Octacalcium phosphate crystals directly stimulate expression of inducible nitric oxide synthase through p38 and JNK mitogen-activated protein kinases in articular chondrocytes

Basic calcium phosphate (BCP) crystals, including hydroxyapatite, octacalcium phosphate (OCP) and carbonate-apatite, have been associated with severe osteoarthritis and several degenerative arthropathies. Most studies have considered the chondrocyte to be a bystander in the pathogenesis of calcium crystal deposition disease, assuming that synovial cell cytokines were the only triggers of chondrocyte activation. In the present study we identified direct activation of articular chondrocytes by OCP crystals, which are the BCP crystals ith the greatest potential for inducing inflammation. OCP crystals induced nitric oxide (NO) production and inducible nitric oxide synthase (NOS) mRNA expression by isolated articular chondrocytes and cartilage fragments, in a dose-dependent manner and with variations over time. OCP crystals also induced IL-1β mRNA expression. Using pharmacological and cytokine inhibitors, we observed that OCP crystals induced NO production and inducible NOS mRNA activation were regulated at both the transcriptional and the translational levels; were independent from IL-1β gene activation; and involved p38 and c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways, as further confirmed by OCP crystal-induced p38 and JNK MAPK phosphorylation. Taken together, our data suggest that the transcriptional inducible NOS response to OCP crystals involved both the p38 and the JNK MAPK pathways, probably under the control of activator protein-1. NO, a major mediator of cartilage degradation, can be directly produced by BCP crystals in chondrocytes. Together with synovial activation, this direct mechanism may be important in the pathogenesis of destructive arthropathies triggered by microcrystals

Constraining Modified Gravity and Growth with Weak Lensing

The idea that we live in a Universe undergoing a period of acceleration is a strongly held notion in cosmology. As this can, potentially, be explained with a modification to General Relativity we look at current cosmological data with the purpose of testing aspects of gravity. Firstly we constrain a phenomenological model (mDGP) motivated by a possible extra dimension. This is characterised by $\alpha$ which interpolates between (LCDM) and (the Dvali Gabadadze Porrati (DGP) model). In addition, we analyse general signatures of modified gravity given by the growth parameter $\gamma$ and power spectrum parameter $\Sigma$. We utilise Weak Lensing data (CFHTLS-wide) in combination with Baryon Acoustic Oscillations (BAOs) and Supernovae data. We show that current weak lensing data is not yet capable of constraining either model in isolation. However we demonstrate that this probe is highly beneficial, for in combination with BAOs and Supernovae we obtain $\alpha < 0.58$ and $\alpha < 0.91$ at $1\sigma$ and $2\sigma$, respectively. Without the lensing data no constraint is possible. Both analyses disfavour the flat DGP braneworld model ($\alpha = 1$) at over $2\sigma$. We highlight these are insensitive to potential systematics in the lensing data. For the growth signature $\gamma$ we show that, in combination, these probes do not yet have sufficient constraining power. Finally, we look beyond these present capabilities and demonstrate that Euclid, a future weak lensing survey, will deeply probe the nature of gravity. A $1\sigma$ error of 0.104 is found for $\alpha$ ($l_{max} = 500$) whereas for the general modified signatures we forecast $1\sigma$ errors of 0.045 for $\gamma$ and 0.25 for $\Sigma_{0}$ ($l_{max} = 500$), which is further tightened to 0.038 for $\gamma$ and 0.069 for $\Sigma_{0}$ ($l_{max} = 10000$).Comment: 15 pages, 9 figure

Quantifying the effect of baryon physics on weak lensing tomography

We use matter power spectra from cosmological hydrodynamic simulations to quantify the effect of baryon physics on the weak gravitational lensing shear signal. The simulations consider a number of processes, such as radiative cooling, star formation, supernovae and feedback from active galactic nuclei (AGN). Van Daalen et al. (2011) used the same simulations to show that baryon physics, in particular the strong feedback that is required to solve the overcooling problem, modifies the matter power spectrum on scales relevant for cosmological weak lensing studies. As a result, the use of power spectra from dark matter simulations can lead to significant biases in the inferred cosmological parameters. We show that the typical biases are much larger than the precision with which future missions aim to constrain the dark energy equation of state, w_0. For instance, the simulation with AGN feedback, which reproduces X-ray and optical properties of groups of galaxies, gives rise to a ~40% bias in w_0. We demonstrate that the modification of the power spectrum is dominated by groups and clusters of galaxies, the effect of which can be modelled. We consider an approach based on the popular halo model and show that simple modifications can capture the main features of baryonic feedback. Despite its simplicity, we find that our model, when calibrated on the simulations, is able to reduce the bias in w_0 to a level comparable to the size of the statistical uncertainties for a Euclid-like mission. While observations of the gas and stellar fractions as a function of halo mass can be used to calibrate the model, hydrodynamic simulations will likely still be needed to extend the observed scaling relations down to halo masses of 10 ^12 M_sun/h.Comment: 17 pages, 14 Figures, MNRAS accepted. Small changes to the published version: typos in Eq. 4 corrected, Figure 2 updated (y-ticks of the previous version were wrong). Bibliography updated with published papers when possibl

Interleukin-18 produced by bone marrow- derived stromal cells supports T-cell acute leukaemia progression

International audienceDevelopment of novel therapies is critical for T-cell acute leukae-mia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activa-tion and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/ 2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleu-kin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xeno-grafted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development

Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia

The cellular receptor Notch1 is a central regulator of T-cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T-cell acute lymphoblastic leukemia (T-ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T-ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti-Notch therapies in T-ALL models. In this work, we report that Notch1 upregulation in T-ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1-driven T-ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1-induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1-driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1-driven leukemia.This work was supported by funds from the followinginstitutions: Agencia Estatal de Investigacion/Euro-pean Regional Development Fund, European Union(PGC2018-096244-B-I00, SAF2016-75442-R), Ministryof Science, Innovation and Universities of Spain,Spanish National Research Council—CSIC, InstitutNational de la Sante et de la Recherche Medicale—INSERM, Ligue Contre le Cancer—Gironde, Univer-site de Bordeaux, Fondation pour la Recherche Medi-cale, the Conseil Regional d’Aquitaine, SIRIC-BRIO,Fondation ARC and Institut Europeen de Chimie etBiologie. MJN was supported by a bourse d’excellencede la Federation Wallonie-Bruxelles (WBI) and a post-doctoral fellowship from Fondation ARC. We thankVincent Pitard (Flow Cytometry Platform, Universitede Bordeaux, France) for technical assistance in flowcytometry experiments. We thank Diana Cabrera(Metabolomics Platform, CIC bioGUNE, Spain) fortechnical assistance in metabolomics analysi

Weak lensing, dark matter and dark energy

Weak gravitational lensing is rapidly becoming one of the principal probes of dark matter and dark energy in the universe. In this brief review we outline how weak lensing helps determine the structure of dark matter halos, measure the expansion rate of the universe, and distinguish between modified gravity and dark energy explanations for the acceleration of the universe. We also discuss requirements on the control of systematic errors so that the systematics do not appreciably degrade the power of weak lensing as a cosmological probe.Comment: Invited review article for the GRG special issue on gravitational lensing (P. Jetzer, Y. Mellier and V. Perlick Eds.). V3: subsection on three-point function and some references added. Matches the published versio

Laser writing of coherent colour centres in diamond

Optically active point defects in crystals have gained widespread attention as photonic systems that can find use in quantum information technologies [1,2]. However challenges remain in the placing of individual defects at desired locations, an essential element of device fabrication. Here we report the controlled generation of single nitrogen-vacancy (NV) centres in diamond using laser writing [3]. The use of aberration correction in the writing optics allows precise positioning of vacancies within the diamond crystal, and subsequent annealing produces single NV centres with up to 45% success probability, within about 200 nm of the desired position. Selected NV centres fabricated by this method display stable, coherent optical transitions at cryogenic temperatures, a pre-requisite for the creation of distributed quantum networks of solid-state qubits. The results illustrate the potential of laser writing as a new tool for defect engineering in quantum technologies

Testing gravity using galaxy-galaxy lensing and clustering amplitudes in KiDS-1000, BOSS and 2dFLenS

The physics of gravity on cosmological scales affects both the rate of assembly of large-scale structure, and the gravitational lensing of background light through this cosmic web. By comparing the amplitude of these different observational signatures, we can construct tests that can distinguish general relativity from its potential modifications. We used the latest weak gravitational lensing dataset from the Kilo-Degree Survey, KiDS-1000, in conjunction with overlapping galaxy spectroscopic redshift surveys BOSS and 2dFLenS, to perform the most precise existing amplitude-ratio test. We measured the associated E_G statistic with 15-20% errors, in five dz = 0.1 tomographic redshift bins in the range 0.2 < z < 0.7, on projected scales up to 100 Mpc/h. The scale-independence and redshift-dependence of these measurements are consistent with the theoretical expectation of general relativity in a Universe with matter density Omega_m = 0.27 +/- 0.04. We demonstrate that our results are robust against different analysis choices, including schemes for correcting the effects of source photometric redshift errors, and compare the performance of angular and projected galaxy-galaxy lensing statistics.Comment: 23 pages, 14 figures, version accepted for publication by A&

Structure formation in cosmologies with oscillating dark energy

{abridged} We study the imprints on the formation and evolution of cosmic structures of dynamical dark energy models, characterized by an oscillating equation of state. The redshift evolution of the equation of state parameter w(z) for dark energy is characterized by two parameters, describing the amplitude and the frequency of the oscillations. We consider six different oscillating dark energy models, each characterized by a different set of parameter values. Under the common assumption that dark energy is not clustering on the scales of interest, we study different aspects of cosmic structure formation. In particular, we self-consistently solve the spherical collapse problem. We then estimate the behavior of several cosmological observables, such as the linear growth factor, the Integrated Sachs-Wolfe (ISW) effect, the number counts of massive structures, and the matter and cosmic shear power spectra. We show that, independently of the amplitude and the frequency of the dark energy oscillations, none of the aforementioned observables show an oscillating behavior as a function of redshift. This is a consequence of the said observables' being integrals over some functions of the expansion rate over cosmic history. We also notice that deviations with respect to the expectations for a fiducial LambdaCDM cosmology are generically small, and in the majority of the cases distinguishing an oscillating dark energy model would be difficult. Exceptions to this conclusion are provided by the cosmic shear power spectrum, which for some of the models shows a difference at the level of \sim 10% over a wide range of angular scales, and the abundance of galaxy clusters, which is modified at the $\sim 10-20$ level at $z \gtrsim 0.6$ for future wide weak lensing surveys.Comment: 18 pages, 15 figures, published on MNRA