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

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 $w=-1$ 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 $\Omega_\Lambda$ 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 $\alpha_{\rm 5-20} = -0.07 \pm 0.06$, $\alpha_{\rm 20-148} = -0.39 \pm0.04$, and $\alpha_{\rm 5-148} = -0.20 \pm 0.03$. 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: 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

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% or the 90 TB collected by ACT from 2007 to 2010. In 2008 we observed for 136 days, producing a total of 142h of data (11 TB for the 148 GHz band only), with a daily average of 10.5 h of observation. From these, 108.5 h were devoted to 850 sq deg stripe (11.2 h by 9 deg.1) centered on a declination of -52 deg.7, while 175 h were devoted to a 280 square deg stripe (4.5 h by 4 deg.8) 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 h 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 muK square root of s in CMB units. Atmospheric brightness fluctuations constitute the main contaminant in the data and dominate the detector and noise covariance at low frequencies in the TOD. The maps were made by solving the lease 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 the our maps are unbiased at l > 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

The Atacama Cosmology Telescope: Physical Properties and Purity of a Galaxy Cluster Sample Selected via the Sunyaev-Zel'dovich Effect

We present optical and X-ray properties for the first confirmed galaxy cluster sample selected by the Sunyaev-Zel'dovich Effect from 148 GHz maps over 455 square degrees of sky made with the Atacama Cosmology Telescope. These maps, coupled with multi-band imaging on 4-meter-class optical telescopes, have yielded a sample of 23 galaxy clusters with redshifts between 0.118 and 1.066. Of these 23 clusters, 10 are newly discovered. The selection of this sample is approximately mass limited and essentially independent of redshift. We provide optical positions, images, redshifts and X-ray fluxes and luminosities for the full sample, and X-ray temperatures of an important subset. The mass limit of the full sample is around 8e14 Msun, with a number distribution that peaks around a redshift of 0.4. For the 10 highest significance SZE-selected cluster candidates, all of which are optically confirmed, the mass threshold is 1e15 Msun and the redshift range is 0.167 to 1.066. Archival observations from Chandra, XMM-Newton, and ROSAT provide X-ray luminosities and temperatures that are broadly consistent with this mass threshold. Our optical follow-up procedure also allowed us to assess the purity of the ACT cluster sample. Eighty (one hundred) percent of the 148 GHz candidates with signal-to-noise ratios greater than 5.1 (5.7) are confirmed as massive clusters. The reported sample represents one of the largest SZE-selected sample of massive clusters over all redshifts within a cosmologically-significant survey volume, which will enable cosmological studies as well as future studies on the evolution, morphology, and stellar populations in the most massive clusters in the Universe.Comment: 20 pages, 15 figures, 6 tables. Accepted for publication in ApJ. Higher resolution figures available at: http://peumo.rutgers.edu/~felipe/e-prints