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| 9. |
- Arking, D. E., et al.
(author)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Journal article (peer-reviewed)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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| 10. |
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| 11. |
- Fernandez, J. L. Abelleira, et al.
(author)
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A Large Hadron Electron Collider at CERN
- 2012
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In: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 39:7
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Journal article (peer-reviewed)
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| 12. |
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| 13. |
- Kettle, B., et al.
(author)
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Single-Shot Multi-keV X-Ray Absorption Spectroscopy Using an Ultrashort Laser-Wakefield Accelerator Source
- 2019
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In: Physical Review Letters. - 0031-9007. ; 123:25
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Journal article (peer-reviewed)abstract
- Single-shot absorption measurements have been performed using the multi-keV x rays generated by a laser-wakefield accelerator. A 200 TW laser was used to drive a laser-wakefield accelerator in a mode which produced broadband electron beams with a maximum energy above 1 GeV and a broad divergence of ≈15 mrad FWHM. Betatron oscillations of these electrons generated 1.2±0.2×106 photons/eV in the 5 keV region, with a signal-to-noise ratio of approximately 300 1. This was sufficient to allow high-resolution x-ray absorption near-edge structure measurements at the K edge of a titanium sample in a single shot. We demonstrate that this source is capable of single-shot, simultaneous measurements of both the electron and ion distributions in matter heated to eV temperatures by comparison with density functional theory simulations. The unique combination of a high-flux, large bandwidth, few femtosecond duration x-ray pulse synchronized to a high-power laser will enable key advances in the study of ultrafast energetic processes such as electron-ion equilibration.
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| 14. |
- Pennells, Lisa, et al.
(author)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Journal article (peer-reviewed)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 15. |
- Berthomier, M., et al.
(author)
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Alfven : magnetosphere-ionosphere connection explorers
- 2012
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In: Experimental astronomy. - Dordrecht : Springer. - 0922-6435 .- 1572-9508. ; 33:2-3, s. 445-489
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Journal article (peer-reviewed)abstract
- The aurorae are dynamic, luminous displays that grace the night skies of Earth's high latitude regions. The solar wind emanating from the Sun is their ultimate energy source, but the chain of plasma physical processes leading to auroral displays is complex. The special conditions at the interface between the solar wind-driven magnetosphere and the ionospheric environment at the top of Earth's atmosphere play a central role. In this Auroral Acceleration Region (AAR) persistent electric fields directed along the magnetic field accelerate magnetospheric electrons to the high energies needed to excite luminosity when they hit the atmosphere. The "ideal magnetohydrodynamics" description of space plasmas which is useful in much of the magnetosphere cannot be used to understand the AAR. The AAR has been studied by a small number of single spacecraft missions which revealed an environment rich in wave-particle interactions, plasma turbulence, and nonlinear acceleration processes, acting on a variety of spatio-temporal scales. The pioneering 4-spacecraft Cluster magnetospheric research mission is now fortuitously visiting the AAR, but its particle instruments are too slow to allow resolve many of the key plasma physics phenomena. The Alfv,n concept is designed specifically to take the next step in studying the aurora, by making the crucial high-time resolution, multi-scale measurements in the AAR, needed to address the key science questions of auroral plasma physics. The new knowledge that the mission will produce will find application in studies of the Sun, the processes that accelerate the solar wind and that produce aurora on other planets.
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| 17. |
- Regev, A, et al.
(author)
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The Human Cell Atlas
- 2017
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In: eLife. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 6
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Journal article (peer-reviewed)
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| 18. |
- Watt, F. E., et al.
