Dynamique moléculaire par imagerie attoseconde

Since the first observation of high-order harmonic spectra in gases, high harmonic generation (HHG) has demonstrated its importance, opening a door to the field of attosecond sience. The bandwidth of the emitted spectrum reaches up to the XUV. The attosecond pulses reach a very high time resolution, allowing the study of electron dynamics in atoms or molecules. The generation mechanism of HHG is based on the emission of an attosecond electron wavepacket by the atoms/molecules. The electron wavepacket is accelerated by the laser field and finally recombines radiatively with its parent ion. Thus the structural information of the probed orbital is encoded in the high harmonic spectrum with a spatial resolution of one Angtröm and a temporal resolution of few femtoseconds. HHG can be used as a probe signal resolved for pump-probe spectroscopy. High harmonic spectroscopy allows the study of the orbital structure and ultra-fast molecular dynamics. In this thesis the fundamental mechanisms playing a role in atoms, molecules and condensed matter are probed using HHG. In order to understand how to extract dynamical and structural information of orbitals from a harmonic signal, we have first studied an easy and well known system: the argon atom. A new theoretical approach developped by Fabre and Pons allowed us to reproduce the experimental results in good agreement. We continued with a study of the molecular structure and dynamics of N2 and CO2. A supersonic Even-Lavie jet permitted to reach rotational temperatures lower than 10K with an excellent alignment distribution. Owing to the good alignment in such gas jet, we were able to resolve the orbital structure with a higher sensitivity and to identify the contribution of several orbitals. In the next step we used the sensitivity of HHG towards the structure of molecular orbitals in order to probe the complex dynamics of NO2 in the vicinity of a conical intersection. We applied HHG combined with transient grating spectroscopy which leads to a higher sensitivity of the excited molecules. We then continued with studying cluster. We were able to disentangle the contribution of large clusters to the harmonic signal due to a 2D spatio-spectral representation of a temperature dependent differential measurement. Our analysis suggests a new generation mechanism in clusters and allows an estimation of the electron correlation length in clusters. This thesis ends with the presentation of a XUV beamline. This technique uses the emitted fs-XUV radiation, provided by HHG, as a probe pulse for ionizing the photofragments by a one photon transition.Depuis sa première observation, la génération d'harmoniques d'ordre élevé (GHOE) dans les gaz a demontré son importance, ouvrant la voie à la science attoseconde. Cette technique produit un rayonnement impulsionnel XUV qui s'étend dans le domaine spectral intermédiaire entre l'ultraviolet et les rayons X. Ces impulsions attosecondes donnent accès à des résolutions temporelles extrêemes, permettant ainsi d'observer des dynamiques électroniques dans des atomes ou des molécules. En effet le processus de généneration d'harmonique repose sur l'oscillation de paquets d'électrons attosecondes issus des molécules, accélérés par le champ de laser intense et se recombinant radiativement avec leurs ions moléculaires parents. Ainsi, le rayonnement harmonique émis lors de la recombinaison permet d'encoder l'information structurale sur le ou les orbitales impliquées avec une résolution spatiale de l'ordre l'Angström et temporelle femtoseconde ou attoseconde. La génération d'harmonique peut être utilisée comme signal de sonde dans des expériences de spectroscopie pompe-sonde résolue en temps. Ces expériences de spectroscopie harmoniques permettent d'étudier la structure des orbitales et les dynamiques moléculaires ultra-rapides. L'objectif de cette thèse est d'utiliser le processus de la GHOE, pour sonder les processus fondamentaux qui interviennent dans les atomes, les molécules et la matière condensée. Tout d'abord, pour comprendre comment extraire des informations dynamiques ou structurelles sur les orbitales à partir du signal harmonique nous avons étudié un système simple et connu: l'argon. Une nouvelle approche théorique développée par Fabre et Pons a permis de reproduire fidèlement l'expérience. Nous avons continué à étudier la structure et la dynamique moléculaire dans N2 et CO2. Les molécules issues d'un jet supersonique Even-Lavie qui permettait d'obtenir des températures rotationelles de moins de 10K ont été alignées par laser avec un fort degré d'alignement. Ce type de jet permet d'améliorer la sensibilité à la structure des orbitales impliquées et d'identifier la contribution de plusieurs orbitales. Ensuite nous avons utilisé la sensibilité de la génération des harmoniques d'ordre élevé à la structure des orbitales moléculaires pour sonder la dynamique complexe du NO2 excité autour d'une intersection conique. Nous avons appliqué la méthode du réseau d'excitation transitoire qui permet d'améliorer la sensibilité aux molécules excitées. Nous avons donc mené une étude dans les agrégats. A l'aide d'une étude différentielle en température et d'une méthode de cartographie spectrale et spatiale, nous avons pu isoler la contibution des grands agrégats. Notre analyse suggère un nouveau mécanisme de génération par des agrégats et permet même une estimation de la longeur de corrélation des électrons dans les agrégats. Ce manuscrit se termine avec la présentation d'une ligne de lumière XUV. Cette technique consiste à utiliser le rayonnement XUV fs produit par la GHOE comme impulsion sonde pour ioniser des fragments de dissociation moléculaire à l'aide d'une transition à un photon

