Roles of mismatch repair proteins in the recognition and processing of DNA interstrand crosslinks in human cells

DNA interstrand crosslinks (ICLs) are among the most toxic type of damage to a cell. Many ICL-inducing agents are widely used as therapeutic agents, e.g. cisplatin, psoralen. A bettor understanding of the cellular mechanism that eliminates ICLs is important for the improvement of human health. However, ICL repair is still poorly understood in mammals. Using a triplex-directed site-specific ICL model, we studied the roles of mismatch repair (MMR) proteins in ICL repair in human cells. We are also interested in using psoralen-conjugated triplex-forming oligonucleotides (TFOs) to direct ICLs to a specific site in targeted DNA and in the mammalian genomes. ^ MSH2 protein is the common subunit of two MMR recognition complexes, and MutSα and MutSβ. We showed that MSH2 deficiency renders human cell hypersensitive to psoralen ICLs. MMR recognition complexes bind specifically to triplex-directed psoralen ICLs in vitro. Together with the fact that psoralen ICL-induced repair synthesis is dramatically decreased in MSH2 deficient cell extracts, we demonstrated that MSH2 function is critical for the recognition and processing of psoralen ICLs in human cells. Interestingly, lack of MSH2 does not reduce the level of psoralen ICL-induced mutagenesis in human cells, suggesting that MSH2 does not contribute to error-generating repair of psoralen ICLs, and therefore, may represent a novel error-free mechanism for repairing ICLs. We also studied the role of MLH1, anther key protein in MMR, in the processing of psoralen ICLs. MLH1-deficient human cells are more resistant to psoralen plus UVA treatment. Importantly, MLH1 function is not required for the mutagenic repair of psoralen ICLs, suggesting that it is not involved in the error-generating repair of this type of DNA damage in human cells. ^ These are the first data indicating mismatch repair proteins may participate in a relatively error-free mechanism for processing psoralen ICL in human cells. Enhancement of MMR protein function relative to nucleotide excision repair proteins may reduce the mutagenesis caused by DNA ICLs in humans. ^ In order to specifically target ICLs to mammalian genes, we identified novel TFO target sequences in mouse and human genomes. Using this information, many critical mammalian genes can now be targeted by TFOs.^

cAMP regulates IL-2 receptor signaling in human T cells

Proper immune system function is dependent on positive and negative regulation of T cell signaling pathways. Full T cell activation requires sequential signaling through the T cell receptor (TCR), costimulatory molecules and the IL-2 receptor (IL-2R). The IL-2R associated Janus tyrosine kinase 3 (Jak3), as well as Signal transducer and activator of transcription 5 (Stat5), are required for normal T cell function and survival. Constitutive activation of Jak3 and Stat5 have been linked to cancers of hematopoietic origin, including certain lymphomas and leukemias. ^ The production of cAMP by adenylate cyclase has been shown to negatively regulate human TCR mediated cell proliferation. Since cAMP has been shown to negatively regulate T cell activation, we sought to investigate whether crosstalk exists between cAMP and IL-2R signaling. The first objective of this study was to determine the effect of cAMP on the activation of IL-2R signaling molecules Jak3 and Stat5. We found that the potent adenylate cyclase activator, forskolin, inhibited IL-2 activation of Jak3 and Stat5. Indeed, in vitro kinase assays and electrophoretic mobility shift assays verified a loss of Jak3 enzymatic activity and Stat5 DNA binding ability, respectively. Further analysis of IL-2R signaling showed that forskolin treatment reduced IL-2 induced association of the IL-2Rβ and γc chain. ^ Because cAMP activates protein kinase A (PKA), the second objective was to determine the role for PKA in the cAMP directed regulation of IL-2R signaling intermediates. Interestingly, forskolin induced serine phosphorylation of Jak3, suggesting that cAMP can directly regulate Jak3 via activation of a serine/threonine kinase. Indeed, phosphoamino acid analysis revealed that PKA was able to induce Jak3 serine phosphorylation in the human leukemia cell line MT-2. In addition, in vitro kinase assays established that PKA can directly inhibit Jak3 enzymatic activity. Collectively, these data indicate that cAMP negatively regulates IL-2R signaling via various effector molecules by a previously unrecognized mechanism. This new data suggests that the Jak3/Stat5 pathway may be regulated by various pharmacological agents that stimulate cAMP production and thus can be used to uncouple some types of T cell mediated diseases. ^

An analysis of Texas's school based HPV vaccine mandate: A public health risk communication failure: HPVETO!

Genital human papillomavirus (HPV) is of public health concern because persistent infection with certain HPV types can cause cervical cancer. In response to a nationwide push for cervical cancer legislation, Texas Governor Rick Perry bypassed the traditional legislative process and issued an executive order mandating compulsory HPV vaccinations for all female public school students prior to their entrance in the sixth grade. By bypassing the legislative process Governor Perry did not effectively mitigate the risk perception issues that arose around the need for and usefulness of the vaccine mandate. This policy paper uses a social policy paradigm to identify perception as the key intervening factor on how the public responds to risk information. To demonstrate how the HPV mandate failed, it analyzes four factors, economics, politics, knowledge and culture, that shape perception and influence the public's response. By understanding the factors that influence the public's perception, public health practitioners and policy makers can more effectively create preventive health policy at the state level. ^

The transcriptional repressor Delta EF1 controls resistance to the EGFR inhibitor erlotinib in human HNSCC lines

