Efecto de un nuevo xanthanólido sesquiterpeno sobre la activación de mastocitos inducida por neurópeptidos pro-inflamatorios

Los mastocitos son células del tejido conectivo que participan en la génesis y modulación de las respuestas inflamatorias celulares. En trabajos previos hemos demostrado que xanthatina (xanthanólido sesquiterpeno aislado de Xanthium cavanillesii Schouw) inhibe la activación de mastocitos inducida por secretagogos experimentales. Sin embargo, se desconoce su efecto sobre la activación de mastocitos inducida por estímulos fisiopatológicos. Estos estímulos incluyen, entre otros, los neuropéptidos pro-inflamatorios sustancia P y neurotensina, responsables de una de las principales vías de inflamación neurogénica. El objetivo del presente trabajo fue estudiar el efecto de xanthatina sobre la activación de mastocitos inducida por sustancia P y neurotensina. Mastocitos peritoneales de rata se incubaron con: 1) PBS (basal); 2) sustancia P (100 Fm); 3) neurotensina (50 Fm); 4) xanthatina (8-320 Fm)+sustancia P; 5) xanthatina (8-320 Fm)+neurotensina. La viabilidad de los mastocitos se evaluó con azul tripán. En las soluciones de incubación se cuantificó serotonina liberada (marcador de activación). En las células se cuantificó serotonina remanente (no liberada) y se analizó la morfología celular por microscopía óptica y electrónica de transmisión. Tratamiento estadístico: ANOVA-1 y Tukey-Kramer. La incubación de mastocitos con xanthatina inhibió (P<0,01), en forma dosisdependiente, la liberación de serotonina inducida por sustancia P y neurotensina, sin modificar la viabilidad celular. Los mastocitos tratados con neuropéptidos mostraron características morfológicas de degranulación, mientras que la morfología de los mastocitos tratados con xanthatina+neuropéptido fue semejante a los basales. En conclusión, xanthatina inhibe la activación de mastocitos inducida por sustancia P y por neurotensina. Este sesquiterpeno podría representar una nueva alternativa en el tratamiento de las inflamaciones neurogénicas.The present study was designed to examine the effects of a novel natural xanthanolide with anti-ulcer and anti-inflammatory properties (xanthatin) on mast cell activation induced by pro-inflammatory peptides, such as substance P and neurotensin. Peritoneal mast cells from male adult were purified in Percoll, preincubated in the presence of xanthatin and then challenged with the mast cell activators substance P (100 Fm) or neurotensin (50 Fm). Concentration-response studies of mast cell serotonin release evoked by pro-inflammatory neuropeptides, evaluation of mast cell viability and morphology by light and electron microscopy, and drug stability analysis by thin layer chromatography (TLC) were performed. Serotonin release studies, carried out together with morphological studies, showed the effectiveness of xanthatin to stabilize mast cells. The present study provides the first strong evidence in favour of the hypothesis that xanthatin inhibits substance P- and neurotensin-induced serotonin release from peritoneal mast cells, acting thus as a mast cell stabilizer. Our findings may provide an insight into the design of novel pharmacological agents which may be used to regulate the mast cell response in neurogenic inflammation.Fil: Vargas, P.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histologia y Embriología Mendoza. "Dr. Mario H. Burgos"Fil: Martino, E.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Área de Anatomía NormalFil: Fogal, T.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histologia y Embriología Mendoza. "Dr. Mario H. Burgos"Fil: Tonn, C.. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química.Fil: Penissi, A.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histologia y Embriología Mendoza. "Dr. Mario H. Burgos

Intercomparison of ground-based ozone and NO2 measurements during the MANTRA 2004 campaign

The MANTRA (Middle Atmosphere Nitrogen TRend Assessment) 2004 campaign took place in Vanscoy, Saskatchewan, Canada (52° N, 107° W) from 3 August to 15 September, 2004. In support of the main balloon launch, a suite of five zenith-sky and direct-Sun-viewing UV-visible ground-based spectrometers was deployed, primarily measuring ozone and NO2 total columns. Three Fourier transform spectrometers (FTSs) that were part of the balloon payload also performed ground-based measurements of several species, including ozone. Ground-based measurements of ozone and NO2 differential slant column densities from the zenith-viewing UV-visible instruments are presented herein. They are found to partially agree within NDACC (Network for the Detection of Atmospheric Composition Change) standards for instruments certified for process studies and satellite validation. Vertical column densities of ozone from the zenith-sky UV-visible instruments, the FTSs, a Brewer spectrophotometer, and ozonesondes are compared, and found to agree within the combined error estimates of the instruments (15%). NO2 vertical column densities from two of the UV-visible instruments are compared, and are also found to agree within combined error (15%)

