A review of diagnostic methods shows that new techniques are required that quantify system degradation from measured response. Information theory, developed by Claude E. Shannon, involves the quantification of information defining limits in signal processing for reliable data communication. One such technique considers information theory fundamentals forming an analogy between a machine and a communication channel to modify Shannon`s channel capacity concept and apply it to measured machine system response. The technique considers the residual signal (difference between a measured signal induced by faults from a baseline signal) to quantify degradation, perform system health assessment, and diagnose faults. Similar to noise hampering data transmission, mechanical faults hinder power transmission through the system. This residual signal can be viewed as noise within the context of information theory, to permit application of information theory to machines to construct a health measure for assessment of machine health. The goal of this dissertation is to create and study metrics for assessment of machine health. This dissertation explores channel capacity which is grounded and supported by proven theorems of information theory, studies different ways to apply and calculate channel capacity in practical industry settings, and creates methods to assess and pinpoint degradation by applying the channel capacity based measures to signals. Channel capacity is the maximum rate of information that can be sent and received over a channel having a known level of noise. A measured signal from a machine consists of a baseline signal exemplary of health, intrinsic that contaminates all measurements, and signals generated by the faults. Noise, the difference between the measured signal and the baseline signal, consists of intrinsic noise and "fault noise". Separation between fault and intrinsic (embedded in the measurement) noise shows channel capacity calculations for the machine require minimal computational efforts, and calculations are consistent in the presence of intrinsic white noise. Considering the response average or DC component of a signal in the channel capacity calculations adds robustness to diagnostic results. The method successfully predicted robot failures. Important to system health assessment is having a good baseline response as reference. The technique is favorable for industry because it applies to measurement data and calculations are done in the time domain. The technique can be used in semi-conducting industry as a tool monitoring system performance and lowering fab operating cost by extending component use and scheduling maintenance as needed. With a window running average channel capacity the technique is able to locate the fault in time. / text

Stem cell-based therapies are an important developing technology for treating cardiovascular ischemic disease, including subsequent co-morbidities such as ulcerative wounds. Mesenchymal stem cells (MSCs) have a proven ability to augment wound healing and neovascularization processes and have been more recently investigated for their endothelial-like behavior. This doctoral work aims to understand mechanisms underlying matrix-driven MSC tubulogenesis within PEGylated fibrin gels, specifically (1) why this behavior occurs and (2) if this behavior has clinical utility. Briefly, a three-dimensional morphological quantification pipeline was first developed for analyzing the maturity of vascular networks (Chapter 2). This method was applied in later studies that examined the full spectrum of MSC behavior in PEGylated fibrin gels, linking biomaterial properties with network development (Chapter 3). Mechanisms underlying the cell-matrix relationship were more fully clarified through gain-of-function cell studies. These studies indicated that PEGylated fibrin promotes endothelial-like MSC behavior through a combination of hypoxic stress and bioactive fibrin cues (Chapter 4). Notably, this endothelial-like MSC behavior closely mirrored vasculogenic mimicry, a process whereby tumors establish non-endothelialized vasculature in response to hypoxic stress. The functionality of these tumor vessels suggests that mature endothelial differentiation of MSCs may not be necessary to achieve therapeutically beneficial tissue perfusion. This hypothesis opens up new mechanisms for exploitation in vascular tissue engineering strategies. / text

