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Many peptide drugs such as insulin and glucagon-like peptide (GLP-1) analogues are successfully administered subcutaneously (SC). Following SC injection, peptides may undergo catabolism in the SC compartment before entering systemic circulation, which could compromise their bioavailability and in turn affect their efficacy.This review will discuss how both technology and strategy have evolved over the past years to further elucidate peptide SC catabolism.Modern bioanalytical technologies (particularly liquid chromatography-high-resolution mass spectrometry) and bioinformatics platforms for data mining has prompted the development of

In this paper we will discuss the application of optimal filtering techniques for the adaptive optics system of the LBT telescope. We have studied the application of both Kalman and H$_\infty$ filters to estimate the temporal evolution of the phase perturbations due to the atmospheric turbulence and the telescope vibrations on tip/tilt modes. We will focus on the H$_\infty$ filter and on its advantages and disadvantages over the Kalman filter., 6 pages, 6 figures, 3 tables, European Control Conference (ECC) 2009, Budapest, Hungary, August 23-26, 2009

The future upgrade of Keck II telescope's adaptive optics system will include a pyramid wavefront sensor working in the near-infrared (J and H band). It will benefit from the recently developed avalanche photodiode arrays, specifically the SAPHIRA (Selex) array, which provides a low noise ($

International audience; We recently described C18 fatty acid acylated peptides as a new class of potent long-lasting single-chain RXFP1 agonists that displayed relaxin-like activities in vivo. Early pharmacokinetics and toxicological studies of these stearic acid acylated peptides revealed a relevant oxidative metabolism occurring in dog and minipig, and also seen at a lower extent in monkey and rat. Mass spectrometry combined to NMR spectroscopy studies revealed that the oxidation occurred, unexpectedly, on the stearic acid chain at ω-1, ω-2 and ω-3 positions. Structure-metabolism relationship studies on acylated analogues with different fatty acids lengths (C15-C20) showed that the extent of oxidation was higher with longer chains. The oxidized metabolites could be generated in vitro using liver microsomes and engineered bacterial CYPs. These systems were correlating poorly with in vivo metabolism observed across species; however, the results suggest that this biotransformation pathway might be catalyzed by some unknown CYP enzymes.

The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain. These ligands are potentially useful imaging biomarkers for HD therapeutic development in both preclinical and clinical settings. We describe here the optimization of the benzo[4,5]imidazo[1,2-a]pyrimidine series that show selective binding to mHTT aggregates over Aβ- and/or tau-aggregates associated with Alzheimer's disease pathology. Compound [11C]-2 was selected as a clinical candidate based on its high free fraction in the brain, specific binding in the HD mouse model, and rapid brain uptake/washout in nonhuman primate positron emission tomography imaging studies.

International audience; The next generation of Extremely Large Telescope (24 to 39m diameter) will suffer from the so-called "pupil fragmentation" problem. Due to their pupil shape complexity (segmentation, large spiders ...), some differential pistons may appear between some isolated part of the full pupil during the observations. Although classical AO system will be able to correct for turbulence effects, they will be blind to this specific telescope induced perturbations. Hence, such differential piston, a.k.a petal modes, will prevent to reach the diffraction limit of the telescope and ultimately will represent the main limitation of AO-assisted observation with an ELT. In this work we analyse the spatial structure of these petal modes and how it affects the ability of a Pyramid Wavefront sensor to sense them. Then we propose a variation around the classical Pyramid concept for increasing the WFS sensitivity to this particular modes. Nevertheless, We show that one single WFS can not accurately and simultaneously measure turbulence and petal modes. We propose a double path wavefront sensor scheme to solve this problem. We show that such a scheme,associated to a spatial filtering of residual turbulence in the second WFS path dedicated to petal mode sensing, allows to fully measure and correct for both turbulence and fragmentation effects and will eventually restore the full capability and spatial resolution of the future ELT.; La prochaine génération de Télescope Extrêmement Large (de 24 a 39m de diamètre) souffrira du problème de fragmentation de la pupille. Du a la complexité de la pupille de ces télescopes (segmentation, grande araignée, ...) des différences de piston peuvent apparaître entre les fragments de la pupille. Les systèmes d'Optique adaptative (OA) censées corrigés l'effet de turbulence seront aveugles a ces perturbations induites par la structure du télescope. Ces effets de piston différentiels souvent nommés mode pétale nous empêcheront d'atteindre la limite de diffraction du télescope et peut représenter la limite des observations assistés par Optique Adaptatives. Dans ce travail nous étudions la structure spatial de ces modes pétales et comment cela affecte la capacité du senseur pyramide a le mesurer. Ensuite nous proposons une modification du senseur pyramide pour améliorer la sensibilité au mode pétale. Néanmoins, nous avons montré qu'un seul ne peut pas être efficace pour mesurer en même temps la turbulence et les modes pétales. Nous proposons un senseur a deux voies pour résoudre ce problème. Nous montrons aussi qu'un tel schéma, associé a un filtrage spatial des résidus de turbulence permet de mesurer plus complétement et corriger la turbulence et les effets de fragmentation et finalement permet de restaurer la capacité et résolution compléte des futurs ELT.

