104 research outputs found
Whole exome sequencing identifies novel genes for fetal hemoglobin response to hydroxyurea in children with sickle cell anemia.
Hydroxyurea has proven efficacy in children and adults with sickle cell anemia (SCA), but with considerable inter-individual variability in the amount of fetal hemoglobin (HbF) produced. Sibling and twin studies indicate that some of that drug response variation is heritable. To test the hypothesis that genetic modifiers influence pharmacological induction of HbF, we investigated phenotype-genotype associations using whole exome sequencing of children with SCA treated prospectively with hydroxyurea to maximum tolerated dose (MTD). We analyzed 171 unrelated patients enrolled in two prospective clinical trials, all treated with dose escalation to MTD. We examined two MTD drug response phenotypes: HbF (final %HbF minus baseline %HbF), and final %HbF. Analyzing individual genetic variants, we identified multiple low frequency and common variants associated with HbF induction by hydroxyurea. A validation cohort of 130 pediatric sickle cell patients treated to MTD with hydroxyurea was genotyped for 13 non-synonymous variants with the strongest association with HbF response to hydroxyurea in the discovery cohort. A coding variant in Spalt-like transcription factor, or SALL2, was associated with higher final HbF in this second independent replication sample and SALL2 represents an outstanding novel candidate gene for further investigation. These findings may help focus future functional studies and provide new insights into the pharmacological HbF upregulation by hydroxyurea in patients with SCA
A Natural Framework for Solar and 17 keV Neutrinos
Motivated by recent experimental claims for the existence of a 17 keV
neutrino and by the solar neutrino problem, we construct a class of models
which contain in their low-energy spectrum a single light sterile neutrino and
one or more Nambu-Goldstone bosons. In these models the required pattern of
breaking of lepton-number symmetry takes place near the electroweak scale and
all mass heirarchies are technically natural. The models are compatible with
all cosmological and astrophysical constraints, and can solve the solar
neutrino problem via either the MSW effect or vacuum oscillations. The deficit
in atmospheric muon neutrinos seen in the Kamiokande and IMB detectors can also
be explained in these models.Comment: 23 page
Composite Leptoquarks at the LHC
If electroweak symmetry breaking arises via strongly-coupled physics, the
observed suppression of flavour-changing processes suggests that fermion masses
should arise via mixing of elementary fermions with composite fermions of the
strong sector. The strong sector then carries colour charge, and may contain
composite leptoquark states, arising either as TeV scale resonances, or even as
light, pseudo-Nambu-Goldstone bosons. The latter, since they are coupled to
colour, get a mass of the order of several hundred GeV, beyond the reach of
current searches at the Tevatron. The same generic mechanism that suppresses
flavour-changing processes suppresses leptoquark-mediated rare processes,
making it conceivable that the many stringent constraints may be evaded. The
leptoquarks couple predominantly to third-generation quarks and leptons, and
the prospects for discovery at LHC appear to be good. As an illustration, a
model based on the Pati-Salam symmetry is described, and its embedding in
models with a larger symmetry incorporating unification of gauge couplings,
which provide additional motivation for leptoquark states at or below the TeV
scale, is discussed.Comment: 10 pp, version to appear in JHE
RS1, Custodial Isospin and Precision Tests
We study precision electroweak constraints within a RS1 model with gauge
fields and fermions in the bulk. The electroweak gauge symmetry is enhanced to
SU(2)_L \times SU(2)_R \times U(1)_{B-L}, thereby providing a custodial isospin
symmetry sufficient to suppress excessive contributions to the T parameter. We
then construct complete models, complying with all electroweak constraints, for
solving the hierarchy problem, without supersymmetry or large hierarchies in
the fundamental couplings. Using the AdS/CFT correspondence our models can be
interpreted as dual to a strongly coupled conformal Higgs sector with global
custodial symmetry, gauge and fermionic matter being fundamental fields
external to the CFT. This scenario has interesting collider signals, distinct
from other RS models in the literature.Comment: 32 pages, 6 figures, latex2e, minor changes, references adde
