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    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 zelluläre Redox-Homöostase hängt 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 über Redox-Schalter in Substratproteinen lebenswichtige zelluläre Funktionen steuern und so an der Redox-Regulation und -Signalübertragung beteiligt sind. Persistente Veränderungen des Redoxmilieus in pathologischen Zuständen, wie z. B. bei Krebs, sind in hohem Maße mit dem Trx-System verbunden. Eine Hochregulierung und/oder Überaktivität des Trx-Systems, die bei vielen Krebsarten auftreten, unterstützt zudem das Fortschreiten des Krebswachstums, was TrxR/Trx zu vielversprechenden Zielproteinen für die Entwicklung neuer Krebsmedikamente macht. Um die biochemischen Prozesse dahinter zu erforschen, sind spezielle Techniken zur Visualisierung und Messung enzymatischer Aktivität nötig. Die hierzu geeigneten, meist genetischen Sensoren messen ratiometrisch das Verhältnis reduzierter/oxidierter Spezies in zellulärem Umfeld oder spezifisch ausgewählte 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 für TrxR/Trx in Zellen und deren potenziellen Verwendung als Krebsmittel von großem Interesse. Bislang gibt es keinen selektiven zellulären 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) für Oxidoreduktasen so mit molekularen Wirkstoffen (Cargo) verknüpft, dass dabei die Wirkstoffaktivität 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 stärksten Reduktasen gespalten werden; und (ii) die zyklische Topologie ermöglicht die kinetische Reversibilität der zwei Thiol-Disulfid-Austauschreaktionen, die eine erste Reaktion mit Monothiolen, wie z. B. GSH, sofort umkehrt und so eine vollständige Reduktion verhindert. Die meisten früheren Arbeiten auf diesem Gebiet verwendeten ein zyklisches, fünfgliedriges Disulfid (1,2 Dithiolan) als Substrat für TrxR. Das gleiche Strukturmotiv wurde jedoch an anderer Stelle als thermodynamisch instabil beschrieben und aufgrund dieser Eigenschaft explizit für dynamische Kaskadenreaktionen verwendet. Deshalb vergleicht diese Arbeit zu Beginn einen neuen 1,2 Dithiolan basierten fluorogenen Indikator mit bestehenden, z. T. kommerziellen, Redox Sonden für TrxR in einer Reihe von Zellkultur-Experimenten unter Modulation der zellulären TrxR Aktivität und stellt so einen Widerspruch in der Literatur klar: 1,2 Dithiolane eignen sich nicht als selektive Substrate für 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 Enzymspezifität, durch seine zyklische Natur und die Annelierung, auch unter Verwendung unterschiedlicher Farb-/Wirkstoffe. Auf dieser Grundlage konnte die molekulare Struktur durch einen weiteren Modifikationspunkt für die flexible Verwendung weiterer funktioneller Einheiten ergänzt werden. Obwohl zelluläre 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 Moleküle wertvoll, um den katalytischen Umsatz zellulärer Dithiol-Reduktasen, der sogenannten Trx Superfamilie, selektiv anzuzeigen (Preprint 2023). Begünstigt durch das modulare Moleküldesign stellt diese Arbeit zudem das erste Reportersystem RX1 zum selektiven Nachweis der TrxR-Aktivität 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 für eine Hochdurchsatz-Validierung bestehender TrxR Inhibitoren und unterstreicht dadurch den kommerziellen Nutzen derartiger Diagnostika (Chem 2022). Das zentrale Trigger-Cargo Konzept dieser Arbeit wurde für 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 für Trx; 1,2 Thiaselenan für TrxR) reagierten signifikant auf TrxR-Modulation in Zellen. Sie wurden darüber hinaus durch das Referenzieren ihrer Aktivität gegenüber nicht-reduzierbaren Kontrollmoleküle für die Erstellung zelllinienabhängiger Profile der Reduktaseaktivität in 177 Zelllinien genutzt. Schließlich waren diese neuen Krebsmittel im Tiermodell gut verträglich und zeigten in zwei verschiedenen Mausmodellen eine krebshemmende Wirkung (Preprint 2022b). Zusammenfassend präsentiert diese Dissertation monothiol-resistente reduzierbare Trigger-Einheiten für das zelluläre 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 zellulärer Proteinaktivität oder zum Einsatz als Antikrebsmittel Verwendung. Es wurden chemokompatible Motive sowohl für TrxR als auch für 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 zusätzliche 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 zellulären Redox-Maschinerie analog umgesetzt werden, und dadurch Schlussfolgerungen aus der Diagnostik direkt auf eine Therapie übertragbar machen. Dies birgt großes Potenzial für künftige Entwicklungen bei einer potenziellen Übertragung des modularen Konzepts auf andere Enzymklassen und therapeutische Einsatzgebiete

