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Erica australis and Erica arborea are morphologically and ecologically similar heather species. Erica australis is restricted to the western Mediterranean Basin where it overlaps with the westernmo ...

In this article the experiment carried out by Takahashi et al. [2009] is replicated to analyze the influence of culture, gender, origin (urban or rural), and socioeconomic level on the impulsivity ...

[Background] Genomic and proteomic analysis are potent tools for metabolic characterization of microorganisms. Although cellulose usually triggers cellulase production in cellulolytic fungi, the secretion of the different enzymes involved in polymer conversion is subjected to different factors, depending on growth conditions. These enzymes are key factors in biomass exploitation for second generation bioethanol production. Although highly effective commercial cocktails are available, they are usually deficient for β-glucosidase activity, and genera like Penicillium and Talaromyces are being explored for its production., [Results] This article presents the description of Talaromyces amestolkiae as a cellulase-producer fungus that secretes high levels of β-glucosidase. β-1,4-endoglucanase, exoglucanase, and β-glucosidase activities were quantified in the presence of different carbon sources. Although the two first activities were only induced with cellulosic substrates, β-glucosidase levels were similar in all carbon sources tested. Sequencing and analysis of the genome of this fungus revealed multiple genes encoding β-glucosidases. Extracellular proteome analysis showed different induction patterns. In all conditions assayed, glycosyl hydrolases were the most abundant proteins in the supernatants, albeit the ratio of the diverse enzymes from this family depended on the carbon source. At least two different β-glucosidases have been identified in this work: one is induced by cellulose and the other one is carbon source-independent. The crudes induced by Avicel and glucose were independently used as supplements for saccharification of slurry from acid-catalyzed steam-exploded wheat straw, obtaining the highest yields of fermentable glucose using crudes induced by cellulose., [Conclusions] The genome of T. amestolkiae contains several genes encoding β-glucosidases and the fungus secretes high levels of this activity, regardless of the carbon source availability, although its production is repressed by glucose. Two main different β-glucosidases have been identified from proteomic shotgun analysis. One of them is produced under different carbon sources, while the other is induced in cellulosic substrates and is a good supplement to Celluclast in saccharification of pretreated wheat straw., This work has been funded by projects RTC-2014-1777-3 and BIO2015-68387-R from MINECO and S2013/MAE-2907 from Comunidad de Madrid. M. Nieto and J.A. Méndez thank their fellowships, FPU of the MINECO and Tatiana Pérez de Guzmán el Bueno Foundation, respectively.

El desarrollo de la “Personalidad Eficaz”, entendido como constructo en el que se relacionan los rasgos de la personalidad con la conducta eficaz en contextos profesionales o académicos, se postula como una de las metas de la formación universitaria del s. XXI. En esta línea, el Aprendizaje-servicio (ApS) es un método pedagógico que podría satisfacer estas necesidades al centrarse en la aplicación de competencias académicas en contextos reales. El presente trabajo, planteado desde un enfoque mixto de investigación, emerge con el objetivo de conocer si el ApS contribuye al desarrollo de la “Personalidad Eficaz” en estudiantes de magisterio del área de Educación Física. El estudio que se presenta se concretó en la Universitat Jaume I (España) y analiza el resultado de un programa de ApS sobre un grupo de estudiantes de segundo curso del Grado de Magisterio. Del análisis cuantitativo se concluye la existencia de diferencias significativas, a favor del grupo experimental, en los resultados globales del Test de Personalidad Eficaz para Universitarios. Por otra parte, el enfoque cualitativo del estudio se alinea y complementa los resultados cuantitativos, favoreciendo una mejor y más contextualizada comprensión de los mismos. The development of the “Effective Personality “, understood as a construct in which personality traits with effective behaviour in professional or academic contexts are related, is postulated as one of the goals of the 21st-century university training. According to this approach, the Service-Learning (S-L) is a pedagogical method that could meet these needs by focusing on the application of academic skills in real contexts. This paper, raised from a mixed research approach, arises in order to know whether the S-L contributes to the development of the “Effective-Personality” of pre-service teachers of the area of Physical Education. The study presented was carried out at Jaume I University (Spain) and analyses the results of a S-L program implemented by a group of second grade pre-service teachers. The quantitative analysis concludes significant differences, in favor of the experimental group, in the comparison of the overall results of the Effective Personality Test for University Students. Moreover, the qualitative study approach aligns and complements the quantitative results, favouring a better and more contextualized understanding of them.

Rationale: Guacamole is a sauce or dressing composed of avocado pulp and other ingredients. Guacamole powder is an important advancement in the generation of added value for the avocado production chain, as it is an alternative product with the potential to be used by end consumers. Aims: The aim of this study was to standardize the spray drying process for guacamole powder using the response surface methodology. Methods: Four independent variables were taken into account for the experiment design: atomizing disk speed (ADS), air inlet temperature (AIT), air outlet temperature (AOT) and vacuum pressure (VP). In addition, the following dependent variables were considered: water activity (a w ), moisture (Xw), solubility (S), hygroscopicity (H), color (L*, a* and b*), extractable oil content (EO), peroxide index (PI) and particle size (D 10 , D 50 and D 90 ). Likewise, the following two dependent variables associated with the process were identified: yield (Y) and deposit formation (DF). Results: The best conditions for the process were obtained with ADS = 27451 rpm, AIT = 168oC, AOT = 90oC and VP = 1.77 ″H 2 O. These conditions yielded guacamole powder with the desired properties, namely: maximum Y, S, L*, b*, EO and minimal DF, a w , Xw, H, a*, PI, D 10 , D 50, D 90. Conclusions: The spray drying process is an effective technology that provides added value to avocado, the ADS being the independent variable that has the greatest impact on the quality of powdered guacamole.

Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16(Ink4a), and p19(Arf) become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.

SUMMARYSenescent cells play important physiological- and pathophysiological roles in tumor suppression, tissue regeneration, and aging. While select genetic and epigenetic elements crucial for senescence induction were identified, the dynamics, underlying epigenetic mechanisms, and regulatory networks defining senescence competence, induction and maintenance remain poorly understood, precluding a deliberate therapeutic manipulation of these dynamic processes. Here, we show, using dynamic analyses of transcriptome and epigenome profiles, that the epigenetic state of enhancers predetermines their sequential activation during senescence. We demonstrate that activator protein 1 (AP-1) ‘imprints’ the senescence enhancer landscape effectively regulating transcriptional activities pertinent to the timely execution of the senescence program. We define and validate a hierarchical transcription factor (TF) network model and demonstrate its effectiveness for the design of senescence reprogramming experiments. Together, our findings define the dynamic nature and organizational principles of gene-regulatory elements driving the senescence program and reveal promising inroads for therapeutic manipulation of senescent cells.

