98 research outputs found
The Mathematics of a Successful Deconvolution: A Quantitative Assessment of Mixture-Based Combinatorial Libraries Screened Against Two Formylpeptide Receptors
In the past 20 years, synthetic combinatorial methods have fundamentally advanced the ability to synthesize and screen large numbers of compounds for drug discovery and basic research. Mixture-based libraries and positional scanning deconvolution combine two approaches for the rapid identification of specific scaffolds and active ligands. Here we present a quantitative assessment of the screening of 32 positional scanning libraries in the identification of highly specific and selective ligands for two formylpeptide receptors. We also compare and contrast two mixture-based library approaches using a mathematical model to facilitate the selection of active scaffolds and libraries to be pursued for further evaluation. The flexibility demonstrated in the differently formatted mixture-based libraries allows for their screening in a wide range of assays
Antigen Discovery for the Identification of Vaccine Candidates and Biomarkers Using a T Cell Driven Approach in Combination with Positional Scanning Peptide Libraries
The prevention and treatment of infectious diseases is highly dependent on the availability of reliable diagnostic tests and protective or therapeutic vaccines. There also exists an urgent need to develop reliable biomarkers to monitor treatment success and to predict disease progression from asymptomatic to symptomatic disease in several disease scenarios. The elucidation of the disease-relevant antigens that elicit the protective immune responses is critical and required for the development of biomarkers, diagnostics, and vaccines. However; one of the main obstacles to the study of antigen specificity in human T cells is their low frequency in PBMC samples. To overcome this problem we have implemented strategies to generate memory T cell libraries and clones specific to the pathogen of interest. Due to the fact that memory T cells represent a repository of the human T cell response to infection, examination of their antigen specificity can efficiently reveal immunogenic and relevant antigens involved in the in vivo response to infection or vaccines. To examine the specificity of the memory T cells we use an unbiased collection of antigens together with an in silico analysis, namely positional scanning based biometrical analysis. Here we present a summary of our approach and ongoing work on the development of strategies for the culture of memory T cells from patients with Chagas disease. While most studies focus on the identification of vaccine candidates using preselected immunogenic proteins derived from animal models or by or bioinformatics prediction, here we present an innovative approach that directly examines the specificity of the memory response following infection or immunization in humans
Identification of Tetrapeptides from a Mixture Based Positional Scanning Library That Can Restore nM Full Agonist Function of the L106P, I69T, I102S, A219V, C271Y, and C271R Human Melanocortin-4 Polymorphic Receptors (hMC4Rs)
Human obesity has been linked to genetic factors and single nucleotide polymorphisms (SNPs). Melanocortin-4 receptor (MC4R) SNPs have been associated with up to 6% frequency in morbidly obese children and adults. A potential therapy for individuals possessing such genetic modifications is the identification of molecules that can restore proper receptor signaling and function. These compounds could serve as personalized medications improving quality of life issues as well as alleviating diseases symptoms associated with obesity including type 2 diabetes. Several hMC4 SNP receptors have been pharmacologically characterized in vitro to have a decreased, or a lack of response, to endogenous agonists such as α-, β-, and γ2-melanocyte stimulating hormones (MSH) and adrenocorticotropin hormone (ACTH). Herein we report the use of a mixture based positional scanning combinatorial tetrapeptide library to discover molecules with nM full agonist potency and efficacy to the L106P, I69T, I102S, A219V, C271Y, and C271R hMC4Rs. The most potent compounds at all these hMC4R SNPs include Ac-His-(pI)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Arg-(pI)Phe-NH2, and Ac-Arg-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, revealing new ligand pharmacophore models for melanocortin receptor drug design strategies
Evidence for dark energy from the cosmic microwave background alone using the Atacama Cosmology Telescope lensing measurements
For the first time, measurements of the cosmic microwave background radiation
(CMB) alone favor cosmologies with dark energy over models without dark
energy at a 3.2-sigma level. We demonstrate this by combining the CMB lensing
deflection power spectrum from the Atacama Cosmology Telescope with temperature
and polarization power spectra from the Wilkinson Microwave Anisotropy Probe.
