818 research outputs found
Characterization of FUS Mutations in Amyotrophic Lateral Sclerosis Using RNA-Seq
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in severe muscle weakness and eventual death by respiratory failure. Although little is known about its pathogenesis, mutations in fused in sarcoma/translated in liposarcoma (FUS) are causative for familial ALS. FUS is a multifunctional protein that is involved in many aspects of RNA processing. To elucidate the role of FUS in ALS, we overexpressed wild-type and two mutant forms of FUS in HEK-293T cells, as well as knocked-down FUS expression. This was followed by RNA-Seq to identify genes which displayed differential expression or altered splicing patterns. Pathway analysis revealed that overexpression of wild-type FUS regulates ribosomal genes, whereas knock-down of FUS additionally affects expression of spliceosome related genes. Furthermore, cells expressing mutant FUS displayed global transcription patterns more similar to cells overexpressing wild-type FUS than to the knock-down condition. This observation suggests that FUS mutants do not contribute to the pathogenesis of ALS through a loss-of-function. Finally, our results demonstrate that the R521G and R522G mutations display differences in their influence on transcription and splicing. Taken together, these results provide additional insights into the function of FUS and how mutations contribute to the development of ALS.ALS Foundation NetherlandsAdessium FoundationSeventh Framework Programme (European Commission) (grant number 259867)Thierry Latran FoundationNational Institutes of Health (U.S.) (NIH/NINDS grant R01NS073873)National Institute of Neurological Disorders and Stroke (U.S.) (NIH/NINDS grant numbers 1R01NS065847
Book Reviews
With the observation of high-energy astrophysical neutrinos by the IceCube Neutrino Observatory, interest has risen in models of PeV-mass decaying dark matter particles to explain the observed flux. We present two dedicated experimental analyses to test this hypothesis. One analysis uses 6 years of IceCube data focusing on muon neutrino ‘track’ events from the Northern Hemisphere, while the second analysis uses 2 years of ‘cascade’ events from the full sky. Known background components and the hypothetical flux from unstable dark matter are fitted to the experimental data. Since no significant excess is observed in either analysis, lower limits on the lifetime of dark matter particles are derived: we obtain the strongest constraint to date, excluding lifetimes shorter than s at 90% CL for dark matter masses above 10 TeV
Search for transient optical counterparts to high-energy IceCube neutrinos with Pan-STARRS1
In order to identify the sources of the observed diffuse high-energy neutrino
flux, it is crucial to discover their electromagnetic counterparts. IceCube
began releasing alerts for single high-energy ( TeV) neutrino
detections with sky localisation regions of order 1 deg radius in 2016. We used
Pan-STARRS1 to follow-up five of these alerts during 2016-2017 to search for
any optical transients that may be related to the neutrinos. Typically 10-20
faint ( mag) extragalactic transients are found within the
Pan-STARRS1 footprints and are generally consistent with being unrelated field
supernovae (SNe) and AGN. We looked for unusual properties of the detected
transients, such as temporal coincidence of explosion epoch with the IceCube
timestamp. We found only one transient that had properties worthy of a specific
follow-up. In the Pan-STARRS1 imaging for IceCube-160427A (probability to be of
astrophysical origin of 50 %), we found a SN PS16cgx, located at 10.0'
from the nominal IceCube direction. Spectroscopic observations of PS16cgx
showed that it was an H-poor SN at z = 0.2895. The spectra and light curve
resemble some high-energy Type Ic SNe, raising the possibility of a jet driven
SN with an explosion epoch temporally coincident with the neutrino detection.
