| 1. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 2. |
- Roberts, Jason D., et al.
(författare)
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Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
- 2019
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 129:8, s. 3171-3184
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Tidskriftsartikel (refereegranskat)abstract
- Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease.
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| 3. |
- Koopmann, T., et al.
(författare)
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Proximity dimensions and the emergence of collaboration: a HypTrails study on German AI research
- 2021
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Ingår i: Scientometrics. - : Springer Science and Business Media LLC. - 0138-9130 .- 1588-2861. ; 126:12
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Tidskriftsartikel (refereegranskat)abstract
- Creation and exchange of knowledge depends on collaboration. Recent work has suggested that the emergence of collaboration frequently relies on geographic proximity. However, being co-located tends to be associated with other dimensions of proximity, such as social ties or a shared organizational environment. To account for such factors, multiple dimensions of proximity have been proposed, including cognitive, institutional, organizational, social and geographical proximity. Since they strongly interrelate, disentangling these dimensions and their respective impact on collaboration is challenging. To address this issue, we propose various methods for measuring different dimensions of proximity. We then present an approach to compare and rank them with respect to the extent to which they indicate co-publications and co-inventions. We adapt the HypTrails approach, which was originally developed to explain human navigation, to co-author and co-inventor graphs. We evaluate this approach on a subset of the German research community, specifically academic authors and inventors active in research on artificial intelligence (AI). We find that social proximity and cognitive proximity are more important for the emergence of collaboration than geographic proximity.
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| 4. |
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| 5. |
- Nass, K., et al.
(författare)
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In cellulo crystallization of Trypanosoma brucei IMP dehydrogenase enables the identification of genuine co-factors
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Sleeping sickness is a fatal disease caused by the protozoan parasite Trypanosoma brucei (Tb). Inosine-5'-monophosphate dehydrogenase (IMPDH) has been proposed as a potential drug target, since it maintains the balance between guanylate deoxynucleotide and ribonucleotide levels that is pivotal for the parasite. Here we report the structure of TbIMPDH at room temperature utilizing free-electron laser radiation on crystals grown in living insect cells. The 2.80 angstrom resolution structure reveals the presence of ATP and GMP at the canonical sites of the Bateman domains, the latter in a so far unknown coordination mode. Consistent with previously reported IMPDH complexes harboring guanosine nucleotides at the second canonical site, TbIMPDH forms a compact oligomer structure, supporting a nucleotide-controlled conformational switch that allosterically modulates the catalytic activity. The oligomeric TbIMPDH structure we present here reveals the potential of in cellulo crystallization to identify genuine allosteric co-factors from a natural reservoir of specific compounds. Trypanosoma brucei inosine-5 '-monophosphate dehydrogenase (IMPDH) is an enzyme in the guanine nucleotide biosynthesis pathway and of interest as a drug target. Here the authors present the 2.8 angstrom room temperature structure of TbIMPDH determined by utilizing X-ray free-electron laser radiation and crystals that were grown in insect cells and find that ATP and GMP are bound at the canonical sites of the Bateman domains.
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| 6. |
- Willwacher, S., et al.
(författare)
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A new method for measuring treadmill belt velocity fluctuations : effects of treadmill type, body mass and locomotion speed
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Treadmills are essential to the study of human and animal locomotion as well as for applied diagnostics in both sports and medicine. The quantification of relevant biomechanical and physiological variables requires a precise regulation of treadmill belt velocity (TBV). Here, we present a novel method for time-efficient tracking of TBV using standard 3D motion capture technology. Further, we analyzed TBV fluctuations of four different treadmills as seven participants walked and ran at target speeds ranging from 1.0 to 4.5 m/s. Using the novel method, we show that TBV regulation differs between treadmill types, and that certain features of TBV regulation are affected by the subjects’ body mass and their locomotion speed. With higher body mass, the TBV reductions in the braking phase of stance became higher, even though this relationship differed between locomotion speeds and treadmill type (significant body mass × speed × treadmill type interaction). Average belt speeds varied between about 98 and 103% of the target speed. For three of the four treadmills, TBV reduction during the stance phase of running was more intense (> 5% target speed) and occurred earlier (before 50% of stance phase) unlike the typical overground center of mass velocity patterns reported in the literature. Overall, the results of this study emphasize the importance of monitoring TBV during locomotor research and applied diagnostics. We provide a novel method that is freely accessible on Matlab’s file exchange server (“getBeltVelocity.m”) allowing TBV tracking to become standard practice in locomotion research.
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