In this thesis, we consider a robust state estimation problem for discrete-time, homogeneous, first-order, finite-state finite-alphabet hidden Markov models (HMMs). Based on Kolmogorov's Theorem on the existence of a process, we first present the Kolmogorov model for the HMMs under consideration. A new change of measure is introduced. The statistical properties of the Kolmogorov representation of an HMM are discussed on the canonical probability space. A special Kolmogorov measure is constructed. Meanwhile, the ergodicity of two expanded Markov chains is investigated. In order to describe the uncertainty of HMMs, we study probability distance problems based on the Kolmogorov model of HMMs. Using a change of measure technique, the relative entropy and the relative entropy rate as probability distances between HMMs, are given in terms of the HMM parameters. Also, we obtain a new expression for a probability distance considered in the existing literature such that we can use an information state method to calculate it. Furthermore, we introduce regular conditional relative entropy as an a posteriori probability distance to measure the discrepancy between HMMs when a realized observation sequence is given. A representation of the regular conditional relative entropy is derived based on the Radon-Nikodym derivative. Then a recursion for the regular conditional relative entropy is obtained using an information state method. Meanwhile, the well-known duality relationship between free energy and relative entropy is extended to the case of regular conditional relative entropy given a sub-[special character]-algebra. Finally, regular conditional relative entropy constraints are defined based on the study of the probability distance problem. Using a Lagrange multiplier technique and the duality relationship for regular conditional relative entropy, a finite horizon robust state estimator for HMMs with regular conditional relative entropy constraints is derived. A complete characterization of the solution to the robust state estimation problem is also presented.

In this thesis, we consider a robust state estimation problem for discrete-time, homogeneous, first-order, finite-state finite-alphabet hidden Markov models (HMMs). Based on Kolmogorov's Theorem on the existence of a process, we first present the Kolmogorov model for the HMMs under consideration. A new change of measure is introduced. The statistical properties of the Kolmogorov representation of an HMM are discussed on the canonical probability space. A special Kolmogorov measure is constructed. Meanwhile, the ergodicity of two expanded Markov chains is investigated. In order to describe the uncertainty of HMMs, we study probability distance problems based on the Kolmogorov model of HMMs. Using a change of measure technique, the relative entropy and the relative entropy rate as probability distances between HMMs, are given in terms of the HMM parameters. Also, we obtain a new expression for a probability distance considered in the existing literature such that we can use an information state method to calculate it. Furthermore, we introduce regular conditional relative entropy as an a posteriori probability distance to measure the discrepancy between HMMs when a realized observation sequence is given. A representation of the regular conditional relative entropy is derived based on the Radon-Nikodym derivative. Then a recursion for the regular conditional relative entropy is obtained using an information state method. Meanwhile, the well-known duality relationship between free energy and relative entropy is extended to the case of regular conditional relative entropy given a sub-[special character]-algebra. Finally, regular conditional relative entropy constraints are defined based on the study of the probability distance problem. Using a Lagrange multiplier technique and the duality relationship for regular conditional relative entropy, a finite horizon robust state estimator for HMMs with regular conditional relative entropy constraints is derived. A complete characterization of the solution to the robust state estimation problem is also presented.

In this thesis, we consider a robust state estimation problem for discrete-time, homogeneous, first-order, finite-state finite-alphabet hidden Markov models (HMMs). Based on Kolmogorov's Theorem on the existence of a process, we first present the Kolmogorov model for the HMMs under consideration. A new change of measure is introduced. The statistical properties of the Kolmogorov representation of an HMM are discussed on the canonical probability space. A special Kolmogorov measure is constructed. Meanwhile, the ergodicity of two expanded Markov chains is investigated. In order to describe the uncertainty of HMMs, we study probability distance problems based on the Kolmogorov model of HMMs. Using a change of measure technique, the relative entropy and the relative entropy rate as probability distances between HMMs, are given in terms of the HMM parameters. Also, we obtain a new expression for a probability distance considered in the existing literature such that we can use an information state method to calculate it. Furthermore, we introduce regular conditional relative entropy as an a posteriori probability distance to measure the discrepancy between HMMs when a realized observation sequence is given. A representation of the regular conditional relative entropy is derived based on the Radon-Nikodym derivative. Then a recursion for the regular conditional relative entropy is obtained using an information state method. Meanwhile, the well-known duality relationship between free energy and relative entropy is extended to the case of regular conditional relative entropy given a sub-[special character]-algebra. Finally, regular conditional relative entropy constraints are defined based on the study of the probability distance problem. Using a Lagrange multiplier technique and the duality relationship for regular conditional relative entropy, a finite horizon robust state estimator for HMMs with regular conditional relative entropy constraints is derived. A complete characterization of the solution to the robust state estimation problem is also presented.

