An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for multiple disorders, but deficiency and dysregulation of T cells limit its utility. Here we report a biomaterial-based scaffold that mimics features of T cell lymphopoiesis in the bone marrow. The bone marrow cryogel (BMC) releases bone morphogenetic protein-2 to recruit stromal cells and presents the Notch ligand Delta-like ligand-4 to facilitate T cell lineage specification of mouse and human hematopoietic progenitor cells. BMCs subcutaneously injected in mice at the time of HSCT enhanced T cell progenitor seeding of the thymus, T cell neogenesis and diversification of the T cell receptor repertoire. Peripheral T cell reconstitution increased ~6-fold in mouse HSCT and ~2-fold in human xenogeneic HSCT. Furthermore, BMCs promoted donor CD4+ regulatory T cell generation and improved survival after allogeneic HSCT. In comparison to adoptive transfer of T cell progenitors, BMCs increased donor chimerism, T cell generation and antigen-specific T cell responses to vaccination. BMCs may provide an off-the-shelf approach for enhancing T cell regeneration and mitigating graft-versus-host disease in HSCT

Very Extended X-ray and H-alpha Emission in M82: Implications for the Superwind Phenomenon

We discuss the properties and implications of a 3.7x0.9 kpc region of spatially-coincident X-ray and H-alpha emission about 11.6 kpc to the north of the galaxy M82 previously discussed by Devine and Bally (1999). The PSPC X-ray spectrum is fit by thermal plasma (kT=0.80+-0.17 keV) absorbed by only the Galactic foreground column density. We evaluate the relationship of the X-ray/H-alpha ridge to the M82 superwind. The main properties of the X-ray emission can all be explained as being due to shock-heating driven as the superwind encounters a massive ionized cloud in the halo of M82. This encounter drives a slow shock into the cloud, which contributes to the excitation of the observed H-alpha emission. At the same time, a fast bow-shock develops in the superwind just upstream of the cloud, and this produces the observed X-ray emission. This interpretation would imply that the superwind has an outflow speed of roughly 800 km/s, consistent with indirect estimates based on its general X-ray properties and the kinematics of the inner kpc-scale region of H-alpha filaments. The gas in the M82 ridge is roughly two orders-of-magnitude hotter than the minimum "escape temperature" at this radius, so this gas will not be retained by M82. (abridged)Comment: 24 pages (latex), 3 figures (2 gif files and one postscript), accepted for publication in Part 1 of The Astrophysical Journa

Hubble Space Telescope Observations of Comet 9P/Tempel 1 during the Deep Impact Encounter

We report on the Hubble Space Telescope program to observe periodic comet 9P/Tempel 1 in conjunction with NASA's Deep Impact mission. Our objectives were to study the generation and evolution of the coma resulting from the impact and to obtain wide-band images of the visual outburst generated by the impact. Two observing campaigns utilizing a total of 17 HST orbits were carried out: the first occurred on 2005 June 13-14 and fortuitously recorded the appearance of a new, short-lived fan in the sunward direction on June 14. The principal campaign began two days before impact and was followed by contiguous orbits through impact plus several hours and then snapshots one, seven, and twelve days later. All of the observations were made using the Advanced Camera for Surveys (ACS). For imaging, the ACS High Resolution Channel (HRC) provides a spatial resolution of 36 km (16 km/pixel) at the comet at the time of impact. Baseline images of the comet, made prior to impact, photometrically resolved the comet's nucleus. The derived diameter, 6.1 km, is in excellent agreement with the 6.0 +/- 0.2 km diameter derived from the spacecraft imagers. Following the impact, the HRC images illustrate the temporal and spatial evolution of the ejecta cloud and allow for a determination of its expansion velocity distribution. One day after impact the ejecta cloud had passed out of the field-of-view of the HRC.Comment: 15 pages, 14 postscript figures. Accepted for publication in Icarus special issue on Deep Impac

Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1

During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.This work was supported by an Australian NHMRC Overseas Biomedical Postdoctoral Fellowship (to I.A. Parish); a Yale School of Medicine Brown-Coxe Postdoctoral Fellowship (to I.A. Parish); the Alexander von Humboldt Foundation (SKA2010, to P.A. Lang); a CIHR grant (to P.S. Ohashi); and by the Howard Hughes Medical Institute and NIH grant RO1AI074699 (to S.M. Kaech). P.S. Ohashi holds a Canada Research Chair in Autoimmunity and Tumor immunity

Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis.

