Infrared supercontinuum generated in concatenated InF3 and As2Se3 fibers

We report on infrared supercontinuum (SC) generation through subsequent nonlinear propagation in concatenated step-index fluoride and As2Se3 fiber. These fibers were pumped by an all-fiber laser source based on an erbium amplifier followed by a thulium power amplifier. ZBLAN and InF3 fibers were compared for the concatenated scheme. The broadest SC produced was achieved by optimizing the length of the InF3 fiber. This arrangement allowed the generation of 200 mW infrared SC with high spectral flatness and spanning from 1.4 μm to 6.4 μm

APPleSOSS: A Producer of ProfiLEs for SOSS. Application to the NIRISS SOSS Mode

The SOSS mode of the NIRISS instrument is poised to be one of the workhorse modes for exoplanet atmosphere observations with the newly launched James Webb Space Telescope. One of the challenges of the SOSS mode, however, is the physical overlap of the first two diffraction orders of the G700XD grism on the detector. Recently, the ATOCA algorithm was developed and implemented as an option in the official JWST pipeline, as a method to extract SOSS spectra by decontaminating the detector -- that is, separating the first and second orders. Here, we present APPleSOSS (A Producer of ProfiLEs for SOSS), which generates the spatial profiles for each diffraction order upon which ATOCA relies. We validate APPleSOSS using simulated SOSS time series observations of WASP-52b, and compare it to ATOCA extractions using two other spatial profiles (a best and worst case scenario on-sky), as well as a simple box extraction performed without taking into account the order contamination. We demonstrate that APPleSOSS traces retain a high degree of fidelity to the true underlying spatial profiles, and therefore yield accurate extracted spectra. We further confirm that the effects of the order contamination for relative measurements (e.g., exoplanet transmission or emission observations) is small -- the transmission spectrum obtained from each of our four tests, including the contaminated box extraction, deviates by $\lesssim$0.1$\sigma$ from the atmosphere model input into our noiseless simulations. We further confirm via a retrieval analysis that the atmosphere parameters (metallicity and C/O) obtained from each transmission spectrum are consistent at the 1$\sigma$ level with the true underlying values.Comment: 12 pages, 9 figures. Submitted to PAS

Gut microbes shape microglia and cognitive function during malnutrition

Fecal-oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL-BG). The MAL-BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non-neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal-oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL-BG mice. Unexpectedly, these changes occurred independently from significant cytokine-induced inflammation or blood-brain barrier (BBB) disruption, key gut-brain pathways. Metabolomic profiling of the MAL-BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant-associated diet (PAO) mitigated cognitive deficits within the MAL-BG model. These findings provide valued insight into the malnourished gut microbiota-brain axis, highlighting PUFA metabolism as a potential therapeutic target

Atmospheric Reconnaissance of TRAPPIST-1 b with JWST/NIRISS: Evidence for Strong Stellar Contamination in the Transmission Spectra

TRAPPIST-1 is a nearby system of seven Earth-sized, temperate, rocky exoplanets transiting a Jupiter-sized M8.5V star, ideally suited for in-depth atmospheric studies. Each TRAPPIST-1 planet has been observed in transmission both from space and from the ground, confidently rejecting cloud-free, hydrogen-rich atmospheres. Secondary eclipse observations of TRAPPIST-1 b with JWST/MIRI are consistent with little to no atmosphere given the lack of heat redistribution. Here we present the first transmission spectra of TRAPPIST-1 b obtained with JWST/NIRISS over two visits. The two transmission spectra show moderate to strong evidence of contamination from unocculted stellar heterogeneities, which dominates the signal in both visits. The transmission spectrum of the first visit is consistent with unocculted starspots and the second visit exhibits signatures of unocculted faculae. Fitting the stellar contamination and planetary atmosphere either sequentially or simultaneously, we confirm the absence of cloud-free hydrogen-rich atmospheres, but cannot assess the presence of secondary atmospheres. We find that the uncertainties associated with the lack of stellar model fidelity are one order of magnitude above the observation precision of 89 ppm (combining the two visits). Without affecting the conclusion regarding the atmosphere of TRAPPIST-1 b, this highlights an important caveat for future explorations, which calls for additional observations to characterize stellar heterogeneities empirically and/or theoretical works to improve model fidelity for such cool stars. This need is all the more justified as stellar contamination can affect the search for atmospheres around the outer, cooler TRAPPIST-1 planets for which transmission spectroscopy is currently the most efficient technique.Comment: 26 pages, 11 figures, accepted for publication in The Astrophysical Journal Letter

