Developing new models of childhood malignancies using human induced pluripotent stem cells

Early onset diseases such as childhood malignancies and neurodevelopmental disorders have been intricate to study. For many years, research has relied and dependent upon different animal systems. Despite the usefulness of these systems, which have allowed the understanding of the biology behind these processes, the differences between species are still an undoubted fact. The emergence of induced pluripotent stem (iPS) cell technology has indeed opened new venues for many fields including disease modeling, personalized cell therapy, and drug screening. iPS cells have the potential to virtually differentiate into any cell type, hence becoming an unlimited source of disease-relevant cell types. Here, we present examples demonstrating the potential of disease modeling using patient-derived iPS cells. Neuroblastoma (NB) and Medulloblastoma (MB) are both cancers linked to dysregulations in pathways important during human development. Whereas NB develops during the peripheral nervous system (PNS) development, MB initiates during central nervous system (CNS) development. We have taken advantage of the early developmental signature of iPS cells to model cancer. We used non-cancerous cells from patients carrying germline mutations in cancer predisposing genes, ALK and PTCH1, and developed in vivo models that offer a unique understanding of cancer initiation and progression. NB patients carrying an ALK germline mutation were used to generate iPS cells (Paper I) and subsequent differentiation to Neural Crest Cells (NCC) was performed (Paper II, III). For this, a NCC generation protocol was optimized using intermediate levels of BMP (Paper II). Next, labelled NCC from patients and controls were orthotopically transplantated into the adrenal gland of immunodeficient mice (Paper III). Mice were followed in vivo using IVIS system, and we detected increased luciferase signal after more than 8 weeks but no signal was observed in mice injected with control NCC. After a year, adrenal glands from mice were harvested and one case of ganglioneuroblastoma was diagnosed, suggesting a low penetrance and mild phenotype of ALK contribution in NB initiation. Using a similar workflow, we generated Neuroepithelial stem (NES) cells from iPS cells derived from Gorlin syndrome patients. Gorlin patients carry germline mutations in PTCH1. Mutations in PTCH1 constitutively activate the Sonic Hedgehog (SHH) signalling pathway. In vivo transplantation of patient cells into the cerebellum of immunocompromised mice showed faithful resemblance of human SHH MB. By establishing NES cell cultures derived from MB tumors in the mice cerebellum, we could show the potential use of this model for identifying new targets for cancer treatment (Paper IV).b Moreover, we exploited 2D and 3D human in vitro systems derived from iPS cells to study the role of p53 during early brain development. We show that p53 has an important function in maintaining the appropriate structure of human brain organoids. Moreover, we demonstrate that p53 maintains genomic instability and primes neural differentiation in human NES cells. Thus, revealing the role of p53 in a human in vitro context of brain development (Paper V). In summary our work presents the big potential of iPS cell technology in the field of modeling disease

Uninhabited territories: contemporary strategies to recover and preserve abandoned settlements and their areas of influence in Altoaragon

[EN] The late but accelerated industrialization of our country in the early 1900’s resulted in a polarization of the population movements: while certain cities increased exponentially their number of inhabitants, an important percentage of the territory gradually experienced a consequent depopulation. Whereas the effects of the former phenomenon in the cities have been deeply examined, the impact of the latter in the territory is a relatively unexplored subject, thus full of possibilities. In some areas, the rural exodus was so sudden that the development of their pre-industrial residential schemes froze-up and, thus, the high-value cultural landscape that they take part in remained almost unaltered until today. Most of these abandoned settlements had an intense and balanced relationship with their surroundings. Their location, morphology and the links among them were built upon an environmental friendly and resource efficient basis. This study will focus on the sustainable anthropization of the territory that was performed by these villages, in order to value them as intangible assets and to identify the most feasible strategies to their recovery. As case study, in Altoaragon, we can find no less than 150 abandoned settlements and, in the same territory, almost 30 villages that have been recovered in the last 30 years. Through a comparative study of the latter, we seek to develop generic strategies to help identify, among the former, those settlements or abandoned areas with more potential, and to draw the basic guidelines to restore and protect the pre-industrial stage as a whole.Marin, S.; Navarro, A. (2018). Uninhabited territories: contemporary strategies to recover and preserve abandoned settlements and their areas of influence in Altoaragon. En 24th ISUF International Conference. Book of Papers. Editorial Universitat Politècnica de València. 75-86. https://doi.org/10.4995/ISUF2017.2017.6080OCS758

Cultural alterity within companies. Overviews regarding the intercultural competences in the workplace

