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| 2. |
- Blach, S., et al.
(author)
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Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study
- 2022
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In: Lancet Gastroenterology & Hepatology. - : Elsevier BV. - 2468-1253. ; 7:5, s. 396-415
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Journal article (peer-reviewed)abstract
- Background Since the release of the first global hepatitis elimination targets in 2016, and until the COVID-19 pandemic started in early 2020, many countries and territories were making progress toward hepatitis C virus (HCV) elimination. This study aims to evaluate HCV burden in 2020, and forecast HCV burden by 2030 given current trends. Methods This analysis includes a literature review, Delphi process, and mathematical modelling to estimate HCV prevalence (viraemic infection, defined as HCV RNA-positive cases) and the cascade of care among people of all ages (age =0 years from birth) for the period between Jan 1, 2015, and Dec 31, 2030. Epidemiological data were collected from published sources and grey literature (including government reports and personal communications) and were validated among country and territory experts. A Markov model was used to forecast disease burden and cascade of care from 1950 to 2050 for countries and territories with data. Model outcomes were extracted from 2015 to 2030 to calculate population-weighted regional averages, which were used for countries or territories without data. Regional and global estimates of HCV prevalence, cascade of care, and disease burden were calculated based on 235 countries and territories. Findings Models were built for 110 countries or territories: 83 were approved by local experts and 27 were based on published data alone. Using data from these models, plus population-weighted regional averages for countries and territories without models (n=125), we estimated a global prevalence of viraemic HCV infection of 0.7% (95% UI 0.7-0.9), corresponding to 56.8 million (95% UI 55.2-67.8) infections, on Jan 1, 2020. This number represents a decrease of 6.8 million viraemic infections from a 2015 (beginning of year) prevalence estimate of 63.6 million (61.8-75.8) infections (0.9% [0.8-1.0] prevalence). By the end of 2020, an estimated 12.9 million (12.5-15.4) people were living with a diagnosed viraemic infection. In 2020, an estimated 641 000 (623 000-765 000) patients initiated treatment. Interpretation At the beginning of 2020, there were an estimated 56.8 million viraemic HCV infections globally. Although this number represents a decrease from 2015, our forecasts suggest we are not currently on track to achieve global elimination targets by 2030. As countries recover from COVID-19, these findings can help refocus efforts aimed at HCV elimination. Copyright (C) 2022 Elsevier Ltd. All rights reserved.
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| 3. |
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| 6. |
- Surendran, Praveen, et al.
(author)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Journal article (peer-reviewed)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 7. |
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| 8. |
- Surendran, Praveen, et al.
(author)
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Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension
- 2016
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1151-1161
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Journal article (peer-reviewed)abstract
- High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used -1/4155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
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| 15. |
- Abdulla, N., et al.
(author)
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Epidemiology of hip fracture in Qatar and development of a country specific FRAX model
- 2022
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In: Archives of Osteoporosis. - : Springer Science and Business Media LLC. - 1862-3522 .- 1862-3514. ; 17:1
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Journal article (peer-reviewed)abstract
- A Summary Hip fracture data were retrieved from electronical medical records for the years 2017-2019 in the State of Qatar and used to create a FRAX (R) model to facilitate fracture risk assessment. Hip fracture rates were comparable with estimates from Saudi Arabia, Abu Dhabi, and Kuwait but fracture probabilities varied due to differences in mortality. Objective This paper describes the epidemiology of osteoporotic fractures in the State of Qatar that was used to develop the country-specific fracture prediction FRAX (R) tool. Methods Hip fracture data were retrieved from electronic medical records for the years 2017-2019 in the State of Qatar. The age and sex specific incidence of hip fracture in Qatari residents and national mortality rates were used to create a FRAX (R) model. Fracture probabilities were compared with those from neighboring countries having FRAX models. Results Hip fracture rates were comparable with estimates from Saudi Arabia, Abu Dhabi and Kuwait. In contrast, probabilities of a major osteoporotic fracture or hip fracture were lower in Qatar than in Kuwait but higher than those in Abu Dhabi and Saudi Arabia due to differences in mortality. Conclusion The FRAX model should enhance accuracy of determining fracture probability among the Qatari population and help guide decisions about treatment.
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| 16. |
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| 17. |
- Bhattarai, Achuyt, et al.
