103 research outputs found
Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient.
The nuclear lamina is essential for the proper structure and organization of the nucleus. Deregulation of A-type lamins can compromise genomic stability, alter chromatin organization and cause premature vascular aging. Here, we show that accumulation of the lamin A precursor, prelamin A, inhibits 53BP1 recruitment to sites of DNA damage and increases basal levels of DNA damage in aged vascular smooth muscle cells. We identify that this genome instability arises through defective nuclear import of 53BP1 as a consequence of abnormal topological arrangement of nucleoporin NUP153. We show for the first time that this nucleoporin is important for the nuclear localization of Ran and that the deregulated Ran gradient is likely to be compromising the nuclear import of 53BP1. Importantly, many of the defects associated with prelamin A expression were significantly reduced upon treatment with Remodelin, a small molecule recently reported to reverse deficiencies associated with abnormal nuclear lamina.British Heart Foundation (Grant ID: RG/11/14/29056), Medical Research Council (Grant ID: MR/L019116/1), Cancer Research UK (Grant IDs: C6/A11224, C6946/A14492), European Research Council, European Community Seventh Framework Programme (Grant ID: HEALTH-F2-2010-259893) , Wellcome Trust (Grant ID: WT092096), University of CambridgeThis is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/acel.1250
Finding Inspiration: Sharing Practice and Developing Authentic Multimedia Artifacts for Supervision of Undergraduate Research in Irish higher education
Supervision is a specialist academic practice that can be learnt through the experience of the practice of supervision itself. However, increasingly, supervisors can find inspiration from each other in structured, supported, collaborative professional development. This Chapter evaluates the perceived impact on faculty and student learning of sharing inspirational practices and creating multimedia artifacts which formed the assessment of an accredited postgraduate module entitled âSupervising Undergraduate Dissertations and Projectsâ at a Technological University in Ireland. A range of themes are explored in the Chapter including the increasing demand for this form of professional development for academics; the importance of a peer learning approach for providing inspiration and sharing of practice; the design and development of multimedia artifacts for undergraduate supervision practice and the national context within which this work is situated
Translational research into gut microbiota: new horizons on obesity treatment: updated 2014
Obesity is currently a pandemic of worldwide proportions affecting millions of people. Recent studies have proposed the hypothesis that mechanisms not directly related to the human genome could be involved in the genesis of obesity, due to the fact that, when a population undergoes the same nutritional stress, not all individuals present weight gain related to the diet or become hyperglycemic. The human intestine is colonized by millions of bacteria which form the intestinal flora, known as gut flora. Studies show that lean and overweight human may present a difference in the composition of their intestinal flora; these studies suggest that the intestinal flora could be involved in the development of obesity. Several mechanisms explain the correlation between intestinal flora and obesity. The intestinal flora would increase the energetic extraction of non-digestible polysaccharides. In addition, the lipopolysaccharide from intestinal flora bacteria could trigger a chronic sub-clinical inflammatory process, leading to obesity and diabetes. Another mechanism through which the intestinal flora could lead to obesity would be through the regulation of genes of the host involved in energy storage and expenditure. In the past five years data coming from different sources established causal effects between intestinal microbiota and obesity/insulin resistance, and it is clear that this area will open new avenues of therapeutic to obesity, insulin resistance and DM2
Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF
The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at
the Fermilab Long-Baseline Neutrino Facility (LBNF) is described
Guideline for diagnosis and treatment of subacromial pain syndrome
Treatment of "subacromial impingement syndrome" of the shoulder has changed drastically in the past decade. The anatomical explanation as "impingement" of the rotator cuff is not sufficient to cover the pathology. "Subacromial pain syndrome", SAPS, describes the condition better. A working group formed from a number of Dutch specialist societies, joined by the Dutch Orthopedic Association, has produced a guideline based on the available scientific evidence. This resulted in a new outlook for the treatment of subacromial pain syndrome. The important conclusions and advice from this work are as follows: (1) The diagnosis SAPS can only be made using a combination of clinical tests. (2) SAPS should preferably be treated non-operatively. (3) Acute pain should be treated with analgetics if necessary. (4) Subacromial injection with corticosteroids is indicated for persistent or recurrent symptoms. (5) Diagnostic imaging is useful after 6 weeks of symptoms. Ultrasound examination is the recommended imaging, to exclude a rotator cuff rupture. (6) Occupational interventions are useful when complaints persist for longer than 6 weeks. (7) Exercise therapy should be specific and should be of low intensity and high frequency, combining eccentric training, attention to relaxation and posture, and treatment of myofascial trigger points (including stretching of the muscles) may be considered. (8) Strict immobilization and mobilization techniques are not recommended. (9) Tendinosis calcarea can be treated by shockwave (ESWT) or needling under ultrasound guidance (barbotage). (10) Rehabilitation in a specialized unit can be considered in chronic, treatment resistant SAPS, with pain perpetuating behavior. (11) There is no convincing evidence that surgical treatment for SAPS is more effective than conservature management. (12) There is no indication for the surgical treatment of asymptomatic rotator cuff tears