The present work addresses issues related to the derivation of reduced models of atomistic systems, their statistical calibration, and their relation to atomistic models of materials. The reduced model, known in the chemical physics community as a coarse-grained model, is calibrated within a Bayesian framework. Particular attention is given to developing likelihood functions, assigning priors on coarse-grained model parameters, and using data from molecular dynamics representations of atomistic systems to calibrate coarse-grained models such that certain physically relevant atomistic observables are accurately reproduced. The developed Bayesian framework is then applied in three case studies of increasing complexity and practical application. A freely jointed chain model is considered first for illustrative purposes. The next example entails the construction of a coarse-grained model for a liquid heptane system, with the explicit design goal of accurately predicting a vapor-liquid transfer free energy. Finally, a coarse-grained model is developed for an alkylthiophene polymer that has been shown to have practical use in certain types of photovoltaic cells. The development therein employs Bayesian decision theory to select an optimal CG potential energy function. Subsequently, this model is subjected to validation tests in a prediction scenario that is relevant to the performance of a polyalkylthiophene-based solar cell. / text

In this work, an attempt is made to lay out a framework in which models of tumor growth can be built, calibrated, validated, and differentiated in their level of goodness in such a manner that all the uncertainties associated with each step of the modeling process can be accounted for in the final model prediction. The study can be divided into four basic parts. The first involves the development of a general family of mathematical models of interacting species representing the various constituents of living tissue, which generalizes those previously available in the literature. In this theory, surface effects are introduced by incorporating in the Helmholtz free ` gradients of the volume fractions of the interacting species, thus providing a generalization of the Cahn-Hilliard theory of phase change in binary media and leading to fourth-order, coupled systems of nonlinear evolution equations. A subset of these governing equations is selected as the primary class of models of tumor growth considered in this work. The second component of this study focuses on the emerging and fundamentally important issue of predictive modeling, the study of model calibration, validation, and quantification of uncertainty in predictions of target outputs of models. The Bayesian framework suggested by Babuska, Nobile, and Tempone is employed to embed the calibration and validation processes within the framework of statistical inverse theory. Extensions of the theory are developed which are regarded as necessary for certain scenarios in these methods to models of tumor growth. The third part of the study focuses on the numerical approximation of the diffuse-interface models of tumor growth and on the numerical implementations of the statistical inverse methods at the core of the validation process. A class of mixed finite element models is developed for the considered mass-conservation models of tumor growth. A family of time marching schemes is developed and applied to representative problems of tumor evolution. Finally, in the fourth component of this investigation, a collection of synthetic examples, mostly in two-dimensions, is considered to provide a proof-of-concept of the theory and methods developed in this work. / text

