • Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
  • Tidskriftsartikel (refereegranskat)abstract
    • Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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33.
  • Lahrouchi, Najim, et al. (författare)
  • Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
  • 2020
  • Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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34.
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35.
  • Lövheim, Mia, 1968-, et al. (författare)
  • Religion och medier
  • 2015. - 1
  • Ingår i: Sociologiska perspektiv på religion i Sverige. - Malmö : Gleerups Utbildning AB. ; , s. 143-160
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)
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36.
  • Manouchehrian, Oscar, et al. (författare)
  • Acute systemic LPS-exposure impairs perivascular CSF distribution in mice
  • 2021
  • Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 18:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The exchange of cerebrospinal (CSF) and interstitial fluid is believed to be vital for waste clearance in the brain. The sleep-dependent glymphatic system, which is comprised of perivascular flow of CSF and is largely dependent on arterial pulsatility and astrocytic aquaporin-4 (AQP4) expression, facilitates much of this brain clearance. During the last decade, several observations have indicated that impaired glymphatic function goes hand in hand with neurodegenerative diseases. Since pathologies of the brain carry inflammatory components, we wanted to know how acute inflammation, e.g., with lipopolysaccharide (LPS) injections, would affect the glymphatic system. In this study, we aim to measure the effect of LPS on perivascular CSF distribution as a measure of glymphatic function.METHODS: Three hours after injection of LPS (1 mg/kg i.p.), C57bl/6 mice were (1) imaged for two CSF tracers, injected into cisterna magna, (2) transcardially perfused with buffer, or (3) used for physiological readouts. Tracer flow was imaged using a low magnification microscope on fixed brains, as well as using vibratome-cut slices for measuring tracer penetration in the brain. Cytokines, glial, and BBB-permeability markers were measured with ELISAs, Western blots, and immunohistochemistry. Cerebral blood flow was approximated using laser Doppler flowmetry, respiration and heart rate with a surgical monitor, and AQP4-polarization was quantified using confocal microscopy of immunolabeled brain sections.RESULTS: LPS-injections significantly lowered perivascular CSF tracer flow and penetration into the parenchyma. No differences in AQP4 polarization, cytokines, astroglial and BBB markers, cerebral blood flow, or respiration were detected in LPS-injected mice, although LPS did elevate cortical Iba1+ area and heart rate.CONCLUSIONS: This study reports another physiological response after acute exposure to the bacterial endotoxin LPS, namely the statistically significant decrease in perivascular distribution of CSF. These observations may benefit our understanding of the role of systemic inflammation in brain clearance.
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37.
  • Menkveld, Albert J., et al. (författare)
  • Nonstandard Errors
  • 2024
  • Ingår i: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390
  • Tidskriftsartikel (refereegranskat)abstract
    • In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
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38.
  • Moreira, Xoaquín, et al. (författare)
  • Impacts of urbanization on insect herbivory and plant defences in oak trees
  • 2019
  • Ingår i: Oikos. - : Wiley. - 0030-1299 .- 1600-0706. ; 128:1, s. 113-123
  • Tidskriftsartikel (refereegranskat)abstract
    • Systematic comparisons of species interactions in urban versus rural environments can improve our understanding of shifts in ecological processes due to urbanization. However, such studies are relatively uncommon and the mechanisms driving urbanization effects on species interactions (e.g. between plants and insect herbivores) remain elusive. Here we investigated the effects of urbanization on leaf herbivory by insect chewers and miners associated with the English oak Quercus robur by sampling trees in rural and urban areas throughout most of the latitudinal distribution of this species. In performing these comparisons, we also controlled for the size of the urban areas (18 cities) and gathered data on CO2 emissions. In addition, we assessed whether urbanization affected leaf chemical defences (phenolic compounds) and nutritional traits (phosphorus and nitrogen), and whether such changes correlated with herbivory levels. Urbanization significantly reduced leaf chewer damage but did not affect leaf miners. In addition, we found that leaves from urban locations had lower levels of chemical defences (condensed and hydrolysable tannins) and higher levels of nutrients (nitrogen and phosphorus) compared to leaves in rural locations. The magnitude of urbanization effects on herbivory and leaf defences was not contingent upon city size. Importantly, while the effects of urbanization on chemical defences were associated with CO2 emissions, changes in leaf chewer damage were not associated with either leaf traits or CO2 levels. These results suggest that effects of urbanization on herbivory occur through mechanisms other than changes in the plant traits measured here. Overall, our simultaneous assessment of insect herbivory, plant traits and abiotic correlates advances our understanding of the main drivers of urbanization effects on plant-herbivore interactions.