BACKGROUND: Mobile elements are active in the human genome, both in the germline and cancers, where they can mutate driver genes. RESULTS: While analysing whole genome paired-end sequencing of oesophageal adenocarcinomas to find genomic rearrangements, we identified three ways in which new mobile element insertions appear in the data, resembling translocation or insertion junctions: inserts where unique sequence has been transduced by an L1 (Long interspersed element 1) mobile element; novel inserts that are confidently, but often incorrectly, mapped by alignment software to L1s or polyA tracts in the reference sequence; and a combination of these two ways, where different sequences within one insert are mapped to different loci. We identified nine unique sequences that were transduced by neighbouring L1s, both L1s in the reference genome and L1s not present in the reference. Many of the resulting inserts were small fragments that include little or no recognisable mobile element sequence. We found 6 loci in the reference genome to which sequence reads from inserts were frequently mapped, probably erroneously, by alignment software: these were either L1 sequence or particularly long polyA runs. Inserts identified from such apparent rearrangement junctions averaged 16 inserts/tumour, range 0-153 insertions in 43 tumours. However, many inserts would not be detected by mapping the sequences to the reference genome, because they do not include sufficient mappable sequence. To estimate total somatic inserts we searched for polyA sequences that were not present in the matched normal or other normals from the same tumour batch, and were not associated with known polymorphisms. Samples of these candidate inserts were verified by sequencing across them or manual inspection of surrounding reads: at least 85 % were somatic and resembled L1-mediated events, most including L1Hs sequence. Approximately 100 such inserts were detected per tumour on average (range zero to approximately 700). CONCLUSIONS: Somatic mobile elements insertions are abundant in these tumours, with over 75 % of cases having a number of novel inserts detected. The inserts create a variety of problems for the interpretation of paired-end sequencing data.Funding was primarily from Cancer Research UK program grants to RCF and ST (C14478/A15874 and C14303/A17197), with additional support awarded to RCF from UK Medical Research Council, NHS National Institute for Health Research (NIHR), the Experimental Cancer Medicine Centre Network and the NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Project grant C1023/A14545 to PAWE. JMJW was funded by a Wellcome Trust Translational Medicine and Therapeutics grant

Dwarf koa (Desmanthus virgatus)

This is the final version. It was first published by BioMed Central at http://www.biomedcentral.com/1471-2164/16/473.Background: Mobile elements are active in the human genome, both in the germline and cancers, where they can\ud mutate driver genes.\ud Results: While analysing whole genome paired-end sequencing of oesophageal adenocarcinomas to find genomic\ud rearrangements, we identified three ways in which new mobile element insertions appear in the data, resembling\ud translocation or insertion junctions: inserts where unique sequence has been transduced by an L1 (Long interspersed\ud element 1) mobile element; novel inserts that are confidently, but often incorrectly, mapped by alignment software to\ud L1s or polyA tracts in the reference sequence; and a combination of these two ways, where different sequences within\ud one insert are mapped to different loci. We identified nine unique sequences that were transduced by neighbouring\ud L1s, both L1s in the reference genome and L1s not present in the reference. Many of the resulting inserts were small\ud fragments that include little or no recognisable mobile element sequence. We found 6 loci in the reference genome to\ud which sequence reads from inserts were frequently mapped, probably erroneously, by alignment software: these were\ud either L1 sequence or particularly long polyA runs. Inserts identified from such apparent rearrangement junctions\ud averaged 16 inserts/tumour, range 0?153 insertions in 43 tumours. However, many inserts would not be detected by\ud mapping the sequences to the reference genome, because they do not include sufficient mappable sequence. To\ud estimate total somatic inserts we searched for polyA sequences that were not present in the matched normal or other\ud normals from the same tumour batch, and were not associated with known polymorphisms. Samples of these candidate\ud inserts were verified by sequencing across them or manual inspection of surrounding reads: at least 85 % were somatic\ud and resembled L1-mediated events, most including L1Hs sequence. Approximately 100 such inserts were detected per\ud tumour on average (range zero to approximately 700).\ud Conclusions: Somatic mobile elements insertions are abundant in these tumours, with over 75 % of cases having a\ud number of novel inserts detected. The inserts create a variety of problems for the interpretation of paired-end\ud sequencing data.Funding\ud was primarily from Cancer Research UK program grants to RCF and ST\ud (C14478/A15874 and C14303/A17197), with additional support awarded to\ud RCF from UK Medical Research Council, NHS National Institute for Health\ud Research (NIHR), the Experimental Cancer Medicine Centre Network and\ud the NIHR Cambridge Biomedical Research Centre, and Cancer Research UK\ud Project grant C1023/A14545 to PAWE. JMJW was funded by a Wellcome\ud Trust Translational Medicine and Therapeutics grant

