Computational methods for the analysis of protein structure and function

The vast majority of known proteins have not yet been experimentally characterized and little is known about their function. The design and implementation of computational tools can provide insight into the function of proteins based on their sequence, their structure, their evolutionary history and their association with other proteins. Knowledge of the three-dimensional (3D) structure of a protein can lead to a deep understanding of its mode of action and interaction, but currently the structures of <1% of sequences have been experimentally solved. For this reason, it became urgent to develop new methods that are able to computationally extract relevant information from protein sequence and structure. The starting point of my work has been the study of the properties of contacts between protein residues, since they constrain protein folding and characterize different protein structures. Prediction of residue contacts in proteins is an interesting problem whose solution may be useful in protein folding recognition and de novo design. The prediction of these contacts requires the study of the protein inter-residue distances related to the specific type of amino acid pair that are encoded in the so-called contact map. An interesting new way of analyzing those structures came out when network studies were introduced, with pivotal papers demonstrating that protein contact networks also exhibit small-world behavior. In order to highlight constraints for the prediction of protein contact maps and for applications in the field of protein structure prediction and/or reconstruction from experimentally determined contact maps, I studied to which extent the characteristic path length and clustering coefficient of the protein contacts network are values that reveal characteristic features of protein contact maps. Provided that residue contacts are known for a protein sequence, the major features of its 3D structure could be deduced by combining this knowledge with correctly predicted motifs of secondary structure. In the second part of my work I focused on a particular protein structural motif, the coiled-coil, known to mediate a variety of fundamental biological interactions. Coiled-coils are found in a variety of structural forms and in a wide range of proteins including, for example, small units such as leucine zippers that drive the dimerization of many transcription factors or more complex structures such as the family of viral proteins responsible for virus-host membrane fusion. The coiled-coil structural motif is estimated to account for 5-10% of the protein sequences in the various genomes. Given their biological importance, in my work I introduced a Hidden Markov Model (HMM) that exploits the evolutionary information derived from multiple sequence alignments, to predict coiled-coil regions and to discriminate coiled-coil sequences. The results indicate that the new HMM outperforms all the existing programs and can be adopted for the coiled-coil prediction and for large-scale genome annotation. Genome annotation is a key issue in modern computational biology, being the starting point towards the understanding of the complex processes involved in biological networks. The rapid growth in the number of protein sequences and structures available poses new fundamental problems that still deserve an interpretation. Nevertheless, these data are at the basis of the design of new strategies for tackling problems such as the prediction of protein structure and function. Experimental determination of the functions of all these proteins would be a hugely time-consuming and costly task and, in most instances, has not been carried out. As an example, currently, approximately only 20% of annotated proteins in the Homo sapiens genome have been experimentally characterized. A commonly adopted procedure for annotating protein sequences relies on the "inheritance through homology" based on the notion that similar sequences share similar functions and structures. This procedure consists in the assignment of sequences to a specific group of functionally related sequences which had been grouped through clustering techniques. The clustering procedure is based on suitable similarity rules, since predicting protein structure and function from sequence largely depends on the value of sequence identity. However, additional levels of complexity are due to multi-domain proteins, to proteins that share common domains but that do not necessarily share the same function, to the finding that different combinations of shared domains can lead to different biological roles. In the last part of this study I developed and validate a system that contributes to sequence annotation by taking advantage of a validated transfer through inheritance procedure of the molecular functions and of the structural templates. After a cross-genome comparison with the BLAST program, clusters were built on the basis of two stringent constraints on sequence identity and coverage of the alignment. The adopted measure explicity answers to the problem of multi-domain proteins annotation and allows a fine grain division of the whole set of proteomes used, that ensures cluster homogeneity in terms of sequence length. A high level of coverage of structure templates on the length of protein sequences within clusters ensures that multi-domain proteins when present can be templates for sequences of similar length. This annotation procedure includes the possibility of reliably transferring statistically validated functions and structures to sequences considering information available in the present data bases of molecular functions and structures.