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39.
  • Mostafa, Hamza, et al. (författare)
  • Dietary Sources of Anthocyanins and Their Association with Metabolome Biomarkers and Cardiometabolic Risk Factors in an Observational Study
  • 2023
  • Ingår i: Nutrients. - : MDPI AG. - 2072-6643 .- 2072-6643. ; 15:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Anthocyanins (ACNs) are (poly)phenols associated with reduced cardiometabolic risk. Associations between dietary intake, microbial metabolism, and cardiometabolic health benefits of ACNs have not been fully characterized. Our aims were to study the association between ACN intake, considering its dietary sources, and plasma metabolites, and to relate them with cardiometabolic risk factors in an observational study. A total of 1351 samples from 624 participants (55% female, mean age: 45 ± 12 years old) enrolled in the DCH-NG MAX study were studied using a targeted metabolomic analysis. Twenty-four-hour dietary recalls were used to collect dietary data at baseline, six, and twelve months. ACN content of foods was calculated using Phenol Explorer and foods were categorized into food groups. The median intake of total ACNs was 1.6mg/day. Using mixed graphical models, ACNs from different foods showed specific associations with plasma metabolome biomarkers. Combining these results with censored regression analysis, metabolites associated with ACNs intake were: salsolinol sulfate, 4-methylcatechol sulfate, linoleoyl carnitine, 3,4-dihydroxyphenylacetic acid, and one valerolactone. Salsolinol sulfate and 4-methylcatechol sulfate, both related to the intake of ACNs mainly from berries, were inversely associated with visceral adipose tissue. In conclusion, plasma metabolome biomarkers of dietary ACNs depended on the dietary source and some of them, such as salsolinol sulfate and 4-methylcatechol sulfate may link berry intake with cardiometabolic health benefits.
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40.
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41.
  • Mäkeläinen, Suvi, et al. (författare)
  • An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
  • 2019
  • Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 15:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in both humans and dogs. Currently, no standard treatment is available, but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs*1395), was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium (RPE). The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.
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42.
  • Nguyen, Thanh N, et al. (författare)
  • Global Impact of the COVID-19 Pandemic on Stroke Volumes and Cerebrovascular Events: A 1-Year Follow-up.
  • 2023
  • Ingår i: Neurology. - 1526-632X. ; 100:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Declines in stroke admission, IV thrombolysis (IVT), and mechanical thrombectomy volumes were reported during the first wave of the COVID-19 pandemic. There is a paucity of data on the longer-term effect of the pandemic on stroke volumes over the course of a year and through the second wave of the pandemic. We sought to measure the effect of the COVID-19 pandemic on the volumes of stroke admissions, intracranial hemorrhage (ICH), IVT, and mechanical thrombectomy over a 1-year period at the onset of the pandemic (March 1, 2020, to February 28, 2021) compared with the immediately preceding year (March 1, 2019, to February 29, 2020).We conducted a longitudinal retrospective study across 6 continents, 56 countries, and 275 stroke centers. We collected volume data for COVID-19 admissions and 4 stroke metrics: ischemic stroke admissions, ICH admissions, IVT treatments, and mechanical thrombectomy procedures. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases.There were 148,895 stroke admissions in the 1 year immediately before compared with 138,453 admissions during the 1-year pandemic, representing a 7% decline (95% CI [95% CI 7.1-6.9]; p < 0.0001). ICH volumes declined from 29,585 to 28,156 (4.8% [5.1-4.6]; p < 0.0001) and IVT volume from 24,584 to 23,077 (6.1% [6.4-5.8]; p < 0.0001). Larger declines were observed at high-volume compared with low-volume centers (all p < 0.0001). There was no significant change in mechanical thrombectomy volumes (0.7% [0.6-0.9]; p = 0.49). Stroke was diagnosed in 1.3% [1.31-1.38] of 406,792 COVID-19 hospitalizations. SARS-CoV-2 infection was present in 2.9% ([2.82-2.97], 5,656/195,539) of all stroke hospitalizations.There was a global decline and shift to lower-volume centers of stroke admission volumes, ICH volumes, and IVT volumes during the 1st year of the COVID-19 pandemic compared with the prior year. Mechanical thrombectomy volumes were preserved. These results suggest preservation in the stroke care of higher severity of disease through the first pandemic year.This study is registered under NCT04934020.