Highlights • Extracts of less polarity from B. rubescens displayed significant antifungal activity. • Two coumarins (xanthyletin and 7-demethylsuberosin) were isolated from antifungal extracts of B. rubescens. • A chromatographic method to detect and quantify both coumarins is described. • Xanthyletin and 7-demethylsuberosin exhibited in vivo and in vitro strong antifungal activity. • 7-Demethylsuberosin was metabolized slowly by C. gloeosporioides to marmesin and decursinol., Anthracnose, caused by the fungus Colletotrichum gloeosporioides (Penz.) Penz. & Sacc., is the most limiting fungal disease of mango and papaya crops in Colombia. The in vivo and in vitro activity against C. gloeosporioides of the extracts from sawdust of Brosimum rubescens Taub. (Moraceae) was evaluated. The extracts of less polarity (n-hexane and dichloromethane) displayed the greatest inhibitory effects. Then, the coumarins xanthyletin (2.74 % d.w.) and 7-demethylsuberosin (2.19 % d.w.) were isolated from these extracts. The compound 7-demethylsuberosin displayed a strong in vivo and in vitro antifungal activity. Furthermore, the metabolism of 7-demethylsuberosin by the fungus C. gloeosporioides was analyzed. The fungus slowly detoxified 7-demethylsuberosin to marmesin and decursinol. Therefore, the high antifungal activity and low level of detoxification make 7-demethylsuberosin, and the extracts that contain it, promising candidates for controlling C. gloeosporioides. Sawdust of B. rubescens may be considered a valuable source of extracts and coumarins with antifungal activity.

Globally, citizens exist for sustained periods in states of aging-related disease and multimorbidity. Given the urgent and unmet clinical, health care, workforce, and economic needs of aging populations, we need interventions and programs that regenerate tissues and organs and prevent and reverse aging-related damage, disease, and frailty (1). In response to these challenges, the World Health Organization (WHO) has called for a comprehensive public-health response within an international legal framework based on human rights law (1). Yet for a clinical trial to be conducted, a disease to be diagnosed, intervention prescribed, and treatment administered; a corresponding disease classification code is needed, adopted nationally from the WHO International Classification of Diseases (ICD). Such classifications and staging are fundamental for health care governance among governments and intergovernmental bodies. We describe a systematic and comprehensive approach to the classification and staging of organismal senescence and aging-related diseases at the organ and tissue levels in order to guide policy and practice and enable appropriate interventions and clinical guidance, systems, resources, and infrastructure.

Streptococcus pyogenes tonsillar infection is well known to trigger and exacerbate psoriasis lesions in both guttate and plaque forms of the disease. Although mucosal and cutaneous tissues are closely involved in psoriasis pathology, the interaction between their specific immune responses has not been deeply explored. This work aims to address and characterize the presence of humoral responses against S. pyogenes in patients with psoriasis and its putative association with cytokine responses detected in vitro in our psoriasis ex vivo model, based on the coculture of cutaneous lymphocyte-associated antigen

Background: The contribution of cigarette smoking to the risk of rheumatoid arthritis (RA) is larger for seropositive than for seronegative patients. Current pathogenic models explain this difference via the production of anti-citrullinated protein antibodies (ACPA) induced by protein citrullination in the lungs as a consequence of smoking. However, there are inconsistent results with this model including the van Wesemael et al. report, which found an association of smoking with the concurrent presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein antibodies (ACarPA), rather than with ACPA. Objectives: We aimed to explore the relationship between smoking and the presence of FR, ACPA and ACarPA and their combinations in patients with RA. Methods: Six cohorts with 2253 RA patients were obtained to replicate the van Wesemael et al. results. After replication, they were combined with the three cohorts from that study comprising 2238 patients to a total of 4491 patients. The results from the different cohorts were combined by fixed-effects meta-analysis. Most analyses involved comparisons between two levels of smoking exposure, never and ever smokers, considering the RF-/ACPA-/ACarP-patients as the reference. Results: Analysis of the replication set confirmed the predominant association of smoking with the concurrent presence of the three RA autoantibodies (OR = 1.99, P = 2.5 x 10-8), whereas the patients with one or two antibodies were not different from the patients without antibodies (OR = 1.22, p = 0.4 and OR = 1.22, p = 0.3, respectively). The combined meta-analysis with all the cohorts clarified the dominant association of smoking with the triple concordant seropositivity (OR = 2.00, p = 4.4 x 10-16). In contrast, there was no association with the patient bearing one autoantibody (OR = 1.12, p = 0.4), and an in-between association with the concurrent presence of two antibodies (OR = 1.26, p = 0.009). Moreover, the association with the presence of three antibodies was significantly larger than with two antibodies (OR = 1.54, p = 1.4 x 10-6), whereas the association with the presence of two antibodies was not larger than with one autoantibody (OR = 1.11, p = 0.3). In the patients remaining after exclusion of the triple seropositive, the smokers were exclusively associated with the RF+ (OR = 1.28, p = 0.03 and OR = 1.30, p = 0.004 in the double and single positive patients, respectively). This association was independent of the reference, either the triple seronegative (OR = 1.29, p = 0.001) or all the RF-patients (OR = 1.32, p = 0.0002). Conclusion: Smoking increases RA susceptibility by promoting pathways leading to the concurrent presence of the three RA autoantibodies and, in its defect, to the production of RF. These actions are not covered by current pathogenic models and suggest that smoking accelerates epitope spreading. Reference [1] van Wesemael, et al. Arthritis Res Ther. 2016;18:285. Acknowledgement: Supported by grants PI17/01606 and RD16/0012/0014 of the Instituto de Salud Carlos III (Spain) that are partially financed by FEDER. Disclosure of Interests: Cristina Regueiro : None declared, Luis Rodriguez Rodriguez: None declared, Raquel Lopez-Mejias: None declared, Laura Nuno: None declared, Ana Triguero-Martinez: None declared, Eva Perez-Pampin: None declared, Alfonso Corrales: None declared, Alejandro Villalva: None declared, Yolanda Lopez-Golan: None declared, Lydia Abasolo: None declared, Sara Remuzgo Martinez: None declared, Ana Ortiz: None declared, Eva Herranz: None declared, ANA MARTiNEZ-FEITO: None declared, Carmen Conde : None declared, ANTONIO MERA VARELA: None declared, Alejandro Balsa Grant/research support from: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Consultant for: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Sandoz, Lilly, Paid instructor for: Pfizer, Speakers bureau: Pfizer, Novartis, UCB, Nordic, Sanofi, Sandoz, Lilly, Isidoro Gonzalez-Alvaro: None declared, Miguel A Gonzalez-Gay Grant/research support from: Prof. MA Gonzalez-Gay received grants/research supports from Abbvie, MSD, Jansen and Roche., Speakers bureau: Consultation fees/participation in company sponsored speaker’s bureau from Pfizer, Lilly, Sobi, Celgene, Novartis, Roche and Sanofi., Benjamin Fernandez: None declared, Antonio Gonzalez: None declared