(author)
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Towards prevention of post-traumatic osteoarthritis : report from an international expert working group on considerations for the design and conduct of interventional studies following acute knee injury
- 2019
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In: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 27:1, s. 23-33
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Journal article (peer-reviewed)abstract
- Objective: There are few guidelines for clinical trials of interventions for prevention of post-traumatic osteoarthritis (PTOA), reflecting challenges in this area. An international multi-disciplinary expert group including patients was convened to generate points to consider for the design and conduct of interventional studies following acute knee injury. Design: An evidence review on acute knee injury interventional studies to prevent PTOA was presented to the group, alongside overviews of challenges in this area, including potential targets, biomarkers and imaging. Working groups considered pre-identified key areas: eligibility criteria and outcomes, biomarkers, injury definition and intervention timing including multi-modality interventions. Consensus agreement within the group on points to consider was generated and is reported here after iterative review by all contributors. Results: The evidence review identified 37 studies. Study duration and outcomes varied widely and 70% examined surgical interventions. Considerations were grouped into three areas: justification of inclusion criteria including the classification of injury and participant age (as people over 35 may have pre-existing OA); careful consideration in the selection and timing of outcomes or biomarkers; definition of the intervention(s)/comparator(s) and the appropriate time-window for intervention (considerations may be particular to intervention type). Areas for further research included demonstrating the utility of patient-reported outcomes, biomarkers and imaging outcomes from ancillary/cohort studies in this area, and development of surrogate clinical trial endpoints that shorten the duration of clinical trials and are acceptable to regulatory agencies. Conclusions: These considerations represent the first international consensus on the conduct of interventional studies following acute knee joint trauma.
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| 19. |
- Buitelaar, M. R., et al.
(author)
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Pauli spin blockade in carbon nanotube double quantum dots
- 2008
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In: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 77:24, s. 245439-
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Journal article (peer-reviewed)abstract
- We report Pauli spin blockade in a carbon nanotube double quantum dot defined by tunnel barriers at the contacts and a structural defect in the nanotube. We observe a pronounced current suppression for negative source-drain bias voltages, which is investigated for both symmetric and asymmetric coupling of the quantum dots to the leads. The measured differential conductance agrees well with a theoretical model of a double quantum dot system in the spin-blockade regime, which allows us to estimate the occupation probabilities of the relevant singlet and triplet states. This work shows that effective spin-to-charge conversion in nanotube quantum dots is feasible and opens the possibility of single-spin readout in a material that is not limited by hyperfine interaction with nuclear spins.
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| 20. |
- Clark, Pip C.J., et al.
(author)
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The passivating effect of cadmium in PbS/CdS colloidal quantum dots probed by nm-scale depth profiling
- 2017
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In: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3364 .- 2040-3372. ; 9:18, s. 6056-6067
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Journal article (peer-reviewed)abstract
- Achieving control of the surface chemistry of colloidal quantum dots (CQDs) is essential to fully exploit their properties in solar cells, but direct measurement of the chemistry and electronic structure in the outermost atomic layers is challenging. Here we probe the surface oxidation and passivation of cation-exchanged PbS/CdS core/shell CQDs with sub nm-scale precision using synchrotron-radiation-excited depth-profiling photoemission. We investigate the surface composition of the topmost 1-2.5 nm of the CQDs as a function of depth, for CQDs of varying CdS shell thickness, and examine how the surface changes after prolonged air exposure. We demonstrate that the Cd is localized at the surface of the CQDs. The surface-localized products of oxidation are identified, and the extent of oxidation quantified. We show that oxidised sulfur species are progressively eliminated as Cd replaces Pb at the surface. A sub-monolayer surface 'decoration' of Cd is found to be effective in passivating the CQDs. We show that the measured energy-level alignments at PbS/CdS colloidal quantum dot surfaces differ from those expected on the basis of bulk band offsets, and are strongly affected by the oxidation products. We develop a model for the passivating action of Cd. The optimum shell thickness (of around 0.1 nm, previously found to give maximised power conversion efficiency in PbS/CdS solar cells) is found to correspond to a trade-off between the rate of oxidation and the introduction of a surface barrier to charge transport.
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| 21. |
- Fairclough, Simon M., et al.