Epidermal Growth Factor Receptor (EGFR) overexpression occurs in about 90% of Head and Neck Squamous Cell Carcinoma (HNSCC) cases. Aberrant EGFR signaling has been implicated in the malignant features of HNSCC. Thus, EGFR appears to be a logical therapeutic target with increased tumor specificity for the treatment of HNSCC. Erlotinib, a small molecule tyrosine kinase inhibitor, specifically inhibits aberrant EGFR signaling in HNSCC. Only a minority of HNSCC patients were able to derive a substantial clinical benefit from erlotinib. ^ This dissertation identifies Epithelial to Mesenchymal Transition (EMT) as the biological marker that distinguishes EGFR-dependent (erlotinib-sensitive) tumors from the EGFR-independent (erlotinib-resistant) tumors. This will allow us to prospectively identify the patients who are most likely to benefit from EGFR-directed therapy. More importantly, our data identifies the transcriptional repressor DeltaEF1 as the mesenchymal marker that controls EMT phenotype and resistance to erlotinib in human HNSCC lines. si-RNA mediated knockdown of DeltaEF1 in the erlotinib-resistant lines resulted in reversal of the mesenchymal phenotype to an epithelial phenotype and significant increase in sensitivity to erlotinib. ^ DeltaEF1 represses the expression of the epithelial markers by recruiting HDACs to chromatin. This observation allows us to translate our findings into clinical application. To test whether the transcriptional repression by DeltaEF1 underlines the mechanism responsible for erlotinib resistance, erlotinib-resistant lines were treated with an HDAC inhibitor (SAHA) followed by erlotinib. This resulted in a synergistic effect and substantial increase in sensitivity to erlotinib in the resistant cell lines. Thus, combining an HDAC inhibitor with erlotinib represents a novel promising pharmacologic strategy for reversing resistance to erlotinib in HNSCC patients. ^

Circumvention of cellular defense responses to DNA -directed nucleoside analogues by the protein kinase inhibitor, UCN-01

DNA-directed nucleoside analogues, such as ara-C, fludarabine, and gemcitabine, are antimetabolites effective in the treatment of a variety of cancers. However, resistance to nucleoside analogue-based chemotherapy in treatments is still a major problem in therapy. Therefore, it is essential to develop rationales for optimizing the use of nucleoside analogues in combination with other anticancer drugs or modalities such as radiation. The present study focuses on establishing mechanism-based combination strategy to overcome resistance to nucleoside analogues. ^ I hypothesized that the cytostatic concentrations of nucleoside analogues may cause S-phase arrest by activating an S-phase checkpoint that consists of a series of kinases. This may allow cells to repair damaged DNA over time and spare cytotoxicity. Thus, the ability of cells to enact an S-phase arrest in response to incorporation of potentially lethal amounts of nucleoside analogue may serve as a mechanism of resistance to S-phase-specific agents. As a corollary, the addition of a kinase inhibitor, such as UCN-01, may dysregulate the checkpoint response and abrogate the survival of S-phase-arrested cells by suppression of the survival signaling pathways. Using gemcitabine as a model of S-phase-specific nucleoside analogues in human acute myelogenous leukemia ML-1 cells, I demonstrated that cells arrested in S-phase in response to cytostatic conditions. Proliferation continued after washing the cells into drug-free medium, suggesting S-phase arrest served as a resistance mechanism of cancer cells to spare cytotoxicity of nucleoside analogues. However, nontoxic concentrations of UCN-01 rapidly killed S-phase-arrested cells by apoptosis. Furthermore, the molecular mechanism for UCN-01-induced apoptosis in S-phase-arrested cells was through inhibition of survival pathways associated with these cells. In this regard, suppression of the PI 3-kinase-Akt-Bad survival pathway as well as the NF-κB signaling pathway were associated with induction of apoptosis in S-phase-arrested cells by UCN-01, whereas the Ras-Raf-MEK-ERK pathway appeared not involved. This study has provided the rationales and strategies for optimizing the design of effective combination therapies to overcome resistance to nucleoside analogues. In fact, a clinical trial of the combination of ara-C with UCN-01 to treat relapsed or refractory AML patients has been initiated at U.T.M.D. Anderson Cancer Center. ^

*Ras proteins and human tumor cell radiosensitivity

Ras proteins (H-, N-, K4A-, and K4B) are associated with cellular resistance to ionizing radiation (IR) and, consequently, may provide a potential target for radiosensitization strategies in cancer treatment. Several approaches have been used to compromise Ras activity and enhance IR-induced cell killing; however, these techniques either target proteins in addition to Ras or only target one member of the Ras family. In this study, I have used an adenovirus (AV1Y28) that expresses a single-chain antibody fragment directed against Ras proteins to investigate the mechanism(s) responsible for Ras-mediated radiation resistance. AV1Y28 enhanced the radiosensitivity of a number of human tumor cell lines without affecting the radiosensitivity of normal human fibroblasts. Whereas AV1Y28-mediated sensitization was independent of ras gene mutational status, it was dependent on active Ras proteins suggesting that AV1Y28 may be useful against a broad range of tumors. AV1Y28-mediated cell killing was not the result of redistributing cells into a more radiosensitive phase of the cell cycle and did not enhance IR-induced apoptosis. Given that Ras proteins transduce environmental signals to the nucleus, the effect of AV1Y28 on the IR-inducible transcription factor NF-κB were determined. Although AV1Y28 inhibited IR-induced NF-κB through the suppression of IKK, additional work established that NF-κB did not play a role in AV1Y28-mediated radiosensitization. However, a novel component of the signaling pathway responsible for IR-induced NF-κB was identified. Previous studies had suggested a relationship between mutant ras genes and IR-induced G2 delay; therefore the effects of AV1Y28 on the progression of cells from G2 to M after IR were determined. Pretreatment of cells with AV1Y28 prevented the IR-induced G2 arrest. AV1Y28-mediated abrogation of IR-induced G2 arrest correlated with those cell line lines that were sensitized by AV1Y28. Moreover, a significant increase in cells undergoing mitotic catastrophe was found after IR in AV1Y28 treated cells. The abrogation of G2 arrest by AV1Y28 was the result of maintaining the active form of cdc2, an inducer of mitosis, after exposure to IR. This study identified the mechanism of AV1Y28-mediated radiosensitization and has provided insight into the signal transduction pathways responsible for Ras-mediated radiation resistance. ^

Communication Architecture for Tracking and Interoperable Services at Hospitals: A Real Deployment Experience

Any new hospital communication architecture has to support existing services, but at the same time new added features should not affect normal tasks. This article deals with issues regarding old and new systems’ interoperability, as well as the effect the human factor has in a deployed architecture. It also presents valuable information, which is a product of a real scenario. Tracking services are also tested in order to monitor and administer several medical resources.

