Cooperative Multi-robot Patrolling: A study of distributed approaches based on mathematical models of game theory to protect infrastructures

El principio de Teoría de Juegos permite desarrollar modelos estocásticos de patrullaje multi-robot para proteger infraestructuras criticas. La protección de infraestructuras criticas representa un gran reto para los países al rededor del mundo, principalmente después de los ataques terroristas llevados a cabo la década pasada. En este documento el termino infraestructura hace referencia a aeropuertos, plantas nucleares u otros instalaciones. El problema de patrullaje se define como la actividad de patrullar un entorno determinado para monitorear cualquier actividad o sensar algunas variables ambientales. En esta actividad, un grupo de robots debe visitar un conjunto de puntos de interés definidos en un entorno en intervalos de tiempo irregulares con propósitos de seguridad. Los modelos de partullaje multi-robot son utilizados para resolver este problema. Hasta el momento existen trabajos que resuelven este problema utilizando diversos principios matemáticos. Los modelos de patrullaje multi-robot desarrollados en esos trabajos representan un gran avance en este campo de investigación. Sin embargo, los modelos con los mejores resultados no son viables para aplicaciones de seguridad debido a su naturaleza centralizada y determinista. Esta tesis presenta cinco modelos de patrullaje multi-robot distribuidos e impredecibles basados en modelos matemáticos de aprendizaje de Teoría de Juegos. El objetivo del desarrollo de estos modelos está en resolver los inconvenientes presentes en trabajos preliminares. Con esta finalidad, el problema de patrullaje multi-robot se formuló utilizando conceptos de Teoría de Grafos, en la cual se definieron varios juegos en cada vértice de un grafo. Los modelos de patrullaje multi-robot desarrollados en este trabajo de investigación se han validado y comparado con los mejores modelos disponibles en la literatura. Para llevar a cabo tanto la validación como la comparación se ha utilizado un simulador de patrullaje y un grupo de robots reales. Los resultados experimentales muestran que los modelos de patrullaje desarrollados en este trabajo de investigación trabajan mejor que modelos de trabajos previos en el 80% de 150 casos de estudio. Además de esto, estos modelos cuentan con varias características importantes tales como distribución, robustez, escalabilidad y dinamismo. Los avances logrados con este trabajo de investigación dan evidencia del potencial de Teoría de Juegos para desarrollar modelos de patrullaje útiles para proteger infraestructuras. ABSTRACT Game theory principle allows to developing stochastic multi-robot patrolling models to protect critical infrastructures. Critical infrastructures protection is a great concern for countries around the world, mainly due to terrorist attacks in the last decade. In this document, the term infrastructures includes airports, nuclear power plants, and many other facilities. The patrolling problem is defined as the activity of traversing a given environment to monitoring any activity or sensing some environmental variables If this activity were performed by a fleet of robots, they would have to visit some places of interest of an environment at irregular intervals of time for security purposes. This problem is solved using multi-robot patrolling models. To date, literature works have been solved this problem applying various mathematical principles.The multi-robot patrolling models developed in those works represent great advances in this field. However, the models that obtain the best results are unfeasible for security applications due to their centralized and predictable nature. This thesis presents five distributed and unpredictable multi-robot patrolling models based on mathematical learning models derived from Game Theory. These multi-robot patrolling models aim at overcoming the disadvantages of previous work. To this end, the multi-robot patrolling problem was formulated using concepts of Graph Theory to represent the environment. Several normal-form games were defined at each vertex of a graph in this formulation. The multi-robot patrolling models developed in this research work have been validated and compared with best ranked multi-robot patrolling models in the literature. Both validation and comparison were preformed by using both a patrolling simulator and real robots. Experimental results show that the multirobot patrolling models developed in this research work improve previous ones in as many as 80% of 150 cases of study. Moreover, these multi-robot patrolling models rely on several features to highlight in security applications such as distribution, robustness, scalability, and dynamism. The achievements obtained in this research work validate the potential of Game Theory to develop patrolling models to protect infrastructures.

