ATXN3 controls DNA replication and transcription by regulating chromatin structure

The deubiquitinating enzyme Ataxin-3 (ATXN3) contains a polyglutamine (PolyQ) region, the expansion of which causes spinocerebellar ataxia type-3 (SCA3). ATXN3 has multiple functions, such as regulating transcription or controlling genomic stability after DNA damage. Here we report the role of ATXN3 in chromatin organization during unperturbed conditions, in a catalytic-independent manner. The lack of ATXN3 leads to abnormalities in nuclear and nucleolar morphology, alters DNA replication timing and increases transcription. Additionally, indicators of more open chromatin, such as increased mobility of histone H1, changes in epigenetic marks and higher sensitivity to micrococcal nuclease digestion were detected in the absence of ATXN3. Interestingly, the effects observed in cells lacking ATXN3 are epistatic to the inhibition or lack of the histone deacetylase 3 (HDAC3), an interaction partner of ATXN3. The absence of ATXN3 decreases the recruitment of endogenous HDAC3 to the chromatin, as well as the HDAC3 nuclear/cytoplasm ratio after HDAC3 overexpression, suggesting that ATXN3 controls the subcellular localization of HDAC3. Importantly, the overexpression of a PolyQ-expanded version of ATXN3 behaves as a null mutant, altering DNA replication parameters, epigenetic marks and the subcellular distribution of HDAC3, giving new insights into the molecular basis of the disease.</p

ATXN3 controls DNA replication and transcription by regulating chromatin structure

The deubiquitinating enzyme Ataxin-3 (ATXN3) contains a polyglutamine (PolyQ) region, the expansion of which causes spinocerebellar ataxia type-3 (SCA3). ATXN3 has multiple functions, such as regulating transcription or controlling genomic stability after DNA damage. Here we report the role of ATXN3 in chromatin organization during unperturbed conditions, in a catalytic-independent manner. The lack of ATXN3 leads to abnormalities in nuclear and nucleolar morphology, alters DNA replication timing and increases transcription. Additionally, indicators of more open chromatin, such as increased mobility of histone H1, changes in epigenetic marks and higher sensitivity to micrococcal nuclease digestion were detected in the absence of ATXN3. Interestingly, the effects observed in cells lacking ATXN3 are epistatic to the inhibition or lack of the histone deacetylase 3 (HDAC3), an interaction partner of ATXN3. The absence of ATXN3 decreases the recruitment of endogenous HDAC3 to the chromatin, as well as the HDAC3 nuclear/cytoplasm ratio after HDAC3 overexpression, suggesting that ATXN3 controls the subcellular localization of HDAC3. Importantly, the overexpression of a PolyQ-expanded version of ATXN3 behaves as a null mutant, altering DNA replication parameters, epigenetic marks and the subcellular distribution of HDAC3, giving new insights into the molecular basis of the disease.Spanish Agencia Estatal de Investigacion´ [PID2019- 109222RB-I00/AEI/10.13039/501100011033]; European Union Regional Funds (FEDER) (to R.F., V.A.J.S.); Agencia Canaria de Investigacion, ´ Innovacion´ y Sociedad de la Informacion´ [ProID2020010109]; FEDER (to R.F.); Agencia Canaria de Investigacion, ´ Innovacion´ y European Social Fund integrated Operational programme of the Canary Islands Sociedad de la Informacion´ de la Consejer´ıa de Econom´ıa, Industria, Comercio y Conocimiento and the 2014–2020, Eje 3 Tema Prioritario 74 (85%) (to E.H.C.); Medical Research Council Programme [MR/X006409/1 to K.R.]; Breast Cancer Now [2019DecPR1406 to K.R.]. Funding for open access charge: Agencia Canaria de Investigacion, ´ Innovacion´ y Sociedad de la Informacion´ [ProID2020010109]; European Union Regional Funds (FEDER)

Development of an activity disease score in patients with uveitis (UVEDAI)