Globalisation has given rise to a new field of debate due tothe growing mobility of the workers and the consequent cultural diversity inside companies. In this sense, a complex world like ours demands a review of the professional profile which should include the so called intercultural competences as a structuring element of companies’ policy and strategic plan. Subsequently it is suggested that, as the intercultural competences affect the cognitive, affective and behavioural aspects, they actually imply a transformation of the person’s identity

Supersymmetric variational energies of 3d confined potentials

Within the approach of Supersymmetric Quantum Mechanics associated with the variational method a recipe to construct the superpotential of three dimensional confined potentials in general is proposed. To illustrate the construction, the energies of the Harmonic Oscillator and the Hulth\'en potential, both confined in three dimensions are evaluated. Comparison with the corresponding results of other approximative and exact numerical results is presented.Comment: 9 pages, Late

Puesto de frutas en Palquibudi

32 p.Veintitantos puestos de frutas, un conjunto de frágiles sombreaderos texturados y coloridos, olores dulces inconfundibles junto al camino, ese es el recuerdo que condujo la búsqueda para construir esta obra de titulación, y constituye la materia reflexiva en torno a la cual se diseñó uno de ellos. Un suelo, un soporte para la exposición y una cubierta que asegure la sombra y el resguardo de la lluvia, componían el encargo formal. La ampliación de su concepto como espacio destinado a la venta de frutas, sin abandonar su cualidad de “volteaderos de recuerdos”, fue la condición propuesta como emplazamiento personal. Finalmente, el “nuevo” puesto de frutas, hecho con materiales “viejos” que en su uso original, ya no tenían utilidad, queda expuesto a su principal destino: contener los vestigios que en él se puedan acumular, y es que el paso del tiempo en muchas obras pesa más que las propias cargas que deben soportar. Completarse, expandirse, contraerse, la obra esperará el tiempo de su variación, no está inconclusa, sino que ha quedado tal y como debía de estar en este momento determinado

Efeito de intervenções farmacológicas antes e/ou após a expressão generalizada de medo sobre a memória aversiva original em ratos

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2017.A generalização do medo é descrita como a tendência de um estímulo não-associado ao evento aversivo original gerar uma resposta condicionada. Para memórias aversivas é comum haver certo grau de generalização, ou seja, as respostas defensivas raramente são limitadas a situações ou estímulos relacionados ao evento aversivo, o que, por sua vez, permite aos indivíduos reagir apropriadamente ao ambiente dinâmico a que estão rotineiramente expostos. Assim, a generalização pode ser interpretada como um processo natural e adaptativo do ponto de vista evolutivo. Por outro lado, no caso de alguns transtornos psiquiátricos, por exemplo, a generalização pode resultar na expressão de respostas defensivas inapropriadas, tornando este fenômeno de tamanha importância clinica. Apesar de não se tratar de um tema recente, grande atenção tem se voltado na compreensão de mecanismos envolvidos, os quais destacam a natureza complexa deste fenômeno. O que se especula é que a expressão generalizada de medo se dá pela evocação da memória original em um contexto diferente. Assim, o objetivo do presente estudo foi o de investigar os efeitos de intervenções farmacológicas antes e/ou após a expressão generalizada de medo sobre a resposta de medo condicionada ao contexto pareado. Para este fim, ratos Wistar machos foram submetidos ao protocolo de condicionamento aversivo contextual (contexto A pareado com 3 choques de 0,7 mA) seguido da administração sistêmica de ioimbina (i.p. 2,0 mg/kg - antagonista de receptores a2-adrenérgicos) para indução da generalização das respostas defensivas. Demonstramos que duas, mas não uma, exposições ao contexto não-pareado (contexto B), seguidas da administração de clonidina (i.p. 0,3 mg/kg - agonista de receptores a2-adrenérgicos) atenuam a expressão de congelamento no contexto pareado (contexto A) no dia seguinte à última manipulação. A administração de D-cicloserina (i.p. 15 mg/kg ? agonista parcial de receptores glutamatérgicos NMDA) previamente a uma única exposição ao contexto não-pareado seguida da administração de clonidina tornou a memória original mais susceptível à ação amnésica da clonidina após a exposição ao contexto pareado. O tratamento prévio com ifenprodil (1 mg/ml ? antagonista da sub-unidade GluN2B do receptor glutamatérgico NMDA) no hipocampo dorsal bloqueou parcialmente os efeitos da clonidina após reativação no contexto pareado, indicando que os efeitos observados estão relacionados, pelo menos em parte, à alteração do perfil de labilização da memória potencializada e que o hipocampo pode ser um sítio de grande interesse para investigações futuras. Juntos, estes dados indicam a possibilidade de atenuar uma memória aversiva a partir de um contexto não associado ao evento aversivo original, sugerindo que, nesta ocasião a memória pode ser reativada, desestabilizada e até mesmo modulada com o uso de drogas amnésicas.Abstract : The fear generalization is described as a tendency of a similar stimulus to the original aversive one in generate conditioned responses. It is common aversive memories have a certain degree of generalization. Defensive responses are rarely limited to situations or stimuli related to the aversive event, which in turn, allow individuals to react appropriately to the dynamic environment where they are routinely exposed. Thus, fear generalization can be interpreted as a natural and adaptive process from the evolutionary point of view. On the other hand, in the case of some psychiatric disorders, for example, the generalization may result in the expression of inappropriate defensive responses, making this phenomenon of such clinical importance. Great focus has been placed on understanding the involved mechanisms, which highlights the complex nature of this phenomenon. The hypothesis of this work is that the expression of generalized fear is related to the retrieval of the original memory in a different context. Consequently, the aim of the present study was to investigate the effect of pharmacological intervention around the exposure to a novel context on the fear response to a familiar one (paired context). To achieve this goal, male Wistar rats were subjected to contextual fear conditioning (context A paired with 3 footshocks of 0.7mA) followed by systemic injection of yohimbine (i.p. 2.0 mg/kg - a2-adrenoceptor antagonist), which leads to an expression of generalized response of fear. We have shown that two, and not one, exposures to the novel context (context B), followed by administration of clonidine (i.p. 0.3 mg/kg - a2-adrenoceptor agonist) attenuated freezing expression in the paired context (context A) on the day after the last manipulation. D-cycloserine injection (i.p. 15 mg/kg - a partial agonist of the glutamatergic NMDA receptor) before a single context B exposure followed by systemic administration of clonidine rendered the original memory more susceptible to reconsolidation disruption by clonidine after paired context exposure. The previous administration of ifenprodil (an specific GluN2B-containing NMDA receptor antagonist) in the dorsal hippocampus partially blocked the effects of clonidine after retrieval in the paired context, what indicates that the clonidine effects are in part due to a change in the memory destabilization into hippocampus and it can be a site of great interest for future investigations. Altogether, these results indicate the possibility of attenuating traumatic-like memory after the exposure to a context not associated with the original aversive event, suggesting that, in this situation, memory would be retrieved, destabilized and further impaired by reconsolidation blockers

