1,217 research outputs found
Boundary Conditions for Interacting Membranes
We investigate supersymmetric boundary conditions in both the Bagger-Lambert
and the ABJM theories of interacting membranes. We find boundary conditions
associated to the fivebrane, the ninebrane and the M-theory wave. For the ABJM
theory we are able to understand the enhancement of supersymmetry to produce
the (4,4) supersymmetry of the self-dual string. We also include supersymmetric
boundary conditions on the gauge fields that cancel the classical gauge anomaly
of the Chern-Simons terms.Comment: 36 pages, latex, v2 minor typos correcte
Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines
The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers
Error-analysis and comparison to analytical models of numerical waveforms produced by the NRAR Collaboration
The Numerical-Relativity-Analytical-Relativity (NRAR) collaboration is a
joint effort between members of the numerical relativity, analytical relativity
and gravitational-wave data analysis communities. The goal of the NRAR
collaboration is to produce numerical-relativity simulations of compact
binaries and use them to develop accurate analytical templates for the
LIGO/Virgo Collaboration to use in detecting gravitational-wave signals and
extracting astrophysical information from them. We describe the results of the
first stage of the NRAR project, which focused on producing an initial set of
numerical waveforms from binary black holes with moderate mass ratios and
spins, as well as one non-spinning binary configuration which has a mass ratio
of 10. All of the numerical waveforms are analysed in a uniform and consistent
manner, with numerical errors evaluated using an analysis code created by
members of the NRAR collaboration. We compare previously-calibrated,
non-precessing analytical waveforms, notably the effective-one-body (EOB) and
phenomenological template families, to the newly-produced numerical waveforms.
We find that when the binary's total mass is ~100-200 solar masses, current EOB
and phenomenological models of spinning, non-precessing binary waveforms have
overlaps above 99% (for advanced LIGO) with all of the non-precessing-binary
numerical waveforms with mass ratios <= 4, when maximizing over binary
parameters. This implies that the loss of event rate due to modelling error is
below 3%. Moreover, the non-spinning EOB waveforms previously calibrated to
five non-spinning waveforms with mass ratio smaller than 6 have overlaps above
99.7% with the numerical waveform with a mass ratio of 10, without even
maximizing on the binary parameters.Comment: 51 pages, 10 figures; published versio
Characterization of the Poly-T Variant in the TOMM40 Gene in Diverse Populations
We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly. Three allele groups were defined for rs10524523, hereafter ‘523’, based on the number of ‘T’-residues: ‘Short’ (S, T≤19), ‘Long’ (L, 20≤T≤29) and ‘Very Long’ (VL, T≥30). Homopolymers, particularly long homopolymers like ‘523’, are difficult to genotype because ‘slippage’ occurs during PCR-amplification. We initially genotyped this locus by PCR-amplification followed by Sanger-sequencing. However, we recognized the need to develop a higher-throughput genotyping method that is also accurate and reliable. Here we describe a new ‘523’ genotyping assay that is simple and inexpensive to perform in a standard molecular genetics laboratory. The assay is based on the detection of differences in PCR-fragment length using capillary electrophoresis. We discuss technical problems, solutions, and the steps taken for validation. We employed the novel assay to investigate the ‘523’ allele frequencies in different ethnicities. Whites and Hispanics have similar frequencies of S/L/VL alleles (0.45/0.11/0.44 and 0.43/0.09/0.48, respectively). In African-Americans, the frequency of the L-allele (0.10) is similar to Whites and Hispanics; however, the S-allele is more prevalent (0.65) and the VL-allele is concomitantly less frequent (0.25). The allele frequencies determined using the new methodology are compared to previous reports for Ghanaian, Japanese, Korean and Han Chinese cohorts. Finally, we studied the linkage pattern between TOMM40-‘523’ and APOE alleles. In Whites and Hispanics, consistent with previous reports, the L is primarily linked to ε4, while the majority of the VL and S are linked to ε3. Interestingly, in African-Americans, Ghanaians and Japanese, there is an increased frequency of the ‘523’S-APOEε4 haplotype. These data may be used as references for ‘523’ allele and ‘523’-APOE haplotype frequencies in diverse populations for the design of research studies and clinical trials
The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer
Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.
Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants
Measurement of the ttbar Production Cross Section in ppbar Collisions at sqrt{s}=1.96 TeV using Lepton + Jets Events with Secondary Vertex b-tagging
We present a measurement of the ttbar production cross section using events
with one charged lepton and jets from ppbar collisions at a center-of-mass
energy of 1.96 TeV. In these events, heavy flavor quarks from top quark decay
are identified with a secondary vertex tagging algorithm. From 162 pb-1 of data
collected by the Collider Detector at Fermilab, a total of 48 candidate events
are selected, where 13.5 +- 1.8 events are expected from background
contributions. We measure a ttbar production cross section of 5.6^{+1.2}_{-1.1}
(stat.) ^{+0.9}_{0.6} (syst.) pb.Comment: 28 pages, 20 figures. Published in Physical Review
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