Near-Infrared Transmission Spectroscopy of HAT-P-18 \,b with NIRISS: Disentangling Planetary and Stellar Features in the Era of JWST

The JWST Early Release Observations (ERO) included a NIRISS/SOSS (0.6-2.8$\,\mu$m) transit of the $\sim\,$850$\,$K Saturn-mass exoplanet HAT-P-18$\,$b. Initial analysis of these data reported detections of water, escaping helium, and haze. However, active K dwarfs like HAT-P-18 possess surface heterogeneities $-$ starspots and faculae $-$ that can complicate the interpretation of transmission spectra, and indeed, a spot-crossing event is present in HAT-P-18$\,$b's NIRISS/SOSS light curves. Here, we present an extensive reanalysis and interpretation of the JWST ERO transmission spectrum of HAT-P-18$\,$b, as well as HST/WFC3 and $\textit{Spitzer}$/IRAC transit observations. We detect H$_2$O (12.5$\,\sigma$), CO$_2$ (7.3$\,\sigma$), a cloud deck (7.4$\,\sigma$), and unocculted starspots (5.8$\,\sigma$), alongside hints of Na (2.7$\,\sigma$). We do not detect the previously reported CH$_4$ ($\log$ CH$_4$ $<$ -6 to 2$\,\sigma$). We obtain excellent agreement between three independent retrieval codes, which find a sub-solar H$_2$O abundance ($\log$ H$_2$O $\approx -4.4 \pm 0.3$). However, the inferred CO$_2$ abundance ($\log$ CO$_2$ $\approx -4.8 \pm 0.4$) is significantly super-solar and requires further investigation into its origin. We also introduce new stellar heterogeneity considerations by fitting for the active regions' surface gravities $-$ a proxy for the effects of magnetic pressure. Finally, we compare our JWST inferences to those from HST/WFC3 and $\textit{Spitzer}$/IRAC. Our results highlight the exceptional promise of simultaneous planetary atmosphere and stellar heterogeneity constraints in the era of JWST and demonstrate that JWST transmission spectra may warrant more complex treatments of the transit light source effect

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Functional regulation of P2X receptor channels by phosphoinositides