(author)
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Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar
- 2007
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In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 4:11, s. e309-
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Journal article (peer-reviewed)abstract
- BackgroundThe Roll Back Malaria strategy recommends a combination of interventions for malaria control. Zanzibar implemented artemisinin-based combination therapy (ACT) for uncomplicated malaria in late 2003 and long-lasting insecticidal nets (LLINs) from early 2006. ACT is provided free of charge to all malaria patients, while LLINs are distributed free to children under age 5 y (“under five”) and pregnant women. We investigated temporal trends in Plasmodium falciparum prevalence and malaria-related health parameters following the implementation of these two malaria control interventions in Zanzibar.Methods and FindingsCross-sectional clinical and parasitological surveys in children under the age of 14 y were conducted in North A District in May 2003, 2005, and 2006. Survey data were analyzed in a logistic regression model and adjusted for complex sampling design and potential confounders. Records from all 13 public health facilities in North A District were analyzed for malaria-related outpatient visits and admissions. Mortality and demographic data were obtained from District Commissioner's Office. P. falciparum prevalence decreased in children under five between 2003 and 2006; using 2003 as the reference year, odds ratios (ORs) and 95% confidence intervals (CIs) were, for 2005, 0.55 (0.28–1.08), and for 2006, 0.03 (0.00–0.27); p for trend < 0.001. Between 2002 and 2005 crude under-five, infant (under age 1 y), and child (aged 1–4 y) mortality decreased by 52%, 33%, and 71%, respectively. Similarly, malaria-related admissions, blood transfusions, and malaria-attributed mortality decreased significantly by 77%, 67% and 75%, respectively, between 2002 and 2005 in children under five. Climatic conditions favorable for malaria transmission persisted throughout the observational period.ConclusionsFollowing deployment of ACT in Zanzibar 2003, malaria-associated morbidity and mortality decreased dramatically within two years. Additional distribution of LLINs in early 2006 resulted in a 10-fold reduction of malaria parasite prevalence. The results indicate that the Millennium Development Goals of reducing mortality in children under five and alleviating the burden of malaria are achievable in tropical Africa with high coverage of combined malaria control interventions.
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| 18. |
- Deane, Colleen S., et al.
(author)
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The acute transcriptional response to resistance exercise : impact of age and contraction mode
- 2019
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In: Aging. - : Impact Journals LLC. - 1945-4589. ; 11:7, s. 2111-2126
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Journal article (peer-reviewed)abstract
- Optimization of resistance exercise (RE) remains a hotbed of research for muscle building and maintenance. However, the interactions between the contractile components of RE (i.e. concentric (CON) and eccentric (ECC)) and age, are poorly defined. We used transcriptomics to compare age-related molecular responses to acute CON and ECC exercise. Eight young (21 +/- 1 y) and eight older (70 +/- 1 y) exercise-naive male volunteers had vastus lateralis biopsies collected at baseline and 5 h post unilateral CON and contralateral ECC exercise. RNA was subjected to next-generation sequencing and differentially expressed (DE) genes tested for pathway enrichment using Gene Ontology (GO). The young transcriptional response to CON and ECC was highly similar and older adults displayed moderate contraction-specific profiles, with no GO enrichment. Age-specific responses to ECC revealed 104 DE genes unique to young, and 170 DE genes in older muscle, with no GO enrichment. Following CON, 15 DE genes were young muscle-specific, whereas older muscle uniquely expressed 147 up-regulated genes enriched for cell adhesion and blood vessel development, and 28 down-regulated genes involved in mitochondria! respiration, amino acid and lipid metabolism. Thus, older age is associated with contraction-specific regulation often without clear functional relevance, perhaps reflecting a degree of stochastic age-related dysregulation.
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| 19. |
- Hendriksen, Rene S., et al.
(author)
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Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage
- 2019
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Journal article (peer-reviewed)abstract
- © 2019, The Author(s). Antimicrobial resistance (AMR) is a serious threat to global public health, but obtaining representative data on AMR for healthy human populations is difficult. Here, we use metagenomic analysis of untreated sewage to characterize the bacterial resistome from 79 sites in 60 countries. We find systematic differences in abundance and diversity of AMR genes between Europe/North-America/Oceania and Africa/Asia/South-America. Antimicrobial use data and bacterial taxonomy only explains a minor part of the AMR variation that we observe. We find no evidence for cross-selection between antimicrobial classes, or for effect of air travel between sites. However, AMR gene abundance strongly correlates with socio-economic, health and environmental factors, which we use to predict AMR gene abundances in all countries in the world. Our findings suggest that global AMR gene diversity and abundance vary by region, and that improving sanitation and health could potentially limit the global burden of AMR. We propose metagenomic analysis of sewage as an ethically acceptable and economically feasible approach for continuous global surveillance and prediction of AMR.
