Systematic study of constitutive cyclo-oxygenase-2 expression: role of NFκB and NFAT transcriptional pathways

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system

Proper motions of the HH1 jet

We describe a new method for determining proper motions of extended objects, and a pipeline developed for the application of this method. We then apply this method to an analysis of four epochs of [S~II] HST images of the HH~1 jet (covering a period of $\sim 20$~yr). We determine the proper motions of the knots along the jet, and make a reconstruction of the past ejection velocity time-variability (assuming ballistic knot motions). This reconstruction shows an "acceleration" of the ejection velocities of the jet knots, with higher velocities at more recent times. This acceleration will result in an eventual merging of the knots in $\sim 450$~yr and at a distance of $\sim 80"$ from the outflow source, close to the present-day position of HH~1.Comment: 12 pages, 8 figure

N-body simulations of galaxies and groups of galaxies with the Marseille GRAPE systems

I review the Marseille GRAPE systems and the N-body simulations done with them. I first describe briefly the available hardware and software, their possibilities and their limitations. I then describe work done on interacting galaxies and groups of galaxies. This includes simulations of the formation of ring galaxies, simulations of bar destruction by massive compact satellites, of merging in compact groups and of the formation of brightest members in clusters of galaxies.Comment: 13 pages, 5 figures, to be published in "Non-linear Dynamics and Chaos in Astrophysics", eds. J.R. Buchler, S. Gottesman, J. Hunter and H. Kandrup, Annals of the New York Academy of Science

High-resolution melting assay for genotyping variants of the CYP2C19 enzyme and predicting voriconazole effectiveness

Voriconazole is a triazole antifungal agent recommended as primary treatment for invasive aspergillosis, as well as some other mold infections. However, it presents some pharmacokinetic singularities that lead to a great variability intra- and interindividually, nonlinear pharmacokinetics, and a narrow therapeutic range. Most experts have recommended tracing the levels of voriconazole in patients when receiving treatment. This azole is metabolized through the hepatic enzyme complex cytochrome P450 (CYPP450), with the isoenzyme CYP2C19 being principally involved. Allelic variations (polymorphisms) of the gene that encodes this enzyme are known to contribute to variability in voriconazole exposure. Three different allelic variants, CYP2C19*17, CYP2C19*2, and CYP2C19*3, could explain most of the phenotypes related to the voriconazole metabolism and some of its pharmacokinetic singularities. We designed a rapid molecular method based on high-resolution melting to characterize these polymorphisms in a total of 142 samples, avoiding sequencing. Three PCRs were designed with similar cycling conditions to run simultaneously. The results showed that our method represents a fast, accurate, and inexpensive means to study these variants related to voriconazole metabolism. In clinical practice, this could offer a useful tool to individually optimize therapy and reduce expenses in patients with fungal infections.National Institute of Health Carlos III (AES13PI13/01817Research Project MPY 1367/13). L.B.-M. has a contract supported by theMinisterio de Ciencia e Innovación, Instituto de Salud Carlos III, cofinanced by the EuropeanDevelopment Regional Fund (EDRF) “A Way to Achieve Europe” and the SpanishNetwork for the Research in Infectious Diseases (REIPI; RD12/0015/0015). B.M.-R. is astudent in the Master’s Program entitled “Microbiología Aplicada a la Salud Pública eInvestigación en Enfermedades Infecciosas,” Alcalá de Henares University, Madrid,Spain. A.C. and C.C. were supported by the Northern Portugal Regional OperationalProgram (NORTE 2020) under the Portugal 2020 Partnership Agreement through theEuropean Regional Development Fund (FEDER; NORTE-01-0145-FEDER-000013) and theFundação Para a Ciência e Tecnologia (FCT; IF/00735/2014 [A.C.] and SFRH/BPD/96176/2013 [C.C.])

Three-dimensional quantitative evaluation method of nonrigid registration algorithms for adaptive radiotherapy

Purpose: Current radiotherapy is progressing to the concept of adaptive radiotherapy, which implies the adaptation of planning along the treatment course. Nonrigid registration is an essential image processing tool for adaptive radiotherapy and image guided radiotherapy, and the three-dimensional (3D) nature of the current radiotherapy techniques requires a 3D quantification of the registration error that existing evaluation methods do not cover appropriately. The authors present a method for 3D evaluation of nonrigid registration algorithms’ performance, based on organ delineations, capable of working with near-spherical volumes even in the presence of concavities. Methods: The evaluation method is composed by a volume shape description stage, developed using a new ad hoc volume reconstruction algorithm proposed by the authors, and an error quantification stage. The evaluation method is applied to the organ delineations of prostate and seminal vesicles, obtained by an automatic segmentation method over images of prostate cancer patients treated with intensity modulated radiation therapy. Results: The volume reconstruction algorithm proposed has been shown to accurately model complex 3D surfaces by the definition of clusters of control points. The quantification method, inspired by the Haussdorf–Chebysev distance, provides a measure of the largest registration error per control direction, defining a valid metric for concave-convex volumes. Summarizing, the proposed evaluation methodology presents accurate results with a high spatial resolution in a negligible computation time in comparison with the nonrigid registration time. Conclusions: Experimental results show that the metric selected for quantifying the registration error is of utmost importance in a quantitative evaluation based on measuring distances between volumes. The accuracy of the volume reconstruction algorithm is not so relevant as long as the reconstruction is tight enough on the actual volume of the organ. The new evaluation method provides a smooth and accurate volume reconstruction for both the reference and the registered organ, and a complete 3D description of nonrigid registration algorithms’ performance, resulting in a useful tool for study and comparison of registration algorithms for adaptive radiotherapy