Calibration of calculation models of wooden guardrails with Operational Modal Analysis

This study analyses the differences between two calculation models for guardrails on building sites that use wooden boards and tubular steel posts. Wood was considered an isotropic material in one model and an orthotropic material in a second model. The elastic constants of the wood were obtained with ultrasound. Frequencies and vibration modes were obtained for both models through linear analysis using the finite element method. The two models were experimentally calibrated through operational modal analysis. The results obtained show that for the three types of wood under analysis, the model which considered them as an orthotropic material fitted the experimental results better than the model which considered them as an isotropic material.

An introduction to flow and transport in fractal models of porous media: Part I

This special issue gathers together a number of recent papers on fractal geometry and its applications to the modeling of flow and transport in porous media. The aim is to provide a systematic approach for analyzing the statics and dynamics of fluids in fractal porous media by means of theory, modeling and experimentation. The topics covered include lacunarity analyses of multifractal and natural grayscale patterns, random packing's of self-similar pore/particle size distributions, Darcian and non-Darcian hydraulic flows, diffusion within fractals, models for the permeability and thermal conductivity of fractal porous media and hydrophobicity and surface erosion properties of fractal structures.

Contribution to the improvement of communication services in nanosatellite constellations using delay and disruption tolerant networking based architectures

Esta tesis se desarrolla dentro del marco de las comunicaciones satelitales en el innovador campo de los pequeños satélites también llamados nanosatélites o cubesats, llamados así por su forma cubica. Estos nanosatélites se caracterizan por su bajo costo debido a que usan componentes comerciales llamados COTS (commercial off-the-shelf) y su pequeño tamaño como los Cubesats 1U (10cm*10 cm*10 cm) con masa aproximada a 1 kg. Este trabajo de tesis tiene como base una iniciativa propuesta por el autor de la tesis para poner en órbita el primer satélite peruano en mi país llamado chasqui I, actualmente puesto en órbita desde la Estación Espacial Internacional. La experiencia de este trabajo de investigación me llevo a proponer una constelación de pequeños satélites llamada Waposat para dar servicio de monitoreo de sensores de calidad de agua a nivel global, escenario que es usado en esta tesis. Es ente entorno y dadas las características limitadas de los pequeños satélites, tanto en potencia como en velocidad de datos, es que propongo investigar una nueva arquitectura de comunicaciones que permita resolver en forma óptima la problemática planteada por los nanosatélites en órbita LEO debido a su carácter disruptivo en sus comunicaciones poniendo énfasis en las capas de enlace y aplicación. Esta tesis presenta y evalúa una nueva arquitectura de comunicaciones para proveer servicio a una red de sensores terrestres usando una solución basada en DTN (Delay/Disruption Tolerant Networking) para comunicaciones espaciales. Adicionalmente, propongo un nuevo protocolo de acceso múltiple que usa una extensión del protocolo ALOHA no ranurado, el cual toma en cuenta la prioridad del trafico del Gateway (ALOHAGP) con un mecanismo de contienda adaptativo. Utiliza la realimentación del satélite para implementar el control de la congestión y adapta dinámicamente el rendimiento efectivo del canal de una manera óptima. Asumimos un modelo de población de sensores finito y una condición de tráfico saturado en el que cada sensor tiene siempre tramas que transmitir. El desempeño de la red se evaluó en términos de rendimiento efectivo, retardo y la equidad del sistema. Además, se ha definido una capa de convergencia DTN (ALOHAGP-CL) como un subconjunto del estándar TCP-CL (Transmission Control Protocol-Convergency Layer). Esta tesis muestra que ALOHAGP/CL soporta adecuadamente el escenario DTN propuesto, sobre todo cuando se utiliza la fragmentación reactiva. Finalmente, esta tesis investiga una transferencia óptima de mensajes DTN (Bundles) utilizando estrategias de fragmentación proactivas para dar servicio a una red de sensores terrestres utilizando un enlace de comunicaciones satelitales que utiliza el mecanismo de acceso múltiple con prioridad en el tráfico de enlace descendente (ALOHAGP). El rendimiento efectivo ha sido optimizado mediante la adaptación de los parámetros del protocolo como una función del número actual de los sensores activos recibidos desde el satélite. También, actualmente no existe un método para advertir o negociar el tamaño máximo de un “bundle” que puede ser aceptado por un agente DTN “bundle” en las