Orientador: Fábio Violaro / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação / Made available in DSpace on 2018-08-22T07:58:43Z (GMT). No. of bitstreams: 1 Carvalho_SarahNegreirosde_M.pdf: 2350561 bytes, checksum: 950d33430acbd816700ef5de4c78fa5d (MD5) Previous issue date: 2013 / Resumo: Com o contínuo desenvolvimento da tecnologia, há uma demanda crescente por sistemas de síntese de fala que sejam capazes de falar como humanos, para integrá-los nas mais diversas aplicações, seja no âmbito da automação robótica, sejam para acessibilidade de pessoas com deficiências, seja em aplicativos destinados a cultura e lazer. A síntese de fala baseada em modelos ocultos de Markov (HMM) mostra-se promissora em suprir esta necessidade tecnológica. A sua natureza estatística e paramétrica a tornam um sistema flexível, capaz de adaptar vozes artificiais, inserir emoções no discurso e obter fala sintética de boa qualidade usando uma base de treinamento limitada. Esta dissertação apresenta o estudo realizado sobre o sistema de síntese de fala baseado em HMM (HTS), descrevendo as etapas que envolvem o treinamento dos modelos HMMs e a geração do sinal de fala. São apresentados os modelos espectrais, de pitch e de duração que constituem estes modelos HMM dos fonemas dependentes de contexto, considerando as diversas técnicas de estruturação deles. Alguns dos problemas encontrados no HTS, tais como a característica abafada e monótona da fala artificial, são analisados juntamente com algumas técnicas propostas para aprimorar a qualidade final do sinal de fala sintetizado / Abstract: With the continuous development of technology, there is a growing demand for text-to-speech systems that are able to speak like humans, in order to integrate them in the most diverse applications whether in the field of automation and robotics, or for accessibility of people with disabilities, as for culture and leisure activities. Speech synthesis based on hidden Markov models (HMM) shows to be promising in addressing this need. Their statistical and parametric nature make it a flexible system capable of adapting artificial voices, insert emotions in speech and get artificial speech of good quality using a limited amount of speech data for HMM training. This thesis presents the study realized on HMM-based speech synthesis system (HTS), describing the steps that involve the training of HMM models and the artificial speech generation. Spectral, pitch and duration models are presented, which form context-dependent HMM models, and also are considered the various techniques for structuring them. Some of the problems encountered in the HTS, such as the characteristic muffled and monotone of artificial speech, are analyzed along with some of the proposed techniques to improve the final quality of the synthesized speech signal / Mestrado / Telecomunicações e Telemática / Mestra em Engenharia Elétrica

South Africa is currently struggling to deal with a significant poaching and livestock theft problem. This work is concerned with the detection and classification of ground based targets using radar micro- Doppler signatures to aid in the monitoring of borders, nature reserves and farmlands. The research starts of by investigating the state of the art of ground target classification. Different radar systems are investigated with respect to their ability to classify targets at different operating frequencies. Finally, a Gaussian Mixture Model Hidden Markov Model based (GMM-HMM) classification approach is presented and tested in an operational environment. The GMM-HMM method is compared to methods in the literature and is shown to achieve reasonable (up to 95%) classification accuracy, marginally outperforming existing ground target classification methods. / Dissertation (MEng)--University of Pretoria, 2017. / Electrical, Electronic and Computer Engineering / MEng / Unrestricted

yes / This paper describes a technique for automatic recognition of off-line printed Arabic text using Hidden Markov Models. In this work different sizes of overlapping and non-overlapping hierarchical windows are used to generate 16 features from each vertical sliding strip. Eight different Arabic fonts were used for testing (viz. Arial, Tahoma, Akhbar, Thuluth, Naskh, Simplified Arabic, Andalus, and Traditional Arabic). It was experimentally proven that different fonts have their highest recognition rates at different numbers of states (5 or 7) and codebook sizes (128 or 256). Arabic text is cursive, and each character may have up to four different shapes based on its location in a word. This research work considered each shape as a different class, resulting in a total of 126 classes (compared to 28 Arabic letters). The achieved average recognition rates were between 98.08% and 99.89% for the eight experimental fonts. The main contributions of this work are the novel hierarchical sliding window technique using only 16 features for each sliding window, considering each shape of Arabic characters as a separate class, bypassing the need for segmenting Arabic text, and its applicability to other languages.