ASCA Observations of the Starburst-Driven Superwind Galaxy NGC 2146: Broad Band (0.6 - 9 keV) Spectral Properties

We report ASCA GIS and SIS observations of the nearby (D = 11.6 Mpc), nearly edge-on, starburst galaxy NGC 2146. These X-ray spectral data complement ROSAT PSPC and HRI imaging discussed by Armus et al., 1995. The broad band (0.6-9 keV) X-ray spectrum of NGC 2146 is best described by a two component model: the soft X-ray emission with a Raymond-Smith thermal plasma model having a temperature of kT $\sim 0.8$ keV; the hard X-ray emission with a thermal plasma model having kT $\sim 8$ keV or a power-law model having a photon index of $\sim 1.7$. We do not find compelling evidence of substantial excess absorption above the Galactic value. The soft (hard) thermal component provides about 30% (70%) of the total luminosity in the 0.5 - 2.0 keV energy band, while in the 2-10 keV energy range only the hard component plays a major role. The spectral results allow us to set tighter constraints on the starburst-driven superwind model, which we show can satisfactorily account for the luminosity, mass, and energy content represented by the soft X-ray spectral component. We estimate that the mass outflow rate ($\sim$ 9 M$_{\odot}$ per year) is about an order of magnitude greater than the predicted rate at which supernovae and stellar winds return mass into the interstellar medium and, therefore, argue that the flow is strongly "mass-loaded" with material in and around the starburst. The estimated outflow velocity of the hot gas is close to the escape velocity from the galaxy, so the fate of the gas is not clear. We suggest that the hard X-ray spectral component is due to the combined emission of X-ray binaries and/or young supernovae remnants associated with the starburst.Comment: 26 pages plus 4 figures, LaTex manuscript, Accepted for publication in the Astrophysical Journa

3D printed fluidics with embedded analytic functionality for automated reaction optimisation

Additive manufacturing or ‘3D printing’ is being developed as a novel manufacturing process for the production of bespoke micro- and milliscale fluidic devices. When coupled with online monitoring and optimisation software, this offers an advanced, customised method for performing automated chemical synthesis. This paper reports the use of two additive manufacturing processes, stereolithography and selective laser melting, to create multifunctional fluidic devices with embedded reaction monitoring capability. The selectively laser melted parts are the first published examples of multifunctional 3D printed metal fluidic devices. These devices allow high temperature and pressure chemistry to be performed in solvent systems destructive to the majority of devices manufactured via stereolithography, polymer jetting and fused deposition modelling processes previously utilised for this application. These devices were integrated with commercially available flow chemistry, chromatographic and spectroscopic analysis equipment, allowing automated online and inline optimisation of the reaction medium. This set-up allowed the optimisation of two reactions, a ketone functional group interconversion and a fused polycyclic heterocycle formation, via spectroscopic and chromatographic analysis

The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey: single-probe measurements from CMASS anisotropic galaxy clustering

