Connecting the dots: Melanoma cell of origin, tumor cell plasticity, trans-differentiation, and drug resistance.

Melanoma, a lethal malignancy that arises from melanocytes, exhibits a multiplicity of clinico-pathologically distinct subtypes in sun-exposed and non-sun-exposed areas. Melanocytes are derived from multipotent neural crest cells and are present in diverse anatomical locations, including skin, eyes, and various mucosal membranes. Tissue-resident melanocyte stem cells and melanocyte precursors contribute to melanocyte renewal. Elegant studies using mouse genetic models have shown that melanoma can arise from either melanocyte stem cells or differentiated pigment-producing melanocytes depending on a combination of tissue and anatomical site of origin and activation of oncogenic mutations (or overexpression) and/or the repression in expression or inactivating mutations in tumor suppressors. This variation raises the possibility that different subtypes of human melanomas (even subsets within each subtype) may also be a manifestation of malignancies of distinct cells of origin. Melanoma is known to exhibit phenotypic plasticity and trans-differentiation (defined as a tendency to differentiate into cell lineages other than the original lineage from which the tumor arose) along vascular and neural lineages. Additionally, stem cell-like properties such as pseudo-epithelial-to-mesenchymal (EMT-like) transition and expression of stem cell-related genes have also been associated with the development of melanoma drug resistance. Recent studies that employed reprogramming melanoma cells to induced pluripotent stem cells have uncovered potential relationships between melanoma plasticity, trans-differentiation, and drug resistance and implications for cell or origin of human cutaneous melanoma. This review provides a comprehensive summary of the current state of knowledge on melanoma cell of origin and the relationship between tumor cell plasticity and drug resistance.

Genetic diversity of medically important scorpions of the genus Centruroides (Buthidae) from Panama including two endemic species.

With more than 33,000 sting cases and 47 deaths recorded between 2000 and 2016, Panama is the country with the highest incidence of envenomations by scorpions in Central America. Species in the genus Centruroides are responsible for most scorpion sting reports, however, identification at the species level is complicated because the genus has considerable intraspecific morphological variation. To date no molecular data have been reported from Panama that would help to estimate their genetic diversity and validate morphometric identification methods. We provide here the first genetic diversity data of the two endemic species (C. granosus and C. panamensis) and other two species reported in Panama (C. bicolor and C. limbatus). A total of 41 specimens were sequenced for COI and 16S rDNA mitochondrial genes. The phylogenetic concatenated analysis separates the Panamanian samples into four well-supported clades represented by C. bicolor, C. granosus and (C. panamensis + C. limbatus). The two endemic species are not the closest relatives in the tree. Low diversity in combination with its very narrow distribution suggest that C. panamensis is susceptible to environmental degradation. A single specimen of Coiba island is intermediate in the tree structure between C. bicolor and C. panamensis and may represent an early stage of speciation. The haplotype network is also consistent with the phylogenetic trees.

EPAC Regulates Melanoma Growth by Stimulating mTORC1 Signaling and Loss of EPAC Signaling Dependence Correlates with Melanoma Progression.

Exchange proteins directly activated by cAMP (EPAC) belong to a family of RAP guanine nucleotide exchange factors (RAPGEF). EPAC1/2 (RAPGEF3/4) activates RAP1 and the alternative cAMP signaling pathway. We previously showed that the differential growth response of primary and metastatic melanoma cells to cAMP is mediated by EPAC. However, the mechanisms responsible for this differential response to EPAC signaling are not understood. In this study, we show that pharmacologic inhibition or siRNA-mediated knockdown of EPAC selectively inhibits the growth and survival of primary melanoma cells by downregulation of cell-cycle proteins and inhibiting the cell-cycle progression independent of ERK1/2 phosphorylation. EPAC inhibition results in upregulation of AKT phosphorylation but a downregulation of mTORC1 activity and its downstream effectors. We also show that EPAC regulates both glycolysis and oxidative phosphorylation, and production of mitochondrial reactive oxygen species, preferentially in primary melanoma cells. Employing a series of genetically matched primary and lymph node metastatic (LNM) melanoma cells, and distant organ metastatic melanoma cells, we show that the LNM and metastatic melanoma cells become progressively less responsive and refractory to EPAC inhibition suggesting loss of dependency on EPAC signaling correlates with melanoma progression. Analysis of The Cancer Genome Atlas dataset showed that lower RAPGEF3, RAPGEF4 mRNA expression in primary tumor is a predictor of better disease-free survival of patients diagnosed with primary melanoma suggesting that EPAC signaling facilitates tumor progression and EPAC is a useful prognostic marker. These data highlight EPAC signaling as a potential target for prevention of melanoma progression. IMPLICATIONS: This study establishes loss of dependency on EPAC-mTORC1 signaling as hallmark of primary melanoma evolution and targeting this escape mechanism is a promising strategy for metastatic melanoma.

Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes.

BRAFV600E is the most common mutation driver in melanoma. This mutation is known to cause a brief burst of proliferation followed by growth arrest and senescence, which prevent an uncontrolled cell proliferation. This phenomenon is known as oncogene-induced senescence (OIS) and OIS escape is thought to lead to melanomagenesis. Much attention has been focused on the melanocyte-intrinsic mechanisms that contribute to senescence escape. Additional genetic events such as the loss of tumor suppressor PTEN and/or epigenetic changes that contribute to senescence escape have been described. However, the role of the skin microenvironment-specifically, the role of epidermal keratinocytes-on melanomagenesis is not fully understood. In this study, we employ a microfluidic platform to study the interaction between melanocytes expressing the BRAFV600E mutation as well as keratinocytes and dermal fibroblasts. We demonstrate that keratinocytes suppress senescence-related genes and promote the proliferation of transformed melanocytes. We also show that a keratinocyte-conditioned medium can alter the secretion of both pro- and anti-tumorigenic factors by transformed melanocytes. In addition, we show that melanocytes and keratinocytes from donors of white European and black African ancestry display different crosstalks; i.e., white keratinocytes appear to promote a more pro-tumorigenic phenotype compared with black keratinocytes. These data suggest that keratinocytes exert their influence on melanomagenesis both by suppressing senescence-related genes in melanocytes and by affecting the balance of the melanocyte-secreted factors that favor tumorigenesis.

A flow-through microfluidic system for the detection of circulating melanoma cells.

We report the fabrication of polyaniline nanofiber (PANI)-modified screen-printed electrode (PANI/SPE) incorporated in a poly-dimethylsiloxane (PDMS) microfluidic channel for the detection of circulating tumor cells. We employed this device to detect melanoma skin cancer cells through specific immunogenic binding of cell surface biomarker melanocortin 1 receptor (MC1R) to anti-MC1R antibody. The antibody-functionalized PANI/SPE was used in batch-continuous flow-through fashion. An aqueous cell suspension of ferri/ferrocyanide at a flow rate of 1.5 mL/min was passed over the immunosensor, which allowed for continuous electrochemical measurements. The sensor performed exceptionally well affording an ultralow limit of quantification of 1 melanoma cell/mL, both in buffer and when mixed with peripheral blood mononuclear cells, and the response was log-linear over the range of 10-9000 melanoma cells/10 mL.

Melanoma Progression Inhibits Pluripotency and Differentiation of Melanoma-Derived iPSCs Produces Cells with Neural-like Mixed Dysplastic Phenotype.

Melanomas are known to exhibit phenotypic plasticity. However, the role cellular plasticity plays in melanoma tumor progression and drug resistance is not fully understood. Here, we used reprogramming of melanocytes and melanoma cells to induced pluripotent stem cell (iPSCs) to investigate the relationship between cellular plasticity and melanoma progression and mitogen-activated protein kinase (MAPK) inhibitor resistance. We found that melanocyte reprogramming is prevented by the expression of oncogenic BRAF, and in melanoma cells harboring oncogenic BRAF and sensitive to MAPK inhibitors, reprogramming can be restored by inhibition of the activated oncogenic pathway. Our data also suggest that melanoma tumor progression acts as a barrier to reprogramming. Under conditions that promote melanocytic differentiation of fibroblast- and melanocyte-derived iPSCs, melanoma-derived iPSCs exhibited neural cell-like dysplasia and increased MAPK inhibitor resistance. These data suggest that iPSC-like reprogramming and drug resistance of differentiated cells can serve as a model to understand melanoma cell plasticity-dependent mechanisms in recurrence of aggressive drug-resistant melanoma.

Biomarcadores en la medición del estrés: una revisión sistemática / Biomarkers in stress measurement: A systematic review