Les maladies altérant le processus de la déglutition sont multiples, affectant la qualité de vie du patient et sa capacité de fonctionner en société. La nature exacte et la gravité des changements post/pré-traitement dépendent de la localisation de l’anomalie. Une réadaptation efficace de la déglutition, cliniquement parlant, dépend généralement de l’inclusion d’une évaluation vidéo-fluoroscopique de la déglutition du patient dans l’évaluation post-traitement des patients en risque de fausse route. La restriction de cette utilisation est due au fait qu’elle est très invasive, comme d’autres moyens disponibles, tels que la fibre optique endoscopique. Ces méthodes permettent d’observer le déroulement de la déglutition et d’identifier les lieux de dysfonctionnement, durant ce processus, avec une précision élevée. "Mieux vaut prévenir que guérir" est le principe de base de la médecine en général. C’est dans ce contexte que se situe ce travail de thèse pour la télésurveillance des malades et plus spécifiquement pour suivre l’évolution fonctionnelle du processus de la déglutition chez des personnes à risques dysphagiques, que ce soit à domicile ou bien en institution, en utilisant le minimum de capteurs non-invasifs. C’est pourquoi le principal signal traité dans ce travail est le son. La principale problématique du traitement du signal sonore est la détection automatique du signal utile du son, étape cruciale pour la classification automatique de sons durant la prise alimentaire, en vue de la surveillance automatique. L’étape de la détection du signal utile permet de réduire la complexité du système d’analyse sonore. Les algorithmes issus de l’état de l’art traitant la détection du son de la déglutition dans le bruit environnemental n’ont pas montré une bonne performance. D’où l’idée d’utiliser un seuil adaptatif sur le signal, résultant de la décomposition en ondelettes. Les problématiques liées à la classification des sons en général et des sons de la déglutition en particulier sont abordées dans ce travail avec une analyse hiérarchique, qui vise à identifier dans un premier temps les segments de sons de la déglutition, puis à le décomposer en trois sons caractéristiques, ce qui correspond parfaitement à la physiologie du processus. Le couplage est également abordé dans ce travail. L’implémentation en temps réel de l’algorithme de détection a été réalisée. Cependant, celle de l’algorithme de classification reste en perspective. Son utilisation en clinique est prévue. / The diseases affecting and altering the swallowing process are multi-faceted, affecting the patient’s quality of life and ability to perform well in society. The exact nature and severity of the pre/post-treatment changes depend on the location of the anomaly. Effective swallowing rehabilitation, clinically depends on the inclusion of a video-fluoroscopic evaluation of the patient’s swallowing in the post-treatment evaluation. There are other available means such as endoscopic optical fibre. The drawback of these evaluation approaches is that they are very invasive. However, these methods make it possible to observe the swallowing process and identify areas of dysfunction during the process with high accuracy. "Prevention is better than cure" is the fundamental principle of medicine in general. In this context, this thesis focuses on remote monitoring of patients and more specifically monitoring the functional evolution of the swallowing process of people at risk of dysphagia, whether at home or in medical institutions, using the minimum number of non-invasive sensors. This has motivated the monitoring of the swallowing process based on the capturing only the acoustic signature of the process and modeling the process as a sequence of acoustic events occuring within a specific time frame. The main problem of such acoustic signal processing is the automatic detection of the relevent sound signals, a crucial step in the automatic classification of sounds during food intake for automatic monitoring. The detection of relevant signal reduces the complexity of the subsequent analysis and characterisation of a particular swallowing process. The-state-of-the-art algorithms processing the detection of the swallowing sounds as distinguished from environmental noise were not sufficiently accurate. Hence, the idea occured of using an adaptive threshold on the signal resulting from wavelet decomposition. The issues related to the classification of sounds in general and swallowing sounds in particular are addressed in this work with a hierarchical analysis that aims to first identify the swallowing sound segments and then to decompose them into three characteristic sounds, consistent with the physiology of the process. The coupling between detection and classification is also addressed in this work. The real-time implementation of the detection algorithm has been carried out. However, clinical use of the classification is discussed with a plan for its staged deployment subject to normal processes of clinical approval.

