The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

During development, signal-regulated transcription factors (TFs) act as basal repressors and upon signalling through morphogens or cell-to-cell signalling shift to activators, mediating precise and transient responses. Conversely, at the final steps of neuron specification, terminal selector TFs directly initiate and maintain neuron-type specific gene expression through enduring functions as activators. C. elegans contains 3 types of serotonin synthesising neurons that share the expression of the serotonin biosynthesis pathway genes but not of other effector genes. Here, we find an unconventional role for LAG-1, the signal-regulated TF mediator of the Notch pathway, as terminal selector for the ADF serotonergic chemosensory neuron, but not for other serotonergic neuron types. Regulatory regions of ADF effector genes contain functional LAG-1 binding sites that mediate activation but not basal repression. lag-1 mutants show broad defects in ADF effector genes activation, and LAG-1 is required to maintain ADF cell fate and functions throughout life. Unexpectedly, contrary to reported basal repression state for LAG-1 prior to Notch receptor activation, gene expression activation in the ADF neuron by LAG-1 does not require Notch signalling, demonstrating a default activator state for LAG-1 independent of Notch. We hypothesise that the enduring activity of terminal selectors on target genes required uncoupling LAG-1 activating role from receiving the transient Notch signalling

Heme oxygenase-1 regulates the progression of K/BxN serum transfer arthritis

Heme oxygenase-1 (HO-1) is induced in many cell types as a defense mechanism against stress. We have investigated the possible role of endogenous HO-1 in the effector phase of arthritis using the K/BxN serum transfer model of arthritis in HO-1 heterozygous and homozygous knock-out mice. Methodology/Principal Findings. Arthritis was induced in C57/Black-6 xFVB (HO-1+/+, HO-1+/− and HO-1−/−) mice by intraperitoneal injection of 150 µl serum from arthritic K/BxN mice at days 0 and 2. Blood was collected and animals were sacrificed at day 10. Histological analysis was performed in ankle sections. The levels of inflammatory mediators were measured in serum and paw homogenates by enzyme-linked immunosorbent assay or Multiplex technology. The incidence of arthritis was higher in HO-1+/− and HO-1−/− groups compared with HO-1+/+. The inflammatory response was aggravated in HO-1+/− mice as shown by arthritic score and the migration of inflammatory cells that could be related to the enhancement of CXCL-1 production. In addition, the HO-1+/− group showed proteoglycan depletion significantly higher than HO-1+/+ mice. Serum levels of matrix metalloproteinase-3, monocyte chemotactic protein-1, plasminogen activator inhibitor-1, E-selectin and intercellular adhesion molecule-1 were increased in arthritic HO-1−/− mice, whereas vascular endothelial growth factor and some cytokines such as interferon-γ showed a reduction compared to HO-1+/+ or HO-1+/− mice. In addition, down-regulated gene expression of ferritin, glutathione S-reductase A1 and superoxide dismutase-2 was observed in the livers of arthritic HO-1+/− animals

Efecto del estrés oxidativo sobre la proliferación celular

Tanto en el organismo como a nivel celular se generan especies reactivas de oxígeno (ROS) de forma endógena o como producto de agentes exógenos. Debe haber un balance entre los sistemas oxidantes y los antioxidantes celulares para la correcta regulación metabólica, ya que si se produce un desequilibro a favor de los sistemas oxidantes, se induce estrés oxidativo, una situación que causa efectos tóxicos sobre todos los componentes de la célula.En este trabajo se ha estudiado el efecto tóxico de la mostaza nitrogenada (MN), un potente agente oxidante, sobre la proliferación de un cultivo de fibroblastos humanos. También se ha querido determinar el posible efecto protector de quercetina ante la oxidación producida por MN, viendo cómo la aplicación combinada de estos agentes afecta a la proliferación del cultivo. Para llevar a cabo estas determinaciones se ha requerido la puesta en marcha del ensayo con el colorante WST-1.También, mediante la puesta en marcha de la técnica del fluorocromo CFSE se ha podido determinar la proliferación de un cultivo empleando citometría de imagen.<br /

Developmental Programming of Obesity and Liver Metabolism by Maternal Perinatal Nutrition Involves the Melanocortin System