Dynamic assessment of three-dimensional (3D) joint kinematics is essential for understanding normal joint function as well as the effects of injury or disease. The knowledge of one or two series of bi-dimensional fluoroscopic projections of the joint in motion (mono-planar or bi-planar fluoroscopy), and the 3D model of the joint segments, were claimed to be sufficient to reconstruct the absolute and relative 6 Degrees Of Freedom (DOFs) pose of bones or prostheses in the 3D space. The software MultiTrack was developed at the Health Sciences and Technologies - Interdepartmental Center for Industrial Research (HST - ICIR) for the joint kinematics estimation with 3D Video Fluoroscopy (3DF) [1] using C++ language with ITK [2] segmentation & registration toolkit and VTK [3] visualization toolkit. An optimization procedure finds the 6 degrees of freedom pose that optimizes a metric quantifying the matching of the 3D model and its relevant projections. The metric, currently implemented in the software, is based on the contour segmentation of the object to be tracked and on the use of 3D adaptive distance maps (ADM) [4,5]. However, the contour extraction is a time consuming procedure for the user. Different methods were proposed in the literature to reduce the user interaction, each with its proper pros and cons. In the current thesis a few of the for-mentioned methods are discussed in order to evaluate each of them in terms of accuracy, speed and user dependency. At the final step the algorithm proposed by Mafhouz et al. [6], initially proposed for prostheses, is implemented inside the MultiTrack framework. To be properly characterized, the above method is tested on in vivo datasets and under various sources of error. / Η δυναμική αξιολόγηση της τρισδιάστατης (3D) κινηματικής των αρθρώσεων είναι απαραίτητη για την κατανόηση της φυσιολογικής λειτουργία των αρθρώσεων, καθώς και τις επιπτώσεις της κακώσεων ή παθήσεων . Η γνώση μιας ή δύο σειρών δυσδιάστατων ακτινοσκοπικών προβολών των αρθρώσεων σε κίνηση ( μονο - επίπεδη ή δι- επίπεδη ακτινοσκόπηση), και ενός τρισδιάστατου (3D) μοντέλου των επιμέρους τμημάτων των αρθρώσεων , κρίνεται επαρκής για να ανακατασκευαστούν τόσο οι απόλυτοι όσο και οι σχετικοί 6 βαθμοί ελευθερίας της θέσης των οστών ή των προσθετικών τμημάτων στον τρισδιάστατο χώρο. Το λογισμικό “MultiTrack” αναπτύχθηκε στις Επιστήμες Υγείας και Τεχνολογίες - Διατμηματικό Κέντρο Βιομηχανικών Ερευνών (HST-ICIR) έτσι ώστε να επιτευχθεί με ακρίβεια η εκτίμηση της κινηματικς των αρθρώσεων με τρισδιάστατη ακτινοσκόπηση (φθοροσκοπία) με βιντεοκαρέ (3DF) [1] χρησιμοποιώντας C++ γλώσσα προγραμματισμού σε συνδυασμό με τα εργαλεία κατακερματισμού & καταγραφής (segmentation & registration) ITK [2] και οπτικοποίησης (visualization) VTK [3]. Μια διαδικασία βελτιστοποίησης βρίσκει τους 6 βαθμούς ελευθερίας της θέσης που βελτιστοποιεί τη συνάρτηση ποσοτικοποίησης της συνάφειας του 3D μοντέλου και των σχετικών προβολών του. Η συνάρτηση ποσοτικοποίησης, έτσι όπως έχει υλοποιηθεί στο λογισμικό, βασίζεται στην κατάτμηση του περιγράμματος (contour segmentation) του υπό εξέταση αντικειμένου και στη χρήση τρισδιάστατων προσαρμοστικών χαρτών απόστασης (Adaptive Distance Map-ADM) [4,5]. Ωστόσο, η εξαγωγή του περιγράμματος είναι μια χρονοβόρα διαδικασία για το χρήστη. Διαφορετικές μέθοδοι έχουν προταθεί στη βιβλιογραφία για τη μείωση της αλληλεπίδρασης του χρήστη, η καθεμία με τα πλεονεκτήματα και τα μειονεκτήματα της. Στην παρούσα διπλωματική εργασία, αναλύονται μερικές από τις προαναφερθείσες μέθοδοι προκειμένου να αξιολογηθεί καθεμία από αυτές όσον αφορά την ακρίβεια, την ταχύτητα και την εξάρτηση της από το χρήστη. Στο τελικό στάδιο, ο αλγόριθμος που προτείνεται από τον Mafhouz [6] και χρησιμοποιήθηκε αρχικά για προθέσεις, υλοποιείται εντός του λογισμικού “MultiTrack”. Η παραπάνω μέθοδος για να χαρακτηριστεί πλήρως, έχει δοκιμαστεί σε in-νίνο δεδομένα και κάτω από διάφορες πηγές σφάλματος.

The present thesis offers a thorough examination of Modern Greek distributive determiner (o) kathe (every, each, any) nominal phrases and accounts for the different readings of these expressions. Kathe NPs exhibit a universal distributive every reading (definite use), a Free Choice any (indefinite use) and a kind interpretation. O kathe NPs exhibit a universal distributive each reading (familiar and definite use), a Free Choice any and an Indiscriminative Free Choice just any reading (indefinite uses). In line with previous proposals for every, I suggest that kathe determiners do not lexicalize a universal operator. Following Szabolcsi (2010) on every NPs, I argue that (o) kathe