HOST PATHOGEN INTERACTIONS IN THE CYSTIC FIBROSIS AIRWAY: PSEUDOMONAS AERUGINOSA IMPAIRS THE RESOLUTION OF PULMONARY INFLAMMATION BY MANIPULATING HOST LIPID SIGNALING

Pseudomonas aeruginosa is a clinically important, opportunistic bacterial pathogen that can cause a wide range of severe infections. The bacterium is inherently resistant to many antibiotics and chronic infections are very difficult to treat. Patients with the genetic disease cystic fibrosis (CF) often have recurrent P. aeruginosa pulmonary infections resulting in robust inflammatory responses that lead to tissue destruction. Despite a hostile hyper-inflammatory environment and vigorous neutrophilic responses, P. aeruginosa can persist in the CF lung and eventually become the dominant bacterium in the airways. We demonstrate that P. aeruginosa manipulates host lipid signaling and inflammatory response in the CF airway by secreting Cif, a virulence factor with epoxide hydrolase activity. Cif reduced the transcellular production of 15-epi lipoxin A4 (15-epi LXA4), a pro-resolving lipid mediator whose endogenous production is critical in limiting tissue inflammation. In the airway, neutrophil 15-epi LXA4 production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotaged the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating neutrophil generation of 15-epi LXA4. Cif mediated inhibition of 15-epi LXA4 eliminated the pro-resolving signal that potently suppresses IL-8-driven neutrophil trans-epithelial migration in vitro. Moreover, our retrospective analyses of CF patient samples supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid correlated with lower levels of 15-epi LXA4, increased IL-8 concentrations and impaired lung function. These findings provide structural, biochemical and immunological evidence that the P. aeruginosa epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections in the CF airway. This study and the recent identification of Cif homologs in Acinetobacter and Burkholderia species suggest that bacterial epoxide hydrolases represent a novel virulence strategy shared by multiple respiratory pathogens

21cmFirstCLASS I. Cosmological tool for Λ\LambdaCDM and beyond

In this work we present 21cmFirstCLASS, a modified version of 21cmFAST, the most popular code in the literature for computing the anisotropies of the 21-cm signal. Our code uses the public cosmic microwave background (CMB) Boltzmann code CLASS, to establish consistent initial conditions at recombination for any set of cosmological parameters and evolves them throughout the dark ages, cosmic dawn, the epoch of heating and reionization. We account for inhomogeneity in the temperature and ionization fields throughout the evolution, crucial for a robust calculation of both the global 21-cm signal and its fluctuations. We demonstrate how future measurements of the CMB and the 21-cm signal can be combined and analyzed with 21cmFirstCLASS to obtain constraints on both cosmological and astrophysical parameters and examine degeneracies between them. As an example application, we show how 21cmFirstCLASS can be used to study non-linear cosmological models, such as scattering dark matter (SDM). For the first time, we present self-consistent calculations of the 21-cm power spectrum in the presence of SDM during the non-linear epoch of cosmic dawn.Comment: 28 pages, 20 figure

21cmFirstCLASS II. Early linear fluctuations of the 21cm signal

In a companion paper we introduce 21cmFirstCLASS, a new code for computing the 21-cm anisotropies, assembled from the merger of the two popular codes 21cmFAST and CLASS. Unlike the standard 21cmFAST, which begins at $z=35$ with homogeneous temperature and ionization boxes, our code begins its calculations from recombination, evolves the signal through the dark ages, and naturally yields an inhomogeneous box at $z=35$. In this paper, we validate the output of 21cmFirstCLASS by developing a new theoretical framework which is simple and intuitive on the one hand, but is robust and precise on the other hand. As has been recently claimed, using consistent inhomogeneous initial conditions mitigates inaccuracies, which according to our analysis can otherwise reach the $\mathcal O\left(20\%\right)$ level. On top of that, we also show for the first time that 21cmFAST over-predicts the 21-cm power spectrum at $z\gtrsim20$ by another $\mathcal O\left(20\%\right)$, due to the underlying assumption that $\delta_b=\delta_c$, namely that the density fluctuations in baryons and cold dark matter are indistinguishable. We propose an elegant solution to this discrepancy by introducing an appropriate scale-dependent growth factor into the evolution equations. Our analysis shows that this modification will ensure sub-percent differences between 21cmFirstCLASS and the Boltzmann solver CAMB at $z\leq50$ for all scales between the horizon and the Jeans scale. This will enable 21cmFirstCLASS to consistently and reliably simulate the 21-cm anisotropies both in the dark ages and cosmic dawn, for any cosmology.Comment: 19 pages, 9 figure