(author)
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Growth and Characterization of Strained and Alloyed Type-II ZnTe/ZnSe Core-Shell Nanocrystals
- 2012
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In: Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 116:51, s. 26898-26907
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Journal article (peer-reviewed)abstract
- We investigate the growth and the physical and optical properties of type-II heterostructured ZnTe/ZnSe colloidal nanocrystals, focusing on the role of the 7% lattice mismatch between the two materials in determining growth homogeneity and band structure. We find that the lattice mismatch between the two materials places limitations on the range of structures that can be grown, and for those in which coherent growth is achieved we present clear evidence that the low bulk modulus ZnTe cores are compressed by the higher modulus ZnSe shells, accentuating the red-shift of the excitonic state with increasing shell thickness. By employing a variety of characterization tools we build a clear picture of the core-shell architecture. We show how strain is manifested in structures with sharp core-shell interfaces and how intentional alloying of the interface can influence the growth and exciton energies. We show that a (2,6)-band effective mass model is able to distinguish between the as-grown "sharp" and "alloyed" interfaces, indicating that the alloyed structures incorporate reduced strain.
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| 22. |
- Forsyth, C., et al.
(author)
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In situ spatiotemporal measurements of the detailed azimuthal substructure of the substorm current wedge
- 2014
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In: Journal of Geophysical Research: Space Physics. - 2169-9380. ; 119:2, s. 927-946
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Journal article (peer-reviewed)abstract
- The substorm current wedge (SCW) is a fundamental component of geomagnetic substorms. Models tend to describe the SCW as a simple line current flowing into the ionosphere toward dawn and out of the ionosphere toward dusk, linked by a westward electrojet. We use multispacecraft observations from perigee passes of the Cluster 1 and 4 spacecraft during a substorm on 15 January 2010, in conjunction with ground-based observations, to examine the spatial structuring and temporal variability of the SCW. At this time, the spacecraft traveled east-west azimuthally above the auroral region. We show that the SCW has significant azimuthal substructure on scales of 100km at altitudes of 4000-7000km. We identify 26 individual current sheets in the Cluster 4 data and 34 individual current sheets in the Cluster 1 data, with Cluster 1 passing through the SCW 120-240s after Cluster 4 at 1300-2000km higher altitude. Both spacecraft observed large-scale regions of net upward and downward field-aligned current, consistent with the large-scale characteristics of the SCW, although sheets of oppositely directed currents were observed within both regions. We show that the majority of these current sheets were closely aligned to a north-south direction, in contrast to the expected east-west orientation of the preonset aurora. Comparing our results with observations of the field-aligned current associated with bursty bulk flows (BBFs), we conclude that significant questions remain for the explanation of SCW structuring by BBF-driven wedgelets. Our results therefore represent constraints on future modeling and theoretical frameworks on the generation of the SCW.
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| 23. |
- Matthews, V B, et al.
(author)
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Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance.
- 2010
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 53:11, s. 2431-2441
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 (-/-)) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. METHODS: Male, 8-week-old Il6 (-/-) and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. RESULTS: Il6 (-/-) mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 (-/-) and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 (-/-) mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 (-/-) relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme beta-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. CONCLUSIONS/INTERPRETATION: Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.
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| 31. |
- Andersen, J. R., et al.
(author)
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Small-x phenomenology - Summary of the 3rd Lund small-x workshop in 2004
- 2006
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In: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 48:1, s. 53-105
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Research review (peer-reviewed)abstract
- A third workshop on small-x physics, within the Small-x Collaboration, was held in Hamburg in May 2004 with the aim of overviewing recent theoretical progress in this area and summarizing the experimental status.
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| 32. |
- Anton, Christian, et al.
