| 1. |
- Birney, Ewan, et al.
(author)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Journal article (peer-reviewed)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
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| 3. |
- Ash, G. I., et al.
(author)
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Establishing a Global Standard for Wearable Devices in Sport and Exercise Medicine: Perspectives from Academic and Industry Stakeholders
- 2021
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In: Sports Medicine. - : Springer Science and Business Media LLC. - 0112-1642 .- 1179-2035. ; 51, s. 2237-2250
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Journal article (peer-reviewed)abstract
- Millions of consumer sport and fitness wearables (CSFWs) are used worldwide, and millions of datapoints are generated by each device. Moreover, these numbers are rapidly growing, and they contain a heterogeneity of devices, data types, and contexts for data collection. Companies and consumers would benefit from guiding standards on device quality and data formats. To address this growing need, we convened a virtual panel of industry and academic stakeholders, and this manuscript summarizes the outcomes of the discussion. Our objectives were to identify (1) key facilitators of and barriers to participation by CSFW manufacturers in guiding standards and (2) stakeholder priorities. The venues were the Yale Center for Biomedical Data Science Digital Health Monthly Seminar Series (62 participants) and the New England Chapter of the American College of Sports Medicine Annual Meeting (59 participants). In the discussion, stakeholders outlined both facilitators of (e.g., commercial return on investment in device quality, lucrative research partnerships, and transparent and multilevel evaluation of device quality) and barriers (e.g., competitive advantage conflict, lack of flexibility in previously developed devices) to participation in guiding standards. There was general agreement to adopt Keadle et al.'s standard pathway for testing devices (i.e., benchtop, laboratory, field-based, implementation) without consensus on the prioritization of these steps. Overall, there was enthusiasm not to add prescriptive or regulatory steps, but instead create a networking hub that connects companies to consumers and researchers for flexible guidance navigating the heterogeneity, multi-tiered development, dynamicity, and nebulousness of the CSFW field.
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| 4. |
- Wei, W., et al.
(author)
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Getz Ice Shelf melt enhanced by freshwater discharge from beneath the West Antarctic Ice Sheet
- 2020
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In: Cryosphere. - : Copernicus GmbH. - 1994-0416. ; 14:4, s. 1399-1408
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Journal article (peer-reviewed)abstract
- Antarctica's Getz Ice Shelf has been rapidly thinning in recent years, producing more meltwater than any other ice shelf in the world. The influx of fresh water is known to substantially influence ocean circulation and biological productivity, but relatively little is known about the factors controlling basal melt rate or how basal melt is spatially distributed beneath the ice shelf. Also unknown is the relative importance of subglacial discharge from the grounded ice sheet in contributing to the export of fresh water from the ice shelf cavity. Here we compare the observed spatial distribution of basal melt rate to a new sub-ice-shelf bathymetry map inferred from airborne gravity surveys and to locations of subglacial discharge from the grounded ice sheet. We find that melt rates are high where bathymetric troughs provide a pathway for warm Circumpolar Deep Water to enter the ice shelf cavity and that melting is enhanced where subglacial discharge fresh water flows across the grounding line. This is the first study to address the relative importance of meltwater production of the Getz Ice Shelf from both ocean and subglacial sources.
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| 5. |
- Dorschel, Boris, et al.
(author)
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The International Bathymetric Chart of the Southern Ocean Version 2
- 2022
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In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 9:1
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Journal article (peer-reviewed)abstract
- The Southern Ocean surrounding Antarctica is a region that is key to a range of climatic and oceanographic processes with worldwide effects, and is characterised by high biological productivity and biodiversity. Since 2013, the International Bathymetric Chart of the Southern Ocean (IBCSO) has represented the most comprehensive compilation of bathymetry for the Southern Ocean south of 60 degrees S. Recently, the IBCSO Project has combined its efforts with the Nippon Foundation - GEBCO Seabed 2030 Project supporting the goal of mapping the world's oceans by 2030. New datasets initiated a second version of IBCSO (IBCSO v2). This version extends to 50 degrees S (covering approximately 2.4 times the area of seafloor of the previous version) including the gateways of the Antarctic Circumpolar Current and the Antarctic circumpolar frontal systems. Due to increased (multibeam) data coverage, IBCSO v2 significantly improves the overall representation of the Southern Ocean seafloor and resolves many submarine landforms in more detail. This makes IBCSO v2 the most authoritative seafloor map of the area south of 50 degrees S.
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| 6. |
- Erdinc, Direnis, et al.
(author)
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Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability
- 2023
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In: Embo Molecular Medicine. - 1757-4676. ; 15:5
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Journal article (peer-reviewed)abstract
- Topoisomerase 3 alpha (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
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| 8. |
- Legendre, C. M., et al.
(author)
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Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic-Uremic Syndrome
- 2013
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 368:23, s. 2169-2181
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Journal article (peer-reviewed)abstract
- Background Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. Methods We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). Results A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73x10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. Conclusions Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome.
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| 10. |
- Engquist, Björn, et al.
(author)
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Global boundary conditions and fast Helmholtz solvers
- 1989
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In: IEEE transactions on magnetics. - : Institute of Electrical and Electronics Engineers (IEEE). - 0018-9464 .- 1941-0069. ; 25:4, s. 2804-2806
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Journal article (peer-reviewed)abstract
- Electromagnetic scattering from a conducting two-dimensional cylinder is modeled by solving Helmholtz's equation with the far-field radiation boundary condition replaced by a global boundary condition allowing. This allows the boundary condition to be applied very near the scatterer. The discrete problem is solved by a biconjugate gradient algorithm. IncompleteLUdecomposition is used as a preconditioning strategy, resulting in very fast convergence. The numerical solution is compared with known solutions and found to converge fasters forka⩽10, wherekis the wave number andais the radius of the cylinder
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