Modeling the survival of T-cell lymphocytes using compound branching processes

Radiotherapy has been a method of choice in cancer treatment for a number of years. Mathematical modeling is an important tool in studying the survival behavior of any cell as well as its radiosensitivity. One particular cell under investigation is the normal T-cell, the radiosensitivity of which may be indicative to the patient's tolerance to radiation doses.^ The model derived is a compound branching process with a random initial population of T-cells that is assumed to have compound distribution. T-cells in any generation are assumed to double or die at random lengths of time. This population is assumed to undergo a random number of generations within a period of time. The model is then used to obtain an estimate for the survival probability of T-cells for the data under investigation. This estimate is derived iteratively by applying the likelihood principle. Further assessment of the validity of the model is performed by simulating a number of subjects under this model.^ This study shows that there is a great deal of variation in T-cells survival from one individual to another. These variations can be observed under normal conditions as well as under radiotherapy. The findings are in agreement with a recent study and show that genetic diversity plays a role in determining the survival of T-cells. ^

Modeling Techniques for the High-Resolution Interpretation of Cryo-Electron Microscopy Reconstructions

Essential biological processes are governed by organized, dynamic interactions between multiple biomolecular systems. Complexes are thus formed to enable the biological function and get dissembled as the process is completed. Examples of such processes include the translation of the messenger RNA into protein by the ribosome, the folding of proteins by chaperonins or the entry of viruses in host cells. Understanding these fundamental processes by characterizing the molecular mechanisms that enable then, would allow the (better) design of therapies and drugs. Such molecular mechanisms may be revealed trough the structural elucidation of the biomolecular assemblies at the core of these processes. Various experimental techniques may be applied to investigate the molecular architecture of biomolecular assemblies. High-resolution techniques, such as X-ray crystallography, may solve the atomic structure of the system, but are typically constrained to biomolecules of reduced flexibility and dimensions. In particular, X-ray crystallography requires the sample to form a three dimensional (3D) crystal lattice which is technically di‑cult, if not impossible, to obtain, especially for large, dynamic systems. Often these techniques solve the structure of the different constituent components within the assembly, but encounter difficulties when investigating the entire system. On the other hand, imaging techniques, such as cryo-electron microscopy (cryo-EM), are able to depict large systems in near-native environment, without requiring the formation of crystals. The structures solved by cryo-EM cover a wide range of resolutions, from very low level of detail where only the overall shape of the system is visible, to high-resolution that approach, but not yet reach, atomic level of detail. In this dissertation, several modeling methods are introduced to either integrate cryo-EM datasets with structural data from X-ray crystallography, or to directly interpret the cryo-EM reconstruction. Such computational techniques were developed with the goal of creating an atomic model for the cryo-EM data. The low-resolution reconstructions lack the level of detail to permit a direct atomic interpretation, i.e. one cannot reliably locate the atoms or amino-acid residues within the structure obtained by cryo-EM. Thereby one needs to consider additional information, for example, structural data from other sources such as X-ray crystallography, in order to enable such a high-resolution interpretation. Modeling techniques are thus developed to integrate the structural data from the different biophysical sources, examples including the work described in the manuscript I and II of this dissertation. At intermediate and high-resolution, cryo-EM reconstructions depict consistent 3D folds such as tubular features which in general correspond to alpha-helices. Such features can be annotated and later on used to build the atomic model of the system, see manuscript III as alternative. Three manuscripts are presented as part of the PhD dissertation, each introducing a computational technique that facilitates the interpretation of cryo-EM reconstructions. The first manuscript is an application paper that describes a heuristics to generate the atomic model for the protein envelope of the Rift Valley fever virus. The second manuscript introduces the evolutionary tabu search strategies to enable the integration of multiple component atomic structures with the cryo-EM map of their assembly. Finally, the third manuscript develops further the latter technique and apply it to annotate consistent 3D patterns in intermediate-resolution cryo-EM reconstructions. The first manuscript, titled An assembly model for Rift Valley fever virus, was submitted for publication in the Journal of Molecular Biology. The cryo-EM structure of the Rift Valley fever virus was previously solved at 27Å-resolution by Dr. Freiberg and collaborators. Such reconstruction shows the overall shape of the virus envelope, yet the reduced level of detail prevents the direct atomic interpretation. High-resolution structures are not yet available for the entire virus nor for the two different component glycoproteins that form its envelope. However, homology models may be generated for these glycoproteins based on similar structures that are available at atomic resolutions. The manuscript presents the steps required to identify an atomic model of the entire virus envelope, based on the low-resolution cryo-EM map of the envelope and the homology models of the two glycoproteins. Starting with the results of the exhaustive search to place the two glycoproteins, the model is built iterative by running multiple multi-body refinements to hierarchically generate models for the different regions of the envelope. The generated atomic model is supported by prior knowledge regarding virus biology and contains valuable information about the molecular architecture of the system. It provides the basis for further investigations seeking to reveal different processes in which the virus is involved such as assembly or fusion. The second manuscript was recently published in the of Journal of Structural Biology (doi:10.1016/j.jsb.2009.12.028) under the title Evolutionary tabu search strategies for the simultaneous registration of multiple atomic structures in cryo-EM reconstructions. This manuscript introduces the evolutionary tabu search strategies applied to enable a multi-body registration. This technique is a hybrid approach that combines a genetic algorithm with a tabu search strategy to promote the proper exploration of the high-dimensional search space. Similar to the Rift Valley fever virus, it is common that the structure of a large multi-component assembly is available at low-resolution from cryo-EM, while high-resolution structures are solved for the different components but lack for the entire system. Evolutionary tabu search strategies enable the building of an atomic model for the entire system by considering simultaneously the different components. Such registration indirectly introduces spatial constrains as all components need to be placed within the assembly, enabling the proper docked in the low-resolution map of the entire assembly. Along with the method description, the manuscript covers the validation, presenting the benefit of the technique in both synthetic and experimental test cases. Such approach successfully docked multiple components up to resolutions of 40Å. The third manuscript is entitled Evolutionary Bidirectional Expansion for the Annotation of Alpha Helices in Electron Cryo-Microscopy Reconstructions and was submitted for publication in the Journal of Structural Biology. The modeling approach described in this manuscript applies the evolutionary tabu search strategies in combination with the bidirectional expansion to annotate secondary structure elements in intermediate resolution cryo-EM reconstructions. In particular, secondary structure elements such as alpha helices show consistent patterns in cryo-EM data, and are visible as rod-like patterns of high density. The evolutionary tabu search strategy is applied to identify the placement of the different alpha helices, while the bidirectional expansion characterizes their length and curvature. The manuscript presents the validation of the approach at resolutions ranging between 6 and 14Å, a level of detail where alpha helices are visible. Up to resolution of 12 Å, the method measures sensitivities between 70-100% as estimated in experimental test cases, i.e. 70-100% of the alpha-helices were correctly predicted in an automatic manner in the experimental data. The three manuscripts presented in this PhD dissertation cover different computation methods for the integration and interpretation of cryo-EM reconstructions. The methods were developed in the molecular modeling software Sculptor (http://sculptor.biomachina.org) and are available for the scientific community interested in the multi-resolution modeling of cryo-EM data. The work spans a wide range of resolution covering multi-body refinement and registration at low-resolution along with annotation of consistent patterns at high-resolution. Such methods are essential for the modeling of cryo-EM data, and may be applied in other fields where similar spatial problems are encountered, such as medical imaging.