INTRODUCCIÓN Y OBJETIVOS: Existe un amplio consenso en la comunidad científica en relación con la posibilidad de evaluar el estrés a través de marcadores biológicos asociados a los principales sistemas regulatorios de este proceso: el simpático adrenomedular (SAM), el hipotalámico-hipófiso-adrenal (HHA) y el sistema inmunológico. Sin embargo, persisten interrogantes en relación con el uso de biomarcadores: a)¿Cuáles son los biomarcadores de estrés más utilizados? b)¿Qué técnicas son recomendables para la determinación de los mismos? c)¿A partir de qué muestras biológicas es aconsejable cuantificarlos? El presente artículo tiene como objetivo efectuar una revisión sistemática de la literatura especializada con el fin de analizar dichos interrogantes. MATERIALES Y MÉTODOS: Se efectuó una revisión sistemática en diferentes bases de datos (Pubmed, PMC y MEDLINE), considerando artículos de los últimos 10años. Se identificaron 710 estudios que fueron sometidos al proceso de selección, 33 de los cuales se incluyeron finalmente en la revisión. RESULTADOS Y CONCLUSIONES: Se han publicado numerosas revisiones que buscan establecer un vínculo entre biomarcadores y diferentes problemas asociados al estrés. Si bien los resultados son prometedores, el campo se enfrenta con importantes desafíos, como, por ejemplo, encontrar consenso en la definición de las mejores prácticas para el uso de biomarcadores. A partir de la presente revisión podemos concluir que los biomarcadores predominantemente utilizados para determinar la activación del eje SAM son el ritmo cardíaco y la presión sanguínea; en cuanto al eje HHA, el cortisol ha sido el marcador biológico más comúnmente medido tanto en sangre como en saliva y en cabello. Finalmente, en lo referente a marcadores representativos de la activación del sistema inmune debido a estrés, la IL-6 y la PCR fueron las más frecuentemente analizadas

INTRODUCTION AND OBJECTIVES: There is a broad consensus in the scientific community regarding the possibility of evaluating stress through biological markers associated with the main regulatory systems of this process -the Sympathetic Medullary Adreno (SAM), the Hypothalamic Hypophysial Adrenal (HHA) and the immune systems. However, questions remain regarding the use of biomarkers: a) Which are the most commonly used stress biomarkers? b) Which techniques are recommended for their determination? c) From which biological samples is it advisable to quantify them? The aim of this article is to carry out a systematic review of the specialised literature in order to analyse these questions. MATERIALS AND METHODS: a systematic review was carried out in different databases (Pubmed, PMC and MEDLINE), considering articles from the last ten years. We identified 710 studies that underwent the selection process, 33 of which were finally included in the review. RESULTS AND CONCLUSIONS: To date, numerous reviews have been published with the aim of establishing a link between biomarkers and different problems associated with stress. Although the results are promising, the field faces important challenges such as, for example, finding consensus on the definition of best practices for the use of biomarkers. From the present review we can conclude that the biomarkers predominantly used to determine the activation of the SAM axis are heart rate and blood pressure; as for the HHA axis, cortisol has been the biological marker most commonly measured in blood, saliva or hair. Finally, regarding representative markers of immune system activation due to stress, IL-6 and PCR were the most frequently analysed

Between food delicacies and food taboos: A structural equation model to assess Western students' acceptance of Amazonian insect food.

Interest in commercializing insect-based foods is growing steadily. Nevertheless, most Western consumers still consider insects a food taboo. In this study, we investigated how persuasion strategies based on technology and social communication can intervene to reduce aversion towards the practice of eating a tropical insect from the Ecuadorian Amazon. We used a research design based on ethnoentomological information to place the insect-based food in its cultural context. The study is based on an online survey of 125 students from an international university based in a cross-border region of the Italian Alps. We used a covariance-based structural equation model to test the influence of the 6-item version of the Food Neophobia Scale and of the aforementioned persuasion strategies on stated willingness to consume insects. Results show that food neophobia negatively affects persuasion strategies but that the latter do have a positive influence on stated consumption intention. Additionally, the model shows that the negative effect of Food Neophobia Scale on the willingness to consume insects is fully mediated by persuasion strategies. Our findings are in line with previous studies which indicate that peers' recommendations on the safety and palatability of edible insects, as well as the practice of disguising them in familiar food, increase the stated willingness to consume them. Moreover, the importance of the commercial context where the insects are sold is a driver of entomophagous practices. Finally, our study suggests that the introduction of contextual cultural information about insects as a food source may help to preclude a priori false assumptions regarding entomophagy. This is also one of the aims of Regulation (EU) 2015/2283 on insects as novel food which recently came into force. We discuss the implications of the findings for both scholars and practitioners.

Desarrollo y validación del Test de Ansiedad Social para estudiantes universitarios (TAS-U) / Development and validation of the Social Anxiety Test in university students (SAT-U)

El estudio de la ansiedad social en estudiantes universitarios ha cobrado una especial relevancia considerando sus implicancias en el ajuste social y el bienestar psicológico de quienes la presentan. A pesar de ello, no existen instrumentos de evaluación que estén dirigidos específicamente a esta población, quienes cotidianamente se enfrentan a situaciones particulares que pueden ser potencialmente generadoras de ansiedad. Se presenta el Test de Ansiedad Social para estudiantes universitarios (TAS-U) aportando evidencias de validez y confiabilidad. Se diseñaron 68 ítems preliminares teniendo en cuenta literatura, escalas de antecedentes y consultas con expertos. Utilizando muestreo no probabilístico, se realizaron análisis factoriales exploratorios y confirmatorios de una muestra de estudiantes universitarios argentinos. Se obtuvo una escala final compuesta por 27 ítems distribuidos en cuatro factores (CFI = .95, TLI = .95, RMSEA = .063 y WRMR = 1.19). Sobre la consistencia interna de la escala, los coeficientes alfa de Cronbach y de fiabilidad compuesta fueron buenos y excelentes para cada factor. Las dimensiones son coincidentes con factores evidenciados en estudios de otras escalas similares y con postulados teóricos conceptuales sobre ansiedad social.