In this thesis we develop several kinds of latent variable models in order to address three types of bio-statistical problem. The three problems are the treatment effect of carcinogens on tumour development, spatial interactions between plant species and motor unit number estimation (MUNE). The three types of data looked at are: highly heterogeneous longitudinal count data, quadrat counts of species on a rectangular lattice and lastly, electrophysiological data consisting of measurements of compound muscle action potential (CMAP) area and amplitude. Chapter 1 sets out the structure and the development of ideas presented in this thesis from the point of view of: model structure, model selection, and efficiency of estimation. Chapter 2 is an introduction to the relevant literature that has in influenced the development of this thesis. In Chapter 3 we use the EM algorithm for an application of an autoregressive hidden Markov model to describe longitudinal counts. The data is collected from experiments to test the effect of carcinogens on tumour growth in mice. Here we develop forward and backward recursions for calculating the likelihood and for estimation. Chapter 4 is the analysis of a similar kind of data using a more sophisticated model, incorporating random effects, but estimation this time is conducted from the Bayesian perspective. Bayesian model selection is also explored. In Chapter 5 we move to the two dimensional lattice and construct a model for describing the spatial interaction of tree types. We also compare the merits of directed and undirected graphical models for describing the hidden lattice. Chapter 6 is the application of a Bayesian hierarchical model (MUNE), where the latent variable this time is multivariate Gaussian and dependent on a covariate, the stimulus. Model selection is carried out using the Bayes Information Criterion (BIC). In Chapter 7 we approach the same problem by using the reversible jump methodology (Green, 1995) where this time we use a dual Gaussian-Binary representation of the latent data. We conclude in Chapter 8 with suggestions for the direction of new work. In this thesis, all of the estimation carried out on real data has only been performed once we have been satisfied that estimation is able to retrieve the parameters from simulated data. Keywords: Amyotrophic lateral sclerosis (ALS), carcinogens, hidden Markov models (HMM), latent variable models, longitudinal data analysis, motor unit disease (MND), partially ordered Markov models (POMMs), the pseudo auto- logistic model, reversible jump, spatial interactions.

Proteins are essential for the growth, survival and maintenance of the cell. Understanding the functional roles of proteins helps to decipher the working of macromolecular assemblies and cellular machinery of living organisms. A thorough investigation of the link between sequence, structure and function of proteins, helps in building a comprehensive understanding of the complex biological systems. Proteins have been observed to be composed of single and multiple domains. Analysis of proteins encoded in diverse genomes shows the ubiquitous nature of multi-domain proteins. Though the majority of eukaryotic proteins are multi-domain in nature, 3-D structures of only a small proportion of multi-domain proteins are known due to difficulties in crystallizing such proteins. While functions of individual domains are generally extensively studied, the complex interplay of functions of domains is not well understood for most multi-domain proteins. Paucity of structural and functional data, affects our understanding of the evolution of structure and function of multi-domain proteins. The broad objective of this thesis is to achieve an enhanced understanding of structure and function of protein domains by computational analysis of sequence and structural data. Special attention is paid in the first few chapters of this thesis on the multi-domain proteins. Classification of multi-domain proteins by implementation of an alignment-free sequence comparison method has been achieved in Chapters 2 and 3. Studies on organization, interactions and interdependence of domain-domain interactions in multi-domain proteins with respect to sequential separation between domains and N to C-terminal domain order have been described in Chapters 4 and 5. The functional and structural repertoire of organisms can be comprehensively studied and compared using functional and structural domain annotations. Chapter 6, 7 and 8 represent the proteome-wide structure and function comparisons of various pathogenic and non-pathogenic microorganisms. These comparisons help in identifying proteins implicated in virulence of the pathogen and thus predict putative targets for disease treatment and prevention. Chapter 1 forms an introduction to the main subject area of this thesis. Starting with describing protein structure and function, details of the four levels of hierarchical organization of protein structure have been provided, along with the databases that document protein sequences and structures. Classification of protein domains considered as the realm of function, structure and evolution has been described. The usefulness of classification of proteins at the domain level has been highlighted in terms of providing an enhanced understanding of protein