4,217 research outputs found

    Accustomed to Obedience?

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    Many histories of Ancient Greece center their stories on Athens, but what would that history look like if they didn’t? There is another way to tell this story, one that situates Greek history in terms of the relationships between smaller Greek cities and in contact with the wider Mediterranean. In this book, author Joshua P. Nudell offers a new history of the period from the Persian wars to wars that followed the death of Alexander the Great, from the perspective of Ionia. While recent scholarship has increasingly treated Greece through the lenses of regional, polis, and local interaction, there has not yet been a dedicated study of Classical Ionia. This book fills this clear gap in the literature while offering Ionia as a prism through which to better understand Classical Greece. This book offers a clear and accessible narrative of the period between the Persian Wars and the wars of the early Hellenistic period, two nominal liberations of the region. The volume complements existing histories of Classical Greece. Close inspection reveals that the Ionians were active partners in the imperial endeavor, even as imperial competition constrained local decision-making and exacerbated local and regional tensions. At the same time, the book offers interventions on critical issues related to Ionia such as the Athenian conquest of Samos, rhetoric about the freedom of the Greeks, the relationship between Ionian temple construction and economic activity, the status of the Panionion, Ionian poleis and their relationship with local communities beyond the circle of the dodecapolis, and the importance of historical memory to our understanding of ancient Greece. The result is a picture of an Aegean world that is more complex and less beholden narratives that give primacy to the imperial actors at the expense of local developments

    Multilingualism and the Public Sector in South Africa

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    This book contributes to the discourse on language in South Africa with a specific focus on multilingualism and the public sector

    Rational development of stabilized cyclic disulfide redox probes and bioreductive prodrugs to target dithiol oxidoreductases

