DOWN-REGULATION OF ATYPICAL CHEMOKINE RECEPTOR ACKR2/D6 EXPRESSION BY HEMATOPOIETIC PROGENITORS PROMOTES MYELOID CELL MOBILIZATION AND DIFFERENTIATION

Chemokines and chemokine receptors are key mediators of inflammation and important regulators of leukocyte migration in homeostatic conditions as well as during infection and cancer. The atypical receptor ACKR2 is a scavenger receptor for many inflammatory CC chemokines, it is expressed either by non-hematopoietic cells or by hematopoietic cells, and it has been shown to prevent the development of exacerbated inflammatory reactions. In an effort to understand the contribution of this receptor in the regulation of myeloid cell mobilization and myeloid cell effector functions, we investigated the role of ACKR2 in a murine model of myeloid cell mobilization, and in a model of experimental metastasis. The deficiency of ACKR2 was associated with increased mobilization of monocytes and neutrophils from the bone marrow (BM) and with increased number of monocytes confined to BM sinusoids compared to Wild-type (WT) mice. BM chimera experiments showed that the increased mobilization was due to the absence of ACKR2 in the hematopoietic compartment. The analysis of hematopoietic progenitor cells (HPCs) revealed that ACKR2 is expressed by Lin 12Sca-1+c-Kit+ cells (LSK) to faint thereafter in more mature myeloid progenitor cells (MPCs) in contrast with the canonical chemokine receptor CCR2. Moreover, HPCs from Ackr2-/- mice expressed higher levels of CCR1, CCR2 and CCR5, but not of CXCR4 and they had higher differentiation rate compared to ACKR2 sufficient LSK. Although neutrophils express low levels of ACKR2 compared to LSK, we found that neutrophils from Ackr2 deficient mice, as well as their HPCs, expressed higher level of CC chemokine receptors and exhibited a more activated phenotype compared to WT. Furthermore, neutrophil depletion and neutrophil adoptive transfer experiments demonstrated that only Ackr2 deficient neutrophils were sufficient to control the metastatic seeding of B16 melanoma cells into the lung. To enhance the metastatic protection observed in Ackr2-/- mice, we treated WT and Ackr2-/- tumor bearing mice with AMD3100, the competitive inhibitor of CXCR4, which is known to induce a rapid neutrophil mobilization from the BM. However, AMD3100 treatment did not further improve the metastatic protection in Ackr2-/- mice, whereas decreased the number of metastases in WT mice. Finally, by using the human promyelocytic cell line HL-60, we demonstrated that ACKR2 directly exerted a negative regulation of CC chemokine receptor expression and cell differentiation. Indeed, HL-60, when transfected with a vector overexpressing ACKR2, had decreased transcript levels of CCR2 and CD11b. These data suggest the ACKR2 is involved in the regulation of chemokine availability and leukocyte recruitment. Moreover, ACKR2 directly controls HPC differentiation, myeloid cell mobilization and their effector function through the inhibition of CC chemokine receptor expression

Indacaterol/glycopyrronium/mometasone fixed dose combination for uncontrolled asthma

Introduction: Asthma symptoms can be relieved through a maintenance treatment combining long-acting β2-agonist and inhaled corticosteroids (LABA/ICS). However, for patients with inadequately controlled asthma, the LABA/ICS combination might not be sufficient, and clinical guidelines recommend the administration of inhaled long-acting muscarinic antagonists (LAMA) as an add-on therapy to better control asthma and improve lung function. For nearly two decades, the only LAMA to be approved on the market has been tiotropium. Areas covered: We reviewed recent clinical studies evaluating the safety and efficacy of LABA/LAMA/ICS fixed dose combinations by searching the PubMed database. Molecular mechanisms and clinical data support the use of a once-daily, single-inhaler fixed dose combination of the LABA/LAMA/ICS indacaterol/glycopyrronium/mometasone (IND/GLY/MF), the first therapy combining three agents in a fixed dose approved in Europe for the treatment of uncontrolled asthma. Expert opinion: IND/GLY/MF was superior to both IND/MF and salmeterol/fluticasone, a well-established LABA/ICS combination improving the lung function in uncontrolled asthma. Moreover, IND/GLY/MF, delivered through the Breezhaler inhaler in a single inhalation, is the first inhaled therapy prescribed alongside a digital companion, a sensor and the Propeller app, allowing for improved treatment adherence, reduced rescue inhaler usage and hospitalizations, increased patient satisfaction and asthma control