The study of social anxiety in college students has gained particular importance if we consider its role in their social adjustment and psychological well-being. Despite this, there are no assessment tools that are specifically aimed at this population, which face events that can potentially generate anxiety on a daily basis. The Social Anxiety Test for University students (SAT-U) is presented herein with evidence of validity and reliability. Sixty-eight (68) preliminary items were designed taking into account the current literature, previous scales and consultation with experts. By using a non-probabilistic sampling, exploratory and confirmatory factorial analyses were performed in a sample of Argentinian college students. A final scale was obtained with 27 items distributed in four factors (CFI = .95, TLI = .95, RMSEA = .063 and WRMR = 1.19). Regarding the internal consistency of the scale, Cronbach's alpha coefficients and the coefficient of composite reliability were good and excellent for each factor. The dimensions coincide with factors seen in studies with other similar scales, and with conceptual and theoretical postulates about social anxiety.

Emotional-evolutional model of social anxiety in university students

Studies of social anxiety in university students have become of particular importance given its disabling impact over social adjustment and psychological well-being. The present research had the objective of developing an explanatory model of this phenomenon with principles based on attachment theory and the theories of emotional regulation. We worked with a sample of 438 university students and structural equation modeling (SEM) was used for data analysis. We produced an explanatory model which presented appropriate adjustment indexes (CFI= .95; GFI= .95; RMSEA= .05). In this model, the predictive role of expectations of social rejection and the difficulties in emotion regulation in the aetiology of social anxiety are clear. These factors are in turn influenced by the fear of abandonment linked to internal working models of insecure attachment of development in early childhood. Significant differences were found in favour of women in percentages of variance explained in social anxiety and expectations of social rejection

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Normal y lognormal: dos distribuciones de frecuencias y una Teoría Neutral Unificada para estudiar los bosques tropicales / Normal, and lognormal: two frequency distributions, and one Unified Neutral Theory for studying Tropical forests

Los inventarios de biodiversidad en sitios contrastantes obtienen datos con distribuciones normales y lognormales, útiles para cuantificar cómo el cambio climático afecta a los bosques del mundo. Sin embargo, casi todos los biólogos están familiarizados con la normal, pero menos discuten el por qué la distribución lognormal de frecuencias relativas de especies ocurre en tantas comunidades bióticas. Pretendemos incorporar a más estudiosos a dicha discusión. Tanto la normal como la lognormal tienen medias y valores extremos. Ello es consistente con el teorema del límite central; válido cuando los datos de un muestreo provienen de procesos aleatorios y el muestreo ha sido estocástico y representativo. Según la Teoría Neutral Unificada de la Biodiversidad y la Biogeografía de Steve Hubbell, basta considerar que la natalidad, mortalidad, migraciones y especiación en una comunidad, y desde la metacomunidad circundante, ocurren al azar y simétricamente entre especies, para explicar que las frecuencias relativas de la comunidad sigan una distribución lognormal. Ello es consistente con la Biogeografía de Islas, y se puede aplicar -por tanto a la articulación de abundancias relativas de especies arbóreas en bosques que se regeneran por sucesión secundaria, donde el sitio talado constituye una isla que luego es colonizada. En el sofisticado siglo XXI, conocimientos numéricos tan simples, como la normal y la lognormal, siguen siendo necesarios para mover las fronteras de la ciencia afrontando temas permanentes: por qué en tantos lugares hay especies más abundantes que otras, y cómo se puede contrarrestar la pérdida de las especies en dificultad.