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    Countless biological processes allow cells to develop, survive, and proliferate. Among these, tightly balanced regulatory enzymatic pathways that can respond rapidly to external impacts maintain dynamic physiological homeostasis. More specifically, redox homeostasis broadly affects cellular metabolism and proliferation, with major contributions by thiol/disulfide oxidoreductase systems, in particular, the Thioredoxin Reductase Thioredoxin (TrxR/Trx) and the Glutathione Reductase-Glutathione-Glutaredoxin (GR/GSH/Grx) systems. These cascades drive vital cellular functions in many ways through signaling, regulating other proteins' activity by redox switches, and by stoichiometric reductant transfers in metabolism and antioxidant systems. Increasing evidence argues that there is a persistent alteration of the redox environment in certain pathological states, such as cancer, that heavily involve the Trx system: upregulation and/or overactivity of the Trx system may support or drive cancer progression, making both TrxR and Trx promising targets for anti-cancer drug development. Understanding the biochemical mechanisms and connections between certain redox cascades requires research tools that interact with them. The state-of-the-art genetic tools are mostly ratiometric reporters that measure reduced:oxidized ratios of selected redox pairs or the general thiol pool. However, the precise cellular roles of the central oxidoreductase systems, including TrxR and Trx, remain inaccessible due to the lack of probes to selectively measure turnover by either of these proteins. However, such probes would allow measuring their effective reductive activity apart from expression levels in native systems, including in cells, animals, or patient samples. They are also of high interest to identify chemical inhibitors for TrxR/Trx in cells and to validate their potential use as anti-cancer agents (to date, there is no selective cellular Trx inhibitor, and most known TrxR inhibitors were not comprehensively evaluated considering selectivity and potential off-targets). However, small molecule redox imaging tools are underdeveloped: their protein specificity, spectral properties, and applicability remain poorly precedented. This work aimed to address this opportunity gap and develop novel, small molecule diagnostic and therapeutic tools to selectively target the Trx system based on a modular trigger cargo design: artificial cyclic disulfide substrates (trigger) for oxidoreductases are tethered to molecular agents (cargo) such that the cargo’s activity is masked and is re-established only through reduction by a target protein. The rational design of these novel reduction sensors to target the cell's strongest disulfide-reducing enzymes was driven by the following principles: (i) cyclic disulfide triggers with stabilized ring systems were used to gain low reduction potentials that should resist reduction except by the strongest cellular reductases, such as Trx; and (ii) the cyclic topology also offers the potential for kinetic reversibility that should select for dithiol-type redox proteins over the cellular monothiol background. Creating imaging agents based on such two-component designs to selectively measure redox protein activity in native cells required to combine the correct trigger reducibility, probe activation kinetics, and imaging modalities and to consider the overall molecular architecture. The major prior art in this field has applied cyclic 5-membered disulfides (1,2 dithiolanes) as substrates for TrxR in a similar way to create such tools. However, this motif was described elsewhere as thermodynamically instable and was due to widely used for dynamic covalent cascade reactions. By comparing a novel 1,2 dithiolane-based probe to the state-of-the-art probes, including commercial TrxR sensors, by screening a conclusive assay panel of cellular TrxR modulations, I clarified that 1,2 dithiolanes are not selective substrates for TrxR in biological settings (Nat Commun 2022). Instead, aiming for more stable ring systems and thus more robust redox probes, during this work, I developed bicyclic 6 membered disulfides (piperidine fused 1,2 dithianes) with remarkably low reduction potentials. I showed that molecular probes using them as reduction sensors can be mostly processed by thioredoxins while being stable against reduction by GSH. The thermodynamically stabilized decalin like topology of the cis-annelated 1,2 dithianes requires particularly strong reductants to be cleaved. They also select for dithiol type redox proteins, like Trx, based on kinetic reversibility and offer fast cyclization due to the preorganization by annelation (JACS 2021). This work further expanded the system’s modularity with structural cores based on piperazine-fused 1,2 dithianes