To develop a disease activity index for patients with uveitis (UVEDAI) encompassing the relevant domains of disease activity considered important among experts in this field. The steps for designing UVEDAI were: (a) Defining the construct and establishing the domains through a formal judgment of experts, (b) A two-round Delphi study with a panel of 15 experts to determine the relevant items, (c) Selection of items: A logistic regression model was developed that set ocular inflammatory activity as the dependent variable. The construct "uveitis inflammatory activity" was defined as any intraocular inflammation that included external structures (cornea) in addition to uvea. Seven domains and 15 items were identified: best-corrected visual acuity, inflammation of the anterior chamber (anterior chamber cells, hypopyon, the presence of fibrin, active posterior keratic precipitates and iris nodules), intraocular pressure, inflammation of the vitreous cavity (vitreous haze, snowballs and snowbanks), central macular edema, inflammation of the posterior pole (the presence and number of choroidal/retinal lesions, vascular inflammation and papillitis), and global assessment from both (patient and physician). From all the variables studied in the multivariate model, anterior chamber cell grade, vitreous haze, central macular edema, inflammatory vessel sheathing, papillitis, choroidal/retinal lesions and patient evaluation were included in UVEDAI. UVEDAI is an index designed to assess the global ocular inflammatory activity in patients with uveitis. It might prove worthwhile to motorize the activity of this extraarticular manifestation of some rheumatic diseases

Deciphering CHFR role in pancreatic ductal adenocarcinoma

Checkpoint with forkhead-associated and ring finger domains (CHFR) has been proposed as a predictive and prognosis biomarker for different tumor types, but its role in pancreatic ductal adenocarcinoma (PDAC) remains unknown. The aim of this study was two-pronged: to review the role of CHFR in PDAC and evaluating CHFR as a potential predictive biomarker in this disease. For this purpose, we first explored the CHFR messenger (m)RNA expression and promoter methylation through the TCGA database. Secondly, the CHFR expression and promoter methylation were prospectively evaluated in a cohort of patients diagnosed with borderline (n = 19) or resectable (n = 16) PDAC by immunohistochemistry (IHC), methylation specific-PCR (MSP), and pyrosequencing. The results from the TCGA database showed significant differences in terms of progression-free survival (PFS) and overall survival (OS) based on the CHFR mRNA expression, which was likely independent from the promoter methylation. Importantly, our results showed that in primarily resected patients and also the entire cohort, a higher CHFR expression as indicated by the higher IHC staining intensity might identify patients with longer disease-free survival (DFS) and OS, respectively. Similarly, in the same cohorts, patients with lower methylation levels by pyrosequencing showed significantly longer OS than patients without this pattern. Both, the CHFR expression intensity and its promoter methylation were established as independent prognostic factors for PFS and OS in the entire cohort. In contrast, no significant differences were found between different methylation patterns for CHFR and the response to taxane-based neoadjuvant treatment. These results suggest the potential role of the higher expression of CHFR and the methylation pattern of its promoter as potential prognostic biomarkers in PDAC, thus warranting further comprehensive studies to extend and confirm our preliminary findings.This work was funded by grants from the Department of Health from the Government of Navarra (Ref. 008-2018), REFBIO II Pyrenees Biomedical Network from Programa INTERREG V-A España-Francia-Andorra (Ref. BMK_PANC) and Sociedad Española de Oncología Médica (SEOM) to AV. IG-B was supported by a predoctoral fellowship from the Department of Economic Development Government of Navarre Ayudas para la contratación de doctorandos y doctorandas por empresas y organismos de investigación y difusión de conocimientos: doctorados industriales 2018–2020. Intensification Programme Navarrabiomed 2017-2021 Obra Social La Caixa Fundación Caja Navarra. This work has also been supported by the Spanish Ministry of Economy [MINECO; BFU2016-80360-R (to JC)] and the Ministry of Science and Innovation [MICINN; PID2019-105201RB-I00 (to JC)]. Instituto de Salud Carlos III, co-funded by European Union (ERDF/ESF, Investing in your future) [Predoctoral contract FI17/00282 (to EA-P)]. Junta de Andalucía (BIO-0139); GETNE2016 and GETNE2019 Research grants (to JC); and CIBERobn

Use of tocilizumab in kidney transplant recipients with COVID-1

Acute respiratory distress syndrome associated with coronavirus infection is related to a cytokine storm with large interleukin-6 (IL-6) release. The IL-6-receptor blocker tocilizumab may control the aberrant host immune response in patients with coronavirus disease 2019 (COVID-19) . In this pandemic, kidney transplant (KT) recipients are a high-risk population for severe infection and showed poor outcomes. We present a multicenter cohort study of 80 KT patients with severe COVID-19 treated with tocilizumab during hospital admission. High mortality rate was identified (32.5%), related with older age (hazard ratio [HR] 3.12 for those older than 60 years, P = .039). IL-6 and other inflammatory markers, including lactic acid dehydrogenase, ferritin, and D-dimer increased early after tocilizumab administration and their values were higher in nonsurvivors. Instead, C-reactive protein (CRP) levels decreased after tocilizumab, and this decrease positively correlated with survival (mean 12.3 mg/L in survivors vs. 33 mg/L in nonsurvivors). Each mg/L of CRP soon after tocilizumab increased the risk of death by 1% (HR 1.01 [confidence interval 1.004-1.024], P = .003). Although patients who died presented with worse respiratory situation at admission, this was not significantly different at tocilizumab administration and did not have an impact on outcome in the multivariate analysis. Tocilizumab may be effective in controlling cytokine storm in COVID-19 but randomized trials are needed