Biodiversity surveys among contrasting sites get normal, and lognormal distributed data used for quantifying how Climate Change affects forests around the world. Yet most biologists are familiarized with the normal distribution, while few discuss why the lognormal distribution of relative frequencies of species is so common in many communities of living beings. We aim to add more researchers into such a discussion. Both normal and lognormal have mean and extreme values -which is consistent with the Central Limit Theorem. Such a theorem is valid when the data come from random processes, and when the sampling excercise of collecting the data has been stocastic and representative. According to Steve Hubbell's Unified Neutral Theory of Biodiversity and Biogeography, random birth, death, migration and speciation in a community -and from the surrounding metacomunity are enough for generating lognormal distributions of relative frequencies of co-existing species. That is consistent with Island Biogography, and is applicable to the assembly of relative abundances of tree species during secondary succession, where the clear-cut site is an island further colonized by tree species. Deep into the sophisticated 21st century, simple numerical knowledge like the normal and lognormal are still needed for moving the borders of science by facing permanent subjects: why in so many places some species are more abundant than others, and how to tackle the loss of endangered species.

Elevated cyclic AMP levels promote BRAFCA/Pten-/- mouse melanoma growth but pCREB is negatively correlated with human melanoma progression.

Melanocyte development and differentiation are regulated by cAMP, which is produced by the adenylate cyclase (AC) enzyme upon activation of the melanocortin-1-receptor (MC1R). Individuals carrying single amino acid substitution variants of MC1R have impaired cAMP signaling and higher risk of melanoma. However, the contribution of AC to this risk is not clear. Downstream of AC, the phosphorylated transcription factor, cyclic AMP Responsive Element Binding Protein (pCREB), which is activated by protein kinase A, regulates the expression of several genes including the melanocyte master regulator MITF. The roles of AC and CREB in melanoma development and growth are not well understood. Here, we investigated the effect of topical application of AC inhibitor on BrafCA/Pten-/- mouse melanoma development. We show that AC inhibitor delays melanoma growth independent of MAPK pathway activity and melanin content. Next, employing a primary melanoma tissue microarray and quantitative immunohistochemistry, we show that pCREB levels are positively correlated with the proliferative status of melanoma, but low pCREB expression is associated with tumor aggressiveness and metastatic recurrence. These data suggest that low cAMP signaling inhibits tumor growth but is a predictor of melanoma aggressiveness.

Escala de Identificação de Dotação e Talento: Estrutura e Consistência Internas / Scale of Giftedness and Talent Identification: Internal Structural and Consistency / Escala de Identificación de Dotación y Talento: Estructura y Consistencia Internas

O estudo objetivou analisar a precisão e as evidências de validade com base na estrutura interna da Escala de Identificação de Dotação e Talento (EIDT). A EIDT é respondida por docentes dos 4º, 5º e 6º anos do Ensino Fundamental, sendo que participaram da pesquisa 16 professores, que avaliaram 433 alunos. Os resultados indicaram que 54,8% da variância foi explicada. Por meio da análise fatorial exploratória, a versão final da escala ficou composta por 55 itens divididos em três fatores: 42 itens do Fator 1, capacidades intelectuais, sociais e criatividade; sete do Fator 2, capacidades psicomotoras e seis do Fator 3, capacidades artísticas. O alfa de Cronbach para a escala total foi de 0,97. O Fator 1 apresentou um alfa de 0,97, o Fator 2 de 0,89 e o Fator 3 de 0,83. Destaca-se a necessidade de estudos adicionais que incluam a análise fatorial confirmatória e o estabelecimento de normas.(AU)

The study aimed to analyze the reliability and the evidences of validity based on the internal structure of the Scale of Giftedness and Talent Identification (Escala de Identificação de Dotação e Talento - EIDT). The EIDT is answered by teachers of 4th, 5th and 6th years of elementary school, including 16 teachers who evaluated 433 students. The results indicated that 54.8% of the variance was explained. Exploratory factor analysis was used for the final version of the scale, which was composed of 55 items divided into three factors: 42 items in Factor 1, intellectual abilities, social abilities and creativity; seven in factor 2, psychomotor abilities and six in factor 3, artistic abilities. The Cronbach's alpha for the total scale was 0.97. Factor 1 showed an alpha of 0.97, factor 2 of 0.89, and factor 3 of 0.83. It highlights the need for additional studies including the confirmatory factor analysis and the establishment of standards.(AU)

El objetivo del estudio fue analizar precisión y evidencias de validez basadas en la estructura interna de la Escala de Identificación de Dotación y Talento (EIDT). La EIDT fue respondida por maestros de 4º, 5º y 6º año de Enseñanza Primaria, y participaron en la investigación 16 profesores que evaluaron a 433 alumnos. Los resultados indicaron que el 54,8% de la varianza fue explicada. Por medio de análisis factorial exploratorio, la versión final de la escala quedó compuesta por 55 ítems, divididos en tres factores: 42 ítems del factor 1, capacidades intelectuales, sociales y creatividad; 7 ítems del factor 2, capacidades psicomotoras y 6 del factor 3, capacidades artísticas. El alfa de Cronbach para la escala total fue de 0,97. El factor 1 presentó un alfa de 0,97, el factor 2 de 0,89 y el factor 3 de 0,83. Se destaca la necesidad de estudios adicionales, que incluyan el análisis factorial confirmatorio y el establecimiento de normas.(AU)

EPAC-RAP1 Axis-Mediated Switch in the Response of Primary and Metastatic Melanoma to Cyclic AMP.