Background: There is great interest in the identification of prognostic biomarkers informing early therapeutic decisions for the improvement of rheumatoid arthritis (RA) evolution. Promising results in early arthritis (EA) patients indicate the anti-carbamylated protein antibodies (ACarPA) may serve this function. In effect, they are associated with high baseline disease activity and, in our patients, with less improvement in the first 6-months of follow-up. This association was independent of sex, age at diagnosis, time since symptoms onset, smoking and the year of onset. However, the influence of the treatment has not been explored yet. Objectives: We aimed to explore the influence of the initial treatment on the persistent high disease activity associated with the presence of ACarPA in EA patients. Methods: Samples were obtained at the first visit of two EA cohorts from Hospital Universitario La Paz and Hospital Universitario La Princesa, which recruit patients within one year from the clinical onset. Information on the initial treatment and the disease activity at the baseline and at 6-months of follow-up was available from 546 patients. Treatment was categorized according to the use of corticosteroids, methotrexate (MTX) and other DMARDs, and considering changes in the first 6 months. In addition, MTX dose was considered either quantitatively or as a dichotomous variable (≥ 12.5 mg and Results: A large fraction (83%) of the EA patients received specific treatment from the initial visit. It comprised DMARD (50.1%), corticosteroids (10.6%), or a combination of both (39.3%). The most common DMARD was MTX (82.2%), whereas less frequently used medications included sulfasalazine (5.4%), leflunomide (3.2%), hydroxychloroquine (8.1%) and other (1.0%). The 35.5% of the treated patients maintained the treatment during the 6-month follow-up. The presence of ACarPA was associated with a 0.45 higher mean baseline DAS28 and with less decrease of DAS28 (ΔDAS28) from the baseline to 6 months of follow-up (β = 0.08, p = 0.016), as already communicated. This latter association persisted without modification after accounting for the initial treatment (DMARD, corticosteroids, and changes in treatment). In addition, it was independent of the consideration of all DMARDs in a single group, or separated into two categories: MTX and the other. Similarly, the association was independent on MTX dose, defined both as a categorical or a quantitative variable. Conclusion: The association of ACarPA with a persistently increased disease activity in EA patients is independent of the initial treatment. These results reinforce the possibility that ACarPA can be useful as prognostic biomarkers for the first 6 months of evolution and indicate the need for personalized management of the patients carrying ACarPA. Acknowledgement: Supported by grants PI17/01606 and RD16/0012/0014 of the Instituto de Salud Carlos III (Spain) that are partially financed by FEDER. Disclosure of Interests: Cristina Regueiro : None declared, Ana Ortiz: None declared, Laura Nuno: None declared, Diana Peiteado: None declared, Alejandro Villalva: None declared, Dora Pascual Salcedo: None declared, ANA MARTINEZ-FEITO: None declared, Alejandro Balsa Grant/research support from: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Consultant for: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Sandoz, Lilly, Paid instructor for: Pfizer, Speakers bureau: Pfizer, Novartis, UCB, Nordic, Sanofi, Sandoz, Lilly, Isidoro Gonzalez-Alvaro: None declared, Antonio Gonzalez: None declared

Background: Fibroblast-like synoviocytes (FLS) are pivotal in inflammation and joint damage of rheumatoid arthritis (RA). These cells acquire an aggressive and invasive phenotype and secrete inflammatory mediators, metalloproteases and cathepsins that perpetuate inflammation and lead to cartilage and bone damage. Given the importance of FLS in the pathogenesis of RA, there is a growing interest in developing new therapies aimed to revert their aggressive phenotype. To this end, a better knowledgement of molecular mechanisms involved in FLS behavior is needed. Recently, the role of non-canonical Wnt pathway has been highlighted in several processes as migration, invasion and inflammatory responses. The non-canonical Wnt signaling pathway included the planar cell polarity (PCP), with the activation of Rho and Rac GTPases, and the Wnt/Ca2+ pathways. We have previously demonstrated that Wnt5a contributes to the aggressive phenotype of FLS by increasing their migration and invasion ability, and by stimulating the inflammatory response. Objectives: To analyse the molecular mechanisms involved in the enhancing effects of non-canonical Wnt5a pathway on the aggressive phenotype of rheumatoid synoviocytes. Methods: The expression of receptors of non-canonical Wnt5a pathway was assessed in FLS from six RA patients by real-time PCR. Expression of these receptors was suppressed by siRNA transfection (Dharmacon) and the antibody (anti-RYK, Abgent). Pharmacological inhibitors were used to identify the signaling pathways. Thus, an inhibitor of ROCK pathway (Y-27632, Selleckchem) was used and a calcium chelator (BAPTA-AM, Enzo) for the inhibition of the PKC pathway. The expression of MAPKs was analyzed by western blot. Migration after stimulation with recombinant Wnt5a protein was analyzed by the wound healing assay using Ibidi inserts. The occupation area was determined by Image J software. Results: We analyzed the expression of Wnt5a receptors, FZD1, FZD2, FZD4, FZD5, FZD7, ROR1, ROR2 and RYK of RA FLS. Although all receptors were expressed in theses cells, whereas ROR2 was weakly expressed, RYK showed the highest expression. Migration assays after receptor suppression by siRNA transfection or blocking antibodies showed the involvement of RYK on Wnt5a signaling in RA FLS. In effect, Wnt5a-induced migration was reduced by more than 25% in FLS treated with the anti-RYK antibody. In addition, Wnt5a-induced migration in FLS treated with ROCK inhibitor (Y-27632) was 32% lower than in FLS not treated. No change in spontaneous migration was observed in FLS treated with Y-27632. However, the treatment with the calcium chelator, BAPTA-AM, did not show any differential effect between the spontaneous or the Wnt5a-induced migration. In addition, we found the activation of MAP kinases, ERK and P38, as well as, AKT and GSK3β in FLS treated with rWnt5a. Nevertheless rWnt5a did not activate JNK. These effects were reversed after treatment with the ROCK inhibitor or after blocking the RYK receptor. Conclusion: These results indicate that Wnt5a contributes to the aggressive phenotype of RA FLS by binding to RYK receptor, through Rho-ROCK pathway and the activation of MAPKs, ERK and P38, as well as the activation of AKT and GSK3β. Acknowledgement: Supported by grant of the ISCIII/PI17/01660/RETICS Program, RD16/0012/0014/Cofinanced FEDER Disclosure of Interests: None declared