Laser Guide Star (LGS) Shack-Hartmann (SH) wavefront sensors for next generation Extremely Large Telescopes (ELTs) require low-noise, large format (about 1Mpx), fast detectors to match the need for a large number of subapertures and a good sampling of the very elongated spots. One path envisaged to fulfill this need has been the adoption of CMOS detectors with a rolling shutter read-out scheme, that allows low read-out noise and fast readout time at the cost of image distortion due to the detector rows exposed in different moments. In this work we analyze the impact of the rolling shutter read-out scheme when used for LGS SH wavefront sensing of the Multiconjugate adaptive Optic Relay For ELT Observations (MORFEO, formerly known as MAORY) for ESO ELT; in particular, we focus on the impact on the adaptive optics correction of the distortion-induced aberrations created by the rolling exposure in the case of fast varying aberrations, like the ones coming from the LGS tilt jitter due to the up-link propagation of laser beams. We show that the LGS jitter-induced aberration for MORFEO can be as large as 100nm rms and we discuss possible mitigation strategies., 8 pages, 6 figures, SPIE Astronomical Telescopes + Instrumentation, 2022, Montreal, Canada

International audience

International audience; The instruments developed for the upcoming Extremely Large Telescopes (ELTs) will need efficient Adaptive Optics (AO) systems to correct the effects of the atmospheric turbulence and allow imaging at the highest angular resolution. One of the most important requirement for ELT AO-assisted instruments will be to deliver diffractionlimited images in a significant part of the sky. For that, the instruments will be equipped with Laser Guide Stars (LGSs) providing most of the information required by AO instruments. But even with LGSs, AO systems still require the use of Natural Guide Stars (NGSs) to compensate for image motion (jitter) and some low order aberrations. These NGSs are eventually limiting the fraction of the sky that can be achieved by AO systems, the so-called Sky Coverage. In this paper, we first present the sky coverage assessment methods used for HARMONI (High Angular Resolution Monolithic Optical and Near-infrared Integral field spectrograph) and MAORY/MICADO (Multi-conjugate Adaptive Optics RelaY/Multi-AO Imaging Camera for Deep Observations), that are both instruments for the Extremely Large Telescope of the European Southern Observatory (ESO). They are based on a semi-analytical description of the main contributors in the AO error budget, allowing for a fast estimation of the residual jitter. As such, these methods are well suited for statistical estimation of the sky coverage on multiple science fields, and/or to efficiently explore the system parameter space. We then compute the sky coverage of the two instruments in cosmological fields from the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS) catalog. The goal is to provide an insight on the possibilities given by two different types of tomographic AO systems, i. e. Laser Tomography AO (LTAO) with HARMONI and Multi-Conjugate AO (MCAO) with MAORY, on the same telescope. In particular, we show that HARMONI and MAORY/MICADO are complementary, meaning that the overall sky coverage of ESO's ELT is much improved for applications common to both systems.

The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimetics. Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). Introduction of suitable spacers and fatty acids led to the identification of single-chain lipidated peptide agonists of RXFP1, with sub-nanomolar activity, high subcutaneous bioavailability, extended half-lives, and in vivo efficacy (e.g., 64).