Experimental and Numerical Analysis of Gas Forced Convection through Microtubes and Micro Heat Exchangers

The last decade has witnessed very fast development in microfabrication technologies. The increasing industrial applications of microfluidic systems call for more intensive and systematic knowledge on this newly emerging field. Especially for gaseous flow and heat transfer at microscale, the applicability of conventional theories developed at macro scale is not yet completely validated; this is mainly due to scarce experimental data available in literature for gas flows. The objective of this thesis is to investigate these unclear elements by analyzing forced convection for gaseous flows through microtubes and micro heat exchangers. Experimental tests have been performed with microtubes having various inner diameters, namely 750 m, 510 m and 170 m, over a wide range of Reynolds number covering the laminar region, the transitional zone and also the onset region of the turbulent regime. The results show that conventional theory is able to predict the flow friction factor when flow compressibility does not appear and the effect of fluid temperature-dependent properties is insignificant. A double-layered microchannel heat exchanger has been designed in order to study experimentally the efficiency of a gas-to-gas micro heat exchanger. This microdevice contains 133 parallel microchannels machined into polished PEEK plates for both the hot side and the cold side. The microchannels are 200 µm high, 200 µm wide and 39.8 mm long. The design of the micro device has been made in order to be able to test different materials as partition foil with flexible thickness. Experimental tests have been carried out for five different partition foils, with various mass flow rates and flow configurations. The experimental results indicate that the thermal performance of the countercurrent and cross flow micro heat exchanger can be strongly influenced by axial conduction in the partition foil separating the hot gas flow and cold gas flow.

"Offshore tower or platform foundations: numerical analysis of a laterally loaded single pile or pile group in soft clay and analysis of actions on a jacket structure"

Laterally loaded piles are a typical situation for a large number of cases in which deep foundations are used. Dissertation herein reported, is a focus upon the numerical simulation of laterally loaded piles. In the first chapter the best model settings are largely discussed, so a clear idea about the effects of interface adoption, model dimension, refinement cluster and mesh coarseness is reached. At a second stage, there are three distinct parametric analyses, in which the model response sensibility is studied for variation of interface reduction factor, Eps50 and tensile cut-off. In addition, the adoption of an advanced soil model is analysed (NGI-ADP). This was done in order to use the complex behaviour (different undrained shear strengths are involved) that governs the resisting process of clay under short time static loads. Once set a definitive model, a series of analyses has been carried out with the objective of defining the resistance-deflection (P-y) curves for Plaxis3D (2013) data. Major results of a large number of comparisons made with curves from API (America Petroleum Institute) recommendation are that the empirical curves have almost the same ultimate resistance but a bigger initial stiffness. In the second part of the thesis a simplified structural preliminary design of a jacket structure has been carried out to evaluate the environmental forces that act on it and on its piles foundation. Finally, pile lateral response is studied using the empirical curves.

Hydrodynamic induced by an array of wave energy converters. Experimental and numerical analysis

The thesis analyses the hydrodynamic induced by an array of Wave energy Converters (WECs), under an experimental and numerical point of view. WECs can be considered an innovative solution able to contribute to the green energy supply and –at the same time– to protect the rear coastal area under marine spatial planning considerations. This research activity essentially rises due to this combined concept. The WEC under exam is a floating device belonging to the Wave Activated Bodies (WAB) class. Experimental data were performed at Aalborg University in different scales and layouts, and the performance of the models was analysed under a variety of irregular wave attacks. The numerical simulations performed with the codes MIKE 21 BW and ANSYS-AQWA. Experimental results were also used to calibrate the numerical parameters and/or to directly been compared to numerical results, in order to extend the experimental database. Results of the research activity are summarized in terms of device performance and guidelines for a future wave farm installation. The device length should be “tuned” based on the local climate conditions. The wave transmission behind the devices is pretty high, suggesting that the tested layout should be considered as a module of a wave farm installation. Indications on the minimum inter-distance among the devices are provided. Furthermore, a CALM mooring system leads to lower wave transmission and also larger power production than a spread mooring. The two numerical codes have different potentialities. The hydrodynamics around single and multiple devices is obtained with MIKE 21 BW, while wave loads and motions for a single moored device are derived from ANSYS-AQWA. Combining the experimental and numerical it is suggested –for both coastal protection and energy production– to adopt a staggered layout, which will maximise the devices density and minimize the marine space required for the installation.

