Simultaneous observations of lower tropospheric continental aerosols with a ground-based, an airborne, and the spaceborne CALIOP lidar system

International audienceWe present an original experiment with multiple lidar systems operated simultaneously to study the capability of the Cloud-Aerosol LIdar with Orthogonal Polarization (CALIOP), on board the Cloud-Aerosol Lidar Pathfinder Satellite Observation (CALIPSO), to infer aerosol optical properties in the lower troposphere over a midlatitude continental site where the aerosol load is low to moderate. The experiment took place from 20 June to 10 July 2007 in southern France. The results are based on three case studies with measurements coincident to CALIOP observations: the first case study illustrates a large-scale pollution event with an aerosol optical thickness at 532 nm (τa532) of ∼0.25, and the two other case studies are devoted to background conditions due to aerosol scavenging by storms with τa532 <0.1. Our experimental approach involved ground-based and airborne lidar systems as well as Sun photometer measurements when the conditions of observation were favorable. Passive spaceborne instruments, namely the Spinning Enhanced Visible and Infrared Imager (SEVERI) and the Moderate-resolution Imaging Spectroradiometer (MODIS), are used to characterize the large-scale aerosol conditions. We show that complex topographical structures increase the complexity of the aerosol analysis in the planetary boundary layer by CALIOP when τa532 is lower than 0.1 because the number of available representative profiles is low to build a mean CALIOP profile with a good signal-to-noise ratio. In a comparison, the aerosol optical properties inferred from CALIOP and those deduced from the other active and passive remote sensing observations in the pollution plume are found to be in reasonable agreement. Level-2 aerosol products of CALIOP are consistent with our retrievals

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

Defects in the innate immune system in the lung with attendant bacterial infections contribute to lung tissue damage, respiratory insufficiency, and ultimately death in the pathogenesis of cystic fibrosis (CF). Professional phagocytes, including alveolar macrophages (AMs), have specialized pathways that ensure efficient killing of pathogens in phagosomes. Phagosomal acidification facilitates the optimal functioning of degradative enzymes, ultimately contributing to bacterial killing. Generation of low organellar pH is primarily driven by the V-ATPases, proton pumps that use cytoplasmic ATP to load H(+) into the organelle. Critical to phagosomal acidification are various channels derived from the plasma membrane, including the anion channel cystic fibrosis transmembrane conductance regulator, which shunt the transmembrane potential generated by movement of protons. Here we show that the transient receptor potential canonical-6 (TRPC6) calcium-permeable channel in the AM also functions to shunt the transmembrane potential generated by proton pumping and is capable of restoring microbicidal function to compromised AMs in CF and enhancement of function in non-CF cells. TRPC6 channel activity is enhanced via translocation to the cell surface (and then ultimately to the phagosome during phagocytosis) in response to G-protein signaling activated by the small molecule (R)-roscovitine and its derivatives. These data show that enhancing vesicular insertion of the TRPC6 channel to the plasma membrane may represent a general mechanism for restoring phagosome activity in conditions, where it is lost or impaired.Fil: Riazanski, Vladimir. University of Chicago; Estados UnidosFil: Gabdoulkhakova, Aida G.. University of Chicago; Estados UnidosFil: Boynton, Lin S.. University of Chicago; Estados UnidosFil: Eguchi, Raphael R.. University of Chicago; Estados UnidosFil: Deriy, Ludmila V.. University of Chicago; Estados UnidosFil: Hogarth, D. Kyle. University of Chicago; Estados UnidosFil: Loaëc, Nadège. ManRos Therapeutics; FranciaFil: Oumata, Nassima. ManRos Therapeutics; FranciaFil: Galons, Hervé. Universite de Paris; FranciaFil: Brown, Mary E.. University of Chicago; Estados UnidosFil: Shevchenko, Pavel. University of Chicago; Estados UnidosFil: Gallan, Alexander J.. University of Chicago; Estados UnidosFil: Yoo, Sang Gune. University of Chicago; Estados UnidosFil: Naren, Anjaparavanda P.. Cincinnati Children’s Hospital Medical Center; Estados UnidosFil: Villereal, Mitchel L.. University of Chicago; Estados UnidosFil: Beacham, Daniel W.. Thermo Scientific; Estados UnidosFil: Bindokas, Vytautas P.. University of Chicago; Estados UnidosFil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Meijer, Laurent. ManRos Therapeutics; FranciaFil: Nelson, Deborah J.. University of Chicago; Estados Unido

Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype

Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies

New insight in ARX-mutated patients' language specific impairment and underlying FOXP1 dysregulation

Numéro spécial Abstracts of EPNS 2017 - 12th European Paediatric Neurology Society CongressLyon, France20- 24 June 2017 12th European Paediatric Neurology Society Congress, 20 - 24 June 2017International audienceObjective: The ARX (Aristaless Related homeoboX) gene encodes a transcription factor which mutations have been associated with syndromes ranging from severe neuronal migration defects such as lissencephaly, to mild or moderate forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent ARX mutation (c.429_452dup24), a duplication of 24 base pairs, constitutes a recognizable clinical syndrome with ARX patients exhibiting ID, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Furthermore, patients also exhibit language impairment and an obvious difficulty to execute oro-lingual praxis. The aim of the present study was to better characterize language abnormalities in ARX c.429_452dup24 patients. Methods: We collected data on 16 French ARX patients, and 16 age- and IQ-matched controls (Fragile X (FraX) patients). Given the similarities between ARX mutated patients and FOXP2-mutated patients, we investigated the molecular relationship between Arx and Foxp2. Results: ARX patients have structural language impairments in both receptive and expressive aspects of language compared to FraX patients: phonetic feature recognition, receptive (ECOSSE test for sentence comprehension) and expressive (TCG-R for sentence production) morphosyntactic skills and oro-lingual dyspraxia (movements of the face, tongue, and lips) were significantly more impaired in ARX patients. FraX patients made words more complex and they were less impaired in their ability to articulate words. On the contrary, language pragmatic analysis showed that ARXdup24 patients had significantly better interactional skills than FraX. patients. Interestingly, we found that although Arx has no effect on Foxp2 expression, Arx was found to activate Foxp1 expression, and that the c.429_452dup24 mutation alters the expression of this gene. Foxp1 is known to heterodimerize with Foxp2 and has been involved in language defects. Conclusion: These data uncover a novel role of ARX in language development, probably through the regulation of Foxp1