Development of HIF-1α/HIF-1β heterodimerization inhibitors using a novel bioluminescence reporter assay system for in vitro high throughput screening and in vivo imaging

Tumor growth often outpaces its vascularization, leading to development of a hypoxic tumor microenvironment. In response, an intracellular hypoxia survival pathway is initiated by heterodimerization of hypoxia-inducible factor (HIF)-1α and HIF-1β, which subsequently upregulates the expression of several hypoxia-inducible genes, promotes cell survival and stimulates angiogenesis in the oxygen-deprived environment. Hypoxic tumor regions are often associated with resistance to various classes of radio- or chemotherapeutic agents. Therefore, development of HIF-1α/β heterodimerization inhibitors may provide a novel approach to anti-cancer therapy. To this end, a novel approach for imaging HIF-1α/β heterodimerization in vitro and in vivo was developed in this study. Using this screening platform, we identified a promising lead candidate and further chemically derivatized the lead candidate to assess the structure-activity relationship (SAR). The most effective first generation drug inhibitors were selected and their pharmacodynamics and anti-tumor efficacy in vivo were verified by bioluminescence imaging (BLI) of HIF-1α/β heterodimerization in the xenograft tumor model. Furthermore, the first generation drug inhibitors, M-TMCP and D-TMCP, demonstrated efficacy as monotherapies, resulting in tumor growth inhibition via disruption of HIF-1 signaling-mediated tumor stromal neoangiogenesis.

The SasS -SasR two-component signal transduction system required for early Myxococcus xanthus multicellular *development

Initiation of Myxococcus xanthus multicellular development requires both nutrient limitation and high cell density. The extracellular signal, A signal, which consists of a set of amino acids at specific concentrations, serves as a cell density signal in M. xanthus early development. A reporter gene, designated 4521, that requires both starvation and A signal for developmental expression was used to identify mutations in the signal transduction pathways. A group of point mutations located in the chromosomal sasB locus that bypasses both requirements was previously isolated. One of these point mutations, sasB7, was mapped to the sasS gene, which is predicted to encode a transmembrane histidine protein kinase required for normal development. SasS is a positive regulator of 4521 and a candidate A signal sensor. This dissertation continues the characterization of the sasB locus, focusing on the sasR gene and the functional relationship of SasS and SasR. ^ The sasR gene is located 2.2-kb downstream of sasS. It is predicted to encode an NtrC-like response regulator, which belongs to the family of sigma54 transcriptional activators. SasR is a positive regulator of 4521 gene and is required for normal development. The sasR mutant displays phenotypes similar to that of sasS mutant. Both SasS and SasR are required for the A-signal-dependent 4521 expression. Genetic epistasis analysis indicates that SasR functions downstream of SasS. Biochemical studies show that SasS has autokinase activity, and phosphorylated SasS is able to transfer its phosphate to SasR. We propose that SasS and SasR form a two-component signal transduction system in the A signal transduction pathway. ^ To search for the genes regulated by SasS and SasR, expression patterns of a group of developmental genes were compared in wild-type and sasS null mutant backgrounds. SasS and SasR were found to positively regulate sasN and 4521. The sasN gene was previously identified as a negative regulator of 4521, located at about 170-bp downstream of sasR. It is required for normal fruiting body development. Based on the above data, a regulatory network consisting of sasS, sasR, sasN, and 4521 is hypothesized, and the interactions of the components in this network can now be further studied. ^

Industrial Development and the Innovation System of the Ethanol Sector in Brazil

The purpose of this paper is to analyze innovations and the innovation system and its dynamics in the ethanol sector in the State of Sao Paulo. More specifically, this paper focuses on the development process in the sector, the public policies taken to promote the sector, and the organizations and key players involved in these policies and their responses to unforeseeable changes in economic, social and technological environments. To this end, this paper takes an historical perspective and reviews data on the cultivation of sugar cane, the production of ethanol, and on sugar cane yields as indicators of the innovations achieved in the sector. The geographical distribution of these indicators is also examined. Next, several cases in Piracicaba and Campinas in the State of Sao Paulo are presented; these give us a more concrete idea of the processes involved in innovation and technology transfer. Based on these observations, the ethanol cluster and the innovation system of the State of Sao Paulo are discussed from the viewpoint of the flowchart approach to industrial cluster policy.