Contributions to the contextualization of human-machine spoken interaction systems

The design and development of spoken interaction systems has been a thoroughly studied research scope for the last decades. The aim is to obtain systems with the ability to interact with human agents with a high degree of naturalness and efficiency, allowing them to carry out the actions they desire using speech, as it is the most natural means of communication between humans. To achieve that degree of naturalness, it is not enough to endow systems with the ability to accurately understand the user’s utterances and to properly react to them, even considering the information provided by the user in his or her previous interactions. The system has also to be aware of the evolution of the conditions under which the interaction takes place, in order to act the most coherent way as possible at each moment. Consequently, one of the most important features of the system is that it has to be context-aware. This context awareness of the system can be reflected in the modification of the behaviour of the system taking into account the current situation of the interaction. For instance, the system should decide which action it has to carry out, or the way to perform it, depending on the user that requests it, on the way that the user addresses the system, on the characteristics of the environment in which the interaction takes place, and so on. In other words, the system has to adapt its behaviour to these evolving elements of the interaction. Moreover that adaptation has to be carried out, if possible, in such a way that the user: i) does not perceive that the system has to make any additional effort, or to devote interaction time to perform tasks other than carrying out the requested actions, and ii) does not have to provide the system with any additional information to carry out the adaptation, which could imply a lesser efficiency of the interaction, since users should devote several interactions only to allow the system to become adapted. In the state-of-the-art spoken dialogue systems, researchers have proposed several disparate strategies to adapt the elements of the system to different conditions of the interaction (such as the acoustic characteristics of a specific user’s speech, the actions previously requested, and so on). Nevertheless, to our knowledge there is not any consensus on the procedures to carry out these adaptation. The approaches are to an extent unrelated from one another, in the sense that each one considers different pieces of information, and the treatment of that information is different taking into account the adaptation carried out. In this regard, the main contributions of this Thesis are the following ones: Definition of a contextualization framework. We propose a unified approach that can cover any strategy to adapt the behaviour of a dialogue system to the conditions of the interaction (i.e. the context). In our theoretical definition of the contextualization framework we consider the system’s context as all the sources of variability present at any time of the interaction, either those ones related to the environment in which the interaction takes place, or to the human agent that addresses the system at each moment. Our proposal relies on three aspects that any contextualization approach should fulfill: plasticity (i.e. the system has to be able to modify its behaviour in the most proactive way taking into account the conditions under which the interaction takes place), adaptivity (i.e. the system has also to be able to consider the most appropriate sources of information at each moment, both environmental and user- and dialogue-dependent, to effectively adapt to the conditions aforementioned), and transparency (i.e. the system has to carry out the contextualizaton-related tasks in such a way that the user neither perceives them nor has to do any effort in providing the system with any information that it needs to perform that contextualization). Additionally, we could include a generality aspect to our proposed framework: the main features of the framework should be easy to adopt in any dialogue system, regardless of the solution proposed to manage the dialogue. Once we define the theoretical basis of our contextualization framework, we propose two cases of study on its application in a spoken dialogue system. We focus on two aspects of the interaction: the contextualization of the speech recognition models, and the incorporation of user-specific information into the dialogue flow. One of the modules of a dialogue system that is more prone to be contextualized is the speech recognition system. This module makes use of several models to emit a recognition hypothesis from the user’s speech signal. Generally speaking, a recognition system considers two types of models: an acoustic one (that models each of the phonemes that the recognition system has to consider) and a linguistic one (that models the sequences of words that make sense for the system). In this work we contextualize the language model of the recognition system in such a way that it takes into account the information provided by the user in both his or her current utterance and in the previous ones. These utterances convey information useful to help the system in the recognition of the next utterance. The contextualization approach that we propose consists of a dynamic adaptation of the language model that is used by the recognition system. We carry out this adaptation by means of a linear interpolation between several models. Instead of training the best interpolation weights, we make them dependent on the conditions of the dialogue. In our approach, the system itself will obtain these weights as a function of the reliability of the different elements of information available, such as the semantic concepts extracted from the user’s utterance, the actions that he or she wants to carry out, the information provided in the previous interactions, and so on. One of the aspects more frequently addressed in Human-Computer Interaction research is the inclusion of user specific characteristics into the information structures managed by the system. The idea is to take into account the features that make each user different from the others in order to offer to each particular user different services (or the same service, but in a different way). We could consider this approach as a user-dependent contextualization of the system. In our work we propose the definition of a user model that contains all the information of each user that could be potentially useful to the system at a given moment of the interaction. In particular we will analyze the actions that each user carries out throughout his or her interaction. The objective is to determine which of these actions become the preferences of that user. We represent the specific information of each user as a feature vector. Each of the characteristics that the system will take into account has a confidence score associated. With these elements, we propose a probabilistic definition of a user preference, as the action whose likelihood of being addressed by the user is greater than the one for the rest of actions. To include the user dependent information into the dialogue flow, we modify the information structures on which the dialogue manager relies to retrieve information that could be needed to solve the actions addressed by the user. Usage preferences become another source of contextual information that will be considered by the system towards a more efficient interaction (since the new information source will help to decrease the need of the system to ask users for additional information, thus reducing the number of turns needed to carry out a specific action). To test the benefits of the contextualization framework that we propose, we carry out an evaluation of the two strategies aforementioned. We gather several performance metrics, both objective and subjective, that allow us to compare the improvements of a contextualized system against the baseline one. We will also gather the user’s opinions as regards their perceptions on the behaviour of the system, and its degree of adaptation to the specific features of each interaction. Resumen El diseño y el desarrollo de sistemas de interacción hablada ha sido objeto de profundo estudio durante las pasadas décadas. El propósito es la consecución de sistemas con la capacidad de interactuar con agentes humanos con un alto grado de eficiencia y naturalidad. De esta manera, los usuarios pueden desempeñar las tareas que deseen empleando la voz, que es el medio de comunicación más natural para los humanos. A fin de