Particle mesh simulations of the Lyman-alpha forest and the signature of Baryon Acoustic Oscillations in the intergalactic medium

We present a set of ultra-large particle-mesh simulations of the LyA forest targeted at understanding the imprint of baryon acoustic oscillations (BAO) in the inter-galactic medium. We use 9 dark matter only simulations which can, for the first time, simultaneously resolve the Jeans scale of the intergalactic gas while covering the large volumes required to adequately sample the acoustic feature. Mock absorption spectra are generated using the fluctuating Gunn-Peterson approximation which have approximately correct flux probability density functions (PDFs) and small-scale power spectra. On larger scales there is clear evidence in the redshift space correlation function for an acoustic feature, which matches a linear theory template with constant bias. These spectra, which we make publicly available, can be used to test pipelines, plan future experiments and model various physical effects. As an illustration we discuss the basic properties of the acoustic signal in the forest, the scaling of errors with noise and source number density, modified statistics to treat mean flux evolution and misestimation, and non-gravitational sources such as fluctuations in the photo-ionizing background and temperature fluctuations due to HeII reionization.Comment: 11 pages, 10 figures, minor changes to address referee repor

DUSTiNGS III: Distribution of Intermediate-Age and Old Stellar Populations in Disks and Outer Extremities of Dwarf Galaxies

We have traced the spatial distributions of intermediate-age and old stars in nine dwarf galaxies in the distant parts of the Local Group, using multi-epoch 3.6 and 4.5 micron data from the DUST in Nearby Galaxies with Spitzer (DUSTiNGS) survey. Using complementary optical imaging from the Hubble Space Telescope, we identify the tip of the red giant branch (TRGB) in the 3.6 micron photometry, separating thermally-pulsating asymptotic giant branch (TP-AGB) stars from the larger red giant branch (RGB) populations. Unlike the constant TRGB in the I-band, at 3.6 micron the TRGB magnitude varies by ~0.7 mag, making it unreliable as a distance indicator. The intermediate-age and old stars are well mixed in two-thirds of the sample with no evidence of a gradient in the ratio of the intermediate-age to old stellar populations outside the central ~1-2'. Variable AGB stars are detected in the outer extremities of the galaxies, indicating that chemical enrichment from these dust-producing stars may occur in the outer regions of galaxies with some frequency. Theories of structure formation in dwarf galaxies must account for the lack of radial gradients in intermediate-age populations and the presence of these stars in the outer extremities of dwarfs. Finally, we identify unique features in individual galaxies, such as extended tidal features in Sex A and Sag DIG and a central concentration of AGB stars in the inner regions of NGC 185 and NGC 147.Comment: 27 pages, 21 figures, 6 table

PAPER-64 Constraints On Reionization II: The Temperature Of The z=8.4 Intergalactic Medium

We present constraints on both the kinetic temperature of the intergalactic medium (IGM) at z=8.4, and on models for heating the IGM at high-redshift with X-ray emission from the first collapsed objects. These constraints are derived using a semi-analytic method to explore the new measurements of the 21 cm power spectrum from the Donald C. Backer Precision Array for Probing the Epoch of Reionization (PAPER), which were presented in a companion paper, Ali et al. (2015). Twenty-one cm power spectra with amplitudes of hundreds of mK^2 can be generically produced if the kinetic temperature of the IGM is significantly below the temperature of the Cosmic Microwave Background (CMB); as such, the new results from PAPER place lower limits on the IGM temperature at z=8.4. Allowing for the unknown ionization state of the IGM, our measurements find the IGM temperature to be above ~5 K for neutral fractions between 10% and 85%, above ~7 K for neutral fractions between 15% and 80%, or above ~10 K for neutral fractions between 30% and 70%. We also calculate the heating of the IGM that would be provided by the observed high redshift galaxy population, and find that for most models, these galaxies are sufficient to bring the IGM temperature above our lower limits. However, there are significant ranges of parameter space that could produce a signal ruled out by the PAPER measurements; models with a steep drop-off in the star formation rate density at high redshifts or with relatively low values for the X-ray to star formation rate efficiency of high redshift galaxies are generally disfavored. The PAPER measurements are consistent with (but do not constrain) a hydrogen spin temperature above the CMB temperature, a situation which we find to be generally predicted if galaxies fainter than the current detection limits of optical/NIR surveys are included in calculations of X-ray heating.Comment: companion paper to Ali et al. (2015), ApJ 809, 61; matches version accepted to ApJ; 11 pages, 7 figure