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| 20. |
- Nagaraj, Vini, et al.
(author)
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Elevated basal insulin secretion in type 2 diabetes caused by reduced plasma membrane cholesterol
- 2016
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In: Molecular Endocrinology. - : Endocrine Society. - 0888-8809 .- 1944-9917. ; 30:10, s. 1059-1069
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Journal article (peer-reviewed)abstract
- Elevated basal insulin secretion under fasting conditions together with insufficient stimulated insulin release is an important hallmark of type 2 diabetes, but the mechanisms controlling basal insulin secretion remain unclear. Membrane rafts exist in pancreatic islet cells and spatially organize membrane ion channels and proteins controlling exocytosis, which may contribute to the regulation of insulin secretion. Membrane rafts (cholesterol and sphingolipid containing microdomains) were dramatically reduced in human type 2 diabetic and diabetic Goto-Kakizaki (GK) rat islets when compared with healthy islets. Oxidation of membrane cholesterol markedly reduced microdomain staining intensity in healthy human islets, but was without effect in type 2 diabetic islets. Intriguingly, oxidation of cholesterol affected glucose-stimulated insulin secretion only modestly, whereas basal insulin release was elevated. This was accompanied by increased intracellular Ca2+ spike frequency and Ca2+ influx and explained by enhanced single Ca2+ channel activity. These results suggest that the reduced presence of membrane rafts could contribute to the elevated basal insulin secretion seen in type 2 diabetes.
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| 21. |
- Taddeo, EP, et al.
(author)
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Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels
- 2020
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:2, s. 131-145
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Journal article (peer-reviewed)abstract
- Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the prediabetic state. Herein, we have discovered a mechanism that specifically regulates non–glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by β-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak–mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the KATP channel. In summary, we have described a novel nonesterified free fatty acid–stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.
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| 22. |
- Willis, Craig R.G., et al.
(author)
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Network analysis of human muscle adaptation to aging and contraction
- 2020
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In: Aging. - : Impact Journals LLC. - 1945-4589. ; 12:1, s. 740-755
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Journal article (peer-reviewed)abstract
- Resistance exercise (RE) remains a primary approach for minimising aging muscle decline. Understanding muscle adaptation to individual contractile components of RE (eccentric, concentric) might optimise RE-based intervention strategies. Herein, we employed a network-driven pipeline to identify putative molecular drivers of muscle aging and contraction mode responses. RNA-sequencing data was generated from young (21±1 y) and older (70±1 y) human skeletal muscle before and following acute unilateral concentric and contralateral eccentric contractions. Application of weighted gene co-expression network analysis identified 33 distinct gene clusters ('modules') with an expression profile regulated by aging, contraction and/or linked to muscle strength. These included two contraction 'responsive' modules (related to 'cell adhesion' and 'transcription factor' processes) that also correlated with the magnitude of post-exercise muscle strength decline. Module searches for 'hub' genes and enriched transcription factor binding sites established a refined set of candidate module-regulatory molecules (536 hub genes and 60 transcription factors) as possible contributors to muscle aging and/or contraction responses. Thus, network-driven analysis can identify new molecular candidates of functional relevance to muscle aging and contraction mode adaptations.
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| 23. |
- Abdulla, Maysaa, et al.
(author)
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Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma
- 2020
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In: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 95:1, s. 57-67
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Journal article (peer-reviewed)abstract
- The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.
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| 24. |
- Abdulla, Parosh Aziz, Professor, 1961-, et al.
