160 research outputs found
Pathprinting: An integrative approach to understand the functional basis of disease
New strategies to combat complex human disease require systems approaches to biology that integrate experiments from cell lines, primary tissues and model organisms. We have developed Pathprint, a functional approach that compares gene expression profiles in a set of pathways, networks and transcriptionally regulated targets. It can be applied universally to gene expression profiles across species. Integration of large-scale profiling methods and curation of the public repository overcomes platform, species and batch effects to yield a standard measure of functional distance between experiments. We show that pathprints combine mouse and human blood developmental lineage, and can be used to identify new prognostic indicators in acute myeloid leukemia. The code and resources are available at http://âcompbio.âsph.âharvard.âedu/âhidelab/âpathprin
Light meson mass dependence of the positive parity heavy-strange mesons
We calculate the masses of the resonances D_{s0}^*(2317) and D_{s1}(2460) as
well as their bottom partners as bound states of a kaon and a D^*- and
B^*-meson, respectively, in unitarized chiral perturbation theory at
next-to-leading order. After fixing the parameters in the D_{s0}^*(2317)
channel, the calculated mass for the D_{s1}(2460) is found in excellent
agreement with experiment. The masses for the analogous states with a bottom
quark are predicted to be M_{B^*_{s0}}=(5696\pm 40) MeV and M_{B_{s1}}=(5742\pm
40) MeV in reasonable agreement with previous analyses. In particular, we
predict M_{B_{s1}}-M_{B_{s0}^*}=46\pm 1 MeV. We also explore the dependence of
the states on the pion and kaon masses. We argue that the kaon mass dependence
of a kaonic bound state should be almost linear with slope about unity. Such a
dependence is specific to the assumed molecular nature of the states. We
suggest to extract the kaon mass dependence of these states from lattice QCD
calculations.Comment: 10 page
DN interaction from meson exchange
A model of the DN interaction is presented which is developed in close
analogy to the meson-exchange KbarN potential of the Juelich group utilizing
SU(4) symmetry constraints. The main ingredients of the interaction are
provided by vector meson (rho, omega) exchange and higher-order box diagrams
involving D*N, D\Delta, and D*\Delta intermediate states. The coupling of DN to
the pi-Lambda_c and pi-Sigma_c channels is taken into account. The interaction
model generates the Lambda_c(2595) resonance dynamically as a DN quasi-bound
state. Results for DN total and differential cross sections are presented and
compared with predictions of an interaction model that is based on the
leading-order Weinberg-Tomozawa term. Some features of the Lambda_c(2595)
resonance are discussed and the role of the near-by pi-Sigma_c threshold is
emphasized. Selected predictions of the orginal KbarN model are reported too.
Specifically, it is pointed out that the model generates two poles in the
partial wave corresponding to the Lambda(1405) resonance.Comment: 14 pages, 8 figure
Four-nucleon scattering with a correlated Gaussian basis method
Elastic-scattering phase shifts for four-nucleon systems are studied in an
- type cluster model in order to clarify the role of the tensor
force and to investigate cluster distortions in low energy and
scattering. In the present method, the description of the cluster wave function
is extended from a simple (0) harmonic-oscillator shell model to a few-body
model with a realistic interaction, in which the wave function of the
subsystems are determined with the Stochastic Variational Method. In order to
calculate the matrix elements of the four-body system, we have developed a
Triple Global Vector Representation method for the correlated Gaussian basis
functions. To compare effects of the cluster distortion with realistic and
effective interactions, we employ the AV8 potential as a realistic
interaction and the Minnesota potential as an effective interaction. Especially
for , the calculated phase shifts show that the and channels
are strongly coupled to the channel for the case of the realistic
interaction. On the contrary, the coupling of these channels plays a relatively
minor role for the case of the effective interaction. This difference between
both potentials originates from the tensor term in the realistic interaction.
Furthermore, the tensor interaction makes the energy splitting of the negative
parity states of He consistent with experiments. No such splitting is
however reproduced with the effective interaction
Meta-analysis of type 2 Diabetes in African Americans Consortium
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 Ă 10(-94)<P<5 Ă 10(-8), odds ratio (OR)â = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 Ă 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe
Identification of regulatory variants associated with genetic susceptibility to meningococcal disease
Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes
Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.
Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes
Operation and performance of the ATLAS semiconductor tracker
The semiconductor tracker is a silicon microstrip detector forming part of the inner tracking system of the ATLAS experiment at the LHC. The operation and performance of the semiconductor tracker during the first years of LHC running are described. More than 99% of the detector modules were operational during this period, with an average intrinsic hit efficiency of (99.74±0.04)%. The evolution of the noise occupancy is discussed, and measurements of the Lorentz angle, Ύ-ray production and energy loss presented. The alignment of the detector is found to be stable at the few-micron level over long periods of time. Radiation damage measurements, which include the evolution of detector leakage currents, are found to be consistent with predictions and are used in the verification of radiation background simulations
Search for Hâγγ produced in association with top quarks and constraints on the Yukawa coupling between the top quark and the Higgs boson using data taken at 7 TeV and 8 TeV with the ATLAS detector
A search is performed for Higgs bosons produced in association with top quarks using the diphoton decay mode of the Higgs boson. Selection requirements are optimized separately for leptonic and fully hadronic final states from the top quark decays. The dataset used corresponds to an integrated luminosity of 4.5 fbâ14.5 fbâ1 of protonâproton collisions at a center-of-mass energy of 7 TeV and 20.3 fbâ1 at 8 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. No significant excess over the background prediction is observed and upper limits are set on the ttÂŻH production cross section. The observed exclusion upper limit at 95% confidence level is 6.7 times the predicted Standard Model cross section value. In addition, limits are set on the strength of the Yukawa coupling between the top quark and the Higgs boson, taking into account the dependence of the ttÂŻH and tH cross sections as well as the Hâγγ branching fraction on the Yukawa coupling. Lower and upper limits at 95% confidence level are set at â1.3 and +8.0 times the Yukawa coupling strength in the Standard Model
Measurement of the cross section of high transverse momentum ZâbbÌ production in protonâproton collisions at âs = 8 TeV with the ATLAS detector
This Letter reports the observation of a high transverse momentum ZâbbÌ signal in protonâproton collisions at âs=8 TeV and the measurement of its production cross section. The data analysed were collected in 2012 with the ATLAS detector at the LHC and correspond to an integrated luminosity of 19.5 fbâÂč. The ZâbbÌ decay is reconstructed from a pair of b -tagged jets, clustered with the anti-ktkt jet algorithm with R=0.4R=0.4, that have low angular separation and form a dijet with pT>200 GeVpT>200 GeV. The signal yield is extracted from a fit to the dijet invariant mass distribution, with the dominant, multi-jet background mass shape estimated by employing a fully data-driven technique that reduces the dependence of the analysis on simulation. The fiducial cross section is determined to be
ÏZâbbÂŻfid=2.02±0.20 (stat.) ±0.25 (syst.)±0.06 (lumi.) pb=2.02±0.33 pb,
in good agreement with next-to-leading-order theoretical predictions
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