The Junctional Adhesion Molecule 3 (JAM-3) on Human Platelets is a Counterreceptor for the Leukocyte Integrin Mac-1

The recently described junctional adhesion molecules (JAMs) in man and mice are involved in homotypic and heterotypic intercellular interactions. Here, a third member of this family, human JAM-3, was identified and described as a novel counterreceptor on platelets for the leukocyte β2-integrin Mac-1 (αMβ2, CD11b/CD18). With the help of two monoclonal antibodies, Gi11 and Gi13, against a 43-kD surface glycoprotein on human platelets, a full-length cDNA encoding JAM-3 was identified. JAM-3 is a type I transmembrane glycoprotein containing two Ig-like domains. Although JAM-3 did not undergo homophilic interactions, myelo-monocytic cells adhered to immobilized JAM-3 or to JAM-3–transfected cells. This heterophilic interaction was specifically attributed to a direct interaction of JAM-3 with the β2-integrin Mac-1 and to a lower extent with p150.95 (αXβ2, CD11c/CD18) but not with LFA-1 (αLβ2, CD11a/CD18) or with β1-integrins. These results were corroborated by analysis of K562 erythroleukemic cells transfected with different heterodimeric β2-integrins and by using purified proteins. Moreover, purified JAM-3 or antibodies against JAM-3 blocked the platelet-neutrophil interaction, indicating that platelet JAM-3 serves as a counterreceptor for Mac-1 mediating leukocyte–platelet interactions. JAM-3 thereby provides a novel molecular target for antagonizing interactions between vascular cells that promote inflammatory vascular pathologies such as in atherothrombosis

Protease- and cell type–specific activation of protease-activated receptor 2 in cutaneous inflammation

Background: Protease-activated receptor 2 (PAR2) signaling controls skin barrier function and inflammation, but the roles of immune cells and PAR2-activating pro teases in cutaneous diseases are poorly understood. Objective: To dissect PAR2 signaling contributions to skin inflammation with new ge netic and pharmacological tools. Methods/Results: We found markedly increased numbers of PAR2+ infiltrating my eloid cells in skin lesions of allergic contact dermatitis (ACD) patients and in the skin of contact hypersensitivity (CHS) in mice, a murine ACD model for T cell–mediated allergic skin inflammation. Cell type–specific deletion of PAR2 in myeloid immune cells as well as mutation-induced complete PAR2 cleavage insensitivity significantly re duced skin inflammation and hapten-specific Tc1/Th1 cell response. Pharmacological approaches identified individual proteases involved in PAR2 cleavage and demon strated a pivotal role of tissue factor (TF) and coagulation factor Xa (FXa) as upstream activators of PAR2 in both the induction and effector phase of CHS. PAR2 mutant mouse strains with differential cleavage sensitivity for FXa versus skin epithelial cell–expressed proteases furthermore uncovered a time-dependent regulation of CHS development with an important function of FXa-induced PAR2 activation during the late phase of skin inflammation. Conclusions: Myeloid cells and the TF–FXa–PAR2 axis are key mediators and poten tial therapeutic targets in inflammatory skin disease

Exposure to aircraft noise exacerbates cardiovascular and oxidative damage in three mouse models of diabetes

