72 research outputs found
Structure-activity relationships based on 3D-QSAR CoMFA/CoMSIA and design of aryloxypropanol-amine agonists with selectivity for the human β3-adrenergic receptor and anti-obesity and anti-diabetic profiles
Indexación: Scopus.Acknowledgments: This work was supported by FONDECYT No. 11130701. We would also like to thank fDoTr CthLeafbr efeora vthaeil afrbeilei tayvoafiltahbeilsitoyf towfa trheer seoqfutwireadret orecqaulciureladt etothcealAcuDla(thet ttph:e/ A/dDt c(lhatbt.pw:/e/dbstc.cloabm.w/seobfst.wcoamre/-stoofotlws aarned-tools and http://teqip.jdvu.ac.in/QSAR_Tools/). SDG. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest.The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r2 ncv = 0.993 and 0.984 and values of r2 test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q2, r2, r2 m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561). © 2018 by the authors.https://www.mdpi.com/1420-3049/23/5/119
Extremely Metal-Poor Galaxies: The HI Content
Extremely metal-poor (XMP) galaxies are chemically, and possibly dynamically,
primordial objects in the local Universe. Our objective is to characterize the
HI content of the XMP galaxies as a class, using as a reference the list of 140
known local XMPs compiled by Morales-Luis et al. (2011). We have observed 29
XMPs, which had not been observed before at 21 cm, using the Effelsberg radio
telescope. This information was complemented with HI data published in
literature for a further 53 XMPs. In addition, optical data from the literature
provided morphologies, stellar masses, star-formation rates and metallicities.
Effelsberg HI integrated flux densities are between 1 and 15 Jy km/s, while
line widths are between 20 and 120 km/s. HI integrated flux densities and line
widths from literature are in the range 0.1 - 200 Jy km/s and 15 - 150 km/s,
respectively. Of the 10 new Effelsberg detections, two sources show an
asymmetric double-horn profile, while the remaining sources show either
asymmetric (7 sources) or symmetric (1 source) single-peak 21 cm line profiles.
An asymmetry in the HI line profile is systematically accompanied by an
asymmetry in the optical morphology. Typically, the g-band stellar
mass-to-light ratios are ~0.1, whereas the HI gas mass-to-light ratios may be
up to 2 orders of magnitude larger. Moreover, HI gas-to-stellar mass ratios
fall typically between 10 and 20, denoting that XMPs are extremely gas-rich. We
find an anti-correlation between the HI gas mass-to-light ratio and the
luminosity, whereby fainter XMPs are more gas-rich than brighter XMPs,
suggesting that brighter sources have converted a larger fraction of their HI
gas into stars. The dynamical masses inferred from the HI line widths imply
that the stellar mass does not exceed 5% of the dynamical mass, while the
\ion{H}{i} mass constitutes between 20 and 60% of the dynamical mass.
(abridged)Comment: 30 pages, accepted for A&
An Overview of the 2014 ALMA Long Baseline Campaign
A major goal of the Atacama Large Millimeter/submillimeter Array (ALMA) is to
make accurate images with resolutions of tens of milliarcseconds, which at
submillimeter (submm) wavelengths requires baselines up to ~15 km. To develop
and test this capability, a Long Baseline Campaign (LBC) was carried out from
September to late November 2014, culminating in end-to-end observations,
calibrations, and imaging of selected Science Verification (SV) targets. This
paper presents an overview of the campaign and its main results, including an
investigation of the short-term coherence properties and systematic phase
errors over the long baselines at the ALMA site, a summary of the SV targets
and observations, and recommendations for science observing strategies at long
baselines. Deep ALMA images of the quasar 3C138 at 97 and 241 GHz are also
compared to VLA 43 GHz results, demonstrating an agreement at a level of a few
percent. As a result of the extensive program of LBC testing, the highly
successful SV imaging at long baselines achieved angular resolutions as fine as
19 mas at ~350 GHz. Observing with ALMA on baselines of up to 15 km is now
possible, and opens up new parameter space for submm astronomy.Comment: 11 pages, 7 figures, 2 tables; accepted for publication in the
Astrophysical Journal Letters; this version with small changes to
affiliation
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Adaptación cultural al español del instrumento de evaluación de funcionalidad física en Unidad de Paciente Crítico: “The Chelsea Critical Care Physical Assessment Tool (CPAx)”
Las Unidades de Cuidados Intensivos (UCI), presentan una
sobrevida cada vez mayor de los pacientes que ingresan a ellas,
donde se ven enfrentados a una nueva entidad fisiopatológica
llamada Debilidad Muscular Adquirida en UCI (DAUCI).