Cyclic AMP (cAMP) is an important second messenger that regulates a wide range of physiologic processes. In mammalian cutaneous melanocytes, cAMP-mediated signaling pathways activated by G-protein-coupled receptors (GPCR), like melanocortin 1 receptor (MC1R), play critical roles in melanocyte homeostasis including cell survival, proliferation, and pigment synthesis. Impaired cAMP signaling is associated with increased risk of cutaneous melanoma. Although mutations in MAPK pathway components are the most frequent oncogenic drivers of melanoma, the role of cAMP in melanoma is not well understood. Here, using the Braf(V600E)/Pten-null mouse model of melanoma, topical application of an adenylate cyclase agonist, forskolin (a cAMP inducer), accelerated melanoma tumor development in vivo and stimulated the proliferation of mouse and human primary melanoma cells, but not human metastatic melanoma cells in vitro The differential response of primary and metastatic melanoma cells was also evident upon pharmacologic inhibition of the cAMP effector protein kinase A. Pharmacologic inhibition and siRNA-mediated knockdown of other cAMP signaling pathway components showed that EPAC-RAP1 axis, an alternative cAMP signaling pathway, mediates the switch in response of primary and metastatic melanoma cells to cAMP. Evaluation of pERK levels revealed that this phenotypic switch was not correlated with changes in MAPK pathway activity. Although cAMP elevation did not alter the sensitivity of metastatic melanoma cells to BRAF(V600E) and MEK inhibitors, the EPAC-RAP1 axis appears to contribute to resistance to MAPK pathway inhibition. These data reveal a MAPK pathway-independent switch in response to cAMP signaling during melanoma progression.Implications: The prosurvival mechanism involving the cAMP-EPAC-RAP1 signaling pathway suggest the potential for new targeted therapies in melanoma. Mol Cancer Res; 15(12); 1792-802. ©2017 AACR.

Identification and Characterization of the V(D)J Recombination Activating Gene 1 in Long-Term Memory of Context Fear Conditioning.

An increasing body of evidence suggests that mechanisms related to the introduction and repair of DNA double strand breaks (DSBs) may be associated with long-term memory (LTM) processes. Previous studies from our group suggested that factors known to function in DNA recombination/repair machineries, such as DNA ligases, polymerases, and DNA endonucleases, play a role in LTM. Here we report data using C57BL/6 mice showing that the V(D)J recombination-activating gene 1 (RAG1), which encodes a factor that introduces DSBs in immunoglobulin and T-cell receptor genes, is induced in the amygdala, but not in the hippocampus, after context fear conditioning. Amygdalar induction of RAG1 mRNA, measured by real-time PCR, was not observed in context-only or shock-only controls, suggesting that the context fear conditioning response is related to associative learning processes. Furthermore, double immunofluorescence studies demonstrated the neuronal localization of RAG1 protein in amygdalar sections prepared after perfusion and fixation. In functional studies, intra-amygdalar injections of RAG1 gapmer antisense oligonucleotides, given 1 h prior to conditioning, resulted in amygdalar knockdown of RAG1 mRNA and a significant impairment in LTM, tested 24 h after training. Overall, these findings suggest that the V(D)J recombination-activating gene 1, RAG1, may play a role in LTM consolidation.

Measuring Threats, Benefits, Emotional Costs and Avoidance of Academic Help-Seeking in Argentinian University Students / Evaluación de amenazas, beneficios, costos emocionales y evitación de la búsqueda de ayuda académica en estudiantes universitarios argentinos / Avaliação de ameaças, benefícios, custos emocionais e evitação da procura de ajuda académica em estudantes universitários argentinos

Objective. The psychometric properties of four academic help-seeking scales measuring benefits, threats, emotional costs and avoidance of academic help-seeking in two samples of Argentinian university students were tested. Method. In phase one, a three correlated-factors measurement model (benefits, threats, emotional costs) and a one-factor model (avoidance) were evaluated. In phase two, two models where social academic self-efficacy (SAS), task value and achievement goals would predict the help-seeking constructs which, in turn, would predict shame in class were evaluated. Results. In phase one, the confirmatory factor analysis strongly supported the models, and all of the factor loadings were high. In phase two, on the one hand, SAS predicted benefits, threats and emotional costs. Moreover, threats and emotional costs predicted shame. Even more, SAS predicted shame via its effects on threats and emotional costs. On the other hand, SAS, task value, and performance-approach predicted avoidance. Moreover, avoidance and SAS had a direct effect on shame. The benefits, threats, emotional costs, and avoidance scales demonstrated adequate levels of internal consistency (α = 0.85, 0.72, 0.90, and 0.90). Conclusion. The scales are reliable, internally valid as demonstrated by the factor analyses, and externally valid in terms of relationships with motivational and emotional constructs.