BackgroundEpidemiology links noise to increased risk of metabolic diseases like diabetes and obesity. Translational studies in humans and experimental animals showed that noise causes reactive oxygen species (ROS)-mediated cardiovascular damage. The interaction between noise and diabetes, specifically potential additive adverse effects, remains to be determined.Methods and ResultsC57BL/6 mice were treated with streptozotocin (i.p. injections, 50 mg/kg/d for 5d) to induce type-1 diabetes, with S961 (subcutaneous osmotic minipumps, 0.57 mg/kg/d for 7d) or fed a high-fat diet (HFD, 20 weeks) to induce type-2 diabetes. Control and diabetic mice were exposed to aircraft noise to an average sound pressure level of 72 dB(A) for 4d. While body weight was unaffected, noise reduced insulin production in all diabetes models. The oral glucose tolerance test showed only an additive aggravation by noise in the HFD model. Noise increased blood pressure and aggravated diabetes-induced aortic, mesenteric, and cerebral arterioles endothelial dysfunction. ROS formation in cerebral arterioles, the aorta, the heart, and isolated mitochondria was consistently increased by noise in all models of diabetes. Mitochondrial respiration was impaired by diabetes and noise, however without additive effects. Noise increased ROS and caused inflammation in adipose tissue in the HFD model. RNA sequencing data and alteration of gene pathway clusters also supported additive damage by noise in the setting of diabetes.ConclusionIn all three models of diabetes, aircraft noise exacerbates oxidative stress, inflammation, and endothelial dysfunction in mice with pre-existing diabetes. Thus, noise may potentiate the already increased cardiovascular risk in diabetic patients

Interview Survey of Chief Executives of Medium-sized Companies Vol.30

Additional file 4. Densitometric analysis of troponin T, periostin, carbonic anhydrase 3 and cytoglobin in sham, MI-placebo and MI-SAR1 mice. The densitometric measurements of proteins are expressed as a percentage of the average values measured in the sham group. Results are expressed as mean ± SEM

Laser-Induced Electron Diffraction in Chiral Molecules

Strong laser pulses enable probing molecules with their own electrons. The oscillating electric field tears electrons off a molecule, accelerates them, and drives them back toward their parent ion within a few femtoseconds. The electrons are then diffracted by the molecular potential, encoding its structure and dynamics with angstrom and attosecond resolutions. Using elliptically polarized laser pulses, we show that laser-induced electron diffraction is sensitive to the chirality of the target. The field selectively ionizes molecules of a given orientation and drives the electrons along different sets of trajectories, leading them to recollide from different directions. Depending on the handedness of the molecule, the electrons are preferentially diffracted forward or backward along the light propagation axis. This asymmetry, reaching several percent, can be reversed for electrons recolliding from two ends of the molecule. The chiral sensitivity of laser-induced electron diffraction opens a new path to resolve ultrafast chiral dynamics

65 YEARS OF THE DOUBLE HELIX Genetics informs precision practice in the diagnosis and management of pheochromocytoma

Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.Peer reviewe

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2\u2009cm; P\u20091.5\u2009cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8\u2009cm vs 652.8\u2009cm (94% vs 85% by 10 years; P\u2009=\u20090.020; 80% vs 50% at 10 years; P\u2009=\u20090.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8\u2009cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs

Dynamique moléculaire par imagerie attoseconde

Depuis sa première observation, la génération d'harmoniques d'ordre élevé (GHOE) dans les gaz a demontré son importance, ouvrant la voie à la science attoseconde. Cette technique produit un rayonnement impulsionnel XUV qui s'étend dans le domaine spectral intermédiaire entre l'ultraviolet et les rayons X. Ces impulsions attosecondes donnent accès à des résolutions temporelles extrêmes, permettant ainsi d'observer des dynamiques électroniques dans des atomes ou des molécules. En effet le processus de généneration d'harmonique repose sur l'oscillation de paquets d'électrons attosecondes issus des molécules, accélérés par le champ de laser intense et se recombinant radiativement avec leurs ions moléculaires parents. Ainsi, le rayonnement harmonique émis lors de la recombinaison permet d'encoder l'information structurale sur le ou les orbitales impliquées avec une résolution spatiale de l'ordre l'Angström et temporelle femtoseconde ou attoseconde. La génération d'harmonique peut être utilisée comme signal de sonde dans des expériences de spectroscopie pompe-sonde résolue en temps. Ces expériences de spectroscopie harmoniques permettent d'étudier la structure des orbitales et les dynamiques moléculaires ultra-rapides. L'objectif de cette thèse est d'utiliser le processus de la GHOE, pour sonder les processus fondamentaux qui interviennent dans les atomes, les molécules et la matière condensée. Tout d'abord, pour comprendre comment extraire des informations dynamiques ou structurelles sur les orbitales à partir du signal harmonique nous avons étudié un système simple et connu: l'argon. Une nouvelle approche théorique développée par Fabre et Pons a permis de reproduire fidèlement l'expérience. Nous avons continué à étudier la structure et la dynamique moléculaire dans N2 et CO2. Les molécules issues d'un jet supersonique Even-Lavie qui permettait d'obtenir des températures rotationelles de moins de 10K ont été alignées par laser avec un fort degré d'alignement. Ce type de jet permet d'améliorer la sensibilité à la structure des orbitales impliquées et d'identifier la contribution de plusieurs orbitales. Ensuite nous avons utilisé la sensibilité de la génération des harmoniques d'ordre élevé à la structure des orbitales moléculaires pour sonder la dynamique complexe du NO2 excité autour d'une intersection conique. Nous avons appliqué la méthode du réseau d'excitation transitoire qui permet d'améliorer la sensibilité aux molécules excitées. Nous avons donc mené une étude dans les agrégats. A l'aide d'une étude différentielle en température et d'une méthode de cartographie spectrale et spatiale, nous avons pu isoler la contibution des grands agrégats. Notre analyse suggère un nouveau mécanisme de génération par des agrégats et permet même une estimation de la longeur de corrélation des électrons dans les agrégats. Ce manuscrit se termine avec la présentation d'une ligne de lumière XUV. Cette technique consiste à utiliser le rayonnement XUV fs produit par la GHOE comme impulsion sonde pour ioniser des fragments de dissociation moléculaire à l'aide d'une transition à un photon.Since the first observation of high-order harmonic spectra in gases, high harmonic generation (HHG) has demonstrated its importance, opening a door to the field of attosecond sience. The bandwidth of the emitted spectrum reaches up to the XUV. The attosecond pules reach a very high time resolution, allowing the study of electron dynamics in atoms or molecules. The generation mechanism of HHG is based on the oscillation of the attosecond electron wavepacket emitted by the atoms/molecules, accelerated by the laser field. The electron wavepacket finally recombines radiatively with its parent ion. Thus the structural information of the probed orbital is encoded in the high harmonic spectrum with a spatial resolution of one Angtröm and a temporal resolution of few femtoseconds. HHG can be used as a probe signal resolved for pump-probe spectroscopy. High harmonic spectroscopy allows the study of the orbital structure and ultra-fast molecular dynamics.In this thesis the fundamental mechanisms playing a role in atoms, molecules and condensed matter are probed using HHG. In order to understand how to extract dynamical and structural information of orbitals from a harmonic signal, we have studied an easy and well known systems: the argon atom. A new theoretical approach developped by Fabre and Pons allowed us to reproduce the experimental results in good agreement. We continued with a study of the molecular structure and dynamics of N2 and CO2. A supersonic Even-Lavie jet permitted to reach rotational temperatures lower than 10K with an excellent alignment distribution. Owing to the good alignment in such gas jet, we were able to resolve the orbital structure with a higher sensitivity and to identify the contribution of several orbitals. In the next step we used the sensitivity of HHG towards the structure of molecular orbitals in order to probe the complex dynamics of NO2 in the vicinity of a conical intersection. We applied HHG combined with transient grating spectroscopy which leads to a higher sensitivity of the excited molecules. We then continued with studying cluster. We were able to disentangle the contribution of large clusters to the harmonic signal due to a 2D spatio-spectral representation of a temperature dependent differential measurement. Our analysis suggests a new generation mechanism in clusters and allows an estimation of the electron correlation length in clusters. This thesis ends with the presentation of a XUV beamline. This technique uses the emitted fs-XUV radiation, provided by HHG, as a probe pulse for ionizing the photofragments by a one photon transition

