Alliance One Tobacco (Malawi)
Academic Research Repository at the Institute of Developing EconomiesNot a member yet
52305 research outputs found
Sort by
Trioxacarcin-based Antibody-Drug Conjugates: Optimization of payload structure and a triazene linker system design
No full textThe trioxacarcins are a set of rigid, pentacyclic natural products first isolated from Streptomyces bottropensis DO-45 in 1981. Their exceptional cytotoxicity inspired a phase 1 clinical trial only a few years later, which was halted abruptly due to unforeseen cardiotoxicity, resulting in a participant’s passing. Forgotten for decades, interest in trioxacarcins resurged more recently with the advent of contemporary, targeted cancer therapies, including Antibody-Drug Conjugates (ADCs), which promise to deliver the toxic payload directly to the tumor, thereby improving the therapeutic index. Following the initial disclosure of the total synthesis of Trioxacarcin A and related natural products back in 2013, the Myers group has been hard at work developing simplified, scalable pharmacophores that maintained the impressive potency of the initial bacterial isolates, and incorporated those into ADCs. Unfortunately, the very functionality responsible for its activity – the unique spiro-epoxide capable of alkylating guanine nucleobases in DNA – proved to be incompatible with the ADC platform, reacting with the nucleophilic amino acid side chains of the monoclonal antibody instead. Additional efforts resulted in the development of a bromohydrin-based prodrug strategy, however these drug-linkers lacked the requisite activity.
This thesis sets out to understand the underpinning reasons for the lack of ADC activity in several complementary ways. In Chapter 2, I present the final attempt at synthesizing trioxacarcin ADCs with an intact spiro-epoxide, using chemical methods to install a functional handle near the reactive functional group, in the hope of shielding it from the monoclonal antibody.
Chapter 3 identifies the bromohydrin reversion kinetics as the likely culprit of the lack of activity. Using a hypothesis-driven approach, we synthesize a panel of new trioxacarcin analogs with the goal of improving the efficiency of the spiro-epoxide reformation. We then identify a payload with the reversion kinetics improved 7-fold over the initial lead compound, and prove that the ADC activity is directly related to the rate of this process. Unfortunately, the improved reversion kinetics come at a cost of lower warhead potency, leading to equipotent ADCs.
In Chapter 4 I describe the design and synthesis of a novel drug-linker system inspired by the glioblastoma drug temolozomide. It incorporates a highly reactive triazene motif, which fragments in aqueous buffers to reveal a diazonium cation that immediately reforms the parent spiro-epoxide. By synthesizing different drug-linkers I show how the fate of the warhead is directly related to the substitution pattern of the triazene. The new constructs exhibit vastly superior epoxide reformation kinetics, with full conversion within 20 minutes versus multiple hours observed for the bromohydrin systems.Chemistry and Chemical Biolog
Firm Responses to Export Controls: Evidence from the Japan–Korea Trade Dispute
Full text linkapplication/pdfIDP000991_001This study examines the responses of firms in a target country to export control regulations and related localization subsidies under the Japan–Korea trade dispute. Using firm-level panel data on Korean listed firms, we analyze firm-level adjustments in research and development (R&D) investment, asset composition, and profitability following Japan’s 2019 export control regulations and Korea’s subsequent subsidy policies. The results show that export controls did not increase R&D investment among firms capable of producing export-controlled materials. Instead, these firms increased their tangible assets, indicating an expansion in their production capacity, which in turn led to higher sales. We also find no evidence that localization subsidies stimulated R&D investment or intensity, although they are associated with improved profitability. Overall, firms responded to export controls mainly through supply chain adjustments rather than short-term increases in R&D. Such response highlights the role of firm-level cooperation in mitigating the impact of export controls.technical repor
Land Issues as the “Lack of Mourning” among the San in Botswana: The Background to the CKGR Burial Case
Full text linkPJa/3/Af4application/pdfZAF202600_101本稿の目的は、ボツワナ共和国で2022年に起こされた埋葬裁判と、2024年の総選挙（国民議会および地方議会選挙）をめぐる再定住地のサンの反応を考察することを通じて、彼らの日常におけるわだかまりが、土地問題などの政治的な意見に変化しつつあることを明らかにすることである。ボツワナ共和国ではこれまで、長年にわたり政府とサン活動家が土地の権利をめぐって争ってきた。それは、再定住地におけるごく一部のサン活動家と彼らを支援する国際的な先住民支援団体によって争われ、再定住地におけるサンの多くは周囲から静かに見守るのみであった。しかし、あるサン活動家が埋葬場所をめぐって起こした裁判と選挙への立候補によって、土地問題をどこか自分事としては捉えていなかった再定住地のサンの人々も、日々の生活のなかにおける不満と重ね合わせるかたちで政治的な意見を持ち始めた。本稿では、再定住地におけるサンに注目し、より人々を土地問題の議論に巻き込むことになった背景と人々の意識の変化を、近年の埋葬裁判と選挙から論じる。journal articl
Job Transfers along Global Value Chains and Their Determinants