(author)
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The Decidability of Verification under PS 2.0
- 2021
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In: Programming Languages And Systems, ESOP 2021. - Cham : Springer Nature. - 9783030720193 - 9783030720186 ; , s. 1-29
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Conference paper (peer-reviewed)abstract
- We consider the reachability problem for finite-state multi-threaded programs under the promising semantics (PS 2.0) of Lee et al., which captures most common program transformations. Since reachability is already known to be undecidable in the fragment of PS 2.0 with only release-acquire accesses (PS 2.0-ra), we consider the fragment with only relaxed accesses and promises (PS 2.0-rlx). We show that reachability under PS 2.0-rlx is undecidable in general and that it becomes decidable, albeit non-primitive recursive, if we bound the number of promises. Given these results, we consider a bounded version of the reachability problem. To this end, we bound both the number of promises and of "view-switches", i.e., the number of times the processes may switch their local views of the global memory. We provide a code-to-code translation from an input program under PS 2.0 (with relaxed and release-acquire memory accesses along with promises) to a program under SC, thereby reducing the bounded reachability problem under PS 2.0 to the bounded context-switching problem under SC. We have implemented a tool and tested it on a set of benchmarks, demonstrating that typical bugs in programs can be found with a small bound.
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| 25. |
- Abdulla, Parosh, Professor, 1961-, et al.
(author)
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Optimal Stateless Model Checking for Causal Consistency
- 2023
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In: Tools and Algorithms for the Construction and Analysis of Systems - 29th International Conference, {TACAS} 2023, Held as Part of the European Joint Conferences on Theory and Practice of Software, {ETAPS} 2022, Paris, France, April 22-27, 2023, Proceedings, Part {I}. - 9783031308239 ; , s. 105-125
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Conference paper (peer-reviewed)
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| 26. |
- Abdulla, Parosh, Professor, 1961-, et al.
(author)
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Probabilistic Total Store Ordering
- 2022
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In: Programming Languages And Systems, ESOP 2022. - Cham : Springer Nature. - 9783030993368 - 9783030993351 ; , s. 317-345
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Conference paper (peer-reviewed)abstract
- We present Probabilistic Total Store Ordering (PTSO) - a probabilistic extension of the classical TSO semantics. For a given (finite-state) program, the operational semantics of PTSO induces an infinite-state Markov chain. We resolve the inherent non-determinism due to process schedulings and memory updates according to given probability distributions. We provide a comprehensive set of results showing the decidability of several properties for PTSO, namely (i) Almost-Sure (Repeated) Reachability: whether a run, starting from a given initial configuration, almost surely visits (resp. almost surely repeatedly visits) a given set of target configurations. (ii) Almost-Never (Repeated) Reachability: whether a run from the initial configuration, almost never visits (resp. almost never repeatedly visits) the target. (iii) Approximate Quantitative (Repeated) Reachability: to approximate, up to an arbitrary degree of precision, the measure of runs that start from the initial configuration and (repeatedly) visit the target. (iv) Expected Average Cost: to approximate, up to an arbitrary degree of precision, the expected average cost of a run from the initial configuration to the target. We derive our results through a nontrivial combination of results from the classical theory of (infinite-state) Markov chains, the theories of decisive and eager Markov chains, specific techniques from combinatorics, as well as, decidability and complexity results for the classical (non-probabilistic) TSO semantics. As far as we know, this is the first work that considers probabilistic verification of programs running on weak memory models.
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| 27. |
- Brook, M. S., et al.
(author)
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Omega-3 supplementation during unilateral resistance exercise training in older women : A within subject and double-blind placebo-controlled trial
- 2021
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In: Clinical Nutrition ESPEN. - : Elsevier. - 2405-4577. ; 46, s. 394-404
