Effects of electronic cigarette liquid on monolayer and 3D tissue-engineered models of human gingival mucosa

Background. There is limited data available on potential biological effects of E-cigarettes on human oral tissues. The aim of this study was to evaluate the effects of E-cigarette liquid on the proliferation of normal and cancerous monolayer and 3D models of human oral mucosa and oral wound healing after short-term and medium-term exposure. Methods. Normal human oral fibroblasts (NOF), immortalized OKF6-TERET-2 human oral keratinocytes, and cancerous TR146 keratinocyte monolayer cultures and 3D tissue engineered oral mucosal models were exposed to different concentrations (0.1%, 1%, 5% and 10%) of E-cigarette liquid (12 mg/ml nicotine) for 1 hour daily for three days and for 7 days. Tissue viability was monitored using the PrestoBlue assay. Wounds were also produced in the middle surface of the monolayer systems vertically using a disposable cell scraper. The alterations in the cell morphology and wound healing were visualized using light microscopy and histological examination. Results. Statistical analysis showed medium-term exposure of TR146 keratinocytes to 5% and 10% E-liquid concentrations significantly increased the viability of the cancer cells compared to the negative control. Short-term exposure of NOFs to 10% E-liquid significantly reduced the cell viability, whereas medium-term exposure to all E-liquid concentrations significantly reduced the NOF cells’ viability. OKF6 cells exhibited significantly lower viability following short-term and mediumterm exposure to all E-cigarette concentrations compared to the negative control. 3D oral mucosal model containing normal oral fibroblasts and keratinocytes showed significant reduction in tissue viability after exposure to 10% E-liquid, whereas medium-term exposure resulted in significantly lower viability in 5% and 10% concentration groups compared to the negative control. There was a statistically significant difference in wound healing times of both NOF and OKF6 cells after exposure to 1%, 5% and 10% E-cigarette liquid. Conclusion. Medium-term exposure to high concentrations of the E-cigarette liquid had cytotoxic effects on normal human oral fibroblasts and OKF6 keratinocytes, but a stimulatory cumulative effect on the growth of cancerous TR146 keratinocyte cells as assessed by the PrestoBlue assay and histological evaluation of 3D oral mucosal models. In addition, E-liquid exposure prolonged the wound healing of NOF and OKF6 oral mucosa cells

Cosmic-Ray Anisotropies in Right Ascension Measured by the Pierre Auger Observatory

We present measurements of the large-scale cosmic-ray (CR) anisotropies in R.A., using data collected by the surface detector array of the Pierre Auger Observatory over more than 14 yr. We determine the equatorial dipole component, ${{\boldsymbol{d}}}_{\perp }$, through a Fourier analysis in R.A. that includes weights for each event so as to account for the main detector-induced systematic effects. For the energies at which the trigger efficiency of the array is small, the "east–west" method is employed. Besides using the data from the array with detectors separated by 1500 m, we also include data from the smaller but denser subarray of detectors with 750 m separation, which allows us to extend the analysis down to ∼0.03 EeV. The most significant equatorial dipole amplitude obtained is that in the cumulative bin above 8 EeV, ${d}_{\perp }={6.0}_{-0.9}^{+1.0}$%, which is inconsistent with isotropy at the 6σ level. In the bins below 8 EeV, we obtain 99% CL upper bounds on d⊥ at the level of 1%–3%. At energies below 1 EeV, even though the amplitudes are not significant, the phases determined in most of the bins are not far from the R.A. of the Galactic center, at αGC = −94°, suggesting a predominantly Galactic origin for anisotropies at these energies. The reconstructed dipole phases in the energy bins above 4 EeV point instead to R.A. that are almost opposite to the Galactic center one, indicative of an extragalactic CR origin

Corticotrophin-Releasing Factor (CRF) through CRF1 Receptor Facilitates the Expression of Morphine-Related Positive and Aversive Memory in Mice

Different studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories; corticotrophin-releasing factor (CRF) plays a critical role in reward- and aversion-driven associative learning. In the present chapter, we have evaluated whether CP-154,526, a selective CRF1 receptor (CRF1R) antagonist, or genetic deletion of CRF1R (KO mice) have comparable effects on conditioned place preference (CPP) and conditioned place aversion (CPA) learning. We also investigated CP-154,526 effects on morphine-induced CPP activation of CRF, CREB phosphorylation, and thioredoxin (Trx1) expression in dentate gyrus (DG), a brain region involved in memory consolidation, and the role of hypothalamic-pituitary-adrenocortical (HPA) axis in CPA expression and extinction. The CRF1R antagonist abolished the acquisition of morphine CPP, Trx-1 and BDNF increased expression, and pCREB/Trx-1 co-localization in the DG. The increase in adrenocorticotropic hormone (ACTH) plasma levels observed after CPA expression was attenuated in CRF1R KO mice, suggesting a role of HPA axis in aversive memories. Altogether, these results suggest a critical role of CRF, through CRF1R, in molecular changes involved in memory formation and consolidation and may facilitate the development of effective treatments for opioid addiction

Measurement of the Fluctuations in the Number of Muons in Extensive Air Showers with the Pierre Auger Observatory