(author)
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Research needs for incorporating the ecosystem service approach into EU biodiversity conservation policy
- 2010
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In: Biodiversity and Conservation. - : Springer Science and Business Media LLC. - 0960-3115 .- 1572-9710. ; 19:10, s. 2979-2994
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Journal article (peer-reviewed)abstract
- Using a range of different methods including extensive reviews, workshops and an electronic conference, 70 key research recommendations and 12 priority research needs to integrate the ecosystem services approach into biodiversity conservation policy and funding were identified by a cross-disciplinary group of over 100 scientists and 50 stakeholders, including research funders and policy-makers. These recommendations focus on the ecological underpinning of ecosystem services, drivers that affect ecosystems and their services, biological traits and ecosystem services, the valuation of ecosystem services, spatial and temporal scales in ecosystem service assessment, indicators of ecosystem services, and habitat management, conservation policy and ecosystem services. The recommendations in this paper help steer the research agenda on ecosystem services into policy-relevant areas, agreed upon by funders, researchers and policy-makers. This research agenda will only succeed with increased collaboration between researchers across disciplines, thereby providing a challenge to the research community and research funders to work in new, interdisciplinary ways.
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| 33. |
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| 34. |
- Begum, Shamima, et al.
(author)
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On the origin and variation of colors in lobster carapace
- 2015
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In: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 17:26, s. 16723-16732
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Journal article (peer-reviewed)abstract
- The chemical basis of the blue-black to pink-orange color change on cooking of lobster, due to thermal denaturation of an astaxanthin-protein complex, alpha-crustacyanin, in the lobster carapace, has so far been elusive. Here, we investigate the relaxation of the astaxanthin pigment from its bound enolate form to its neutral hydroxyketone form, as origin of the spectral shift, by analyzing the response of UV-vis spectra of a water-soluble 3-hydroxy-4-oxo-beta-ionone model of astaxanthin to increases in pH, and by performing extensive quantum chemical calculations over a wide range of chemical conditions. The enolization of astaxanthin is consistent with the X-ray diffraction data of beta-crustacyanin (PDB code: 1GKA) whose crystals possess the distinct blue color. We find that enolate formation is possible within the protein environment and associated with a large bathochromic shift, thus offering a cogent explanation for the blue-black color and the response to thermal denaturation and revealing the chemistry of astaxanthin upon complex formation.
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| 35. |
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| 36. |
- Grose, R, et al.
(author)
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A crucial role of beta 1 integrins for keratinocyte migration in vitro and during cutaneous wound repair
- 2002
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In: Development: For advances in developmental biology and stem cells. - 1477-9129. ; 129:9, s. 2303-2315
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Journal article (peer-reviewed)abstract
- Integrins are ubiquitous transmembrane receptors that play crucial roles in cell-cell and cell-matrix interactions. In this study, we have determined the effects of the loss of beta1 integrins in keratinocytes in vitro and during cutaneous wound repair. Flow cytometry of cultured beta1-deficient keratinocytes confirmed the absence of beta1 integrins and showed downregulation of alpha6beta4 but not of alphanu integrins. beta1-null keratinocytes were characterised by poor adhesion to various substrates, by a reduced proliferation rate and by a strongly impaired migratory capacity. In vivo, the loss of 01 integrins in keratinocytes caused a severe defect in wound healing. beta1-null keratinocytes showed impaired migration and were more densely packed in the hyperproliferative epithelium. Surprisingly, their proliferation rate was not reduced in early wounds and even increased in late wounds. The failure in re-epithelialisation resulted in a prolonged inflammatory response, leading to dramatic alterations in the expression of important wound-regulated genes. Ultimately, beta1-deficient epidermis did cover the wound bed, but the epithelial architecture was abnormal. These findings demonstrate a crucial role of beta1 integrins in keratinocyte migration and wound re-epithelialisation.
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| 37. |
- Hellström, Anders R., et al.
(author)
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Inactivation of Pmel Alters Melanosome Shape But Has Only a Subtle Effect on Visible Pigmentation
- 2011
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:9, s. e1002285-
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Journal article (peer-reviewed)abstract
- PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel(-/-)). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel(-/-) melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.
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| 39. |
- Jocken, Johan W. E., et al.