Introduction: Urinary lithiasis involves a major source of morbidity and economic costs. The aim of this study was to evaluate the adherence to the European Association of Urology Guidelines on Urolithiasis with regard to treatment among Spanish urologists. Methods: A total of 723 patients were included in a prospective study between May 1, 2014, and July 31, 2014. The study involved 8 hospitals responsible of urolithiasis in a geographical area of Spain (Comunidad Valenciana) with approximately 4,500,000 inhabitants. Data were collected about the demographic characteristics of the patients, the characteristics of the stones, and the indicated treatment, in order to analyze the adherence to the clinical guidelines. A 90% threshold was used in concordance with the indications in the guidelines. Results: Adherence to guidelines was poor in chemolysis, distal and ureteral calculi, and >2 cm renal calculi. Adherence was high in Conclusions: In our study, the overall adherence to the clinical guidelines regarding the therapeutic indication for urinary lithiasis has been low. In the case of both renal and ureteral stones, the adherence in small lithiasis has been greater, compared with larger ones. In our survey, a trend has been observed in favor of endoscopic procedures even in large lithiasis.

Jesus Gil discusses the first evidence for cellular senescence being associated with ageing, and how these studies opened new routes for basic and translational research.

Este trabajo tiene como objetivo principal conocer laintervención de los bancos tanto públicos como privados en elproceso de internacionalización de las empresas en el Brasil. Enalgunos países en desarrollo los bancos asumen determinadasfunciones que no están tan estrictamente relacionadas con lasfinanzas, como pueden ser las labores de formación a las empresasen el proceso de salida al exterior. Mediante cuestionario seentrevista a una muestra estadísticamente significativa de lasempresas exportadoras del Brasil. Los resultados ponen demanifiesto que los bancos públicos y privados facilitanfundamentalmente el apoyo financiero, pero también la formación yla promoción comercial. Otros resultados destacados han sido laexistencia de diferencias significativas en el acceso al crédito por lasempresas según su tamaño y la titularidad del banco (pública oprivada). Se discuten los resultados.

This paper proposes an instrument to assess social entrepreneurship competency in higher education (SECS). 19 Features of social entrepreneurship competency were identified. The pilot test (n = 497) confirmed the validity and reliability of the SECS. Exploratory factor analysis proposed a set of categories consistent with the initial approach. Confirmatory factor analysis showed acceptable relationships among the scale categories and items, while the fit indices suggested that the data fit adequately to the default model. Pearson’s test verified significant, positive correlations among the revised categories in all cases. Therefore, the scale carries the potential to contribute to social entrepreneurship research.

L'Aprenentatge-Servei (ApS) és una metodologia pedagògica experiencial i activa. Una de les seves principals virtuts és que fa efectiu el principi educatiu que diu que l'aprenentatge ha d'estar vinculat al medi social, físic i humà en què viu la persona que aprèn, qüestió essencial per poder dotar de significat real els aprenentatges. L’ApS el podem assimilar a un paraigua sota el qual s'aixopluguen altres estratègies, procediments i accions metodològiques. És a dir, el seu ús no soluciona una qüestió bàsica i pràctica com la d’organitzar ‘la classe de demà’; no és una estratègia concreta, és més aviat una forma d'entendre l'acció educativa. Des d'aquesta perspectiva, cal entendre’l com un paradigma global que impregna la nostra forma d'ensenyar, però que requereix d'altres estratègies per a la seva implementació. Aquest text presenta un projecte aplicat d'inclusió educativa realitzat a través d'ApS amb alumnat universitari del Grau de Mestre o Mestra d'Educació Infantil, executat a un Centre d'Educació Infantil i Primària. En els primers apartats analitzarem la base conceptual de l’ApS, per continuar descriurem el projecte Patis Inclusius i finalment acabarem realitzant una avaluació del mateix. Education in general, and especially initial teacher training, cannot be understood without a clear and determined component of social transformation. Service-Learning (SL) reinforces this type of training, becoming a very spread pedagogical approach nowadays. In this article we describe the application of SL through the program Patis Inclusius, applied by pre-service teachers and executed in a Primary and Childhood Education School. The aim of this SL application was to favour the scholar inclusion of pupils of childhood and primary education who presented developmental and/or communication disorders. The Patis Inclusius program was designed in accordance with the guidelines established by the National Youth Leadership Council of the United States, developed in the document "K-12 Service-Learning Standards for Quality Practice." These criteria are structured around the following axes: curricular connection, duration and intensity, useful and meaningful service, social alliances, student participation, process supervision, diversity and reflection". The text presents an initial theoretical justification, a contextual approach to the application framework and a final description specifying the aforementioned criteria.