Laser guide star (LGS) wave-front sensing (LGSWFS) is a key element of tomographic adaptive optics system. However, when considering Extremely Large Telescope (ELT) scales, the LGS spot elongation becomes so large that it challenges the standard recipes to design LGSWFS. For classical Shack-Hartmann wave-front sensor (SHWFS), which is the current baseline for all ELT LGS-assisted instruments, a trade-off between the pupil spatial sampling [number of sub-apertures (SAs)], the SA field-of-view (FoV) and the pixel sampling within each SA is required. For ELT scales, this trade-off is also driven by strong technical constraints, especially concerning the available detectors and in particular their number of pixels. For SHWFS, a larger field of view per SA allows mitigating the LGS spot truncation, which represents a severe loss of performance due to measurement biases. For a given number of available detectors pixels, the SA FoV is competing with the proper sampling of the LGS spots, and/or the total number of SAs. We proposed a sensitivity analysis, and we explore how these parameters impacts the final performance. In particular, we introduce the concept of super resolution, which allows one to reduce the pupil sampling per WFS and opens an opportunity to propose potential LGSWFS designs providing the best performance for ELT scales., Comment: 21 pages, 11 figures, 1 table, part of the 2022 JATIS Special Section on Extremely Large Telescopes

Paolo Stefanini, per tutti "Paolino", ci ha lasciato. È successo il 3 maggio e ci ha lasciato con lo stile sobrio e riservato che lo ha sempre contraddistinto. A queste notizie non si è mai preparati e nel caso di Paolo è ancora più vero. Lo ricorda qui Simone Esposito, e tanti altri colleghi e amici che hanno riportato un pensiero a lui dedicato in questa pagina

The Provence Adaptive optics Pyramid Run System (PAPYRUS) is a pyramid-based Adaptive Optics (AO) system that will be installed at the Coude focus of the 1.52m telescope (T152) at the Observatoire de Haute Provence (OHP). The project is being developed by PhD students and Postdocs across France with support from staff members consolidating the existing expertise and hardware into an R&D testbed. This testbed allows us to run various pyramid wavefront sensing (WFS) control algorithms on-sky and experiment on new concepts for wavefront control with additional benefit from the high number of available nights at this telescope. It will also function as a teaching tool for students during the planned AO summer school at OHP. To our knowledge, this is one of the first pedagogic pyramid-based AO systems on-sky. The key components of PAPYRUS are a 17x17 actuators Alpao deformable mirror with a Alpao RTC, a very low noise camera OCAM2k, and a 4-faces glass pyramid. PAPYRUS is designed in order to be a simple and modular system to explore wavefront control with a pyramid WFS on sky. We present an overview of PAPYRUS, a description of the opto-mechanical design and the current status of the project., 19 pages, 11 figures

Lipidation, a common strategy to improve half-life of therapeutic peptides, affects their tendency to oligomerize, their interaction with plasmatic proteins, and their catabolism. In this work, we have leveraged the use of NMR and SPR spectroscopy to elucidate oligomerization propensity and albumin interaction of different analogs of the two marketed lipidated GLP-1 agonists liraglutide and semaglutide. As most lipidated therapeutic peptides are administered by subcutaneous injection, we have also assessed in vitro their catabolism in the SC tissue using the LC-HRMS-based SCiMetPep assay. We observed that oligomerization had a shielding effect against catabolism. At the same time, binding to albumin may provide only limited protection from proteolysis due to the higher unbound peptide fraction present in the subcutaneous compartment with respect to the plasma. Finally, identification of catabolites in rat plasma after SC dosing of semaglutide showed a good correlation with the in vitro data, with Tyr

Future large adaptive telescopes will trigger new constraints for the calibration of adaptive optics (AO) systems equipped with pre-focal deformable mirrors (DMs). The image of the DM actuator grid, as seen by the wavefront sensor (WFS), may evolve during the operations because of the flexures of the opto-mechanical components present in the optical path. This will result in a degraded AO performance that will affect the scientific operation. To overcome this challenge, it will be necessary to regularly monitor and compensate for these DM/WFS mis-registrations, either by physically realigning some optical components or by updating the control matrix of the system. In this paper, we present a new strategy to track mis-registrations using a pseudo-synthetic model of the AO system. The method is based on an invasive approach where signals are acquired on-sky, before or during the scientific operations, and fed to the model to extract the mis-registration parameters. We introduce a method to compute the most sensitive modes to these mis-registrations that allows us to reduce the number of degrees of freedom required by the algorithm and to minimize the effect on the scientific performance. We demonstrate that, by using only a few of these well-selected signals, the method provides very good accuracy for parameter estimation, well under the targeted accuracy, and has a negligible effect on the scientific path. In addition, the method appears to be very robust to varying operating conditions of noise and atmospheric turbulence and it performs equally for both pyramid and Shack–Hartmann WFSs.

This manuscript further examines the role of rituals and authenticity, in relation to consumer behaviour, in the spa and wellness sector. In doing so, examples of wellness rituals have been provide...