alcanzar el grado de naturalidad deseado, no basta con dotar a los sistemas de la abilidad de comprender las intervenciones de los usuarios y reaccionar a ellas de manera apropiada (teniendo en consideración, incluso, la información proporcionada en previas interacciones). Adicionalmente, el sistema ha de ser consciente de las condiciones bajo las cuales transcurre la interacción, así como de la evolución de las mismas, de tal manera que pueda actuar de la manera más coherente en cada instante de la interacción. En consecuencia, una de las características primordiales del sistema es que debe ser sensible al contexto. Esta capacidad del sistema de conocer y emplear el contexto de la interacción puede verse reflejada en la modificación de su comportamiento debida a las características actuales de la interacción. Por ejemplo, el sistema debería decidir cuál es la acción más apropiada, o la mejor manera de llevarla a término, dependiendo del usuario que la solicita, del modo en el que lo hace, etcétera. En otras palabras, el sistema ha de adaptar su comportamiento a tales elementos mutables (o dinámicos) de la interacción. Dos características adicionales son requeridas a dicha adaptación: i) el usuario no ha de percibir que el sistema dedica recursos (temporales o computacionales) a realizar tareas distintas a las que aquél le solicita, y ii) el usuario no ha de dedicar esfuerzo alguno a proporcionar al sistema información adicional para llevar a cabo la interacción. Esto último implicaría una menor eficiencia de la interacción, puesto que los usuarios deberían dedicar parte de la misma a proporcionar información al sistema para su adaptación, sin ningún beneficio inmediato. En los sistemas de diálogo hablado propuestos en la literatura, se han propuesto diferentes estrategias para llevar a cabo la adaptación de los elementos del sistema a las diferentes condiciones de la interacción (tales como las características acústicas del habla de un usuario particular, o a las acciones a las que se ha referido con anterioridad). Sin embargo, no existe una estrategia fija para proceder a dicha adaptación, sino que las mismas no suelen guardar una relación entre sí. En este sentido, cada una de ellas tiene en cuenta distintas fuentes de información, la cual es tratada de manera diferente en función de las características de la adaptación buscada. Teniendo en cuenta lo anterior, las contribuciones principales de esta Tesis son las siguientes: Definición de un marco de contextualización. Proponemos un criterio unificador que pueda cubrir cualquier estrategia de adaptación del comportamiento de un sistema de diálogo a las condiciones de la interacción (esto es, el contexto de la misma). En nuestra definición teórica del marco de contextualización consideramos el contexto del sistema como todas aquellas fuentes de variabilidad presentes en cualquier instante de la interacción, ya estén relacionadas con el entorno en el que tiene lugar la interacción, ya dependan del agente humano que se dirige al sistema en cada momento. Nuestra propuesta se basa en tres aspectos que cualquier estrategia de contextualización debería cumplir: plasticidad (es decir, el sistema ha de ser capaz de modificar su comportamiento de la manera más proactiva posible, teniendo en cuenta las condiciones en las que tiene lugar la interacción), adaptabilidad (esto es, el sistema ha de ser capaz de considerar la información oportuna en cada instante, ya dependa del entorno o del usuario, de tal manera que adecúe su comportamiento de manera eficaz a las condiciones mencionadas), y transparencia (que implica que el sistema ha de desarrollar las tareas relacionadas con la contextualización de tal manera que el usuario no perciba la manera en que dichas tareas se llevan a cabo, ni tampoco deba proporcionar al sistema con información adicional alguna). De manera adicional, incluiremos en el marco propuesto el aspecto de la generalidad: las características del marco de contextualización han de ser portables a cualquier sistema de diálogo, con independencia de la solución propuesta en los mismos para gestionar el diálogo. Una vez hemos definido las características de alto nivel de nuestro marco de contextualización, proponemos dos estrategias de aplicación del mismo a un sistema de diálogo hablado. Nos centraremos en dos aspectos de la interacción a adaptar: los modelos empleados en el reconocimiento de habla, y la incorporación de información específica de cada usuario en el flujo de diálogo. Uno de los módulos de un sistema de diálogo más susceptible de ser contextualizado es el sistema de reconocimiento de habla. Este módulo hace uso de varios modelos para generar una hipótesis de reconocimiento a partir de la señal de habla. En general, un sistema de reconocimiento emplea dos tipos de modelos: uno acústico (que modela cada uno de los fonemas considerados por el reconocedor) y uno lingüístico (que modela las secuencias de palabras que tienen sentido desde el punto de vista de la interacción). En este trabajo contextualizamos el modelo lingüístico del reconocedor de habla, de tal manera que tenga en cuenta la información proporcionada por el usuario, tanto en su intervención actual como en las previas. Estas intervenciones contienen información (semántica y/o discursiva) que puede contribuir a un mejor reconocimiento de las subsiguientes intervenciones del usuario. La estrategia de contextualización propuesta consiste en una adaptación dinámica del modelo de lenguaje empleado en el reconocedor de habla. Dicha adaptación se lleva a cabo mediante una interpolación lineal entre diferentes modelos. En lugar de entrenar los mejores pesos de interpolación, proponemos hacer los mismos dependientes de las condiciones actuales de cada diálogo. El propio sistema obtendrá estos pesos como función de la disponibilidad y relevancia de las diferentes fuentes de información disponibles, tales como los conceptos semánticos extraídos a partir de la intervención del usuario, o las acciones que el mismo desea ejecutar. Uno de los aspectos más comúnmente analizados en la investigación de la Interacción Persona-Máquina es la inclusión de las características específicas de cada usuario en las estructuras de información empleadas por el sistema. El objetivo es tener en cuenta los aspectos que diferencian a cada usuario, de tal manera que el sistema pueda ofrecer a cada uno de ellos el servicio más apropiado (o un mismo servicio, pero de la manera más adecuada a cada usuario). Podemos considerar esta estrategia como una contextualización dependiente del usuario. En este trabajo proponemos la definición de un modelo de usuario que contenga toda la información relativa a cada usuario, que pueda ser potencialmente utilizada por el sistema en un momento determinado de la interacción. En particular, analizaremos aquellas acciones que cada usuario decide ejecutar a lo largo de sus diálogos con el sistema. Nuestro objetivo es determinar cuáles de dichas acciones se convierten en las preferencias de cada usuario. La información de cada usuario quedará representada mediante un vector de características, cada una de las cuales tendrá asociado un valor de confianza. Con ambos elementos proponemos una definición probabilística de una preferencia de uso, como aquella acción cuya verosimilitud es mayor que la del resto de acciones solicitadas por el usuario. A fin de incluir la información dependiente de usuario en el flujo de diálogo, llevamos a cabo una modificación de las estructuras de información en las que se apoya el gestor de diálogo para recuperar información necesaria para resolver ciertos diálogos. En dicha modificación las preferencias de cada usuario pasarán a ser una fuente adicional de información contextual, que será tenida en cuenta por el sistema en aras de una interacción más eficiente (puesto que la nueva fuente de información contribuirá a reducir la necesidad del sistema de solicitar al usuario información adicional, dando lugar en consecuencia a una reducción del número de intervenciones necesarias para llevar a cabo una acción determinada). Para determinar los beneficios de las aplicaciones del marco de contextualización propuesto, llevamos a cabo una evaluación de un sistema de diálogo que incluye las estrategias mencionadas. Hemos recogido diversas métricas, tanto objetivas como subjetivas, que nos permiten determinar las mejoras aportadas por un sistema contextualizado en comparación con el sistema sin contextualizar. De igual manera, hemos recogido las opiniones de los participantes en la evaluación acerca de su percepción del comportamiento del sistema, y de su capacidad de adaptación a las condiciones concretas de cada interacción.