Influence of Pr6O11 addition on structural and magnetic properties of mechanically alloyed Fe65Co35 nanoparticles

This work focuses on the synthesize of nanostructured (Fe65Co35)100-x (Pr6O11)x (x = 0, 5) powders using high energy ball milling. The influence of Pr6O11 on structural, morphological and magnetic properties of Fe65Co35 nanoparticles were carried out by X-ray diffraction (XRD), scanning electron microscopy (SEM) with a dispersive energy analyzer (EDS), vibratory sample magnetometer (VSM) and differential scanning calorimetry (DSC). Results show that the praseodymium oxide addition increased the decrement rate of the crystallite size with milling time of about 27 % and decreased the increment rate of the internal micro-strain of 50 %. Moreover, because of its high grain fragmentation tendency, Pr6O11 increases the hardness and brittleness of Fe-Co powders. Moreover, it minimized the cold welding between Fe-Co ductile particles leading to a significant decrease in the average particle size (~1µm). The magnetic measurements conducted at room temperature show that the saturation magnetisation (Ms) and the coercivity (Hc) increased with milling time in both compositions. A low Ms and high Hc values were detected in (Fe65Co35)95 (Pr6O11)5 nanoparticles. The results demonstrated a soft ferromagnetic nature in all of the synthesized nanoparticles with Ms in the range 207 – 216 emu/g and Hc is found to be 113 Oe

Effectiveness of mindfulness-based stress reduction and attachment-based compassion therapy for the treatment of depressive, anxious, and adjustment disorders in mental health settings: A randomized controlled trial

