1,587 research outputs found
Changes in the expression of the type 2 diabetes-associated gene VPS13C in the β cell are associated with glucose intolerance in humans and mice
Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels in islets from female (n = 40, P < 0.041) but not from male subjects. Explored using promoter-reporter assays in β-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the β-cell were generated by crossing animals bearing a floxed allele at exon 1 to mice expressing Cre recombinase under Ins1 promoter control (Ins1Cre). Whereas Vps13cfl/fl:Ins1Cre (βVps13cKO) mice displayed normal weight gain compared with control littermates, deletion of Vps13c had little effect on glucose tolerance. Pancreatic histology revealed no significant change in β-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and βVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and β-cell function (HOMA-B) in vivo. Furthermore, glucose-stimulated increases in intracellular free Ca2+ were significantly increased in islets from female KO mice, suggesting impaired Ca2+ sensitivity of the secretory machinery. The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered disease risk at this locus, particularly in females, and suggest that C2CD4A may also be involved
On the Brightness and Waiting-time Distributions of a Type III Radio Storm observed by STEREO/WAVES
Type III solar radio storms, observed at frequencies below approximately 16
MHz by space borne radio experiments, correspond to the quasi-continuous,
bursty emission of electron beams onto open field lines above active regions.
The mechanisms by which a storm can persist in some cases for more than a solar
rotation whilst exhibiting considerable radio activity are poorly understood.
To address this issue, the statistical properties of a type III storm observed
by the STEREO/WAVES radio experiment are presented, examining both the
brightness distribution and (for the first time) the waiting-time distribution.
Single power law behavior is observed in the number distribution as a function
of brightness; the power law index is approximately 2.1 and is largely
independent of frequency. The waiting-time distribution is found to be
consistent with a piecewise-constant Poisson process. This indicates that
during the storm individual type III bursts occur independently and suggests
that the storm dynamics are consistent with avalanche type behavior in the
underlying active region.Comment: 14 pages, 4 figures, 1 table. Accepted for publication in
Astrophysical Journal Letter
Relativistic Proton Production During the 14 July 2000 Solar Event: The Case for Multiple Source Mechanisms
Protons accelerated to relativistic energies by transient solar and
interplanetary phenomena caused a ground-level cosmic ray enhancement on 14
July 2000, Bastille Day. Near-Earth spacecraft measured the proton flux
directly and ground-based observatories measured the secondary responses to
higher energy protons. We have modelled the arrival of these relativistic
protons at Earth using a technique which deduces the spectrum, arrival
direction and anisotropy of the high-energy protons that produce increased
responses in neutron monitors. To investigate the acceleration processes
involved we have employed theoretical shock and stochastic acceleration
spectral forms in our fits to spacecraft and neutron monitor data. During the
rising phase of the event (10:45 UT and 10:50 UT) we find that the spectrum
between 140 MeV and 4 GeV is best fitted by a shock acceleration spectrum. In
contrast, the spectrum at the peak (10:55 UT and 11:00 UT) and in the declining
phase (11:40 UT) is best fitted with a stochastic acceleration spectrum. We
propose that at least two acceleration processes were responsible for the
production of relativistic protons during the Bastille Day solar event: (1)
protons were accelerated to relativistic energies by a shock, presumably a
coronal mass ejection (CME). (2) protons were also accelerated to relativistic
energies by stochastic processes initiated by magnetohydrodynamic (MHD)
turbulence.Comment: 38 pages, 9 figures, accepted for publication in the Astrophysical
Journal, January, 200
Expansion of magnetic clouds in the outer heliosphere
A large amount of magnetized plasma is frequently ejected from the Sun as
coronal mass ejections (CMEs). Some of these ejections are detected in the
solar wind as magnetic clouds (MCs) that have flux rope signatures. Magnetic
clouds are structures that typically expand in the inner heliosphere. We derive
the expansion properties of MCs in the outer heliosphere from one to five
astronomical units to compare them with those in the inner heliosphere. We