Terms of reference for the mediterranean tuna habitat observatory initiative

[EN] We present the Terms of Reference for a case study on a Mediterranean eco-region focusing on the environmental component of the Ecosystem Report Card. The objective of this case study is to describe and monitor the variability of environmental processes in the Mediterranean Sea that affect the ecology of large pelagic fishes, with a particular attention on tunas, and the possible role of climate change on this variability. Here we define the objectives and activities of the initiative, the participant roles, primary indicators and the methodological approach[FR] Ce document présente les termes de référence d’une étude de cas sur une écorégion méditerranéenne consacrée à la composante environnementale de la fiche informative sur les écosystèmes. L'objectif de cette étude de cas est de décrire et de suivre la variabilité des processus environnementaux en mer Méditerranée qui affectent l'écologie des grands poissons pélagiques, en accordant une attention particulière aux thonidés, et de déterminer le rôle possible du changement climatique sur cette variabilité. Nous définissons ici les objectifs et les activités de l'initiative, les rôles des participants, les indicateurs primaires et l'approche méthodologique.[ES] En el documento se presentan los términos de referencia para un estudio de caso sobre una ecorregión mediterránea centrado en el componente medioambiental de la ficha informativa sobre ecosistemas. El objetivo de este estudio de caso es describir y hacer un seguimiento de la variabilidad de los procesos medioambientales en el mar Mediterráneo que afectan a la ecología de los grandes peces pelágicos, con especial atención a los túnidos, y el posible papel del cambio climático en esta variabilidad. A continuación, se definen los objetivos y actividades de la iniciativa, las funciones de los participantes, los indicadores principales y el enfoque metodológico.Peer reviewe

