Zooming in on VY CMa ejecta

The Atacama Large Millimeter/Submillimeter Array (ALMA), Cagliari, Italy 14–18 October 2019ALMA has allowed us to study the ejecta around evolved stars with unprecedented resolution. This extremely high resolution at the millimeter domain provides a unique tool to study the processes taking place in the innermost regions of these evolved stars. In particular, the processes leading to the mass ejections of the Red Supergiant stars are unknown. The pulsation process responsible for mass ejection in the intermediate mass AGB phase does not work in the high mass evolved stars. Therefore, studying the characteristics of the mass ejections near the photosphere of the massive stars is essential to constrain the processes leading to the observed gas ejection. In this sense, we have obtained interferometric maps in the range 231.7 ¿ 235.3 GHz of the ejecta around the Red Supergiant star VY CMa with an spatial resolution of 0.02>. These maps revealed a level of complexity higher than previously anticipated from previous observations. The complexity seems to be due both to structural and chemical processes. The molecular lines covered within these maps range from upper energies 19 up to 3400 K, tracing different excitation conditions. We will present a global view of the different structures observedThe research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 610256 (NANOCOSMOS). We would also like to thank the Spanish MINECO for funding support from grants CSD2009-00038, AYA2012-32032, AYA2016-75066-C2-1-P & AYA2016-78994-P. M.A. also thanks for funding support from the Ramón y Cajal programme of Spanish MINECO (RyC-2014- 16277)

Genetic Variants of Alcohol Metabolizing Enzymes and Alcohol-Related Liver Cirrhosis Risk

Alcohol-related liver disease (ARLD) is a major public health issue caused by excessive alcohol consumption. ARLD encompasses a wide range of chronic liver lesions, alcohol-related liver cirrhosis being the most severe and harmful state. Variations in the genes encoding the enzymes, which play an active role in ethanol metabolism, might influence alcohol exposure and hence be considered as risk factors of developing cirrhosis. We conducted a case-control study in which 164 alcohol-related liver cirrhosis patients and 272 healthy controls were genotyped for the following functional single nucleotide variations (SNVs): ADH1B gene, rs1229984, rs1041969, rs6413413, and rs2066702; ADH1C gene, rs35385902, rs283413, rs34195308, rs1693482, and rs35719513; CYP2E1 gene, rs3813867. Furthermore, copy number variations (CNVs) for ADH1A, ADH1B, ADH1C, and CYP2E1 genes were analyzed. A significant protective association with the risk of developing alcohol-related liver cirrhosis was observed between the mutant alleles of SNVs ADH1B rs1229984 (Pc value = 0.037) and ADH1C rs283413 (Pc value = 0.037). We identified CNVs in all genes studied, ADH1A gene deletions being more common in alcohol-related liver cirrhosis patients than in control subjects, although the association lost statistical significance after multivariate analyses. Our findings support that susceptibility to alcohol-related liver cirrhosis is related to variations in alcohol metabolism genes

Detoxifying enzymes at the cross-roads of inflammation, oxidative stress, and drug hypersensitivity: role of glutathione transferase P1-1 and aldose reductase

9 p.-2 figPhase I and II enzymes are involved in the metabolism of endogenous reactive compounds as well as xenobiotics, including toxicants and drugs. Genotyping studies have established several drug metabolizing enzymes as markers for risk of drug hypersensitivity. However, other candidates are emerging that are involved in drug metabolism but also in the generation of danger or costimulatory signals. Enzymes such as aldo-keto reductases (AKR) and glutathione transferases (GST) metabolize prostaglandins and reactive aldehydes with proinflammatory activity, as well as drugs and/or their reactive metabolites. In addition, their metabolic activity can have important consequences for the cellular redox status, and impacts the inflammatory response as well as the balance of inflammatory mediators, which can modulate epigenetic factors and cooperate or interfere with drug-adduct formation. These enzymes are, in turn, targets for covalent modification and regulation by oxidative stress, inflammatory mediators, and drugs. Therefore, they constitute a platform for a complex set of interactions involving drug metabolism, protein haptenation, modulation of the inflammatory response, and/or generation of danger signals with implications in drug hypersensitivity reactions. Moreover, increasing evidence supports their involvement in allergic processes. Here, we will focus on GSTP1-1 and aldose reductase (AKR1B1) and provide a perspective for their involvement in drug hypersensitivityThis work has been supported by grants SAF2012-36519 from MINECO and SAF-2015-68590-R from MINECO/FEDER and ISCIII RETIC RIRAAF RD12/0013/0008 to DP,and RD12/0013/0002 to J A.Peer reviewe

