Vitamin D Represses Retinoic Acid-Dependent Transactivation of the Retinoic Acid Receptor-ß2 Promoter: The AF-2 Domain of the Vitamin D Receptor Is Required for Transrepression

10 pages, 8 figures.Retinoic acid (RA)-dependent activation of the RA receptor ß2 (RARß2) gene in embryonal carcinoma cells is mediated by binding of retinoid receptor heterodimers (RAR/RXR) to a RA response element (RARE) located closely to the TATA box. We have analyzed the effect of vitamin D on the response of the RARß2 promoter to RA in pituitary GH4C1 cells that coexpress receptors for retinoids and vitamin D. Incubation with vitamin D markedly reduced the response to RA caused by transcriptional interference of the vitamin D receptor (VDR) on the RARE. This DNA element binds VDR/RXR heterodimers with high affinity, and these inactive heterodimers can displace active RAR/RXR from the RARE. Overexpression of RXR in GH4C1 cells, as well as incubation with BMS649 (a RXR-specific ligand), increased the inhibitory effect of vitamin D, suggesting that the VDR/RXR heterodimer is the repressive species and that titration of RXR is not responsible for this inhibition. Although DNA binding could be required for full potency of the inhibitory activity of VDR, it is not absolutely required because a truncated receptor (VDR {Delta}1–111), lacking the DNA binding domain, also displays repressor activity. Furthermore, the ability to mediate transrepression by vitamin D was strongly decreased when a mutant VDR in which the last 12 C-terminal aminoacids have been deleted (VDR {Delta}AF-2) was used. Because this region contains the domain responsible for ligand-dependent recruitment of coactivators, titration of common coactivators for VDR and RAR could be involved in the inhibitory effect of vitamin D. In agreement with this hypothesis, overexpression of E1A, which can act as a RARß2 promoter-specific coactivator, significantly reversed repression by vitamin D.This work was supported by Grants PM94–0094 and PM97–0135 from the Direccion General de Enseñanza Superior e Investigación Científica.Peer reviewe

Retinoic acid protects human breast cancer cells against etoposide-induced apoptosis by NF-kappaB-dependent but cIAP2-independent mechanisms

<p>Abstract</p> <p>Background</p> <p>Retinoids, through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis, and have significant promise for cancer therapy and chemoprevention. These ligands can determine the ultimate fate of target cells by stimulating or repressing gene expression directly, or indirectly through crosstalking with other signal transducers.</p> <p>Results</p> <p>Using different breast cancer cell models, we show here that depending on the cellular context retinoids can signal either towards cell death or cell survival. Indeed, retinoids can induce the expression of pro-apoptotic (i.e. TRAIL, TNF-Related Apoptosis-Inducing Ligand, Apo2L/TNFSF10) and anti-apoptotic (i.e. cIAP2, inhibitor of apoptosis protein-2) genes. Promoter mapping, gel retardation and chromatin immunoprecipitation assays revealed that retinoids induce the expression of this gene mainly through crosstalk with NF-kappaB. Supporting this crosstalk, the activation of NF-kappaB by retinoids in T47D cells antagonizes the apoptosis triggered by the chemotherapeutic drugs etoposide, camptothecin or doxorubicin. Notably apoptosis induced by death ligands (i.e. TRAIL or antiFAS) is not antagonized by retinoids. That knockdown of cIAP2 expression by small interfering RNA does not alter the inhibition of etoposide-induced apoptosis by retinoids in T47D cells reveals that stimulation of cIAP2 expression is not the cause of their anti-apoptotic action. However, ectopic overexpression of a NF-kappaB repressor increases apoptosis by retinoids moderately and abrogates almost completely the retinoid-dependent inhibition of etoposide-induced apoptosis. Our data exclude cIAP2 and suggest that retinoids target other regulator(s) of the NF-kappaB signaling pathway to induce resistance to etoposide on certain breast cancer cells.</p> <p>Conclusions</p> <p>This study shows an important role for the NF-kappaB pathway in retinoic acid signaling and retinoic acid-mediated resistance to cancer therapy-mediated apoptosis in breast cancer cells, independently of cIAP2. Our data support the use of NF-kappaB pathway activation as a marker for screening that will help to develop novel retinoids, or retinoid-based combination therapies with improved efficacy.</p

A Comparative Study of Electric Load Curve Changes in an Urban Low-Voltage Substation in Spain during the Economic Crisis (2008-2013)