El presente artículo aborda la relación entre la pedagogía crítica y los pilaresfundamentales de la metodología del aprendizaje servicio. Su principal objetivo esdemostrar, de un modo concluyente, la idoneidad del aprendizaje servicio comometodología para alcanzar objetivos pedagógicos tales como la emancipación, latransformación y la justicia social. El trabajo parte de la clarificación de los pilaresfundamentales de la pedagogía crítica, entendida como paradigma filosófico-educativoque emerge de la Teoría Crítica de la Escuela de Frankfurt. Posteriormente, el artículoda cuenta de los fundamentos pedagógicos del aprendizaje servicio, aportandoargumentos que evidencian su capacidad para satisfacer las metas pedagógicas de lapedagogía crítica. Por último, se ejemplifica dicha correlación a partir de una breverevisión de investigaciones sobre los efectos del aprendizaje servicio, así como a partirde la descripción detallada de una investigación llevada a cabo en el contexto español,que pone de manifiesto las posibilidades reales del aprendizaje servicio comometodología al servicio de la pedagogía crítica., This paper describes the relation between the critical pedagogy and the fundamentals of the service learning methodology. Its main objective is to demonstrate, conclusively, the suitability of service learning as a pedagogical methodology to achieve objectives such as empowerment, transformation and social justice. Firstly, the paper clarifies the fundamentals of the critical pedagogy, understood as a philosophical-educational paradigm emerging from the Critical Theory of the Frankfurt School. Subsequently, the article reports on the pedagogical foundations of service learning, providing arguments that demonstrate their ability to meet the educational goals of critical pedagogy. Finally, this correlation is exemplified from a brief review of research on the effects of service learning, as well as from the detailed description of a research conducted in the Spanish context, highlighting the real possibilities of this methodology to achieve the aims of the critical pedagogy, El presente artículo aborda la relación entre la pedagogía crítica y los pilares fundamentales de la metodología del aprendizaje servicio. Su principal objetivo es demostrar, de un modo concluyente, la idoneidad del aprendizaje servicio como metodología para alcanzar objetivos pedagógicos tales como la emancipación, la transformación y la justicia social. El trabajo parte de la clarificación de los pilares fundamentales de la pedagogía crítica, entendida como paradigma filosófico-educativo que emerge de la Teoría Crítica de la Escuela de Frankfurt. Posteriormente, el artículo da cuenta de los fundamentos pedagógicos del aprendizaje servicio, aportando argumentos que evidencian su capacidad para satisfacer las metas pedagógicas de la pedagogía crítica. Por último, se ejemplifica dicha correlación a partir de una breve revisión de investigaciones sobre los efectos del aprendizaje servicio, así como a partir de la descripción detallada de una investigación llevada a cabo en el contexto español, que pone de manifiesto las posibilidades reales del aprendizaje servicio como metodología al servicio de la pedagogía crítica

Este trabajo tiene como objetivo analizar la influencia mutua de las barreras a la exportación enel caso de un país emergente como Brasil. Se controlan cinco tipologías de barreras (de capital,de cultura, de producto, administrativas y de finanzas). El marco empírico se realiza en unamuestra estadísticamente significativa de las empresas exportadoras de Brasil. El modelopropuesto se analiza a través de ecuaciones estructurales con Partial Least Squares (PLS). Losresultados muestran que, como se ha propuesto en las hipótesis, existe un impacto significativoentre las distintas barreras a la exportación. Se plantean propuestas para reducir el impacto delas barreras a la exportación. The objective of this work is to analyze the mutual influence of export barriers in the case of anemerging country such as Brazil. Five types of barriers are controlled (capital, culture, product,administrative and financial). The empirical framework is carried out in a statisticallysignificant sample of exporting companies in Brazil. The proposed model is analyzed throughstructural equations with Partial Least Squares (PLS). The results show that, as has beenproposed in the hypotheses, there is a significant impact between the different export barriers.Proposals are made to reduce the impact of export barriers.

Senescence is a cellular stress response that results in the stable arrest of old, damaged or pre-neoplastic cells. Oncogene-induced senescence is tumour suppressive but can also exacerbate tumorigenesis through the secretion of proinflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed ‘senolytics’, have proved beneficial in animal models of many age-associated diseases. In the present study, we show that the cardiac glycoside ouabain is a senolytic agent with broad activity. Senescent cells are sensitized to ouabain-induced apoptosis, a process mediated in part by induction of the proapoptotic Bcl-2 family protein NOXA. We demonstrate that cardiac glycosides synergize with anti-cancer drugs to kill tumour cells and eliminate senescent cells that accumulate after irradiation or in old mice. Ouabain also eliminates senescent pre-neoplastic cells. The findings of the present study suggest that cardiac glycosides may be effective anti-cancer drugs by acting through multiple mechanisms. Given the broad range of senescent cells targeted by cardiac glycosides, their use against age-related diseases warrants further exploration.

Departament d' Educació i Didàctiques Específiques. Codi d’assignatura: MI1819

International audience; Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.

Assess the sustainability of electricity provision for rural families through off-grid Photovoltaic Systems (PVS) in Bolivia during the last 10 years, is the essential core of this research. The sustainability analysis is considered under a multidimensional approach: documental analysis complemented by a field research and semi-structured interviews with local experts. In the Bolivian case more than 36 thousand PVS have been installed in the last 10 years under different schemes, but more than 90% of these, are out of operation, shown the absence of sustainability approach in these interventions. For this and considering the international experience, is sketched a proposal under an integrality approach. The proposal contemplates substantial modifications in the way of granting the SFV to the families, their faculties as well as the institutional roles; a tariffed service has been suggested as it happens throughout an off-network system.

Pilocytic astrocytoma (PA, WHO grade I), the most common paediatric brain tumour, is characterized by constitutive activation of the MAPK pathway. PA tumours show a slow growth, without tendency to progress to high-grade malignancies. However, a significant group of patients for whom a total resection is not feasible require additional therapy. The typical proliferative index of a PA, measured by Ki-67 staining, is 1–2%, whereas a large part of the tumour is Ki-67 negative and expresses markers of oncogene-induced senescence (OIS) such as SA-β-Gal positivity and the cell cycle inhibitors p16INK4a (CDKN2A) and p21Cip1 (CDKN1A). Conventional treatments (i.e. chemotherapy) tend to target only proliferative cells and the effect of new molecularly targeted therapies (e.g., MAPK pathway inhibitors) on senescent cells remains unclear. Here, we discuss the opportunities to combine these therapies with new compounds targeting the senescent cells, referred to as senolytics, using three different PA models. (1) Ex vivo culture of human PA tumours (2) Two cell lines: the DKFZ-BT66 PA human cell line, carrying the oncogenic driver KIAA1549:BRAF-fusion, used as a model of OIS; and the proliferative BT40 cell line harbouring the BRAFV600E mutation; (3) In vivo xenograft model induced by orthotopic transplantation of BT40 cells. We have previously shown that OIS cells exhibit an increased sensitivity to senolytic compounds, such as navitoclax, a clinically approved BCL2/XL inhibitor, relative to proliferative controls (Buhl et al, Clin Cancer Res. 2019). Our current research demonstrates that treatments with low doses of chemotherapy (e.g., vinblastine) or MAPK inhibitors (e.g., dabrafenib or trametinib) triggers a therapy-induced senescence response in proliferative cells (e.g., abolished proliferation, SA-β-Gal positivity, SASP production), making these senescent cells sensitive to senolytic compounds, including navitoclax. Together, our research provides a strong rationale supporting the combined use of senolytics with current conventional and targeted therapies against human PA.

