Ultra-sensitive and selective Hg2+ chemosensors derived from substituted 8-hydroxyquinoline analogues

International audienceNovel analogues of 8-hydroxyquinoline with phosphinate or thiophosphinate functions and styryl fluorophores in the para position to the nitrogen atom were prepared via multi-step syntheses, using phosphorylation and Wittig coupling reactions. A strong affinity between the quinoline analogues and heavy metal ions such as Pb2+, Cd2+ and Hg2+ was highlighted. The interaction of the metal ions with the nitrogen of the styrylquinoline leads to a large red shift of the absorption and emission spectra in agreement with an increase of the photoinduced charge transfer character of the styryl fluorophore. In the presence of metal ions the appearance of a green fluorescence emission is also observed upon excitation at 420 nm or 840 nm, thanks to a significant increase of the two-photon response. Under optimal conditions, a mercury concentration of 15 ppt in a partially aqueous medium can be detected using the thiophosphinate derivative without interference from other metal ions

Blow-up of critical Besov norms at a potential Navier-Stokes singularity

We show that the spatial norm of any strong Navier-Stokes solution in the space X must become unbounded near a singularity, where X may be any critical homogeneous Besov space in which local existence of strong solutions to the 3-d Navier-Stokes system is known. In particular, the regularity of these spaces can be arbitrarily close to -1, which is the lowest regularity of any Navier-Stokes critical space. This extends a well-known result of Escauriaza-Seregin-Sverak (2003) concerning the Lebesgue space $L^3$, a critical space with regularity 0 which is continuously embedded into the spaces we consider. We follow the "critical element" reductio ad absurdum method of Kenig-Merle based on profile decompositions, but due to the low regularity of the spaces considered we rely on an iterative algorithm to improve low-regularity bounds on solutions to bounds on a part of the solution in spaces with positive regularity

Bone Biomarkers Help Grading Severity of Coronary Calcifications in Non Dialysis Chronic Kidney Disease Patients

BACKGROUND: Osteoprotegerin (OPG) and fibroblast growth factor-23 (FGF23) are recognized as strong risk factors of vascular calcifications in non dialysis chronic kidney disease (ND-CKD) patients. The aim of this study was to investigate the relationships between FGF23, OPG, and coronary artery calcifications (CAC) in this population and to attempt identification of the most powerful biomarker of CAC: FGF23? OPG? METHODOLOGY/PRINCIPAL FINDINGS: 195 ND-CKD patients (112 males/83 females, 70.8 [27.4-94.6] years) were enrolled in this cross-sectional study. All underwent chest multidetector computed tomography for CAC scoring. Vascular risk markers including FGF23 and OPG were measured. Logistic regression analyses were used to study the potential relationships between CAC and these markers. The fully adjusted-univariate analysis clearly showed high OPG (≥10.71 pmol/L) as the only variable significantly associated with moderate CAC ([100-400[) (OR = 2.73 [1.03;7.26]; p = 0.04). Such association failed to persist for CAC scoring higher than 400. Indeed, severe CAC was only associated with high phosphate fractional excretion (FEPO(4)) (≥38.71%) (OR = 5.47 [1.76;17.0]; p = 0.003) and high FGF23 (≥173.30 RU/mL) (OR = 5.40 [1.91;15.3]; p = 0.002). In addition, the risk to present severe CAC when FGF23 level was high was not significantly different when OPG was normal or high. Conversely, the risk to present moderate CAC when OPG level was high was not significantly different when FGF23 was normal or high. CONCLUSIONS: Our results strongly suggest that OPG is associated to moderate CAC while FGF23 rather represents a biomarker of severe CAC in ND-CKD patients

Father’s perceptions and care involvement for their very preterm infants at French neonatal intensive care units