Closing the window on fuzzy dark matter with the 21cm signal

Fuzzy dark matter (FDM) is a well motivated candidate for dark matter (DM) as its tiny mass and large de-Broglie wavelength suppress small-scale matter fluctuations, thereby solving some of the small-scale discrepancies in $\Lambda$CDM. Although it has been ruled out as the single component of DM by several observables, there is still a region in the FDM parameter space (the "FDM window", $10^{-25}\,\mathrm{eV}\lesssim m_\mathrm{FDM}\lesssim10^{-23}\,\mathrm{eV}$) where FDM is allowed to comprise a large portion of the total DM. In this work, for the first time, we study the signature of FDM (comprised of ultra-light axions) in fractions less than unity on the 21cm signal and its detectability by 21cm interferometers such as HERA, taking into account the degeneracy with both astrophysical and cosmological parameters, using a new pipeline that combines modified versions of the CAMB and 21cmFAST codes. Our forecasts imply that HERA in its design performance will be sensitive to FDM fractions as small as 1% in the FDM window, and improve over existing bounds for other masses by up to an order of magnitude.Comment: 9 pages, 3 figures; fixed typo in Eq. 5, updated bounds, added figures; version accepted for publication in PR

VRpursuits: Interaction in Virtual Reality Using Smooth Pursuit Eye Movements

Gaze-based interaction using smooth pursuit eye movements (Pursuits) is attractive given that it is intuitive and overcomes the Midas touch problem. At the same time, eye tracking is becoming increasingly popular for VR applications. While Pursuits was shown to be effective in several interaction contexts, it was never explored in-depth for VR before. In a user study (N=26), we investigated how parameters that are specific to VR settings influence the performance of Pursuits. For example, we found that Pursuits is robust against different sizes of virtual 3D targets. However performance improves when the trajectory size (e.g., radius) is larger, particularly if the user is walking while interacting. While walking, selecting moving targets via Pursuits is generally feasible albeit less accurate than when stationary. Finally, we discuss the implications of these findings and the potential of smooth pursuits for interaction in VR by demonstrating two sample use cases: 1) gaze-based authentication in VR, and 2) a space meteors shooting game

The enzymatic oxidation of Desferal to a nitroxide free radical

AbstractDesferrioxamine mesylate (Desferal), a transition metal ion chelator, has been used to inhibit the in vitro redox cycling of transition metal ions. ESR spectroscopy was utilized to detect and identify Desferal's one-electron oxidation product. We demonstrate that a horseradish peroxidase/H2O2 system, a xanthine oxidase/hypoxanthine system, and a hydroxyl radical-generating system are all capable of oxidizing Desferal to a nitroxide free radical. The same 9-line ESR spectrum (g = 2.0065, aN = 7.85 G, aH(2) = 6.35 G) was detected in all of the above systems. We, therefore, stress that care must be taken when using Desferal as a transition metal ion chelator to keep its concentration low enough to minimize these reactions, or to use a different metal ion chelator

Magnetic Fields from Compensated Isocurvature Perturbations

Compensated isocurvature perturbations (CIPs) are perturbations to the primordial baryon density that are accompanied by dark-matter-density perturbations so that the total matter density is unperturbed. Such CIPs, which may arise in some multi-field inflationary models, can be long-lived and only weakly constrained by current cosmological measurements. Here we show that the CIP-induced modulation of the electron number density interacts with the electron-temperature fluctuation associated with primordial adiabatic perturbations to produce, via the Biermann-battery mechanism, a magnetic field in the post-recombinaton Universe. Assuming the CIP amplitude saturates the current BBN bounds, this magnetic field can be stronger than $10^{-15}\,\mathrm{nG}$ at $z\simeq20$ and stronger by an order of magnitude than that (produced at second order in the adiabatic-perturbation amplitude) in the standard cosmological model, and thus can serve as a possible seed for galactic dynamos.Comment: 7 pages, 2 figures, version accepted for publication in PR

Pseudomonas Aeruginosa Sabotages the Generation of Host Proresolving Lipid Mediators

Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A4 (15-epi LXA4), plays a critical role in limiting neutrophil activation and tissue inflammation, thus promoting the return to tissue homeostasis. Here, we show that a secreted P. aeruginosa epoxide hydrolase, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), can disrupt 15-epi LXA4 transcellular biosynthesis and function. In the airway, 15-epi LXA4 production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotages the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating a proresolving signal that potently suppresses IL-8-driven neutrophil transepithelial migration in vitro. Retrospective analyses of samples from patients with CF supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid were correlated with lower levels of 15-epi LXA4, increased IL-8 concentrations, and impaired lung function. Together, these findings provide structural, biochemical, and immunological evidence that the bacterial epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections. The data also suggest that Cif contributes to sustained pulmonary inflammation and associated loss of lung function in patients with CF