with the two amines allowing independent derivatization. Diagnostic tools using them as reduction sensors proved equally robust but with highly improved activation kinetics and were thus cellularly activated. Cellular studies evolved that they are substrates for both Trxs and their protein cousins Grxs, so measuring the cellular dithiol protein pool rather than solely Trx activity (preprint 2023). Finally, a trigger based on a slightly adapted reduction sensor, a desymmetrized 1,2 thiaselenane, was designed for selective reduction by TrxR’s selenol/thiol active site, then combined with a precipitating large Stokes’ shift fluorophore and a solubilizing group, to evolve the first selective probe RX1 to measure cellular TrxR activity, which even allowed high throughput inhibitor screening (Chem 2022). The central principle of this work was further advanced to therapeutic prodrugs based on the duocarmycin cargo (CBI) with tunable potency (JACS Au 2022) that can be used to create off-to-on therapeutic prodrugs. Such CBI prodrugs employing stabilized 1,2 dichalcogenide triggers proved to be cytotoxins that depend on Trx system activity in cells. They could further be exploited for cell-line dependent reductase activity profiling by screening their redox activation indices, the reduction-dependent part of total prodrug activation, in 177 cell lines. Beyond that, these prodrugs were well-tolerated in animals and showed anti-cancer efficacy in vivo in two distinct mouse tumor models (preprint 2022). Taken together, I introduced unique monothiol-resistant reducible motifs to target the cellular Trx system with chemocompatible units for each for TrxR and Trx/Grx, where the cyclic nature of the dichalcogenides avoids activation by GSH. By using them with distinct molecular cargos, I developed novel selective fluorescent reporter probes; and introduced a new class of bioreductive therapeutic constructs based on a common modular design. These were either applied to selectively measure cellular reductase activity or to deliver cytotoxic anti cancer agents in vivo. Ongoing work aims to differentiate between the two major redox effector proteins Trx and Grx, requiring additional layers of selectivity that may be addressed by tuned molecular recognition. The flexible use of various molecular cargos allows harnessing the same cellular redox machinery by either probes or prodrugs. This allows predictive conclusions from diagnostics to be directly translated into therapy and offers great potential for future adaptation to other enzyme classes and therapeutic venues.Die zellulĂ€re Redox-Homöostase hĂ€ngt von Thiol/Disulfid-Oxidoreduktasen ab, die den Stoffwechsel, die Proliferation und die antioxidative Antwort von Zellen beeinflussen. Die wichtigsten Netzwerke sind die Thioredoxin Reduktase-Thioredoxin (TrxR/Trx) und Glutathion Reduktase-Glutathion-Glutaredoxin (GR/GSH/Grx) Systeme, die ĂŒber Redox-Schalter in Substratproteinen lebenswichtige zellulĂ€re Funktionen steuern und so an der Redox-Regulation und -SignalĂŒbertragung beteiligt sind. Persistente VerĂ€nderungen des Redoxmilieus in pathologischen ZustĂ€nden, wie z. B. bei Krebs, sind in hohem Maße mit dem Trx-System verbunden. Eine Hochregulierung und/oder ÜberaktivitĂ€t des Trx-Systems, die bei vielen Krebsarten auftreten, unterstĂŒtzt zudem das Fortschreiten des Krebswachstums, was TrxR/Trx zu vielversprechenden Zielproteinen fĂŒr die Entwicklung neuer Krebsmedikamente macht. Um die biochemischen Prozesse dahinter zu erforschen, sind spezielle Techniken zur Visualisierung und Messung enzymatischer AktivitĂ€t nötig. Die hierzu geeigneten, meist genetischen Sensoren messen ratiometrisch das VerhĂ€ltnis reduzierter/oxidierter Spezies in zellulĂ€rem Umfeld oder spezifisch ausgewĂ€hlte Redoxpaare. Die weitere Erforschung der exakten Funktion von TrxR/Trx und deren Substrate ist jedoch durch mangelnde Nachweismethoden limitiert. Diese sind außerdem zur Validierung chemischer Hemmstoffe fĂŒr TrxR/Trx in Zellen und deren potenziellen Verwendung als Krebsmittel von großem Interesse. Bislang gibt es keinen selektiven zellulĂ€ren Trx-Inhibitor und potenzielle Off-Target-Effekte der bekannten TrxR-Inhibitoren wurden nicht abschließend bewertet. Ziel dieser Arbeit ist die Entwicklung niedermolekularer, diagnostischer und therapeutischer Werkzeuge, die selektiv auf das Trx-System abzielen und auf einem modularen Trigger-Cargo Design basieren. Hierzu werden zyklische Disulfid-Substrate (Trigger) fĂŒr Oxidoreduktasen so mit molekularen Wirkstoffen (Cargo) verknĂŒpft, dass dabei die WirkstoffaktivitĂ€t maskiert, und erst nach Reduktion durch ein Zielprotein wiederhergestellt wird. Diese neuartigen, synthetischen Reduktionssensoren basieren auf den folgenden Grundprinzipien: (i) Zyklische Disulfide sind thermodynamisch stabilisiert und können nur durch die stĂ€rksten