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 Journal

Background: Pharmacogenetics investigates the response to pharmacological treatments based on individual genetic background. Actually, numerous pharmacogenetic tests help to predict the response to drugs used in different medical areas, contributing to the so-called personalized medicine. Objective: This review aims to update the available data on the genotype-guided treatment with both the anticoagulant and antiplatelet agents. Moreover, it shed light on the pitfalls still contrasting the implementation of cardiovascular pharmacogenetics. Methods: A review of the literature on the studies investigating the effects of the genotype-guided anticoagulant and antiplatelet treatment was performed. Results: Considering the large use of antithrombotic drugs, pharmacogenetics has particular importance in this field. Several polymorphisms influence the response to both anticoagulant and antiplatelet agents, and tests, based on their identification, are now available. Conclusions: Recent randomized clinical trials demonstrated that pharmacogenetics might successfully contribute to optimizing the antiplatelet therapy also in patients particularly complicated to treat. However, despite accumulating evidence on the utility and feasibility of some pharmacogenetics tests, several barriers still contrast their implementation into clinical practice.

The MCAO Assisted Visible Imager and Spectrograph (MAVIS) is a facility-grade visible MCAO instrument, currently under development for the Adaptive Optics Facility at the VLT. The adaptive optics system will feed both an imager and an integral field spectrograph, with unprecedented sky coverage of 50% at the Galactic Pole. The imager will deliver diffraction-limited image quality in the V band, cover a 30" x 30" field of view, with imaging from U to z bands. The conceptual design for the spectrograph has a selectable field-of-view of 2.5" x 3.6", or 5" x 7.2", with a spatial sampling of 25 or 50 mas respectively. It will deliver a spectral resolving power of R=5,000 to R=15,000, covering a wavelength range from 380 - 950 nm. The combined angular resolution and sensitivity of MAVIS fill a unique parameter space at optical wavelengths, that is highly complementary to that of future next-generation facilities like JWST and ELTs, optimised for infrared wavelengths. MAVIS will facilitate a broad range of science, including monitoring solar system bodies in support of space missions; resolving protoplanetary- and accretion-disk mechanisms around stars; combining radial velocities and proper motions to detect intermediate-mass black holes; characterising resolved stellar populations in galaxies beyond the local group; resolving galaxies spectrally and spatially on parsec scales out to 50 Mpc; tracing the role of star clusters across cosmic time; and characterising the first globular clusters in formation via gravitational lensing. We describe the science cases and the concept designs for the imager and spectrograph.

The Facility AO systems at the LBT are based around the two Adaptive Secondary Mirrors (ASM) and the Pyramid Wavefront Sensors (PWFS), the latter being recently upgraded as part of the SOUL project in order to provide improved image quality performance and greater faint target sensitivity, at the LUCI and LBTI ports. These represent operational AO Systems with unique challenges for maintaining their optimal operational status. Based on our experience, especially over the last seven years, we present our approach to provide the readiness of the AO systems at all times including routine calibration, monitoring, and maintenance activities necessary to keep their performance at an optimal level. We also address intervention activities to improve the ASMs’ reliability and robustness.

International audience; On-sky testing of new instrumentation concepts is required before they can be incorporated within facility-class instrumentation with certainty that they will work as expected within a real telescope environment. Increasingly, many of these concepts are not designed to work in seeing-limited conditions and require an upstream adaptive optics system for testing. Access to on-sky AO systems to test such systems is currently limited to a few research groups and observatories worldwide, leaving many concepts unable to be tested. A pilot program funded through the H2020 OPTICON program offering up to 15 nights of on-sky time at the CANARY Adaptive Optics demonstrator is currently running but this ends in 2021. Pre-run and on-sky support is provided to visitor experiments by the CANARY team. We have supported 6 experiments over this period, and plan one more run in early 2021. We have recently been awarded for funding through the H2020 OPTICON-RADIO PILOT call to continue and extend this program up until 2024, offering access to CANARY at the 4.2m William Herschel Telescope and 3 additional instruments and telescopes suitable for instrumentation development. Time on these facilities will be open to researchers from across the European research community and time will be awarded by answering a call for proposals that will be assessed by an independent panel of instrumentation experts. Unlike standard observing proposals we plan to award time up to 2 years in advance to allow time for the visitor instrument to be delivered. We hope to announce the first call in mid-2021. Here we describe the facilities offered, the support available for on-sky testing and detail the eligibility and application process.