comunicaciones por satélite tanto para el almacenamiento y la entrega, por lo que los “bundles” que son demasiado grandes son eliminados o demasiado pequeños son ineficientes. He caracterizado este tipo de escenario obteniendo una distribución de probabilidad de la llegada de tramas al nanosatélite así como una distribución de probabilidad del tiempo de visibilidad del nanosatélite, los cuales proveen una fragmentación proactiva óptima de los DTN “bundles”. He encontrado que el rendimiento efectivo (goodput) de la fragmentación proactiva alcanza un valor ligeramente inferior al de la fragmentación reactiva. Esta contribución permite utilizar la fragmentación activa de forma óptima con todas sus ventajas tales como permitir implantar el modelo de seguridad de DTN y la simplicidad al implementarlo en equipos con muchas limitaciones de CPU y memoria. La implementación de estas contribuciones se han contemplado inicialmente como parte de la carga útil del nanosatélite QBito, que forma parte de la constelación de 50 nanosatélites que se está llevando a cabo dentro del proyecto QB50. ABSTRACT This thesis is developed within the framework of satellite communications in the innovative field of small satellites also known as nanosatellites (<10 kg) or CubeSats, so called from their cubic form. These nanosatellites are characterized by their low cost because they use commercial components called COTS (commercial off-the-shelf), and their small size and mass, such as 1U Cubesats (10cm * 10cm * 10cm) with approximately 1 kg mass. This thesis is based on a proposal made by the author of the thesis to put into orbit the first Peruvian satellite in his country called Chasqui I, which was successfully launched into orbit from the International Space Station in 2014. The experience of this research work led me to propose a constellation of small satellites named Waposat to provide water quality monitoring sensors worldwide, scenario that is used in this thesis. In this scenario and given the limited features of nanosatellites, both power and data rate, I propose to investigate a new communications architecture that allows solving in an optimal manner the problems of nanosatellites in orbit LEO due to the disruptive nature of their communications by putting emphasis on the link and application layers. This thesis presents and evaluates a new communications architecture to provide services to terrestrial sensor networks using a space Delay/Disruption Tolerant Networking (DTN) based solution. In addition, I propose a new multiple access mechanism protocol based on extended unslotted ALOHA that takes into account the priority of gateway traffic, which we call ALOHA multiple access with gateway priority (ALOHAGP) with an adaptive contention mechanism. It uses satellite feedback to implement the congestion control, and to dynamically adapt the channel effective throughput in an optimal way. We assume a finite sensor population model and a saturated traffic condition where every sensor always has frames to transmit. The performance was evaluated in terms of effective throughput, delay and system fairness. In addition, a DTN convergence layer (ALOHAGP-CL) has been defined as a subset of the standard TCP-CL (Transmission Control Protocol-Convergence Layer). This thesis reveals that ALOHAGP/CL adequately supports the proposed DTN scenario, mainly when reactive fragmentation is used. Finally, this thesis investigates an optimal DTN message (bundles) transfer using proactive fragmentation strategies to give service to a ground sensor network using a nanosatellite communications link which uses a multi-access mechanism with priority in downlink traffic (ALOHAGP). The effective throughput has been optimized by adapting the protocol parameters as a function of the current number of active sensors received from satellite. Also, there is currently no method for advertising or negotiating the maximum size of a bundle which can be accepted by a bundle agent in satellite communications for storage and delivery, so that bundles which are too large can be dropped or which are too small are inefficient. We have characterized this kind of scenario obtaining a probability distribution for frame arrivals to nanosatellite and visibility time distribution that provide an optimal proactive fragmentation of DTN bundles. We have found that the proactive effective throughput (goodput) reaches a value slightly lower than reactive fragmentation approach. This contribution allows to use the proactive fragmentation optimally with all its advantages such as the incorporation of the security model of DTN and simplicity in protocol implementation for computers with many CPU and memory limitations. The implementation of these contributions was initially contemplated as part of the payload of the nanosatellite QBito, which is part of the constellation of 50 nanosatellites envisaged under the QB50 project.