Attosecond imaging of molecular dynamics

Depuis sa première observation, la génération d'harmoniques d'ordre élevé (GHOE) dans les gaz a demontré son importance, ouvrant la voie à la science attoseconde. Cette technique produit un rayonnement impulsionnel XUV qui s'étend dans le domaine spectral intermédiaire entre l'ultraviolet et les rayons X. Ces impulsions attosecondes donnent accès à des résolutions temporelles extrêemes, permettant ainsi d'observer des dynamiques électroniques dans des atomes ou des molécules. En effet le processus de généneration d'harmonique repose sur l'oscillation de paquets d'électrons attosecondes issus des molécules, accélérés par le champ de laser intense et se recombinant radiativement avec leurs ions moléculaires parents. Ainsi, le rayonnement harmonique émis lors de la recombinaison permet d'encoder l'information structurale sur le ou les orbitales impliquées avec une résolution spatiale de l'ordre l'Angström et temporelle femtoseconde ou attoseconde. La génération d'harmonique peut être utilisée comme signal de sonde dans des expériences de spectroscopie pompe-sonde résolue en temps. Ces expériences de spectroscopie harmoniques permettent d'étudier la structure des orbitales et les dynamiques moléculaires ultra-rapides. L'objectif de cette thèse est d'utiliser le processus de la GHOE, pour sonder les processus fondamentaux qui interviennent dans les atomes, les molécules et la matière condensée. Tout d'abord, pour comprendre comment extraire des informations dynamiques ou structurelles sur les orbitales à partir du signal harmonique nous avons étudié un système simple et connu: l'argon. Une nouvelle approche théorique développée par Fabre et Pons a permis de reproduire fidèlement l'expérience. Nous avons continué à étudier la structure et la dynamique moléculaire dans N2 et CO2. Les molécules issues d'un jet supersonique Even-Lavie qui permettait d'obtenir des températures rotationelles de moins de 10K ont été alignées par laser avec un fort degré d'alignement. Ce type de jet permet d'améliorer la sensibilité à la structure des orbitales impliquées et d'identifier la contribution de plusieurs orbitales. Ensuite nous avons utilisé la sensibilité de la génération des harmoniques d'ordre élevé à la structure des orbitales moléculaires pour sonder la dynamique complexe du NO2 excité autour d'une intersection conique. Nous avons appliqué la méthode du réseau d'excitation transitoire qui permet d'améliorer la sensibilité aux molécules excitées. Nous avons donc mené une étude dans les agrégats. A l'aide d'une étude différentielle en température et d'une méthode de cartographie spectrale et spatiale, nous avons pu isoler la contibution des grands agrégats. Notre analyse suggère un nouveau mécanisme de génération par des agrégats et permet même une estimation de la longeur de corrélation des électrons dans les agrégats. Ce manuscrit se termine avec la présentation d'une ligne de lumière XUV. Cette technique consiste à utiliser le rayonnement XUV fs produit par la GHOE comme impulsion sonde pour ioniser des fragments de dissociation moléculaire à l'aide d'une transition à un photon.Since the first observation of high-order harmonic spectra in gases, high harmonic generation (HHG) has demonstrated its importance, opening a door to the field of attosecond sience. The bandwidth of the emitted spectrum reaches up to the XUV. The attosecond pulses reach a very high time resolution, allowing the study of electron dynamics in atoms or molecules. The generation mechanism of HHG is based on the emission of an attosecond electron wavepacket by the atoms/molecules. The electron wavepacket is accelerated by the laser field and finally recombines radiatively with its parent ion. Thus the structural information of the probed orbital is encoded in the high harmonic spectrum with a spatial resolution of one Angtröm and a temporal resolution of few femtoseconds. HHG can be used as a probe signal resolved for pump-probe spectroscopy. High harmonic spectroscopy allows the study of the orbital structure and ultra-fast molecular dynamics. In this thesis the fundamental mechanisms playing a role in atoms, molecules and condensed matter are probed using HHG. In order to understand how to extract dynamical and structural information of orbitals from a harmonic signal, we have first studied an easy and well known system: the argon atom. A new theoretical approach developped by Fabre and Pons allowed us to reproduce the experimental results in good agreement. We continued with a study of the molecular structure and dynamics of N2 and CO2. A supersonic Even-Lavie jet permitted to reach rotational temperatures lower than 10K with an excellent alignment distribution. Owing to the good alignment in such gas jet, we were able to resolve the orbital structure with a higher sensitivity and to identify the contribution of several orbitals. In the next step we used the sensitivity of HHG towards the structure of molecular orbitals in order to probe the complex dynamics of NO2 in the vicinity of a conical intersection. We applied HHG combined with transient grating spectroscopy which leads to a higher sensitivity of the excited molecules. We then continued with studying cluster. We were able to disentangle the contribution of large clusters to the harmonic signal due to a 2D spatio-spectral representation of a temperature dependent differential measurement. Our analysis suggests a new generation mechanism in clusters and allows an estimation of the electron correlation length in clusters. This thesis ends with the presentation of a XUV beamline. This technique uses the emitted fs-XUV radiation, provided by HHG, as a probe pulse for ionizing the photofragments by a one photon transition