Deleterious Heteroplasmic Mitochondrial Mutations are associated With an increased Risk of Overall and Cancer-Specific Mortality
Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia
Probing exotic phenomena at the interface of nuclear and particle physics with the electric dipole moments of diamagnetic atoms: A unique window to hadronic and semi-leptonic CP violation
The current status of electric dipole moments of diamagnetic atoms which
involves the synergy between atomic experiments and three different theoretical
areas -- particle, nuclear and atomic is reviewed. Various models of particle
physics that predict CP violation, which is necessary for the existence of such
electric dipole moments, are presented. These include the standard model of
particle physics and various extensions of it. Effective hadron level combined
charge conjugation (C) and parity (P) symmetry violating interactions are
derived taking into consideration different ways in which a nucleon interacts
with other nucleons as well as with electrons. Nuclear structure calculations
of the CP-odd nuclear Schiff moment are discussed using the shell model and
other theoretical approaches. Results of the calculations of atomic electric
dipole moments due to the interaction of the nuclear Schiff moment with the
electrons and the P and time-reversal (T) symmetry violating
tensor-pseudotensor electron-nucleus are elucidated using different
relativistic many-body theories. The principles of the measurement of the
electric dipole moments of diamagnetic atoms are outlined. Upper limits for the
nuclear Schiff moment and tensor-pseudotensor coupling constant are obtained
combining the results of atomic experiments and relativistic many-body
theories. The coefficients for the different sources of CP violation have been
estimated at the elementary particle level for all the diamagnetic atoms of
current experimental interest and their implications for physics beyond the
standard model is discussed. Possible improvements of the current results of
the measurements as well as quantum chromodynamics, nuclear and atomic
calculations are suggested.Comment: 46 pages, 19 tables and 16 figures. A review article accepted for
EPJ
Influenza A Viruses from Wild Birds in Guatemala Belong to the North American Lineage
The role wild bird species play in the transmission and ecology of avian influenza virus (AIV) is well established; however, there are significant gaps in our understanding of the worldwide distribution of these viruses, specifically about the prevalence and/or significance of AIV in Central and South America. As part of an assessment of the ecology of AIV in Guatemala, we conducted active surveillance in wild birds on the Pacific and Atlantic coasts. Cloacal and tracheal swab samples taken from resident and migratory wild birds were collected from February 2007 to January 2010.1913 samples were collected and virus was detected by real time RT-PCR (rRT-PCR) in 28 swab samples from ducks (Anas discors). Virus isolation was attempted for these positive samples, and 15 isolates were obtained from the migratory duck species Blue-winged teal. The subtypes identified included H7N9, H11N2, H3N8, H5N3, H8N4, and H5N4. Phylogenetic analysis of the viral sequences revealed that AIV isolates are highly similar to viruses from the North American lineage suggesting that bird migration dictates the ecology of these viruses in the Guatemalan bird population
The Evolutionary Genetics and Emergence of Avian Influenza Viruses in Wild Birds
We surveyed the genetic diversity among avian influenza virus (AIV) in wild birds, comprising 167 complete viral genomes from 14 bird species sampled in four locations across the United States. These isolates represented 29 type A influenza virus hemagglutinin (HA) and neuraminidase (NA) subtype combinations, with up to 26% of isolates showing evidence of mixed subtype infection. Through a phylogenetic analysis of the largest data set of AIV genomes compiled to date, we were able to document a remarkably high rate of genome reassortment, with no clear pattern of gene segment association and occasional inter-hemisphere gene segment migration and reassortment. From this, we propose that AIV in wild birds forms transient “genome constellations,” continually reshuffled by reassortment, in contrast to the spread of a limited number of stable genome constellations that characterizes the evolution of mammalian-adapted influenza A viruses
Casemix, management, and mortality of patients receiving emergency neurosurgery for traumatic brain injury in the Global Neurotrauma Outcomes Study: a prospective observational cohort study
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