structure and function and also their evolutionary relatedness. The details of structure, function and evolution of multi-domain proteins have also been outlined in chapter 1. ! Chapter 2 aims to achieve a biologically meaningful classification scheme for multi-domain protein sequences. The overall function of a multi-domain protein is determined by the functional and structural interplay of its constituent domains. Traditional sequence-based methods utilize only the domain-level information to classify proteins. This does not take into account the contributions of accessory domains and linker regions towards the overall function of a multi-domain protein. An alignment-free protein sequence comparison tool, CLAP (CLAssification of Proteins) previously developed in this laboratory, was assessed and improved when the author joined the group. CLAP was developed especially to handle multi-domain protein sequences without a requirement of defining domain boundaries and sequential order of domains (domain architecture). ! The working principle of CLAP involves comparison of all against all windows of 5-residue sequence patterns between two protein sequences. The sequences compared could be full-length comprising of all the domains in the two proteins. This compilation of comparison is represented as the Local Matching Scores (LMS) between protein sequences (nslab.iisc.ernet.in/clap/). It has been previously shown that the execution time of CLAP is ~7 times faster than other protein sequence comparison methods that employ alignment of sequences. In Chapter 2, CLAP-based classification has been carried out on two test datasets of proteins containing (i) Tyrosine phosphatase domain family and (ii) SH3-domain family. The former dataset comprises both single and multi-domain proteins that sometimes consist of domain repeats of the tyrosine phosphatase domain. The latter dataset consists only of multi-domain proteins with one copy of the SH3-domain. At the domain-level CLAP-based classification scheme resulted in a clustering similar to that obtained from an alignment-based method, ClustalW. CLAP-based clusters obtained for full-length datasets were shown to comprise of proteins with similar functions and domain architectures. Hence, a protein classification scheme is shown to work efficiently that is independent of domain definitions and requires only the full-length amino acid sequences as input.! Chapter 3 explores the limitations of CLAP in large-scale protein sequence comparisons. The potential advantages of full-length protein sequence classification, combined with the availability of the alignment-free sequence comparison tool, CLAP, motivated the conceptualization of full-length sequence classification of the entire protein repertoire. Before undertaking this mammoth task, working of CLAP was tested for a large dataset of 239,461 protein sequences. Chapter 3 discusses the technical details of computation, storage and retrieval of CLAP scores for a large dataset in a feasible timeframe. CLAP scores were examined for protein pairs of same domain architecture and ~22% of these showed 0 CLAP similarity scores. This led to investigation of the sensitivity of CLAP with respect to sequence divergence. Several test datasets of proteins belonging to the same SCOP fold were constructed and CLAP-based classification of these proteins was examined at inter and intra-SCOP family level. CLAP was successful in efficiently clustering evolutionary related proteins (defined as proteins within the same SCOP superfamily) if their sequence identity >35%. At lower sequence identities, CLAP fails to recognize any evolutionary relatedness. Another test dataset consisting of two-domain proteins with domain order swapped was constructed. Domain order swap refers to domain architectures of type AB and BA, consisting of domains A and B. A condition that the sequence identities of homologous domains were greater than 35% was imposed. CLAP could effectively cluster together proteins of the same domain architectures in this case. Thus, the sequence identity threshold of 35% at the domain-level improves the accuracy of CLAP. The analysis also showed that for highly divergent sequences, the expectation of 5-residue pattern match was likely a stringent criterion. Thus, a modification in the 5-residue identical pattern match criterion, by considering even similar residue and gaps within matched patterns may be required to effectuate CLAP-based clustering of remotely related protein sequences. Thus, this study highlights the limitations of CLAP with respect to large-scale analysis and its sensitivity to sequence divergence. ! Chapters 4 and 5 discuss the computational analysis of inter-domain interactions with respect to sequential distance and domain order. Knowledge of domain composition and 3-D structures of individual domains in a multi-domain protein may not be sufficient to predict the tertiary structure of the multi-domain protein. Substantial information about the nature of domain-domain interfaces helps in prediction of the tertiary as well as the quaternary structure of a protein. Therefore, chapter 4 explores the possible relationship between the sequential distance separating two domains in a multi-domain protein and the extent of their interaction. With increasing sequential separation