The Gemini Planet Imager (GPI) is a dedicated high-contrast imaging facility designed for the direct detection and characterization of young Jupiter mass exoplanets. After six yrs of operation at Gemini South, GPI has helped establish that Jovian planets are rare at wide separations, but have higher occurrence rates at small separations. This motivates an upgrade of GPI to achieve deeper contrasts, especially at small inner working angles, while leveraging its current capabilities. GPI has been funded to undergo a major science-driven upgrade as part of a relocation to Gemini North (GN). Gemini plans to remove GPI at the end of 2020A. We present the status of the proposed upgrades to GPI including a EMCCD-based pyramid wavefront sensor, broadband low spectral resolution prisms and new apodized-pupil Lyot coronagraph designs. We discuss the expected performance improvements in the context of GPI 2.0's enhanced science capabilities which are scheduled to be made available at GN in 2022., SPIE Astronomical Telescopes + Instrumentation, December 14-18, 2020, Online Only, United States, Series: Proceedings of SPIE

SHARK-NIR in an instrument that will provide direct imaging, coronagraphic imaging, dual band imaging and low resolution spectroscopy in Y, J and H bands, and it will be soon installed at the Large Binocular Telescope. Used in combination with SHARK-VIS (operating in V band) and LMIRCam of LBTI (operating from K to M bands), SHARKNIR will exploit coronagraphic simultaneous observations in three different wavelengths. Exoplanets search and characterization, young stellar systems, jets and disks are the main science cases, but the extreme performance of the LBT AO systems, above all in the faint end regime, will allow to open to science difficult to be achieved from other similar instruments, such as AGN and QSO morphological studies. A variety of coronagraphic techniques have been implemented, as the Gaussian Lyot, Shaped Pupil and Four Quadrant masks, with the aim to possibly have a suitable coronagraphic masks for each science case, since the coronagraphic requirement in term of contrast and inner and outer working angle are depending on the target and on the science to be achieved. We report here about the SHARK-NIR status, that should be installed at LBT in mid-2021

MAORY is a post-focal adaptive optics module that forms part of the first light instrument suite for the ELT. The main function of MAORY is to relay the light beam from the ELT focal plane to the client instrument while compensating the effects of the atmospheric turbulence and other disturbances affecting the wavefront from the scientific sources of interest.

The Multi Conjugate Adaptive Optics RelaY (MAORY) for the ESO Extremely Large Telescope (ELT) is an Adaptive Optics module offering Multi-Conjugate (MCAO) and Single-Conjugate (SCAO) compensation modes. In MCAO, it relies on the use of a constellation of Laser Guide Stars (LGS) and up to three Natural Guide Stars (NGS) for atmospheric turbulence sensing, and multiple deformable mirrors for correction, providing uniform, high Strehl and high sky coverage. MAORY will be installed at the Nasmyth focus of the E-ELT and will feed the MICADO first-light diffraction limited imager and a future second instrument. MAORY is being built by a Consortium composed by INAF in Italy, IPAG in France and the School of Physics at the National University of Ireland Galway. In this paper we report about the status of the design of the MAORY Real Time Computer, which is the component in charge of implementing the main AO control loops, as well as of auxiliary computations to keep the loops operating optimally, and of telemetry data collection for postprocessing, monitoring, testing and troubleshooting. We will start by discussing the evolution of requirements towards MAORY RTC, with an emphasis on the main driving ones. Then, we will describe how the analysis of requirements has led to the derivation of the main design parameters. Finally, we will illustrate possible RTC designs satisfying user requirements, while also complying with standards set forth by ESO.

A consortium of several Australian and European institutes – together with the European Southern Observatory (ESO) – has initiated the design of MAVIS, a Multi-Conjugate Adaptive Optics (MCAO) system for the ground- based 8-m Very Large Telescope (VLT). MAVIS (MCAO-assisted Visible Imager and Spectrograph) will deliver visible images and integral field spectrograph data with 2-3x better angular resolution than the Hubble Space Telescope, making it a powerful complement at visible wavelengths to future facilities like the space-based James Webb Space Telescope and the 30 to 40m-class ground-based telescopes currently under construction, which are all targeting science at near-infrared wavelengths. MAVIS successfully passed its Phase A in May 2020. We present the motivations, requirements, principal design choices, conceptual design, expected performance and an overview of the exciting science enabled by MAVIS.