Post conjunction detection of β\beta Pictoris b with VLT/SPHERE

With an orbital distance comparable to that of Saturn in the solar system, \bpic b is the closest (semi-major axis $\simeq$\,9\,au) exoplanet that has been imaged to orbit a star. Thus it offers unique opportunities for detailed studies of its orbital, physical, and atmospheric properties, and of disk-planet interactions. With the exception of the discovery observations in 2003 with NaCo at the Very Large Telescope (VLT), all following astrometric measurements relative to \bpic have been obtained in the southwestern part of the orbit, which severely limits the determination of the planet's orbital parameters. We aimed at further constraining \bpic b orbital properties using more data, and, in particular, data taken in the northeastern part of the orbit. We used SPHERE at the VLT to precisely monitor the orbital motion of beta \bpic b since first light of the instrument in 2014. We were able to monitor the planet until November 2016, when its angular separation became too small (125 mas, i.e., 1.6\,au) and prevented further detection. We redetected \bpic b on the northeast side of the disk at a separation of 139\,mas and a PA of 30$^{\circ}$ in September 2018. The planetary orbit is now well constrained. With a semi-major axis (sma) of $a = 9.0 \pm 0.5$ au (1 $\sigma$), it definitely excludes previously reported possible long orbital periods, and excludes \bpic b as the origin of photometric variations that took place in 1981. We also refine the eccentricity and inclination of the planet. From an instrumental point of view, these data demonstrate that it is possible to detect, if they exist, young massive Jupiters that orbit at less than 2 au from a star that is 20 pc away.Comment: accepted by A&

In-depth study of moderately young but extremely red, very dusty substellar companion HD206893B

Accepted for publication in Astronomy & Astrophysics. Reproduced with permission from Astronomy & Astrophysics. © 2018 ESO.The substellar companion HD206893b has recently been discovered by direct imaging of its disc-bearing host star with the SPHERE instrument. We investigate the atypical properties of the companion, which has the reddest near-infrared colours among all known substellar objects, either orbiting a star or isolated, and we provide a comprehensive characterisation of the host star-disc-companion system. We conducted a follow-up of the companion with adaptive optics imaging and spectro-imaging with SPHERE, and a multiinstrument follow-up of its host star. We obtain a R=30 spectrum from 0.95 to 1.64 micron of the companion and additional photometry at 2.11 and 2.25 micron. We carried out extensive atmosphere model fitting for the companions and the host star in order to derive their age, mass, and metallicity. We found no additional companion in the system in spite of exquisite observing conditions resulting in sensitivity to 6MJup (2MJup) at 0.5" for an age of 300 Myr (50 Myr). We detect orbital motion over more than one year and characterise the possible Keplerian orbits. We constrain the age of the system to a minimum of 50 Myr and a maximum of 700 Myr, and determine that the host-star metallicity is nearly solar. The comparison of the companion spectrum and photometry to model atmospheres indicates that the companion is an extremely dusty late L dwarf, with an intermediate gravity (log g 4.5-5.0) which is compatible with the independent age estimate of the system. Though our best fit corresponds to a brown dwarf of 15-30 MJup aged 100-300 Myr, our analysis is also compatible with a range of masses and ages going from a 50 Myr 12MJup planetary-mass object to a 50 MJup Hyades-age brown dwarf...Peer reviewedFinal Accepted Versio

A maritime decision support system to assess risk in the presence of environmental uncertainties: the REP10 experiment

The aim of this work is to report on an activity carried out during the 2010 Recognized Environmental Picture experiment, held in the Ligurian Sea during summer 2010. The activity was the first at-sea test of the recently developed decision support system (DSS) for operation planning, which had previously been tested in an artificial experiment. The DSS assesses the impact of both environmental conditions (meteorological and oceanographic) and non-environmental conditions (such as traffic density maps) on people and assets involved in the operation and helps in deciding a course of action that allows safer operation. More precisely, the environmental variables (such as wind speed, current speed and significant wave height) taken as input by the DSS are the ones forecasted by a super-ensemble model, which fuses the forecasts provided by multiple forecasting centres. The uncertainties associated with the DSS's inputs (generally due to disagreement between forecasts) are propagated through the DSS's output by using the unscented transform. In this way, the system is not only able to provide a traffic light map (run/not run the operation), but also to specify the confidence level associated with each action. This feature was tested on a particular type of operation with underwater gliders: the glider surfacing for data transmission. It is also shown how the availability of a glider path prediction tool provides surfacing options along the predicted path. The applicability to different operations is demonstrated by applying the same system to support diver operations

The JWST Early-Release Science Program for Direct Observations of Exoplanetary Systems Ii: A 1 To 20 Μm Spectrum of the Planetary-Mass Companion Vhs 1256-1257 B