Maternal obesity predisposes offspring to metabolic dysfunction and Non-Alcoholic Fatty Liver Disease (NAFLD). Melanocortin-4 receptor (Mc4r)-deficient mouse models exhibit obesity during adulthood. Here, we aim to determine the influence of the Mc4r gene on the liver of mice subjected to perinatal diet-induced obesity. Female mice heterozygous for Mc4r fed an obesogenic or a control diet for 5 weeks were mated with heterozygous males, with the same diet continued throughout pregnancy and lactation, generating four offspring groups: control wild type (C_wt), control knockout (C_KO), obese wild type (Ob_wt), and obese knockout (Ob_KO). At 21 days, offspring were genotyped, weaned onto a control diet, and sacrificed at 6 months old. Offspring phenotypic characteristics, plasma biochemical profile, liver histology, and hepatic gene expression were analyzed. Mc4r_ko offspring showed higher body, liver and adipose tissue weights respect to the wild type animals. Histological examination showed mild hepatic steatosis in offspring group C_KO. The expression of hepatic genes involved in regulating inflammation, fibrosis, and immune cell infiltration were upregulated by the absence of the Mc4r gene. These results demonstrate that maternal obesogenic feeding during the perinatal period programs offspring obesity development with involvement of the Mc4r system

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

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

Joint actions of diverse transcription factor families establish neuron-type identities and promote enhancer selectivity

16 páginas, 6 figuras, 2 tablasTo systematically investigate the complexity of neuron specification regulatory networks, we performed an RNA interference (RNAi) screen against all 875 transcription factors (TFs) encoded in Caenorhabditis elegans genome and searched for defects in nine different neuron types of the monoaminergic (MA) superclass and two cholinergic motoneurons. We identified 91 TF candidates to be required for correct generation of these neuron types, of which 28 were confirmed by mutant analysis. We found that correct reporter expression in each individual neuron type requires at least nine different TFs. Individual neuron types do not usually share TFs involved in their specification but share a common pattern of TFs belonging to the five most common TF families: homeodomain (HD), basic helix loop helix (bHLH), zinc finger (ZF), basic leucine zipper domain (bZIP), and nuclear hormone receptors (NHR). HD TF members are overrepresented, supporting a key role for this family in the establishment of neuronal identities. These five TF families are also prevalent when considering mutant alleles with previously reported neuronal phenotypes in C. elegans, Drosophila, and mouse. In addition, we studied terminal differentiation complexity focusing on the dopaminergic terminal regulatory program. We found two HD TFs (UNC-62 and VAB-3) that work together with known dopaminergic terminal selectors (AST-1, CEH-43, CEH-20). Combined TF binding sites for these five TFs constitute a cis-regulatory signature enriched in the regulatory regions of dopaminergic effector genes. Our results provide new insights on neuron-type regulatory programs in C. elegans that could help better understand neuron specification and evolution of neuron types.the Bioinformatics and Biostatistics Unit from Principe Felipe Research Center (CIPF) for providing access to the cluster, cofunded by European Regional Development Funds (FEDER); Funding sources: European Research Council: ERC-StG2011-281920; ERC-Co-2020-101002203; Ministerio de Economía, Industria y Competitividad, Gobierno de España: SAF2017-84790-R; PID2020-115635RB-I00; RED2018-102553-T; Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana: PROMETEO/2018/055; ACIF/2019/079.Peer reviewe

Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease

Contains fulltext : 97785.pdf (publisher's version ) (Open Access)AIMS: Although oxidative stress participates in the etiopathogenesis of rheumatoid arthritis, its importance in this inflammatory disease has not been fully elucidated. In this study, we analyzed the relevance of the transcription factor Nrf2, master regulator of redox homeostasis, in the effector phase of an animal model of rheumatoid arthritis, using the transfer of serum from K/BxN transgenic mice to Nrf2(-/-) mice. RESULTS: Nrf2 deficiency accelerated the incidence of arthritis, and animals showed a widespread disease affecting both front and hind paws. Therefore, the inflammatory response was enhanced, with increased migration of leukocytes and joint destruction in front paws. We observed an increased production of tumor necrosis factor-alpha, interleukin-6, and CXCL-1 in the joint, with small changes in eicosanoid levels. Serum levels of CXCL-1 and receptor activator for nuclear factor kappaB ligand were enhanced and osteocalcin decreased in arthritic Nrf2(-/-) mice. The expression of cyclooxygenase-2, inducible nitric oxide synthase, and peroxynitrite in the joints was higher in Nrf2 deficiency, whereas heme oxygenase-1 was downregulated. Innovation: Nrf2 may be a therapeutic target for arthritis. CONCLUSION: Our results support a protective role of Nrf2 against joint inflammation and degeneration in arthritis

Potentially inappropriate prescribing in institutionalised older patients in Spain: the STOPP-START criteria compared with the STOPP-START criteria compared with