ObjectivesWe aimed to evaluate (1) fathers’ perceptions and care involvement for their very premature infants and their views of the hospitalization period based on parental reports and (2) their evolution over time.MethodsWe used an online parental survey to assess answers from parents of very preterm infants who were successfully discharged from French neonatal units. We analysed answers from February 2014 to January 2019 to an anonymous internet-based survey from the GREEN committee of the French Neonatal Society. Responses were compared for period 1 (P1, 1998 to 2013) and period 2 (P2, 2014 to 2019).ResultsWe analyzed 2,483 surveys, 124 (5%) from fathers and 2,359 (95%) from mothers. At birth, 1,845 (80%) fathers were present in the hospital, but only 879 (38%) were near the mother. The presence of fathers in the NICU increased from P1 to P2 (34.5% vs. 43.1%, p = 0.03). Nearly two thirds of fathers accompanied their infants during transfer to the NICU (1,204 fathers, 60.6%). Fathers and mothers had similar perceptions regarding relationships with caregivers and skin-to-skin contact with their infants. However, more fathers than mothers felt welcome in the NICU and in care involvement regarding requests for their wishes when they met their infant (79% vs. 60%, p = 0.02) and in the presentation of the NICU (91% vs. 76%; p = 0.03). Mothers and fathers significantly differed in the caring procedures they performed (p = 0.01), procedures they did not perform but wanted to perform (p < 0.001), and procedures they did not perform and did not want to perform (p < 0.01).ConclusionMost fathers were present at the births of their very preterm infants, but fewer fathers were near the mother at this time. Less than two thirds of fathers accompanied their infants to the NICU. There should be further changes to better meet the specific needs of the fathers of infants requiring care in the NICU. Continuing assessment with an online questionnaire may be useful to monitor changes over time in father’s involvement in NICUs

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder with unclear underlying mechanisms. Here, the authors unravel the contribution of a stress-responsive pathway to RSTS where impaired HSF2 acetylation, due to RSTS-associated CBP/EP300 mutations, alters the expression of neurodevelopmental players, in keeping with hallmarks of cell-cell adhesion defects.Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.</p

Synthèse et étude photophysiques de supramolécules photoactives et de senseurs de cations basées sur des triazoles et azacouronnes

Ce travail porte sur la synthèse et l'étude photophysique des molécules fluorescentes, visant à construire de nouveaux capteurs chimiques pour la détection sélective des ions métalliques importants en biologie ou pour l environnement. Une série de fluoroionophores contenant le motif triazole et différents fluorophores ont été utilisés pour étudier les fonctions du groupe triazole dans les senseurs chimiques. Nos études photophysiques de ces ligands complexants démontrent que le triazole pourrait contribuer dans le cadre de fluorophores conjugués, comme les sites de complexation de métal ou de linkers. Plusieurs senseurs chimiques sélectifs ont été successivement mis au point pour la détection du Cu2+ ou du Hg2+. En incorporant le fluorophore dansyle sur calix[4]bisazacrown, une nouvelle capteur chimique de potassium a été construit. Un sulfonate fluorescente calix [4] bisazacrown a été conçu et synthétisé pour la détection sélective et ratiométrique de l aluminium dans une solution tampon de lutidine à pH 6,0 avec une sensibilité satisfaisante. Enfin, nous avon cherché à réaliser une modulation de la complexation de cation par la redistribution de charge photoinduite à l'état excité. Deux motifs de liaison sur la base de fullerène et de pyridinium bétaïne ont été conçus à cet effet. Les résultats préliminaires ont mis en évidence un effet de type PET dans les composés à base de fullerène et les composés à base de pyridinium betaine sont trés prometteur dans la translocation de cation.This work deals with the synthesis and photophysical study of fluorescent molecules, aiming to construct new chemical sensors for the selective detection of environmentally or biologically important metal ions. A series of fluoroionophores consisting of triazole moiety and different fluorophores was utilized to investigate the functions of triazole group in chemosensors. Our comprehensively photophysical and complexing studies of these ligands demonstrated that triazole groups could contribute as part of conjugated fluorophores, as metal binding sites or linkers. Several selective chemosensors were successively developed for the detection of Cu2+ or Hg2+. By incorporating dansyl fluorophore into calix[4]bisazacrown, a new potassium chemosensor was constructed. A sulfonate fluorescent calix[4]bisazacrown was created for the selective and ratiometric detection of Al3+ in lutidine buffer solution at pH 6.0 with a satisfying sensitivity. Finally, we aim to realize modulation of cation binding through the photoinduced charge redistribution in the excited state. Two binding motifs based on fullerene and betaine pyridinium were designed for this purpose. Preliminary results demonstrated that PET in fullerene might be not suitable but pydinium betaine hold great potential in the cation translocations.CACHAN-ENS (940162301) / SudocSudocFranceF