Metabolism and in vitro fungitoxicity of perinaphthenone against three economically important fungi of the citrus, Botryodiplodia spp., Botrytis spp. and Fusarium spp. were investigated. Perinaphthenone exhibited significant antifungal activity at 62.5 μM and above. Even, the inhibitory effect against Fusarium spp. was significantly enhanced by exposure to direct light. In addition, the metabolism of perinaphthenone by the three fungi was studied. Results show that perinaphthenone was transformed almost completely during the first 24 h; two major products, whose concentration increased progressively during the twelve days of the test, were isolated and identified as 2,3-dihydro-1H-phenalen-1-ol and 2,3-dihydro-phenalen-1-one. Although both metabolic products displayed a considerable fungistatic effect, their slightly lower activities in comparison to perinaphthenone indicate that the transformation was a detoxification process. Studies on the relationship between the effect of some substituents in the perinaphthenone core and the mycelial growth inhibition of Botryodiplodia spp. were also carried out. Results show that the α, β-unsaturated carbonyl system is an important structural requirement but not the only to be necessary for the strong antifungal activity of perinaphthenone. In general, the antifungal properties of perinaphthenone may be modulated through the incorporation of substituents in the naphthalene core or in the α, β-unsaturated carbonyl system. It is concluded that perinaphthenone could be used as an antifungal agent or as a structural template for the development of new fungicide compounds., Phenalenones; Botrytis spp.; Botryodiplodia spp.; Fusarium spp.; Antifungal activity; Metabolism; Reduction; Derivatives.

The field of artificial intelligence is currently experiencing relentless growth, with innumerable models emerging in the research and development phases across various fields, including science, finance, and engineering. In this work, the authors review a large number of learning techniques aimed at project management. The analysis is largely focused on hybrid systems, which present computational models of blended learning techniques. At present, these models are at a very early stage and major efforts in terms of development is required within the scientific community. In addition, we provide a classification of all the areas within project management and the learning techniques that are used in each, presenting a brief study of the different artificial intelligence techniques used today and the areas of project management in which agents are being applied. This work should serve as a starting point for researchers who wish to work in the exciting world of artificial intelligence in relation to project leadership and management.

Con el fin de determinar la calidad de la miel de Apis mellifera variedad scutellata, procedentes de las subregiones del Suroeste y Oriente Antioqueño, producidas durante los años 2013 y 2014, se realizó un estudio fIsicoquímico y palinológico de 18 muestras. El análisis fIsicoquímico reveló que todos los parámetros analizados se encontraban dentro de los valores establecidos por la normatividad Colombiana, con muy pocas excepciones. En general todas las mieles analizadas fueron de buena calidad y las variaciones en los parámetros analizados, fueron relacionadas con el origen botánico y geográfico de las mismas o errores en el proceso de manipulación. Desde el punto de vista palinológico se observó que la mayoría de mieles del Suroeste fueron uniflorales y las del oriente multiflorales; la riqueza total de polen de las muestras fue muy variable en ambas regiones, oscilando desde muy pobres a muy ricas. En oriente el taxón más común fue Asteraceae, seguido de Fabaceae, Solanaceae, Myrtaceae (principalmente Eucalyptus), Hypochaeris, Borreria y Hedyosmum y en el Suroeste fueron Coffea arabica y Cecropia agustifolia seguidos de Mimosa, Fabaceae, Cordia, Mangifera indica y Acalypha.

Ante la necesidad de dotar a los docentes de Educación Física de herramientas que les permitan valorar con rigor el resultado de su trabajo en el ámbito socio-emocional, el presente trabajo expone el proceso de diseño y validación de un sistema de categorías para valorar las habilidades socio-emocionales de alumnado de primer ciclo de educación primaria de Educación Física, a través de la observación en situaciones de juego motor. Los resultados obtenidos tras el análisis lógico y empírico de los datos ponen de manifiesto la fiabilidad y estabilidad de las categorías propuestas. Además, se muestra todo el proceso como ejemplo para la elaboración de instrumentos de observación que sean útiles para medir competencias transversales en situaciones reales. En conclusión, a partir de la fundamentación teórica sobre la que se apoya el trabajo, y a la vista de los resultados obtenidos, el instrumento de observación presentado cumple con el objetivo de medir el desarrollo de la competencia socio-emocional a través de la detección de actitudes y comportamientos en un contexto educativo real.Abstract. Due to the need to provide tools to physical education teachers to assess rigorously the results of their work in the socio-emotional context, this paper presents the design process and validation of a system of categories for assessing socio skills emotional needs of students in early primary education, through direct observation in situations of motor game. The results obtained after the logical and empirical analysis of the data show the reliability and stability of the proposed categories. Moreover, the entire process is shown as an example for the development of recording instruments that are useful to measure generic skills in real situations. In conclusion, from the rationale on which the work is based, and in view of the results obtained, the observation instrument proposed complies with the aim of measuring the development of socio-emotional competence through detection of attitudes and behaviour in a real educational context.

This study explores the differences in unhappiness (self-reported unhappiness) and life satisfaction variables associated with age. A total of 2143 people from four age groups took part in the investigation: youth, adults, seniors and elderly people. Results reveal that seniors have a higher level of satisfaction with life and perceived happiness than young people. The results contradict the hypothesis of the relationship between development and happiness that associate material prosperity and life satisfaction; the data provided, however, show a young population that is unhappier than the older population.

Literature has reported 31 benefits obtained by companies after a successful JIT implementation. However, this research reduces the list by means of a data reduction technique to identify those essential benefits that must be pursued. The 31 benefits are integrated in a questionnaire that is administered to 144 production managers in maquiladoras in Mexico to measure the extent to which they are obtained according to respondents. One the one hand, a validation process and descriptive analysis are carried out for every benefit by considering their median values as a measure of central tendency and interquartile range values as a measure of dispersion. On the other hand, data reduction was achieved by means of a factor analysis based on principal components and varimax rotation. Four main factors related to JIT benefits are identified after the factor analysis, which explain 67.27 % of total variance of data. Identified factors concern inventory management, production process, human resources, and economic benefits.