Low-Energy Physics in Neutrino LArTPCs
In this white paper, we outline some of the scientific opportunities and challenges related to detection and reconstruction of low-energy (less than 100 MeV) signatures in liquid argon time-projection chamber (LArTPC) detectors. Key takeaways are summarized as follows. 1) LArTPCs have unique sensitivity to a range of physics and astrophysics signatures via detection of event features at and below the few tens of MeV range. 2) Low-energy signatures are an integral part of GeV-scale accelerator neutrino interaction final states, and their reconstruction can enhance the oscillation physics sensitivities of LArTPC experiments. 3) BSM signals from accelerator and natural sources also generate diverse signatures in the low-energy range, and reconstruction of these signatures can increase the breadth of BSM scenarios accessible in LArTPC-based searches. 4) Neutrino interaction cross sections and other nuclear physics processes in argon relevant to sub-hundred-MeV LArTPC signatures are poorly understood. Improved theory and experimental measurements are needed. Pion decay-at-rest sources and charged particle and neutron test beams are ideal facilities for experimentally improving this understanding. 5) There are specific calibration needs in the low-energy range, as well as specific needs for control and understanding of radiological and cosmogenic backgrounds. 6) Novel ideas for future LArTPC technology that enhance low-energy capabilities should be explored. These include novel charge enhancement and readout systems, enhanced photon detection, low radioactivity argon, and xenon doping. 7) Low-energy signatures, whether steady-state or part of a supernova burst or larger GeV-scale event topology, have specific triggering, DAQ and reconstruction requirements that must be addressed outside the scope of conventional GeV-scale data collection and analysis pathways
QCD and strongly coupled gauge theories : challenges and perspectives
We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe
Identification and reconstruction of low-energy electrons in the ProtoDUNE-SP detector
Measurements of electrons from interactions are crucial for the Deep
Underground Neutrino Experiment (DUNE) neutrino oscillation program, as well as
searches for physics beyond the standard model, supernova neutrino detection,
and solar neutrino measurements. This article describes the selection and
reconstruction of low-energy (Michel) electrons in the ProtoDUNE-SP detector.
ProtoDUNE-SP is one of the prototypes for the DUNE far detector, built and
operated at CERN as a charged particle test beam experiment. A sample of
low-energy electrons produced by the decay of cosmic muons is selected with a
purity of 95%. This sample is used to calibrate the low-energy electron energy
scale with two techniques. An electron energy calibration based on a cosmic ray
muon sample uses calibration constants derived from measured and simulated
cosmic ray muon events. Another calibration technique makes use of the
theoretically well-understood Michel electron energy spectrum to convert
reconstructed charge to electron energy. In addition, the effects of detector
response to low-energy electron energy scale and its resolution including
readout electronics threshold effects are quantified. Finally, the relation
between the theoretical and reconstructed low-energy electron energy spectrum
is derived and the energy resolution is characterized. The low-energy electron
selection presented here accounts for about 75% of the total electron deposited
energy. After the addition of lost energy using a Monte Carlo simulation, the
energy resolution improves from about 40% to 25% at 50~MeV. These results are
used to validate the expected capabilities of the DUNE far detector to
reconstruct low-energy electrons.Comment: 19 pages, 10 figure
Impact of cross-section uncertainties on supernova neutrino spectral parameter fitting in the Deep Underground Neutrino Experiment
A primary goal of the upcoming Deep Underground Neutrino Experiment (DUNE) is
to measure the MeV neutrinos produced by a Galactic
core-collapse supernova if one should occur during the lifetime of the
experiment. The liquid-argon-based detectors planned for DUNE are expected to
be uniquely sensitive to the component of the supernova flux, enabling
a wide variety of physics and astrophysics measurements. A key requirement for
a correct interpretation of these measurements is a good understanding of the
energy-dependent total cross section for charged-current
absorption on argon. In the context of a simulated extraction of
supernova spectral parameters from a toy analysis, we investigate the
impact of modeling uncertainties on DUNE's supernova neutrino
physics sensitivity for the first time. We find that the currently large
theoretical uncertainties on must be substantially reduced
before the flux parameters can be extracted reliably: in the absence of
external constraints, a measurement of the integrated neutrino luminosity with
less than 10\% bias with DUNE requires to be known to about 5%.
The neutrino spectral shape parameters can be known to better than 10% for a
20% uncertainty on the cross-section scale, although they will be sensitive to
uncertainties on the shape of . A direct measurement of
low-energy -argon scattering would be invaluable for improving the
theoretical precision to the needed level.Comment: 25 pages, 21 figure
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