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: The skeletal muscle anabolic effects of n-3 polyunsaturated fatty acids (n-3 PUFA) appear favoured towards women; a property that could be exploited in older women who typically exhibit poor muscle growth responses to resistance exercise training (RET). Here we sought to generate novel insights into the efficacy and mechanisms of n-3 PUFA alongside short-term RET in older women.METHODS: We recruited 16 healthy older women (Placebo n = 8 (PLA): 67±1y, n-3 PUFA n = 8: 64±1y) to a randomised double-blind placebo-controlled trial (n-3 PUFA; 3680 mg/day versus PLA) of 6 weeks fully-supervised progressive unilateral RET (i.e. 6 × 8 reps, 75% 1-RM, 3/wk-1). Strength was assessed by knee extensor 1-RM and isokinetic dynamometry ∼ every 10 d. Thigh fat free mass (TFFM) was measured by DXA at 0/3/6 weeks. Bilateral vastus lateralis (VL) biopsies at 0/2/4/6 weeks with deuterium oxide (D2O) dosing were used to determine MPS responses for 0-2 and 4-6 weeks. Further, fibre cross sectional area (CSA), myonuclei number and satellite cell (SC) number were assessed, alongside muscle anabolic/catabolic signalling via immunoblotting.RESULTS: RET increased 1-RM equally in the trained leg of both groups (+23 ± 5% n-3 PUFA vs. +25 ± 5% PLA (both P < 0.01)) with no significant increase in maximum voluntary contraction (MVC) (+10 ± 6% n-3 PUFA vs. +13 ± 5% PLA). Only the n-3 PUFA group increased TFFM (3774 ± 158 g to 3961 ± 151 g n-3 PUFA (P < 0.05) vs. 3406 ± 201 g to 3561 ± 170 PLA) and type II fibre CSA (3097 ± 339 μm2 to 4329 ± 264 μm2 n-3 PUFA (P < 0.05) vs. 2520 ± 316 μm2 to 3467 ± 303 μm2 in PL) with RET. Myonuclei number increased equally in n-3 PUFA and PLA in both type I and type II fibres, with no change in SC number. N-3 PUFA had no added benefit on muscle protein synthesis (MPS), however, during weeks 4-6 of RET, absolute synthesis rates (ASR) displayed a trend to increase with n-3 PUFA only (5.6 ± 0.3 g d-1 to 7.1 ± 0.5 g d-1 n-3 PUFA (P = 0.09) vs. 5.5 ± 0.5 g d-1 to 6.5 ± 0.5 g d-1 PLA). Further, the n-3 PUFA group displayed greater 4EBP1 activation after acute RE at 6 weeks.CONCLUSION: n3-PUFA enhanced RET gains in muscle mass through type II fibre hypertrophy, with data suggesting a role for MPS rather than via SC recruitment. As such, the present study adds to a literature base illustrating the apparent enhancement of muscle hypertrophy with RET in older women fed adjuvant n3-PUFA.
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| 28. |
- Butler, Daniel S.C., et al.
(author)
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Neuroepithelial control of mucosal inflammation in acute cystitis
- 2018
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8, s. 1-15
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Journal article (peer-reviewed)abstract
- The nervous system is engaged by infection, indirectly through inflammatory cascades or directly, by bacterial attack on nerve cells. Here we identify a neuro-epithelial activation loop that participates in the control of mucosal inflammation and pain in acute cystitis. We show that infection activates Neurokinin-1 receptor (NK1R) and Substance P (SP) expression in nerve cells and bladder epithelial cells in vitro and in vivo in the urinary bladder mucosa. Specific innate immune response genes regulated this mucosal response, and single gene deletions resulted either in protection (Tlr4−/− and Il1b−/− mice) or in accentuated bladder pathology (Asc−/− and Nlrp3−/− mice), compared to controls. NK1R/SP expression was lower in Tlr4−/− and Il1b−/− mice than in C56BL/6WT controls but in Asc−/− and Nlrp3−/− mice, NK1R over-activation accompanied the exaggerated disease phenotype, due, in part to transcriptional de-repression of Tacr1. Pharmacologic NK1R inhibitors attenuated acute cystitis in susceptible mice, supporting a role in disease pathogenesis. Clinical relevance was suggested by elevated urine SP levels in patients with acute cystitis, compared to patients with asymptomatic bacteriuria identifying NK1R/SP as potential therapeutic targets. We propose that NK1R and SP influence the severity of acute cystitis through a neuro-epithelial activation loop that controls pain and mucosal inflammation.
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| 29. |
-
Decolonzing Design - : Special Issue for the journal Design and Culture
- 2018
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Editorial collection (peer-reviewed)abstract
- After centuries of subaltern and decades of transdisciplinary gestation, decolonial thinking has finally been incorporated into studies of materiality and – though belatedly – cohered as a question that can be posed directly both to and within the field of Design Studies. Some of the questions that come to mind in this formative moment for decolonial thinking in/and/as design include:• What does the endeavor of decolonizing design mean?• What does it mean for design to be thought of in relation to decoloniality and for decoloniality to be thought of in relation to design?• How are ideas and practices of decolonizing design already emerging?• What are its implications within and beyond the field of Design Studies?These questions have brought us – the members of the Decolonising Design (DD) project and research collective – together and have influenced our efforts to build an online platform that supports and promotes thinking by similarly interested design scholars.
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| 30. |
- Kazim, Abdulla S., et al.