Pharmacogenomics of prostaglandin and leukotriene receptors

Los antecedentes genéticos individuales junto con los efectos ambientales se cree que están detrás de muchas enfermedades complejas. Una serie de variantes genéticas, principalmente los SNPs (single nucleotide polymorphisms), han demostrado estar asociados con diferentes patologías y afecciones inflamatorias, que representan potenciales dianas terapéuticas. Las prostaglandinas (PTGs) y leucotrienos (LTs) son eicosanoides derivados del ácido araquidónico y relacionados con ácidos grasos poliinsaturados participan tanto en la homeostasis normal y en condiciones inflamatorias. Estos mediadores lípidos bioactivos son sintetizados a través de dos grandes vías enzimáticas multipaso: PTGs por la ciclooxigenasa y la lipooxigenasa DE 5 LTS. Los principales efectos fisiológicos de PTGs incluyen vasodilatación y la fuga vascular (PTGE2); la maduración de los mastocitos, eosinófilos, y reacciones alérgicas (PTGD2); vascular y la contracción del músculo liso de las vías respiratorias (PTGF2), e inhibición de la agregación plaquetaria (PTGI2). LTB4 está principalmente involucrado en el reclutamiento de los neutrófilos, fuga vascular y en la función de la barrera epitelial, mientras que cisteinil LTs (CysLTs) (LTC4, LTD4 y LTE4) inducen la broncoconstricción y extravasación de neutrófilos, y también participar en la fuga vascular. PTGs y LTs ejercen sus funciones biológicas mediante su unión a receptores afines, que pertenecen a las siete transmembranas acopladas a proteínas G, la superfamilia de receptores. Los SNPs en genes que codifican estos receptores pueden influir en su funcionalidad, ya que tienen un papel en la susceptibilidad a las enfermedades y la respuesta al tratamiento de los medicamentos. En esta revisión resumimos los SNPs en PTGs y receptores de LTs y su relevancia en enfermedades humanas. También ofrecemos información sobre la expresión génica. Por último, podemos especular sobre la dirección futura de este tema.Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs), have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs) and leukotrienes (LTs) are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesized through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2); mast cell maturation, eosinophil recruitment, and allergic responses (PTGD2); vascular and respiratory smooth muscle contraction (PTGF2), and inhibition of platelet aggregation (PTGI2). LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs) (LTC4, LTD4, and LTE4) induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic.Trabajo patrocinado por: Programa Miguel Servet. Ref CP14/00034, para José Antonio Cornejo García Ministerio de Economía y Competitividad y Instituto Nacional de Salud Carlos III y Fondos FEDER. Programa Sara Borrell. Ref. CD14/00242, para James R. Perkins Ministerio de Economía y Competitividad e Instituto Nacional de Salud Carlos III y Fondos FEDER. Becas FISPI12/02247, FISPI13/02598 y FISPI15/00726 Servicio Público de Salud de Andalucía. Beca PI-0279-2012 Junta de Extremadura y Fondos FEDER. Beca GR15026peerReviewe

Pharmacogenetic Factors Affecting Asthma Treatment Response. Potential Implications for Drug Therapy