However, distinguishing Type Ia and Type Ic SNe at this redshift is notoriously
difficult. Based on all available data we conclude that the transient is more
likely to be a Type Ia with relatively weak SiII absorption and a fairly normal
rest-frame r-band light curve. If, as predicted, there is no high-energy
neutrino emission from Type Ia SNe, then PS16cgx must be a random coincidence,
and unrelated to the IceCube-160427A. We find no other plausible optical
transient for any of the five IceCube events observed down to a 5
limiting magnitude of mag, between 1 day and 25 days after
detection.Comment: 20 pages, 6 figures, accepted to A&
Neutrinos below 100 TeV from the southern sky employing refined veto techniques to IceCube data
Many Galactic sources of gamma rays, such as supernova remnants, are expected
to produce neutrinos with a typical energy cutoff well below 100 TeV. For the
IceCube Neutrino Observatory located at the South Pole, the southern sky,
containing the inner part of the Galactic plane and the Galactic Center, is a
particularly challenging region at these energies, because of the large
background of atmospheric muons. In this paper, we present recent advancements
in data selection strategies for track-like muon neutrino events with energies
below 100 TeV from the southern sky. The strategies utilize the outer detector
regions as veto and features of the signal pattern to reduce the background of
atmospheric muons to a level which, for the first time, allows IceCube
searching for point-like sources of neutrinos in the southern sky at energies
between 100 GeV and several TeV in the muon neutrino charged current channel.
No significant clustering of neutrinos above background expectation was
observed in four years of data recorded with the completed IceCube detector.
Upper limits on the neutrino flux for a number of spectral hypotheses are
reported for a list of astrophysical objects in the southern hemisphere.Comment: 19 pages, 17 figures, 2 table
Differential limit on the extremely-high-energy cosmic neutrino flux in the presence of astrophysical background from nine years of IceCube data
We report a quasi-differential upper limit on the extremely-high-energy (EHE)
neutrino flux above GeV based on an analysis of nine years of
IceCube data. The astrophysical neutrino flux measured by IceCube extends to
PeV energies, and it is a background flux when searching for an independent
signal flux at higher energies, such as the cosmogenic neutrino signal. We have
developed a new method to place robust limits on the EHE neutrino flux in the
presence of an astrophysical background, whose spectrum has yet to be
understood with high precision at PeV energies. A distinct event with a
deposited energy above GeV was found in the new two-year sample, in
addition to the one event previously found in the seven-year EHE neutrino
search. These two events represent a neutrino flux that is incompatible with
predictions for a cosmogenic neutrino flux and are considered to be an
astrophysical background in the current study. The obtained limit is the most
stringent to date in the energy range between and GeV. This result constrains neutrino models predicting a three-flavor
neutrino flux of $E_\nu^2\phi_{\nu_e+\nu_\mu+\nu_\tau}\simeq2\times 10^{-8}\
{\rm GeV}/{\rm cm}^2\ \sec\ {\rm sr}10^9\ {\rm GeV}$. A significant part
of the parameter-space for EHE neutrino production scenarios assuming a
proton-dominated composition of ultra-high-energy cosmic rays is excluded.Comment: The version accepted for publication in Physical Review
A Search for Neutrino Emission from Fast Radio Bursts with Six Years of IceCube Data
We present a search for coincidence between IceCube TeV neutrinos and fast
radio bursts (FRBs). During the search period from 2010 May 31 to 2016 May 12,
a total of 29 FRBs with 13 unique locations have been detected in the whole
sky. An unbinned maximum likelihood method was used to search for spatial and
temporal coincidence between neutrinos and FRBs in expanding time windows, in
both the northern and southern hemispheres. No significant correlation was
found in six years of IceCube data. Therefore, we set upper limits on neutrino
fluence emitted by FRBs as a function of time window duration. We set the most
stringent limit obtained to date on neutrino fluence from FRBs with an
energy spectrum assumed, which is 0.0021 GeV cm per burst for emission
timescales up to \textasciitilde10 seconds from the northern hemisphere
stacking search.Comment: 15 pages, 9 figure
Diffusion of peroxides through dentine in vitro with and without prior use of a desensitizing varnish