Analysis of endogenous retinoic acid receptor expression and function in murine melanoma cells

There have been numerous reports over the past several years on the ability of vitamin A analogs (retinoids) to modulate cell proliferation, malignant transformation, morphogenesis, and differentiation in a wide variety of cell types and organisms. Two families of nuclear retinoid-inducible, trans-acting, transcription-enhancing receptors that bear strong DNA sequence homology to thyroid and steroid hormone receptors have recently been discovered. The retinoic acid receptors (RARs) and retinoid X receptors (RXRs) each have at least three types designated $\alpha,$ $\beta,$ and $\gamma,$ which are encoded by separate genes and expressed in a tissue and cell type-specific manner. We have been interested in the mechanism by which retinoids inhibit tumor cell proliferation and induce differentiation. As a model system we have employed several murine melanoma cell lines (S91-C2, K1735P, and B16-F1), which are sensitive to the growth-inhibitory and differentiation-inducing effects of RA, as well as a RA-resistant subclone of one of the cell lines (S91-C154), in order to study the role of the nuclear RARs in these effects. The initial phase of this project consisted of the characterization of the expression pattern of the three known RAR and RXR types in the murine melanoma cell lines in order to determine whether any differences exist which may elucidate a role for any of the receptors in RA-induced growth inhibition and differentiation. The novel finding was made that the RAR-$\beta$ gene is rapidly induced from undetectable levels by RA treatment at the mRNA and protein level, and that the induction of RAR-$\beta$ by other biologically active retinoids correlated with their ability to inhibit the growth of the highly RA-sensitive S91-C2 cell line. This suggests a role for RAR-$\beta$ in the growth inhibiting effect of retinoids. The second phase of this project involves the stable expression of RAR-$\beta$ in the S91-C2 cells and the RAR-$\beta$ receptor-null cell line, K1735P. These studies have indicated an inverse correlation between RAR-$\beta$ expression and proliferation rate. ^

Experimental and numerical analysis of reinforced concrete elements subjected to blast loading