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43.
  • Olofsson, Sigvard, 1948, et al. (författare)
  • Structure and Role of O-Linked Glycans in Viral Envelope Proteins
  • 2023
  • Ingår i: Annual Review of Virology. - : Annual Reviews. - 2327-056X. ; 10:1, s. 283-304
  • Tidskriftsartikel (refereegranskat)abstract
    • N- and O-glycans are both important constituents of viral envelope glycoproteins. O-linked glycosylation can be initiated by any of 20 different human polypeptide O-acetylgalactosaminyl transferases, resulting in an important functional O-glycan heterogeneity. O-glycans are organized as solitary glycans or in clusters of multiple glycans forming mucin-like domains. They are functional both in the viral life cycle and in viral colonization of their host. Negatively charged O-glycans are crucial for the interactions between glycosaminoglycan-binding viruses and their host. A novel mechanism, based on controlled electrostatic repulsion, explains how such viruses solve the conflict between optimized viral attachment to target cells and efficient egress of progeny virus. Conserved solitary O-glycans appear important for viral uptake in target cells by contributing to viral envelope fusion. Dual roles of viral O-glycans in the host B cell immune response, either epitope blocking or epitope promoting, may be exploitable for vaccine development. Finally, specific virus-induced O-glycans may be involved in viremic spread.
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44.
  • Palmer, Katie, et al. (författare)
  • Association of polypharmacy and hyperpolypharmacy with frailty states : a systematic review and meta-analysis
  • 2019
  • Ingår i: European Geriatric Medicine. - : Springer Science and Business Media LLC. - 1878-7649 .- 1878-7657. ; 10:1, s. 9-36
  • Forskningsöversikt (refereegranskat)abstract
    • Purpose: To investigate: (1) the cross-sectional association between polypharmacy, hyperpolypharmacy and presence of prefrailty or frailty; (2) the risk of incident prefrailty or frailty in persons with polypharmacy, and vice versa.Methods: A systematic review and meta-analysis was performed according to PRISMA guidelines. We searched PubMed, Web of Science, and Embase from 01/01/1998 to 5/2/2018. Pooled estimates were obtained through random effect models and Mantel-Haenszel weighting. Homogeneity was assessed with the I-2 statistic and publication bias with Egger's and Begg's tests.Results: Thirty-seven studies were included. The pooled proportion of polypharmacy in persons with prefrailty and frailty was 47% (95% CI 33-61) and 59% (95% CI 42-76), respectively. Increased odds ratio of polypharmacy were seen for prefrail (pooled OR=1.52; 95% CI 1.32-1.79) and frail persons (pooled OR=2.62, 95% CI 1.81-3.79). Hyperpolypharmacy was also increased in prefrail (OR=1.95; 95% CI 1.41-2.70) and frail (OR=6.57; 95% CI 9.57-10.48) persons compared to robust persons. Only seven longitudinal studies reported data on the risk of either incident prefrailty or frailty in persons with baseline polypharmacy. A significant higher odds of developing prefrailty was found in robust persons with polypharmacy (pooled OR=1.30; 95% CI 1.12-1.51). We found no papers investigating polypharmacy incidence in persons with prefrailty/frailty.Conclusions: Polypharmacy is common in prefrail and frail persons, and these individuals are also more likely to be on extreme drug regimens, i.e. hyperpolypharmacy, than robust older persons. More research is needed to investigate the causal relationship between polypharmacy and frailty syndromes, thereby identifying ways to jointly reduce drug burden and prefrailty/frailty in these individuals.
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45.