Lifetime of Stringy de Sitter Vacua

In this note we perform a synopsis of the life-times from vacuum decay of several de Sitter vacuum constructions in string/M-theory which have a single dS minimum arising from lifting a pre-existing AdS extremum and no other local minima existent after lifting. For these vacua the decay proceeds via a Coleman--De Luccia instanton towards the universal Minkowski minimum at infinite volume. This can be calculated using the thin--wall approximation, provided the cosmological constant of the local dS minimum is tuned sufficiently small. We compare the estimates for the different model classes and find them all stable in the sense of exponentially long life times as long as they have a very small cosmological constant and a scale of supersymmetry breaking > TeV.Comment: 1+16 pages, 2 figures, LaTeX, uses JHEP3 class, v2: references added, inclusion of an additional subclass of de Sitter vacu

Green's function for metamaterial superlens: Evanescent wave in the image

We develop a new method to calculate the evanescent wave, the subdivided evanescent waves (SEWs), and the radiative wave, which can be obtained by separating the global field of the image of metamaterial superlens. The method is based on Green's function, and it can be applied in other linear systems. This study could help us to investigate the effect of evanescent wave on metamaterial superlens directly, and give us a new way to design new devices.Comment: 15 pages, 3 figure

Non-invasive ventilation in obesity hypoventilation syndrome without severe obstructive sleep apnoea

Background Non-invasive ventilation (NIV) is an effective form of treatment in patients with obesity hypoventilation syndrome (OHS) who have concomitant severe obstructive sleep apnoea (OSA). However, there is a paucity of evidence on the efficacy of NIV in patients with OHS without severe OSA. We performed a multicentre randomised clinical trial to determine the comparative efficacy of NIV versus lifestyle modification (control group) using daytime arterial carbon dioxide tension (PaCO2) as the main outcome measure. Methods Between May 2009 and December 2014 we sequentially screened patients with OHS without severe OSA. Participants were randomised to NIV versus lifestyle modification and were followed for 2 months. Arterial blood gas parameters, clinical symptoms, health-related quality of life assessments, polysomnography, spirometry, 6-min walk distance test, blood pressure measurements and healthcare resource utilisation were evaluated. Statistical analysis was performed using intention-to-treat analysis. Results A total of 365 patients were screened of whom 58 were excluded. Severe OSA was present in 221 and the remaining 86 patients without severe OSA were randomised. NIV led to a significantly larger improvement in PaCO2 of -6 (95% CI -7.7 to -4.2) mm Hg versus -2.8 (95% CI -4.3 to -1.3) mm Hg, (p<0.001) and serum bicarbonate of -3.4 (95% CI -4.5 to -2.3) versus -1 (95% CI -1.7 to -0.2 95% CI) mmol/L (p<0.001). PaCO2 change adjusted for NIV compliance did not further improve the inter-group statistical significance. Sleepiness, some health-related quality of life assessments and polysomnographic parameters improved significantly more with NIV than with lifestyle modification. Additionally, there was a tendency towards lower healthcare resource utilisation in the NIV group. Conclusions NIV is more effective than lifestyle modification in improving daytime PaCO2, sleepiness and polysomnographic parameters. Long-term prospective studies are necessary to determine whether NIV reduces healthcare resource utilisation, cardiovascular events and mortality

Promoting prosocial behaviour among Colombian adolescents: the evaluation of a universal school-based program using a multi-informant perspective

The present study evaluated the efficacy of an Italian school-based intervention programme adapted in three Colombian sites (Medellín, Manizales, and Santa Marta) in promoting prosocial behaviour among adolescents. Using a pre-test-post-test design with a multi-informant approach, the present study assessed 451 students (Mage&nbsp;=&nbsp;12.77, SD&nbsp;=&nbsp;1.06) of the intervention group and 428 students (Mage&nbsp;=&nbsp;12.64, SD&nbsp;=&nbsp;1.01) by using self-report and peer rating measures of prosocial behaviour. After establishing the measurement invariance across time and informants, a latent difference score model showed the positive effect of the intervention programme in improving prosocial behaviour evaluated by peers (Cohen’s d =&nbsp;.379) among Colombian adolescents, across all three sites. Implications of the study will be discussed

Mancha3D code: Multi-purpose Advanced Non-ideal MHD Code for High resolution simulations in Astrophysics

The Mancha3D code is a versatile tool for numerical simulations of magnetohydrodynamic processes in solar/stellar atmospheres. The code includes non-ideal physics derived from plasma partial ionization, a realistic equation of state and radiative transfer, which allows performing high quality realistic simulations of magneto-convection, as well as idealized simulations of particular processes, such as wave propagation, instabilities or energetic events. The paper summarizes the equations and methods used in the Mancha3D code. It also describes its numerical stability and parallel performance and efficiency. The code is based on a finite difference discretization and memory-saving Runge-Kutta (RK) scheme. It handles non-ideal effects through super-time stepping and Hall diffusion schemes, and takes into account thermal conduction by solving an additional hyperbolic equation for the heat flux. The code is easily configurable to perform different kinds of simulations. Several examples of the code usage are given. It is demonstrated that splitting variables into equilibrium and perturbation parts is essential for simulations of wave propagation in a static background. A perfectly matched layer (PML) boundary condition built into the code greatly facilitates a non-reflective open boundary implementation. Spatial filtering is an important numerical remedy to eliminate grid-size perturbations enhancing the code stability. Parallel performance analysis reveals that the code is strongly memory bound, which is a natural consequence of the numerical techniques used, such as split variables and PML boundary conditions. Both strong and weak scalings show adequate performance up till several thousands of CPUs