Objectives: To study the effectiveness of attachment-based compassion therapy (ABCT) for reducing affective distress in a sample of outpatients with depressive, anxiety, or adjustment disorders, and to explore its mechanisms of action. Methods: This randomized controlled trial involved the assessment time points of pretreatment, posttreatment and 6-month follow-up. A total of 90 patients from three mental health units in Castellón, Spain, were recruited and randomly assigned to “ABCT + treatment as usual (TAU), ” “Mindfulness-based stress reduction (MBSR) + TAU” or “TAU” alone. Affective distress, as measured by the “Depression, Anxiety and Stress Scales” (DASS-21) was the main outcome; self-compassion and mindfulness were also assessed. Multilevel mixed-effects models were used to estimate the effectiveness of the program, and path analyses were conducted to study the potential mechanistic role of mindfulness and self-compassion. Results: ABCT was not superior to MBSR in any outcome or at any assessment point. ABCT was superior to TAU alone both posttreatment (B = -13.20; 95% confidence interval [CI]: -19.57, -6.84) and at 6-month follow-up (B = -7.20; 95% CI: -13.63, -0.76) for reducing DASS-21, and MBSR was superior to TAU alone both posttreatment (B = -11.51; 95% CI: -17.97, -5.05) and at 6-month follow-up (B = -8.59; 95% CI: -15.09, -2.10), with large effects (d = 0.90). Changes produced by ABCT in DASS-21 were mediated by self-compassion, whereas changes produced by MBSR were mediated by both mindfulness and self-compassion. Conclusion: ABCT is effective for reducing affective distress in patients with anxiety, depressive and adjustment disorders, although its effect is not superior to that offered by MBSR. Self-compassion seems to be a significant mediator of the effects of ABCT. © 2021 Wiley Periodicals LL

Descripción e impacto económico de los pacientes con patologías respiratorias ingresados con indicación de kinesiología en la Unidad de Hospitalización Domiciliaria del Hospital Dr. Sótero del Río

Introduction: Home Hospitalization Units (UHD) were created with the main purpose of decongest hospital wards, providing patients with a more human and favorable environment for their recovery and also contributing to hospital stay savings.Objective: To describe the work of Kinesiologist in the treatment of patients with respiratory diseases inMethods and Material: A retrospective descriptive study of patients admitted in UHD with indication of respiratory kinesiology or that have required it between the months of January to December 2018. For the statistical analysis, Microsoft Excel and the Minitab 17.0 program were used.Results: Of a total of 4,650 inpatients, only 21.3% had the medical indication of respiratory kinesiology (73.4% were adults and 26.6% pediatrics). A total of 8,744 visits were made with an average for adults of 10.9 ± 13.03 and for pediatrics of 5.6 ± 3.3. The average stay was 13.9 ± 20.06 days. The specific kinessic interventions performed were oxygen therapy (71.9%), nebulization (61%), secretion aspiration (30%), noninvasive mechanical ventilation management (6%) and tracheostomy management (3%). Regarding the economic impact, saving was calculated in 69.1% only in this group of patients out of the total in the unit.Conclusion: Home hospitalization has proven to be a useful tool and economically efficient when optimizing health resources. It is clear that kinesiology professional contributes essentially to UHD, where most of the income is due to respiratory pathologies.Introducción: Las Unidades de Hospitalización Domiciliaria (UHD) nacen con el principal objetivo de descongestionar las salas hospitalarias, brindando a los usuarios un ambiente más humano y favorable para su recuperación y contribuyendo en el ahorro de la estancia hospitalaria.Objetivo: Describir el quehacer del Kinesiologo en el tratamiento de los pacientes con patologías respiratorias en una Unidad de Hospitalizacion Domiciliaria.Material y Métodos: Estudio descriptivo retrospectivo de usuarios ingresados a UHD con indicación de kinesiología respiratoria o que hayan requerido de esta prestación durante los meses de enero a diciembre de 2018. Para el análisis estadístico se utilizó Microsoft Excel y el programa Minitab 17.0.Resultados: De un total de 4.650 usuarios ingresados, el 21,3% contaba con indicación médica de kinesiología respiratoria, de los cuales el 73,4% eran adultos y el 26,6% pediátricos. Se realizaron un total de 8.744 visitas con un promedio para adultos de 10,9±13,03 y para pediátricos de 5,6±3,3. El promedio de estadía fue de 13.9 ± 20,06 días. Las intervenciones kinésicas específicas realizadas fueron oxigenoterapia (71,9%), nebulización (61%), aspiración de secreciones (30%), manejo de ventilación mecánica no invasiva (6%) y manejo de traqueostomía (3%). Respecto al impacto económico, se calculó un ahorro sólo en este grupo de usuarios de un 69,1% del total de la unidad.Conclusión: La hospitalización domiciliaria ha demostrado ser una herramienta útil y económicamente eficiente a la hora de optimizar los recursos en salud. Se deja en manifiesto que el profesional de kinesiología contribuye esencialmente en las UHD, donde la mayoría de los ingresos son a causa de patologías respiratorias