Long after its initial discovery as part of DNA and as the main source of energy in the cell, the nucleotide adenosine-5'-triphosphate (ATP) is now rightfully considered as an important extracellular signalling molecule. It is now known that purinergic transmission plays significant physiological roles, notably in neuro- and gliotransmission, in the modulation of the innate and adaptive immune response, in smooth muscle constriction and in regulating blood clotting. It is also actively involved in the generation and maintenance of various pathological states, including chronic neuropathic and inflammatory pain.How purinergic signalling can be implicated in such a diverse array of mechanisms via only one signalling molecule comes from the variety of receptors that are activated by ATP. Two major types of ATP-sensitive receptors exist: the P2X ionotropic receptor channels and the metabotropic P2Y receptors. The P2X family of ATP-gated ion channels is composed of seven subunits that assemble as trimers to form receptors with various functional and pharmacological profiles. Like all ion channels, the activity of P2X receptor channels is tightly regulated by orthosteric and allosteric regulation mechanisms. This thesis provides evidence of a novel type of post-translational regulation mechanism where the levels of intracellular phosphoinositides (PIPn) modulate the channel activity of P2X receptors. The first article included in my thesis focuses on the P2X1 subtype, which is mainly involved in smooth muscle constriction in blood vessels and vas deferens, as well as in the control of platelet aggregation and blood clotting. We demonstrate that the activity of the P2X1 receptor channel is positively regulated by membrane PI(4,5)P2 (PIP2). Depleting the intracellular levels of PIP2 decreased the ATP-activated current carried through the P2X1 channel and had an inhibitory effect on ATP-mediated mesenteric artery constriction, a P2X1-dependent process. Direct binding between the P2X1 cytosolic tail and PIP2 is shown to be necessary for the full expression of P2X1 activity.The next article in this thesis describes the PIPn-dependent regulation of the P2X4 receptor channel, which is highly involved in the generation of neuropathic and inflammatory pain through its expression in spinal cord microglia. Results obtained show that complete P2X4 function is dependent on the levels of PIP2 and PI(3,4,5)P3 (PIP3). Both species of phospholipids potentiate the P2X4-mediated ionic current and calcium entry by directly binding to the C-terminal domain of P2X4 subunits. Activation of co-expressed microglial metabotropic receptors can trigger changes in PIP2 or PIP3 levels, which could affect the contribution of P2X4 in pain-inducing mechanisms.In the third report, we investigate the molecular characteristics of the interaction between membrane PIPn and the various P2X receptors that were shown to be directly modulated by the phospholipids. By analyzing the functional and PIPn-binding effects of various mutations performed on the C-terminal domain of the PIPn-sensitive P2X1, P2X4 and P2X7 subtypes as well as on the PIPn-insensitive P2X5 subtype, we identify the PIPn-binding regulatory motif of P2X receptors. The last article included in this thesis examines the dynamic changes in channel permeability brought by sustained activation of the microglial P2X4 receptor. We show that upon sustained ATP application, P2X4 channels form large conductance pores allowing the flux of large organic molecules. The large pore formation of co-expressed microglial P2X7 receptors has been extensively studied; we show here that P2X4-mediated permeation is mechanistically distinct and, in contrast with P2X7, does not induce membrane blebbing or cell death. Furthermore, we demonstrate that membrane PIPn potentiate the formation of this high-conductance P2X4 pore, suggesting that this property can be regulated by metabotropic changes in PIPn levels.Longtemps après la découverte de sa présence dans l'ADN et de son rôle en tant que principale source d'énergie chimique dans la cellule, le nucléotide adenosine-5'-triphosphate (ATP) est maintenant considéré comme une importante molécule de signalisation extracellulaire. La transmission purinergique est activement impliquée dans plusieurs processus physiologiques, notamment dans la neuro- et glio-transmission, la modulation de la réponse immunitaire innée et adaptative, la constriction vasculaire et la coagulation sanguine. Elle participe aussi à la génération et au maintien de divers états pathologiques, tels la douleur chronique neuropathique et inflammatoire.La signalisation purinergique est impliquée dans des processus aussi diversifiés par l'entremise d'une seule molécule de signalisation grâce à une grande variété de récepteurs activés par l'ATP. Les deux principaux types de récepteurs sensibles à l'ATP sont les récepteurs ionotropiques P2X et les récepteurs métabotropiques P2Y. La famille P2X de canaux ioniques activés par l'ATP est composée de sept sous-unités qui s'assemblent comme trimères pour former des récepteurs possédant divers profils fonctionnels et pharmacologiques. Comme tous les canaux ioniques, l'activité des P2X est étroitement régulée par des mécanismes de régulation orthostériques et allostériques. Cette thèse démontre l'existence d'un nouveau type de mécanisme de régulation post-traductionnel, où les niveaux de phosphoinositides (PIPn) intracellulaires modulent l'activité de canal ionique des récepteurs P2X.Le premier article porte sur le sous-type P2X1, qui contribue à la contraction des muscles lisses dans les vaisseaux sanguins et le canal déférent, ainsi qu'à l'agrégation plaquettaire. Nous démontrons que l'activité du récepteur canal P2X1 est positivement régulée par les PI(4,5)P2 (PIP2) membranaires. La déplétion des niveaux intracellulaires de PIP2 diminue l'amplitude du courant ionique induit par P2X1. Nous montrons que le couplage direct entre le domaine C-terminal cytosolique de P2X1 et PIP2 est nécéssaire pour l'expression complète de l'activité de P2X1.Le second article de cette thèse décrit la régulation PIPn-dépendante du récepteur canal P2X4, qui joue un rôle majeur dans la génération et le maintien de la douleur neuropathique et inflammatoire par son expression dans les microglies de la moelle épinière. Nous démontrons que le fonctionnement de P2X4 dépend des niveaux de PIP2 et de PI(3,4,5)P3 (PIP3). Les deux types de phospholipides potentialisent le courant ionique ainsi que l'entrée de calcium par le canal P2X4 en se liant directement au domaine C-terminal des sous-unités P2X4. Dans le troisième rapport, nous étudions les caractéristiques moléculaires de l'interaction entre les PIPn membranaires et les récepteurs P2X directement modulés par ces phospholipides. En analysant les effets fonctionnels de diverses mutations effectuées sur le domaine C-terminal des sous-types PIPn-dépendant P2X1, P2X4 et P2X7 et sur le sous-type PIPn-indépendant P2X5, nous identifions le motif nécessaire à la liaison P2X-PIPn et à la régulation fonctionnelle du canal par les PIPn.Le dernier article de cette thèse examine les changements dynamiques de la perméabilité du canal ionique apportés par une activation soutenue des récepteurs microgliaux P2X4. Nous montrons que, lors d'une application soutenue d'ATP, les canaux P2X4 forment des pores à haute conductance permettant le flux de molécules organiques à haut poids moléculaire. La formation de larges pores par les récepteurs P2X7 a été étudiée intensivement; nous démontrons ici que la perméation induite par P2X4 est mécanistiquement distincte et, à l'opposé de P2X7, ne mène à aucun réarrangement de la structure membranaire ni à la mort cellulaire. Les PIPn membranaires potentialisent la formation de ces pores à haute conductance par P2X4, suggérant que cette propriété peut être régulée par des changements intracellulaires des niveaux de PIPn

