Sialyltransferase ST3Gal-IV controls CXCR2-mediated firm leukocyte arrest during inflammation

Recent in vitro studies have suggested a role for sialylation in chemokine receptor binding to its ligand (Bannert, N., S. Craig, M. Farzan, D. Sogah, N.V. Santo, H. Choe, and J. Sodroski. 2001. J. Exp. Med. 194:1661–1673). This prompted us to investigate chemokine-induced leukocyte adhesion in inflamed cremaster muscle venules of α2,3 sialyltransferase (ST3Gal-IV)-deficient mice. We found a marked reduction in leukocyte adhesion to inflamed microvessels upon injection of the CXCR2 ligands CXCL1 (keratinocyte-derived chemokine) or CXCL8 (interleukin 8). In addition, extravasation of ST3Gal-IV−/− neutrophils into thioglycollate-pretreated peritoneal cavities was significantly decreased. In vitro assays revealed that CXCL8 binding to isolated ST3Gal-IV−/− neutrophils was markedly impaired. Furthermore, CXCL1-mediated adhesion of ST3Gal-IV−/− leukocytes at physiological flow conditions, as well as transendothelial migration of ST3Gal-IV−/− leukocytes in response to CXCL1, was significantly reduced. In human neutrophils, enzymatic desialylation decreased binding of CXCR2 ligands to the neutrophil surface and diminished neutrophil degranulation in response to these chemokines. In addition, binding of α2,3-linked sialic acid–specific Maackia amurensis lectin II to purified CXCR2 from neuraminidase-treated CXCR2-transfected HEK293 cells was markedly impaired. Collectively, we provide substantial evidence that sialylation by ST3Gal-IV significantly contributes to CXCR2-mediated leukocyte adhesion during inflammation in vivo

