This thesis aimed to identify the trypanocidal mode of action of non-natural chamuvarinin analogs, and to assess the previously uncharacterized secondary alternative oxidase (AOX2) as a possible drug target of the trypanosomatids. The drugs used to treat infections with Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are highly toxic and are increasingly becoming less effective as the parasites develop resistance, therefore new drugs against the diseases are desperately needed. Non-natural analogs of chamuvarinin were tested for trypanocidal activity to determine the structure activity relationships of the compounds against insect-form T. cruzi and Leishmania spp. This identified several potent and selective analogs, which retained good activity against the medically relevant intracellular forms of the parasites. Photoaffinity labeling was utilized to identify the mode of action and protein target(s) of the chamuvarinin analogs. The analogs were shown to deplete ATP levels and to induce mitochondrial dysmorphia and mitochondrial oxidative stress. Photoaffinity labeling confirmed the mitochondrial localization of the protein target(s) of these compounds, however the exact protein target(s) were unable to be identified by protein pull-down and mass spectrometry. The previously uncharacterized secondary alternative oxidases (AOX2) are conserved throughout the human-infective trypanosomatids and are absent from mammalian cells, thus making an attractive drug target if the protein is essential. The AOX2 of T. brucei, T. cruzi and L. major were expressed in Escherichia coli to characterize the enzymatic activity of the proteins. T. brucei AOX2 was successfully purified and shown to be an ubiquinol oxidase, which contains bound iron (III). The role of AOX2 within the trypanosomatids was determined by biochemical phenotyping and genetic manipulation of T. brucei, T. cruzi and L. major, which indicated that AOX2 is an essential mitochondrial oxidase in the three trypanosomatids, with a putative role in energy production, and therefore is an attractive multi-trypanosomatid drug target.

Opinion Target Extraction (OTE) is a well-established subtask of sentiment analysis. While detecting sentiment polarity is useful in itself, the ability to extract the targets of the opinions allows for more thorough decision making. For example, an owner of a restaurant needs to know whether the guests are complaining about the food, or the ambience, or any other aspect of their establishment, etc. Despite the lexical information being crucial for the task, syntactic structures have potential in being used to correctly decide among multiple candidate entities. Rules based on such structures have been used previously for the task. The objective of this thesis is to investigate, whether syntactic information influences the behavior of the state-of-the-art models such as recurrent neural networks for the OTE task. We did not find any substantial evidence to suggest that adding the syntactic information influences the behavior of the models.

No description available.

The rapidly increasing number of existing drugs with genomic, biomedical, and pharmacological data make computational analyses possible, which reduces the search space for drugs and facilitates drug repositioning (DR). Thus, artificial intelligence, machine learning, and data mining have been used to identify biological interactions such as drug-target interactions (DTI), drug-disease associations, and drug-response. The prediction of these biological interactions is seen as a critical phase needed to make drug development more sustainable. Furthermore, late-stage drug development failures are usually a consequence of ineffective targets. Thus, proper target identification is needed. In this dissertation, we tried to address three crucial problems associated with the DR pipeline and presents several novel computational methods developed for DR. First, we developed three network-based DTI prediction methods using machine learning, graph embedding, and graph mining. These methods significantly improved prediction performance, and the best-performing method reduces the error rate by more than 33% across all datasets compared to the best state-of-the-art method. Second, because it is more insightful to predict continuous values that indicate how tightly the drug binds to a specific target, we conducted a comparison study of current regression-based methods that predict drug-target binding affinities (DTBA). We discussed how to develop more robust DTBA methods and subsequently developed Affinity2Vec, the first regression-based method that formulates the entire task as a graph-based method and combines several computational techniques from feature representation learning, graph mining, and machine learning with no 3D structural data of proteins. Affinity2Vec outperforms the state-of-the-art methods. Finally, since drug development failure is associated with sub-optimal target identification, we developed the first DL-based computational method (OncoRTT) to identify cancer-specific therapeutic targets for the ten most common cancers worldwide. Implementing our approach required creating a suitable dataset that could be used by the computational method to identify oncology-related DTIs. Thus, we created the OncologyTT datasets to build and evaluate our OncoRTT method. Our methods demonstrated their efficiency by achieving high prediction performance and identifying therapeutic targets for several cancer types. Overall, in this dissertation, we developed several computational methods to solve biomedical domain problems, specifically drug repositioning, and demonstrated their efficiencies and capabilities.

No description available.

No description available.