analyze MCs observed by the Ulysses spacecraft using insitu magnetic field and
plasma measurements. The MC boundaries are defined in the MC frame after
defining the MC axis with a minimum variance method applied only to the flux
rope structure. As in the inner heliosphere, a large fraction of the velocity
profile within MCs is close to a linear function of time. This is indicative
of} a self-similar expansion and a MC size that locally follows a power-law of
the solar distance with an exponent called zeta. We derive the value of zeta
from the insitu velocity data. We analyze separately the non-perturbed MCs
(cases showing a linear velocity profile almost for the full event), and
perturbed MCs (cases showing a strongly distorted velocity profile). We find
that non-perturbed MCs expand with a similar non-dimensional expansion rate
(zeta=1.05+-0.34), i.e. slightly faster than at the solar distance and in the
inner heliosphere (zeta=0.91+-0.23). The subset of perturbed MCs expands, as in
the inner heliosphere, at a significantly lower rate and with a larger
dispersion (zeta=0.28+-0.52) as expected from the temporal evolution found in
numerical simulations. This local measure of the expansion also agrees with the
distribution with distance of MC size,mean magnetic field, and plasma
parameters. The MCs interacting with a strong field region, e.g. another MC,
have the most variable expansion rate (ranging from compression to
over-expansion)
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Near-earth cosmic ray decreases associated with remote coronal mass ejections
Galactic cosmic ray (GCR) flux is modulated by both particle drift patterns and solar wind structures on a range of timescales. Over solar cycles, GCR flux varies as a function of the total open solar magnetic flux and the latitudinal extent of the heliospheric current sheet. Over hours, drops of a few percent in near-Earth GCR flux (Forbush decreases, FDs) are well known to be associated with the near-Earth passage of solar wind structures resulting from corotating interaction regions (CIRs) and transient coronal mass ejections (CMEs). We report on four FDs seen at ground-based neutron monitors which cannot be immediately associated with significant structures in the local solar wind. Similarly, there are significant near-Earth structures which do not produce any corresponding GCR variation. Three of the FDs are during the STEREO era, enabling in situ and remote observations from three well-separated heliospheric locations. Extremely large CMEs passed the STEREO-A spacecraft, which was behind the West limb of the Sun, approximately 2–3 days before each near- Earth FD. Solar wind simulations suggest that the CMEs combined with pre-existing CIRs, enhancing the pre-existing barriers to GCR propagation. Thus these observations provide strong evidence for the modulation of GCR flux by remote solar wind structures
Width of Radio-Loud and Radio-Quiet CMEs
In the present paper we report on the difference in angular sizes between
radio-loud and radio-quiet CMEs. For this purpose we compiled these two samples
of events using Wind/WAVES and SOHO/LASCO observations obtained during
1996-2005. It is shown that the radio-loud CMEs are almost two times wider than
the radio-quiet CMEs (considering expanding parts of CMEs). Furthermore we show
that the radio-quiet CMEs have a narrow expanding bright part with a large
extended diffusive structure. These results were obtained by measuring the CME
widths in three different ways.Comment: Solar Physic, in pres
Exploring the behavioural drivers of veterinary surgeon antibiotic prescribing: a qualitative study of companion animal veterinary surgeons in the UK
Background:
Multi-drug resistant bacteria are an increasing concern in both human and veterinary medicine. Inappropriate prescribing and use of antibiotics within veterinary medicine may be a contributory factor to antimicrobial resistance (AMR). The ‘One Health’ Initiative aims to work across species and environments to reduce AMR, however; little is currently known about the factors which influence antibiotic prescribing among veterinary surgeons in companion animal practice.
This paper reports on qualitative data analysis of interviews with veterinary surgeons whose practice partially or wholly focuses on companion animals (N = 16). The objective of the research was to explore the drivers of companion animal veterinary surgeons’ antibiotic prescribing behaviours. The veterinary surgeons interviewed were all practising within the UK (England (n = 4), Scotland (n = 11), Northern Ireland (n = 1)). A behavioural thematic analysis of the data was undertaken, which identified barriers and facilitators to specific prescribing-related behaviours.