NPs are (inherently) indefinite expressions (in the sense of Heim 1982) that make part of a quantificational concord. A distributive operator binds the element variables of their NP set; a clause-typing operator in the left periphery, a Definiteness, a Generic or a Modal Operator binds the context set variables of the NP, rendering a universal, a kind or an FC reading to the expression, accordingly. The presence of different sentential operators under C determines the readings that arise. I argue that binding by these operators corresponds to two Agree operations in syntax: One is between the Distributive operator in C and Q on the DP as well as with Aspect on the vP. The other one is between the sentential operator and the relevant feature on Q but also on TP/ vP. The quantificational chains formed are argued to be, to some extent, similar to that of wh- chains. In Chapter 1, I present the essential syntactic and semantic background, as well as an outline of my proposal to the riddle of every and (o)kathe NPs interpretational variability. In Chapter 2, I discuss and analyze the syntax of Determiner Phrases and Quantifier Phrases and in particular the syntactic structure of Greek kathe, o kathe, oli i NPs, as well as that of English every, each, all and all the NPs. In Chapter 3 I investigate the different readings the kathe and o kathe NPs give rise to and the semantics behind that, as well as previous approaches on the issue. In Chapter 4, I explain the interpretational variability of the expression in hand as a result of the binding of the NPs’ context set variables by different Operators (a Definiteness, a Generic or a Modal Operator) and Operation Agree. In Chapter 5, I discuss how the theory proposed for Greek kathe, o kathe and English every, each NPs could explain relevant phenomena of quantificational variability in Chinese and Japanese, as well as Greek Polarity phenomena. In Chapter 6, I conclude the discussion. / Η παρούσα διατριβή προσφέρει μια αναλυτική εξέταση των επιμεριστικών δεικτών κάθε και ο κάθε της Νέας Ελληνικής και των Ονοματικών Φράσεών τους, όπως επίσης και μία εξήγηση για τις ποικίλες διαφορετικές ερμηνείες των εκφράσεων αυτών, αλλά και των αντιστοίχων της Αγγλικής. Οι Ονοματικές Φράσεις (ΟΦ) με το κάθε (κάθε ΟΦ) στην οριστική τους χρήση παρουσιάζουν μία ερμηνεία καθολικής ποσοτικής δείξης, όπως επίσης μία ερμηνεία ελεύθερης επιλογής, αόριστης χρήσης, και μία ερμηνεία είδους. Οι Ονοματικές Φράσεις με το ο κάθε (ο κάθε ΟΦ) παρουσιάζουν μία ερμηνεία καθολικής ποσοτικής δείξης ως οριστική και οικεία χρήση, μία ερμηνεία ελεύθερης επιλογής και μία υποτιμητικής ελεύθερης επιλογής ως αόριστες χρήσεις. Σε συμφωνία με προηγούμενες αναλύσεις για τον αντίστοιχο προσδιοριστή της Αγγλικής, προτείνω ότι τα κάθε και ο κάθε δεν λεξικοποιούν τον καθολικό ποσοτικό τελεστή της λογικής. Αντίθετα, ισχυρίζομαι ότι οι Ονοματικές Φράσεις με τα κάθε και ο κάθε είναι κατά βάση αόριστες εκφράσεις, οι οποίες συμμετέχουν σε διαφορετικές ποσοδεικτικές αλυσίδες εκφράσεων κάθε φορά. Ένας επιμεριστικός τελεστής στην αριστερή περιφέρεια δεσμεύει την στοιχειώδη μεταβλητή του συνόλου της ΟΦ. Ένας οριστικός, ένας γενικός ή ένας τροπικός τελεστής, επίσης στην αριστερή περιφέρεια, δεσμεύει τη μεταβλητή περικειμένου, δίνοντας αντίστοιχα τις ερμηνείες της καθολικής ποσοτικής δείξης, του είδους και της ελεύθερης επιλογής. Η παρουσία διαφορετικών προτασιακών τελεστών, λοιπόν, καθορίζει την ανάδυση των διαφορετικών ερμηνειών. Επίσης, ισχυρίζομαι ότι η όλη διαδικασία της δέσμευσης αντιστοιχεί σε λειτουργίες Συμφωνείν στη σύνταξη. Οι ποσοδεικτικές αλυσίδες που σχηματίζονται είναι σε κάποιο βαθμό όμοιες με αυτές των ερωτηματικών προτάσεων. Στο Κεφάλαιο 1 παραθέτω το απαραίτητο συντακτικό και σημασιολογικό υπόβαθρο, όπως επίσης και μια προεπισκόπηση της πρότασής μου. Στο Κεφάλαιο 2 παρουσιάζεται μια συντακτική ανάλυση των εκφράσεων αυτών και των αντιστοίχων αγγλικών. Το Κεφάλαιο 3 διερευνά την σημασιολογία και τις διαφορετικές ερμηνείες. Στο Κεφάλαιο 4 προσφέρω την θεωρητική μου ανάλυση, ενώ στο Κεφάλαιο 5 παρατίθεται μία σύγκριση με ανάλογα φαινόμενα στην Κινεζική και την Ιαπωνική, όπως επίσης και με εκφράσεις πολικότητας της Νέας Ελληνικής. Στο Κεφάλαιο 6 συνοψίζονται τα συμπεράσματα της έρευνας.

