| 1. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Bernstein, Mark, et al.
(författare)
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ICIDS2020 Panel : Building the Discipline of Interactive Digital Narratives
- 2020
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Ingår i: Interactive Storytelling. - Cham : Springer. - 9783030625153 - 9783030625160 ; , s. 3-11
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Konferensbidrag (refereegranskat)abstract
- Building our discipline has been an ongoing discussion since the early days of ICIDS. From earlier international joint efforts to integrate research from multiple fields of study to today’s endeavours by researchers to provide scholarly works of reference, the discussion on how to continue building Interactive Digital Narratives as a discipline with its own vocabulary, scope, evaluation and methods is far from over. This year, we have chosen to continue this discussion through a panel in order to explore what are the epistemological implications of the multiple disciplinary roots of our field, and what are the next steps we should take as a community.
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| 3. |
- Chu, Wan-Yu, et al.
(författare)
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Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates
- 2022
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Ingår i: Clinical Pharmacokinetics. - : Springer Nature. - 0312-5963 .- 1179-1926. ; 61:2, s. 321-333
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates.OBJECTIVE: The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated.METHODS: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling.RESULTS: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62-1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25-2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23-0.3) and 11 L (95% CI 9.9-12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31-0.42).CONCLUSION: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.
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| 4. |
- Fricke, Tabea C., et al.
(författare)
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Oxidation of methionine residues activates the high-threshold heat-sensitive ion channel TRPV2
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 116:48, s. 24359-24365
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Tidskriftsartikel (refereegranskat)abstract
- Thermosensitive transient receptor potential (TRP) ion channels detect changes in ambient temperature to regulate body temperature and temperature-dependent cellular activity. Rodent orthologs of TRP vanilloid 2 (TRPV2) are activated by nonphysiological heat exceeding 50 °C, and human TRPV2 is heat-insensitive. TRPV2 is required for phagocytic activity of macrophages which are rarely exposed to excessive heat, but what activates TRPV2 in vivo remains elusive. Here we describe the molecular mechanism of an oxidation-induced temperature-dependent gating of TRPV2. While high concentrations of H2O2 induce a modest sensitization of heat-induced inward currents, the oxidant chloramine-T (ChT), ultraviolet A light, and photosensitizing agents producing reactive oxygen species (ROS) activate and sensitize TRPV2. This oxidation-induced activation also occurs in excised inside-out membrane patches, indicating a direct effect on TRPV2. The reducing agent dithiothreitol (DTT) in combination with methionine sulfoxide reductase partially reverses ChT-induced sensitization, and the substitution of the methionine (M) residues M528 and M607 to isoleucine almost abolishes oxidation-induced gating of rat TRPV2. Mass spectrometry on purified rat TRPV2 protein confirms oxidation of these residues. Finally, macrophages generate TRPV2-like heat-induced inward currents upon oxidation and exhibit reduced phagocytosis when exposed to the TRP channel inhibitor ruthenium red (RR) or to DTT. In summary, our data reveal a methionine-dependent redox sensitivity of TRPV2 which may be an important endogenous mechanism for regulation of TRPV2 activity and account for its pivotal role for phagocytosis in macrophages.
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| 5. |
- Hoffmann, Gösta, et al.
(författare)
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Fluvio-lacustrine deposits reveal precipitation pattern in SE Arabia during early MIS 3
- 2015
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Ingår i: Quaternary International. - : Elsevier BV. - 1040-6182 .- 1873-4553. ; 382, s. 145-153
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Tidskriftsartikel (refereegranskat)abstract
- On a global scale, Marine Isotope Stage (MIS) 3 (ca. 55-30 ka) was characterised by frequent and abrupt changes in climate. At the same time, humans may have dispersed out of Africa and populated the planet. For the Arabian Peninsula, a key region in both contexts, the paucity of suitable terrestrial records leaves our knowledge of the environmental conditions during this important period enigmatic. Here, we elucidate the environmental history for part of the Oman Mountains by analysing luminescence-dated fine-grained playa-like sediments from Wadi Mistal that formed in a landslide-dammed ephemeral lake. We identified 112 individual fining-upward sequences in the distal facies of the lake that are interpreted to represent major precipitation events during early MIS 3. The nature of sedimentation together with the presence of desiccation cracks and the absence of any faunal remains imply that the lakes had a temporary nature. It appears that the time of deposition was characterised by strong short-lived precipitation events, rather than continuous rainfall under a monsoonal regime. This points towards a climatic situation during early MIS 3 that was not so different from that of the present, at least in this part of Arabia.
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| 6. |
- Koenitz, Hartmut, et al.