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Synthesis and function of apocarotenoid signals in plants

In plants, carotenoids are essential for photosynthesis and photoprotection. However, carotenoids are not the end products of the pathway; apocarotenoids are produced by carotenoid cleavage dioxygenases (CCDs) or non-enzymatic processes. Apocarotenoids are more soluble or volatile than carotenoids but they are not simply breakdown products, as there can be modifications postcleavage and their functions include hormones, volatiles, and signals. Evidence is emerging for a class of apocarotenoids, here referred to as apocarotenoid signals (ACSs), that have regulatory roles throughout plant development beyond those ascribed to abscisic acid (ABA) and strigolactone (SL). In this context we review studies of carotenoid feedback regulation, chloroplast biogenesis, stress signaling, and leaf and root development providing evidence that apocarotenoids may fine-tune plant development and responses to environmental stimuli

Flecainide acetate for resistant arrhythmias in the young: Efficacy and pharmacokinetics

AbstractDrug efficacy and pharmacokinetics were assessed in 63 patients, aged 5 days to 30 years (mean 8 years), who received flecainide acetate for control of resistant arrhythmias. Doses of flecainide ranged from 59 to 225 mg/m2 body surface area per day (mean 141) in divided doses every 8 to 12 h and serum trough levels ranged from 0.10 to 0.99 μg/ml (mean 0.36).Flecainide controlled or partially controlled arrhythmia in 53 (84%) of the 63 patients: 7 of 7 patients who had the permanent form of junctional reciprocating tachycardia, 12 of 13 who had an atrial ectopic tachycardia, 10 of 10 who had ventricular tachycardia and 18 of 25 patients who had reentrant supraventricular tachycardia. Five of seven patients who had the latter arrhythmia were unsuccessfully treated with flecainide. They had Wolfl-Parkinson-White syndrome and developed asymptomatic, incessant, slower orthodromic reciprocating tachycardia while receiving the drug. Transient blurred vision was reported in three patients and two patients had transient hyperactivity. No significant hemodynamic side effects were seen in any patient.Twenty-five patients underwent oral pharmacokinetic investigation. Young infants (<1 year of age) had a mean plasma elimination half-life (11/2) approximating that (11 to 12 h) found in older children and healthy adults; children aged I to 12 years had a shorter mean t 1/2 of 8 h. Dosing schedules based on milligrams per square meter body surface area correlated better with plasma flecainide levels than did dosing based on milligrams per kilogram body weight.In conclusion, 1) flecainide was effective pediatric therapy for permanent junctional reciprocating tachycardia, atrial ectopic and chaotic atrial tachycardia, ventricular tachycardia and, in most patients, reentrant supraventricular tachycardia; 2) some patients with WolffParkinson-White syndrome developed asymptomatic incessant slow supraventricular tachycardia while receiving flecainide; 3) flecainide resulted in rare side effects and no negative hemodynamic effects in any patient; 4) despite a shorter elimination half-life, every 12 h dosing schedule (with lower flecainide trough levels than usually seen in adults) provided adequate arrhythmia control in 80% of young patients aged 1 to 12 years; and 5) further study of oral flecainide pharmacokinetics is needed for patients < 1 year of age

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Deconvoluting apocarotenoid-mediated retrograde signaling networks regulating plastid translation and leaf development

Signals originating within plastids modulate organelle differentiation by transcriptionally regulating nuclear-encoded genes. These retrograde signals are also integral regulators of plant development, including leaf morphology. The clb5 mutant displays severe leaf morphology defects due to Apocarotenoid Signal 1 (ACS1) accumulation in the developmentally arrested plastid. Transcriptomic analysis of clb5 validates that ACS1 accumulation deregulates hundreds of nuclear genes, including the suppression of most genes encoding plastid ribosomal proteins. Herein, we order the molecular events causing the leaf phenotype associated with the accumulation of ACS1, which includes two consecutive retrograde signaling cascades. Firstly, ACS1 originating in the plastid drives inhibition of plastid translation (IPT) via nuclear transcriptome remodeling of chlororibosomal proteins, requiring light as an essential component. Subsequently, IPT results in leaf morphological defects via a GUN1-dependent pathway shared with seedlings undergoing chemical IPT treatments and is restricted to an early window of the leaf development. Collectively, this work advances our understanding of the complexity within plastid retrograde signaling exemplified by sequential signal exchange and consequences that in a particular temporal and spatial context contribute to the modulation of leaf development