Multi Domain-Specific Modeling of the Security Concerns of Service-Oriented Architectures

Service-Oriented Architectures (SOA), and Web Services (WS), the technology generally used to implement them, achieve the integration of heterogeneous technologies, providing interoperability, and yielding the reutilization of pre-existent systems. Model-driven development methodologies provide inherent benefits such as increased productivity, greater reuse, and better maintainability, to name a few. Efforts on achieving model-driven development of SOAs already exist, but there is currently no standard solution that addresses non-functional aspects of these services as well. This paper presents an approach to integrate these non-functional aspects in the development of web services, with an emphasis on security.

Application of the Extended Kalman filter to fuzzy modeling: Algorithms and practical implementation

Modeling phase is fundamental both in the analysis process of a dynamic system and the design of a control system. If this phase is in-line is even more critical and the only information of the system comes from input/output data. Some adaptation algorithms for fuzzy system based on extended Kalman filter are presented in this paper, which allows obtaining accurate models without renounce the computational efficiency that characterizes the Kalman filter, and allows its implementation in-line with the process

Balancing groundwater conservation and rural livelihoods under water and climate uncertainties: An integrated hydro-economic modeling framework

In arid countries worldwide, social conflicts between irrigation-based human development and the conservation of aquatic ecosystems are widespread and attract many public debates. This research focuses on the analysis of water and agricultural policies aimed at conserving groundwater resources and maintaining rurallivelihoods in a basin in Spain's central arid region. Intensive groundwater mining for irrigation has caused overexploitation of the basin's large aquifer, the degradation of reputed wetlands and has given rise to notable social conflicts over the years. With the aim of tackling the multifaceted socio-ecological interactions of complex water systems, the methodology used in this study consists in a novel integration into a common platform of an economic optimization model and a hydrology model WEAP (Water Evaluation And Planning system). This robust tool is used to analyze the spatial and temporal effects of different water and agricultural policies under different climate scenarios. It permits the prediction of different climate and policy outcomes across farm types (water stress impacts and adaptation), at basin's level (aquifer recovery), and along the policies’ implementation horizon (short and long run). Results show that the region's current quota-based water policies may contribute to reduce water consumption in the farms but will not be able to recover the aquifer and will inflict income losses to the rural communities. This situation would worsen in case of drought. Economies of scale and technology are evidenced as larger farms with cropping diversification and those equipped with modern irrigation will better adapt to water stress conditions. However, the long-term sustainability of the aquifer and the maintenance of rurallivelihoods will be attained only if additional policy measures are put in place such as the control of illegal abstractions and the establishing of a water bank. Within the policy domain, the research contributes to the new sustainable development strategy of the EU by concluding that, in water-scarce regions, effective integration of water and agricultural policies is essential for achieving the water protection objectives of the EU policies. Therefore, the design and enforcement of well-balanced region-specific polices is a major task faced by policy makers for achieving successful water management that will ensure nature protection and human development at tolerable social costs. From a methodological perspective, this research initiative contributes to better address hydrological questions as well as economic and social issues in complex water and human systems. Its integrated vision provides a valuable illustration to inform water policy and management decisions within contexts of water-related conflicts worldwide.

Advances in the modeling, characterization and reliability of concentrator multijunction solar cells