Gestión intelectual de las prácticas comunicativas en arquitectura : S, M, L, XL, el gran evento = The intellectual management of communication practices in architecture : S, M, L, XL, the big event

La tesis doctoral se centra en la posibilidad de entender que la práctica de arquitectura puede encontrar en las prácticas comunicativas un apoyo instrumental, que sobrepasa cualquier simplificación clásica del uso de los medios como una mera aplicación superficial, post-producida o sencillamente promocional. A partir de esta premisa se exponen casos del último cuarto del siglo XX y se detecta que amenazas como el riesgo de la banalización, la posible saturación de la imagen pública o la previsible asociación incorrecta con otros individuos en presentaciones grupales o por temáticas, han podido influir en un crecimiento notable de la adquisición de control, por parte de los arquitectos, en sus oportunidades mediáticas. Esto es, como si la arquitectura hubiera empezado a superar y optimizar algo inevitable, que las fórmulas expositivas y las publicaciones, o más bien del exponer(se) y publicar(se), son herramientas disponibles para activar algún tipo de gestión intelectual de la comunicación e información circulante sobre si misma. Esta práctica de “autoedición” se analiza en un periodo concreto de la trayectoria de OMA -Office for Metropolitan Architecture-, estudio considerado pionero en el uso eficiente, oportunista y personalizado de los medios. Así, la segunda parte de la tesis se ocupa del análisis de su conocida monografía S,M,L,XL (1995), un volumen que contó con gran participación por parte de sus protagonistas durante la edición, y de cuyo proceso de producción apenas se había investigado. Esta publicación señaló un punto de inflexión en su género alterando todo formato y restricciones anteriores, y se ha convertido en un volumen emblemático para la disciplina que ninguna réplica posterior ha podido superar. Aquí se presenta a su vez como el desencadenante de la construcción de un “gran evento” que concluye en la transformación de la identidad de OMA en 10 años, paradójicamente entre el nacimiento de la Fundación Groszstadt y el arranque de la actividad de AMO, dos entidades paralelas clave anexas a OMA. Este planteamiento deviene de cómo la investigación desvela que S,M,L,XL es una pieza más, central pero no independiente, dentro de una suma de acciones e individuos, así como otras publicaciones, exposiciones, eventos y también artículos ensayados y proyectos, en particular Bigness, Generic City, Euralille y los concursos de 1989. Son significativos aspectos como la apertura a una autoría múltiple, encabezada por Rem Koolhaas y el diseñador gráfico Bruce Mau, acompañados en los agradecimientos de la editora Jennifer Sigler y cerca de una centena de nombres, cuyas aportaciones no necesariamente se basan en la construcción de fragmentos del libro. La supresión de ciertos límites permite superar también las tareas inicialmente relevantes en la edición de una publicación. Un objetivo general de la tesis es también la reflexión sobre relaciones anteriormente cuestionadas, como la establecida entre la arquitectura y los mercados o la economía. Tomando como punto de partida la idea de “design intelligence” sugerida por Michael Speaks (2001), se extrae de sus argumentos que lo esencial es el hallazgo de la singularidad o inteligencia propia de cada estudio de arquitectura o diseño. Asimismo se explora si en la construcción de ese tipo de fórmulas magistrales se alojaban también combinaciones de interés y productivas entre asuntos como la eficiencia y la creatividad, o la organización y las ideas. En esta dinámica de relaciones bidireccionales, y en ese presente de exceso de información, se fundamenta la propuesta de una equivalencia más evidenciada entre la “socialización” del trabajo del arquitecto, al compartirlo públicamente e introducir nuevas conversaciones, y la relación inversa a partir del trabajo sobre la “socialización” misma. Como si la consciencia sobre el uso de los medios pudiera ser efectivamente