The determination of HNO3 column amounts from tunable diode laser heterodyne spectrometer spectra taken at Jungfruajoch, Switzerland

In May of 1991 a tunable diode laser heterodyne spectrometer built by the National Physical Laboratory was operated at the International Scientific Station of the Jungfraujoch (46.5 deg N, 8.0 deg E, altitude 3.56 km). Nitric acid spectra in the region of 868 wavenumbers were recorded at sunset and sunrise on two separate days at a resolution of 0.0013 wavenumbers with a signal-to-noise ratio of approximately 130:1. A vertical column amount of HNO3 of 1.61 x 10(exp 16) molecules/sq cm was determined using an atmospheric transmission model developed at the University of Denver. The mean of a number of mid-latitude, northern hemisphere profiles was used as the initial profile for the inversion. A comparison of different initial profiles provides information on the sensitivity of the retrieved column amount of 1.61 x 10(exp 16) molecules/sq cm lies within the range of values published in the World Meteorological Organization Report no. 16 (1986), but is considerably larger than the value of (0.99 - 1.29) x 10(exp 16) reported by Rinsland et al. (1991) for June during the period 1986 to 1990

Simultaneous atmospheric measurements using two Fourier transform infrared spectrometers at the Polar Environment Atmospheric Research Laboratory during spring 2006, and comparisons with the Atmospheric Chemistry Experiment-Fourier Transform Spectrometer

International audienceThe 2006 Canadian Arctic ACE (Atmospheric Chemistry Experiment) Validation Campaign collected measurements at the Polar Environment Atmospheric Research Laboratory (PEARL, 80.05° N, 86.42° W, 610 m above sea level) at Eureka, Canada from 17 February to 31 March 2006. Two of the ten instruments involved in the campaign, both Fourier transform spectrometers (FTSs), were operated simultaneously, recording atmospheric solar absorption spectra. The first instrument was an ABB Bomem DA8 high-resolution infrared FTS. The second instrument was the Portable Atmospheric Research Interferometric Spectrometer for the Infrared (PARIS-IR), the ground-based version of the satellite-borne FTS on the ACE satellite (ACE-FTS). From the measurements collected by these two ground-based instruments, total column densities of seven stratospheric trace gases (O3, HNO3, NO2, HCl, HF, NO, and ClONO2 were retrieved using the optimal estimation method and these results were compared. Since the two instruments sampled the same portions of atmosphere by synchronizing observations during the campaign, the biases in retrieved columns from the two spectrometers represent the instrumental differences. These differences were consistent with those seen in previous FTS intercomparison studies. Partial column results from the ground-based spectrometers were also compared with partial columns derived from ACE-FTS version 2.2 (including updates for O3, HDO and N2O5 profiles and the differences found were consistent with the other validation comparison studies for the ACE-FTS version 2.2 data products. Column densities of O3, HCl, ClONO2, and HNO3 from the three FTSs were normalized with respect to HF and used to probe the time evolution of the chemical constituents in the atmosphere over Eureka during spring 2006

Validation of ACE and OSIRIS Ozone and NO2 Measurements Using Ground Based Instruments at 80° N