Los sistemas de concentración fotovoltaica (CPV) parecen ser una de las vías más prometedoras para generar electricidad a gran escala a precios competitivos. La investigación actual se centra en aumentar la eficiencia y la concentración de los sistemas para abaratar costes. Al mismo tiempo se investiga sobre la fiabilidad de los diferentes componentes que integran un sistema de concentración, ya que para que los sistemas de concentración sean competitivos es necesario que tengan una fiabilidad al menos similar a los sistemas basados en células de silicio. En la presente tesis doctoral se ha llevado a cabo el estudio de aspectos avanzados de células solares multi-unión diseñadas para trabajar a concentraciones ultra-altas. Para ello, se ha desarrollado un modelo circuital tridimensional distribuido con el que simular el comportamiento de las células solares triple-unión bajo distintas condiciones de funcionamiento, así mismo se ha realizado una caracterización avanzada de este tipo de células para comprender mejor su modo de operación y así poder contribuir a mejorar su eficiencia. Finalmente, se han llevado a cabo ensayos de vida acelerados en células multiunión comerciales para conocer la fiabilidad de este tipo de células solares. Para la simulación de células solares triple-unión se ha desarrollado en la presente tesis doctoral un modelo circuital tridimensinal distribuido el cuál integra una descripción completa de la unión túnel. De este modo, con el modelo desarrollado, hemos podido simular perfiles de luz sobre la célula solar que hacen que la densidad de corriente fotogenerada sea mayor a la densidad de corriente pico de la unión túnel. El modelo desarrollado también contempla la distribución lateral de corriente en las capas semiconductoras que componen y rodean la unión túnel. Por tanto, se ha podido simular y analizar el efecto que tiene sobre el funcionamiento de la célula solar que los concentradores ópticos produzcan perfiles de luz desuniformes, tanto en nivel de irradiancia como en el contenido espectral de la luz (aberración cromática). Con el objetivo de determinar cuáles son los mecanismos de recombinación que están limitando el funcionamiento de cada subcélula que integra una triple-unión, y así intentar reducirlos, se ha llevado a cabo la caracterización eléctrica de células solares monouni ón idénticas a las subcelulas de una triple-unión. También se ha determinado la curva corriente-tensión en oscuridad de las subcélulas de GaInP y GaAs de una célula dobleunión mediante la utilización de un teorema de reciprocidad electro-óptico. Finalmente, se ha analizado el impacto de los diferentes mecanismos de recombinación en el funcionamiento de la célula solar triple-unión en concentración. Por último, para determinar la fiabilidad de este tipo de células, se ha llevado a cabo un ensayo de vida acelerada en temperatura en células solares triple-unión comerciales. En la presente tesis doctoral se describe el diseño del ensayo, el progreso del mismo y los datos obtenidos tras el análisis de los resultados preliminares. Abstract Concentrator photovoltaic systems (CPV) seem to be one of the most promising ways to generate electricity at competitive prices. Nowadays, the research is focused on increasing the efficiency and the concentration of the systems in order to reduce costs. At the same time, another important area of research is the study of the reliability of the different components which make up a CPV system. In fact, in order for a CPV to be cost-effective, it should have a warranty at least similar to that of the systems based on Si solar cells. In the present thesis, we will study in depth the behavior of multijunction solar cells under ultra-high concentration. With this purpose in mind, a three-dimensional circuital distributed model which is able to simulate the behavior of triple-junction solar cells under different working conditions has been developed. Also, an advanced characterization of these solar cells has been carried out in order to better understand their behavior and thus contribute to improving efficiency. Finally, accelerated life tests have been carried out on commercial lattice-matched triple-junction solar cells in order to determine their reliability. In order to simulate triple-junction solar cells, a 3D circuital distributed model which integrates a full description of the tunnel junction has been developed. We have analyzed the behavior of the multijunction solar cell under light profiles which cause the current density photo-generated in the solar cell to be higher than the tunnel junction’s peak current density. The advanced model developed also takes into account the lateral current spreading through the semiconductor layers which constitute and surround the tunnel junction. Therefore, the effects of non-uniform light profiles, in both irradiance and the spectral content produced by the concentrators on the solar cell, have been simulated and analyzed. In order to determine which recombination mechanisms are limiting the behavior of each subcell in a triple-junction stack, and to try to reduce them when possible, an electrical characterization of single-junction solar cells that resemble the subcells in a triplejunction stack has been carried out. Also, the dark I-V curves of the GaInP and GaAs subcells in a dual-junction solar cell have been determined by using an electro-optical reciprocity theorem. Finally, the impact of the different recombination mechanisms on the behavior of the triple-junction solar cell under concentration has been analyzed. In order to determine the reliability of these solar cells, a temperature accelerated life test has been carried out on commercial triple-junction solar cells. In the present thesis, the design and the evolution of the test, as well as the data obtained from the analysis of the preliminary results, are presented.