Streptococcus pyogenes tonsillar infection is well known to trigger and exacerbate psoriasis lesions in both guttate and plaque forms of the disease. Although mucosal and cutaneous tissues are closely involved in psoriasis pathology, the interaction between their specific immune responses has not been deeply explored. This work aims to address and characterize the presence of humoral responses against S. pyogenes in patients with psoriasis and its putative association with cytokine responses detected in vitro in our psoriasis ex vivo model, based on the coculture of cutaneous lymphocyte-associated antigen+/- T cells with autologous epidermal cells. Patients with psoriasis presented increased IgA response to S. pyogenes when compared with control subjects. In patients with plaque psoriasis, despite being negative for anti-streptolysin O antibody titer, IgA plasma levels against S. pyogenes correlated with cutaneous lymphocyte-associated antigen+ T-cell-dependent IL-17F response in vitro. No association is observed for IgG levels in plaque psoriasis. Similar association is observed for IgA anti-S. pyogenes extract and IL-17A in patients with guttate psoriasis. We propose S. pyogenes-specific IgA as a potential new perspective for better understanding the role of S. pyogenes in psoriasis development.

Background:Autoantibodies to some post-translational modifications (PTMs) of proteins have a relevant role in rheumatoid arthritis (RA). Antibodies to other PMTs such as carbonylation (aCarbo) [1], nitration (aNitra) [2] and homocysteinylation (aHCis) [3] have also been described but they have been scarcely studied.Objectives:We aimed to evaluate the presence of antibodies against three poorly studied PTMs in patients with RA and explore their value as biomarkers.Methods:Serum samples from 196 healthy controls and RA patients meeting the 1987 ACR classification criteria that had either early RA (< 2 years from symptom onset) (n=182) or established RA (n=143) were analyzed. The antibodies were evaluated by indirect ELISA following the described protocols [1-3]. They include as antigens: HOCl- or ribose- carbonylated bovine type II collagen (HOCl-CII and GLI-CII, respectively) for aCarbo antibodies; homocysteinylated human serum albumin (Hcy-HSA) for aHCis antibodies; andin vitronitrated synovial proteins and synthetic nitrated peptides (3-NT-PS and 3-NT-pep, respectively) for aNitra antibodies. The efficiency of the reactions to produce these PTMs was verified. The study was approved by the CEIC of Galicia. The results were analyzed as differences between the optical densities (OD) obtained without correction, or the specific OD after subtracting reactivity to the native protein.Results:The aCarbo antibodies were studied in patients with early RA, as reported [1]. Despite this, uncorrected ODs against the two carbonylated forms of CII were not greater in the patients than in the controls (Table 1). Consequently, the corrected reactivity to GLI-CII that was significantly higher in patients than controls did not reflect aCarbo antibodies but differences in reactivity to native bovine CII.The other antibodies were analyzed in patients with established RA as previously done [2,3]. However, none of them showed specific reactivity (Table 1). In effect, although an excess of uncorrected reactivity to 3-NT-pep was observed in the patients with RA, it disappeared when corrected (Table 1). Also, the vast majority of patients and controls showed no reactivity to 3-NT-SP (not shown). In turn, the aHCis antibodies were significantly elevated in patients, but only in the uncorrected analysis because the difference disappeared when corrected for reactivity against native HSA (Table 1).Table 1.Antibodies against three post-translational protein modifications in RA patients and controlsRAControlsAntigenCorrectionMedian DOIQRMedian DOIQRPHOCl-CIIno0.1410.127/0.1730.1600.141/0.1880.0001HOCl-CIIyes-0.003-0.011/0.008-0.004-0.020/0.0050.02GLI-CIIno0.2340.171/0.2850.2220.163/0.3050.5GLI-CIIyes0.0720.016/0.1150.028-0.010/0.1000.00053-NT-pepno0.2500.201/0.3290.2090.190/0.2300.023-NT-pepyes0.1370.097/0.1850.1130.100/0.1330.1Hcy-HSAno0.1600.145/0.1780.1450.130/0.1550.00011Hcy-HSAyes-0.041-0.074/-0.015-0.038-0.069/-0.200.5Conclusion:The presence in RA patients of specific antibodies against the three PTMs has not been replicated. None of the observed reactivities were attributable to the PTMs. If confirmed, these results would indicate that only particular PTMs are relevant for RA and that carbonylation, nitration or homocysteinylation are not among them.References:[1]Strollo R, et al. Arthritis Rheum. 2013; 65:1702[2]Khan F, et al. Clin Chim Acta. 2006; 370:100[3]Nowakowska-Plaza A, et al. Scand J Rheumatol. 2014; 43:17Acknowledgments:Funded by the Instituto de Salud Carlos III projects PI17/01606 and RD16/0012/0014, which are partially co-funded by FEDERDisclosure of Interests:None declared

Nowadays, all companies are subject to new global trends related to smart manufacturing, connectivity, information technologies applications, big cloud-based data analysis, Cyber-Physical Systems, among others. These factors generate changes in the supply chain of manufacturing and service companies. According to literature reviewing, the applicable central model of the new trends, which allows these companies to face these changes, has been in continues movement. To understand the behavior of these trends, a documentary review related to Industry 4.0 and Smart Manufacturing as trends that outline the fourth industrial revolution, is facing through this work. As result of this review, the authors to develop holistically a semantic representation of the main terms of descriptive figures and graphs, some components and terminology related to Industry 4.0 and Smart Manufacturing. As main conclusion, this reached integrated view, aimed to establish a semantic guideline of the fourth industrial revolution that may be also applicable to the enterprise no matter its size.

Among other cells, macrophages regulate the inflammatory and reparative phases during wound healing but genetic determinants and detailed molecular pathways that modulate these processes are not fully elucidated. Here, we took advantage of normal variation in wound healing in 1,378 genetically outbred mice, and carried out macrophage RNA-sequencing profiling of mice with extreme wound healing phenotypes (i.e., slow and fast healers, n = 146 in total). The resulting macrophage coexpression networks were genetically mapped and led to the identification of a unique module under strong trans-acting genetic control by the Runx2 locus. This macrophage-mediated healing network was specifically enriched for cholesterol and fatty acid biosynthetic processes. Pharmacological blockage of fatty acid synthesis with cerulenin resulted in delayed wound healing in vivo, and increased macrophage infiltration in the wounded skin, suggesting the persistence of an unresolved inflammation. We show how naturally occurring sequence variation controls transcriptional networks in macrophages, which in turn regulate specific metabolic pathways that could be targeted in wound healing.