(author)
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Palmitoylation of Ca2+ channel subunit CaVβ2a induces pancreatic beta-cell toxicity via Ca2+ overload
- 2017
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In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 491:3, s. 740-746
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Journal article (peer-reviewed)abstract
- High blood glucose triggers the release of insulin from pancreatic beta cells, but if chronic, causes cellular stress, partly due to impaired Ca2+ homeostasis. Ca2+ influx is controlled by voltage-gated calcium channels (CaV) and high density of CaV in the plasma membrane could lead to Ca2+ overload. Trafficking of the pore-forming CaVα1 subunit to the plasma membrane is regulated by auxiliary subunits, such as the CaVβ2a subunit. This study investigates, using Ca2+ imaging and immunohistochemistry, the role of palmitoylation of CaVβ2a in maintaining Ca2+ homeostasis and beta cell function. RNA sequencing data showed that gene expression of human CACNB2, in particular CACNB2A (CaVβ2a), is highest in islets when compared to other tissues. Since CaVβ2a can be regulated through palmitoylation of its two cysteines, CaVβ2a and its mutant form were overexpressed in pancreatic beta cells. Palmitoylated CaVβ2a tethered to the plasma membrane and colocalized with CaV1.2 while the mutant form remained in the cytosol. Interestingly, CaVβ2a overexpression raised basal intracellular Ca2+ and increased beta cell apoptosis. Our study shows that palmitoylation of CaVβ2a is necessary for CaVα1 trafficking to the plasma membrane. However, excessive number of palmitoylated CaVβ2a leads to Ca2+ overload and beta cell death.
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| 31. |
- Kazim, Abdulla S.
(author)
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Roles of voltage-gated Ca2+ channel subunits in pancreatic β cells
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Hallmarks of type 2 diabetes (T2D) include elevated blood glucose and free fatty acids (FFAs) as a result of impaired β cell insulin secretion and decreased β cell mass. The glucose-stimulated insulin secretion (GSIS) in β cells is triggered by depolarization-evoked Ca2+ entry through voltage-gated Ca2+ (CaV) channels. The majority of CaV channels are believed to reside in cholesterol-rich membrane microdomains called membrane rafts. CaV channels consist of the main pore-forming α1 subunit and three auxiliary subunits, β, α2δ, and γ. The roles of the CaV auxiliary subunits and the membrane rafts in pancreatic β cells are not fully understood, but we have recently shown that the TCF7L2 gene, associated with the strongest genetic risk factor of T2D, regulates Cacna2d1 (α2δ1). This thesis aims to elucidate the roles of β1, β2a, and α2δ1 subunits, as well as membrane rafts, in regulating the α1 subunit and, in turn, insulin secretion and β cell survival. Human islets from donors with T2D contained decreased membrane rafts. A similar phenotype was also observed in the diabetic rat model Goto Kakizaki (GK) rat islets. Cholesterol depletion in healthy human islets by cholesterol oxidase (CO) reduced membrane rafts, resembling islets from donors with T2D. Cholesterol depletion resulted in elevated basal insulin release in both human and rat islets. The reason for this appeared to be the declustering of CaV1.2, elevation in basal Ca2+ oscillations, and an increase in single-CaV channel activity as observed in patch-clamp experiments. When suppressing the Tcf7l2 gene, α2δ1 (mRNA and protein) was downregulated and intracellular Ca2+ was reduced as measured by confocal microfluorimetry. The decrease in Cacna2d1 expression resulted in CaV channel internalization in the recycling endosomes. This lowered the whole-cell Ca2+ current and decreased insulin secretion.Human gene expression analysis showed that both Cacnb1 (β1) and Cacnb2a (β2a) genes are abundant in pancreatic islets. When examining the GK rat islets, the expression of both genes was downregulated. Immunoblot experiments showed that high glucose treatment also reduced protein levels of β1 and β2a in INS-1 832/13 cells. Silencing the β1 subunit reduced insulin secretion, which may be due to the observed decrease in whole-cell Ca2+ currents. By contrast, β2a suppression did not affect insulin release. When comparing the palmitoylation state of β2a, cells overexpressing the non-palmitoylated β2a had a decreased membrane expression of both β2a and α1C. However, overexpression of palmitoylated β2a increased intracellular Ca2+, although without affecting secretion. FFA (palmitate) treatment reduced intracellular Ca2+ under stimulatory conditions thus decreasing GSIS. Cells that either lack β1 or express excess palmitoylated β2a have increased risk of apoptosis. These data reveal novel roles of membrane rafts and β1, β2a, and α2δ1 subunits in regulating CaV channel trafficking and activity, thus influencing β cell function and survival.