instrumental, y contribuir al desarrollo de la práctica de arquitectura, desde una perspectiva idealmente comprometida e intelectual. ABSTRACT The dissertation argues the possibility to understand that the practice of architecture can find an instrumental support in the practices of communication, overcoming any classical simplification of the use of media, generally reduced to superficial treatments or promotional efforts. Thus some cases of the last decades of the 20th century are presented. Some threats detected, such as the risk of triviality, the saturation of the public image or the foreseeable wrong association among individuals when they are introduced as part of thematic groups, might have encouraged a noticeable increase of command taken by architects when there is chance to intervene in a media environment. In other words, it can be argued that architecture has started to overcome and optimize the inevitable, the fact that exhibition formulas and publications, or simply the practice of (self)exhibition or (self)publication, are tools at our disposal for the activation of any kind of intellectual management of communication and circulating information about itself. This practice of “self-edition” is analyzed in a specific timeframe of OMA’s trajectory, an office that is considered as a ground-breaking actor in the efficient and opportunistic use of media. Then the second part of the thesis dissects their monograph S,M,L,XL (1995), a volume in which its main characters were deeply involved in terms of edition and design, a process barely analyzed up to now. This publication marked a turning point in its own genre, disrupting old formats and traditional restrictions. It became such an emblematic volume for the discipline that none of the following attempts of replica has ever been able to improve this precedent. Here, the book is also presented as the element that triggers the construction of a “big event” that concludes in the transformation of OMA identity in 10 years. Paradoxically, between the birth of the Groszstadt Foundation and the early steps of AMO, both two entities parallel and connected to OMA. This positions emerge from how the research unveils that S,M,L,XL is one more piece, a key one but not an unrelated element, within a sum of actions and individuals, as well as other publications, exhibitions, articles and projects, in particular Bigness, Generic City, Euralille and the competitions of 1989. Among the remarkable innovations of the monograph, there is an outstanding openness to a regime of multiple authorship, headed by Rem Koolhaas and the graphic designer Bruce Mau, who share the acknowledgements page with the editor, Jennifer Sigler, and almost 100 people, not necessarily responsible for specific fragments of the book. In this respect, the dissolution of certain limits made possible that the expected tasks in the edition of a publication could be trespassed. A general goal of the thesis is also to open a debate on typically questioned relations, particularly between architecture and markets or economy. Using the idea of “design intelligence”, outlined by Michael Speaks in 2001, the thesis pulls out its essence, basically the interest in detecting the singularity, or particular intelligence of every office of architecture and design. Then it explores if in the construction of this kind of ingenious formulas one could find interesting and useful combinations among issues like efficiency and creativity, or organization and ideas. This dynamic of bidirectional relations, rescued urgently at this present moment of excess of information, is based on the proposal for a more evident equivalence between the “socialization” of the work in architecture, anytime it is shared in public, and the opposite concept, the work on the proper act of “socialization” itself. As if a new awareness of the capacities of the use of media could turn it into an instrumental force, capable of contributing to the development of the practice of architecture, from an ideally committed and intelectual perspective.