between any two domains, the extent of inter-domain interactions showed a gradual decrease. The trend was more apparent when sequential separation between domains is measured in terms of number of intervening domains. Irrespective of the linker length, extensive interactions were seen more often between contiguous domains than between non-contiguous domains. Contiguous domains show a broader interface area and lower proportion of non-interacting domains (interface area: 0 Å2 to - 4400 Å2, 2.3% non-interacting domains) than non-contiguous domains (interface area: 0 Å2 to - 2000 Å2, 34.7% non-interacting domains). Additionally, as inter-protein interactions are mediated through constituent domains, rules of protein-protein interactions were applied to domain-domain interactions. Tight binding between domains is denoted as putative permanent domain-domain interactions and domains that may dissociate and associate with relatively weak interactions to regulate functional activity are denoted as putative transient domain-domain interactions. An interface area threshold of 600 Å2 was utilized as a binary classifier to distinguish between putative permanent and putative transient domain-domain interactions. Therefore, the state of interaction of a domain pair is defined as either putative permanent or putative transient interaction. Contiguous domains showed a predominance of putative permanent nature of inter-domain interface, whereas non-contiguous domains showed a prevalence of putative transient interfaces. The state of interaction of various SCOP superfamily pairs was studied across different proteins in the dataset. SCOP superfamily pairs mostly showed a conserved state of interaction, i.e. either putative permanent or putative transient in all their occurrences across different proteins. Thus, it is noted that contiguous domains interact extensively more often than non-contiguous domains and specific superfamily pairs tend to interact in a conserved manner. In conclusion, a combination of interface area and other inter-domain properties along with experimental validation will help strengthen the binary classification scheme of putative permanent and transient domain-domain interactions.! Chapter 5 provides structural analysis of domain pairs occurring in different sequential domain orders in mutli-domain proteins. The function and regulation of a multi-domain protein is predominantly determined by the domain-domain interactions. These in turn are influenced by the sequential order of domains in a protein. With domains defined using evolutionary and structural relatedness (SCOP superfamily), their conservation of structure and function was studied across domain order reversal. A domain order reversal indicates different sequential orders of the concerned domains, which may be identified in proteins of same or different domain compositions. Domain order reversals of domains A and B can be indicated in protein pair consisting of the domain architectures xAxBx and xBxAx, where x indicates 0 or more domains. A total of 161 pairs of domain order reversals were identified in 77 pairs of PDB entries. For most of the comparisons between proteins with different domain composition and architecture, large differences in the relative spatial orientation of domains were observed. Although preservation of state of interaction was observed for ~75% of the comparisons, none of the inter-domain interfaces of domains in different order displayed high interface similarity. These domain order reversals in multi-domain proteins are contributed by a limited number of 15 SCOP superfamilies. Majority of the superfamilies undergoing order reversal either function as transporters or regulatory domains and very few are enzymes. A higher proportion of domain order reversals were observed in domains separated by 0 or 1 domains than those separated by more than 1 domain. A thorough analysis of various structural features of domains undergoing order reversal indicates that only one order of domains is strongly preferred over all possible orders. This may be due to either evolutionary selection of one of the orders and its conservation throughout generations, or the fact that domain order reversals rarely conserve the interface between the domains. Further studies (Chapters 6 to 8) utilize the available computational techniques for structural and functional annotation of proteins encoded in a few bacterial genomes. Based on these annotations, proteome-wide structure and function comparisons were performed between two sets of pathogenic and non-pathogenic bacteria. The first study compares the pathogenic Mycobacterium tuberculosis to the closely related organism Mycobacterium smegmatis which is non-pathogenic. The second study primarily identified biologically feasible host-pathogen interactions between the human host and the pathogen Leptospira interrogans and also compared leptospiral-host interactions of the pathogenic Leptospira interrogans and of the saprophytic Leptospira biflexa with the human host. Chapter 6 describes the function and structure annotation of proteins encoded in the genome of M. smegmatis MC2-155. M. smegmatis is a widely used model organism for understanding the pathophysiology of M. tuberculosis, the primary causative agent of tuberculosis in humans. M. smegmatis and