El hormigón es uno de los materiales de construcción más empleados en la actualidad debido a sus buenas prestaciones mecánicas, moldeabilidad y economía de obtención, entre otras ventajas. Es bien sabido que tiene una buena resistencia a compresión y una baja resistencia a tracción, por lo que se arma con barras de acero para formar el hormigón armado, material que se ha convertido por méritos propios en la solución constructiva más importante de nuestra época. A pesar de ser un material profusamente utilizado, hay aspectos del comportamiento del hormigón que todavía no son completamente conocidos, como es el caso de su respuesta ante los efectos de una explosión. Este es un campo de especial relevancia, debido a que los eventos, tanto intencionados como accidentales, en los que una estructura se ve sometida a una explosión son, por desgracia, relativamente frecuentes. La solicitación de una estructura ante una explosión se produce por el impacto sobre la misma de la onda de presión generada en la detonación. La aplicación de esta carga sobre la estructura es muy rápida y de muy corta duración. Este tipo de acciones se denominan cargas impulsivas, y pueden ser hasta cuatro órdenes de magnitud más rápidas que las cargas dinámicas impuestas por un terremoto. En consecuencia, no es de extrañar que sus efectos sobre las estructuras y sus materiales sean muy distintos que las que producen las cargas habitualmente consideradas en ingeniería. En la presente tesis doctoral se profundiza en el conocimiento del comportamiento material del hormigón sometido a explosiones. Para ello, es crucial contar con resultados experimentales de estructuras de hormigón sometidas a explosiones. Este tipo de resultados es difícil de encontrar en la literatura científica, ya que estos ensayos han sido tradicionalmente llevados a cabo en el ámbito militar y los resultados obtenidos no son de dominio público. Por otra parte, en las campañas experimentales con explosiones llevadas a cabo por instituciones civiles el elevado coste de acceso a explosivos y a campos de prueba adecuados no permite la realización de ensayos con un elevado número de muestras. Por este motivo, la dispersión experimental no es habitualmente controlada. Sin embargo, en elementos de hormigón armado sometidos a explosiones, la dispersión experimental es muy acusada, en primer lugar, por la propia heterogeneidad del hormigón, y en segundo, por la dificultad inherente a la realización de ensayos con explosiones, por motivos tales como dificultades en las condiciones de contorno, variabilidad del explosivo, o incluso cambios en las condiciones atmosféricas. Para paliar estos inconvenientes, en esta tesis doctoral se ha diseñado un novedoso dispositivo que permite ensayar hasta cuatro losas de hormigón bajo la misma detonación, lo que además de proporcionar un número de muestras estadísticamente representativo, supone un importante ahorro de costes. Con este dispositivo se han ensayado 28 losas de hormigón, tanto armadas como en masa, de dos dosificaciones distintas. Pero además de contar con datos experimentales, también es importante disponer de herramientas de cálculo para el análisis y diseño de estructuras sometidas a explosiones. Aunque existen diversos métodos analíticos, hoy por hoy las técnicas de simulación numérica suponen la alternativa más avanzada y versátil para el cálculo de elementos estructurales sometidos a cargas impulsivas. Sin embargo, para obtener resultados fiables es crucial contar con modelos constitutivos de material que tengan en cuenta los parámetros que gobiernan el comportamiento para el caso de carga en estudio. En este sentido, cabe destacar que la mayoría de los modelos constitutivos desarrollados para el hormigón a altas velocidades de deformación proceden del ámbito balístico, donde dominan las grandes tensiones de compresión en el entorno local de la zona afectada por el impacto. En el caso de los elementos de hormigón sometidos a explosiones, las tensiones de compresión son mucho más moderadas, siendo las tensiones de tracción generalmente las causantes de la rotura del material. En esta tesis doctoral se analiza la validez de algunos de los modelos disponibles, confirmando que los parámetros que gobiernan el fallo de las losas de hormigón armado ante explosiones son la resistencia a tracción y su ablandamiento tras rotura. En base a los resultados anteriores se ha desarrollado un modelo constitutivo para el hormigón ante altas velocidades de deformación, que sólo tiene en cuenta la rotura por tracción. Este modelo parte del de fisura cohesiva embebida con discontinuidad fuerte, desarrollado por Planas y Sancho, que ha demostrado su capacidad en la predicción de la rotura a tracción de elementos de hormigón en masa. El modelo ha sido modificado para su implementación en el programa comercial de integración explícita LS-DYNA, utilizando elementos finitos hexaédricos e incorporando la dependencia de la velocidad de deformación para permitir su utilización en el ámbito dinámico. El modelo es estrictamente local y no requiere de remallado ni conocer previamente la trayectoria de la fisura. Este modelo constitutivo ha