A large sub-Neptune transiting the thick-disk M4 V TOI-2406

We thank the anonymous referee for their corrections and help in improving the paper. We warmly thank the entire technical staff of the Observatorio Astronomico Nacional at San Pedro Martir in Mexico for their unfailing support to SAINT-EX operations, namely: E. Cadena, T. Calvario, E. Colorado, B. Garcia, G. Guisa, A. Franco, L. Figueroa, B. Hernandez, J. Herrera, E. Lopez, E. Lugo, B. Martinez, J. M. Nunez, J. L. Ochoa, M. Pereyra, F. Quiroz, T. Verdugo, I. Zavala. B.V.R. thanks the Heising-Simons Foundation for support. Y.G.M.C acknowledges support from UNAM-PAPIIT IG-101321. B.-O. D. acknowledges support from the Swiss National Science Foundation (PP00P2-163967 and PP00P2-190080). R.B. acknowledges the support from the Swiss National Science Foundation under grant P2BEP2_195285. M.N.G. acknowledges support from MIT's Kavli Institute as a Juan Carlos Torres Fellow. A.H.M.J.T acknowledges funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement nffi 803193/BEBOP), from the MERAC foundation, and from the Science and Technology Facilities Council (STFC; grant nffi ST/S00193X/1). T.D. acknowledges support from MIT's Kavli Institute as a Kavli postdoctoral fellow Part of this work received support from the National Centre for Competence in Research PlanetS, supported by the Swiss National Science Foundation (SNSF). The research leading to these results has received funding from the ARC grant for Concerted Research Actions, financed by the Wallonia-Brussels Federation. TRAPPIST is funded by the Belgian Fund for Scientific Research (Fond National de la Recherche Scientifique, FNRS) under the grant FRFC 2.5.594.09.F, with the participation of the Swiss National Science Fundation (SNF). M.G. and E.J. are F.R.S.-FNRS Senior Research Associate. This publication benefits from the support of the French Community of Belgium in the context of the FRIA Doctoral Grant awarded to MT. We acknowledge the use of public TESS data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. We acknowledge the use of public TESS Alert data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. Resources supporting this work were provided by the NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center for the production of the SPOC data products. Funding for the TESS mission is provided by NASA's Science Mission Directorate. This research has made use of the Exoplanet Follow-up Observation Program website, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. This paper includes data collected by the TESS mission that are publicly available from the Mikulski Archive for Space Telescopes (MAST). We thank the TESS GI program G03274 PI, Ryan Cloutier, for proposing the target of this work for 2-min-cadence observations in Sector 30. This work is based upon observations carried out at the Observatorio Astronomico Nacional on the Sierra de San Pedro Martir (OAN-SPM), Baja California, Mexico. This work makes use of observations from the LCOGT network. Part of the LCOGT telescope time was granted by NOIRLab through the Mid-Scale Innovations Program (MSIP). MSIP is funded by NSF. This work includes data collected at the Vatican Advanced Technology Telescope (VATT) on Mt. Graham. This paper includes data taken on the EDEN telescope network. We acknowledge support from the Earths in Other Solar Systems Project (EOS) and Alien Earths (grant numbers NNX15AD94G and 80NSSC21K0593), sponsored by NASA. Some of the observations in the paper made use of the High-Resolution Imaging instrument Zorro (Gemini program GS-2020B-LP-105). Zorro was funded by the NASA Exoplanet Exploration Program and built at the NASA Ames Research Center by Steve B. Howell, Nic Scott, Elliott P. Horch, and Emmett Quigley. Zorro was mounted on the Gemini South telescope of the international Gemini Observatory, a program of NSF's OIR Lab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigacion y Desarrollo (Chile), Ministerio de Ciencia, Tecnologia e Innovacion (Argentina), Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). This research has made use of the NASA Exoplanet Archive, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. This work made use of the following Python packages: astropy (Astropy Collaboration 2013, 2018), lightkurve (Lightkurve Collaboration 2018), matplotlib (Hunter 2007), pandas (Wes McKinney 2010), seaborn (Waskom & The Seaborn Development team 2021), scipy (Virtanen et al. 2020) and numpy (Harris et al. 2020).Context. Large sub-Neptunes are uncommon around the coolest stars in the Galaxy and are rarer still around those that are metal-poor. However, owing to the large planet-to-star radius ratio, these planets are highly suitable for atmospheric study via transmission spectroscopy in the infrared, such as with JWST. Aims. Here we report the discovery and validation of a sub-Neptune orbiting the thick-disk, mid-M dwarf star TOI-2406. The star's low metallicity and the relatively large size and short period of the planet make TOI-2406 b an unusual outcome of planet formation, and its characterisation provides an important observational constraint for formation models. Methods. We first infer properties of the host star by analysing the star's near-infrared spectrum, spectral energy distribution, and Gaia parallax. We use multi-band photometry to confirm that the transit event is on-target and achromatic, and we statistically validate the TESS signal as a transiting exoplanet. We then determine physical properties of the planet through global transit modelling of the TESS and ground-based time-series data. Results. We determine the host to be a metal-poor M4 V star, located at a distance of 56 pc, with properties T-eff = 3100 +/- 75 K, M-* = 0.162 +/- 0.008M(circle dot), R-* = 0.202 +/- 0.011R(circle dot), and [Fe/H] = -0.38 +/- 0.07, and a member of the thick disk. The planet is a relatively large sub-Neptune for the M-dwarf planet population, with R-p = 2.94 +/- 0.17R(circle plus) and P= 3.077 d, producing transits of 2% depth. We note the orbit has a non-zero eccentricity to 3 sigma, prompting questions about the dynamical history of the system. Conclusions. This system is an interesting outcome of planet formation and presents a benchmark for large-planet formation around metal-poor, low-mass stars. The system warrants further study, in particular radial velocity follow-up to determine the planet mass and constrain possible bound companions. Furthermore, TOI-2406 b is a good target for future atmospheric study through transmission spectroscopy. Although the planet's mass remains to be constrained, we estimate the S/N using amass-radius relationship, ranking the system fifth in the population of large sub-Neptunes, with TOI-2406 b having a much lower equilibrium temperature than other spectroscopically accessible members of this population.Heising-Simons FoundationPrograma de Apoyo a Proyectos de Investigacion e Innovacion Tecnologica (PAPIIT)Universidad Nacional Autonoma de Mexico IG-101321Swiss National Science Foundation (SNSF)European Commission PP00P2-163967 PP00P2-190080 P2BEP2_195285MIT's Kavli Institute as a Juan Carlos Torres FellowEuropean Research Council (ERC) nffi 803193/BEBOPMERAC foundationUK Research & Innovation (UKRI)Science & Technology Facilities Council (STFC)Science and Technology Development Fund (STDF) nffi ST/S00193X/1MIT's Kavli Institute as a Kavli postdoctoral fellowSwiss National Science Foundation (SNSF)Australian Research CouncilFonds de la Recherche Scientifique - FNRS FRFC 2.5.594.09.FSwiss National Science Foundation (SNSF)French Community of Belgium in the context of the FRIA Doctoral GrantNASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research CenterNASA's Science Mission DirectorateNational Aeronautics and Space Administration under the Exoplanet Exploration ProgramTESS GI program G03274National Science Foundation (NSF)Earths in Other Solar Systems Project (EOS)Alien Earths - NASA NNX15AD94G 80NSSC21K0593High-Resolution Imaging instrument Zorro (Gemini program) GS-2020B-LP-105NASA Exoplanet Exploration ProgramNational Aeronautics & Space Administration (NASA)National Science Foundation (NSF