Détection fluorimétrique en circuit microfluidique des ions Pb2+, Hg2+ et Cd2+ en milieu aqueux

Ce travail de thèse s inscrit dans le cas d un projet européen nommé microfluiD . Ce projet vise principalement la détection des polluants organiques par voie microfluidique (les micotoxines dans les aliments de bétail, les bactéries et les métaux lourds). Devant les dangers écologiques des ions Pb2+, Hg2+ et Cd2+ dans l environnement, il est important de multiplier le nombre d analyses dans les eaux du robinet. L utilisation de la fluorescence et des microlasers organiques présente de nombreux avantages. Outre leur faible coût, leur sensibilité ainsi que leur sélectivité, il est possible de concevoir à partir de ces techniques des dispositifs transportables sur le terrain. Deux approches sont principalement développées : Une première est basée sur la fluorescence - elle a consisté à synthétiser des ligands fluorescents de type DPPS-PEG et CalixDANS-3-OH pour la détection du mercure et du plomb. Les études de la complexation des ions Hg2+, Pb2+ ont d abord été effectuées en solution. La complexation de Cd2+ en circuit microfluidique à partir du composé commercial Rhod-5N a aussi été étudiée. Des résultats très prometteurs ont été obtenus pour la détection de Hg2+ par DPPS-PEG. Nous avons aussi étudié la possibilité de détecter Pb2+ à partir du CalixDANS-3-OH greffé sur les parois du circuit microfluidique. Malgré une dégradation de la sonde, nous avons réussi à détecter une faible concentration de plomb. Une très bonne sélectivité vis-à-vis des cations interférents testés a été obtenue. La seconde approche est basée sur la détection par microlasers. Nous avons synthétisé deux copolymères blocs pour la détection du plomb et du mercure. Des problèmes de solubilité nous empêchant de fabriquer des microcavités organiques à partir de ces polymères, une deuxième stratégie consistant à greffer les ligands spécifiques de Pb2+ et de Hg2+ sur les microcavités laser PMMA a été développée. Cette dernière nous a permis d apporter une preuve de principe pour de la détection du mercure en fonctionnalisant le mercaptopropyltriéthoxysilane à la surface du PMMA. Ce travail nous a aussi amené à synthétiser des colorants laser à base de Bodipy pour la fabrication des microcavités lasers par polymérisation à deux photons (2PP).This thesis is supported by a European project called microfluiD for the detection of organic pollutants by microfluidic devices (mycotoxins in animal feed, bacteria and heavy metals). Because of hazards Pb2+, Hg2+ and Cd2+ ions in the environment, it is important to increase the number of assays in tap water. The use of fluorescence or microlaser has many advantages: in addition to their low cost, sensitivity and selectivity, it is possible to design portable devices based on these systems in the field. Two approaches are mainly developed in this work: The first one is based on fluorescence. Two fluorescent sensors were synthesized: CalixDANS-3-OH for Pb2+ detection and DPPS-PEG for Hg2+ detection. Complexation of Hg2+and Pb2+ was at first performed in solution. The complexation of Cd2+ in microfluidic device from the commercial compound Rhod-5N is studied and very promising results of Hg2+ sensing by DPPS-PEG are obtained. We also studied the possibility to detect Pb2+ by CalixDANS-3-OH grafted onto the walls of the microfluidic device. Despite a degradation of the probe, we were able to detect low concentrations of Pb2+. A very good selectivity towards several interfering cations was obtained. The second approach is based on the use of microlasers. We synthesized two porous block polymers for Pb2+ and Hg2+ detection. Because of a bad solubility of the copolymers,, we didn t succeed to fabricate microcavities from these polymers. A second strategy which consists in grafting the specific ligands of Pb2+ and Hg2+ on the PMMA microcavity is very promising. Proof of principle of the detection of Hg2+ is obtained by functionalizing mercaptopropyltriethoxysilane on the surface of PMMA. This work also led us to synthesize Bodipy laser dyes for the manufacturing of microcavities by two-photon polymerization (2PP).CACHAN-ENS (940162301) / SudocSudocFranceF