(author)
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Insulin-mediated suppression of lipolysis in adipose tissue and skeletal muscle of obese type 2 diabetic men and men with normal glucose tolerance
- 2013
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In: Diabetologia. - Heidelberg : Springer Berlin/Heidelberg. - 0012-186X .- 1432-0428. ; 56:10, s. 2255-2265
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: Impaired regulation of lipolysis and accumulation of lipid intermediates may contribute to obesity-related insulin resistance and type 2 diabetes mellitus. We investigated insulin-mediated suppression of lipolysis in abdominal subcutaneous adipose tissue (AT) and skeletal muscle (SM) of obese men with normal glucose tolerance (NGT) and obese type 2 diabetic men. Methods: Eleven NGT men and nine long-term diagnosed type 2 diabetic men (7 ± 1 years), matched for age (58 ± 2 vs 62 ± 2 years), BMI (31.4 ± 0.6 vs 30.5 ± 0.6 kg/m2) and V × O 2 max (28.9 ± 1.5 vs 29.5 ± 2.4 ml kg-1 min-1) participated in this study. Interstitial glycerol concentrations in AT and SM were assessed using microdialysis during a 1 h basal period and a 6 h stepwise hyperinsulinaemic-euglycaemic clamp (8, 20 and 40 mU m-2 min -1). AT and SM biopsies were collected to investigate underlying mechanisms. Results: Hyperinsulinaemia suppressed interstitial SM glycerol concentrations less in men with type 2 diabetes (-7 ± 6%, -13 ± 9% and -27 ± 9%) compared with men with NGT (-21 ± 7%, -38 ± 8% and -53 ± 8%) (p = 0.014). This was accompanied by increased circulating fatty acid and glycerol concentrations, a lower glucose infusion rate (21.8 ± 3.1 vs 30.5 ± 2.0 μmol kg body weight-1 min-1; p < 0.05), higher hormone-sensitive lipase (HSL) serine 660 phosphorylation, increased saturated diacylglycerol (DAG) lipid species in the muscle membrane and increased protein kinase C (PKC) activation in type 2 diabetic men vs men with NGT. No significant differences in insulin-mediated reduction in AT interstitial glycerol were observed between groups. Conclusions/interpretation: Our results suggest that a blunted insulin-mediated suppression of SM lipolysis may promote the accumulation of membrane saturated DAG, aggravating insulin resistance, at least partly mediated by PKC. This may represent an important mechanism involved in the progression of insulin resistance towards type 2 diabetes. Trial registration: ClinicalTrials.gov NCT01680133 © 2013 The Author(s).
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| 40. |
- Kalliolia, Eirini, et al.
(author)
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A 24-Hour Study of the Hypothalamo-Pituitary Axes in Huntington's Disease.
- 2015
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:10
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Journal article (peer-reviewed)abstract
- Huntington's disease is an inherited neurodegenerative disorder characterised by motor, cognitive and psychiatric disturbances. Patients exhibit other symptoms including sleep and mood disturbances, muscle atrophy and weight loss which may be linked to hypothalamic pathology and dysfunction of hypothalamo-pituitary axes.
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| 41. |
- Kalliolia, Eirini, et al.
(author)
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Plasma Melatonin Is Reduced in Huntington's Disease
- 2014
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In: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 29:12, s. 1511-1515
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Journal article (peer-reviewed)abstract
- This study was undertaken to determine whether the production of melatonin, a hormone regulating sleep in relation to the light/dark cycle, is altered in Huntington's disease. We analyzed the circadian rhythm of melatonin in a 24-hour study of cohorts of control, premanifest, and stage II/III Huntington's disease subjects. The mean and acrophase melatonin concentrations were significantly reduced in stage II/III Huntington's disease subjects compared with controls. We also observed a nonsignificant trend toward reduced mean and acrophase melatonin in premanifest Huntington's disease subjects. Onset of melatonin rise was significantly more temporally spread in both premanifest and stage II/III Huntington's disease subjects compared with controls. A nonsignificant trend also was seen for reduced pulsatile secretion of melatonin. Melatonin concentrations are reduced in Huntington's disease. Altered melatonin patterns may provide an explanation for disrupted sleep and circadian behavior in Huntington's disease, and represent a biomarker for disease state. Melatonin therapy may help the sleep disorders seen in Huntington's disease. (c) 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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| 42. |
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| 43. |
- Nambron, Rajasree, et al.