Algunos test desarrollados para la evaluación de función motriz,
que permiten objetivar la progresión del paciente, son la escala
de fuerza muscular del Medical Research Council (MRC), el
Functional status score for the intensive care unit (FSS-ICU) y
el “Chelsea Critical Care Physical Assessment Tool (CPAx). La ventaja del CPAx radica en que este test incluye mayor información
asociada al funcionamiento humano como recomienda la OMS,
incorporando tanto el componente ventilatorio (que también se ve
deteriorado por DAUCI) como neuromuscular lo que permite
al profesional kinesiólogo tener una herramienta objetiva más
completa del nivel funcional del paciente.
Para que sea confiable, todo test debe ser validado en el país donde
quiere aplicarse, pero antes de esto debe ser adaptado culturalmente.
El objetivo de este trabajo fue efectuar la adaptación transcultural
(AT) al español del test de funcionalidad física de aplicación
kinésica CPAx. Se utilizó el proceso establecido por Beaton y cols
que incluye la formación de un comité de expertos multidisciplinario
que da una visión integral a la adaptación y una prueba piloto en
que kinesiólogos de UCI sin capacitación previa del test lo lean,
posteriormente lo apliquen y entreguen sus observaciones.
Conclusiones: Realizar la AT permite dimensionar la importancia
que tiene cada una de las etapas de este proceso. El test es el mismo,
equivalente al original, pero contiene nuestras características
culturales y condiciones técnicas, que lo hace ser comprensible y
aplicable en nuestro país. Esta adaptación transcultural también
es útil a nivel latinoamericano; para los países de habla hispana
que quieran validarlo tenerlo adaptado al español, hace el proceso
menos complejo.
Palabras clave: Evaluación funcional, Unidad de cuidados
intensivos, CPAx, adaptación transcultural
A Very Large Number of GABAergic Neurons Are Activated in the Tuberal Hypothalamus during Paradoxical (REM) Sleep Hypersomnia
We recently discovered, using Fos immunostaining, that the tuberal and mammillary hypothalamus contain a massive population of neurons specifically activated during paradoxical sleep (PS) hypersomnia. We further showed that some of the activated neurons of the tuberal hypothalamus express the melanin concentrating hormone (MCH) neuropeptide and that icv injection of MCH induces a strong increase in PS quantity. However, the chemical nature of the majority of the neurons activated during PS had not been characterized. To determine whether these neurons are GABAergic, we combined in situ hybridization of GAD67 mRNA with immunohistochemical detection of Fos in control, PS deprived and PS hypersomniac rats. We found that 74% of the very large population of Fos-labeled neurons located in the tuberal hypothalamus after PS hypersomnia were GAD-positive. We further demonstrated combining MCH immunohistochemistry and GAD67 in situ hybridization that 85% of the MCH neurons were also GAD-positive. Finally, based on the number of Fos-ir/GAD+, Fos-ir/MCH+, and GAD+/MCH+ double-labeled neurons counted from three sets of double-staining, we uncovered that around 80% of the large number of the Fos-ir/GAD+ neurons located in the tuberal hypothalamus after PS hypersomnia do not contain MCH. Based on these and previous results, we propose that the non-MCH Fos/GABAergic neuronal population could be involved in PS induction and maintenance while the Fos/MCH/GABAergic neurons could be involved in the homeostatic regulation of PS. Further investigations will be needed to corroborate this original hypothesis
miRNeye: a microRNA expression atlas of the mouse eye