During the Aceramic Neolithic (PPN) period of the Near East, many economic and societal changes took place. During the PPNA is when we recognize a process of agglomeration of hundreds people in big sites such as Jericho. The archaeological record proves more than likely contacts between the contemporary societies of the Levant and some Eastern and Central Anatolian sites. The extent of those far contacts is hard to estimate, but we assume that such contacts and the trade network, which we can study mainly through the obsidian trade, using terrestrial and maritime routes, with the interaction of big villages though a few intermediary steps, already full operating at that time, must have helped to transform the local hierarchies, economic interdependences and rituals, and for instance it could accelerated the end of Gobekli Tepe around mid PPNB. And therefore during the Late PPNB consolidated the central villages, key nodes in the trade networks, and these, in different ecological regions, reached between 10 and 15 ha, v. gr. in Basta, Beisamoun or ‘Ain Ghazal. And in such a way, those built interdependent Ancient “World” Systems.

Oncogene-induced senescence (OIS) is a cellular response that limits the replication of cells expressing oncogenes. As a result, OIS is a potent tumor suppressor mechanism limiting cancer progression. Here we describe IMR90 ER:RAS, a widely used model to study OIS in cell culture. This model takes advantage of IMR90 human primary fibroblast infected with a 4-hydroxy-tamoxifen (4-OHT) inducible ER:RAS construct. RAS activation upon 4-OHT treatment results in a coordinated induction of senescence, recapitulating different aspects of the phenotype such as the growth arrest and the establishment of a senescence-associated secretory phenotype (SASP).

Oncogene-induced senescence (OIS) is a cellular response that limits the replication of cells expressing oncogenes. As a result, OIS is a potent tumor suppressor mechanism limiting cancer progression. Here we describe IMR90 ER:RAS, a widely used model to study OIS in cell culture. This model takes advantage of IMR90 human primary fibroblast infected with a 4-hydroxy-tamoxifen (4-OHT) inducible ER:RAS construct. RAS activation upon 4-OHT treatment results in a coordinated induction of senescence, recapitulating different aspects of the phenotype such as the growth arrest and the establishment of a senescence-associated secretory phenotype (SASP).

The effect of extracts, essential oil, and their major constituents from parsley (Petroselinum crispum (Mill.) Fuss.) against the phytopathogenic fungus Collectotrichum acutatum was evaluated by the poisoned agar method. Results showed that all extracts, along with the essential oil, significantly inhibit the radial growth of C. acutatum at concentrations higher than 100 μg mL-1. The higher activity was found for the essential oil followed by the n-hexane extract. Analysis by gas chromatography with mass spectroscopy (GC-MS) of n-hexane extract and the essential oil of P. crispum showed that the major components correspond to the phenylpropanoids myristicin and parsley-apiole. Both compounds were isolated by conventional chromatographic techniques and their structures elucidated by spectroscopicmethods. Myristicin and parsley-apiole displayed a significant inhibitory effect against C. acutatum. The highest fungistatic activity was found to parsley-apiole with IC50 value of 40 μg mL-1. In conclusion, parsley may be a good source of antifungal compounds to control C. acutatum. Se evaluó el efecto de extractos, el aceite esencial y los componentes principales del perejil (Petroselinum crispum (Mill.) Fuss.) contra el hongo fitopatógeno Collectotrichum acutatum mediante el método del agar envenenado. Los resultados mostraron que todos los extractos, junto con elaceite esencial, inhibieron significativamente el crecimiento radial de C. acutatum en concentraciones superiores a 100 μg mL-1. La mayor actividad se encontró para el aceite esencial, seguido por el extracto de n-hexano. El análisis por cromatografía de gases con espectroscopia de masas (CG-EM)del extracto de n-hexano y el aceite esencial de P. crispum mostró que los componentes principales corresponden a los fenilpropanoides miristicina y parsley-apiol. Ambos compuestos fueron aislaron por técnicas cromatográficas convencionales y sus estructuras elucidadas por métodos espectroscópicos. La miristicina y el parsley-apiol mostraron un efecto inhibidor significativo contra C. acutatum. La actividad fungistática más alta se encontró para parsley-apiol con un valor CI50 de 40 μg mL-1. Enconclusión, el perejil puede ser una buena fuente de compuestos antimicóticos para controlar el C. acutatum.

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP. Electronic supplementary material The online version of this article (10.1007/s00401-018-1830-2) contains supplementary material, which is available to authorized users.

Ensuring the fitness of the pluripotent cells that will contribute to future development is important both for the integrity of the germline and for proper embryogenesis. Consequently, it is becoming increasingly apparent that pluripotent cells can compare their fitness levels and signal the elimination of those cells that are less fit than their neighbours. In mammals the nature of the pathways that communicate fitness remain largely unknown. Here we identify that in the early mouse embryo and upon exit from naive pluripotency, the confrontation of cells with different fitness levels leads to an inhibition of mTOR signalling in the less fit cell type, causing its elimination. We show that during this process, p53 acts upstream of mTOR and is required to repress its activity. Finally, we demonstrate that during normal development around 35% of cells are eliminated by this pathway, highlighting the importance of this mechanism for embryonic development.

Cellular senescence is a highly stable cell cycle arrest that is elicited in response to different stresses. By imposing a growth arrest, senescence limits the replication of old or damaged cells. Besides exiting the cell cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement, or autophagy modulation. In addition, senescent cells produce and secrete a complex combination of factors, collectively referred as the senescence-associated secretory phenotype, that mediate most of their non–cell-autonomous effects. Because senescent cells influence the outcome of a variety of physiological and pathological processes, including cancer and age-related diseases, pro-senescent and anti-senescent therapies are actively being explored. In this Review, we discuss the mechanisms regulating different aspects of the senescence phenotype and their functional implications. This knowledge is essential to improve the identification and characterization of senescent cells in vivo and will help to develop rational strategies to modulate the senescence program for therapeutic benefit.

Esta investigación tiene como objetivo principal analizar el impacto de las barreras ala exportación en la capacidad de las empresas en adaptar su producto al comercio exterior. Se proponendos tipos de barreras genéricas, las barreras internas y las barreras externas. El planteamiento delproblema de investigación permite también analizar las relaciones entre las distintas barreras a laexportación. Mediante cuestionario se entrevista a una muestra estadísticamente significativa de lasempresas exportadoras del Brasil. El modelo causal propuesto se prueba a través de ecuacionesestructurales. Los resultados señalan que las barreras que más impactan en el proceso de exportaciónson las barreras internas. Se aportan implicaciones para la gestión de las organizaciones.