Nucleant layer effect on nanocolumnar ZnO films grown by electrodeposition

Different ZnO nanostructured films were electrochemically grown, using an aqueous solution based on ZnCl2, on three types of transparent conductive oxides grow on commercial ITO (In2O3:Sn)-covered glass substrates: (1) ZnO prepared by spin coating, (2) ZnO prepared by direct current magnetron sputtering, and (3) commercial ITO-covered glass substrates. Although thin, these primary oxide layers play an important role on the properties of the nanostructured films grown on top of them. Additionally, these primary oxide layers prevent direct hole combination when used in optoelectronic devices. Structural and optical characterizations were carried out by scanning electron microscopy, atomic force microscopy, and optical transmission spectroscopy. We show that the properties of the ZnO nanostructured films depend strongly on the type of primary oxide-covered substrate used. Previous studies on different electrodeposition methods for nucleation and growth are considered in the final discussion.We thank Prof. A. Segura of the Universitat de Valencia for the facilities with the sputtering equipment. This work was supported by the project PROMETEO/2009/074 from the Generalitat Valenciana.Reyes Tolosa, MD.; Damonte, LC.; Brine, H.; Bolink, HJ.; Hernández Fenollosa, MDLÁ. (2013). Nucleant layer effect on nanocolumnar ZnO films grown by electrodeposition. Nanoscale Research Letters. 8:135-144. https://doi.org/10.1186/1556-276X-8-135S1351448Franklin JB, Zou B, Petrov P, McComb DW, Ryanand MP, McLachlan MA,J: Optimised pulsed laser deposition of ZnO thin films on transparent conducting substrates. Mater Chem 2011, 21: 8178–8182. 10.1039/c1jm10658aJaroslav B, Andrej V, Marie N, Šuttab P, Miroslav M, František U: Cryogenic pulsed laser deposition of ZnO. Vacuum 2012, 86(6):684–688. 10.1016/j.vacuum.2011.07.033Jae Bin L, Hyeong Joon K, Soo Gil K, Cheol Seong H, Seong-Hyeon H, Young Hwa S, Neung Hun L: Deposition of ZnO thin films by magnetron sputtering for a film bulk acoustic resonator. Thin Solid Films 2003, 435: 179–185. 10.1016/S0040-6090(03)00347-XXionga DP, Tanga XG, Zhaoa WR, Liua QX, Wanga YH, Zhoub SL: Deposition of ZnO and MgZnO films by magnetron sputtering. Vacuum 2013, 89: 254–256.Reyes Tolosa MD, Orozco-Messana J, Lima ANC, Camaratta R, Pascual M, Hernandez-Fenollosa MA: Electrochemical deposition mechanism for ZnO nanorods: diffusion coefficient and growth models. J Electrochem Soc 2011, 158(11):E107-E110.Ming F, Ji Z: Mechanism of the electrodeposition of ZnO nanosheets below room temperature. J Electrochem Soc 2010, 157(8):D450-D453. 10.1149/1.3447738Pullini D, Pruna A, Zanin S, Busquets Mataix D: High-efficiency electrodeposition of large scale ZnO nanorod arrays for thin transparent electrodes. J Electrochem Soc 2012, 159: E45-E51. 10.1149/2.093202jesPruna A, Pullini D, Busquets Mataix D: Influence of deposition potential on structure of ZnO nanowires synthesized in track-etched membranes. J Electrochem Soc 2012, 159: E92-E98. 10.1149/2.003205jesMarotti RE, Giorgi P, Machado G, Dalchiele EA: Crystallite size dependence of band gap energy for electrodeposited ZnO grown at different temperatures. Solar Energy Materials and Solar Cells 2009, 90(15):2356–2361.Yeong Hwan K, Myung Sub K, Jae Su Y: Structural and optical properties of ZnO nanorods by electrochemical growth using multi-walled carbon nanotube-composed seed layers. Nanoscale Res Lett 2012, 7: 13. 10.1186/1556-276X-7-13Elias J, Tena-Zaera R, Lévy-Clément C: Electrodeposition of ZnO nanowires with controlled dimensions for photovoltaic applications: role of buffer layer. Thin Solid Films 2007, 515(24):8553–8557. 10.1016/j.tsf.2007.04.027Zhai Y, Zhai S, Chen G, Zhang K, Yue Q, Wang L, Liu J, Jia J: Effects of morphology of nanostructured ZnO on direct electrochemistry and biosensing properties of glucose oxidase. J Electroanal Chem 2011, 656: 198–205. 10.1016/j.jelechem.2010.11.020Reyes Tolosa MD, Orozco-Messana J, Damonte LC, Hernandez-Fenollosa MA: ZnO nanoestructured layers processing with morphology control by pulsed electrodeposition. J Electrochem Soc 2011, 158(7):D452-D455. 10.1149/1.3593004Gouxa A, Pauporté T, Chivot J, Lincot D: Temperature effects on ZnO electrodeposition. Electrochim Acta 2005, 50(11):2239–2248. 10.1016/j.electacta.2004.10.007Kwok WM, Djurisic , Aleksandra B, Leung , Yu H, Li D, Tam KH, Phillips DL, Chan WK: Influence of annealing on stimulated emission in ZnO nanorods. 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La construcción política de la desigualdad : pobreza y sexualidad en las políticas públicas de la provincia de Córdoba

El proyecto pretende analizar la definición de políticas públicas sobre pobreza y ambiente como instancias de visibilización de posiciones y discursividades en conflicto sobre la (des)igualdad. Asimismo pretende entender la formulación de políticas públicas como instancias en que los Estados institucionalizan una definición sobre la (des)igualdad que muchas veces, paradójicamente, resulta en la instauración de exclusiones y el fortalecimiento de regímenes de dominación. Entre las diversas hipótesis que guían el proyecto la más abarcativa sostiene que las decisiones, los modos y campos de intervención definidos en la política pública constituyen en sí mismos un espacio discursivo en el que se establecen definiciones y plasman matrices ideológicas respecto de la (des)igualdad. Pues a partir de ellos se visibilizan operaciones específicas de inclusión/exclusión, igualdad/desigualdad, prohibición/habilitación, etc.; se identifican y caracterizan sujetos; así como también un determinado orden normativo de relaciones y prácticas. No obstante encontrarse legalmente instituida la igualdad como principio subyacente a todo el ordenamiento de derechos, en la práctica las desigualdades se hacen patentes. Éstas son especialmente relevantes en tres áreas de políticas públicas: el trabajo, el hábitat y sexualidad. Consecuentemente, se propone 1. analizar el dispositivo de regulación tal como se materializa en las decisiones, leyes y políticas públicas del Estado Provincial; 2. Esclarecer las disputas y/o articulaciones de orientaciones y prácticas de distintos ámbitos institucionales –expresamente referimos al conjunto de actores que se activan y pujan frente al contenido y carácter de las decisiones públicas; 3. estudiar las prácticas de resistencia frente a las regulaciones instituidas.Fil: Ciuffolini, María Alejandra. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; ArgentinaFil: Avalle, Gerardo. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; Argentin