Input-Output Based Economic Impact Evaluation System for Small City Development: A Case Study on Saemangeum's Flux City Design

The paper aims to develop a quasi-dynamic interregional input-output model for evaluating the macro-economic impacts of small city development. The features of the model are summarized as follows: (1) the consumption expenditure of households is regarded as an endogenous variable, (2) the technological change is determined by the change of industrial Location Quotient caused by firm's investment activities. (3) a strong feedback function between the city design and the economic analysis is provided. For checking the performance of the model, Saemangeum's Flux City Design Plan is used as the simulation target in our paper.

Application of gas-cooled Accelerator Driven System (ADS) transmutation devices to sustainable nuclear energy development

The conceptual design of a pebble bed gas-cooled transmutation device is shown with the aim to evaluate its potential for its deployment in the context of the sustainable nuclear energy development, which considers high temperature reactors for their operation in cogeneration mode, producing electricity, heat and Hydrogen. As differential characteristics our device operates in subcritical mode, driven by a neutron source activated by an accelerator that adds clear safety advantages and fuel flexibility opening the possibility to reduce the nuclear stockpile producing energy from actual LWR irradiated fuel with an efficiency of 45?46%, either in the form of Hydrogen, electricity, or both.

Program development using abstract interpretation (and the ciao system preprocessor)

The technique of Abstract Interpretation has allowed the development of very sophisticated global program analyses which are at the same time provably correct and practical. We present in a tutorial fashion a novel program development framework which uses abstract interpretation as a fundamental tool. The framework uses modular, incremental abstract interpretation to obtain information about the program. This information is used to validate programs, to detect bugs with respect to partial specifications written using assertions (in the program itself and/or in system librarles), to genérate and simplify run-time tests, and to perform high-level program transformations such as múltiple abstract specialization, parallelization, and resource usage control, all in a provably correct way. In the case of validation and debugging, the assertions can refer to a variety of program points such as procedure entry, procedure exit, points within procedures, or global computations. The system can reason with much richer information than, for example, traditional types. This includes data structure shape (including pointer sharing), bounds on data structure sizes, and other operational variable instantiation properties, as well as procedure-level properties such as determinacy, termination, non-failure, and bounds on resource consumption (time or space cost). CiaoPP, the preprocessor of the Ciao multi-paradigm programming system, which implements the described functionality, will be used to illustrate the fundamental ideas.

Design, development and field evaluation of a Spanish into sign language translation system

This paper describes the design, development and field evaluation of a machine translation system from Spanish to Spanish Sign Language (LSE: Lengua de Signos Española). The developed system focuses on helping Deaf people when they want to renew their Driver’s License. The system is made up of a speech recognizer (for decoding the spoken utterance into a word sequence), a natural language translator (for converting a word sequence into a sequence of signs belonging to the sign language), and a 3D avatar animation module (for playing back the signs). For the natural language translator, three technological approaches have been implemented and evaluated: an example-based strategy, a rule-based translation method and a statistical translator. For the final version, the implemented language translator combines all the alternatives into a hierarchical structure. This paper includes a detailed description of the field evaluation. This evaluation was carried out in the Local Traffic Office in Toledo involving real government employees and Deaf people. The evaluation includes objective measurements from the system and subjective information from questionnaires. The paper details the main problems found and a discussion on how to solve them (some of them specific for LSE).

Sustainable Air Traffic Management System Development Methodology

As it is defined in ATM 2000+ Strategy (Eurocontrol 2001), the mission of the Air Traffic Management (ATM) System is: “For all the phases of a flight, the ATM system should facilitate a safe, efficient, and expedite traffic flow, through the provision of adaptable ATM services that can be dimensioned in relation to the requirements of all the users and areas of the European air space. The ATM services should comply with the demand, be compatible, operate under uniform principles, respect the environment and satisfy the national security requirements.” The objective of this paper is to present a methodology designed to evaluate the status of the ATM system in terms of the relationship between the offered capacity and traffic demand, identifying weakness areas and proposing solutions. The first part of the methodology relates to the characterization and evaluation of the current system, while a second part proposes an approach to analyze the possible development limit. As part of the work, general criteria are established to define the framework in which the analysis and diagnostic methodology presented is placed. They are: the use of Air Traffic Control (ATC) sectors as analysis unit, the presence of network effects, the tactical focus, the relative character of the analysis, objectivity and a high level assessment that allows assumptions on the human and Communications, Navigation and Surveillance (CNS) elements, considered as the typical high density air traffic resources. The steps followed by the methodology start with the definition of indicators and metrics, like the nominal criticality or the nominal efficiency of a sector; scenario characterization where the necessary data is collected; network effects analysis to study the relations among the constitutive elements of the ATC system; diagnostic by means of the “System Status Diagram”; analytical study of the ATC system development limit; and finally, formulation of conclusions and proposal for improvement. This methodology was employed by Aena (Spanish Airports Manager and Air Navigation Service Provider) and INECO (Spanish Transport Engineering Company) in the analysis of the Spanish ATM System in the frame of the Spanish airspace capacity sustainability program, although it could be applied elsewhere.