Capteurs fluorescents à base de liquides ioniques à tâche spécifique pour la quantification de traces de métaux lourds dans l'eau

Cette thèse a pour but la réalisation de capteurs fluorescents à base de liquides ioniques à tâche spécifique pour la quantification de traces de métaux lourds dans l eau. Dans un premier temps, des sondes moléculaires fluorescentes efficaces pour la détection du mercure, du plomb et du cadmium ont été ciblées. Une première famille de molécules d éthers lariat d oxyde de phosphine a montré de bonnes affinités pour le plomb et le cadmium. Tandis qu un dérivé de séléniure de phosphine s est révélé être un très bon chemodosimètre pour le mercure avec une limite de détection basse de 3,4 nmol.L-1. Des sondes moléculaires fluorescentes dérivées de la 8-hydroxyquinoléine comportant un groupement phosphinate ou thiophosphinate capables de complexer le mercure en milieu aqueux ont permis d atteindre une limite de détection exceptionnelle de 0,1 nmol.L-1. Enfin, un composé dérivé de la phénantroline capable de complexer très efficacement le cadmium avec la possibilité de détecter des traces de ce cation est présenté. Après indentification des sondes spécifiques pour les métaux lourds d intérêt pour le projet, celles-ci ont étés fonctionnalisées afin de les incorporer dans un liquide ionique hydrophobe pour former des liquides ioniques à tâche spécifique pour l extraction et la détection de métaux lourds. En parallèle du travail concernant les sondes moléculaires, un dispositif d analyseur de métaux lourds portatif a été mis au point, notamment un nouveau module de détection optique développé. Ce dispositif permet là aussi de détecter des traces de mercure sub-nanomolaire.The aim of this PhD is the realization of fluorescent sensors based on task specific ionic liquids for the extraction and the quantification of trace of heavy metals ions in water. As a first step, efficient fluorescent molecular probes for the detection of mercury, lead and cadmium were targeted. Two lariat ethers derivated from phosphine oxide show good affinity for lead and cadmium, while a phosphine selenide derivative has proven to be a very good chemodosimeter for mercury with a low detection limit of 3.4 nmol.L-1. Secondly, fluorescent molecular probes derived from 8-hydroxyquinoline having a phosphinate or thiophosphinate group are described. These molecules are able to coordinate mercury in aqueous medium and allow to detect a concentration of mercury in water of 0.1 nmol.L-1. Finally, a phenanthroline derivative for detection of cadmium in aqueous medium is described. With this compound, traces of cadmium can be detected. After identification of the most efficient probes for targeted heavy metals ions, they have been functionalized to be incorporated in a hydrophobic ionic liquid to form task specific ionic liquids for the extraction and detection of heavy metals ions. In parallel of this work on molecular probes, an portable analyzer of heavy metals ions has been developed, including a new optical detection module. This device can also detect sub-nanomolar traces of mercury.CACHAN-ENS (940162301) / SudocSudocFranceF