En recherche clinique ou environnementale, les biomarqueurs protéiques présentent un intérêt croissant. Bien que les immuno-dosages restent les méthodes de référence pour leur quantification, les récentes avancées en spectrométrie de masse (MS) font de cette technique une alternative crédible à l'ELISA. Ce travail apporte quelques éléments méthodologiques pour repousser certaines limitations de la MS. D'abord, deux dosages ont été proposés. Celui réalisé chez G. fossarum représente le premier exemple de dosage de la Vitellogénine chez un invertébré par LC-MS/MS. L'un des défis de la méthode présentée est de doser spécifiquement une protéine dans un organisme dont le génome est majoritairement inconnu. Le second dosage concerne les peptides contenant une méthionine. Nous avons développé un protocole d'oxydation des méthionines afin de s'affranchir du biais lié à leur oxydation partielle. Cette méthode a ensuite été appliquée à une protéine impliquée dans la maladie d'Alzheimer (l'Apolipoprotéine E4) dans une cohorte de 673 plasmas. Ce dosage est à ce jour l'une des plus grandes études réalisées par LC-MS/MS et montre toute la robustesse de cette approche. Enfin, l'influence de la phase mobile sur la sensibilité des dosages de peptides a été étudiée : d'abord en phase inverse, où le méthanol est une bonne alternative à l'acétonitrile ; ensuite en HILIC, où les difficultés liées à l'étude d'ions multichargés en milieu majoritairement organique ont été abordées. Les problèmes liés à la capacité de charge des colonnes ont également été soulevés. La chromatographie HILIC reste prometteuse pour la quantification de peptides puisqu'un facteur dix en sensibilité peut être apporté.

The emergence of tandem mass spectrometry (MS/MS) technology has significantly accelerated protein identification and quantification in proteomics. It enables high-throughput analysis of proteins and their quantities in a complex protein mixture. A mass spectrometer can easily and rapidly generate large volumes of mass spectral data for a biological sample. This bulk of data makes manual interpretation impossible and has also brought numerous challenges in automated data analysis. Algorithmic solutions have been proposed and provide indispensable analytical support in current proteomic experiments. However, new algorithms are still needed to either improve result accuracy or provide additional data analysis capabilities for both protein identification and quantification. Accurate identification of proteins in a sample is the preliminary requirement of a proteomic study. In many cases, a mass spectrum cannot provide complete information to identify the peptide without ambiguity because of the inefficiency of the peptide fragmentation technique and the prevalent existence of noise. We propose ADEPTS to this problem using the complementary information provided in different types of mass spectra. Meanwhile, the occurrence of posttranslational modifications (PTMs) on proteins is another major issue that prevents the interpretation of a large portion of spectra. Using current software tools, users have to specify possible PTMs in advance. However, the number of possible PTMs has to be limited since specifying more PTMs to the software leads to a longer running time and lower result accuracy. Thus, we develop DeNovoPTM and PeaksPTM to provide efficient and accurate solutions. Glycosylation is one of the most frequently observed PTMs in proteomics. It plays important roles in many disease processes and thus has attracted growing research interest. However, lack of algorithms that can identify intact glycopeptides has become the major obstacle that hinders glycoprotein studies. We propose a novel algorithm, GlycoMaster DB, to fulfil this urgent requirement. Additional research is presented on protein quantification, which studies the changes of protein quantity by comparing two or more mass spectral datasets. A crucial problem in the quantification is to correct the retention time distortions between different datasets. Heuristic solutions from previous research have been used in practice but none of them has yet claimed a clear optimization goal. To address this issue, we propose a combinatorial model and practical algorithms for this problem.