A dual polybasic motif determines phosphoinositide binding and regulation in the P2X channel family.

Phosphoinositides modulate the function of several ion channels, including most ATP-gated P2X receptor channels in neurons and glia, but little is known about the underlying molecular mechanism. We identified a phosphoinositide-binding motif formed of two clusters of positively charged amino acids located on the P2X cytosolic C-terminal domain, proximal to the second transmembrane domain. For all known P2X subtypes, the specific arrangement of basic residues in these semi-conserved clusters determines their sensitivity to membrane phospholipids. Neutralization of these positive charges disrupts the functional properties of the prototypical phosphoinositide-binding P2X4 subtype, mimicking wortmannin-induced phosphoinositide depletion, whereas adding basic residues at homologous positions to the natively insensitive P2X5 subtype establishes de novo phosphoinositide-mediated regulation. Moreover, biochemical evidence of in vitro P2X subunit-phospholipid interaction and functional intracellular phosphoinositide-binding assays demonstrate that the dual polybasic cluster is necessary and sufficient for regulation of P2X signaling by phospholipids

A Dual Polybasic Motif Determines Phosphoinositide Binding and Regulation in the P2X Channel Family

International audiencePhosphoinositides modulate the function of several ion channels, including most ATP-gated P2X receptor channels in neurons and glia, but little is known about the underlying molecular mechanism. We identified a phosphoinositide-binding motif formed of two clusters of positively charged amino acids located on the P2X cytosolic C-terminal domain, proximal to the second transmembrane domain. For all known P2X subtypes, the specific arrangement of basic residues in these semi-conserved clusters determines their sensitivity to membrane phospholipids. Neutralization of these positive charges disrupts the functional properties of the prototypical phosphoinositide-binding P2X4 subtype, mimicking wortmannin-induced phosphoinositide depletion, whereas adding basic residues at homologous positions to the natively insensitive P2X5 subtype establishes de novo phosphoinositide-mediated regulation. Moreover, biochemical evidence of in vitro P2X subunit-phospholipid interaction and functional intracellular phosphoinositide-binding assays demonstrate that the dual polybasic cluster is necessary and sufficient for regulation of P2X signaling by phospholipids

Inhibition of P2X4 function by P2Y6 UDP receptors in microglia.

International audienceATP-gated P2X4 receptor channels expressed in spinal microglia actively participate in central sensitization, making their functional regulation a key process in chronic pain pathologies. P2Y6 metabotropic Gq -coupled receptors, also expressed in microglia, are involved in the initial response to nerve injury, triggering phagocytosis upon activation by UDP. It has been reported recently that expression of both P2X4 and P2Y6 is upregulated in activated microglia following nerve injury. We show here, in resting as well as LPS-activated primary microglia, that P2Y6 decreases P2X4-mediated calcium entry and inhibits the dilation of P2X4 channels into a large-conductance pore measured with a YO-PRO-1 uptake assay. Furthermore, P2Y6 activation modulates the ATP-dependent migration of microglia, a process likely involved in their shift from migratory to phagocytic phenotype. Reconstituting the P2X4-P2Y6 interaction in recombinant systems shows that P2Y6 activation decreases P2X4 current amplitude, activation and desensitization rates, and reduces P2X4 channel permeability to the large cation NMDG(+) . Phospholipase C-mediated hydrolysis of the phosphoinositide PI(4,5)P2 , a necessary cofactor for P2X4 channel function, underlies this inhibitory crosstalk. As extracellular levels of both ATP and UDP are increased in the spinal cord following nerve injury, the control of P2X4 activity by P2Y6 might play a critical role in regulating neuropathic pain-inducing microglial responses