Objective: The aims of this study were to identify potentially inappropriate prescribing using the Beers and STOPP criteria. The START criteria were applied to detect prescription omission in the geriatric population. We compared the utility of these criteria in institutionalised older people. Methods: Descriptive study reviewing the medication and clinical records of 81 residents (aged 65 years and more) by pharmacists in a nursing home in the Lleida region (Spain). Results: The mean patients´ age was 84 (SD=8) years, with an average of 5 drugs per resident (total prescriptions: 416 medicines). The Beers criteria identified potentially inappropriate medication use in 25% of patients and 48% of patients used at least 1 inappropriate medication according to STOPP criteria. The most frequent potentially inappropriate medications for both criteria were long-acting benzodiazepines and NSAIDs. START detected 58 potential prescribing omissions in 44% of patients. Calcium-vitamin D supplementation in osteoporosis was the most frequent rule (15%), but omissions corresponding to the cardiovascular system implied 23% of patients. Conclusion: The STOPP-START criteria reveal that potentially inappropriate prescribing (PIP) is a highly prevalent problem among Spanish nursing home residents, and a statistically significant positive correlation was found between the number of medicines prescribed and the number of PIP detected in this study. The STOPP criteria detect a larger number of PI medications in this geriatric population than the Beers criteria. The prescribing omissions detected by the START criteria are relevant and require intervention. Pharmacists´ review of medications may help identify potentially inappropriate prescribing and, through an interdisciplinary approach, working with physicians may improve prescribing practices among geriatric residents of nursing homesObjetivo: Este estudio está orientado a identificar la prescripción potencialmente inapropiada usando los criterios de Beers y STOPP. Las omisiones de prescripciones se detectan en esta población geriátrica aplicando los criterios START. Se compara la utilidad de estos criterios en ancianos institucionalizados. Métodos: Estudio descriptivo de revisión de la medicación y las historias clínicas por farmacéuticos, de 81 pacientes (con 65 o más años) ingresados en una residencia en la provincia de Lleida (España). Resultados: La media de edad de los pacientes fue de 84 años (DE=8), con cinco medicamentos de promedio de tratamiento por residente (prescripciones totales: 416 medicamentos). Los criterios de Beers detectaron el uso de medicación potencialmente inapropiada en el 25% de los pacientes. Los criterios STOPP identificaron una posible medicación inapropiada en el 48% de los pacientes. La mayor frecuencia de uso de medicamentos potencialmente inapropiados para ambos criterios correspondió a las benzodiacepinas de larga duración y los AINE. Los criterios START detectaron 58 prescripciones potencialmente omitidas en el 44% de los pacientes. Entre ellas, la ausencia de suplementos de Calcio-vitamina D en osteoporosis fue la regla más frecuentemente implicada (15% de los pacientes); sin embargo, las omisiones relacionadas con el sistema cardiovascular asociadas a elevado riesgo cardiovascular son las que implicaron hasta un 23% de pacientes. Conclusión: La aplicación de los criterios STOPPSTART ha detectado una elevada proporción de prescripciones potencialmente inapropiadas en pacientes ancianos en una residencia sanitaria en España, con una significativa correlación positiva entre el número de medicamentos prescritos al paciente y el número de prescripciones potencialmente inapropiadas. Los criterios STOPP identificaron más medicación potencialmente inapropiada que los criterios de Beers. Las omisiones detectadas por los criterios START son relevantes y requiere una intervención. La revisión de la medicación por un farmacéutico puede ayudar a identificar potenciales prescripciones inapropiadas y, con un abordaje interdisciplinario, en colaboración con los médicos se podría mejorar la prescripción en pacientes ancianos de residencias geriátricas

PBX1 acts as terminal selector for olfactory bulb dopaminergic neurons

15 páginas, 8 figuras. Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.186841.supplementalNeuronal specification is a protracted process that begins with the commitment of progenitor cells and culminates with the generation of mature neurons. Many transcription factors are continuously expressed during this process but it is presently unclear how these factors modify their targets as cells transition through different stages of specification. In olfactory bulb adult neurogenesis, the transcription factor PBX1 controls neurogenesis in progenitor cells and the survival of migrating neuroblasts. Here, we show that, at later differentiation stages, PBX1 also acts as a terminal selector for the dopaminergic neuron fate. PBX1 is also required for the morphological maturation of dopaminergic neurons and to repress alternative interneuron fates, findings that expand the known repertoire of terminal-selector actions. Finally, we reveal that the temporal diversification of PBX1 functions in neuronal specification is achieved, at least in part, through the dynamic regulation of alternative splicing. In Caenorhabditis elegans, PBX/CEH-20 also acts as a dopaminergic neuron terminal selector, which suggests an ancient role for PBX factors in the regulation of terminal differentiation of dopaminergic neurons.This work was supported by PhD fellowships from the Ministerio de Educación, Cultura y Deporte (FPU16/02008 to I.R.-B.) and the Ministerio de Economıa y ́Competitividad (BES-2012-053847 to L.R.. and BES-2015-072799 to R.B.-R.); by European Research Council grant (ERC-StG-2011-281920); by Ministerio de Economıa y Competitividad grants (SAF2017-84790-R and SAF2016-75004R) and ́ by the Generalitat Valenciana (PROMETEO/2018/055).Peer reviewe