Overexpression of glucocorticoid-induced leucine zipper (GILZ) increases susceptibility to imiquimod-induced psoriasis and involves cutaneous activation of TGF-β1

Psoriasis vulgaris is a chronic inflammatory skin disease affecting millions of people. Its pathophysiology is complex and involves a skin compartment with epidermal and immune cells which produce cytokines, e.g. belonging to the IL-23-Th17-cell axis. Glucocorticoids (GCs) are the most common therapeutics used in cutaneous inflammatory disorders and GC-induced leucine zipper (GILZ) has emerged as a mediator of GCs due to its anti-inflammatory actions, theoretically lacking GC side-effects. We evaluated whether GILZ may provide a better therapeutic index in comparison to GCs during the onset and progression of psoriasis by generating and characterizing a mouse model with generalized overexpression of this protein (GILZ-Tg mice) and the imiquimod (IMQ) psoriasis model. Unexpectedly, in GILZ-Tg mice, the severity of IMQ-induced psoriasis-like skin lesions as well as induction of cytokines commonly up-regulated in human psoriasis (Il-17, Il-22, Il-23, Il-6, S100a8/a9, and Stat3) was significantly more pronounced relative to GILZ-Wt mice. The increased susceptibility to IMQ-induced psoriasis of GILZ-Tg mice was significantly associated with skin-specific over-activation of TGF-beta 1-mediated signaling via SMAD2/3. Our findings demonstrate that GILZ may behave as pro-inflammatory protein in certain tissues and that, similar to prolonged GC therapy, GILZ as an alternative treatment for psoriasis may also have adverse effects

Epidermal mineralocorticoid receptor plays beneficial and adverse effects in skin and mediates glucocorticoid responses

10 páginas, 6 figuras. Contiene material suplementarioGlucocorticoids (GCs) regulate skin homeostasis and combat cutaneous inflammatory diseases; however, adverse effects of chronic GC treatments limit their therapeutic use. GCs bind and activate the GC receptor and the mineralocorticoid receptor (MR), transcription factors that recognize identical hormone responsive elements. Whether epidermal MR mediates beneficial or deleterious GC effects is of great interest for improving GC-based skin therapies. MR epidermal knockout mice exhibited increased keratinocyte proliferation and differentiation and showed resistance to GC-induced epidermal thinning. However, crucially, loss of epidermal MR rendered mice more sensitive to inflammatory stimuli and skin damage. MR epidermal knockout mice showed increased susceptibility to phorbol 12-myristate 13-acetate-induced inflammation with higher cytokine induction. Likewise, cultured MR epidermal knockout keratinocytes had increased phorbol 12-myristate 13-acetate-induced NF-κB activation, highlighting an anti-inflammatory function for MR. GC-induced transcription was reduced in MR epidermal knockout keratinocytes, at least partially due to decreased recruitment of GC receptor to hormone responsive element-containing sequences. Our results support a role for epidermal MR in adult skin homeostasis and demonstrate nonredundant roles for MR and GC receptor in mediating GC actions.This work was supported by grant SAF2011-28115 and SAF2014-59474-R (MINECO, Spanish Government). JB and EC are recipients of FPI (BES-2012-0578) and FPU (AP201-06094) fellowships of MINECO, respectively. We thank COST ADMIRE BM- 1301 and NURCAMEIN (SAF2015-71878-REDT) for support for dissemination.Peer reviewe

The mineralocorticoid receptor plays a transient role in mouse skin development

3 páginas, 2 figuras. Contiene material suplemenarioGlucocorticoid (GC) hormones can bind two structurally and functionally related steroid receptors: the GC Receptor (GR or Nr3c1) and the mineralocorticoid receptor (MR or Nr3c2), which recognize the same DNA response elements and act as ligand-dependent transcription factors. While the crucial role of GR for skin homeostasis has been widely characterized, the exact role of MR in this tissue deserves further study. We assessed NR3C2 expression in developing and adult WT mouse skin and found a transient peak at embryonic day (E)16.5, which along with low levels of HSD11B2, the enzyme inactivating GCs, supports a role for GC-MR complexes in epidermal maturation. Consistent with this observation, MR-/- embryonic skin showed alterations in early epidermal differentiation that resolved postnatally. The lack of a more severe skin phenotype of MR-/- mice suggests functional compensation by GR in this tissue in the perinatal period.This work was supported by JSPS KAKENHI grant numbers 25870545 and 15K09772. Spanish Ministerio de Ciencia e Innovación. Grant Numbers: SAF2011-28115, SAF2014-59474-RPeer Reviewe

Una mirada al pasado preincaico. La identidad indígena peruana.