Systems biology adopts an integrated approach to study and understand the function of biological systems, particularly, the response of such systems to perturbations, such as the inhibition of a reaction in a pathway, or the administration of a drug. The complexity and large scale of biological systems make modelling and simulation an essential and critical part of systems-level studies. Systems-level modelling of pathogenic organisms has the potential to significantly enhance drug discovery programmes. In this thesis, we show how systems--level models can positively impact anti-tubercular drug target identification. *Mycobacterium tuberculosis*, the principal aetiological agent of tuberculosis in humans, is estimated to cause two million deaths every year. The existing drugs, although of immense value in controlling the disease to some extent, have several shortcomings, the most important of them being the emergence of drug resistance rendering even the front-line drugs inactive. As drug discovery efforts are increasingly becoming rational, focussing at a molecular level, the identification of appropriate targets becomes a fundamental pre-requisite. We have constructed many system-level models, to identify drug targets for tuberculosis. We construct a constraint-based stoichiometric model of mycolic acid biosynthesis, and simulate it using flux balance analysis, to identify critical points in mycobacterial metabolism for targeting drugs. We then analyse protein--protein functional linkage networks to identify influential hubs, which can be targeted to disrupt bacterial metabolism. An important aspect of tuberculosis is the emergence of drug resistance. A network analysis of potential information pathways in the cell helps to identify important proteins as co-targets, targeting which could counter the emergence of resistance. We integrate analyses of metabolism, protein--protein interactions and protein structures to develop a generic drug target identification pipeline, for identifying most suitable drug targets. Finally, we model the interplay between the pathogen and the human immune system, using Boolean networks, to elucidate critical factors influencing the outcome of infection. The strategies described can be applied to understand various pathogens and can impact many drug discovery programmes.

Part I of this thesis describes the development of bioactive small molecules of relevance to the study of the apicomlexan parasite Toxoplasma gondii into useful chemical tools. The research includes the target identification and validation studies, using both chemical and biological methods. Chapter 1 provides an overview of chemical genetics with a particular emphasis on methods for the identification of the protein targets of bioactive small molecules. The concept of biochemical protein target identification techniques was introduced with a detailed discussion of interesting applications from the literature. Chapter 2 focuses on the development of a tetrahydro-β-carboline based lead molecule into a chemical tool through target identification studies. The structure activity relationship (SAR) data associated with this core structure, the design of a chemical inducer of dimerisation (CID) and the synthesis of this CID are discussed in detail. Chapter 3 described work done to identify the potential protein target(s) of Conoidin A. Experiments to assess whether Conoidin A can inhibit a proposed target in vitro are also included. Further optimisation of this structural class to develop more potent inhibitors is discussed in the second part of this chapter. Part II of this thesis describes the development of methods for the synthesis of medium-sized ring containing compounds using oxidative fragmentation and rearrangement strategies. Chapter 5 provides an overview of the existing oxidative fragmentation methodology, with an emphasis on the use of oxidative fragmentation reactions for the synthesis of medium-sized ring systems (8-11 ring atoms). Chapter 6 focuses on using the established oxidative fragmentation method in the oxizino carbazolone system to investigate the diasteroselectivity of this reaction. Possible mechanisms for this transformation are investigated and discussed using both chemical and computational methods. An interesting rearrangement reaction has also been observed during this study. Chapter 7 focuses on developing an asymmetric oxidative fragmentation method, for use in the diazabenz[e]aceathrylenes system. Asymmetric oxidative fragmentation reactions using [Ru(pybox)(pydic)] catalysts are discussed. Attempts to optimise the enantiomeric excesses of the reaction by varying reaction conditions and substituents in the substrate are also included.