  • Peerboom, Nadia, 1990, et al. (författare)
  • Binding Kinetics and Lateral Mobility of HSV-1 on End-Grafted Sulfated Glycosaminoglycans
  • 2017
  • Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 113:6, s. 1223-1234
  • Tidskriftsartikel (refereegranskat)abstract
    • Many viruses, including herpes simplex (HSV), are recruited to their host cells via interaction between their envelope glycoproteins and cell-surface glycosaminoglycans (GAGs). This initial attachment is of a multivalent nature, i.e., it requires the establishment of multiple bonds between amino acids of viral glycoproteins and sulfated saccharides on the GAG chain. To gain understanding of how this binding process is modulated, we performed binding kinetics and mobility studies using end-grafted GAG chains that mimic the end attachment of these chains to proteoglycans. Total internal reflection fluorescence microscopy was used to probe binding and release, as well as the diffusion of single HSV-1 particles. To verify the hypothesis that the degree of sulfation, but also the arrangement of sulfate groups along the GAG chain, plays a key role in HSV binding, we tested two native GAGs (chondroitin sulfate and heparan sulfate) and compared our results to chemically sulfated hyaluronan. HSV-1 recognized all sulfated GAGs, but not the nonsulfated hyaluronan, indicating that binding is specific to the presence of sulfate groups. Furthermore we observed that a notable fraction of GAG-bound virions exhibit lateral mobility, although the multivalent binding to the immobilized GAG brushes ensures firm virus attachment to the interface. Diffusion was faster on the two native GAGs, one of which, chondroitin sulfate, was also characterized by the highest association rate per GAG chain. This highlights the complexity of multivalent virus-GAG interactions and suggests that the spatial arrangement of sulfates along native GAG chains may play a role in modulating the characteristics of the HSV-GAG interaction. Altogether, these results, obtained with a minimal and well-controlled model of the cell membrane, provide, to our knowledge, new insights into the dynamics of the HSV-GAG interaction.
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46.
  • Pihlava, Lassi, et al. (författare)
  • Shell-dependent photofragmentation dynamics of a heavy-atom-containing bifunctional nitroimidazole radiosensitizer
  • 2024
  • Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 26:11, s. 8879-8890
  • Tidskriftsartikel (refereegranskat)abstract
    • Radiation therapy uses ionizing radiation to break chemical bonds in cancer cells, thereby causing DNA damage and leading to cell death. The therapeutic effectiveness can be further increased by making the tumor cells more sensitive to radiation. Here, we investigate the role of the initial halogen atom core hole on the photofragmentation dynamics of 2-bromo-5-iodo-4-nitroimidazole, a potential bifunctional radiosensitizer. Bromine and iodine atoms were included in the molecule to increase the photoionization cross-section of the radiosensitizer at higher photon energies. The fragmentation dynamics of the molecule was studied experimentally in the gas phase using photoelectron-photoion-photoion coincidence spectroscopy and computationally using Born-Oppenheimer molecular dynamics. We observed significant changes between shallow core (I 4d, Br 3d) and deep core (I 3d) ionization in fragment formation and their kinetic energies. Despite the fact, that the ions ejected after deep core ionization have higher kinetic energies, we show that in a cellular environment, the ion spread is not much larger, keeping the damage well-localized. A study on photodissociation dynamics of 2-bromo-5-iodo-nitroimidazole - a model radiosensitizer - using coincidence spectroscopy and computational methods.
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47.
  • Pretzsch, Hans, et al. (författare)
  • With increasing site quality asymmetric competition and mortality reduces Scots pine (Pinus sylvestris L.) stand structuring across Europe
  • 2022
  • Ingår i: Forest Ecology and Management. - : Elsevier. - 0378-1127 .- 1872-7042. ; 520
  • Tidskriftsartikel (refereegranskat)abstract
    • Heterogeneity of structure can increase mechanical stability, stress resistance and resilience, biodiversity and many other functions and services of forest stands. That is why many silvicultural measures aim at enhancing structural diversity. However, the effectiveness and potential of structuring may depend on the site conditions. Here, we revealed how the stand structure is determined by site quality and results from site-dependent partitioning of growth and mortality among the trees. We based our study on 90 mature, even-aged, fully stocked monocultures of Scots pine (Pinus sylvestris L.) sampled in 21 countries along a productivity gradient across Europe. A mini-simulation study further analyzed the site-dependency of the interplay between growth and mortality and the resulting stand structure. The overarching hypothesis was that the stand structure changes with site quality and results from the site-dependent asymmetry of competition and mortality.First, we show that Scots pine stands structure across Europe become more homogeneous with increasing site quality. The coefficient of variation and Gini coefficient of stem diameter and tree height continuously decreased, whereas Stand Density Index and stand basal area increased with site index.Second, we reveal a site-dependency of the growth distribution among the trees and the mortality. With increasing site index, the asymmetry of both competition and growth distribution increased and suggested, at first glance, an increase in stand heterogeneity. However, with increasing site index, mortality eliminates mainly small instead of all-sized trees, cancels the size variation and reduces the structural heterogeneity.Third, we modelled the site-dependent interplay between growth partitioning and mortality. By scenario runs for different site conditions, we can show how the site-dependent structure at the stand level emerges from the asymmetric competition and mortality at the tree level and how the interplay changes with increasing site quality across Europe.Our most interesting finding was that the growth partitioning became more asymmetric and structuring with increasing site quality, but that the mortality eliminated predominantly small trees, reduced their size variation and thus reversed the impact of site quality on the structure. Finally, the reverse effects of mode of growth partitioning and mortality on the stand structure resulted in the highest size variation on poor sites and decreased structural heterogeneity with increasing site quality. Since our results indicate where heterogeneous structures need silviculture interventions and where they emerge naturally, we conclude that these findings may improve system understanding and modelling and guide forest management aiming at structurally rich forests.