The lensing data break the geometric degeneracy of different cosmological
models with similar CMB temperature power spectra. Our CMB-only measurement of
the dark energy density confirms other measurements from
supernovae, galaxy clusters and baryon acoustic oscillations, and demonstrates
the power of CMB lensing as a new cosmological tool.Comment: 4 pages, 3 figures; replaced with version accepted by Physical Review
Letters, added sentence on models with non-standard primordial power spectr
Detection of the Power Spectrum of Cosmic Microwave Background Lensing by the Atacama Cosmology Telescope
We report the first detection of the gravitational lensing of the cosmic
microwave background through a measurement of the four-point correlation
function in the temperature maps made by the Atacama Cosmology Telescope. We
verify our detection by calculating the levels of potential contaminants and
performing a number of null tests. The resulting convergence power spectrum at
2-degree angular scales measures the amplitude of matter density fluctuations
on comoving length scales of around 100 Mpc at redshifts around 0.5 to 3. The
measured amplitude of the signal agrees with Lambda Cold Dark Matter cosmology
predictions. Since the amplitude of the convergence power spectrum scales as
the square of the amplitude of the density fluctuations, the 4-sigma detection
of the lensing signal measures the amplitude of density fluctuations to 12%.Comment: 4 pages, 4 figures, replaced title and author list with version
accepted by Physical Review Letters. Likelihood code can be downloaded from
http://bccp.lbl.gov/~sudeep/ACTLensLike.htm
The Atacama Cosmology Telescope: Extragalactic Sources at 148 GHz in the 2008 Survey
We report on extragalactic sources detected in a 455 square-degree map of the
southern sky made with data at a frequency of 148 GHz from the Atacama
Cosmology Telescope 2008 observing season. We provide a catalog of 157 sources
with flux densities spanning two orders of magnitude: from 15 to 1500 mJy.
Comparison to other catalogs shows that 98% of the ACT detections correspond to
sources detected at lower radio frequencies. Three of the sources appear to be
associated with the brightest cluster galaxies of low redshift X-ray selected
galaxy clusters. Estimates of the radio to mm-wave spectral indices and
differential counts of the sources further bolster the hypothesis that they are
nearly all radio sources, and that their emission is not dominated by
re-emission from warm dust. In a bright (>50 mJy) 148 GHz-selected sample with
complete cross-identifications from the Australia Telescope 20 GHz survey, we
observe an average steepening of the spectra between 5, 20, and 148 GHz with
median spectral indices of , , and . When the
measured spectral indices are taken into account, the 148 GHz differential
source counts are consistent with previous measurements at 30 GHz in the
context of a source count model dominated by radio sources. Extrapolating with
an appropriately rescaled model for the radio source counts, the Poisson
contribution to the spatial power spectrum from synchrotron-dominated sources
with flux density less than 20 mJy is C^{\rm Sync} = (2.8 \pm 0.3) \times
10^{-6} \micro\kelvin^2.Comment: Accepted to Ap
The Atacama Cosmology Telescope: A Measurement of the Cosmic Microwave Background Power Spectrum at 148 and 218 GHz from the 2008 Southern Survey
We present measurements of the cosmic microwave background (CMB) power
spectrum made by the Atacama Cosmology Telescope at 148 GHz and 218 GHz, as
well as the cross-frequency spectrum between the two channels. Our results
clearly show the second through the seventh acoustic peaks in the CMB power
spectrum. The measurements of these higher-order peaks provide an additional
test of the {\Lambda}CDM cosmological model. At l > 3000, we detect power in
excess of the primary anisotropy spectrum of the CMB. At lower multipoles 500 <
l < 3000, we find evidence for gravitational lensing of the CMB in the power
spectrum at the 2.8{\sigma} level. We also detect a low level of Galactic dust
in our maps, which demonstrates that we can recover known faint, diffuse
signals.Comment: 19 pages, 13 figures. Submitted to ApJ. This paper is a companion to
Hajian et al. (2010) and Dunkley et al. (2010
The Atacama Cosmology Telescope: Data Characterization and Map Making
We present a description of the data reduction and mapmaking pipeline used
for the 2008 observing season of the Atacama Cosmology Telescope (ACT). The
data presented here at 148 GHz represent 12% of the 90 TB collected by ACT from
2007 to 2010. In 2008 we observed for 136 days, producing a total of 1423 hours
of data (11 TB for the 148 GHz band only), with a daily average of 10.5 hours
of observation. From these, 1085 hours were devoted to a 850 deg^2 stripe (11.2
hours by 9.1 deg) centered on a declination of -52.7 deg, while 175 hours were
devoted to a 280 deg^2 stripe (4.5 hours by 4.8 deg) centered at the celestial
equator. We discuss sources of statistical and systematic noise, calibration,
telescope pointing, and data selection. Out of 1260 survey hours and 1024
detectors per array, 816 hours and 593 effective detectors remain after data
selection for this frequency band, yielding a 38% survey efficiency. The total
sensitivity in 2008, determined from the noise level between 5 Hz and 20 Hz in
the time-ordered data stream (TOD), is 32 micro-Kelvin sqrt{s} in CMB units.