Novel system for bite-force sensing and monitoring based on magnetic eear field communication

Intraoral devices for bite-force sensing have several applications in odontology and maxillofacial surgery, as bite-force measurements provide additional information to help understand the characteristics of bruxism disorders and can also be of help for the evaluation of post-surgical evolution and for comparison of alternative treatments. A new system for measuring human bite forces is proposed in this work. This system has future applications for the monitoring of bruxism events and as a complement for its conventional diagnosis. Bruxism is a pathology consisting of grinding or tight clenching of the upper and lower teeth, which leads to several problems such as lesions to the teeth, headaches, orofacial pain and important disorders of the temporomandibular joint. The prototype uses a magnetic field communication scheme similar to low-frequency radio frequency identification (RFID) technology (NFC). The reader generates a low-frequency magnetic field that is used as the information carrier and powers the sensor. The system is notable because it uses an intra-mouth passive sensor and an external interrogator, which remotely records and processes information regarding a patient?s dental activity. This permits a quantitative assessment of bite-force, without requiring intra-mouth batteries, and can provide supplementary information to polysomnographic recordings, current most adequate early diagnostic method, so as to initiate corrective actions before irreversible dental wear appears. In addition to describing the system?s operational principles and the manufacture of personalized prototypes, this report will also demonstrate the feasibility of the system and results from the first in vitro and in vivo trials.

Cooperative controllers for highways based on human experience

The AUTOPIA program has been working on the development of intelligent autonomous vehicles for the last 10 years. Its latest advances have focused on the development of cooperative manœuvres based on communications involving several vehicles. However, so far, these manœuvres have been tested only on private tracks that emulate urban environments. The first experiments with autonomous vehicles on real highways, in the framework of the grand cooperative driving challenge (GCDC) where several vehicles had to cooperate in order to perform cooperative adaptive cruise control (CACC), are described. In this context, the main challenge was to translate, through fuzzy controllers, human driver experience to these scenarios. This communication describes the experiences deriving from this competition, specifically that concerning the controller and the system implemented in a Citröen C3.