We present the first measurement of the fluctuations in the number of muons in extensive air showers produced by ultrahigh energy cosmic rays. We find that the measured fluctuations are in good agreement with predictions from air shower simulations. This observation provides new insights into the origin of the previously reported deficit of muons in air shower simulations and constrains models of hadronic interactions at ultrahigh energies. Our measurement is compatible with the muon deficit originating from small deviations in the predictions from hadronic interaction models of particle production that accumulate as the showers develop

Design, upgrade and characterization of the silicon photomultiplier front-end for the AMIGA detector at the Pierre Auger Observatory

AMIGA (Auger Muons and Infill for the Ground Array) is an upgrade of the Pierre Auger Observatory to complement the study of ultra-high-energy cosmic rays (UHECR) by measuring the muon content of extensive air showers (EAS). It consists of an array of 61 water Cherenkov detectors on a denser spacing in combination with underground scintillation detectors used for muon density measurement. Each detector is composed of three scintillation modules, with 10 m2 detection area per module, buried at 2.3 m depth, resulting in a total detection area of 30 m2. Silicon photomultiplier sensors (SiPM) measure the amount of scintillation light generated by charged particles traversing the modules. In this paper, the design of the front-end electronics to process the signals of those SiPMs and test results from the laboratory and from the Pierre Auger Observatory are described. Compared to our previous prototype, the new electronics shows a higher performance, higher efficiency and lower power consumption, and it has a new acquisition system with increased dynamic range that allows measurements closer to the shower core. The new acquisition system is based on the measurement of the total charge signal that the muonic component of the cosmic ray shower generates in the detector

Constraining models for the origin of ultra-high-energy cosmic rays with a novel combined analysis of arrival directions, spectrum, and composition data measured at the Pierre Auger Observatory

The combined fit of the measured energy spectrum and shower maximum depth distributions of ultra-high-energy cosmic rays is known to constrain the parameters of astrophysical models with homogeneous source distributions. Studies of the distribution of the cosmic-ray arrival directions show a better agreement with models in which a fraction of the flux is non-isotropic and associated with the nearby radio galaxy Centaurus A or with catalogs such as that of starburst galaxies. Here, we present a novel combination of both analyses by a simultaneous fit of arrival directions, energy spectrum, and composition data measured at the Pierre Auger Observatory. The model takes into account a rigidity-dependent magnetic field blurring and an energy-dependent evolution of the catalog contribution shaped by interactions during propagation. We find that a model containing a flux contribution from the starburst galaxy catalog of around 20% at 40 EeV with a magnetic field blurring of around 20◦ for a rigidity of 10 EV provides a fair simultaneous description of all three observables. The starburst galaxy model is favored with a significance of 4.5σ (considering experimental systematic effects) compared to a reference model with only homogeneously distributed background sources. By investigating a scenario with Centaurus A as a single source in combination with the homogeneous background, we confirm that this region of the sky provides the dominant contribution to the observed anisotropy signal. Models containing a catalog of jetted active galactic nuclei whose flux scales with the γ-ray emission are, however, disfavored as they cannot adequately describe the measured arrival directions

Design and implementation of the AMIGA embedded system for data acquisition

The Auger Muon Infill Ground Array (AMIGA) is part of the AugerPrime upgrade of the Pierre Auger Observatory. It consists of particle counters buried 2.3 m underground next to the water-Cherenkov stations that form the 23.5 km2 large infilled array. The reduced distance between detectors in this denser area allows the lowering of the energy threshold for primary cosmic ray reconstruction down to about 1017 eV. At the depth of 2.3 m the electromagnetic component of cosmic ray showers is almost entirely absorbed so that the buried scintillators provide an independent and direct measurement of the air showers muon content. This work describes the design and implementation of the AMIGA embedded system, which provides centralized control, data acquisition and environment monitoring to its detectors. The presented system was firstly tested in the engineering array phase ended in 2017, and lately selected as the final design to be installed in all new detectors of the production phase. The system was proven to be robust and reliable and has worked in a stable manner since its first deployment

Deep-learning based reconstruction of the shower maximum Xmax using the water-Cherenkov detectors of the Pierre Auger Observatory

The atmospheric depth of the air shower maximum Xmax is an observable commonly used for the determination of the nuclear mass composition of ultra-high energy cosmic rays. Direct measurements of Xmax are performed using observations of the longitudinal shower development with fluorescence telescopes. At the same time, several methods have been proposed for an indirect estimation of Xmax from the characteristics of the shower particles registered with surface detector arrays. In this paper, we present a deep neural network (DNN) for the estimation of Xmax. The reconstruction relies on the signals induced by shower particles in the ground based water-Cherenkov detectors of the Pierre Auger Observatory. The network architecture features recurrent long short-term memory layers to process the temporal structure of signals and hexagonal convolutions to exploit the symmetry of the surface detector array. We evaluate the performance of the network using air showers simulated with three different hadronic interaction models. Thereafter, we account for long-term detector effects and calibrate the reconstructed Xmax using fluorescence measurements. Finally, we show that the event-by-event resolution in the reconstruction of the shower maximum improves with increasing shower energy and reaches less than 25 g/cm2 at energies above 2×1019 eV