Atmospheric brightness fluctuations constitute the main contaminant in the data
and dominate the detector noise covariance at low frequencies in the TOD. The
maps were made by solving the least-squares problem using the Preconditioned
Conjugate Gradient method, incorporating the details of the detector and noise
correlations. Cross-correlation with WMAP sky maps, as well as analysis from
simulations, reveal that our maps are unbiased at multipoles ell > 300. This
paper accompanies the public release of the 148 GHz southern stripe maps from
2008. The techniques described here will be applied to future maps and data
releases.Comment: 20 pages, 18 figures, 6 tables, an ACT Collaboration pape
The Atacama Cosmology Telescope: Sunyaev Zel'dovich Selected Galaxy Clusters at 148 GHz in the 2008 Survey
We report on twenty-three clusters detected blindly as Sunyaev-Zel'dovich
(SZ) decrements in a 148 GHz, 455 square-degree map of the southern sky made
with data from the Atacama Cosmology Telescope 2008 observing season. All SZ
detections announced in this work have confirmed optical counterparts. Ten of
the clusters are new discoveries. One newly discovered cluster, ACT-CL
J0102-4915, with a redshift of 0.75 (photometric), has an SZ decrement
comparable to the most massive systems at lower redshifts. Simulations of the
cluster recovery method reproduce the sample purity measured by optical
follow-up. In particular, for clusters detected with a signal-to-noise ratio
greater than six, simulations are consistent with optical follow-up that
demonstrated this subsample is 100% pure. The simulations further imply that
the total sample is 80% complete for clusters with mass in excess of 6x10^14
solar masses referenced to the cluster volume characterized by five hundred
times the critical density. The Compton y -- X-ray luminosity mass comparison
for the eleven best detected clusters visually agrees with both self-similar
and non-adiabatic, simulation-derived scaling laws.Comment: 13 pages, 7 figures, Accepted for publication in Ap
The Atacama Cosmology Telescope: Cosmology from Galaxy Clusters Detected via the Sunyaev-Zel'dovich Effect
We present constraints on cosmological parameters based on a sample of
Sunyaev-Zel'dovich-selected galaxy clusters detected in a millimeter-wave
survey by the Atacama Cosmology Telescope. The cluster sample used in this
analysis consists of 9 optically-confirmed high-mass clusters comprising the
high-significance end of the total cluster sample identified in 455 square
degrees of sky surveyed during 2008 at 148 GHz. We focus on the most massive
systems to reduce the degeneracy between unknown cluster astrophysics and
cosmology derived from SZ surveys. We describe the scaling relation between
cluster mass and SZ signal with a 4-parameter fit. Marginalizing over the
values of the parameters in this fit with conservative priors gives sigma_8 =
0.851 +/- 0.115 and w = -1.14 +/- 0.35 for a spatially-flat wCDM cosmological
model with WMAP 7-year priors on cosmological parameters. This gives a modest
improvement in statistical uncertainty over WMAP 7-year constraints alone.
Fixing the scaling relation between cluster mass and SZ signal to a fiducial
relation obtained from numerical simulations and calibrated by X-ray
observations, we find sigma_8 = 0.821 +/- 0.044 and w = -1.05 +/- 0.20. These
results are consistent with constraints from WMAP 7 plus baryon acoustic
oscillations plus type Ia supernoava which give sigma_8 = 0.802 +/- 0.038 and w
= -0.98 +/- 0.053. A stacking analysis of the clusters in this sample compared
to clusters simulated assuming the fiducial model also shows good agreement.
These results suggest that, given the sample of clusters used here, both the
astrophysics of massive clusters and the cosmological parameters derived from
them are broadly consistent with current models.Comment: 12 pages, 7 figures. Submitted to Ap
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