Measurement of Distributed Antenna Systems at 2.4 GHz in a Realistic Subway Tunnel Environment.

Accurate characterization of the radio channel in tunnels is of great importance for new signaling and train control communications systems. To model this environment, measurements have been taken at 2.4 GHz in a real environment in Madrid subway. The measurements were carried out with four base station transmitters installed in a 2-km tunnel and using a mobile receiver installed on a standard train. First, with an optimum antenna configuration, all the propagation characteristics of a complex subway environment, including near shadowing, path loss,shadow fading, fast fading, level crossing rate (LCR), and average fade duration (AFD), have been measured and computed. Thereafter, comparisons of propagation characteristics in a double-track tunnel (9.8-m width) and a single-track tunnel (4.8-m width) have been made. Finally, all the measurement results have been shown in a complete table for accurate statistical modeling.

Intraply fracture of fiber-reinforced composites: microscopic mechanisms and modeling

The fracture behavior parallel to the fibers of an E-glass/epoxy unidirectional laminate was studied by means of three-point tests on notched beams. Selected tests were carried out within a scanning electron microscope to ascertain the damage and fracture micromechanisms upon loading. The mechanical behavior of the notched beam was simulated within the framework of the embedded cell model, in which the actual composite microstructure was resolved in front of the notch tip. In addition, matrix and interface properties were independently measured in situ using a nanoindentor. The numerical simulations very accurately predicted the macroscopic response of the composite as well as the damage development and crack growth in front of the notch tip, demonstrating the ability of the embedded cell approach to simulate the fracture behavior of heterogeneous materials. Finally, this methodology was exploited to ascertain the influence of matrix and interface properties on the intraply toughness.

Data Processing Modeling in Decision Support Systems.