M. tuberculosis species of the mycobacterial genus share several features like a similar cell-wall architecture, the ability to oxidise carbon monoxide aerobically and share a huge number of homologues. These features render M. smegmatis particularly useful in identifying critical cellular pathways of M. tuberculosis to inhibit its growth in the human host. In spite of the similarities between M. smegmatis and M. tuberculosis, there are stark differences between the two due to their diverse niche and lifestyle. While there are innumerable studies reporting the structure, function and interaction properties of M. tuberculosis proteins, there is a lack of high quality annotation of M. smegmatis proteins. This makes the understanding of the biology of M. smegmatis extremely important for investigating its competence as a good model organism for M. tuberculosis. With the implementation of available sequence and structural profile-based search procedures, functional and structural characterization could be achieved for ~92% of the M. smegmatis proteome. Structural and functional domain definitions were obtained for a total of 5695 of 6717 proteins in M. smegmatis. Residue coverage >70% was achieved for 4567 proteins, which constitute ~68% of the proteome. Domain unassigned regions more than 30 residues were assessed for their potential to be associated to a domain. For 1022 proteins with no recognizable domains, putative structural and functional information was inferred for 328 proteins by the use of distance relationship detection and fold recognition methods. Although 916 sequences of 1022 proteins with no recognizable domains were found to be specific to M. smegmatis species, 98 of these are specific to its MC2-155 strain. Of the 1828 M. smegmatis proteins classified as conserved hypothetical proteins, 1038 proteins were successfully characterized. A total of 33 Domains of Unknown Function (DUFs) occurring in M. smegmatis could be associated to structural domains. A high representation of the tetR and GntR family of transcription regulators was noted in the functional repertoire of M. smegmatis proteome. As M. smegmatis is a soil-dwelling bacterium, transcriptional regulators are crucial for helping it to adapt and survive the environmental stress. Similarly, the ABC transporter and MFS domain families are highly represented in the M. smegmatis proteome. These are important in enabling the bacteria to uptake carbohydrate from diverse environmental sources. A lower number of virulent proteins were identified in M. smegmatis, which justifies its non-pathogenicity. Thus, a detailed functional and structural annotation of the M. smegmatis proteome was achieved in Chapter 6. Chapter 7 delineates the similarities and difference in the structure and function of proteins encoded in the genomes of the pathogenic M. tuberculosis and the non-pathogenic M. smegmatis. The protocol employed in Chapter 6 to achieve the proteome-wide structure and function annotation of M. smegmatis was also applied to M. tuberculosis proteome in Chapter 7. The number of proteins encoded by the genome of M. smegmatis strain MC2-155 (6717 proteins) is comparatively higher than that in M. tuberculosis strain H37Rv (4018 proteins). A total of 2720 high confidence orthologues sharing ≥30% sequence identity were identified in M. tuberculosis with respect to M. smegmatis. Based on the orthologue information, specific functional clusters, essential proteins, metabolic pathways, transporters and toxin-antitoxin systems of M. tuberculosis were inspected for conservation in M. smegmatis. Among the several categories analysed, 53 metabolic pathways, 44 membrane transporter proteins belonging to secondary transporters and ATP-dependent transporter classes, 73 toxin-antitoxin systems, 23 M. tuberculosis-specific targets, 10 broad-spectrum targets and 34 targets implicated in persistence of M. tuberculosis could not detect any orthologues in M. smegmatis. Several of the MFS superfamily transporters act as drug efflux pumps and are hence associated with drug resistance in M. tuberculosis. The relative abundances of MFS and ABC superfamily transporters are higher in M. smegmatis than in M. tuberculosis. As these transporters are involved in carbohydrate uptake, their higher representation in M. smegmatis than in M. tuberculosis highlights the lack of proficiency of M. tuberculosis to assimilate diverse carbon sources. In the case of porins, MspA-like and OmpA-like porins are selectively present in either M. smegmatis or M. tuberculosis. These differences help to elucidate protein clusters for which M. smegmatis may not be the best model organism to study M. tuberculosis proteins.! At the domain-level, ATP-binding domain of ABC transporters, tetracycline transcriptional regulator (tetR) domain family, major facilitator superfamily (MFS) domain family, AMP-binding domain family and enoyl-CoA hydrolase domain family are highly represented in both M. smegmatis and M. tuberculosis proteomes. These domains play an essential role in the carbohydrate uptake systems and drug-efflux pumps among other diverse functions in mycobacteria. There are several differentially represented domain families in M. tuberculosis and M. smegmatis. For example, the pentapeptide-repeat domain, PE, PPE and PIN domains although abundantly present