We present the highest fidelity spectrum to date of a planetary-mass object. VHS 1256 b is a (∼8″, a = 150 au), young, planetary-mass companion that shares photometric colors and spectroscopic features with the directly imaged exoplanets HR 8799c, d, and e. As an L-to-T transition object, VHS 1256 b exists along the region of the color-magnitude diagram where substellar atmospheres transition from cloudy to clear. We observed VHS 1256 b with JWST\u27s NIRSpec IFU and MIRI MRS modes for coverage from 1 to 20 μm at resolutions of ∼1000-3700. Water, methane, carbon monoxide, carbon dioxide, sodium, and potassium are observed in several portions of the JWST spectrum based on comparisons from template brown dwarf spectra, molecular opacities, and atmospheric models. The spectral shape of VHS 1256 b is influenced by disequilibrium chemistry and clouds. We directly detect silicate clouds, the first such detection reported for a planetary-mass companion

The HOSTS survey: evidence for an extended dust disk and constraints on the presence of giant planets in the Habitable Zone of β\beta Leo

The young (50-400 Myr) A3V star $\beta$ Leo is a primary target to study the formation history and evolution of extrasolar planetary systems as one of the few stars with known hot ($\sim$1600$^\circ$K), warm ($\sim$600$^\circ$K), and cold ($\sim$120$^\circ$K) dust belt components. In this paper, we present deep mid-infrared measurements of the warm dust brightness obtained with the Large Binocular Telescope Interferometer (LBTI) as part of its exozodiacal dust survey (HOSTS). The measured excess is 0.47\%$\pm$0.050\% within the central 1.5 au, rising to 0.81\%$\pm$0.026\% within 4.5 au, outside the habitable zone of $\beta$~Leo. This dust level is 50 $\pm$ 10 times greater than in the solar system's zodiacal cloud. Poynting-Robertson drag on the cold dust detected by Spitzer and Herschel under-predicts the dust present in the habitable zone of $\beta$~Leo, suggesting an additional delivery mechanism (e.g.,~comets) or an additional belt at $\sim$5.5 au. A model of these dust components is provided which implies the absence of planets more than a few Saturn masses between $\sim$5 au and the outer belt at $\sim$40 au. We also observationally constrain giant planets with the LBTI imaging channel at 3.8~$\mu$m wavelength. Assuming an age of 50 Myr, any planet in the system between approximately 5 au to 50 au must be less than a few Jupiter masses, consistent with our dust model. Taken together, these observations showcase the deep contrasts and detection capabilities attainable by the LBTI for both warm exozodiacal dust and giant exoplanets in or near the habitable zone of nearby stars.Comment: 11 pages, 9 figures, accepted for publication in Astronomical Journa

TOI-2084 b and TOI-4184 b: two new sub-Neptunes around M dwarf stars

We present the discovery and validation of two TESS exoplanets orbiting nearby M dwarfs: TOI-2084b, and TOI-4184b. We characterized the host stars by combining spectra from Shane/Kast and Magellan/FIRE, SED (Spectral Energy Distribution) analysis, and stellar evolutionary models. In addition, we used Gemini-South/Zorro & -North/Alopeke high-resolution imaging, archival science images, and statistical validation packages to support the planetary interpretation. We performed a global analysis of multi-colour photometric data from TESS and ground-based facilities in order to derive the stellar and planetary physical parameters for each system. We find that TOI-2084b and TOI-4184b are sub-Neptune-sized planets with radii of Rp = 2.47 +/- 0.13R_Earth and Rp = 2.43 +/- 0.21R_Earth, respectively. TOI-2084b completes an orbit around its host star every 6.08 days, has an equilibrium temperature of T_eq = 527 +/- 8K and an irradiation of S_p = 12.8 +/- 0.8 S_Earth. Its host star is a dwarf of spectral M2.0 +/- 0.5 at a distance of 114pc with an effective temperature of T_eff = 3550 +/- 50 K, and has a wide, co-moving M8 companion at a projected separation of 1400 au. TOI-4184b orbits around an M5.0 +/- 0.5 type dwarf star (Kmag = 11.87) each 4.9 days, and has an equilibrium temperature of T_eq = 412 +/- 8 K and an irradiation of S_p = 4.8 +/- 0.4 S_Earth. TOI-4184 is a metal poor star ([Fe/H] = -0.27 +/- 0.09 dex) at a distance of 69 pc with an effective temperature of T_eff = 3225 +/- 75 K. Both planets are located at the edge of the sub-Jovian desert in the radius-period plane. The combination of the small size and the large infrared brightness of their host stars make these new planets promising targets for future atmospheric exploration with JWST.Comment: Accepted for publication in A&