La construcción política de la desigualdad : Pobreza y Sexualidad en las políticas públicas de la Provincia de Córdoba

El proyecto pretende analizar la definición de políticas públicas sobre pobreza y ambiente como instancias de visibilización de posiciones y discursividades en conflicto sobre la (des)igualdad. Asimismo pretende entender la formulación de políticas públicas como instancias en que los Estados institucionalizan una definición sobre la (des)igualdad que muchas veces, paradójicamente, resulta en la instauración de exclusiones y el fortalecimiento de regímenes de dominación. Entre las diversas hipótesis que guían el proyecto la más abarcativa sostiene que las decisiones, los modos y campos de intervención definidos en la política pública constituyen en sí mismos un espacio discursivo en el que se establecen definiciones y plasman matrices ideológicas respecto de la (des)igualdad. Pues a partir de ellos se visibilizan operaciones específicas de inclusión/exclusión, igualdad/desigualdad, prohibición/habilitación, etc.; se identifican y caracterizan sujetos; así como también un determinado orden normativo de relaciones y prácticas. No obstante encontrarse legalmente instituida la igualdad como principio subyacente a todo el ordenamiento de derechos, en la práctica las desigualdades se hacen patentes. Éstas son especialmente relevantes en tres áreas de políticas públicas: el trabajo, el hábitat y sexualidad. Consecuentemente, se propone: 1. analizar el dispositivo de regulación tal como se materializa en las decisiones, leyes y políticas públicas del Estado Provincial; 2. Esclarecer las disputas y/o articulaciones de orientaciones y prácticas de distintos ámbitos institucionales –expresamente referimos al conjunto de actores que se activan y pujan frente al contenido y carácter de las decisiones públicas; 3. estudiar las prácticas de resistencia frente a las regulaciones instituidas.Fil: Ciuffolini, María Alejandra. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; ArgentinaFil: Avalle, Gerardo. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; ArgentinaFil: Ibaña, Griselda Beatriz. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; Argentin

La construcción política de la desigualdad : pobreza y sexualidad en las políticas públicas de la provincia de Córdoba

El proyecto pretende analizar la definición de políticas públicas sobre pobreza y ambiente como instancias de visibilización de posiciones y discursividades en conflicto sobre la (des)igualdad. Asimismo pretende entender la formulación de políticas públicas como instancias en que los Estados institucionalizan una definición sobre la (des)igualdad que muchas veces, paradójicamente, resulta en la instauración de exclusiones y el fortalecimiento de regímenes de dominación. Entre las diversas hipótesis que guían el proyecto la más abarcativa sostiene que las decisiones, los modos y campos de intervención definidos en la política pública constituyen en sí mismos un espacio discursivo en el que se establecen definiciones y plasman matrices ideológicas respecto de la (des)igualdad. Pues a partir de ellos se visibilizan operaciones específicas de inclusión/exclusión, igualdad/desigualdad, prohibición/habilitación, etc.; se identifican y caracterizan sujetos; así como también un determinado orden normativo de relaciones y prácticas. No obstante encontrarse legalmente instituida la igualdad como principio subyacente a todo el ordenamiento de derechos, en la práctica las desigualdades se hacen patentes. Éstas son especialmente relevantes en tres áreas de políticas públicas: el trabajo, el hábitat y sexualidad. Consecuentemente, se propone 1. analizar el dispositivo de regulación tal como se materializa en las decisiones, leyes y políticas públicas del Estado Provincial; 2. Esclarecer las disputas y/o articulaciones de orientaciones y prácticas de distintos ámbitos institucionales –expresamente referimos al conjunto de actores que se activan y pujan frente al contenido y carácter de las decisiones públicas; 3. estudiar las prácticas de resistencia frente a las regulaciones instituidas.Fil: Ciuffolini, María Alejandra. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; ArgentinaFil: Avalle, Gerardo. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; Argentin