Objetivo. Se evaluaron las propiedades psicométricas de cuatro escalas de búsqueda de ayuda académica que miden beneficios, amenazas, costos emocionales y evitación de la búsqueda de ayuda académica en dos muestras de estudiantes universitarios argentinos. Método. En la fase uno se evaluó un modelo de medición con tres factores relacionados (beneficios, amenazas, costos emocionales) y un modelo unidimensional (evitación). En la fase dos se evaluaron dos modelos donde autoeficacia social académica (ASA), valor de la tarea y metas de logro predecirían los constructos de búsqueda de ayuda, los cuales predecirían la vergüenza en clase. Resultados. Los análisis factorial confirmatorios, realizados en la fase uno apoyaron los modelos, con elevadas cargas factoriales. En la fase dos, se encontró que ASA predijo beneficios, amenazas y costos emocionales. Adicionalmente, amenazas y costos emocionales predijeron vergüenza. Incluso, ASA predijo vergüenza, vía sus efectos en amenazas y costos emocionales. Por otro lado, ASA, valor de la tarea y aproximación-rendimiento predijeron evitación. Además, evitación y ASA tuvieron un efecto directo sobre vergüenza. Las escalas de beneficios, amenazas, costos emocionales y evitación demostraron niveles adecuados de consistencia interna (α = 0.85, 0.72, 0.90 y 0.90). Conclusión. Las escalas son confiables, válidas internamente como demostraron los análisis factoriales, y válidas externamente en términos de relaciones con constructos motivacionales y emocionales.

Escopo. Foram avaliadas as propriedades psicométricas de quatro escadas de procura de ajuda académica que medem benefícios, ameaças, custos emocionais e evitação da procura de ajuda académica em duas amostras de estudantes universitários argentinos. Metodologia. Fase um: foi avaliado um modelo de medição com três fatores relacionados (benefícios, ameaças, custos emocionais) e um modelo unidimensional (evitação). Fase dois: foram avaliados dois modelos onde autoeficácia social académica (asa), valor da tarefa e metas de logro poderiam predizer os construtos de procura de ajuda, os quais poderiam predizer a vergonha na aula. Resultados. Fase um: Análises fatoriais confirmatórios apoiaram os modelos, com elevadas cargas fatoriais. Fase dois. Por um lado, asa previu benefícios, ameaças e custos emocionais. Adicionalmente, ameaças e custos emocionais predisseram vergonha. Mesmo, asa previu vergonha, via seus efeitos em ameaças e custos emocionais. Por outro lado, asa, valor de tarefa e aproximação-rendimento previram evitação. Além, evitação e asa tiveram um efeito direito sobre vergonha. As escadas de benefícios, ameaças, custos emocionais e evitação demostraram níveis adequados de consistência interna (α = 0.85, 0.72, 0.90 y 0.90). Conclusão. As escadas são confiáveis, válidas internamente como demostraram análises fatoriais, e válidas externamente em términos de relações com construtos motivacionais e emocionais.

Adaptación de la Escala de Afrontamiento ante la ansiedad e incertidumbre pre-examen: (COPEAU) / Adaptation of the coping with pre-exams anxiety and uncertainty scale: (COPEAU)

En esta investigación se adaptó la escala de afrontamiento ante la ansiedad e incertidumbre pre-exámenses (COPEAU) para su empleo en estudiantes universitarios argentinos. El COPEAU (Stõber, 2004) es un autoinforme compuesto de 21 items, agrupados en tres escalas: afrontamiento orientado al problema, búsqueda de apoyo social y evitácion. Se tradujeron los items del inglés al español con el método de traducción directa y la versión en español fue administrada a 294 estudiantes de diferentes carreras de la Universidad Nacional de Córdoba, Argentina. El Análisis Factorial Exploratorio permitió obtener dos soluciones factoriales alternativas, ambas parcialmente apoyadas por los datos. Una de las soluciones conserva la estructura original de tres factores, mientras que la otra posee una estructura interna de cuatro factores que diferencia al apoyo social en dos categorías: emocional e instrumental, congruentes también con la teoria de base. Aunque las escalas presentaron buenos niveles de consistencia interna en ambas soluciones se optó por la estructura de tres factores , más congruente con la propuesta original del autor del instrumento. También se analizaron evidencias externas de validez del COPEAU en relación a género y rendimiento académico