  •  
48.
  • Promerova, Marta, et al. (författare)
  • MHC Class IIB Exon 2 Polymorphism in the Grey Partridge (Perdix perdix) Is Shaped by Selection, Recombination and Gene Conversion
  • 2013
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7, s. e69135-
  • Tidskriftsartikel (refereegranskat)abstract
    • Among bird species, the most studied major histocompatibility complex (MHC) is the chicken MHC. Although the number of studies on MHC in free-ranging species is increasing, the knowledge on MHC variation in species closely related to chicken is required to understand the peculiarities of bird MHC evolution. Here we describe the variation of MHC class IIB (MHCIIB) exon 2 in a population of the Grey partridge (Perdix perdix), a species of high conservation concern throughout Europe and an emerging galliform model in studies of sexual selection. We found 12 alleles in 108 individuals, but in comparison to other birds surprisingly many sites show signatures of historical positive selection. Individuals displayed between two to four alleles both on genomic and complementary DNA, suggesting the presence of two functional MHCIIB loci. Recombination and gene conversion appear to be involved in generating MHCIIB diversity in the Grey partridge; two recombination breakpoints and several gene conversion events were detected. In phylogenetic analysis of galliform MHCIIB, the Grey partridge alleles do not cluster together, but are scattered through the tree instead. Thus, our results indicate that the Grey partridge MHCIIB is comparable to most other galliforms in terms of copy number and population polymorphism.
  •  
49.
  • Rastogi, Monisha, et al. (författare)
  • Lithium ions solvated in helium
  • 2018
  • Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 20:40, s. 25569-25576
  • Tidskriftsartikel (refereegranskat)abstract
    • We report on a combined experimental and theoretical study of Li+ ions solvated by up to 50 He atoms. The experiments show clear enhanced abundances associated with HenLi+ clusters where n = 2, 6, 8, and 14. We find that classical methods, e.g. basin-hopping (BH), give results that qualitatively agree with quantum mechanical methods such as path integral Monte Carlo, diffusion Monte Carlo and quantum free energy, regarding both energies and the solvation structures that are formed. The theory identifies particularly stable structures for n = 4, 6 and 8 which line up with some of the most abundant features in the experiments.
  •  
50.
  • Rincón-Tomás, Blanca, et al. (författare)
  • Revisiting the mercury cycle in marine sediments : A potential multifaceted role for Desulfobacterota
  • 2024
  • Ingår i: Journal of Hazardous Materials. - : Elsevier. - 0304-3894 .- 1873-3336. ; 465
  • Tidskriftsartikel (refereegranskat)abstract
    • Marine sediments impacted by urban and industrial pollutants are typically exposed to reducing conditions and represent major reservoirs of toxic mercury species. Mercury methylation mediated by anaerobic microorganisms is favored under such conditions, yet little is known about potential microbial mechanisms for mercury detoxification. We used culture-independent (metagenomics, metabarcoding) and culture-dependent approaches in anoxic marine sediments to identify microbial indicators of mercury pollution and analyze the distribution of genes involved in mercury reduction (merA) and demethylation (merB). While none of the isolates featured merB genes, 52 isolates, predominantly affiliated with Gammaproteobacteria, were merA positive. In contrast, merA genes detected in metagenomes were assigned to different phyla, including Desulfobacterota, Actinomycetota, Gemmatimonadota, Nitrospirota, and Pseudomonadota. This indicates a widespread capacity for mercury reduction in anoxic sediment microbiomes. Notably, merA genes were predominately identified in Desulfobacterota, a phylum previously associated only with mercury methylation. Marker genes involved in the latter process (hgcAB) were also mainly assigned to Desulfobacterota, implying a potential central and multifaceted role of this phylum in the mercury cycle. Network analysis revealed that Desulfobacterota were associated with anaerobic fermenters, methanogens and sulfur-oxidizers, indicating potential interactions between key players of the carbon, sulfur and mercury cycling in anoxic marine sediments.
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