    Faludi Blogging

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    “Chasing Territorialism” gathers short texts by Emeritus Professor Andreas Faludi, originally written as blog posts over a period of two years. In Andreas’ words: “Stimulated by an, albeit brief, encounter with Albania celebrating Europe Day, I began blogging about the continuing relevance of criticising territorialism, as I’d done in The Poverty of Territorialism (Faludi 2018; Edgar Elgar), in particular - but not exclusively - in relation to European integration.” Here, territorialism stands for states claiming a monopoly on controlling their territories much as they try to control the loyalty of their citizens. As such, territorialism is a fundamental principle of political organisation. Continued reflection on the poverty of this principle has acquired urgent overtones with the resurgence of armed conflict in Europe and elsewhere. If anything, the general reaction to this and other continental and even global crises seems to be to further enforce territorialism. But, what if territorialism is the cause of, rather than the solution to our problems? If so, would heeding the call for determined state action not become a case of: ‘Out of the frying pan and into the fire’? This book does not give an answer. What it hopefully does is stimulate debate about what the answer should be

    International Academic Symposium of Social Science 2022

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    This conference proceedings gathers work and research presented at the International Academic Symposium of Social Science 2022 (IASSC2022) held on July 3, 2022, in Kota Bharu, Kelantan, Malaysia. The conference was jointly organized by the Faculty of Information Management of Universiti Teknologi MARA Kelantan Branch, Malaysia; University of Malaya, Malaysia; Universitas Pembangunan Nasional Veteran Jakarta, Indonesia; Universitas Ngudi Waluyo, Indonesia; Camarines Sur Polytechnic Colleges, Philippines; and UCSI University, Malaysia. Featuring experienced keynote speakers from Malaysia, Australia, and England, this proceeding provides an opportunity for researchers, postgraduate students, and industry practitioners to gain knowledge and understanding of advanced topics concerning digital transformations in the perspective of the social sciences and information systems, focusing on issues, challenges, impacts, and theoretical foundations. This conference proceedings will assist in shaping the future of the academy and industry by compiling state-of-the-art works and future trends in the digital transformation of the social sciences and the field of information systems. It is also considered an interactive platform that enables academicians, practitioners and students from various institutions and industries to collaborate

    Public sector accounting and financial management in the context of a developing country: an empirical study of the Volta River Authority in Ghana