Wireless communication enhancement methods for mobile robots in radiation environments

En entornos hostiles tales como aquellas instalaciones científicas donde la radiación ionizante es el principal peligro, el hecho de reducir las intervenciones humanas mediante el incremento de las operaciones robotizadas está siendo cada vez más de especial interés. CERN, la Organización Europea para la Investigación Nuclear, tiene alrededor de unos 50 km de superficie subterránea donde robots móviles controlador de forma remota podrían ayudar en su funcionamiento, por ejemplo, a la hora de llevar a cabo inspecciones remotas sobre radiación en los diferentes áreas destinados al efecto. No solo es preciso considerar que los robots deben ser capaces de recorrer largas distancias y operar durante largos periodos de tiempo, sino que deben saber desenvolverse en los correspondientes túneles subterráneos, tener en cuenta la presencia de campos electromagnéticos, radiación ionizante, etc. y finalmente, el hecho de que los robots no deben interrumpir el funcionamiento de los aceleradores. El hecho de disponer de un sistema de comunicaciones inalámbrico fiable y robusto es esencial para la correcta ejecución de las misiones que los robots deben afrontar y por supuesto, para evitar tales situaciones en las que es necesario la recuperación manual de los robots al agotarse su energía o al perder el enlace de comunicaciones. El objetivo de esta Tesis es proveer de las directrices y los medios necesarios para reducir el riesgo de fallo en la misión y maximizar las capacidades de los robots móviles inalámbricos los cuales disponen de almacenamiento finito de energía al trabajar en entornos peligrosos donde no se dispone de línea de vista directa. Para ello se proponen y muestran diferentes estrategias y métodos de comunicación inalámbrica. Teniendo esto en cuenta, se presentan a continuación los objetivos de investigación a seguir a lo largo de la Tesis: predecir la cobertura de comunicaciones antes y durante las misiones robotizadas; optimizar la capacidad de red inalámbrica de los robots móviles con respecto a su posición; y mejorar el rango operacional de esta clase de robots. Por su parte, las contribuciones a la Tesis se citan más abajo. El primer conjunto de contribuciones son métodos novedosos para predecir el consumo de energía y la autonomía en la comunicación antes y después de disponer de los robots en el entorno seleccionado. Esto es importante para proporcionar conciencia de la situación del robot y evitar fallos en la misión. El consumo de energía se predice usando una estrategia propuesta la cual usa modelos de consumo provenientes de diferentes componentes en un robot. La predicción para la cobertura de comunicaciones se desarrolla usando un nuevo filtro de RSS (Radio Signal Strength) y técnicas de estimación con la ayuda de Filtros de Kalman. El segundo conjunto de contribuciones son métodos para optimizar el rango de comunicaciones usando novedosas técnicas basadas en muestreo espacial que son robustas frente a ruidos de campos de detección y radio y que proporcionan redundancia. Se emplean métodos de diferencia central finitos para determinar los gradientes 2D RSS y se usa la movilidad del robot para optimizar el rango de comunicaciones y la capacidad de red. Este método también se valida con un caso de estudio centrado en la teleoperación háptica de robots móviles inalámbricos. La tercera contribución es un algoritmo robusto y estocástico descentralizado para la optimización de la posición al considerar múltiples robots autónomos usados principalmente para extender el rango de comunicaciones desde la estación de control al robot que está desarrollando la tarea. Todos los métodos y algoritmos propuestos se verifican y validan usando simulaciones y experimentos de campo con variedad de robots móviles disponibles en CERN. En resumen, esta Tesis ofrece métodos novedosos y demuestra su uso para: predecir RSS; optimizar la posición del robot; extender el rango de las comunicaciones inalámbricas; y mejorar las capacidades de red de los robots móviles inalámbricos para su uso en aplicaciones dentro de entornos peligrosos, que como ya se mencionó anteriormente, se destacan las instalaciones científicas con emisión de radiación ionizante. En otros términos, se ha desarrollado un conjunto de herramientas para mejorar, facilitar y hacer más seguras las misiones de los robots en entornos hostiles. Esta Tesis demuestra tanto en teoría como en práctica que los robots móviles pueden mejorar la calidad de las comunicaciones inalámbricas mediante la profundización en el estudio de su movilidad para optimizar dinámicamente sus posiciones y mantener conectividad incluso cuando no existe línea de vista. Los métodos desarrollados en la Tesis son especialmente adecuados para su fácil integración en robots móviles y pueden ser aplicados directamente en la capa de aplicación de la red inalámbrica. ABSTRACT In hostile environments such as in scientific facilities where ionising radiation is a dominant hazard, reducing human interventions by increasing robotic operations are desirable. CERN, the European Organization for Nuclear Research, has around 50 km of underground scientific facilities, where wireless mobile robots could help in the operation of the accelerator complex, e.g. in conducting remote inspections and radiation surveys in different areas. The main challenges to be considered here are not only that the robots should be able to go over long distances and operate for relatively long periods, but also the underground tunnel environment, the possible presence of electromagnetic fields, radiation effects, and the fact that the robots shall in no way interrupt the operation of the accelerators. Having a reliable and robust wireless communication system is essential for successful execution of such robotic missions and to avoid situations of manual recovery of the robots in the event that the robot runs out of energy or when the robot loses its communication link. The goal of this thesis is to provide means to reduce risk of mission failure and maximise mission capabilities of wireless mobile robots with finite energy storage capacity working in a radiation environment with non-line-of-sight (NLOS) communications by employing enhanced wireless communication methods. Towards this goal, the following research objectives are addressed in this thesis: predict the communication range before and during robotic missions; optimise and enhance wireless communication qualities of mobile robots by using robot mobility and employing multi-robot network. This thesis provides introductory information on the infrastructures where mobile robots will need to operate, the tasks to be carried out by mobile robots and the problems encountered in these environments. The reporting of research work carried out to improve wireless communication comprises an introduction to the relevant radio signal propagation theory and technology followed by explanation of the research in the following stages: An analysis of the wireless communication requirements for mobile robot for different tasks in a selection of CERN facilities; predictions of energy and communication autonomies (in terms of distance and time) to reduce risk of energy and communication related failures during missions; autonomous navigation of a mobile robot to find zone(s) of maximum radio signal strength to improve communication coverage area; and autonomous navigation of one or more mobile robots acting as mobile wireless relay (repeater) points in order to provide a tethered wireless connection to a teleoperated mobile robot carrying out inspection or radiation monitoring activities in a challenging radio environment. The specific contributions of this thesis are outlined below. The first sets of contributions are novel methods for predicting the energy autonomy and communication range(s) before and after deployment of the mobile robots in the intended environments. This is important in order to provide situational awareness and avoid mission failures. The energy consumption is predicted by using power consumption models of different components in a mobile robot. This energy prediction model will pave the way for choosing energy-efficient wireless communication strategies. The communication range prediction is performed using radio signal propagation models and applies radio signal strength (RSS) filtering and estimation techniques with the help of Kalman filters and Gaussian process models. The second set of contributions are methods to optimise the wireless communication qualities by using novel spatial sampling based techniques that are robust to sensing and radio field noises and provide redundancy features. Central finite difference (CFD) methods are employed to determine the 2-D RSS gradients and use robot mobility to optimise the communication quality and the network throughput. This method is also validated with a case study application involving superior haptic teleoperation of wireless mobile robots where an operator from a remote location can smoothly navigate a mobile robot in an environment with low-wireless signals. The third contribution is a robust stochastic position optimisation algorithm for multiple autonomous relay robots which are used for wireless tethering of radio signals and thereby to enhance the wireless communication qualities. All the proposed methods and algorithms are verified and validated using simulations and field experiments with a variety of mobile robots available at CERN. In summary, this thesis offers novel methods and demonstrates their use to predict energy autonomy and wireless communication range, optimise robots position to improve communication quality and enhance communication range and wireless network qualities of mobile robots for use in applications in hostile environmental characteristics such as scientific facilities emitting ionising radiations. In simpler terms, a set of tools are developed in this thesis for improving, easing and making safer robotic missions in hostile environments. This thesis validates both in theory and experiments that mobile robots can improve wireless communication quality by exploiting robots mobility to dynamically optimise their positions and maintain connectivity even when the (radio signal) environment possess non-line-of-sight characteristics. The methods developed in this thesis are well-suited for easier integration in mobile robots and can be applied directly at the application layer of the wireless network. The results of the proposed methods have outperformed other comparable state-of-the-art methods.