Results:
Five components of prescribing behaviours were identified: 1) confirming clinical need for antibiotics; 2) responding to clients; 3) confirming diagnosis; 4) determining dose, duration and type of antibiotic; and 5) preventing infection around surgery (with attendant appropriate and inappropriate antibiotic prescribing behaviours). Barriers to appropriate prescribing identified include: business, diagnostic, fear, habitual practice and pharmaceutical factors. Facilitators include: AMR awareness, infection prevention, professional learning and regulation and government factors.
Conclusion:
This paper uses a behavioural lens to examine drivers which are an influence on veterinary surgeons’ prescribing behaviours. The paper contributes new understandings about factors which influence antibiotic prescribing behaviours among companion animal veterinary surgeons. This analysis provides evidence to inform future interventions, which are focused on changing prescribing behaviours, in order to address the pressing public health concern of AMR
Structure on Interplanetary Shock Fronts: Type II Radio Burst Source Regions
We present \emph{in situ} observations of the source regions of
interplanetary (IP) type II radio bursts, using data from the Wind spacecraft
during the period 1996-2002. We show the results of this survey as well as
in-depth analysis of several individual events. Each event analyzed in detail
is associated with an interplanetary coronal mass ejection (ICME) and an IP
shock driven by the ICME. Immediately prior to the arrival of each shock,
electron beams along the interplanetary magnetic field (IMF) and associated
Langmuir waves are detected, implying magnetic connection to a
quasiperpendicular shock front acceleration site. These observations are
analogous to those made in the terrestrial foreshock region, indicating that a
similar foreshock region exists on IP shock fronts. The analogy suggests that
the electron acceleration process is a fast Fermi process, and this suggestion
is borne out by loss cone features in the electron distribution functions. The
presence of a foreshock region requires nonplanar structure on the shock front.
Using Wind burst mode data, the foreshock electrons are analyzed to estimate
the dimensions of the curved region. We present the first measurement of the
lateral, shock-parallel scale size of IP foreshock regions. The presence of
these regions on IP shock fronts can explain the fine structure often seen in
the spectra of type II bursts.Comment: 19 pages, 5 figures. To be published in The Astrophysical Journa
The evolution of HIV-1 reverse transcriptase in route to acquisition of Q151M multi-drug resistance is complex and involves mutations in multiple domains
Background: The Q151M multi-drug resistance (MDR) pathway in HIV-1 reverse transcriptase (RT) confers reduced susceptibility to all nucleoside reverse transcriptase inhibitors (NRTIs) excluding tenofovir (TDF). This pathway emerges after long term failure of therapy, and is increasingly observed in the resource poor world, where antiretroviral therapy is rarely accompanied by intensive virological monitoring. In this study we examined the genotypic, phenotypic and fitness correlates associated with the development of Q151M MDR in the absence of viral load monitoring.Results: Single-genome sequencing (SGS) of full-length RT was carried out on sequential samples from an HIV-infected individual enrolled in ART rollout. The emergence of Q151M MDR occurred in the order A62V, V75I, and finally Q151M on the same genome at 4, 17 and 37 months after initiation of therapy, respectively. This was accompanied by a parallel cumulative acquisition of mutations at 20 other codon positions; seven of which were located in the connection subdomain. We established that fourteen of these mutations are also observed in Q151M-containing sequences submitted to the Stanford University HIV database. Phenotypic drug susceptibility testing demonstrated that the Q151M-containing RT had reduced susceptibility to all NRTIs except for TDF. RT domain-swapping of patient and wild-type RTs showed that patient-derived connection subdomains were not associated with reduced NRTI susceptibility. However, the virus expressing patient-derived Q151M RT at 37 months demonstrated similar to 44% replicative capacity of that at 4 months. This was further reduced to similar to 22% when the Q151M-containing DNA pol domain was expressed with wild-type C-terminal domain, but was then fully compensated by coexpression of the coevolved connection subdomain.Conclusions: We demonstrate a complex interplay between drug susceptibility and replicative fitness in the acquisition Q151M MDR with serious implications for second-line regimen options. The acquisition of the Q151M pathway occurred sequentially over a long period of failing NRTI therapy, and was associated with mutations in multiple RT domains
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