This paper presents a comparative study of the electricity consumption (EC) in an urban low-voltage substation before and during the economic crisis (2008-2013). This low-voltage substation supplies electric power to near 400 users. The EC was measured for an 11-year period (2002-2012) with a sampling time of 1 minute. The study described in the paper consists of detecting the changes produced in the load curves of this substation along the time due to changes in the behaviour of consumers. The EC was compared using representative curves per time period (precrisis and crisis). These representative curves were obtained after a computational process, which was based on a search for days with similar curves to the curve of a determined (base) date. This similitude was assessed by the proximity on the calendar, day of the week, daylight time, and outdoor temperature. The last selection parameter was the error between the nearest neighbour curves and the base date curve. The obtained representative curves were linearized to determine changes in their structure (maximum and minimum consumption values, duration of the daily time slot, etc.). The results primarily indicate an increase in the EC in the night slot during the summer months in the crisis perio

Synergy between RA and TLR3 promotes type I IFN-dependent apoptosis through upregulation of TRAIL pathway in breast cancer cells

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.Due to its ability to regulate the growth, differentiation and apoptosis of cancer cells, retinoic acid (RA) is considered a signaling molecule with promising therapeutic potential in oncology. In this study, we show that RA is able to induce the intrinsic ability of breast cancer cells to recognize double-stranded RNA (dsRNA) through the upregulation of Toll-like receptor 3 (TLR3) expression. RA, co-administered with the dsRNA mimicker polyinosinic–polycytidylic acid (poly(I:C)), synergizes to mount a specific response program able to sense dsRNA through the concurrent upregulation of TLR3, the dsRNA helicases melanoma differentiation-associated antigen-5 (MDA-5) and RA-inducible gene-1 (RIG-1), and the dsRNA-activated protein kinase (PKR) expression, leading breast cancer cells to specifically express downstream transcriptional targets of dsRNA sensors, such as interferon-β (IFNβ), interleukin-8 (IL-8), chemokine (C-C motif) ligand 5 (CCL5), and C-X-C motif Chemokine 10 (CXCL10). A TLR3-dependent apoptotic program is also induced by RA and poly(I:C) co-treatment that correlates with the induction of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and contributes to block breast cancer cell proliferation. The mechanisms of apoptosis induced by RA/poly(I:C) in breast cancer cells involve type I IFN autocrine signaling, caspase-8 and caspase-3 activation, as well as TRAIL signaling. Our results reveal important links among RA, TLR3 and TRAIL and highlight the combined use of RA and poly(I:C) as a potential effective tumor therapy by improving the apoptotic response of cancer cells with low sensitivity to the action of synthetic dsRNA.This work was supported by funds from the MICINN (SAF2007-63634 and SAF2010-21195), CSIC (201120E105), and Fundación Médica Mutua Madrileña (2005 0584). ARBV was supported by funds from the MICINN. AMJ-L is a recipient of a grant from the Spanish MICINN (Ramón y Cajal Program).Peer reviewe

Student mentoring program at the Faculty of Pharmacy, University of Seville (2006/07 - present): SWOT analysis carried out by mentor students

El “Programa de Alumnos Tutores” (LCC, Facultad de Farmacia US) se viene realizando ininterrumpidamente desde 2006/07 hasta la actualidad. Propósito: tutela de alumnos de nuevo ingreso por parte de alumnos de cursos superiores (AATT) bajo la supervisión de Profesores Tutores. Pretende generar una actitud responsable en los AATT y favorecerles el desarrollo de habilidades sociales. El objetivo de este trabajo es recoger las opiniones de los AATT (algunos comenzaron en ediciones anteriores y continúan desinteresadamente). Se aborda mediante un análisis DAFO. Conclusión: se han detectado factores estratégicos críticos, para una vez identificados, usarlos y apoyar en ellos la marcha del “Programa de Alumnos Tutores”, consolidando las fortalezas, minimizando las debilidades, aprovechando las ventajas de las oportunidades, y eliminando o reduciendo las amenazas.The "Student Mentor Program" (Faculty of Pharmacy, US) has been running since 2006/07 – to present. Purpose: to mentor new students by senior students (Mentor Students) under the supervision of mentor professors. It aims to generate a responsible attitude in students and tutors to encourage the development of social skills. Objective: To collect the views of mentor students (some started in previous years and continue to selflessly), through a SWOT analysis. Conclusion: it has been found critical strategic factors. It intends to use these factors for strengthening the "Student Mentor Program"

Recent advances of synthesis of Boron derivatives and their applications in bioimaging

The increasing interest in the luminescent boron materials is due to their potential application in diverse areas such as solar cells, optoelectronic devices, and biological imaging materials. Continuous search for the compounds with better properties, luminescent organoboron materials have been gaining more importance, especially in the development of new technologies and novel techniques for bioimaging, which is a powerful tool to analyze the cellular organelles with important value into the cell biology and medical research. Synthesis, properties, and applications of luminescent boron compounds and their application in bioimaging are reviewed.