A test of alternative models of diversification in tropical rainforests: Ecological gradients vs. rainforest refugia

Comparison of mitochondrial and morphological divergence in eight populations of a widespread leaf-litter skink is used to determine the relative importance of geographic isolation and natural selection in generating phenotypic diversity in the Wet Tropics Rainforest region of Australia. The populations occur in two geographically isolated regions, and within each region, in two different habitats (closed rainforest and tall open forest) that span a well characterized ecological gradient. Morphological differences among ancient geographic isolates (separated for several million years, judging by their mitochondrial DNA sequence divergence) were slight, but morphological and life history differences among habitats were large and occurred despite moderate to high levels of mitochondrial gene flow. A field experiment identified avian predation as one potential agent of natural selection. These results indicate that natural selection operating across ecological gradients can be more important than geographic isolation in similar habitats in generating phenotypic diversity. In addition, our results indicate that selection is sufficiently strong to overcome the homogenizing effects of gene flow, a necessary first step toward speciation in continuously distributed populations. Because ecological gradients may be a source of evolutionary novelty, and perhaps new species, their conservation warrants greater attention. This is particularly true in tropical regions, where most reserves do not include ecological gradients and transitional habitats.

Models of immune memory: On the role of cross-reactive stimulation, competition, and homeostasis in maintaining immune memory

There has been much debate on the contribution of processes such as the persistence of antigens, cross-reactive stimulation, homeostasis, competition between different lineages of lymphocytes, and the rate of cell turnover on the duration of immune memory and the maintenance of the immune repertoire. We use simple mathematical models to investigate the contributions of these various processes to the longevity of immune memory (defined as the rate of decline of the population of antigen-specific memory cells). The models we develop incorporate a large repertoire of immune cells, each lineage having distinct antigenic specificities, and describe the dynamics of the individual lineages and total population of cells. Our results suggest that, if homeostatic control regulates the total population of memory cells, then, for a wide range of parameters, immune memory will be long-lived in the absence of persistent antigen (T1/2 > 1 year). We also show that the longevity of memory in this situation will be insensitive to the relative rates of cross-reactive stimulation, the rate of turnover of immune cells, and the functional form of the term for the maintenance of homeostasis.

Polymer Models of Meiotic and Mitotic Chromosomes

Polymers tied together by constraints exhibit an internal pressure; this idea is used to analyze physical properties of the bottle-brush–like chromosomes of meiotic prophase that consist of polymer-like flexible chromatin loops, attached to a central axis. Using a minimal number of experimental parameters, semiquantitative predictions are made for the bending rigidity, radius, and axial tension of such brushes, and the repulsion acting between brushes whose bristles are forced to overlap. The retraction of lampbrush loops when the nascent transcripts are stripped away, the oval shape of diplotene bivalents between chiasmata, and the rigidity of pachytene chromosomes are all manifestations of chromatin pressure. This two-phase (chromatin plus buffer) picture that suffices for meiotic chromosomes has to be supplemented by a third constituent, a chromatin glue to understand mitotic chromosomes, and explain how condensation can drive the resolution of entanglements. This process resembles a thermal annealing in that a parameter (the affinity of the glue for chromatin and/or the affinity of the chromatin for buffer) has to be tuned to achieve optimal results. Mechanical measurements to characterize this protein–chromatin matrix are proposed. Finally, the propensity for even slightly chemically dissimilar polymers to phase separate (cluster like with like) can explain the apparent segregation of the chromatin into A+T- and G+C-rich regions revealed by chromosome banding.

d-β-Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease

The heroin analogue 1-methyl-4-phenylpyridinium, MPP+, both in vitro and in vivo, produces death of dopaminergic substantia nigral cells by inhibiting the mitochondrial NADH dehydrogenase multienzyme complex, producing a syndrome indistinguishable from Parkinson's disease. Similarly, a fragment of amyloid protein, Aβ1–42, is lethal to hippocampal cells, producing recent memory deficits characteristic of Alzheimer's disease. Here we show that addition of 4 mM d-β-hydroxybutyrate protected cultured mesencephalic neurons from MPP+ toxicity and hippocampal neurons from Aβ1–42 toxicity. Our previous work in heart showed that ketone bodies, normal metabolites, can correct defects in mitochondrial energy generation. The ability of ketone bodies to protect neurons in culture suggests that defects in mitochondrial energy generation contribute to the pathophysiology of both brain diseases. These findings further suggest that ketone bodies may play a therapeutic role in these most common forms of human neurodegeneration.