The Optical Spectrograph and Infra-Red Imager System (OSIRIS) and the Atmospheric Chemistry Experiment (ACE) have been taking measurements from space since 2001 and 2003, respectively. This paper presents intercomparisons between ozone and NO2 measured by the ACE and OSIRIS satellite instruments and by ground-based instruments at the Polar Environment Atmospheric Research Laboratory (PEARL), which is located at Eureka, Canada (80◦ N, 86◦ W) and is operated by the Canadian Network for the Detection of Atmospheric Change (CANDAC). The ground-based instruments included in this study are four zenith-sky differential optical absorption spectroscopy (DOAS) instruments, one Bruker Fourier transform infrared spectrometer (FTIR) and four Brewer spectrophotometers. Ozone total columns measured by the DOAS instruments were retrieved using new Network for the Detection of Atmospheric Composition Change (NDACC) guidelines and agree to within 3.2 %. The DOAS ozone columns agree with the Brewer spectrophotometers with mean relative differences that are smaller than 1.5 %. This suggests that for these instruments the new NDACC data guidelines were successful in producing a homogenous and accurate ozone dataset at 80◦ N. Satellite 14–52km ozone and 17–40km NO2 partial columns within 500km of PEARL were calculated for ACE-FTS Version 2.2 (v2.2) plus updates, ACE-FTS v3.0, ACE-MAESTRO (Measurements of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation) v1.2 and OSIRIS SaskMART v5.0x ozone and Optimal Estimation v3.0 NO2 data products. The new ACE-FTS v3.0 and the validated ACE-FTS v2.2 partial columns are nearly identical, with mean relative differences of 0.0±0.2% and −0.2±0.1% for v2.2 minus v3.0 ozone and NO2, respectively. Ozone columns were constructed from 14–52km satellite and 0–14km ozonesonde partial columns and compared with the ground-based total column measurements. The satellite-plus-sonde measurements agree with the ground-based ozone total columns with mean relative differences of 0.1–7.3 %. For NO2, partial columns from 17km upward were scaled to noon using a photo-chemical model. Mean relative differences between OSIRIS, ACE-FTS and ground-based NO2 measurements do not exceed 20 %. ACE-MAESTRO measures more NO2 than the other instruments, with mean relative differences of 25–52 %. Seasonal variation in the differences between NO2 partial columns is observed, suggesting that there are systematic errors in the measurements and/or the photochemical model corrections. For ozone spring-time measurements, additional coincidence criteria based on stratospheric temperature and the location of the polar vortex were found to improve agreement between some of the instruments. For ACE-FTS v2.2 minus Bruker FTIR, the 2007–2009 spring-time mean relative difference improved from−5.0±0.4%to−3.1±0.8% with the dynamical selection criteria. This was the largest improvement, likely because both instruments measure direct sunlight and therefore have well-characterized lines-of-sight compared with scattered sunlight measurements. For NO2, the addition of a±1◦ latitude coincidence criterion improved spring-time intercomparison results, likely due to the sharp latitudinal gradient of NO2 during polar sunrise. The differences between satellite and ground-based measurements do not show any obvious trends over the missions, indicating that both the ACE and OSIRIS instruments continue to perform well

Summertime stratospheric processes at northern mid-latitudes: comparisons between MANTRA balloon measurements and the Canadian Middle Atmosphere Model

In this paper we report on a study conducted using the Middle Atmospheric Nitrogen TRend Assessment (MANTRA) balloon measurements of stratospheric constituents and temperature and the Canadian Middle Atmosphere Model (CMAM). Three different kinds of data are used to assess the inter-consistency of the combined dataset: single profiles of long-lived species from MANTRA 1998, sparse climatologies from the ozonesonde measurements during the four MANTRA campaigns and from HALOE satellite measurements, and the CMAM climatology. In doing so, we evaluate the ability of the model to reproduce the measured fields and to thereby test our ability to describe mid-latitude summertime stratospheric processes. The MANTRA campaigns were conducted at Vanscoy, Saskatchewan, Canada (52◦ N, 107◦ W)in late August and early September of 1998, 2000, 2002 and 2004. During late summer at mid-latitudes, the stratosphere is close to photochemical control, providing an ideal scenario for the study reported here. From this analysis we find that: (1) reducing the value for the vertical diffusion coefficient in CMAM to a more physically reasonable value results in the model better reproducing the measured profiles of long-lived species; (2) the existence of compact correlations among the constituents, as expected from independent measurements in the literature and from models, confirms the self-consistency of the MANTRA measurements; and (3) the 1998 measurements show structures in the chemical species profiles that can be associated with transport, adding to the growing evidence that the summertime stratosphere can be much more disturbed than anticipated. The mechanisms responsible for such disturbances need to be understood in order to assess the representativeness of the measurements and to isolate longterm trends

Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS

Metal-substituted protein MRI contrast agents engineered for enhanced relaxivity and ligand sensitivity

Engineered metalloproteins constitute a flexible new class of analyte-sensitive molecular imaging agents detectable by magnetic resonance imaging (MRI), but their contrast effects are generally weaker than synthetic agents. To augment the proton relaxivity of agents derived from the heme domain of cytochrome P450 BM3 (BM3h), we formed manganese(III)-containing proteins that have higher electron spin than their native ferric iron counterparts. Metal substitution was achieved by coexpressing BM3h variants with the bacterial heme transporter ChuA in Escherichia coli and supplementing the growth medium with Mn3+-protoporphyrin IX. Manganic BM3h variants exhibited up to 2.6-fold higher T1 relaxivities relative to native BM3h at 4.7 T. Application of ChuA-mediated porphyrin substitution to a collection of thermostable chimeric P450 domains resulted in a stable, high-relaxivity BM3h derivative displaying a 63% relaxivity change upon binding of arachidonic acid, a natural ligand for the P450 enzyme and an important component of biological signaling pathways. This work demonstrates that protein-based MRI sensors with robust ligand sensitivity may be created with ease by including metal substitution among the toolkit of methods available to the protein engineer.National Institutes of Health (U.S.) (NIH Grant R01-DA28299 )National Institutes of Health (U.S.) (NIH NRSA Fellowship (Award F32-GM087102))California Institute of Technology (Caltech Jacobs Grant