Spatial distribution of Cydia fagiglandana (Zeller) in an exploited holm oak (Quercus ilex L.) forest.

Cydia fagiglandana (Zeller) (Lepidoptera: Tortricidae) is a carpophagous insect which affects the quality andviability of the fruits of beech, oak and chestnut trees. The majority of the works on this species in holm oak woodsdealt with assessing its damages. No investigations have yet been performed on the spatial distribution of this pest,although this element is one of the key features to take in account in order to develop proper integrated managementprograms. The present study, performed during a four years period in an exploited holm oak forest area in SouthernSpain, investigated the spatial distribution of C. fagiglandana integrating classic methods based on dispersion ratesand distribution fitting together with the elaboration of population density maps based on GIS. Our results showedthat the infestation rate progressively decreased from 0.339 in 2001 to 0.102 in 2004. Density maps for C. fagiglandanaalso show an heterogeneous and aggregated distribution of this insect and a spatio-temporal stability in this area. It isconcluded that during the four years of the study inter-specific competition with the weevil Curculio elephas was thefactor that most affected the spatial distribution of C. fagiglandana in the experimental plot

Uso de herramientas bioinformáticas en la evaluación de secuencias “DNA barcode” para la identificación a nivel de especie

El “DNA barcoding” (código de barras de ADN) es una técnica usada para identificar la especie a la cual pertenece un espécimen biológico, usando una secuencia corta de ADN proveniente de una región estandarizada, la cual se compara con una secuencia de referencia. Los “DNA barcodes” son secuencias relativamente cortas dentro de los genomas de las especies, que se obtienen fácilmente mediante amplificación por PCR. Para que sean precisas, las secuencias “DNA barcode”, deben poseer baja variabilidad intraespecífica y alta variabilidad interespecífica. Para que una secuencia sea oficialmente considerada un “DNA barcode”, debe estar incluida en la base de datos BOLD (The Barcode of Life Data Systems), para lo cual debe pasar estrictos análisis bioinformáticos que valoran su idoneidad. El objetivo de este artículo es hacer una revisión de algunas herramientas bioinformáticas, propuestas por Barcodinglife.org para determinar si una secuencia cumple los requisitos para ser considerada un “DNA barcode”. Estos métodos incluyen la construcción de árboles de genes, determinación del “barcode gap”, estimación de índice de clasificación genealógica, análisis de variabilidad génica, redes de haplotipos, DNA-BAR y BLOG

Caracterización Mineralógica de Cálculos Salivales y Nasales

Dos rinolitos y dos cálculos salivales se han estudiado por diversas técnicas. El análisis por fluorescencia de Rayos-X revela la presencia de Calcio y Fósforo como elementos mayoritarios e impurezas de varios elementos (Na, Mg, Al, Si, S, Cl, K, Ti, Cr, Mn, Fe, Co, Cu y Zn). La difracción de rayos-X indica que las especies mineralógicas más frecuentes en los cálculos son fosfato tricálcico y apatitos. Un estudio paralelo por espectroscopia infrarroja entre los cálculos y sus productos calcinados también se ha llevado a cabo.Two rhinoliths and two salivary calculi were studied. X-ray fluorescence analysis reveals the presence of Ca and P as majority elements and several impurities in the specimens (Na, Mg, Al, Si, S, CI, K, Ti, Cr, Mn, Fe, Co, Cu & Zn). The X-ray powder patterns of the samples, show mainly tric\acium phosphate hydrate and apatites as mineralogical species. A comparative infrared study between the unheated and calcinated samples is shown

Caracterización Mineralógica de Cálculos Salivales y Nasales

Two rhinoliths and two salivary calculi were studied. X-ray fluorescence analysis reveals the presence of Ca and P as majority elements and several impurities in the specimens (Na, Mg, Al, Si, S, CI, K, Ti, Cr, Mn, Fe, Co, Cu and Zn). The X-ray powder patterns of the samples, show mainly tricalcium phosphate hydrate and apatites as mineralogical species. A comparative infrared study between the unheated and calcinated samples is shown.Dos rinolitos y dos cálculos salivales se han estudiado por diversas técnicas. El análisis por fluorescencia de Rayos-X revela la presencia de Calcio y Fósforo como elementos mayoritarios e impurezas de varios elementos (Na, Mg, Al, Si, S, Cl, K, Ti, Cr, Mn, Fe, Co, Cu y Zn). La difracción de rayos-X indica que las especies mineralógicas más frecuentes en los cálculos son fosfato tricálcico y apatitos. Un estudio paralelo por espectroscopia infrarroja entre los cálculos y sus productos calcinados también se ha llevado a cabo