Stretching lattice models of protein folding

A new class of experiments that probe folding of individual protein domains uses mechanical stretching to cause the transition. We show how stretching forces can be incorporated in lattice models of folding. For fast folding proteins, the analysis suggests a complex relation between the force dependence and the reaction coordinate for folding.

Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3β in cellular and animal models of neuronal degeneration

Inactivation of glycogen synthase kinase-3β (GSK3β) by S9 phosphorylation is implicated in mechanisms of neuronal survival. Phosphorylation of a distinct site, Y216, on GSK3β is necessary for its activity; however, whether this site can be regulated in cells is unknown. Therefore we examined the regulation of Y216 phosphorylation on GSK3β in models of neurodegeneration. Nerve growth factor withdrawal from differentiated PC12 cells and staurosporine treatment of SH-SY5Y cells led to increased phosphorylation at Y216, GSK3β activity, and cell death. Lithium and insulin, agents that lead to inhibition of GSK3β and adenoviral-mediated transduction of dominant negative GSK3β constructs, prevented cell death by the proapoptotic stimuli. Inhibitors induced S9 phosphorylation and inactivation of GSK3β but did not affect Y216 phosphorylation, suggesting that S9 phosphorylation is sufficient to override GSK3β activation by Y216 phosphorylation. Under the conditions examined, increased Y216 phosphorylation on GSK3β was not an autophosphorylation response. In resting cells, Y216 phosphorylation was restricted to GSK3β present at focal adhesion sites. However, after staurosporine, a dramatic alteration in the immunolocalization pattern was observed, and Y216-phosphorylated GSK3β selectively increased within the nucleus. In rats, Y216 phosphorylation was increased in degenerating cortical neurons induced by ischemia. Taken together, these results suggest that Y216 phosphorylation of GSK3β represents an important mechanism by which cellular insults can lead to neuronal death.

Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARα and PLZF-RARα oncoproteins

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations always involving the RARα gene, which variably fuses to one of several distinct loci, including PML or PLZF (X genes) in t(15;17) or t(11;17), respectively. APL in patients harboring t(15;17) responds well to retinoic acid (RA) treatment and chemotherapy, whereas t(11;17) APL responds poorly to both treatments, thus defining a distinct syndrome. Here, we show that RA, As2O3, and RA + As2O3 prolonged survival in either leukemic PML-RARα transgenic mice or nude mice transplanted with PML-RARα leukemic cells. RA + As2O3 prolonged survival compared with treatment with either drug alone. In contrast, neither in PLZF-RARα transgenic mice nor in nude mice transplanted with PLZF-RARα cells did any of the three regimens induce complete disease remission. Unexpectedly, therapeutic doses of RA and RA + As2O3 can induce, both in vivo and in vitro, the degradation of either PML-RARα or PLZF-RARα proteins, suggesting that the maintenance of the leukemic phenotype depends on the continuous presence of the former, but not the latter. Our findings lead to three major conclusions with relevant therapeutic implications: (i) the X-RARα oncoprotein directly determines response to treatment and plays a distinct role in the maintenance of the malignant phenotype; (ii) As2O3 and/or As2O3 + RA combination may be beneficial for the treatment of t(15;17) APL but not for t(11;17) APL; and (iii) therapeutic strategies aimed solely at degrading the X-RARα oncoprotein may not be effective in t(11;17) APL.

Health beliefs and folk models of diabetes in British Bangladeshis: a qualitative study

Objective: To explore the experience of diabetes in British Bangladeshis, since successful management of diabetes requires attention not just to observable behaviour but to the underlying attitudes and belief systems which drive that behaviour.