sido utilizado para simular dos campañas experimentales, probando la hipótesis de que el fallo de elementos de hormigón ante explosiones está gobernado por el comportamiento a tracción, siendo de especial relevancia el ablandamiento del hormigón. Concrete is nowadays one of the most widely used building materials because of its good mechanical properties, moldability and production economy, among other advantages. As it is known, it has high compressive and low tensile strengths and for this reason it is reinforced with steel bars to form reinforced concrete, a material that has become the most important constructive solution of our time. Despite being such a widely used material, there are some aspects of concrete performance that are not yet fully understood, as it is the case of its response to the effects of an explosion. This is a topic of particular relevance because the events, both intentional and accidental, in which a structure is subjected to an explosion are, unfortunately, relatively common. The loading of a structure due to an explosive event occurs due to the impact of the pressure shock wave generated in the detonation. The application of this load on the structure is very fast and of very short duration. Such actions are called impulsive loads, and can be up to four orders of magnitude faster than the dynamic loads imposed by an earthquake. Consequently, it is not surprising that their effects on structures and materials are very different than those that cause the loads usually considered in engineering. This thesis broadens the knowledge about the material behavior of concrete subjected to explosions. To that end, it is crucial to have experimental results of concrete structures subjected to explosions. These types of results are difficult to find in the scientific literature, as these tests have traditionally been carried out by armies of different countries and the results obtained are classified. Moreover, in experimental campaigns with explosives conducted by civil institutions the high cost of accessing explosives and the lack of proper test fields does not allow for the testing of a large number of samples. For this reason, the experimental scatter is usually not controlled. However, in reinforced concrete elements subjected to explosions the experimental dispersion is very pronounced. First, due to the heterogeneity of concrete, and secondly, because of the difficulty inherent to testing with explosions, for reasons such as difficulties in the boundary conditions, variability of the explosive, or even atmospheric changes. To overcome these drawbacks, in this thesis we have designed a novel device that allows for testing up to four concrete slabs under the same detonation, which apart from providing a statistically representative number of samples, represents a significant saving in costs. A number of 28 slabs were tested using this device. The slabs were both reinforced and plain concrete, and two different concrete mixes were used. Besides having experimental data, it is also important to have computational tools for the analysis and design of structures subjected to explosions. Despite the existence of several analytical methods, numerical simulation techniques nowadays represent the most advanced and versatile alternative for the assessment of structural elements subjected to impulsive loading. However, to obtain reliable results it is crucial to have material constitutive models that take into account the parameters that govern the behavior for the load case under study. In this regard it is noteworthy that most of the developed constitutive models for concrete at high strain rates arise from the ballistic field, dominated by large compressive stresses in the local environment of the area affected by the impact. In the case of concrete elements subjected to an explosion, the compressive stresses are much more moderate, while tensile stresses usually cause material failure. This thesis discusses the validity of some of the available models, confirming that the parameters governing the failure of reinforced concrete slabs subjected to blast are the tensile strength and softening behaviour after failure. Based on these results we have developed a constitutive model for concrete at high strain rates, which only takes into account the ultimate tensile strength. This model is based on the embedded Cohesive Crack Model with Strong Discontinuity Approach developed by Planas and Sancho, which has proved its ability in predicting the tensile fracture of plain concrete elements. The model has been modified for its implementation in the commercial explicit integration program LS-DYNA, using hexahedral finite elements and incorporating the dependence of the strain rate, to allow for its use in dynamic domain. The model is strictly local and does not require remeshing nor prior knowledge of the crack path. This constitutive model has been used to simulate two experimental campaigns, confirming the hypothesis that the failure of concrete elements subjected to explosions is governed by their tensile response, being of particular relevance the softening behavior of concrete.