Reduktasen gespalten werden; und (ii) die zyklische Topologie ermöglicht die kinetische ReversibilitĂ€t der zwei Thiol-Disulfid-Austauschreaktionen, die eine erste Reaktion mit Monothiolen, wie z. B. GSH, sofort umkehrt und so eine vollstĂ€ndige Reduktion verhindert. Die meisten frĂŒheren Arbeiten auf diesem Gebiet verwendeten ein zyklisches, fĂŒnfgliedriges Disulfid (1,2 Dithiolan) als Substrat fĂŒr TrxR. Das gleiche Strukturmotiv wurde jedoch an anderer Stelle als thermodynamisch instabil beschrieben und aufgrund dieser Eigenschaft explizit fĂŒr dynamische Kaskadenreaktionen verwendet. Deshalb vergleicht diese Arbeit zu Beginn einen neuen 1,2 Dithiolan basierten fluorogenen Indikator mit bestehenden, z. T. kommerziellen, Redox Sonden fĂŒr TrxR in einer Reihe von Zellkultur-Experimenten unter Modulation der zellulĂ€ren TrxR AktivitĂ€t und stellt so einen Widerspruch in der Literatur klar: 1,2 Dithiolane eignen sich nicht als selektive Substrate fĂŒr TrxR, da sie labil sowohl gegen die Reduktion durch andere Redoxproteine, als auch gegen den Monothiol Hintergrund in Zellen sind (Nat. Commun. 2022). Als alternatives Strukturmotiv wird in dieser Arbeit ein bizyklisches sechsgliedriges Disulfid (anneliertes 1,2 Dithian) etabliert. Durch sein niedriges Reduktionspotenzial, also seine hohe Resistenz gegen Reduktion, werden molekulare Sonden basierend auf diesem 1,2 Dithian als Reduktionssensor fast ausschließlich von Trx aktiviert, nicht aber von TrxR oder GSH (JACS 2021). Dieses Kernmotiv bestimmt dabei die Reduzierbarkeit, und damit die EnzymspezifitĂ€t, durch seine zyklische Natur und die Annelierung, auch unter Verwendung unterschiedlicher Farb-/Wirkstoffe. Auf dieser Grundlage konnte die molekulare Struktur durch einen weiteren Modifikationspunkt fĂŒr die flexible Verwendung weiterer funktioneller Einheiten ergĂ€nzt werden. Obwohl zellulĂ€re Studien ergaben, dass diese neuartigen 1,2 Dithian Einheiten in Zellen sowohl Trx als auch das strukturell verwandte Grx adressieren, sind die daraus resultierenden diagnostischen MolekĂŒle wertvoll, um den katalytischen Umsatz zellulĂ€rer Dithiol-Reduktasen, der sogenannten Trx Superfamilie, selektiv anzuzeigen (Preprint 2023). BegĂŒnstigt durch das modulare MolekĂŒldesign stellt diese Arbeit zudem das erste Reportersystem RX1 zum selektiven Nachweis der TrxR-AktivitĂ€t in Zellen vor. Es basiert auf der Verwendung eines zyklischen, unsymmetrischen Selenenylsulfid-Sensors (1,2 Thiaselenan), der selektiv von dem einzigartigen Selenolat der TrxR angegriffen wird, und dadurch letztlich nur von TrxR reduziert werden kann. RX1 eignete sich zudem fĂŒr eine Hochdurchsatz-Validierung bestehender TrxR Inhibitoren und unterstreicht dadurch den kommerziellen Nutzen derartiger Diagnostika (Chem 2022). Das zentrale Trigger-Cargo Konzept dieser Arbeit wurde fĂŒr therapeutische Zwecke weiterentwickelt und nutzt dabei den einzigartigen Wirkmechanismus der Duocarmycin-Naturstoffklasse (CBI) (JACS Au 2022) zur Entwicklung reduktiv aktivierbarer Therapeutika. CBI Prodrugs basierend auf stabilisierten Redox-Schaltern (1,2 Dithiane fĂŒr Trx; 1,2 Thiaselenan fĂŒr TrxR) reagierten signifikant auf TrxR-Modulation in Zellen. Sie wurden darĂŒber hinaus durch das Referenzieren ihrer AktivitĂ€t gegenĂŒber nicht-reduzierbaren KontrollmolekĂŒle fĂŒr die Erstellung zelllinienabhĂ€ngiger Profile der ReduktaseaktivitĂ€t in 177 Zelllinien genutzt. Schließlich waren diese neuen Krebsmittel im Tiermodell gut vertrĂ€glich und zeigten in zwei verschiedenen Mausmodellen eine krebshemmende Wirkung (Preprint 2022b). Zusammenfassend prĂ€sentiert diese Dissertation monothiol-resistente reduzierbare Trigger-Einheiten fĂŒr das zellulĂ€re Trx-System zur Entwicklung neuartiger, selektiver Reporter-Sonden, sowie eine neue Klasse reduktiv aktivierbarer Krebsmittel auf Basis eines adaptierbaren Trigger-Cargo Designs. Diese fanden entweder zur selektiven Messung zellulĂ€rer ProteinaktivitĂ€t oder zum Einsatz als Antikrebsmittel Verwendung. Es wurden chemokompatible Motive sowohl fĂŒr TrxR als auch fĂŒr Trx/Grx identifiziert, wobei deren zyklische Natur eine Aktivierung durch GSH verhindert. Eine weitere Differenzierung zwischen den beiden Redox-Proteinen Trx und Grx und anderen Proteinen der Trx-Superfamilie erfordert eine zusĂ€tzliche Ebene der Selektierung, z. B. durch molekulare Erkennung, und ist Gegenstand laufender Arbeiten. Die flexible Verwendung verschiedener molekularer Wirkstoffe ermöglicht dabei die „Pipeline-Entwicklung“ von Diagnostika und Therapeutika, die von der zellulĂ€ren Redox-Maschinerie analog umgesetzt werden, und dadurch Schlussfolgerungen aus der Diagnostik direkt auf eine Therapie ĂŒbertragbar machen. Dies birgt großes Potenzial fĂŒr kĂŒnftige Entwicklungen bei einer potenziellen Übertragung des modularen Konzepts auf andere Enzymklassen und therapeutische Einsatzgebiete