Ventilation system design and large scale fire tests

The design, construction and operation of the tunnels of M-30, the major ring road in the city of Madrid (Spain), represent a very interesting project in wich a wide variety of situations -geometrical, topographical, etc.- had to be covered, in variable conditions of traffic. For that reasons, the M-30 project is a remarkable technical challenge, which, after its completion, turned into an international reference. From the "design for safety" perspective, a holistic approach has been used to deal with new technologies, integration of systems and development of the procedures to reach the maximum level. However, one of the primary goals has been to achieve reasonable homogeneity characteristics which can permit operate a netword of tunels as one only infraestructure. In the case of the ventilation system the mentioned goals have implied innovative solutions and coordination efforts of great interest. Consequently, this paper describes the principal ideas underlying the conceptual solution developed focusing on the principal peculiarities of the project.

Depth sensors-based upper limb motion capture system for functional neurorehabilitation

Versatile and accurate motion capture systems, with the required properties to be integrated within both clinical and domiciliary environments, would represent a significant advance in following the progress of the patients as well as in allowing the incorporation of new data exploitation and analysis methods to enhance the functional neurorehabilitation therapeutic processes. Besides, these systems would permit the later development of new applications focused on the automatization of the therapeutic tasks in order to increase the therapist/patient ratio, thus decreasing the costs [1]. However, current motion capture systems are not still ready to work within uncontrolled environments.

Development and experimental evaluation of a complete solar thermophotovoltaic system

We present a practical implementation of a solar thermophotovoltaic (TPV) system. The system presented in this paper comprises a sunlight concentrator system, a cylindrical cup-shaped absorber/emitter (made of tungsten coated with HfO2), and an hexagonal-shaped water-cooled TPV generator comprising 24 germanium TPV cells, which is surrounding the cylindrical absorber/emitter. This paper focuses on the development of shingled TPV cell arrays, the characterization of the sunlight concentrator system, the estimation of the temperature achieved by the cylindrical emitters operated under concentrated sunlight, and the evaluation of the full system performance under real outdoor irradiance conditions. From the system characterization, we have measured short-circuit current densities up to 0.95 A/cm2, electric power densities of 67 mW/cm2, and a global conversion efficiency of about 0.8%. To our knowledge, this is the first overall solar-to-electricity efficiency reported for a complete solar thermophotovoltaic system. The very low efficiency is mainly due to the overheating of the cells (up to 120 °C) and to the high optical concentrator losses, which prevent the achievement of the optimum emitter temperature. The loss analysis shows that by improving both aspects, efficiencies above 5% could be achievable in the very short term and efficiencies above 10% could be achieved with further improvements.

Development of a management system for virtual machines on private clouds

Cloud computing and, more particularly, private IaaS, is seen as a mature technol- ogy with a myriad solutions to choose from. However, this disparity of solutions and products has instilled in potential adopters the fear of vendor and data lock- in. Several competing and incompatible interfaces and management styles have increased even more these fears. On top of this, cloud users might want to work with several solutions at the same time, an integration that is difficult to achieve in practice. In this Master Thesis I propose a management architecture that tries to solve these problems; it provides a generalized control mechanism for several cloud infrastructures, and an interface that can meet the requirements of the users. This management architecture is designed in a modular way, and using a generic infor- mation model. I have validated the approach through the implementation of the components needed for this architecture to support a sample private IaaS solution: OpenStack.