The Myeloid Receptor PILRβ Mediates the Balance of Inflammatory Responses through Regulation of IL-27 Production

Paired immunoglobulin-like receptors beta, PILRβ, and alpha, PILRα, are related to the Siglec family of receptors and are expressed primarily on cells of the myeloid lineage. PILRβ is a DAP12 binding partner expressed on both human and mouse myeloid cells. The potential ligand, CD99, is found on many cell types, such as epithelial cells where it plays a role in migration of immune cells to sites of inflammation. Pilrb deficient mice were challenged with the parasite Toxoplasma gondii in two different models of infection induced inflammation; one involving the establishment of chronic encephalitis and a second mimicking inflammatory bowel disease in order to understand the potential role of this receptor in persistent inflammatory responses. It was found that in the absence of activating signals from PILRβ, antigen-presenting cells (APCs) produced increased amounts of IL-27, p28 and promoted IL-10 production in effector T cells. The sustained production of IL-27 led ultimately to enhanced survival after challenge due to dampened immune pathology in the gut. Similar protection was also observed in the CNS during chronic T. gondii infection after i.p. challenge again providing evidence that PILRβ is important for regulating aberrant inflammatory responses

Extravasation of leukocytes in comparison to tumor cells

The multi-step process of the emigration of cells from the blood stream through the vascular endothelium into the tissue has been termed extravasation. The extravasation of leukocytes is fairly well characterized down to the molecular level, and has been reviewed in several aspects. Comparatively little is known about the extravasation of tumor cells, which is part of the hematogenic metastasis formation. Although the steps of the process are basically the same in leukocytes and tumor cells, i.e. rolling, adhesion, transmigration (diapedesis), the molecules that are involved are different. A further important difference is that leukocyte interaction with the endothelium changes the endothelial integrity only temporarily, whereas tumor cell interaction leads to an irreversible damage of the endothelial architecture. Moreover, tumor cells utilize leukocytes for their extravasation as linkers to the endothelium. Thus, metastasis formation is indirectly susceptible to localization signals that are literally specific for the immune system. We herein compare the extravasation of leukocytes and tumor cells with regard to the involved receptors and the localization signals that direct the cells to certain organs and sites of the body

Design, synthesis, and biological evaluation of symmetrically and unsymmetrically substituted methoctramine-related polyamines as muscular nicotinic receptor noncompetitive antagonists