    UNDERSTANDING IDENTITY, POWER, AND USE OF SPACE OVER TIME WITHIN HOUSEPIT 54, BRIDGE RIVER SITE (K’ETXELKNÁ’Z), BRITISH COLUMBIA

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    This research examines cultural change and continuity as embodied within a singular multi-generational housepit (Housepit 54) located within the Bridge River site (K’etxelkná’z) in the Mid-Fraser Canyon, British Columbia, Canada. Previous research has highlighted the distinctive differences between Bridge River 2 and 3 time periods wherein the village was faced with dramatic population growth and climate change. These pressures crafted a Malthusian ceiling-type event which corresponded with the emergence of persistent institutionalized inequality. This research aims to illuminate issues of gender, kinship, social identity, and household social relationships in order to highlight how macro-scale cultural change is evinced in micro-scale space-use and activity patterns. This research examines how such a drastic restructuring of the sociopolitical realities within the Bridge River village (K’etxelkná’z) interfaces with interpersonal identity and cultural evolution at the household level

    Constitutions of Value

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    Gathering an interdisciplinary range of cutting-edge scholars, this book addresses legal constitutions of value. Global value production and transnational value practices that rely on exploitation and extraction have left us with toxic commons and a damaged planet. Against this situation, the book examines law’s fundamental role in institutions of value production and valuation. Utilising pathbreaking theoretical approaches, it problematizes mainstream efforts to redeem institutions of value production by recoupling them with progressive values. Aiming beyond radical critique, the book opens up the possibility of imagining and enacting new and different value practices. This wide-ranging and accessible book will appeal to international lawyers, socio-legal scholars, those working at the intersections of law and economy and others, in politics, economics, environmental studies and elsewhere, who are concerned with rethinking our current ideas of what has value, what does not, and whether and how value may be revalued

    Vitalism and Its Legacy in Twentieth Century Life Sciences and Philosophy

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    This Open Access book combines philosophical and historical analysis of various forms of alternatives to mechanism and mechanistic explanation, focusing on the 19th century to the present. It addresses vitalism, organicism and responses to materialism and its relevance to current biological science. In doing so, it promotes dialogue and discussion about the historical and philosophical importance of vitalism and other non-mechanistic conceptions of life. It points towards the integration of genomic science into the broader history of biology. It details a broad engagement with a variety of nineteenth, twentieth and twenty-first century vitalisms and conceptions of life. In addition, it discusses important threads in the history of concepts in the United States and Europe, including charting new reception histories in eastern and south-eastern Europe. While vitalism, organicism and similar epistemologies are often the concern of specialists in the history and philosophy of biology and of historians of ideas, the range of the contributions as well as the geographical and temporal scope of the volume allows for it to appeal to the historian of science and the historian of biology generally

    Art and Creativity for HIV/AIDS Awareness, Prevention, and Empowerment of Young People in Uganda