Smart aeronautical structures: development and experimental validation of a structural health monitoring system for damage detection

En muchas áreas de la ingeniería, la integridad y confiabilidad de las estructuras son aspectos de extrema importancia. Estos son controlados mediante el adecuado conocimiento de danos existentes. Típicamente, alcanzar el nivel de conocimiento necesario que permita caracterizar la integridad estructural implica el uso de técnicas de ensayos no destructivos. Estas técnicas son a menudo costosas y consumen mucho tiempo. En la actualidad, muchas industrias buscan incrementar la confiabilidad de las estructuras que emplean. Mediante el uso de técnicas de última tecnología es posible monitorizar las estructuras y en algunos casos, es factible detectar daños incipientes que pueden desencadenar en fallos catastróficos. Desafortunadamente, a medida que la complejidad de las estructuras, los componentes y sistemas incrementa, el riesgo de la aparición de daños y fallas también incrementa. Al mismo tiempo, la detección de dichas fallas y defectos se torna más compleja. En años recientes, la industria aeroespacial ha realizado grandes esfuerzos para integrar los sensores dentro de las estructuras, además de desarrollar algoritmos que permitan determinar la integridad estructural en tiempo real. Esta filosofía ha sido llamada “Structural Health Monitoring” (o “Monitorización de Salud Estructural” en español) y este tipo de estructuras han recibido el nombre de “Smart Structures” (o “Estructuras Inteligentes” en español). Este nuevo tipo de estructuras integran materiales, sensores, actuadores y algoritmos para detectar, cuantificar y localizar daños dentro de ellas mismas. Una novedosa metodología para detección de daños en estructuras se propone en este trabajo. La metodología está basada en mediciones de deformación y consiste en desarrollar técnicas de reconocimiento de patrones en el campo de deformaciones. Estas últimas, basadas en PCA (Análisis de Componentes Principales) y otras técnicas de reducción dimensional. Se propone el uso de Redes de difracción de Bragg y medidas distribuidas como sensores de deformación. La metodología se validó mediante pruebas a escala de laboratorio y pruebas a escala real con estructuras complejas. Los efectos de las condiciones de carga variables fueron estudiados y diversos experimentos fueron realizados para condiciones de carga estáticas y dinámicas, demostrando que la metodología es robusta ante condiciones de carga desconocidas. ABSTRACT In many engineering fields, the integrity and reliability of the structures are extremely important aspects. They are controlled by the adequate knowledge of existing damages. Typically, achieving the level of knowledge necessary to characterize the structural integrity involves the usage of nondestructive testing techniques. These are often expensive and time consuming. Nowadays, many industries look to increase the reliability of the structures used. By using leading edge techniques it is possible to monitoring these structures and in some cases, detect incipient damage that could trigger catastrophic failures. Unfortunately, as the complexity of the structures, components and systems increases, the risk of damages and failures also increases. At the same time, the detection of such failures and defects becomes more difficult. In recent years, the aerospace industry has done great efforts to integrate the sensors within the structures and, to develop algorithms for determining the structural integrity in real time. The ‘philosophy’ has being called “Structural Health Monitoring” and these structures have been called “smart structures”. These new types of structures integrate materials, sensors, actuators and algorithms to detect, quantify and locate damage within itself. A novel methodology for damage detection in structures is proposed. The methodology is based on strain measurements and consists in the development of strain field pattern recognition techniques. The aforementioned are based on PCA (Principal Component Analysis) and other dimensional reduction techniques. The use of fiber Bragg gratings and distributed sensing as strain sensors is proposed. The methodology have been validated by using laboratory scale tests and real scale tests with complex structures. The effects of the variable load conditions were studied and several experiments were performed for static and dynamic load conditions, demonstrating that the methodology is robust under unknown load conditions.

An Implemented of a Real-Time Experimental Setup for Robotic Teleoperation System

The development of this work presents the implementation of an experimental platform, which will permit to investigate on a methodology for the design and analysis of a teleoperated system, considering the delay in the communication channel. The project has been developed in partnership with the laboratory of Automatic and Robotics of the Universidad Politécnica de Madrid and the Laboratory at the Centro de Tecnologías Avanzadas de Manufactura at the Pontificia Universidad Católica del Perú. The mechanical structure of the arm that is located in the remote side has been built and the electric servomechanism has been mounted to control their movement. The experimental test of the Teleoperation system has been developed. The PC104 card commands the power interface and sensors of the DC motor of each articulation of the arm. Has developed the drives for the management of the operations of the master and the slave: send/reception of position, speed, acceleration and current data through a CAN network. The programs for the interconnection through a LAN network, between the Windows Operating System and the Real-time Operating System (QNX), has been developed. The utility of the developed platform (hardware and software) has been demonstrated.