Different bleaching regimens are used in dentistry possibly penetrating the dentine and affecting the pulp. The aim of the present study was to investigate peroxide diffusion through dentine pre-treated with a desensitizing varnish (Vivasens®) in a standardized in vitro setup during application of different bleaching materials. The penetration was tested using 1.3-mm-thick bovine dentine slabs. The following bleaching materials were tested with and without prior application of the desensitizing varnish on the external side of the dentine slabs: Vivastyle, Whitestrips, Simply White, Opalescence (external bleaching), and sodium perborate (internal bleaching, only tested without varnish; n = 8 samples per subgroup). The penetration of peroxides was measured photometrically using 4-aminoantipyrin as a substrate, the penetration of peroxides was monitored over 240 min. All bleaching agents yielded a diffusion of peroxides through the dentine, the kinetics of penetration were approximately linear for all materials tested. The significantly highest diffusion of peroxides was observed with Opalescence, the lowest with sodium perborate. The adoption of the desensitizing varnish reduced the diffusion of peroxides significantly for all external bleaching materials. Peroxides penetrated the dentine during application of bleaching materials; the penetration of peroxides can be reduced by application of a desensitizing agent
Dissection of genetic associations with language-related traits in population-based cohorts
Recent advances in the field of language-related disorders have led to the identification of candidate genes for specific language impairment (SLI) and dyslexia. Replication studies have been conducted in independent samples including population-based cohorts, which can be characterised for a large number of relevant cognitive measures. The availability of a wide range of phenotypes allows us to not only identify the most suitable traits for replication of genetic association but also to refine the associated cognitive trait. In addition, it is possible to test for pleiotropic effects across multiple phenotypes which could explain the extensive comorbidity observed across SLI, dyslexia and other neurodevelopmental disorders. The availability of genome-wide genotype data for such cohorts will facilitate this kind of analysis but important issues, such as multiple test corrections, have to be taken into account considering that small effect sizes are expected to underlie such associations
From Shock Breakout to Peak and Beyond: Extensive Panchromatic Observations of the Type Ib Supernova 2008D associated with Swift X-ray Transient 080109
We present extensive early photometric (ultraviolet through near-infrared)
and spectroscopic (optical and near-infrared) data on supernova (SN) 2008D as
well as X-ray data analysis on the associated Swift/X-ray transient (XRT)
080109. Our data span a time range of 5 hours before the detection of the X-ray
transient to 150 days after its detection, and detailed analysis allowed us to
derive constraints on the nature of the SN and its progenitor; throughout we
draw comparisons with results presented in the literature and find several key
aspects that differ. We show that the X-ray spectrum of XRT 080109 can be fit
equally well by an absorbed power law or a superposition of about equal parts
of both power law and blackbody. Our data first established that SN 2008D is a
spectroscopically normal SN Ib (i.e., showing conspicuous He lines), and show
that SN 2008D had a relatively long rise time of 18 days and a modest optical
peak luminosity. The early-time light curves of the SN are dominated by a
cooling stellar envelope (for \Delta t~0.1- 4 day, most pronounced in the blue
bands) followed by 56^Ni decay. We construct a reliable measurement of the
bolometric output for this stripped-envelope SN, and, combined with estimates
of E_K and M_ej from the literature, estimate the stellar radius R_star of its
probable Wolf-Rayet progenitor. According to the model of Waxman et al. and of
Chevalier & Fransson, we derive R_star^{W07}= 1.2+/-0.7 R_sun and
R_star^{CF08}= 12+/-7 R_sun, respectively; the latter being more in line with
typical WN stars. Spectra obtained at 3 and 4 months after maximum light show
double-peaked oxygen lines that we associate with departures from spherical
symmetry, as has been suggested for the inner ejecta of a number of SN Ib
cores.Comment: Accepted to ApJ, v3 contains more data than v2 and more references,
conclusions not significantly changed, 28 pages in emulateapj, 17 figure
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