Models of f(R) Cosmic Acceleration that Evade Solar-System Tests

We study a class of metric-variation f(R) models that accelerates the expansion without a cosmological constant and satisfies both cosmological and solar-system tests in the small-field limit of the parameter space. Solar-system tests alone place only weak bounds on these models, since the additional scalar degree of freedom is locked to the high-curvature general-relativistic prediction across more than 25 orders of magnitude in density, out through the solar corona. This agreement requires that the galactic halo be of sufficient extent to maintain the galaxy at high curvature in the presence of the low-curvature cosmological background. If the galactic halo and local environment in f(R) models do not have substantially deeper potentials than expected in LCDM, then cosmological field amplitudes |f_R| > 10^{-6} will cause the galactic interior to evolve to low curvature during the acceleration epoch. Viability of large-deviation models therefore rests on the structure and evolution of the galactic halo, requiring cosmological simulations of f(R) models, and not directly on solar-system tests. Even small deviations that conservatively satisfy both galactic and solar-system constraints can still be tested by future, percent-level measurements of the linear power spectrum, while they remain undetectable to cosmological-distance measures. Although we illustrate these effects in a specific class of models, the requirements on f(R) are phrased in a nearly model-independent manner.Comment: 13 pages, 10 figures. Submitted to Phys. Rev.

Redshift space 21 cm power spectra from reionization

We construct a simple but self-consistent analytic ionization model for rapid exploration of 21cm power spectrum observables in redshift space. It is fully described by the average ionization fraction $x_e(z)$ and HII patch size $R(z)$ and has the flexibility to accommodate various reionization scenarios. The model associates ionization regions with dark matter halos of the number density required to recover $x_e$ and treats redshift space distortions self-consistently with the virial velocity of such halos. Based on this model, we study the line-of-sight structures in the brightness fluctuations since they are the most immune to foreground contamination. We explore the degeneracy between the HII patch size and nonlinear redshift space distortion in the one dimensional power spectrum. We also discuss the limitations experimental frequency and angular resolutions place on their distinguishability. Angular resolution dilutes even the radial signal and will be a serious limitation for resolving small bubbles before the end of reionization. Nonlinear redshift space distortions suggest that a resolution of order 1 -- 10\arcsec and a frequency resolution of 10kHz will ultimately be desirable to extract the full information in the radial field at $z\sim 10$. First generation instruments such as LOFAR and MWA can potentially measure radial HII patches of a few comoving Mpc and larger at the end of reionization and are unlikely to be affected by nonlinear redshift space distortions.Comment: 13 pages, 10 figures. Revised version. Includes minor changes. Adds appendix on accomodating a distribution of radii for the HII regions. Accepted for publication in Ap

Dog10K: an international sequencing effort to advance studies of canine domestication, phenotypes and health

Dogs are the most phenotypically diverse mammalian species, and they possess more known heritable disorders than any other non-human mammal. Efforts to catalog and characterize genetic variation across well-chosen populations of canines are necessary to advance our understanding of their evolutionary history and genetic architecture. To date, no organized effort has been undertaken to sequence the world's canid populations. The Dog10K Consortium (http://www.dog10kgenomes.org) is an international collaboration of researchers from across the globe who will generate 20× whole genomes from 10 000 canids in 5 years. This effort will capture the genetic diversity that underlies the phenotypic and geographical variability of modern canids worldwide. Breeds, village dogs, niche populations and extended pedigrees are currently being sequenced, and de novo assemblies of multiple canids are being constructed. This unprecedented dataset will address the genetic underpinnings of domestication, breed formation, aging, behavior and morphological variation. More generally, this effort will advance our understanding of human and canine health

Common ADRB2 Haplotypes Derived from 26 Polymorphic Sites Direct β2-Adrenergic Receptor Expression and Regulation Phenotypes

Background: The β2-adrenergic receptor (β2AR) is expressed on numerous cell-types including airway smooth muscle cells and cardiomyocytes. Drugs (agonists or antagonists) acting at these receptors for treatment of asthma, chronic obstructive pulmonary disease, and heart failure show substantial interindividual variability in response. The ADRB2 gene is polymorphic in noncoding and coding regions, but virtually all ADRB2 association studies have utilized the two common nonsynonymous coding SNPs, often reaching discrepant conclusions. Methodology/Principal Findings: We constructed the 8 common ADRB2 haplotypes derived from 26 polymorphisms in the promoter, 5′UTR, coding, and 3′UTR of the intronless ADRB2 gene. These were cloned into an expression construct lacking a vector-based promoter, so that β2AR expression was driven by its promoter, and steady state expression could be modified by polymorphisms throughout ADRB2 within a haplotype. “Whole-gene” transfections were performed with COS-7 cells and revealed 4 haplotypes with increased cell surface β2AR protein expression compared to the others. Agonist-promoted downregulation of β2AR protein expression was also haplotype-dependent, and was found to be increased for 2 haplotypes. A phylogenetic tree of the haplotypes was derived and annotated by cellular phenotypes, revealing a pattern potentially driven by expression. Conclusions/Significance: Thus for obstructive lung disease, the initial bronchodilator response from intermittent administration of β-agonist may be influenced by certain β2AR haplotypes (expression phenotypes), while other haplotypes may influence tachyphylaxis during the response to chronic therapy (downregulation phenotypes). An ideal clinical outcome of high expression and less downregulation was found for two haplotypes. Haplotypes may also affect heart failure antagonist therapy, where β2AR increase inotropy and are anti-apoptotic. The haplotype-specific expression and regulation phenotypes found in this transfection-based system suggest that the density of genetic information in the form of these haplotypes, or haplotype-clusters with similar phenotypes can potentially provide greater discrimination of phenotype in human disease and pharmacogenomic association studies