No full textapplication/pdfIDP000893_001This study first uses a world input-output model to trace job creation, absorption, and transfer along global value chains (GVCs) via three channels including the traditional trade, simple and complex GVCs trade according to whether and how cross-border production sharing happens. We find that jobs created via simple and complex GVCs have rapidly expanded, especially for the service sectors; more and more countries’ jobs generated via GVCs have tended to be highly dependent on China’s final demand. Further using a gravity model for 1995-2018 based on the OECD data, we show that the determinants of bilateral job transfers in the gravity model perform very differently via different channels of GVCs; the existence of complex GVCs provides opportunities for geographically distant countries with different languages and legal systems to create mutual jobs by their engagement in GVCs. These findings could help policymakers’ better understanding of the complex interdependency of the trade-related job creation among countries and potentially help better monitor and improve their GVC governance in more flexible and diversified ways.technical repor
Magnetic Flux and Nonlinear Dynamics of Classical and Quantum Superconducting Hardware
No full textSuperconducting quantum computing is a promising path towards achieving fault-tolerant quantum computation. Control and readout of signals at mK temperatures and subsequent amplification to room temperature electronics has allowed for impressive feats such as the first demonstration of quantum supremacy / advantage. The scalability of current systems that enable quantum computation are hindered by signal latency, excess heat loads, and overcrowding of cables in the dilution refrigerator. In this thesis, we propose cryogenic solutions using magnetic flux that improve scalability of superconducting quantum processors. In an effort to bridge the energy gap between the mK and 4 K stages of the dilution refrigerator, we simulate a flux soliton amplifier that can provide up to 10x gain to flux soliton pulses with low-loss in a resistance free traveling-wave bias scheme. To address latency and spatial cable considerations, we simulate a flux soliton cryogenic pulse generator that uses breather oscillations to create microwave pulses in the range of 15 - 24 gigahertz with over 97\% energy efficiency. In addition, we present an experimental investigation of transmission properties for resonantly phase-matched Josephson traveling-wave amplifiers in magnetic fields to develop useful intuition towards the challenge of operating cryogenic parametric amplifiers in high magnetic fields. Our work presents paths for utilizing magnetic flux as a resource to advance large-scale high-fidelity quantum computing.Engineering and Applied Sciences - Applied Physic
Breathing Underwater: From Oxygen Sensing to Behavior in Larval Zebrafish
No full textOxygen (O₂) is essential for nearly all animal life, serving as the final electron acceptor in the mitochondrial electron transport chain and enabling the efficient generation of ATP to meet the energetic demands of multicellular organisms. However, despite its abundance in the atmosphere, oxygen availability is often unpredictable in aquatic environments. Many organisms, particularly aquatic vertebrates, must contend with acute drops in environmental oxygen or chronic hypoxic conditions during development. Understanding how vertebrates sense, respond to, and survive fluctuations in oxygen levels remains an important area of biological inquiry. Larval zebrafish (Danio rerio), with their optical transparency, genetic tractability, and quantifiable behaviors, provide a powerful model to investigate the neural circuits and behavioral strategies underlying hypoxia adaptation.
This dissertation explores how larval zebrafish behaviorally and physiologically respond to hypoxia, employing a multidisciplinary approach that integrates behavioral assays, in vivo calcium imaging, laser ablation techniques, and serial electron microscopy-based circuit reconstruction. The studies presented here reveal that acute hypoxia triggers a robust and stereotyped motor behavior characterized by rhythmic pectoral fin movements. These movements likely serve an adaptive role by enhancing water flow across respiratory surfaces, thereby facilitating oxygen uptake. Calcium imaging experiments suggested specific motor neurons whose activity correlates with hypoxia-induced fin movements. Laser ablation of suggested nerve bundles confirmed the neural pathways controlling this behavior.
Beyond acute responses, this dissertation examines the developmental consequences of chronic hypoxia exposure. Larval zebrafish raised under sustained low oxygen conditions exhibited altered growth patterns, including slow growth along the anteroposterior axis and a delayed onset of swim bladder inflation. Behavioral assays assessing the optomotor response revealed that chronic hypoxia impairs sensorimotor coordination during critical stages of development, potentially affecting the larvae’s ability to navigate and forage effectively. These findings suggest that oxygen availability during early development has lasting impacts on morphology and neural circuit function.
Together, these studies illuminate the strategies by which vertebrates transform oxygen-sensing into coordinated motor responses and offer a foundation for further investigations into the strategies for counteracting hypoxia, the interplay between environmental stress and nervous system development, and potential translational relevance for understanding hypoxia-related challenges in human health.Biology, Molecular and Cellula