Types of metaphor in civil engineering communication

La metáfora y otros mecanismos imaginativos subyacentes al pensa- miento y lenguaje humanos pueden ser utilizados en el discurso diario y especializado (Lakoff y Johnson 1980; Lakoff y Nuñez 2000). Asimismo pueden aparecer en la comunicación no verbal (Forceville y Urios-Aparisi 2009; Littlemore et al. Este volumen).Partiendo de estudios cognitivos y de la teoría de integración conceptual (Fauconnier 1997; Fauconnier y Turner 2002), este artículo examina la presencia de la metáfora en la ingeniería. Primeramente, se analiza un corpus lingüístico procedente de artículos de investigación de ingeniería civil. Los datos revelan el uso de la metáfora antropomórfica, sobre todo en expresiones relativas a la salud, como “diagnóstico”, “auscultación” o “proceso de curación”. Se exploran además ejemplos de ingeniería cuya fuente son proyecciones conceptuales corporales. Finalmente, abordamos la función de la metáfora visual bajo la teoría de integración conceptual mediante representaciones de ingeniería que evocan la anatomía humana o animal. Metaphor and other imaginative mechanisms that underlie human thought and language such as metonymy are used in everyday and specialised discourse (Lakoff and Johnson 1980; Lakoff and Nuñez 2000) They can also be involved in non- verbal forms of communication (Forceville and Urios-Aparisi 2009; Littlemore et al. this volume). Drawing on metaphor cognitive studies and on conceptual integration theory (Fauconnier 1997; Fauconnier and Turner 2002) this paper examines the occurrence of metaphor in engineering. First, we analyse results from a linguistic corpus formed by research papers from civil engineering journals. These data reveal the use of anthropomorphic metaphor, especially related to health or medical mappings such as “diagnosing”, “auscultation” or “curing”. Then, we explore how engineering notions are instantiated by bodily conceptual mappings according to conceptual integration theory. Finally, the function of visual metaphor is examined with conceptual integration theory by using engineering images evoking parts of human or animal anatomy.