Asthma is a frequent disease, mainly characterized by airway inflammation, in which drug therapy is crucial in its management. The potential of pharmacogenomics testing in asthma therapy has been, to date, little explored. In this review, we discuss pharmacogenetic factors affecting asthma treatment, both related to drugs used as controller medications for regular maintenance, such as inhaled corticosteroids, anti-leukotriene agents, long-acting beta-agonists, and the new biologic agents used to treat severe persistent asthma. In addition, we discuss current pharmacogenomics knowledge for rescue medications provided to all patients for as-needed relief, such as short-acting beta-agonists. Evidence for genetic variations as a factor related to drugs response has been provided for the following genes and groups of drugs: Inhaled corticosteroids: FCER2; anti-leukotriene agents: ABCC1, and LTC4S; beta-agonists: ADRB2. However, the following genes require further studies confirming or rejecting association with the response to asthma therapy: ADCY9, ALOX5, ARG1, ARG2, CRHR1, CRHR2, CYP3A4, CYP3A5, CYSLTR1, CYSLTR2, GLCCI1, IL4RA, LTA4H, ORMDL3, SLCO2B1, SPATS2L, STIP1, T, TBX21, THRA, THRB, and VEGFA. Although only a minority of these genes are, at present, listed as associated with drugs used in asthma therapy, in the Clinical Pharmacogenomics Implementation Consortium gene-drug pair list, this review reveals that sufficient evidence to start testing the potential of clinical pharmacogenomics in asthma therapy already exists. This evidence supports the inclusion in pilot pharmacogenetics tests of at least four genes. Hopefully these tests, if proven useful, will increase the efficiency and the safety of asthma therapy

The Maser-emitting Structure and Time Variability of the SiS Lines J =14-13 and 15-14 in IRC+10216

2 pags., 1 tab. -- Why Galaxies Care About AGB Stars: A Continuing Challenge through Cosmic Time Proceedings IAU Symposium No. 343, 2019 F. Kerschbaum, M. Groenewegen & H. Olofsson, eds.AGB stars are important contributors of processed matter to the ISM. However, the physical and chemical mechanisms involved in its ejection are still poorly known. This process is expected to have remarkable effects in the innermost envelope, where the dust grains are formed, the gas is accelerated, the chemistry is active, and the radiative excitation becomes important. A good tracer of this region in C-rich stars is SiS, an abundant refractory molecule that can display maser lines, very sensitive to changes in the physical conditions. We present high angular resolution interferometer observations (HPBW â‰30.″.25) of the v = 0 J = 14-13 and 15-14 SiS maser lines towards the archetypal AGB star IRC+10216, carried out with CARMA and ALMA to explore the inner 1> region around the central star. We also present an ambitious monitoring of these lines along one single pulsation period carried out with the IRAM 30 m telescope.The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ ERC grant agreement n◦ 610256: NANOCOSMO

Trends in Qualifying Biomarkers in Drug Safety. Consensus of the 2011 Meeting of the Spanish Society of Clinical Pharmacology

In this paper we discuss the consensus view on the use of qualifying biomarkers in drug safety, raised within the frame of the XXIV meeting of the Spanish Society of Clinical Pharmacology held in Málaga (Spain) in October, 2011. The widespread use of biomarkers as surrogate endpoints is a goal that scientists have long been pursuing. Thirty years ago, when molecular pharmacogenomics evolved, we anticipated that these genetic biomarkers would soon obviate the routine use of drug therapies in a way that patients should adapt to the therapy rather than the opposite. This expected revolution in routine clinical practice never took place as quickly nor with the intensity as initially expected. The concerted action of operating multicenter networks holds great promise for future studies to identify biomarkers related to drug toxicity and to provide better insight into the underlying pathogenesis. Today some pharmacogenomic advances are already widely accepted, but pharmacogenomics still needs further development to elaborate more precise algorithms and many barriers to implementing individualized medicine exist. We briefly discuss our view about these barriers and we provide suggestions and areas of focus to advance in the field

Discovery of SiCSi in IRC+10216: A missing link between gas and dust carriers of Si-C bonds