Η παρούσα διδακτορική διατριβή μελετά την παράκτια ζώνη, της Αλεξάνδρειας (Αιγύπτου) με σκοπό: (1) την ανάπλαση του παράκτιου παλαιοπεριβάλλοντος στο οποίο αναπτύχθηκε η Ελληνιστική Αλεξάνδρεια και πώς αυτό επηρέασε στην ίδρυση και στην εξέλιξη της πόλης, (2) τον εντοπισμό ναυαγίων, καταβυθισμένων λιμενικών εγκαταστάσεων και άλλων μαρτυριών ανθρώπινης δραστηριότητας. Για την επίτευξη των παραπάνω στόχων xρησιμοποιήθηκαν εξειδικευμένες θαλάσσιες γεωφυσικές τεχνολογίες, όπως ηχοβολιστής πλευρικές σάρωσης, τομογράφος υποδομής πυθμένα, απλό και διαφορικό GPS. Η ανάλυση και επεξεργασία των συλλεγέντων δεδομέμων πραγματοποιήθηκε με τη βοήθεια των υπολογιστικών πακέτων Matlab και ArcGIS. Δημιουργήθηκαν πρωτότυπα και εύχρηστα μεθοδολογικά σχήματα (PalaeogAn και TargAn), με τη βοήθεια σύγχρονων μεθόδων επεξεργασίας και ανάλυσης εικόνας, με σκοπό την επεξεργασία των αναλογικών γεωφυσικών καταγραφών, σε ένα αυτοματοποιημένο ψηφιακό περιβάλλον. Η ανάλυση των γεωφυσικών καταγραφών έδειξε την ύπαρξη μίας kurkar δομής σχήματος Τ παρόμοιας σε σχήμα, σύσταση και προσανατολισμό με το δομικό σύστημα νήσος Φάρος-Επταστάδιο-Λιμένες της Αλεξάνδρειας, μετατοπισμένη προς τα ΒΑ. Η μελέτη των μεταβολών της στάθμης της θάλασσας και η ανάλυση των τομογραφιών, έδειξε ότι η παράκτια ζώνη της Αλεξάνδρειας διαμορφώνεται από μία σειρά επάλληλων παλαιοακτών, σε βάθη νερού 16, 14, 12, 10, 8 m, οι οποίες αντιστοιχούν στην ακτογραμμή της περιοχής το 3300π.Χ (βασίλειο Harpoon), 2700π.Χ, 2000π.Χ, 1400π.Χ (οικισμός Ραχώτιδας), και 300π.Χ (Πτολεμαϊκή Αλεξάνδρεια) αντίστοιχα. Η δομή Τ ήταν πάνω από την επιφάνεια της θάλασσας και διαμόρφωνε ασφαλές αγκυροβόλιο (3300-2000π.Χ), ενώ αργότερα βυθίστηκε (2000-300π.Χ) αρχικά στα -2m (1400π.Χ) και στη συνέχεια στα -4m βάθος (300π.Χ), ενεργώντας ως φυσικός κυματοθραύστης που προστάτευε την ακτή από τη διάβρωση και τη θαλασσοταραχή. Επίσης φαίνεται ότι η είσοδος του Ανατολικού Λιμένα στα Πτολεμαϊκά χρόνια ήταν πολύ στενή (600m), στα ΒΑ της Άκρας Λοχιάδος και στο εσωτερικό του Ανατολικού Λιμένα εκείνη την εποχή υπήρχαν βραχονησίδες, το 92% της Άκρας Λοχιάδος είναι σήμερα καταβυθισμένο. Τέλος επιτεύχθηκε α) ο εντοπισμός ενός αρχαίου ναυαγίου, δύο περιοχών με έρματα αρχαίων πλοίων, δύο αρχαίων προβόλων, δύο σχηματισμών που πιθανώς αποτελούν αρχαία ναύδετα, β) ο εντοπισμός 57 στόχων, η αρχαιολογική σημασία των οποίων αξιολογήθηκε με τη βοήθεια του TargAn και πολυδιάστατων στατιστικών μεθόδων γ) η υπόδειξη νέων περιοχών αρχαιολογικού ενδιαφέροντος. / The aim of this PhD is twofold: (a) to reconstruct the palaeoenvironmental setting where Hellenistic Alexandria was developed, (b) to detect the presence of any prehistorical and historical shipwrecks and evidence of human activity. In order to accomplish the above a geophysical survey was carried out, using a sidescan sonar and a subbottom profiler system, while the positioning was provided by a GPS and DGPS. The geophysical data were analyzed using a Matlab and an ArcGIS software. New, user-friendly methodological schemes, referred to as PalaeogAn και TargAn, were developed using image analysis techniques, in order to analyse analogue geophysical data in a digital environment. The geophysical data analysis shows the presence of a Τ-shape kurkar ridge, which stands at a minimum water depth of 11m below the seasurface at the north end of the Eastern Harbour of Alexandria. This kurkar formation is almost identical with that of the Pharos island–Heptastadion-Alexandria Harbours. Sea level changes and geophysical data analysis suggest that Alexandria’s coastal zone is characterized by a series of parallel submerged palaeoshorelines, at water depths of 16, 14, 12, 10 and 8 m, which represent the coastlines of 3300 BC (kingdom of Harpoon), 2700 BC, 2000 BC, 1400 BC (ancient Rachotis), and 300 BC (Ptolemaic Alexandria) respectively. The Τ-shape structure between 3300-2000BC was above msl creating a safe anchorage for ancient ships. In 1400 BC and 300 BC it was 2m and 4m under msl respectively, acting as a natural breakwater and protecting the coast from wave action. During the Hellenistic times (300 BC) the Eastern Harbour entrance was much smaller (600m) than today. At the northeastern end of Cape Lochias and in the inner Eastern Harbour dangerous shoals and reefs were scattered. Cape Lochias was much larger than it is today as the most of it (92%) is at present submerged. The insonification revealed (a) the existence of an ancient shipwreck, two areas with ship ballast, two structures which might have been used as buoys, two structures that were propably used as moles, (b) the presence of 57 acoustic anomalies, which were analyzed using the TargAn and multivariate statistical methods, (c) new areas of archaeological importance to be surrveyed in the near future. The results of the statistical analysis classified the acoustic anomalies into groups showing their archaeological validity.