Este proyecto Fin de Grado tiene como objetivo analizar las distintas interacciones entre las culturas costeñas preincaicas Paracas, Nasca, Mochica y Chimú a través de un enfoque arqueológico y antropológico donde la cultura matriz de todas ellas fue la sociedad Chavín procedente de la sierra según el arqueólogo Julio Cesar Tello. Teniendo en cuenta que la historiografía indigenista peruana adquiere suma relevancia en este trabajo al hacer hincapié en la integración del indígena como sujeto histórico y reivindicar su pasado precolombino y, por tanto, su identidad frente al silencio perpetrado por las élites criollas a la hora de forjar el nacionalismo peruano.<br /

Conductance and application of organic molecule pairs as nanofuses

We propose that a pair of organic molecules can mimic the behavior of a macroscopic fuse at nanoscale, one component of the pair being the on state and the other the off state. For this task wemake use of density-functional theory to calculate the physical properties of selected molecules, which have also been synthesized by our team. By this means we obtain the transmission spectra and the current of the proposed devices, which allows us to compare the behavior of the on and off states.Of particular interest is the on/off switch ratios, defined as the current ratios of the on and off structures at the corresponding bias voltage. In a first stage, we examine the best linker between the device and the electrode for high on/off switch ratios. Once this is determined, we test the influence of the electron richness of the system to provide a high on/off switch ratio. The entire analysis is also supported by the molecular projected self-consistent Hamiltonian, which provides a good way of understanding the molecular behavior. All the calculations support that interesting on/off switch ratios of two orders of magnitude could be obtained with these prototypical nanofusesWe thank the Regional Government of Andalucía for financial support (Projects No. P06-FQM-01726 and No. P09-FQM-04571), the “Centro de Supercomputación de la Universidad de Granada,” and the “Centro de Computación Científica-UAM” for computation time. The authors are also grateful to the Spanish Secretaría de Estado de Universidades e Investigación, Ministerio de Educación y Ciencia, for financial support within research projects TEC2007-66812 and TEC2010-16211. N.F. thanks the Regional Government of Andalucía for her research contract, and LAC thanks the University of Granada for his research contrac

Differences in the signaling pathways of α1A- and α1B-adrenoceptors are related to different endosomal targeting

Aims: To compare the constitutive and agonist-dependent endosomal trafficking of α1A- and α1B-adrenoceptors (ARs) and to establish if the internalization pattern determines the signaling pathways of each subtype. Methods: Using CypHer5 technology and VSV-G epitope tagged α1A- and α1B-ARs stably and transiently expressed in HEK 293 cells, we analyzed by confocal microscopy the constitutive and agonist-induced internalization of each subtype, and the temporal relationship between agonist induced internalization and the increase in intracellular calcium (determined by FLUO-3 flouorescence), or the phosphorylation of ERK1/2 and p38 MAP kinases (determined by Western blot). Results and Conclusions: Constitutive as well as agonist-induced trafficking of α1A and α1B ARs maintain two different endosomal pools of receptors: one located close to the plasma membrane and the other deeper into the cytosol. Each subtype exhibited specific characteristics of internalization and distribution between these pools that determines their signaling pathways: α1A-ARs, when located in the plasma membrane, signal through calcium and ERK1/2 pathways but, when translocated to deeper endosomes, through a mechanism sensitive to β-arrestin and concanavalin A, continue signaling through ERK1/2 and also activate the p38 pathway. α1B-ARs signal through calcium and ERK1/2 only when located in the membrane and the signals disappear after endocytosis and by disruption of the membrane lipid rafts by methyl-β-cyclodextrin

The mineralocorticoid receptor modulates timing and location of genomic binding by glucocorticoid receptor in response to synthetic glucocorticoids in keratinocytes