We report the discovery in space of a disilicon species, SiCSi, from observations between 80 and 350 GHz with the IRAM 30 m radio telescope. Owing to the close coordination between laboratory experiments and astrophysics, 112 lines have now been detected in the carbon-rich star CW Leo. The derived frequencies yield improved rotational and centrifugal distortion constants up to sixth order. From the line profiles and interferometric maps with the Submillimeter Array, the bulk of the SiCSi emission arises from a region of 6'' in radius. The derived abundance is comparable to that of SiC2. As expected from chemical equilibrium calculations, SiCSi and SiC2 are the most abundant species harboring a Si−C bond in the dust formation zone and certainly both play a key role in the formation of SiC dust grains.We thank spanish MINECO for funding under grants AYA2009-07304, AYA2012-32032, CSD2009-00038, and ERC under ERC-2013-SyG, G. A. 610256 NANOCOSMOS. The new laboratory measurements in Cambridge were supported by NASA grant NNX13AE59G

Atmospheric molecular blobs shape up circumstellar envelopes of AGB stars

19 pags., 4 + 10 figs.During their thermally pulsing phase, asymptotic giant branch (AGB) stars eject material that forms extended dusty envelopes1. Visible polarimetric imaging found clumpy dust clouds within two stellar radii of several oxygen-rich stars2-6. Inhomogeneous molecular gas has also been observed in multiple emission lines within several stellar radii of different oxygen-rich stars, including W Hya and Mira7-10. At the stellar surface level, infrared images have shown intricate structures around the carbon semiregular variable R Scl and in the S-type star π1 Gru11,12. Infrared images have also shown clumpy dust structures within a few stellar radii of the prototypical carbon AGB star IRC+10°216 (refs. 13,14), and studies of molecular gas distribution beyond the dust formation zone have also shown complex circumstellar structures15. Because of the lack of sufficient spatial resolution, however, the distribution of molecular gas in the stellar atmosphere and the dust formation zone of AGB carbon stars is not known, nor is how it is subsequently expelled. Here we report observations with a resolution of one stellar radius of the recently formed dust and molecular gas in the atmosphere of IRC+10°216. Lines of HCN, SiS and SiC2 appear at different radii and in different clumps, which we interpret as large convective cells in the photosphere, as seen in Betelgeuse16. The convective cells coalesce with pulsation, causing anisotropies that, together with companions17,18, shape its circumstellar envelope.This publication is part of project ‘I+D+i’ (research, development and innovation, nos. PID2020-117034RJ-I00, PID2019-107115GB-C21, PID2019-106110GB-I00 and PID2019-105203GB-C22) supported by the Spanish Ministerio de Ciencia e Innovación (MCIN/ AEI/10.13039/501100011033). This work was also supported by the European Research Council under Synergy Grant ERC-2013-SyG, G.A. 610256 (NANOCOSMOS). This work is based on observations carried out with the IRAM, SMA and ALMA telescopes. IRAM is supported by INSU/CNRS (France), MPG (Germany) and IGN (Spain). SMA is a joint project between the Smithsonian Astrophysical Observatory (USA) and the Academia Sinica Institute of Astronomy and Astrophysics (Taiwan) and is funded by the Smithsonian Institution and Academia Sinica. This paper makes use of the following ALMA data: ADS/JAO.ALMA#2013.1.01215.S, ADS/JAO. ALMA#2013.1.00432.S and ADS/JAO.ALMA#2018.1.01485. ALMA is a partnership that includes ESO (representing its member states), NSF (USA) and NINS (Japan), together with NRC (Canada), NSC and ASIAA (Taiwan) and KASI (Republic of Korea), in cooperation with the Republic of Chile. The Joint ALMA Observatory is operated by ESO, AUI/NRAO and NAOJ. We made use of CASA software (https://casa.nrao.edu/). The GILDAS package was used to reduce and analyse data (https://www.iram.fr/IRAMFR/GILDAS). We acknowledge the GILDAS software team, in particular S. Bardeau, for their help and assistance. We also thank IRAM staff, who provided relevant information for flux calibration from the Northern Extended Millimetre Array observatory database.Peer reviewe

Molecular excitation in the Interstellar Medium: recent advances in collisional, radiative and chemical processes

We review the different excitation processes in the interstellar mediumComment: Accepted in Chem. Re