Human-robot interaction for telemanipulation in large workspaces

Independientemente de la existencia de técnicas altamente sofisticadas y capacidades de cómputo cada vez más elevadas, los problemas asociados a los robots que interactúan con entornos no estructurados siguen siendo un desafío abierto en robótica. A pesar de los grandes avances de los sistemas robóticos autónomos, hay algunas situaciones en las que una persona en el bucle sigue siendo necesaria. Ejemplos de esto son, tareas en entornos de fusión nuclear, misiones espaciales, operaciones submarinas y cirugía robótica. Esta necesidad se debe a que las tecnologías actuales no pueden realizar de forma fiable y autónoma cualquier tipo de tarea. Esta tesis presenta métodos para la teleoperación de robots abarcando distintos niveles de abstracción que van desde el control supervisado, en el que un operador da instrucciones de alto nivel en la forma de acciones, hasta el control bilateral, donde los comandos toman la forma de señales de control de bajo nivel. En primer lugar, se presenta un enfoque para llevar a cabo la teleoperación supervisada de robots humanoides. El objetivo es controlar robots terrestres capaces de ejecutar tareas complejas en entornos de búsqueda y rescate utilizando enlaces de comunicación limitados. Esta propuesta incorpora comportamientos autónomos que el operador puede utilizar para realizar tareas de navegación y manipulación mientras se permite cubrir grandes áreas de entornos remotos diseñados para el acceso de personas. Los resultados experimentales demuestran la eficacia de los métodos propuestos. En segundo lugar, se investiga el uso de dispositivos rentables para telemanipulación guiada. Se presenta una aplicación que involucra un robot humanoide bimanual y un traje de captura de movimiento basado en sensores inerciales. En esta aplicación, se estudian las capacidades de adaptación introducidas por el factor humano y cómo estas pueden compensar la falta de sistemas robóticos de alta precisión. Este trabajo es el resultado de una colaboración entre investigadores del Biorobotics Laboratory de la Universidad de Harvard y el Centro de Automática y Robótica UPM-CSIC. En tercer lugar, se presenta un nuevo controlador háptico que combina velocidad y posición. Este controlador bilateral híbrido hace frente a los problemas relacionados con la teleoperación de un robot esclavo con un gran espacio de trabajo usando un dispositivo háptico pequeño como maestro. Se pueden cubrir amplias áreas de trabajo al cambiar automáticamente entre los modos de control de velocidad y posición. Este controlador háptico es ideal para sistemas maestro-esclavo con cinemáticas diferentes, donde los comandos se transmiten en el espacio de la tarea del entorno remoto. El método es validado para realizar telemanipulación hábil de objetos con un robot industrial. Por último, se introducen dos contribuciones en el campo de la manipulación robótica. Por un lado, se presenta un nuevo algoritmo de cinemática inversa, llamado método iterativo de desacoplamiento cinemático. Este método se ha desarrollado para resolver el problema cinemático inverso de un tipo de robot de seis grados de libertad donde una solución cerrada no está disponible. La eficacia del método se compara con métodos numéricos convencionales. Además, se ha diseñado una taxonomía robusta de agarres que permite controlar diferentes manos robóticas utilizando una correspondencia, basada en gestos, entre los espacios de trabajo de la mano humana y de la mano robótica. El gesto de la mano humana se identifica mediante la lectura de los movimientos relativos del índice, el pulgar y el dedo medio del usuario durante las primeras etapas del agarre. ABSTRACT Regardless of the availability of highly sophisticated techniques and ever increasing computing capabilities, the problems associated with robots interacting with unstructured environments remains an open challenge. Despite great advances in autonomous robotics, there are some situations where a humanin- the-loop is still required, such as, nuclear, space, subsea and robotic surgery operations. This is because the current technologies cannot reliably perform all kinds of task autonomously. This thesis presents methods for robot teleoperation strategies at different levels of abstraction ranging from supervisory control, where the operator gives high-level task actions, to bilateral teleoperation, where the commands take the form of low-level control inputs. These strategies contribute to improve the current human-robot interfaces specially in the case of slave robots deployed at large workspaces. First, an approach to perform supervisory teleoperation of humanoid robots is presented. The goal is to control ground robots capable of executing complex tasks in disaster relief environments under constrained communication links. This proposal incorporates autonomous behaviors that the operator can use to perform navigation and manipulation tasks which allow covering large human engineered areas of the remote environment. The experimental results demonstrate the efficiency of the proposed methods. Second, the use of cost-effective devices for guided telemanipulation is investigated. A case study involving a bimanual humanoid robot and an Inertial Measurement Unit (IMU) Motion Capture (MoCap) suit is introduced. Herein, it is corroborated how the adaptation capabilities offered by the human-in-the-loop factor can compensate for the lack of high-precision robotic systems. This work is the result of collaboration between researchers from the Harvard Biorobotics Laboratory and the Centre for Automation and Robotics UPM-CSIC. Thirdly, a new haptic rate-position controller is presented. This hybrid bilateral controller copes with the problems related to the teleoperation of a slave robot with large workspace using a small haptic device as master. Large workspaces can be covered by automatically switching between rate and position control modes. This haptic controller is ideal to couple kinematic dissimilar master-slave systems where the commands are transmitted in the task space of the remote environment. The method is validated to perform dexterous telemanipulation of objects with a robotic manipulator. Finally, two contributions for robotic manipulation are introduced. First, a new algorithm, the Iterative Kinematic Decoupling method, is presented. It is a numeric method developed to solve the Inverse Kinematics (IK) problem of a type of six-DoF robotic arms where a close-form solution is not available. The effectiveness of this IK method is compared against conventional numerical methods. Second, a robust grasp mapping has been conceived. It allows to control a wide range of different robotic hands using a gesture based correspondence between the human hand space and the robotic hand space. The human hand gesture is identified by reading the relative movements of the index, thumb and middle fingers of the user during the early stages of grasping.

Development of a human movement monitoring system based on wearable devices

It is essential to remotely and continuously monitor the movements of individuals in many social areas, for example, taking care of aging people, physical therapy, athletic training etc. Many methods have been used, such as video record, motion analysis or sensor-based methods. Due to the limitations in remote communication, power consumption, portability and so on, most of them are not able to fulfill the requirements. The development of wearable technology and cloud computing provides a new efficient way to achieve this goal. This paper presents an intelligent human movement monitoring system based on a smartwatch, an Android smartphone and a distributed data management engine. This system includes advantages of wide adaptability, remote and long-term monitoring capacity, high portability and flexibility. The structure of the system and its principle are introduced. Four experiments are designed to prove the feasibility of the system. The results of the experiments demonstrate the system is able to detect different actions of individuals with adequate accuracy.

The elliptic model for communication fluxes

In this paper, a model (called the elliptic model) is proposed to estimate the number of social ties between two locations using population data in a similar manner to how transportation research deals with trips. To overcome the asymmetry of transportation models, the new model considers that the number of relationships between two locations is inversely proportional to the population in the ellipse whose foci are in these two locations. The elliptic model is evaluated by considering the anonymous communications patterns of 25 million users from three different countries, where a location has been assigned to each user based on their most used phone tower or billing zip code. With this information, spatial social networks are built at three levels of resolution: tower, city and region for each of the three countries. The elliptic model achieves a similar performance when predicting communication fluxes as transportation models do when predicting trips. This shows that human relationships are influenced at least as much by geography as is human mobility.