17 páginas, 6 figurasGlucocorticoids (GCs) exert potent antiproliferative and anti-inflammatory properties, explaining their therapeutic efficacy for skin diseases. GCs act by binding to the GC receptor (GR) and the mineralocorticoid receptor (MR), co-expressed in classical and non-classical targets including keratinocytes. Using knockout mice, we previously demonstrated that GR and MR exert essential nonoverlapping functions in skin homeostasis. These closely related receptors may homo- or heterodimerize to regulate transcription, and theoretically bind identical GC-response elements (GRE). We assessed the contribution of MR to GR genomic binding and the transcriptional response to the synthetic GC dexamethasone (Dex) using control (CO) and MR knockout (MREKO ) keratinocytes. GR chromatin immunoprecipitation (ChIP)-seq identified peaks common and unique to both genotypes upon Dex treatment (1 h). GREs, AP-1, TEAD, and p53 motifs were enriched in CO and MREKO peaks. However, GR genomic binding was 35% reduced in MREKO , with significantly decreased GRE enrichment, and reduced nuclear GR. Surface plasmon resonance determined steady state affinity constants, suggesting preferred dimer formation as MR-MR > GR-MR ~ GR-GR; however, kinetic studies demonstrated that GR-containing dimers had the longest lifetimes. Despite GR-binding differences, RNA-seq identified largely similar subsets of differentially expressed genes in both genotypes upon Dex treatment (3 h). However, time-course experiments showed gene-dependent differences in the magnitude of expression, which correlated with earlier and more pronounced GR binding to GRE sites unique to CO including near Nr3c1. Our data show that endogenous MR has an impact on the kinetics and differential genomic binding of GR, affecting the time-course, specificity, and magnitude of GC transcriptional responses in keratinocytes.This research is part of the grants PID2020-114652RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 to PP, and PDC2021-121688-I00 to EE-P. The author's work was also supported by Inserm, Université Paris-Saclay. EC-Z was recipient of a postdoctoral fellowship from 15306860, 2023, 1, Downloaded from https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202201199RR by Csic Organización Central Om (Oficialia Mayor) (Urici), Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | CARCELLER-ZAZO et al. 15 of 17 the Alfonso Martín Escudero Foundation (Spain); OP-A was funded by EDGJID/2021/098 (Generalitat Valenciana) and by ‘ESF Investing in your future.”. We thank NuRCaMeIN (SAF2017-90604-REDT) for support for dissemination. PP is a member of the Scientific Network on ´Strategies for therapeutic targeting of the Aldosterone-Mineralocorticoid Receptor signaling pathway (ADMIRE network) funded by the German Research Foundation (DFG-ID 470188766). This work has benefited from the facilities and expertize of the high-throughput sequencing core facility of I2BC (Centre de Recherche de Gif – http://www.i2bc. paris-saclay.fr/). This work was supported by the DIM Thérapie Génique Paris Ile-de-France Région, IBiSA, and the Labex GR-ExPeer reviewe

Ahora / Ara

La cinquena edició del microrelatari per l’eradicació de la violència contra les dones de l’Institut Universitari d’Estudis Feministes i de Gènere «Purificación Escribano» de la Universitat Jaume I vol ser una declaració d’esperança. Aquest és el moment en el qual les dones (i els homes) hem de fer un pas endavant i eliminar la violència sistèmica contra les dones. Ara és el moment de denunciar el masclisme i els micromasclismes començant a construir una societat més igualitària. Cadascun dels relats del llibre és una denúncia i una declaració que ens encamina cap a un món millor

Ruta turística de teatros españoles

Un itinerario turístico es el resultado de la combinación de diversos factores, que definen de una manera clara algún componente de la misma. Estos factores son atractivos de la ruta, medio de transporte, medio de alojamiento, duración, época del año y por supuesto, ámbito territorial. Por ejemplo en este caso serían los teatros de la ruta y su importancia histórica, etc.Para la ruta hemos hecho una selección de las siguientes ciudades, teniendo en cuenta, principalmente, la importancia y las infraestructuras de los teatros de dichas ciudades así como otros recursos de gran interés turístico y cultural que puedan aportar a nuestros posibles consumidores un aliciente a la hora de elegir este paquete turístico. Las ciudades elegidas son: Sevilla, Mérida, Toledo, Madrid, Barcelona, Valencia y Almagro.Ibáñez Carceller, EC. (2012). Ruta turística de teatros españoles. Universitat Politècnica de València. http://hdl.handle.net/10251/17856Archivo delegad