For over a decade, diquaternary ammonium gemini surfactants have shown promise as non-viral gene delivery agents in both in vitro and in vivo systems. Their continued development, however, requires an understanding of their biological fate. The absence of identification and quantification methods that can achieve that goal is what drove the development of simple and rapid mass spectrometry (MS)-based methods; the focus of my Ph.D. dissertation. Prior to the development of these MS-based methods, an understanding of the gas phase behavior of diquaternary ammonium gemini surfactants is required. The development of a universal fragmentation pathway for gemini surfactants was achieved using low resolution and high resolution MS instruments. Single stage (MS), tandem stage (MS/MS and quasi-multi-stage (quasi MS3) mass spectrometry analysis allowed for the confirmation of the molecular composition and structure of each gemini surfactant through the identification of common and unique mass to charge values. Understanding the fragmentation behavior allowed for the specific identification and/or quantification of gemini surfactants by MS-based methods; including liquid chromatography low resolution tandem mass spectrometry (LC-LR-MS/MS), fast chromatography low resolution tandem mass spectrometry, fast chromatography high resolution mass spectrometry, desorption electrospray ionization low resolution mass spectrometry and matrix assisted laser desorption ionization high resolution mass spectrometry. We hypothesized that a LC-LR-MS/MS method would be the most effective quantitative method for the quantification of N,N-bis(dimethylhexadecyl)-1,3-propane-diammonium dibromide (G16-3) within PAM212 cellular lysate; achieving the lowest lower limit of quantification (LLOQ). Although the LC-LR-MS/MS method achieved a LLOQ suitable for analysis of G16-3 within PAM212 cell lysate, its limitations made it an inefficient method. In comparison, the four alternative mass spectrometry methods were faster, more efficient and less expensive than a conventional LC-LR-MS/MS method for the post transfection quantification of G16-3 within PAM212 cell lysate to be determined; 1.45 ± 0.06 μM. Future application of the universal fragmentation pathway and each MS-based quantification method will be beneficial for the future development of diquaternary ammonium gemini surfactants to further understand their post transfection fate.

This series of experiments investigated dystrophin localization in the normal cerebellum and examined Purkinje neuron function in normal and dystrophin-deficient mice to better understand the physiological basis for cognitive deficits associated with Duchenne muscular dystrophy (DMD), a common genetic disorder among children. Cognitive impairments are consistently reported in DMD, yet precise mechanisms for their occurrence are unknown. Dystrophin protein, which is absent in DMD, is normally localized to muscles and specific neurons in the brain. Purkinje neurons are rich in dystrophin, specifically in somatic and dendritic membranes. Studies demonstrate perturbed cerebellar function in the absence of dystrophin, suggesting that DMD should be regarded as a cerebellar disorder in addition to being considered a neuromuscular disorder. However, theory and evidence are not generated from overlapping information: research investigating cerebellar involvement in DMD has focused on the vermal region, associated with motor function. The lateral region, implicated in cognition, has not been explicitly examined in DMD. The first experiment revisited the issue of dystrophin distribution in the mouse cerebellum using immunohistochemistry to investigate qualitative and quantitative differences between cerebellar regions. Both regions showed dystrophin localized to Purkinje neuron somatic and dendritic membranes, but dystrophin density was 30% greater in the lateral than the vermal region. The second experiment examined intrinsic electrophysiological properties of vermal and lateral Purkinje neurons from wild-type (WT) mice and from the mdx mouse model of DMD which lack dystrophin. Significant differences in action potential firing frequency, regularity, and shape were found between cerebellar regions. Purkinje neurons from mdx mouse cerebellum exhibited membrane hyperpolarization and irregular action potential firing, regardless of region. Spontaneous action potential firing frequency was reduced in Purkinje neurons from lateral cerebellum in mdx mice relative to controls, demonstrating that a loss of dystrophin causes a potent dysregulation of Purkinje neuron function in the region associated with cognition. This research extends our understanding of cerebellar pathology in DMD and its potential relevance to cognitive deficits in the disorder. Moreover, this research further supports the role of the cerebellum as a structure important for cognition and contributes to our understanding of dystrophin’s role in the brain.