Cosmic ray feedback in the FIRE simulations: constraining cosmic ray propagation with GeV gamma ray emission

We present the implementation and the first results of cosmic ray (CR) feedback in the Feedback In Realistic Environments (FIRE) simulations. We investigate CR feedback in non-cosmological simulations of dwarf, sub-$L\star$ starburst, and $L\star$ galaxies with different propagation models, including advection, isotropic and anisotropic diffusion, and streaming along field lines with different transport coefficients. We simulate CR diffusion and streaming simultaneously in galaxies with high resolution, using a two moment method. We forward-model and compare to observations of $\gamma$-ray emission from nearby and starburst galaxies. We reproduce the $\gamma$-ray observations of dwarf and $L\star$ galaxies with constant isotropic diffusion coefficient $\kappa \sim 3\times 10^{29}\,{\rm cm^{2}\,s^{-1}}$. Advection-only and streaming-only models produce order-of-magnitude too large $\gamma$-ray luminosities in dwarf and $L\star$ galaxies. We show that in models that match the $\gamma$-ray observations, most CRs escape low-gas-density galaxies (e.g.\ dwarfs) before significant collisional losses, while starburst galaxies are CR proton calorimeters. While adiabatic losses can be significant, they occur only after CRs escape galaxies, so they are only of secondary importance for $\gamma$-ray emissivities. Models where CRs are ``trapped'' in the star-forming disk have lower star formation efficiency, but these models are ruled out by $\gamma$-ray observations. For models with constant $\kappa$ that match the $\gamma$-ray observations, CRs form extended halos with scale heights of several kpc to several tens of kpc.Comment: 31 pages, 26 figures, accepted for publication in MNRA

The Origins of the Circumgalactic Medium in the FIRE Simulations

We use a particle tracking analysis to study the origins of the circumgalactic medium (CGM), separating it into (1) accretion from the intergalactic medium (IGM), (2) wind from the central galaxy, and (3) gas ejected from other galaxies. Our sample consists of 21 FIRE-2 simulations, spanning the halo mass range log(Mh/Msun) ~ 10-12 , and we focus on z=0.25 and z=2. Owing to strong stellar feedback, only ~L* halos retain a baryon mass >~50% of their cosmic budget. Metals are more efficiently retained by halos, with a retention fraction >~50%. Across all masses and redshifts analyzed >~60% of the CGM mass originates as IGM accretion (some of which is associated with infalling halos). Overall, the second most important contribution is wind from the central galaxy, though gas ejected or stripped from satellites can contribute a comparable mass in ~L* halos. Gas can persist in the CGM for billions of years, resulting in well-mixed halo gas. Sight lines through the CGM are therefore likely to intersect gas of multiple origins. For low-redshift ~L* halos, cool gas (T<10^4.7 K) is distributed on average preferentially along the galaxy plane, however with strong halo-to-halo variability. The metallicity of IGM accretion is systematically lower than the metallicity of winds (typically by >~1 dex), although CGM and IGM metallicities depend significantly on the treatment of subgrid metal diffusion. Our results highlight the multiple physical mechanisms that contribute to the CGM and will inform observational efforts to develop a cohesive picture.Comment: 23 pages, 22 figures. Minor revisions from previous version. Online interactive visualizations available at zhafen.github.io/CGM-origins and zhafen.github.io/CGM-origins-pathline

An Eccentric Binary Millisecond Pulsar in the Galactic Plane

Binary pulsar systems are superb probes of stellar and binary evolution and the physics of extreme environments. In a survey with the Arecibo telescope, we have found PSR J1903+0327, a radio pulsar with a rotational period of 2.15 ms in a highly eccentric (e = 0.44) 95-day orbit around a solar mass companion. Infrared observations identify a possible main-sequence companion star. Conventional binary stellar evolution models predict neither large orbital eccentricities nor main-sequence companions around millisecond pulsars. Alternative formation scenarios involve recycling a neutron star in a globular cluster then ejecting it into the Galactic disk or membership in a hierarchical triple system. A relativistic analysis of timing observations of the pulsar finds its mass to be 1.74+/-0.04 Msun, an unusually high value.Comment: 28 pages, 4 figures inc Supplementary On-Line Material. Accepted for publication in Science, published on Science Express: 10.1126/science.115758