A Coping with Pre-exams Anxiety and Uncertainly Measure (COPEAU) has been adapted to be used on Argentinean university students. COPEAU (Stõber, 2004) is a self-report consisting of 21 items grouped into three scales: problem oriented coping, social support seeking, and avoidance. The items were translated from English to Spanish and the Spanish version was administered to a two hundred and ninety-four student from different careers in the Nacional University of Cordoba, Argentina. Factor Analysis supported two alternative solutions. One preserved the original three-factor structure , the other one showed a four-factor structure, differentiating two categories in the social support scale: emotional and instrumental, both congruent with coping theory. Though both solutions showed good internal consistency levels, the three-factor structure was chosen for being closer to the instrument's author proposal. Aditionally, external validity evidences related to gender and academic performance were analyzed

Adaptación de la escala de afrontamiento ante la ansiedad e incertidumbre pre-examen (COPEAU) / Adaptation of the coping with pre-exams anxiety and uncertainty scale (COPEAU)

En esta investigación se adaptó la escala de afrontamiento ante la ansiedad e incertidumbre pre-exámenses (COPEAU) para su empleo en estudiantes universitarios argentinos. El COPEAU (Stöber, 2004) es un autoinforme compuesto de 21 items, agrupados en tres escalas: afrontamiento orientado al problema, búsqueda de apoyo social y evitácion. Se tradujeron los items del inglés al español con el método de traducción directa y la versión en español fue administrada a 294 estudiantes de diferentes carreras de la Universidad Nacional de Córdoba, Argentina. El Análisis Factorial Exploratorio permitió obtener dos soluciones factoriales alternativas, ambas parcialmente apoyadas por los datos. Una de las soluciones conserva la estructura original de tres factores, mientras que la otra posee una estructura interna de cuatro factores que diferencia al apoyo social en dos categorías: emocional e instrumental, congruentes también con la teoria de base. Aunque las escalas presentaron buenos niveles de consistencia interna en ambas soluciones se optó por la estructura de tres factores , más congruente con la propuesta original del autor del instrumento. También se analizaron evidencias externas de validez del COPEAU en relación a género y rendimiento académico (AU)

A Coping with Pre-exams Anxiety and Uncertainly Measure (COPEAU) has been adapted to be used on Argentinean university students. COPEAU (Stöber, 2004) is a self-report consisting of 21 items grouped into three scales: problem oriented coping, social support seeking, and avoidance. The items were translated from English to Spanish and the Spanish version was administered to a two hundred and ninety-four student from different careers in the Nacional University of Cordoba, Argentina. Factor Analysis supported two alternative solutions. One preserved the original three-factor structure , the other one showed a four-factor structure, differentiating two categories in the social support scale: emotional and instrumental, both congruent with coping theory. Though both solutions showed good internal consistency levels, the three-factor structure was chosen for being closer to the instrument's author proposal. Aditionally, external validity evidences related to gender and academic performance were analyzed (AU)

Validación del inventario de autoeficacia para inteligencias múltiples revisado (IAMI-R) / Validation of the multiple intelligence self-efficacy interventory revised (MISEI-R)

En este trabajo se describe el proceso de validación preliminar de una versión revisada del Inventario de Autoeficacia para Inteligencias Múltiples, el IAMI-R. Este instrumento fue construido con la finalidad de evaluar la autoeficacia de los adolescentes para realizar actividades académicas relacionadas con las inteligencias múltiples, en un contexto de desarrollo decarrera. El IAMI-R fue administrado a una muestra de estudiantes del nivel educativo polimodal en Argentina. Se realizaron estudios psicométricos para analizar la estructura factorial (mediante análisis factorial exploratorio y confirmatorio) y la consistencia interna de sus escalas. Losresultados obtenidos, junto con otros recientemente presentados, demuestran que las escalas del IAMI-R poseen propiedades psicométricas aceptables de consistencia interna y validez deconstrucción. Estudios futuros deberían investigar la estabilidad de sus escalas así como aspectos relacionados con la validez de criterio del IAMI-R.

This work describes the process of initial validation of a revised version of the Multiple Intelligences Self-Efficacy Inventory (IAMI-R). This instrument was created to assess adolescent´s self-efficacy in relationship with academic activities associated with the multiple intelligences, in a context of career development. The IAMI-R was administered to a sample of high school students, in the city of Córdoba, Argentina. Psychometric studies analyzing the factorial structure (through exploratory and confirmatory factor analysis) and internal consistencyof their scales were accomplished. The results of this study, beside others recently presented, show that the IAMI-R scales possess satisfactory properties of construct validity and internal consistency. Subsequent phases of this research will include analysis of the instrument´s stability and criterion validity.