Benchmark Parameters for CMB Polarization Experiments

The recently detected polarization of the cosmic microwave background (CMB) holds the potential for revealing the physics of inflation and gravitationally mapping the large-scale structure of the universe, if so called B-mode signals below 10^{-7}, or tenths of a uK, can be reliably detected. We provide a language for describing systematic effects which distort the observed CMB temperature and polarization fields and so contaminate the B-modes. We identify 7 types of effects, described by 11 distortion fields, and show their association with known instrumental systematics such as common mode and differential gain fluctuations, line cross-coupling, pointing errors, and differential polarized beam effects. Because of aliasing from the small-scale structure in the CMB, even uncorrelated fluctuations in these effects can affect the large-scale B modes relevant to gravitational waves. Many of these problems are greatly reduced by having an instrumental beam that resolves the primary anisotropies (FWHM << 10'). To reach the ultimate goal of an inflationary energy scale of 3 \times 10^{15} GeV, polarization distortion fluctuations must be controlled at the 10^{-2}-10^{-3} level and temperature leakage to the 10^{-4}-10^{-3} level depending on effect. For example pointing errors must be controlled to 1.5'' rms for arcminute scale beams or a percent of the Gaussian beam width for larger beams; low spatial frequency differential gain fluctuations or line cross-coupling must be eliminated at the level of 10^{-4} rms.Comment: 11 pages, 5 figures, submitted to PR

An in vivo demonstration of efficacy and acute safety of burst wave lithotripsy using a porcine model

Burst wave lithotripsy (BWL) is a new non-invasive method for stone comminution using bursts of sub-megahertz ultrasound. A porcine model of urolithiasis and techniques to implement BWL treatment has been developed to evaluate its effectiveness and acute safety. Six human calcium oxalate monohydrate stones (6–7 mm) were hydrated, weighed, and surgically implanted into the kidneys of three pigs. Transcutaneous stone treatments were performed with a BWL transducer coupled to the skin via an external water bath. Stone targeting and treatment monitoring were performed with a co-aligned ultrasound imaging probe. Treatment exposures were applied in three 10-minute intervals for each stone. If sustained cavitation in the parenchyma was observed by ultrasound imaging feedback, treatment was paused and the pressure amplitude was decreased for the remaining time. Peak negative focal pressures between 6.5 and 7 MPa were applied for all treatments. After treatment, stone fragments were removed from the kidneys. At least 50% of each stone was reduced to <2 mm fragments. 100% of four stones were reduced to <4 mm fragments. Magnetic resonance imaging showed minimal injury to the functional renal volume. This study demonstrated that BWL could be used to effectively fragment kidney stones with minimal injury

Anionic Photofragmentation of CO: A Selective Probe of Core-Level Resonances

Anion-yield spectroscopy using x rays is shown to be a selective probe of molecular core-level processes, providing unique experimental verification of shape resonances. For CO, partial anion and cation yields are presented for photon energies near the C K edge. The O- yield exhibits features above threshold related only to doubly excited states, in contrast to cation yields which also exhibit pronounced structure due to the well-known σ* shape resonance. Because the shape resonance is completely suppressed for O-, anion spectroscopy thus constitutes a highly selective probe, yielding information unobtainable with absorption or electron spectroscopy

Gcg-XTEN: An Improved Glucagon Capable of Preventing Hypoglycemia without Increasing Baseline Blood Glucose

While the majority of current diabetes treatments focus on reducing blood glucose levels, hypoglycemia represents a significant risk associated with insulin treatment. Glucagon plays a major regulatory role in controlling hypoglycemia in vivo, but its short half-life and hyperglycemic effects prevent its therapeutic use for non-acute applications. The goal of this study was to identify a modified form of glucagon suitable for prophylactic treatment of hypoglycemia without increasing baseline blood glucose levels.Through application of the XTEN technology, we report the construction of a glucagon fusion protein with an extended exposure profile (Gcg-XTEN). The in vivo half-life of the construct was tuned to support nightly dosing through design and testing in cynomolgus monkeys. Efficacy of the construct was assessed in beagle dogs using an insulin challenge to induce hypoglycemia. Dose ranging of Gcg-XTEN in fasted beagle dogs demonstrated that the compound was biologically active with a pharmacodynamic profile consistent with the designed half-life. Prophylactic administration of 0.6 nmol/kg Gcg-XTEN to dogs conferred resistance to a hypoglycemic challenge at 6 hours post-dose without affecting baseline blood glucose levels. Consistent with the designed pharmacokinetic profile, hypoglycemia resistance was not observed at 12 hours post-dose. Importantly, the solubility and stability of the glucagon peptide were also significantly improved by fusion to XTEN.The data show that Gcg-XTEN is effective in preventing hypoglycemia without the associated hyperglycemia expected for unmodified glucagon. While the plasma clearance of this Gcg-XTEN has been optimized for overnight dosing, specifically for the treatment of nocturnal hypoglycemia, constructs with significantly longer exposure profiles are feasible. Such constructs may have multiple applications such as allowing for more aggressive insulin treatment regimens, treating hypoglycemia due to insulin-secreting tumors, providing synergistic efficacy in combination therapies with long-acting GLP1 analogs, and as an appetite suppressant for treatment of obesity. The improved physical properties of the Gcg-XTEN molecule may also allow for novel delivery systems not currently possible with native glucagon