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    Using the Volta River Authority, a major Ghanaian corporation responsible for the generation and distribution of electricity in Ghana and neighbouring countries, as a case study, this thesis seeks to gain an empirical understanding of the nature and effectiveness of accounting and financial management systems in the context of a public sector organisation in a developing country. The principal rationale of the thesis is an attempt to substantiate and illuminate major issues and concerns about the nature of accounting and financial management systems in public sector organisations of developing countries today. The thesis problematises an overly simple view that developing countries have deficient accounting and financial management systems in their public sector organisations. The methodological, epistemological, and ontological orientations of the thesis are consistent with what Chua (1986) labels the “interpretive” paradigm. A recognition of multiple realities in the functioning of accounting enables an exploration of the claim that developing countries have deficient public sector accounting and financial management systems in a three-dimensional fashion. Firstly, the perceptions of organisational actors are drawn upon to aid evaluation of the basic deficiency claim. The research at this level emphasizes the technical-rational view of accounting as a tool for control over organisational financial resources. Thick descriptions of the systems for managing financial resources (including planning, budgeting, pricing, extent of computerisation, financial reporting and audit practices) of the VRA are gathered from organisational actors together with perceptions of the accounting and financial management systems by external constituencies such as the World Bank and the Authority’s multinational audit firms as a basis for evaluating the deficiency claim in the context of the VRA. Secondly, the thesis draws upon social theory (the view of organisations as negotiated orders) to further interpret the deficiency claim by bringing into the analysis the socio-historical circumstances of the organisation and how they help to provide insights into how the systems for financial resource management arise at the VRA. At this level of analysis, the thesis provides an interpretive construction of the technical procedures for financial resource management against the backdrop of the institutional setting within which the Authority conducts its operations. To this end, the influence of external constituencies such as the World Bank and the Volta Aluminium Company (VRA’s major customer) on the Authority’s accounting and financial management systems are explored. Thirdly, the thesis evaluates the effectiveness of the Authority’s accounting and financial management systems with reference to the extent to which they assist in the accomplishment of the principal rationale for establishing the organisation (i.e. socio-economic development of Ghana). At the third level of analysis, the Brundtland Commission’s notion of sustainable development is drawn upon as an alternative to the dominant economistic notion of development to provide a benchmark for the analysis. Employing the Commission’s perspective, the thesis attempts to understand the extent to which VRA’s systems of financial resource management reflect the notion of people-centredness and environmental awareness (i.e. the two major strands of the Commission’s notion of sustainable development). Multiple methods, including interviews, observation, document analysis and survey are employed to collect empirical evidence for this study. The major conclusions of the study are that from a technical-rational perspective, the claim that developing countries generally have deficient public sector accounting and financial management systems could not be established in the context of the VRA. This conclusion derived from the overwhelming positive perception of the Authority’s financial resource management systems by organisational actors, international funding agencies such as the World Bank, and the Authority’s multinational accounting/audit firms. Indeed, the claims about the lack of published annual accounts, inadequate information for managerial decision making, poor budgetary practices, and lack of independent auditors in developing country public sector contexts could not be supported in the case of the VRA. However, by going behind the technical procedures (façade) to uncover the forces which explain how the systems arise, the thesis argued that the deficiency claim might be supported in another sense; a sense which appreciates and problematises the socio-historical and institutional setting which are strongly responsible not only for the nature of the Authority’s current systems but how they have changed over time. In particular, the thesis argues that the systems of financial resource management are constructed partly to legitimise outcomes of prior negotiations between the Authority and its external constituencies. The constraints presented by these prior agreements and contracts render some of the Authority’s systems of financial resource management inconsistent with explanations grounded in conventional accounting and financial management logic. The thesis also finds, however, that some of the inadequacies observed with VRA’s systems of financial resource management reflected general limitations of conventional accounting with its over-emphasis on the entity concept rather than a peculiar organisational or even developing country problem. By employing an interpretive methodological approach to gain an understanding of the nature and effectiveness of accounting in a third world public sector organisational context, this thesis illuminates hitherto relatively unappreciated issues, including furthering an appreciation of accounting as a socio-political artefact in this context, and thus contributes to the critical and interpretive accounting literature

    Designing a Simulation showcasing the Pharmacological Effects of Beta-2-Agonists in Asthma Treatment; Virtual Reality as a supplement to traditional teaching methods

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    As educational technology evolves, there is a growing interest in applying VR in teaching complex scientific concepts that benefit from a visual and immersive learning environment. Motivated by the promising results of VR in medical education across multiple disciplines, we aimed to investigate the applicability and effectiveness of this technology in pharmacology education. This discipline, which involves understanding how drugs work within the human body, is often considered complex and challenging for students. However, it is a critical component of medical education and is essential in treating and preventing various diseases. The study was driven by two research inquiries. The primary inquiry aimed to explore the potential design possibilities of a virtual reality (VR) simulation for visualizing the pharmacological effects of beta-2-agonists in asthma treatment. The secondary question focused on evaluating the perspectives of students and educators regarding the efficacy of the VR application in learning pharmacology concepts compared to conventional teaching approaches. The application underwent two rounds of evaluation sessions with both students and teachers. Participants responded positively to the immersive learning experience, particularly appreciating the detailed visualizations and interactivity offered by the VR application. Their feedback highlighted the potential of VR to create a more intuitive understanding of complex pharmacological processes. Despite the evaluation phase featuring a limited number of participants, the received feedback suggested a promising potential for VR as an additional tool. The study, therefore, serves as a proof of concept, showcasing the possibilities of VR in enhancing pharmacology education and paving the way for future research and development in this area.Masteroppgave i Programvareutvikling samarbeid med HVLPROG399MAMN-PRO

