795 research outputs found
Analysis of factor V in zebrafish demonstrates minimal levels needed for early hemostasis
In humans, coagulation factor V (FV) deficiency is a rare, clinically heterogeneous bleeding disorder, suggesting that genetic modifiers may contribute to disease expressivity. Zebrafish possess many distinct advantages including high fecundity, optical clarity, external development, and homology with the mammalian hemostatic system, features that make it ideal for genetic studies. Our aim was to study the role of FV in zebrafish through targeted mutagenesis and apply the model to the study of human F5 variants. CRISPR-mediated genome editing of the zebrafish f5 locus was performed, generating mutants homozygous for a 49 base pair deletion in exon 4. Thrombus formation secondary to vascular endothelial injury was absent in f52/2 mutant embryos and larvae. Despite this severe hemostatic defect, homozygous mutants survived before succumbing to severe hemorrhage in adulthood. Human F5 variants of uncertain significance from patients with FV deficiency were evaluated, and the causative mutations identified and stratified by their ability to restore thrombus formation in larvae. Analysis of these novel mutations demonstrates variable residual FV function, with minimal activity being required to restore hemostasis in response to laser-induced endothelial injury. This in vivo evaluation may be beneficial for patients whose factor activity levels lack correlation with bleeding symptomatology, although limitations exist. Furthermore, homozygous mutant embryos tolerate what is a severe and lethal defect in mammals, suggesting the possibility of species-specific factors enabling survival, and allowing further study not possible in the mouse. Identification of these factors or other genetic modifiers could lead to novel therapeutic modalities
DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity
DNA replication timing and three-dimensional (3D) genome organization are associated with distinct epigenome patterns across large domains. However, whether alterations in the epigenome, in particular cancer-related DNA hypomethylation, affects higher-order levels of genome architecture is still unclear. Here, using Repli-Seq, single-cell Repli-Seq, and Hi-C, we show that genome-wide methylation loss is associated with both concordant loss of replication timing precision and deregulation of 3D genome organization. Notably, we find distinct disruption in 3D genome compartmentalization, striking gains in cell-to-cell replication timing heterogeneity and loss of allelic replication timing in cancer hypomethylation models, potentially through the gene deregulation of DNA replication and genome organization pathways. Finally, we identify ectopic H3K4me3-H3K9me3 domains from across large hypomethylated domains, where late replication is maintained, which we purport serves to protect against catastrophic genome reorganization and aberrant gene transcription. Our results highlight a potential role for the methylome in the maintenance of 3D genome regulation
Toward an internally consistent astronomical distance scale
Accurate astronomical distance determination is crucial for all fields in
astrophysics, from Galactic to cosmological scales. Despite, or perhaps because
of, significant efforts to determine accurate distances, using a wide range of
methods, tracers, and techniques, an internally consistent astronomical
distance framework has not yet been established. We review current efforts to
homogenize the Local Group's distance framework, with particular emphasis on
the potential of RR Lyrae stars as distance indicators, and attempt to extend
this in an internally consistent manner to cosmological distances. Calibration
based on Type Ia supernovae and distance determinations based on gravitational
lensing represent particularly promising approaches. We provide a positive
outlook to improvements to the status quo expected from future surveys,
missions, and facilities. Astronomical distance determination has clearly
reached maturity and near-consistency.Comment: Review article, 59 pages (4 figures); Space Science Reviews, in press
(chapter 8 of a special collection resulting from the May 2016 ISSI-BJ
workshop on Astronomical Distance Determination in the Space Age
Why do people fitted with hearing aids not wear them?
Objective: Age-related hearing loss is an increasingly important public health problem affecting approximately 40% of 55–74 year olds. The primary clinical management intervention for people with hearing loss is hearing aids, however, the majority (80%) of adults aged 55–74 years who would benefit from a hearing aid, do not use them. Furthermore, many people given a hearing aid do not wear it. The aim was to collate the available evidence as to the potential reasons for non-use of hearing aids among people who have been fitted with at least one. Design: Data were gathered via the use of a scoping study. Study sample: A comprehensive search strategy identified 10 articles reporting reasons for non-use of hearing aids. Results: A number of reasons were given, including hearing aid value, fit and comfort and maintenance of the hearing aid, attitude, device factors, financial reasons, psycho-social/situational factors, healthcare professionals attitudes, ear problems, and appearance. Conclusions: The most important issues were around hearing aid value, i.e. the hearing aid not providing enough benefit, and comfort related to wearing the hearing aid. Identifying factors that affect hearing aid usage are necessary for devising appropriate rehabilitation strategies to ensure greater use of hearing aids
Model-consistent estimation of the basic reproduction number from the incidence of an emerging infection
We investigate the merit of deriving an estimate of the basic reproduction number \documentclass[12pt]{minimal}
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, and we quantify the discrepancies that arise
3D MHD Coronal Oscillations About a Magnetic Null Point: Application of WKB Theory
This paper is a demonstration of how the WKB approximation can be used to
help solve the linearised 3D MHD equations. Using Charpit's Method and a
Runge-Kutta numerical scheme, we have demonstrated this technique for a
potential 3D magnetic null point, .