Η παρούσα μεταπτυχιακή διατριβή επικεντρώνεται στην μελέτη της παράκτιας ζώνης της νήσου Λέρου στο Νοτιοανατολικό Αιγαίο, παρουσιάζοντας τα αποτελέσματα της ερμηνείας των γεωφυσικών στοιχείων που συλλέχθηκαν από το Εργαστήριο Θαλάσσιας Γεωλογίας και Φυσικής Ωκεανογραφίας (Ε.ΘΑ.ΓΕ.Φ.Ω.) τον Ιούνιο του 2011. Η έρευνα φιλοδοξεί να συνεισφέρει στην ανάδειξη της υποθαλάσσιας πολιτιστικής και φυσικής κληρονομιάς του νησιού, καθώς η συλλογή, επεξεργασία και ερμηνεία του συνόλου των δεδομένων επέτρεψε την αναγνώριση και την λεπτομερή χαρτογράφηση υποθαλάσσιων στόχων μεγάλης ιστορικής και περιβαλλοντικής σημασίας. Ως εκ τούτου, η διατριβή κινείται σε δύο κατευθύνσεις. Η πρώτη κατεύθυνση αφορά στον εντοπισμό στόχων πιθανής ιστορικής σπουδαιότητας που εντοπίστηκαν στην επιφάνεια του πυθμένα ενώ η δεύτερη κατεύθυνση αφορά στον εντοπισμό και την αποτύπωση βιογενών σχηματισμών και συγκεκριμένα λειμώνων P. Oceanica και ασβεστιτικών ροδοφυκών (corallegene formations). Οι θαλάσσιες έρευνες πραγματοποιήθηκαν σε δύο διακριτά στάδια, στην συστηματική αποτύπωση του πυθμένα με ηχοβολιστή πλευρικής σάρωσης (EG&G 272 TD) και την οπτική επιβεβαίωση των αποτελεσμάτων της ηχοβολιστικής αποτύπωσης με σύστημα συρόμενης υποβρύχιας κάμερας. Η ανάλυση και επεξεργασία των ηχογραφιών οδήγησε στον εντοπισμό ναυαγίων που συνδέονται με τη Μάχη της Λέρου (9-10/1943), ένα από τα σημαντικότερα πολεμικά γεγονότα που έλαβαν χώρα κατά τη διάρκεια του Δευτέρου Παγκοσμίου πολέμου, στην ανατολική Μεσόγειο και τα οποία αποτελούν πολύτιμα ιστορικά στοιχεία σε παγκόσμια κλίμακα, μεταξύ των οποίων το βυθισμένο ελληνικό αντιτορπιλικό Βασίλισσα ‘Ολγα (D15). Στο πλαίσιο της δεύτερης κατεύθυνσης εντοπίστηκαν και χαρτογραφήθηκαν οι λειμώνες P. Oceanica και οι σχηματισμοί των ασβεστιτικών ροδοφυκών σχεδόν ανά όρμο περιμετρικά της νήσου. Η σχεδίαση των αντιστοίχων υποθαλάσσιων θεματικών χαρτών της παράκτιας ζώνης της Λέρου αναμένεται να αποτελέσουν ένα σημαντικό εργαλείο στην προστασία και στην ανάδειξη της σημαντικής υποθαλάσσιας ιστορικής και φυσικής κληρονομιάς του νησιού / The present study describes the submarine geophysical survey which was carried out in Leros Island, Aegean Sea and presents the results of the geophysical data analysis. The data were collected by the Laboratory of Marine Geology & Physical Oceanography, department of Geology, University of Patras during the period 11-17 June 2011. The research aims to contribute to the enhancement of underwater cultural and natural heritage of the island, as the collection, processing and interpretation of all of the data has allowed the identification of underwater targets of great historic and environmental importance. Geophysical survey in Leros Island, using a side scan sonar (EG&G 272 TD), coupled with ground-truthing by deploying a Towing Camera System of historic shipwrecks from World War II and of the major seabed habitats, namely Posidonia oceanica and coralligène formations. The survey revealed a great number of shipwrecks associated with the Battle of Leros (9-10/1943), one of the most important military events that took place during the World War II, in the Eastern Mediterranean which are considered as valuable historic data on a global scale, including the sunken Greek destroyer Queen Olga (D15). The design of the thematic maps of the coastal zone of Leros is expected to become an important tool in both protecting and promoting the significant underwater cultural and natural heritage of the island.