Birth and Evolution of Isolated Radio Pulsars

We investigate the birth and evolution of Galactic isolated radio pulsars. We begin by estimating their birth space velocity distribution from proper motion measurements of Brisken et al. (2002, 2003). We find no evidence for multimodality of the distribution and favor one in which the absolute one-dimensional velocity components are exponentially distributed and with a three-dimensional mean velocity of 380^{+40}_{-60} km s^-1. We then proceed with a Monte Carlo-based population synthesis, modelling the birth properties of the pulsars, their time evolution, and their detection in the Parkes and Swinburne Multibeam surveys. We present a population model that appears generally consistent with the observations. Our results suggest that pulsars are born in the spiral arms, with a Galactocentric radial distribution that is well described by the functional form proposed by Yusifov & Kucuk (2004), in which the pulsar surface density peaks at radius ~3 kpc. The birth spin period distribution extends to several hundred milliseconds, with no evidence of multimodality. Models which assume the radio luminosities of pulsars to be independent of the spin periods and period derivatives are inadequate, as they lead to the detection of too many old simulated pulsars in our simulations. Dithered radio luminosities proportional to the square root of the spin-down luminosity accommodate the observations well and provide a natural mechanism for the pulsars to dim uniformly as they approach the death line, avoiding an observed pile-up on the latter. There is no evidence for significant torque decay (due to magnetic field decay or otherwise) over the lifetime of the pulsars as radio sources (~100 Myr). Finally, we estimate the pulsar birthrate and total number of pulsars in the Galaxy.Comment: 27 pages, including 15 figures, accepted by Ap

High throughput mutagenesis for identification of residues regulating human prostacyclin (hIP) receptor

The human prostacyclin receptor (hIP receptor) is a seven-transmembrane G protein-coupled receptor (GPCR) that plays a critical role in vascular smooth muscle relaxation and platelet aggregation. hIP receptor dysfunction has been implicated in numerous cardiovascular abnormalities, including myocardial infarction, hypertension, thrombosis and atherosclerosis. Genomic sequencing has discovered several genetic variations in the PTGIR gene coding for hIP receptor, however, its structure-function relationship has not been sufficiently explored. Here we set out to investigate the applicability of high throughput random mutagenesis to study the structure-function relationship of hIP receptor. While chemical mutagenesis was not suitable to generate a mutagenesis library with sufficient coverage, our data demonstrate error-prone PCR (epPCR) mediated mutagenesis as a valuable method for the unbiased screening of residues regulating hIP receptor function and expression. Here we describe the generation and functional characterization of an epPCR derived mutagenesis library compromising >4000 mutants of the hIP receptor. We introduce next generation sequencing as a useful tool to validate the quality of mutagenesis libraries by providing information about the coverage, mutation rate and mutational bias. We identified 18 mutants of the hIP receptor that were expressed at the cell surface, but demonstrated impaired receptor function. A total of 38 non-synonymous mutations were identified within the coding region of the hIP receptor, mapping to 36 distinct residues, including several mutations previously reported to affect the signaling of the hIP receptor. Thus, our data demonstrates epPCR mediated random mutagenesis as a valuable and practical method to study the structurefunction relationship of GPCRs. © 2014 Bill et al

M2K: II. A Triple-Planet System Orbiting HIP 57274

Doppler observations from Keck Observatory have revealed a triple planet system orbiting the nearby mid-type K dwarf, HIP 57274. The inner planet, HIP 57274b, is a super-Earth with \msini\ = 11.6 \mearth (0.036 \mjup), an orbital period of 8.135 $\pm$ 0.004 d, and slightly eccentric orbit $e=0.19 \pm 0.1$. We calculate a transit probability of 6.5% for the inner planet. The second planet has \msini\ = 0.4 \mjup\ with an orbital period of 32.0 $\pm 0.02$ d in a nearly circular orbit, and $e = 0.05 \pm 0.03$. The third planet has \msini\ = 0.53 \mjup\ with an orbital period of 432 $\pm 8$ d (1.18 years) and an eccentricity $e = 0.23 \pm 0.03$. This discovery adds to the number of super Earth mass planets with \msini < 12 \mearth\ that have been detected with Doppler surveys. We find that 56 $\pm 18$% super-Earths are members of multi-planet systems. This is certainly a lower limit because of observational detectability limits, yet significantly higher than the fraction of Jupiter mass exoplanets, $20 \pm 8$%, that are members of Doppler-detected, multi-planet systems.Comment: 11 figures, submitte to ApJ on Sept 10, 201

Transitions between Inherent Structures in Water

The energy landscape approach has been useful to help understand the dynamic properties of supercooled liquids and the connection between these properties and thermodynamics. The analysis in numerical models of the inherent structure (IS) trajectories -- the set of local minima visited by the liquid -- offers the possibility of filtering out the vibrational component of the motion of the system on the potential energy surface and thereby resolving the slow structural component more efficiently. Here we report an analysis of an IS trajectory for a widely-studied water model, focusing on the changes in hydrogen bond connectivity that give rise to many IS separated by relatively small energy barriers. We find that while the system \emph{travels} through these IS, the structure of the bond network continuously modifies, exchanging linear bonds for bifurcated bonds and usually reversing the exchange to return to nearly the same initial configuration. For the 216 molecule system we investigate, the time scale of these transitions is as small as the simulation time scale ($\approx 1$ fs). Hence for water, the transitions between each of these IS is relatively small and eventual relaxation of the system occurs only by many of these transitions. We find that during IS changes, the molecules with the greatest displacements move in small ``clusters'' of 1-10 molecules with displacements of $\approx 0.02-0.2$ nm, not unlike simpler liquids. However, for water these clusters appear to be somewhat more branched than the linear ``string-like'' clusters formed in a supercooled Lennar d-Jones system found by Glotzer and her collaborators.Comment: accepted in PR