Due to the advancement of both, information technology in general, and databases in particular; data storage devices are becoming cheaper and data processing speed is increasing. As result of this, organizations tend to store large volumes of data holding great potential information. Decision Support Systems, DSS try to use the stored data to obtain valuable information for organizations. In this paper, we use both data models and use cases to represent the functionality of data processing in DSS following Software Engineering processes. We propose a methodology to develop DSS in the Analysis phase, respective of data processing modeling. We have used, as a starting point, a data model adapted to the semantics involved in multidimensional databases or data warehouses, DW. Also, we have taken an algorithm that provides us with all the possible ways to automatically cross check multidimensional model data. Using the aforementioned, we propose diagrams and descriptions of use cases, which can be considered as patterns representing the DSS functionality, in regard to DW data processing, DW on which DSS are based. We highlight the reusability and automation benefits that this can be achieved, and we think this study can serve as a guide in the development of DSS.

HAZOP studies using a functional modeling framework

In this paper we present a tool to perform guided HAZOP studies using a functional modeling framework: D-higraphs. It is a formalism that gathers in a single model structural (ontological) and functional information about the process considered. In this paper it is applied to an industrial case showing that the proposed methodology fits its purposes and fulfills some of the gaps and drawbacks existing in previous reported HAZOP assistant tools.

Functional modeling applied to HAZOP automation

In this paper we present a new tool to perform guided HAZOP analyses. This tool uses a functional model of the process that merges its functional and its structural information in a natural way. The functional modeling technique used is called D-higraphs. This tool solves some of the problems and drawbacks of other existing methodologies for the automation of HAZOPs. The applicability and easy understanding of the proposed methodology is shown in an industrial case.

Modeling Piezoelectric Harvesting Materials in Road Traffic Applications.

En esta comunicación se presenta el método para obtener modelos equivalentes eléctricos de materiales piezoeléctricos utilizados en entornos con tráfico vial para aplicaciones "Energy Harvesting". Los resultados experimentales se procesan para determinar la estructura topológica óptima y la tecnología de los elementos semiconductores utilizados en la etapa de entrada del sistema de alimentación "harvesting". Asimismo se presenta el modelo de la fuente de alimentación no regulada bajo demanda variable de corriente. Abstract: The method to obtain electrical equivalent models of piezoelectric materials used in energy harvesting road traffic environment is presented in this paper. The experimental results are processed in order to determine the optimal topological structure and technology of the semiconductor elements used in the input stage of the power harvesting system. The non regulated power supply model under variable current demand is also presented.

Hybrid incremental modeling based on least squares and fuzzy K-NN for monitoring tool wear in turning processes

There is now an emerging need for an efficient modeling strategy to develop a new generation of monitoring systems. One method of approaching the modeling of complex processes is to obtain a global model. It should be able to capture the basic or general behavior of the system, by means of a linear or quadratic regression, and then superimpose a local model on it that can capture the localized nonlinearities of the system. In this paper, a novel method based on a hybrid incremental modeling approach is designed and applied for tool wear detection in turning processes. It involves a two-step iterative process that combines a global model with a local model to take advantage of their underlying, complementary capacities. Thus, the first step constructs a global model using a least squares regression. A local model using the fuzzy k-nearest-neighbors smoothing algorithm is obtained in the second step. A comparative study then demonstrates that the hybrid incremental model provides better error-based performance indices for detecting tool wear than a transductive neurofuzzy model and an inductive neurofuzzy model.

Modeling Reflective Bistability in Vertical-Cavity Semiconductor Optical Amplifiers

The characteristics of optical bistability in a vertical- cavity semiconductor optical amplifier (VCSOA) operated in reflection are reported. The dependences of the optical bistability in VCSOAs on the initial phase detuning and on the applied bias current are analyzed. The optical bistability is also studied for different numbers of superimposed periods in the top distributed bragg reflector (DBR) that conform the internal cavity of the device. The appearance of the X-bistable and the clockwise bistable loops is predicted theoretically in a VCSOA operated in reflection for the first time, to the best of our knowledge. Moreover, it is also predicted that the control of the VCSOA’s top reflectivity by the addition of new superimposed periods in its top DBR reduces by one order of magnitude the input power needed for the assessment of the X- and the clockwise bistable loop, compared to that required in in-plane semiconductor optical amplifiers. These results, added to the ease of fabricating two-dimensional arrays of this kind of device could be useful for the development of new optical logic or optical signal regeneration devices.

Implementation of a building automation system based on semantic modeling

This paper presents an Ontology-Based multi-technology platform designed to avoid some issues of Building Automation Systems. The platform allows the integration of several building automation protocols, eases the development and implementation of different kinds of services and allows sharing information related to the infrastructure and facilities within a building. The system has been implemented and tested in the Energy Efficiency Research Facility at CeDInt-UPM.