The universal template approach to drug design foresees that a polyamine can be modified in such a way to recognize any neurotransmitter receptor. Thus, hybrids of polymethylene tetraamines and philanthotoxins, exemplified by methoctramine (1) and PhTX-343 (2), respectively, were synthesized to produce novel inhibitors of muscular nicotinic acetylcholine receptors. Polyamines 3-25 were synthesized and their biological profiles were evaluated at frog rectus abdominis muscle nicotinic receptors and guinea pig left atria (M-2) and ileum longitudinal muscle (M-3) muscarinic acetylcholine receptors. All of the compounds, like prototypes 1 and 2, were noncompetitive antagonists of nicotinic receptors while being, like 1, competitive antagonists at,muscarinic M-2 and M-3 receptor subtypes. interestingly, polyamines bearing a low number of methylenes between the nitrogen atoms, as in 3, 6, and 7, displayed a biological profile similar to that of 2: a noncompetitive antagonism at nicotinic receptors in the 7-25 mu M range while not showing any antagonism for muscarinic receptors up to 10 mu M. increasing the number of methylenes separating these nitrogen atoms in methoctramine related tetraamines resulted in a significant improvement; in potency at nicotinic receptors. The most potent tetraamine was 19, bearing a 12 methylene spacer between the nitrogen atoms, which was 12-fold and 250-fold more potent than prototypes 1 and 2, respectively. Tetraamines 9-11, bearing a rather rigid spacer between the nitrogen atoms instead of the very flexible polymethylene chain, displayed a profile similar to that of 1 at nicotinic receptors, whereas a significant decrease in potency was observed at muscarinic M-2 receptors. This finding may have relevance in understanding the mode of interaction with these receptors. Similarly, the constrained analogue 12 of methoctramine showed a decrease in potency at nicotinic and muscarinic M-2 receptors, revealing that the tricyclic system, which incorporates the 2-methoxybenzylamine moiety of 1, does not represent a good pharmacophore for activity at these sites. A most intriguing finding was the observation that the photolabile tetraamine 22 was more potent than methoctramine at nicotinic receptors and, what is more important, it inhibited a closed stale of the receptor

Two‐stage Variscan metamorphism in the Canigou massif: evidence for crustal thickening in the Pyrenees

International audienceThe Variscan metamorphism in the Pyrenees is dominantly of the low-pressure-high-temperature (LP-HT) type. The relics of an earlier, Barrovian-type, metamorphism that could be related to orogenic crustal thickening are unclear and insufficiently constrained. A microstructural and petrological study of micaschists underlying an Ordovician augen orthogneiss in the core of the Canigou massif (Eastern Pyrenees, France) reveal the presence of two syntectonic metamorphic stages characterized by the crystallization of staurolite (M1) and andalusite (M2), respectively. Garnet is stable during the two metamorphic stages with a period of resorption between M1 and M2. The metamorphic assemblages M1 and M2 record similar peak temperatures of 580 °C at different pressure conditions of 5.5 kbar and 3 kbar, respectively. Using chemical zoning of garnet and calculated P–T pseudosections, a prograde P–T path is constrained with a peak pressure at ~6.5 kbar and 550 °C. This P–T path, syntectonic with respect to the first foliation S1, corresponds to a cold gradient (of ~9 °C/km), suggestive of crustal thickening. Resorption of garnet between M1 and M2 can be interpreted either in terms of a simple clockwise P–T path or a polymetamorphic two stage evolution. We argue in favour of the latter, where the medium‐pressure (Barrovian) metamorphism is followed by a period of significant erosion and crustal thinning leading to decompression and cooling. Subsequent advection of heat, probably from the mantle, lead to a new increase in temperature, coeval with the development of the main regional fabric S2. LA‐ICP‐MS U‐Th‐Pb dating of monazite yields a well‐defined date at c. 300 Ma. Petrological evidence indicates that monazite crystallization took place close to the M1 peak‐pressure conditions. However, the similarity between this age and that of the extensive magmatic event well documented in the eastern Pyrenees suggests that it probably corresponds to the age of monazite recrystallization during the M2 LP–HT event. This article is protected by copyright. All rights reserved