    The path of the law : the establishment, abolition and remedy of involuntary sterilisation and castration in Sweden, Norway and Finland

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    Defence date: 13 May 2019Examining Board: Professor Ruth Rubio-Marín, University of Seville & European University Institute (Supervisor); Professor Laura Downs, European University Institute; Professor Anne Hellum, University of Oslo; Professor Dinah Shelton, The George Washington UniversityInvoluntary sterilisation and castration, narrowly problematised at the Nuremberg trials, were long topics incoherently regulated by international law. A supranational conceptual and remedial framework, mainly pertaining to human rights, is only recently emerging regarding the practices. Against this background, the thesis takes a closer look at Sweden, Norway and Finland, three Nordic countries that established similar sterilisation and castration laws and/or administrative regulations during the last century. The regulations have built on state control and allowed for interventions against the will of the targeted individuals. The targeted groups have been heterogeneous but can generally be divided into three subgroups: poor and marginalised women (1930s–1970s), sexual offenders and ‘deviants’ (1930s–1970s) and trans people (1970s–today). While the majority of the practices have been abolished, the three otherwise similar states have legally conceptualised said practices very differently, particularly in terms of state responsibility and remedies for victims. The thesis looks deeper into these differences and draws on legal mobilisation and social movement theory, particularly grievance formation with reference to rights. The thesis engages in doctrinal, legal-historical, socio-legal and comparative modes of analysis. Doing so, it investigates five legal and extra-legal factors to understand the differences between the countries of comparison: i) rights culture; ii) remedial and public liability culture; iii) victim mobilisation; iv) perception of victims and mass media attention; and v) public image and political party alliances. These factors have affected the unfolding of the establishment, abolition and remedy of involuntary sterilisation and castration in Sweden, Norway and Finland – practices sometimes referred to as the ‘skeleton in the closet’ of the Nordic welfare states

    Infrastructural Cinema: Seeing Energy on Film in the Long 1930s

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    American energy and infrastructure are at points of major reckoning. Electrical grids suffer major outages, while climate change threatens every known way of harnessing energy resources. But how did we get here? My dissertation, “Infrastructural Cinema: Seeing Energy on Film in the Long 1930s” analyzes the characterization of energy resources in American government and corporate films from the 1920s-1930s, or “infrastructural cinema.” Specifically, I interrogate how infrastructural cinema has affected our understanding of how to control and manage energy, and to what extent our reliance on such infrastructures limits present-day energy solutions. Infrastructural cinema is concerned with how energy and its networks are made cinematic: how does film both mediate our understanding of natural resources and act as an infrastructure itself? It is a concept born at the nexus of modernity, media, aesthetics, technology, ecology, and the nonhuman. I pursue infrastructural cinema as a media technology and a cultural technology—an ideological apparatus—often kept hidden from sight. This analysis reveals the intentionality of both energy and filmic systems that may otherwise be invisible or normalized, even to the point of being interpreted as neutral. Such a history of infrastructural cinema focuses on the constructedness of both cinema and infrastructure and questions the acceptance of certain infrastructures as central to human culture, primarily those that extract, transform, harness, or deliver natural resources to humans as energy. For example, the “pipelines alive with racing oil” deemed necessary in More Power To You (1939) crisscross native land and threaten ecologies. My first chapter historicizes nonfiction film and focuses on the sociocultural context of the 1920s-1930s. Chapters 2, 3, and 4 analyze films about hydroelectric dams, oil and gas infrastructure, and electrical infrastructure respectively. Understanding this archive offers ways to address the infrastructural zeitgeist of the present and encourages new visions for life after energy extraction
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