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    Art, youth engagement and informality in the context of HIV prevention have been generally ignored by most researchers and stakeholders within the HIV programming and policy arenas, thus silencing the plight of urban youth infected with and affected by HIV/AIDS. In response, this thesis draws on the case of peri-urban settings of Kampala, Uganda to bring geographies of applied sculpture, HIV/AIDS prevention, and youth empowerment into dialogue, informed by the notions of art having the capacity to move beyond the spaces of galleries into an expanded field, and thus, beyond the visual and into the social spheres. In liaison with local NGOs (The Uganda AIDS Support Organisation - TASO, National Guidance and Empowerment Network for People Living with HIV/AIDS - NGEN+ and Lungujja Community based Health care Organisation – LUCOHECO, it adopts a mixed methodological approach, including applied art and participatory techniques - observation, video, storytelling, and interviews, to understand the lived experiences of young people (15-24 years) in marginalized spaces in Kampala. The thesis first examines the general context of using ethnography and applied social sculpture to explore every day experiences by facilitating the engagement of young people in open communication about the epidemic. This is intended to enable them to act in confronting stigma, taboos, and their precarious existence, while raising their awareness about HIV/AIDS. The thesis then explores the everyday precarious existence of young people in informal settings in Kampala. It proceeds to examine how workshops with these young people allowed collective engagement which, in turn, influenced the creation of artworks envisioned to act as communication tools for raising awareness of HIV/AIDS with the potential for livelihood benefits. Finally, the thesis examines young people’s active involvement in participatory workshops for HIV/AIDS prevention, providing ethnographic evidence regarding the artmaking process, the conversations that ensued as they worked, and the creation of applied objects/forms that enabled them to build their confidence to freely express about the precarities affecting their lives, countering taboos, and encouraging them to change their behaviours and practices while potentially acting as change agents in their own communities. It highlights the significance of stimulating open conversations about HIV/AIDS - as a starting point towards confronting stigma and other aspects of precarity, while advocating for the incorporation of the approach into practice by public health experts, policymakers, and development practitioners. The thesis shows the strengths of applied sculpture as an approach that has potential for making sense of ordinary everyday experiences, finding meaning and crafting clarity of young people’s lived experiences in the context of HIV/AIDS. It concludes that applied sculpture is potentially an important tool in tackling HIV/AIDS and its attendant problems by engendering and facilitating open conversations and social economic development through an engagement with the voices and agency of young people in Uganda and beyond

    Deconstructing and Reconstructing Local Identities in the Physical Landscape: The role(s) of Roman remains in the social changes of the sixth and seventh centuries in the former province of Britain

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    This thesis examines the evidence for engagement with and avoidance of Roman remains in the landscape of two regions within the former province of Britain, Sussex and the eastern part of the northern military frontier. This information is used to consider the attitudes that localised societies held towards the remain of the past, and how this engagement related to the social changes of the period. Chapter 1 introduces the research context and the aims, setting out research questions. Chapter 2 presents the state of current knowledge and prior approaches to studies of the landscape and the early medieval period, and places the study within the wider theoretical and methodological contexts of landscape studies, the use of GIS, and the consideration of ‘the past in the past’. It then examines attitudes towards the Roman past as evidence in other forms of cultural expression, ranging from modes of displaying identity and authority to the recycling of Roman metalwork, considering the degree of consistency in attitudes towards the past. This is followed in chapter 3 by an explanation of the methodology adopted. The following chapters look at engagement with Roman remains, in post-Roman Sussex in chapter 4, and the north-east military frontier, from southern Northumberland south to the North York Moors, in chapter 5. The evidence is contextualised against the distribution of activity in the physical landscape and the presence of prehistoric remains. Chapter 6 pulls together these threads together with previous regional studies, with a focus on identifying regional and chronological similarities and contrasts, and the reasons underlying these patterns. Finally, chapter 7 considers the strengths and weaknesses of the study, and areas for future work

    An ensemble architecture for forgery detection and localization in digital images