in M. tuberculosis, are very rare in M. smegmatis. Therefore, such uniquely or differentially represented functional and structural domains in M. tuberculosis as compared to M. smegmatis may be linked to pathogenicity or adaptation of M. tuberculosis in the host. Hence, major differences between M. tuberculosis and M. smegmatis were identified, not only in terms of domain populations but also in terms of domain combinations. Thus, Chapter 7 highlights the similarities and differences between M. smegmatis and M. tuberculosis proteomes in terms of structure and function. These differences provide an understanding of selective utilization of M. smegmatis as a model organism to study M. tuberculosis. ! In Chapter 8, computational tools have been employed to predict biologically feasible host-pathogen interactions between the human host and the pathogenic, Leptospira interrogans. Sensitive profile-based search procedures were used to specifically identify practical drug targets in the genome of Leptospira interrogans, the causative agent of the globally widespread zoonotic disease, Leptospirosis. Traditionally, the genus Leptospira is classified into two species complex- the pathogenic L. interrogans and the non-pathogenic saprophyte L. biflexa. The pathogen gains entry into the human host through direct or indirect contact with fluids of infected animals. Several ambiguities exist in the understanding of L. interrogans pathogenesis. An integration of multiple computational approaches guided by experimentally derived protein-protein interactions, was utilized for recognition of host-pathogen protein-protein interactions. The initial step involved the identification of similarities of host and L. interrogans proteins with crystal structures of experimentally known transient protein-protein complexes. Further, conservation of interfacial nature was used to obtain high confidence predictions for putative host-pathogen protein-protein interactions. These predictions were subjected to further selection based on subcellular localization of proteins of the human host and L. interrogans, and tissue-specific expression profiles of the host proteins. A total of 49 protein-protein interactions mediated by 24 L. interrogans proteins and 17 host proteins were identified and these may be subjected to further experimental investigations to assess their in vivo relevance. The functional relevance of similarities and differences between the pathogenic and non-pathogenic leptospires in terms of interactions with the host has also been explored. For this, protein-protein interactions across human host and the non-pathogenic saprophyte L. biflexa were also predicted. Nearly 39 leptospiral-host interactions were recognized to be similar across both the pathogen and saprophyte in the context of processes that influence the host. The overlapping leptospiral-host interactions of L. interrogans and L. biflexa proteins with the human host proteins are primarily associated with establishment of its entry into the human host. These include adhesion of the leptospiral proteins to host cells, survival in host environment such as iron acquisition and binding to components of extracellular matrix and plasma. The disjoint sets of leptospiral-host interactions are species-specific interactions, more importantly indicative of the establishment of infection by L. interrogans in the human host and immune clearance of L. biflexa by the human host. With respect to L. interrogans, these specific interactions include interference with blood coagulation cascade and dissemination to target organs by means of disruption of cell junction assembly. On the other hand, species-specific interactions of L. biflexa proteins include those with components of host immune system. ! In spite of the limited availability of experimental evidence, these help in identifying functionally relevant interactions between host and pathogen by integrating multiple lines of evidence. Thus, inferences from computational prediction of host-pathogen interactions act as guidelines for experimental studies investigating the in vivo relevance of these predicted protein-protein interactions. This will further help in developing effective measures for treatment and disease prevention. In summary, Chapters 2 and 3 describe the implementation, advantages and limitations of the alignment-free full-length sequence comparison method, CLAP. Chapter 4 and 5 are dedicated to understand the domain-domain interactions in multi-domain protein sequences and structures. In Chapters 6, 7 and 8 the computational analyses of the mycobacterial species and leptospiral species helped in an enhanced understanding of the functional repertoire of these bacteria. These studies were undertaken by utilizing the biological sequence data available in public databases and implementation of powerful homology-detection techniques. The supplemental data associated with the chapters is provided in a compact disc attached with this thesis.!

The goal of the thesis is being familiar with methods a techniques used in speech processing. Describe the current state of research and development of speech technology. Project and implement server speech recognizer that uses BSAPI. Integrate client that will use server for speech recognition to mobile dictionaries of Lingea company.