Characterization of aerosol growth events over Ellesmere Island during the summers of 2015 and 2016

The occurrence of frequent aerosol nucleation and growth events in the Arctic during summertime may impact the region's climate through increasing the number of cloud condensation nuclei in the Arctic atmosphere. Measurements of aerosol size distributions and aerosol composition were taken during the summers of 2015 and 2016 at Eureka and Alert on Ellesmere Island in Nunavut, Canada. These results provide a better understanding of the frequency and spatial extent of elevated Aitken mode aerosol concentrations as well as of the composition and sources of aerosol mass during particle growth. Frequent appearances of small particles followed by growth occurred throughout the summer. These particle growth events were observed beginning in June with the melting of the sea ice rather than with the polar sunrise, which strongly suggests that influence from the marine boundary layer was the primary cause of the events. Correlated particle growth events at the two sites, separated by 480&thinsp;km, indicate conditions existing over large scales play a key role in determining the timing and the characteristics of the events. In addition, aerosol mass spectrometry measurements were used to analyze the size-resolved chemical composition of aerosols during two selected growth events. It was found that particles with diameters between 50 and 80&thinsp;nm (physical diameter) during these growth events were predominately organic with only a small sulfate contribution. The oxidation of the organics also changed with particle size, with the fraction of organic acids increasing with diameter from 80 to 400&thinsp;nm. The growth events at Eureka were observed most often when the temperature inversion between the sea and the measurement site (at 610&thinsp;m&thinsp;a.s.l.) was non-existent or weak, presumably creating conditions with low aerosol condensation sink and allowing fresh marine emissions to be mixed upward to the observatory's altitude. While the nature of the gaseous precursors responsible for the growth events is still poorly understood, oxidation of dimethyl sulfide alone to produce particle-phase sulfate or methanesulfonic acid was inconsistent with the measured aerosol composition, suggesting the importance of other gas-phase organic compounds condensing for particle growth.</p

Using FTIR measurements of stratospheric composition to identify midlatitude polar vortex intrusions over Toronto

Publisher's Version/PDFUsing 11 years of trace gas measurements made at the University of Toronto Atmospheric Observatory (43.66&deg;N, 79.40&deg;W) and Environment Canada&rsquo;s Centre for Atmospheric Research Experiments (44.23&deg;N, 79.78&deg;W), along with derived meteorological products, we identify a number of polar intrusion events, which are excursions of the polar vortex or filaments from the polar vortex extending down to midlatitudes. These events are characterized by enhanced stratospheric columns (12&ndash;50 km) of hydrogen fluoride (HF), by diminished stratospheric columns of nitrous oxide (N2O), and by a scaled potential vorticity above 1.2 &times;10-4s-1.The events comprise 16% of winter/spring (November to April inclusive) Fourier transform infrared (FTIR) spectroscopic measurements from January 2002 to March 2013, and we find at least two events per year. The events are corroborated by Mod&egrave;le Isentrope du transport M&eacute;so-&eacute;chelle de l&rsquo;Ozone Stratosph&eacute;rique par Advection, Modern-Era Retrospective Analysis for Research and Applications potential vorticity maps, and Global Modeling Initiative N2O maps. During polar intrusion events, the stratospheric ozone (O3) columns over Toronto are usually greater than when there is no event. Our O3 measurements agree with the Optical Spectrograph and Infrared Imaging System satellite instrument and are further verified with the Earth Probe Total Ozone Mapping Spectrometer and Ozone Monitoring Instrument satellite observations. We find six cases out of 53 for which chemical O3 depletion within the polar vortex led to a reduction in stratospheric O3 columns over Toronto. We have thus identified a dynamical cause for most of the winter/spring variability of stratospheric trace gas columns observed at our midlatitude site. While there have been a number of prior polar intrusion studies, this is the first study to report in the context of 11 years of ground-based FTIR column measurements, providing insight into the frequency of midlatitude polar vortex intrusions and observations of upper stratospheric (25&ndash;50 km) intrusions. It is also the first to present HF measurements during multiple polar intrusions, which provided an excellent tracer for their identification.</p