<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are key regulators of biological processes. To define miRNA function in the eye, it is essential to determine a high-resolution profile of their spatial and temporal distribution.</p> <p>Results</p> <p>In this report, we present the first comprehensive survey of miRNA expression in ocular tissues, using both microarray and RNA <it>in situ </it>hybridization (ISH) procedures. We initially determined the expression profiles of miRNAs in the retina, lens, cornea and retinal pigment epithelium of the adult mouse eye by microarray. Each tissue exhibited notably distinct miRNA enrichment patterns and cluster analysis identified groups of miRNAs that showed predominant expression in specific ocular tissues or combinations of them. Next, we performed RNA ISH for over 220 miRNAs, including those showing the highest expression levels by microarray, and generated a high-resolution expression atlas of miRNAs in the developing and adult wild-type mouse eye, which is accessible in the form of a publicly available web database. We found that 122 miRNAs displayed restricted expression domains in the eye at different developmental stages, with the majority of them expressed in one or more cell layers of the neural retina.</p> <p>Conclusions</p> <p>This analysis revealed miRNAs with differential expression in ocular tissues and provided a detailed atlas of their tissue-specific distribution during development of the murine eye. The combination of the two approaches offers a valuable resource to decipher the contributions of specific miRNAs and miRNA clusters to the development of distinct ocular structures.</p
Un examen actualizado de la percepción de las barreras para la implementación de la farmacogenómica y la utilidad de los pares fármaco/gen en América Latina y el Caribe
La farmacogenómica (PGx) se considera un campo emergente en los países en desarrollo. La investigación sobre PGx en la región de América Latina y el Caribe (ALC) sigue siendo escasa, con información limitada en algunas poblaciones. Por lo tanto, las extrapolaciones son complicadas, especialmente en poblaciones mixtas. En este trabajo, revisamos y analizamos el conocimiento farmacogenómico entre la comunidad científica y clínica de ALC y examinamos las barreras para la aplicación clínica. Realizamos una búsqueda de publicaciones y ensayos clínicos en este campo en todo el mundo y evaluamos la contribución de ALC. A continuación, realizamos una encuesta regional estructurada que evaluó una lista de 14 barreras potenciales para la aplicación clínica de biomarcadores en función de su importancia. Además, se analizó una lista emparejada de 54 genes/fármacos para determinar una asociación entre los biomarcadores y la respuesta a la medicina genómica. Esta encuesta se comparó con una encuesta anterior realizada en 2014 para evaluar el progreso en la región. Los resultados de la búsqueda indicaron que los países de América Latina y el Caribe han contribuido con el 3,44% del total de publicaciones y el 2,45% de los ensayos clínicos relacionados con PGx en todo el mundo hasta el momento. Un total de 106 profesionales de 17 países respondieron a la encuesta. Se identificaron seis grandes grupos de obstáculos. A pesar de los continuos esfuerzos de la región en la última década, la principal barrera para la implementación de PGx en ALC sigue siendo la misma, la "necesidad de directrices, procesos y protocolos para la aplicación clínica de la farmacogenética/farmacogenómica". Las cuestiones de coste-eficacia se consideran factores críticos en la región. Los puntos relacionados con la reticencia de los clínicos son actualmente menos relevantes. Según los resultados de la encuesta, los pares gen/fármaco mejor clasificados (96%-99%) y percibidos como importantes fueron CYP2D6/tamoxifeno, CYP3A5/tacrolimus, CYP2D6/opioides, DPYD/fluoropirimidinas, TMPT/tiopurinas, CYP2D6/antidepresivos tricíclicos, CYP2C19/antidepresivos tricíclicos, NUDT15/tiopurinas, CYP2B6/efavirenz y CYP2C19/clopidogrel. En conclusión, aunque la contribución global de los países de ALC sigue siendo baja en el campo del PGx, se ha observado una mejora relevante en la región. La percepción de la utilidad de las pruebas PGx en la comunidad biomédica ha cambiado drásticamente, aumentando la concienciación entre los médicos, lo que sugiere un futuro prometedor en las aplicaciones clínicas de PGx en ALC.Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region’s continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the “need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics”. Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%–99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC
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