(author)
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A Metabolic Study of Huntington's Disease.
- 2016
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
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Journal article (peer-reviewed)abstract
- Huntington's disease patients have a number of peripheral manifestations suggestive of metabolic and endocrine abnormalities. We, therefore, investigated a number of metabolic factors in a 24-hour study of Huntington's disease gene carriers (premanifest and moderate stage II/III) and controls.
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| 44. |
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| 45. |
- Petrova, V, et al.
(author)
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Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS
- 2020
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 5614-
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Journal article (peer-reviewed)abstract
- Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin’s endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system.
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| 46. |
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| 47. |
- Vesikari, Timo, et al.
(author)
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Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine.
- 2006
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In: N Engl J Med. - 1533-4406. ; 354:1, s. 23-33
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Journal article (peer-reviewed)abstract
- BACKGROUND: Rotavirus is a leading cause of childhood gastroenteritis and death worldwide. METHODS: We studied healthy infants approximately 6 to 12 weeks old who were randomly assigned to receive three oral doses of live pentavalent human-bovine (WC3 strain) reassortant rotavirus vaccine containing human serotypes G1, G2, G3, G4, and P[8] or placebo at 4-to-10-week intervals in a blinded fashion. Active surveillance was used to identify subjects with serious adverse and other events. RESULTS: The 34,035 infants in the vaccine group and 34,003 in the placebo group were monitored for serious adverse events. Intussusception occurred in 12 vaccine recipients and 15 placebo recipients within one year after the first dose including six vaccine recipients and five placebo recipients within 42 days after any dose (relative risk, 1.6; 95 percent confidence interval, 0.4 to 6.4). The vaccine reduced hospitalizations and emergency department visits related to G1-G4 rotavirus gastroenteritis occurring 14 or more days after the third dose by 94.5 percent (95 percent confidence interval, 91.2 to 96.6 percent). In a nested substudy, efficacy against any G1-G4 rotavirus gastroenteritis through the first full rotavirus season after vaccination was 74.0 percent (95 percent confidence interval, 66.8 to 79.9 percent); efficacy against severe gastroenteritis was 98.0 percent (95 percent confidence interval, 88.3 to 100 percent). The vaccine reduced clinic visits for G1-G4 rotavirus gastroenteritis by 86.0 percent (95 percent confidence interval, 73.9 to 92.5 percent). CONCLUSIONS: This vaccine was efficacious in preventing rotavirus gastroenteritis, decreasing severe disease and health care contacts. The risk of intussusception was similar in vaccine and placebo recipients. (ClinicalTrials.gov number, NCT00090233.) Copyright 2006 Massachusetts Medical Society.
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| 48. |
- Wanrooij, Paulina H., et al.
(author)
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Elimination of rNMPs from mitochondrial DNA has no effect on its stability
- 2020
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:25, s. 14306-14313
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Journal article (peer-reviewed)abstract
- Ribonucleotides (rNMPs) incorporated in the nuclear genome are a well-established threat to genome stability and can result in DNA strand breaks when not removed in a timely manner. However, the presence of a certain level of rNMPs is tolerated in mitochondrial DNA (mtDNA) although aberrant mtDNA rNMP content has been identified in disease models. We investigated the effect of incorporated rNMPs on mtDNA stability over the mouse life span and found that the mtDNA rNMP content increased during early life. The rNMP content of mtDNA varied greatly across different tissues and was defined by the rNTP/dNTP ratio of the tissue. Accordingly, mtDNA rNMPs were nearly absent in SAMHD1(-/-) mice that have increased dNTP pools. The near absence of rNMPs did not, however, appreciably affect mtDNA copy number or the levels of mtDNA molecules with deletions or strand breaks in aged animals near the end of their life span. The physiological rNMP load therefore does not contribute to the progressive loss of mtDNA quality that occurs as mice age.
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