Under our cold plasma assumption, we have considered two types of wave
propagation: fast magnetoacoustic and Alfv\'en waves. We find that the fast
magnetoacoustic wave experiences refraction towards the magnetic null point,
and that the effect of this refraction depends upon the Alfv\'en speed profile.
The wave, and thus the wave energy, accumulates at the null point. We have
found that current build up is exponential and the exponent is dependent upon
. Thus, for the fast wave there is preferential heating at the null
point. For the Alfv\'en wave, we find that the wave propagates along the
fieldlines. For an Alfv\'en wave generated along the fan-plane, the wave
accumulates along the spine. For an Alfv\'en wave generated across the spine,
the value of determines where the wave accumulation will occur:
fan-plane (), along the axis () or along the
axis (). We have shown analytically that currents build up
exponentially, leading to preferential heating in these areas. The work
described here highlights the importance of understanding the magnetic topology
of the coronal magnetic field for the location of wave heating.Comment: 26 pages, 12 figure
The exposure of the hybrid detector of the Pierre Auger Observatory
The Pierre Auger Observatory is a detector for ultra-high energy cosmic rays.
It consists of a surface array to measure secondary particles at ground level
and a fluorescence detector to measure the development of air showers in the
atmosphere above the array. The "hybrid" detection mode combines the
information from the two subsystems. We describe the determination of the
hybrid exposure for events observed by the fluorescence telescopes in
coincidence with at least one water-Cherenkov detector of the surface array. A
detailed knowledge of the time dependence of the detection operations is
crucial for an accurate evaluation of the exposure. We discuss the relevance of
monitoring data collected during operations, such as the status of the
fluorescence detector, background light and atmospheric conditions, that are
used in both simulation and reconstruction.Comment: Paper accepted by Astroparticle Physic
Recommended from our members
Pegasus IV: Discovery and Spectroscopic Confirmation of an Ultra-faint Dwarf Galaxy in the Constellation Pegasus
We report the discovery of Pegasus IV, an ultra-faint dwarf galaxy found in archival data from the Dark Energy Camera processed by the DECam Local Volume Exploration Survey. Pegasus IV is a compact, ultra-faint stellar system (r1 2 = 41-+68 pc; MV = −4.25 ± 0.2 mag) located at a heliocentric distance of 90-+64 kpc. Based on spectra of seven nonvariable member stars observed with Magellan/IMACS, we confidently resolve Pegasus IV’s velocity dispersion, measuring sv = 3.3-+1.11.7 km s−1 (after excluding three velocity outliers); this implies a mass-to-light ratio of M1 2 LV,1 2 = 167-+99224M☉ L☉ for the system. From the five stars with the highest signal-to-noise spectra, we also measure a systemic metallicity of [Fe/H] =-2.63-+0.300.26 dex, making Pegasus IV one of the most metal-poor ultra-faint dwarfs. We tentatively resolve a nonzero metallicity dispersion for the system. These measurements provide strong evidence that Pegasus IV is a dark-matter-dominated dwarf galaxy, rather than a star cluster. We measure Pegasus IV’s proper motion using data from Gaia Early Data Release 3, finding (μα*, μδ) = (0.33 ± 0.07, −0.21 ± 0.08) mas yr−1. When combined with our measured systemic velocity, this proper motion suggests that Pegasus IV is on an elliptical, retrograde orbit, and is currently near its orbital apocenter. Lastly, we identify three potential RR Lyrae variable stars within Pegasus IV, including one candidate member located more than 10 half-light radii away from the system’s centroid. The discovery of yet another ultra-faint dwarf galaxy strongly suggests that the census of Milky Way satellites is still incomplete, even within 100 kpc
Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV
Results are presented from a search for a W' boson using a dataset
corresponding to 5.0 inverse femtobarns of integrated luminosity collected
during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV.
The W' boson is modeled as a heavy W boson, but different scenarios for the
couplings to fermions are considered, involving both left-handed and
right-handed chiral projections of the fermions, as well as an arbitrary
mixture of the two. The search is performed in the decay channel W' to t b,
leading to a final state signature with a single lepton (e, mu), missing
transverse energy, and jets, at least one of which is tagged as a b-jet. A W'
boson that couples to fermions with the same coupling constant as the W, but to
the right-handed rather than left-handed chiral projections, is excluded for
masses below 1.85 TeV at the 95% confidence level. For the first time using LHC
data, constraints on the W' gauge coupling for a set of left- and right-handed
coupling combinations have been placed. These results represent a significant
improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe
Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV
A search for a Higgs boson decaying into two photons is described. The
analysis is performed using a dataset recorded by the CMS experiment at the LHC
from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an
integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross
section of the standard model Higgs boson decaying to two photons. The expected
exclusion limit at 95% confidence level is between 1.4 and 2.4 times the
standard model cross section in the mass range between 110 and 150 GeV. The
analysis of the data excludes, at 95% confidence level, the standard model
Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The
largest excess of events above the expected standard model background is
observed for a Higgs boson mass hypothesis of 124 GeV with a local significance
of 3.1 sigma. The global significance of observing an excess with a local
significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is
estimated to be 1.8 sigma. More data are required to ascertain the origin of
this excess.Comment: Submitted to Physics Letters
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