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| 32. |
- Mantz, A. B., et al.
(author)
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The XXL Survey. V. Detection of the Sunyaev-Zel'Dovich Effect of the Redshift 1.9 Galaxy Cluster XLSSU J021744.1-034536 With Carma
- 2014
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In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 794:2
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Journal article (peer-reviewed)abstract
- We report the detection of the Sunyaev-Zel'dovich (SZ) effect of galaxy cluster XLSSU J021744.1-034536, using 30 GHz Combined Array for Research in Millimeter-wave Astronomy (CARMA) data. This cluster was discovered via its extended X-ray emission in the XMM-Newton Large Scale Structure survey, the precursor to the XXL survey. It has a photometrically determined redshift z = 1.91(-0.21)(+0.19), making it among the most distant clusters known, and nominally the most distant for which the SZ effect has been measured. The spherically integrated Comptonization is Y-500 = (3.0 +/- 0.4) x 10(-12), a measurement that is relatively insensitive to assumptions regarding the size and redshift of the cluster, as well as the background cosmology. Using a variety of locally calibrated cluster scaling relations extrapolated to z similar to 2, we estimate a mass M-500 similar to (1-2) x 10(14) M-circle dot from the X-ray flux and SZ signal. The measured properties of this cluster are in good agreement with the extrapolation of an X-ray luminosity-SZ effect scaling relation calibrated from clusters discovered by the South Pole Telescope at higher masses and lower redshifts. The full XXL-CARMA sample will provide a more complete, multi-wavelength census of distant clusters in order to robustly extend the calibration of cluster scaling relations to these high redshifts.
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| 33. |
- Mohammad, Reem Sabah, et al.
(author)
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Frictional pressure drop and cost savings for graphene nanoplatelets nanofluids in turbulent flow environments
- 2021
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In: Nanomaterials. - : MDPI AG. - 2079-4991. ; 11:11
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Journal article (peer-reviewed)abstract
- Covalent-functionalized graphene nanoplatelets (CF-GNPs) inside a circular heated-pipe and the subsequent pressure decrease loss within a fully developed turbulent flow were discussed in this research. Four samples of nanofluids were prepared and investigated in the ranges of 0.025 wt.%, 0.05 wt.%, 0.075 wt.%, and 0.1 wt.%. Different tools such as field emission scanning electron microscopy (FE-SEM), ultraviolet-visible-spectrophotometer (UV-visible), energy-dispersive X-ray spectroscopy (EDX), zeta potential, and nanoparticle sizing were used for the data preparation. The thermophysical properties of the working fluids were experimentally determined using the testing conditions established via computational fluid dynamic (CFD) simulations that had been designed to solve governing equations involving distilled water (DW) and nanofluidic flows. The average error between the numerical solution and the Blasius formula was ~4.85%. Relative to the DW, the pressure dropped by 27.80% for 0.025 wt.%, 35.69% for 0.05 wt.%, 41.61% for 0.075 wt.%, and 47.04% for 0.1 wt.%. Meanwhile, the pumping power increased by 3.8% for 0.025 wt.%, 5.3% for 0.05 wt.%, 6.6% for 0.075%, and 7.8% for 0.1 wt.%. The research findings on the cost analysis demonstrated that the daily electric costs were USD 214, 350, 416, 482, and 558 for DW of 0.025 wt.%, 0.05 wt.%, 0.075 wt.%, and 0.1 wt.%, respectively.
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| 34. |
- Nieuwenhuijse, David F., et al.
(author)
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Setting a baseline for global urban virome surveillance in sewage
- 2020
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10
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Journal article (peer-reviewed)abstract
- © 2020, The Author(s). The rapid development of megacities, and their growing connectedness across the world is becoming a distinct driver for emerging disease outbreaks. Early detection of unusual disease emergence and spread should therefore include such cities as part of risk-based surveillance. A catch-all metagenomic sequencing approach of urban sewage could potentially provide an unbiased insight into the dynamics of viral pathogens circulating in a community irrespective of access to care, a potential which already has been proven for the surveillance of poliovirus. Here, we present a detailed characterization of sewage viromes from a snapshot of 81 high density urban areas across the globe, including in-depth assessment of potential biases, as a proof of concept for catch-all viral pathogen surveillance. We show the ability to detect a wide range of viruses and geographical and seasonal differences for specific viral groups. Our findings offer a cross-sectional baseline for further research in viral surveillance from urban sewage samples and place previous studies in a global perspective.