MiR-137 Targets Estrogen-Related Receptor Alpha and Impairs the Proliferative and Migratory Capacity of Breast Cancer Cells

ERRα is an orphan nuclear receptor emerging as a novel biomarker of breast cancer. Over-expression of ERRα in breast tumor is considered as a prognostic factor of poor clinical outcome. The mechanisms underlying the dysexpression of this nuclear receptor, however, are poorly understood. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level and play important roles in tumor initiation and progression. In the present study, we have identified that the expression of ERRα is regulated by miR-137, a potential tumor suppressor microRNA. The bioinformatics search revealed two putative and highly conserved target-sites for miR-137 located within the ERRα 3′UTR at nt 480–486 and nt 596–602 respectively. Luciferase-reporter assay demonstrated that the two predicted target sites were authentically functional. They mediated the repression of reporter gene expression induced by miR-137 in an additive manner. Moreover, ectopic expression of miR-137 down-regulated ERRα expression at both protein level and mRNA level, and the miR-137 induced ERRα-knockdown contributed to the impaired proliferative and migratory capacity of breast cancer cells. Furthermore, transfection with miR-137mimics suppressed at least two downstream target genes of ERRα–CCNE1 and WNT11, which are important effectors of ERRα implicated in tumor proliferation and migration. Taken together, our results establish a role of miR-137 in negatively regulating ERRα expression and breast cancer cell proliferation and migration. They suggest that manipulating the expression level of ERRα by microRNAs has the potential to influence breast cancer progression

Statins Disrupt CCR5 and RANTES Expression Levels in CD4(+) T Lymphocytes In Vitro and Preferentially Decrease Infection of R5 Versus X4 HIV-1

BACKGROUND: Statins have previously been shown to reduce the in vitro infection of human immunodeficiency virus type 1 (HIV-1) through modulation of Rho GTPase activity and lipid raft formation at the cell surface, as well as by disrupting LFA-1 incorporation into viral particles. PRINCIPLE FINDINGS: Here we demonstrate that treatment of an enriched CD4(+) lymphocyte population with lovastatin (Lov), mevastatin (Mev) and simvastatin (activated and non-activated, Sim(A) and Sim(N), respectively) can reduce the cell surface expression of the CC-chemokine receptor CCR5 (P<0.01 for Sim(A) and Lov). The lowered CCR5 expression was associated with down-regulation of CCR5 mRNA expression. The CC-chemokine RANTES protein and mRNA expression levels were slightly increased in CD4(+) enriched lymphocytes treated with statins. Both R5 and X4 HIV-1 were reduced for their infection of statin-treated cells; however, in cultures where statins were removed and where a decrease in CCR5 expression was observed, there was a preferential inhibition of infection with an R5 versus X4 virus. CONCLUSIONS: The results indicate that the modulation of CC-chemokine receptor (CCR5) and CC-chemokine (RANTES) expression levels should be considered as contributing to the anti-viral effects of statins, preferentially inhibiting R5 viruses. This observation, in combination with the immunomodulatory activity exerted by statins, suggests they may possess more potent anti-HIV-1 activity when applied during the early stages of infection or in lowering viral transmission. Alternatively, statin treatment could be considered as a way to modulate immune induction such as during vaccination protocols

What Works in Implementing Patient Decision Aids in Routine Clinical Settings? A Rapid Realist Review and Update from the International Patient Decision Aid Standards Collaboration

Background Decades of effectiveness research has established the benefits of using patient decision aids (PtDAs), yet broad clinical implementation has not yet occurred. Evidence to date is mainly derived from highly controlled settings; if clinicians and health care organizations are expected to embed PtDAs as a means to support person-centered care, we need to better understand what this might look like outside of a research setting. Aim This review was conducted in response to the IPDAS Collaboration’s evidence update process, which informs their published standards for PtDA quality and effectiveness. The aim was to develop context-specific program theories that explain why and how PtDAs are successfully implemented in routine healthcare settings. Methods Rapid realist review methodology was used to identify articles that could contribute to theory development. We engaged key experts and stakeholders to identify key sources; this was supplemented by electronic database (Medline and CINAHL), gray literature, and forward/backward search strategies. Initial theories were refined to develop realist context-mechanism-outcome configurations, and these were mapped to the Consolidated Framework for Implementation Research. Results We developed 8 refined theories, using data from 23 implementation studies (29 articles), to describe the mechanisms by which PtDAs become successfully implemented into routine clinical settings. Recommended implementation strategies derived from the program theory include 1) co-production of PtDA content and processes (or local adaptation), 2) training the entire team, 3) preparing and prompting patients to engage, 4) senior-level buy-in, and 5) measuring to improve. Conclusions We recommend key strategies that organizations and individuals intending to embed PtDAs routinely can use as a practical guide. Further work is needed to understand the importance of context in the success of different implementation studies.Additional co-authors: Karina Dahl Steffensen, Christine Stirling, Trudy van der Weijdenon, International Patient Decision Aids (IPDAS) Collaboratio