A unified framework for linear function approximation of value functions in stochastic control

This paper contributes with a unified formulation that merges previ- ous analysis on the prediction of the performance ( value function ) of certain sequence of actions ( policy ) when an agent operates a Markov decision process with large state-space. When the states are represented by features and the value function is linearly approxi- mated, our analysis reveals a new relationship between two common cost functions used to obtain the optimal approximation. In addition, this analysis allows us to propose an efficient adaptive algorithm that provides an unbiased linear estimate. The performance of the pro- posed algorithm is illustrated by simulation, showing competitive results when compared with the state-of-the-art solutions.

Experimental and numerical analysis of concrete Slabs subjected to Blast

This paper summarizes the research activities focused on the behaviour of concrete and concrete structures subjected to blast loading carried out by the Department of Materials Science of the Technical University of Madrid (PUM). These activities comprise the design and construction of a test bench that allows for testing up to four planar concrete specimens with one single explosion, the study of the performance of different protection concepts for concrete structures and, finally, the development of a numerical model for the simulation of concrete structural elements subjected to blast. Up to date 6 different types of concrete have been studied, from plain normal strength concrete, to high strength concrete, including also fibre reinforced concretes with different types of fibres. The numerical model is based on the Cohesive Crack Model approach, and has been developed for the LSDYNA finite element code through a user programmed subroutine. Despite its simplicity, the model is able to predict the failure patterns of the concrete slabs tested with a high level of accuracy

Numerical analysis of shell and spatial structures

Since the advent of the computer into the engineering field, the application of the numerical methods to the solution of engineering problems has grown very rapidly. Among the different computer methods of structural analysis the Finite Element (FEM) has been predominantly used. Shells and space structures are very attractive and have been constructed to solve a large variety of functional problems (roofs, industrial building, aqueducts, reservoirs, footings etc). In this type of structures aesthetics, structural efficiency and concept play a very important role. This class of structures can be divided into three main groups, namely continuous (concrete) shells, space frames and tension (fabric, pneumatic, cable etc )structures. In the following only the current applications of the FEM to the analysis of continuous shell structures will be discussed. However, some of the comments on this class of shells can be also applied to some extend to the others, but obviously specific computational problems will be restricted to the continuous shells. Different aspects, such as, the type of elements,input-output computational techniques etc, of the analysis of shells by the FEM will be described below. Clearly, the improvements and developments occurring in general for the FEM since its first appearance in the fifties have had a significative impact on the particular class of structures under discussion.

Los Angeles and Long Beach Harbors model study : numerical analysis of tidal circulation for the 2020 Master Plan /

"June 1984."

Problems for the numerical analysis of the future; [papers presented at the symposium on modern calculating machinery and numerical methods, held on July 29-31, 1948, at the University of California, Los Angeles]

Includes bibliographies.

FAA lightning protection study : lightning, induced transients on buried shielded transmission lines, numerical analysis and results /

Mode of access: Internet.

OMNITAB : a computer program for statistical and numerical analysis /

Includes bibliographies and index.

Theoretical and numerical analysis of large-scale heat transfer problems with temperature-dependent pore-fluid densities

Purpose - In many scientific and engineering fields, large-scale heat transfer problems with temperature-dependent pore-fluid densities are commonly encountered. For example, heat transfer from the mantle into the upper crust of the Earth is a typical problem of them. The main purpose of this paper is to develop and present a new combined methodology to solve large-scale heat transfer problems with temperature-dependent pore-fluid densities in the lithosphere and crust scales. Design/methodology/approach - The theoretical approach is used to determine the thickness and the related thermal boundary conditions of the continental crust on the lithospheric scale, so that some important information can be provided accurately for establishing a numerical model of the crustal scale. The numerical approach is then used to simulate the detailed structures and complicated geometries of the continental crust on the crustal scale. The main advantage in using the proposed combination method of the theoretical and numerical approaches is that if the thermal distribution in the crust is of the primary interest, the use of a reasonable numerical model on the crustal scale can result in a significant reduction in computer efforts. Findings - From the ore body formation and mineralization points of view, the present analytical and numerical solutions have demonstrated that the conductive-and-advective lithosphere with variable pore-fluid density is the most favorite lithosphere because it may result in the thinnest lithosphere so that the temperature at the near surface of the crust can be hot enough to generate the shallow ore deposits there. The upward throughflow (i.e. mantle mass flux) can have a significant effect on the thermal structure within the lithosphere. In addition, the emplacement of hot materials from the mantle may further reduce the thickness of the lithosphere. Originality/value - The present analytical solutions can be used to: validate numerical methods for solving large-scale heat transfer problems; provide correct thermal boundary conditions for numerically solving ore body formation and mineralization problems on the crustal scale; and investigate the fundamental issues related to thermal distributions within the lithosphere. The proposed finite element analysis can be effectively used to consider the geometrical and material complexities of large-scale heat transfer problems with temperature-dependent fluid densities.