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| 35. |
- Salama, Suzy M., et al.
(author)
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A Zinc Morpholine Complex Prevents HCl/Ethanol-Induced Gastric Ulcers in a Rat Model
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- Zinc is a naturally occurring element with roles in wound healing and rescuing tissue integrity, particularly in the gastrointestinal system, where it can be detected in the mucosal and submucosal layers. Zinc chelates are known to have beneficial effects on the gastrointestinal mucosa and in cases of gastric ulcer. We synthesized complexes of zinc featuring a heterocyclic amine binding amino acids then investigated their ability to enhance the gastric self-repair. Zinc-morpholine complex, Zn(L)SCN, namely showed strong free-radical scavenging, promotion of the DNA and RNA polymerases reconstruction and suppression of cell damage. The complex's mode of action is proposed to involve hydrogen bond formation via its bis(thiocyanato-k) zinc moiety. Zn(L) SCN complex had potent effects on gastric enzymatic activity both in vitro and in vivo. The complex disrupted the ulcerative process as demonstrated by changes in the intermediate metabolites of the oxidative pathway - specifically, reduction in the MDA levels and elevation of reduced glutathione together with an attenuation of oxidative DNA damage. Additionally, Zn(L) SCN restored the gastric mucosa, inhibited the production of pro-inflammatory cytokines (IL-6, TNF and the caspases), and preserved the gastric mucous balance. Zn(L) SCN thus exhibited anti-oxidative, anti-inflammatory and anti-apoptotic activities, all of which have cytoprotective effects on the gastric lining.
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| 36. |
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| 37. |
- Schultz, Tristan, et al.
(author)
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What Is at Stake with Decolonizing Design? : A Roundtable
- 2018
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In: Design and Culture. - : Informa UK Limited. - 1754-7075 .- 1754-7083. ; 10:1, s. 81-101
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Journal article (peer-reviewed)abstract
- This roundtable was conducted by the eight founding members of Decolonising Design Group in October 2017, using an online messaging platform. Each member approached design and decoloniality from different yet interrelating viewpoints, by threading their individual arguments with the preceding ones. The piece thus offers and travels through a variety of subject matter including politics of design, artificiality, modernity, Eurocentrism, capitalism, Indigenous Knowledge, pluriversality, continental philosophy, pedagogy, materiality, mobility, language, gender oppression, sexuality, and intersectionality.
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| 38. |
- Schutte, Aletta E., et al.
(author)
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Addressing global disparities in blood pressure control : perspectives of the International Society of Hypertension
- 2023
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 119:2, s. 381-409
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Research review (peer-reviewed)abstract
- Raised blood pressure (BP) is the leading cause of preventable death in the world. Yet, its global prevalence is increasing, and it remains poorly detected, treated, and controlled in both high- and low-resource settings. From the perspective of members of the International Society of Hypertension based in all regions, we reflect on the past, present, and future of hypertension care, highlighting key challenges and opportunities, which are often region-specific. We report that most countries failed to show sufficient improvements in BP control rates over the past three decades, with greater improvements mainly seen in some high-income countries, also reflected in substantial reductions in the burden of cardiovascular disease and deaths. Globally, there are significant inequities and disparities based on resources, sociodemographic environment, and race with subsequent disproportionate hypertension-related outcomes. Additional unique challenges in specific regions include conflict, wars, migration, unemployment, rapid urbanization, extremely limited funding, pollution, COVID-19-related restrictions and inequalities, obesity, and excessive salt and alcohol intake. Immediate action is needed to address suboptimal hypertension care and related disparities on a global scale. We propose a Global Hypertension Care Taskforce including multiple stakeholders and societies to identify and implement actions in reducing inequities, addressing social, commercial, and environmental determinants, and strengthening health systems implement a well-designed customized quality-of-care improvement framework.
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| 39. |
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| 40. |
- van Rheenen, Wouter, et al.
(author)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Journal article (peer-reviewed)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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