1,977 research outputs found
The composition, mechanisms of action and infusion parameters of cardioplegic solutions as determinants of recovery in rabbit isolated hearts (Langendorff)
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Extragalactic Science, Cosmology and Galactic Archaeology with the Subaru Prime Focus Spectrograph (PFS)
The Subaru Prime Focus Spectrograph (PFS) is a massively-multiplexed
fiber-fed optical and near-infrared 3-arm spectrograph (N_fiber=2400,
380<lambda<1260nm, 1.3 degree diameter FoV), offering unique opportunities in
survey astronomy. Here we summarize the science case feasible for a survey of
Subaru 300 nights. We describe plans to constrain the nature of dark energy via
a survey of emission line galaxies spanning a comoving volume of 9.3 (Gpc/h)^3
in the redshift range 0.8<z<2.4. In each of 6 redshift bins, the cosmological
distances will be measured to 3% precision via BAO, and redshift-space
distortions will be used to constrain structure growth to 6% precision. In the
GA program, radial velocities and chemical abundances of stars in the Milky Way
and M31 will be used to infer the past assembly histories of spiral galaxies
and the structure of their dark matter halos. Data will be secured for 10^6
stars in the Galactic thick-disk, halo and tidal streams as faint as V~22,
including stars with V < 20 to complement the goals of the Gaia mission. A
medium-resolution mode with R = 5000 to be implemented in the red arm will
allow the measurement of multiple alpha-element abundances and more precise
velocities for Galactic stars, elucidating the detailed chemo-dynamical
structure and evolution of each of the main stellar components of the Milky Way
Galaxy and of its dwarf spheroidal galaxies. For the extragalactic program, our
simulations suggest the wide avelength range will be powerful in probing the
galaxy population and its clustering over a wide redshift range. We propose to
conduct a color-selected survey of 1<z<2 galaxies and AGN over 16 deg^2 to
J~23.4, yielding a fair sample of galaxies with stellar masses above ~10^{10}Ms
at z~2. A two-tiered survey of higher redshift LBGs and LAEs will quantify the
properties of early systems close to the reionization epoch.Comment: This document describes the scientific program and requirements for
the Subaru Prime Focus Spectrograph (PFS) project. Made significant revision
based on studies for the Preliminary Design Review (PRD) held in Feb 2013.
The higher-resolution paper file is available from
http://member.ipmu.jp/masahiro.takada/pfs_astroph_rv.pd
Prime Focus Spectrograph (PFS) for the Subaru Telescope: Overview, recent progress, and future perspectives
PFS (Prime Focus Spectrograph), a next generation facility instrument on the
8.2-meter Subaru Telescope, is a very wide-field, massively multiplexed,
optical and near-infrared spectrograph. Exploiting the Subaru prime focus, 2394
reconfigurable fibers will be distributed over the 1.3 deg field of view. The
spectrograph has been designed with 3 arms of blue, red, and near-infrared
cameras to simultaneously observe spectra from 380nm to 1260nm in one exposure
at a resolution of ~1.6-2.7A. An international collaboration is developing this
instrument under the initiative of Kavli IPMU. The project is now going into
the construction phase aiming at undertaking system integration in 2017-2018
and subsequently carrying out engineering operations in 2018-2019. This article
gives an overview of the instrument, current project status and future paths
forward.Comment: 17 pages, 10 figures. Proceeding of SPIE Astronomical Telescopes and
Instrumentation 201
Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation
Why do banks promise to pay par on demand?
We survey the theories of why banks promise to pay par on demand and examine evidence about
the conditions under which banks have promised to pay the par value of deposits and banknotes on
demand when holding only fractional reserves. The theoretical literature can be broadly divided into four
strands: liquidity provision, asymmetric information, legal restrictions, and a medium of exchange. We
assume that it is not zero cost to make a promise to redeem a liability at par value on demand. If so, then
the conditions in the theories that result in par redemption are possible explanations of why banks
promise to pay par on demand. If the explanation based on customers’ demand for liquidity is correct,
payment of deposits at par will be promised when banks hold assets that are illiquid in the short run. If
the asymmetric-information explanation based on the difficulty of valuing assets is correct, the
marketability of banks’ assets determines whether banks promise to pay par. If the legal restrictions
explanation of par redemption is correct, banks will not promise to pay par if they are not required to do
so. If the transaction explanation is correct, banks will promise to pay par value only if the deposits are
used in transactions. After the survey of the theoretical literature, we examine the history of banking in
several countries in different eras: fourth-century Athens, medieval Italy, Japan, and free banking and
money market mutual funds in the United States. We find that all of the theories can explain some of the
observed banking arrangements, and none explain all of them
Recommended from our members
Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension
Background:
Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (
BMPR2
) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (
EIF2AK4
) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH.
Methods:
Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in
BMPR2
and biallelic
EIF2AK4
variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and
sorting intolerant from tolerant
predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured.
Results:
Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in
BMPR2
were identified in 130 patients (14.8%). Biallelic mutations in
EIF2AK4
were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic
EIF2AK4
mutations. These patients had a reduced transfer coefficient for carbon monoxide (K
co
; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without
EIF2AK4
mutations. However, radiological assessment alone could not accurately identify biallelic
EIF2AK4
mutation carriers. Patients with PAH with biallelic
EIF2AK4
mutations had a shorter survival.
Conclusions:
Biallelic
EIF2AK4
mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K
co
and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
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Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease
Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre
Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.
Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge
Cancer Centre and Medical Research Council Infrastructure Award. The
University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre
The James Webb Space Telescope Mission
Twenty-six years ago a small committee report, building on earlier studies,
expounded a compelling and poetic vision for the future of astronomy, calling
for an infrared-optimized space telescope with an aperture of at least .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the James Webb Space Telescope. A
generation of astronomers will celebrate their accomplishments for the life of
the mission, potentially as long as 20 years, and beyond. This report and the
scientific discoveries that follow are extended thank-you notes to the 20,000
team members. The telescope is working perfectly, with much better image
quality than expected. In this and accompanying papers, we give a brief
history, describe the observatory, outline its objectives and current observing
program, and discuss the inventions and people who made it possible. We cite
detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space
Telescope Overview, 29 pages, 4 figure
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