(författare)
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A shared vocabulary for IDN : INDCOR white paper 1
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- COST Action 18230 INDCOR (Interactive Narrative Design for Complexity Representations) is an interdisciplinary network of researchers and practitioners intended to further the use of interactive digital narratives (IDN1) to represent highly complex topics. IDN possess crucial advantages in this regard, but more knowledge is needed to realize these advantages in broad usage by media producers and the general public. The lack of a shared vocabulary is a crucial obstacle on the path to a generalized, accessible body of IDN knowledge. This white paper frames the situation from the perspective of INDCOR and describes the creation of an online encyclopedia as a means to overcome this issue. Two similar and successful projects (The Living Handbook of Narratology and the Stanford Encyclopedia of Philosophy) serve as examples for this effort, showing how community-authored encyclopedias can provide high-quality content. The authors introduce a taxonomy based on an overarching analytical framework (SPP model) as the foundational element of the encyclopedia, and detail editorial procedures for the project, including a peer-review process, designed to assure high academic quality and relevance of encyclopedia entries. Also, a sample entry provides guidance for authors.
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| 7. |
- Koenitz, Hartmut, et al.
(författare)
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A Shared Vocabulary for Interactive Digital Narrative (IDN) : An Encyclopedia Project
- 2021
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Ingår i: Games and Narrative. - Cham : Springer. - 9783030815387 - 9783030815370 ; , s. 207-229
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Bokkapitel (refereegranskat)abstract
- The design and study of interactive digital narratives (IDN) is a multidisciplinary field. Scholars and practitioners concerned with the topic originate from fields such as literary studies, computer sciences, games studies, media studies, fine art, filmmaking. Consequently, they not only bring a wealth of productive perspectives to the table, but also differences in terminology. This fact alone can be a cause for confusion, yet it is further amplified by diverging meanings of the same term in different disciplinary contexts. In the field, there is a long-standing issue, we propose concrete steps towards the development of a shared vocabulary in the form of an online encyclopedia, taking inspiration from the Living Handbook of Narratology and the Stanford Encyclopedia of Philosophy. This work is developed in the INDCOR EU COST action, a network currently encompassing more than 160 members from 37 countries.
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| 8. |
- Lövgren, Anna, et al.
(författare)
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Diagnostic accuracy of three screening questions (3Q/TMD) in relation to the DC/TMD in a specialized orofacial pain clinic
- 2018
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Ingår i: Acta Odontologica Scandinavica. - : Taylor & Francis. - 0001-6357 .- 1502-3850. ; 76:6, s. 380-386
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine the diagnostic accuracy of three screening questions (3Q/TMD) in relation to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), in a specialized clinic.Material and methods: Consecutive patients, >18 years, referred with a possible TMD complaint to the Orofacial Pain and Dysfunction clinic, Academic Centre for Dentistry Amsterdam, the Netherlands, were included in the study. All patients (n = 449; mean age 44 years; 72% females), answered the 3Q/TMD and the DC/TMD questionnaire before a DC/TMD examination. The 3Q/TMD constitutes of two questions on weekly pain from the jaw, face and temple region (Q1), and on function (Q2), and one function-related question on weekly catching and/or locking of the jaw (Q3). Q1 and Q2 were evaluated in relation to a DC/TMD pain diagnosis and Q3 in relation to a subgroup of DC/TMD intra-articular diagnosis, referred to as the reference standard.Results: In total, 44% of patients received a pain-related DC/TMD diagnosis and 33% an intra-articular reference DC/TMD diagnosis. Sensitivity for the two pain screening questions was high (0.83–0.94), whereas specificity was low (0.41–0.55). For the function-related question, sensitivity was low (0.48), whereas specificity was high (0.96).Conclusions: In a specialized pain clinic, the two pain questions (Q1, Q2) are positive in most patients with pain-related TMD. Therefore, in case of a positive response, further diagnostic procedures for TMD pain are warranted. For the functional screening question (Q3), a positive response is indicative for an intra-articular DC/TMD diagnosis, while in case of a negative outcome, an intra-articular TMD might still be present.
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| 9. |
- Russell, Andrew J.C., et al.
(författare)
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Regulators of male and female sexual development are critical for the transmission of a malaria parasite
- 2023
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Ingår i: Cell Host and Microbe. - : Cell Press. - 1931-3128 .- 1934-6069. ; 31:2, s. 305-319.e10
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Tidskriftsartikel (refereegranskat)abstract
- Malaria transmission to mosquitoes requires a developmental switch in asexually dividing blood-stage parasites to sexual reproduction. In Plasmodium berghei, the transcription factor AP2-G is required and sufficient for this switch, but how a particular sex is determined in a haploid parasite remains unknown. Using a global screen of barcoded mutants, we here identify genes essential for the formation of either male or female sexual forms and validate their importance for transmission. High-resolution single-cell transcriptomics of ten mutant parasites portrays the developmental bifurcation and reveals a regulatory cascade of putative gene functions in the determination and subsequent differentiation of each sex. A male-determining gene with a LOTUS/OST-HTH domain as well as the protein interactors of a female-determining zinc-finger protein indicate that germ-granule-like ribonucleoprotein complexes complement transcriptional processes in the regulation of both male and female development of a malaria parasite.
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| 10. |
- Sánchez Van Kammen, Mayte, et al.
(författare)
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Characteristics and Outcomes of Patients with Cerebral Venous Sinus Thrombosis in SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 78:11, s. 1314-1323
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson).Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS.Design, Setting, and Participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination.Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria.Main Outcomes and Measures: Clinical characteristics and mortality rate.Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later.Conclusions and Relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination..
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