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    Questa tesi presenta un approccio d'insieme unificato - "ensemble" - per il rilevamento e la localizzazione di contraffazioni in immagini digitali. Il focus della ricerca Ăš su due delle piĂč comuni ma efficaci tecniche di contraffazione: "copy-move" e "splicing". L'architettura proposta combina una serie di metodi di rilevamento e localizzazione di manipolazioni per ottenere prestazioni migliori rispetto a metodi utilizzati in modalitĂ  "standalone". I principali contributi di questo lavoro sono elencati di seguito. In primo luogo, nel Capitolo 1 e 2 viene presentata un'ampia rassegna dell'attuale stato dell'arte nel rilevamento di manipolazioni ("forgery"), con particolare attenzione agli approcci basati sul deep learning. Un'importante intuizione che ne deriva Ăš la seguente: questi approcci, sebbene promettenti, non possono essere facilmente confrontati in termini di performance perchĂ© tipicamente vengono valutati su dataset personalizzati a causa della mancanza di dati annotati con precisione. Inoltre, spesso questi dati non sono resi disponibili pubblicamente. Abbiamo poi progettato un algoritmo di rilevamento di manipolazioni copy-move basato su "keypoint", descritto nel capitolo 3. Rispetto a esistenti approcci simili, abbiamo aggiunto una fase di clustering basato su densitĂ  spaziale per filtrare le corrispondenze rumorose dei keypoint. I risultati hanno dimostrato che questo metodo funziona bene su due dataset di riferimento e supera uno dei metodi piĂč citati in letteratura. Nel Capitolo 4 viene proposta una nuova architettura per predire la direzione della luce 3D in una data immagine. Questo approccio sfrutta l'idea di combinare un metodo "data-driven" con un modello di illuminazione fisica, consentendo cosĂŹ di ottenere prestazioni migliori. Al fine di sopperire al problema della scarsitĂ  di dati per l'addestramento di architetture di deep learning altamente parametrizzate, in particolare per il compito di scomposizione intrinseca delle immagini, abbiamo sviluppato due algoritmi di generazione dei dati. Questi sono stati utilizzati per produrre due dataset - uno sintetico e uno di immagini reali - con lo scopo di addestrare e valutare il nostro approccio. Il modello di stima della direzione della luce proposto Ăš stato sfruttato in un nuovo approccio di rilevamento di manipolazioni di tipo splicing, discusso nel Capitolo 5, in cui le incoerenze nella direzione della luce tra le diverse regioni dell'immagine vengono utilizzate per evidenziare potenziali attacchi splicing. L'approccio ensemble proposto Ăš descritto nell'ultimo capitolo. Questo include un modulo "FusionForgery" che combina gli output dei metodi "base" proposti in precedenza e assegna un'etichetta binaria (forged vs. original). Nel caso l'immagine sia identificata come contraffatta, il nostro metodo cerca anche di specializzare ulteriormente la decisione tra attacchi splicing o copy-move. In questo secondo caso, viene eseguito anche un tentativo di ricostruire le regioni "sorgente" utilizzate nell'attacco copy-move. Le prestazioni dell'approccio proposto sono state valutate addestrandolo e testandolo su un dataset sintetico, generato da noi, comprendente sia attacchi copy-move che di tipo splicing. L'approccio ensemble supera tutti i singoli metodi "base" in termini di prestazioni, dimostrando la validitĂ  della strategia proposta.This thesis presents a unified ensemble approach for forgery detection and localization in digital images. The focus of the research is on two of the most common but effective forgery techniques: copy-move and splicing. The ensemble architecture combines a set of forgery detection and localization methods in order to achieve improved performance with respect to standalone approaches. The main contributions of this work are listed in the following. First, an extensive review of the current state of the art in forgery detection, with a focus on deep learning-based approaches is presented in Chapter 1 and 2. An important insight that is derived is the following: these approaches, although promising, cannot be easily compared in terms of performance because they are typically evaluated on custom datasets due to the lack of precisely annotated data. Also, they are often not publicly available. We then designed a keypoint-based copy-move detection algorithm, which is described in Chapter 3. Compared to previous existing keypoints-based approaches, we added a density-based clustering step to filter out noisy keypoints matches. This method has been demonstrated to perform well on two benchmark datasets and outperforms one of the most cited state-of-the-art methods. In Chapter 4 a novel architecture is proposed to predict the 3D light direction of the light in a given image. This approach leverages the idea of combining, in a data-driven method, a physical illumination model that allows for improved regression performance. In order to fill in the gap of data scarcity for training highly-parameterized deep learning architectures, especially for the task of intrinsic image decomposition, we developed two data generation algorithms that were used to produce two datasets - one synthetic and one of real images - to train and evaluate our approach. The proposed light direction estimation model has then been employed to design a novel splicing detection approach, discussed in Chapter 5, in which light direction inconsistencies between different regions in the image are used to highlight potential splicing attacks. The proposed ensemble scheme for forgery detection is described in the last chapter. It includes a "FusionForgery" module that combines the outputs of the different previously proposed "base" methods and assigns a binary label (forged vs. pristine) to the input image. In the case of forgery prediction, our method also tries to further specialize the decision between splicing and copy-move attacks. If the image is predicted as copy-moved, an attempt to reconstruct the source regions used in the copy-move attack is also done. The performance of the proposed approach has been assessed by training and testing it on a synthetic dataset, generated by us, comprising both copy-move and splicing attacks. The ensemble approach outperforms all of the individual "base" methods, demonstrating the validity of the proposed strategy
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