With the largest spectroscopic galaxy survey volume drawn from the SDSS-III Baryon Oscillation Spectroscopic Survey (BOSS), we can extract cosmological constraints from the measurements of redshift and geometric distortions at quasi-linear scales (e.g. above 50 $h^{-1}$Mpc). We analyze the broad-range shape of the monopole and quadrupole correlation functions of the BOSS Data Release 12 (DR12) CMASS galaxy sample, at the effective redshift $z=0.59$, to obtain constraints on the Hubble expansion rate $H(z)$, the angular-diameter distance $D_A(z)$, the normalized growth rate $f(z)\sigma_8(z)$, and the physical matter density $\Omega_mh^2$. We obtain robust measurements by including a polynomial as the model for the systematic errors, and find it works very well against the systematic effects, e.g., ones induced by stars and seeing. We provide accurate measurements $\{D_A(0.59)r_{s,fid}/r_s$ $\rm Mpc$, $H(0.59)r_s/r_{s,fid}$ $km s^{-1} Mpc^{-1}$, $f(0.59)\sigma_8(0.59)$, $\Omega_m h^2\}$ = $\{1427\pm26$, $97.3\pm3.3$, $0.488 \pm 0.060$, $0.135\pm0.016\}$, where $r_s$ is the comoving sound horizon at the drag epoch and $r_{s,fid}=147.66$ Mpc is the sound scale of the fiducial cosmology used in this study. The parameters which are not well constrained by our galaxy clustering analysis are marginalized over with wide flat priors. Since no priors from other data sets, e.g., cosmic microwave background (CMB), are adopted and no dark energy models are assumed, our results from BOSS CMASS galaxy clustering alone may be combined with other data sets, i.e., CMB, SNe, lensing or other galaxy clustering data to constrain the parameters of a given cosmological model. The uncertainty on the dark energy equation of state parameter, $w$, from CMB+CMASS is about 8 per cent. The uncertainty on the curvature fraction, $\Omega_k$, is 0.3 per cent. We do not find deviation from flat $\Lambda$CDM.Comment: 15 pages, 11 figures. The latest version matches and the accepted version by MNRAS. A bug in the first version has been identified and fixed in the new version. We have redone the analysis with newest data (BOSS DR12

Fatigue, shift work characteristics, and occupational injury and illness in emergency medical services

The relationship between work scheduling, fatigue, and risk of injury and illness among Emergency Medical Services (EMS) workers is not well understood. Evidence in other settings suggests that work duration contributes to fatigue and increases the risk of accidents and occupational injuries. Rates of occupational injury are high. Extended shifts and overtime hours are common. Workers often report fatigue and poor sleep quality. Evidence is needed to inform policy-making and promote safety. Shift schedules and occupational injury and illness reports were obtained for 14 EMS agencies over a three-year period. The cohort contained 966,082 shifts, 4,382 employees, and 950 total injuries. Analyses examined the association between shift length, weekly work hours, crewmember familiarity, and occupational injury and illness. An increased risk of occupational injury and illness was hypothesized for individual shifts >8 hours and ≥48 weekly work hours. The proposed mechanism for increased risk was on-shift fatigue. A systematic literature review was performed to better understand differences in prior estimates of fatigue in EMS by methodologic approach. Risk of occupational injury and illness was increased for shifts >8 & ≤12 hours (RR 1.43; 95% CI 1.04-1.97), shifts >12 & ≤16 hours (RR 1.82; 95% CI 1.17-2.82), and shifts >16 and ≤24 hours (RR 2.29; 95% CI 1.52-3.46), compared to shifts ≤8 hours in duration. There was no increase in risk of occupational illness or injury with increasing weekly work hours. Crewmember familiarity was not associated with the outcome. Nightshift work was protective. Shift length is associated with occupational injury and illness in this cohort. As shift length increases, the risk of workplace injury and illness increases. These findings are based on observational data and are not generalizable to all EMS agencies. Evidence should be used to justify comprehensive prospective study. These projects are significant to public health. Calls for research were addressed from the National Occupational Research Agenda and the National EMS Advisory Council, government bodies who identified gaps in the knowledge of these issues. These data may serve as a foundation for future studies to inform decision-making at EMS agencies nationally and protect the health of the EMS workforce