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    Translational investigation of circadian rhythm modulating drugs on metabolic disorder

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    The metabolic syndrome represents a cluster of metabolic anomalies (including hyperglycaemia, obesity, hypercholesterolemia), that affects 25% of the world’s population and is recognised as a major risk factor for development of diabetes and cardiovascular diseases. Several key enzymes identified in this disorder are directly under circadian regulation and evidence from both pre-clinical research and epidemiological studies strongly implicate disturbed circadian rhythms in metabolic disorders. Further, the recent demonstration that pharmacological enhancement of the clock ameliorate symptoms of metabolic syndrome suggests this could indeed be a novel therapeutic paradigm. In light of this, our study aimed to investigate the effects of three novel circadian modulators using a range of in-vitro models for metabolic syndrome and translate these findings to an in-vivo model of obesity. Following a medium-throughput screen of ~5000 molecules using reporter cell-lines that track clock gene expression, 3 novel circadian modulators; Linopirdine, Diclazuril and Zaprinast were identified. Phenotypic characterization of these molecules in adipocytes demonstrated a lack of correlation between pharmacological amplitude enhancement of the adipocyte clock and metabolic phenotypes, despite displaying positive metabolic outcomes in in-vitro model system, thereby highlighting the significance of drug targets in metabolic outcomes. Using in-silico mining, followed by transcription-factor screening and siRNA knockdown, we identified a novel mechanism mediating Linopirdine’s chrono-modulatory effect. We provide the first direct evidence of MEIS1 being a regulator of circadian clock expression and demonstrate Linopirdine as a novel modulator of MEIS1 and HIF. Furthermore, in a diet-induced obesity mouse model, Linopirdine mimicked HIF and MEIS1 activation in-vivo, emphasising the significance of the drug target in predicting in-vivo outcomes. Finally, using Zaprinast as a pharmacological tool, we provided new insight on the role of cGMP in regulating peripheral circadian clocks. Thus, this DPhil thesis provides original insight into the use of chrono-modulators in the treatment of metabolic syndrome and introduces novel targets for circadian modulation

    Unveiling novel participants in the DNA damage response

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    The human genome is constantly challenged by DNA damage resulting from environmental factors and metabolic processes. To safeguard the integrity of the genome, a complex defence system known as the DNA damage response (DDR) has evolved. The DDR comprises intricate mechanisms, including DNA repair pathways, damage tolerance processes, cell cycle checkpoints and programmed cell death, together aimed at maintaining genomic stability. Among the various types of DNA lesions, interstrand crosslinks (ICLs) pose a significant threat as they impede DNA replication and transcription. Inadequate repair of ICLs is closely linked to Fanconi anaemia (FA), a genetic disorder associated with severe health consequences. Moreover, ICL-inducing agents have a broad clinical application in cancer therapy, although the emergence of drug resistance poses a challenge. Therefore, comprehending the mechanisms involved in ICL repair is critical for developing alternative treatment strategies and enhancing drug sensitivity. The focus of this DPhil thesis is to investigate the participation and function of two novel proteins in the cellular response to ICL-induced DNA damage. Rapid accumulation of the first protein at ICL sites is observed, and its knockout results in heightened cellular sensitivity to ICL-inducing agents, indicating its positive contribution to cell survival against ICLs. Further investigations revealed that this protein operates independently of the established FA and NEIL3 pathway for ICL repair, suggesting its potential role in alternative repair mechanisms or early-stage DDR processes. The second novel protein exhibits a distinct relocation from the nucleoplasm to the peripheral nucleoli, forming a ring-shaped accumulation pattern in response to ICLs. Additional experiments demonstrate that this protein translocates into the nucleolar cap under nucleolar stress induced by various types of DNA damage and transcription inhibition. These findings support the notion that the nucleolus acts as a stress sensor, and the nucleolar translocation of this novel protein potentially contributes to cellular fate decisions or the interplay between DDR and nucleolar function. Together, the research presented in this thesis provides insights into the roles of two new protein players in preserving genomic stability. Understanding their interactions with established repair pathways and their potential therapeutic implications in FA and cancer treatment will pave the way for developing targeted interventions and improving patient outcomes

    Witnessing a wounded world: a theology of ecological trauma

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    This thesis lies at the intersection of ecotheology and trauma theology. My basic claim is that the approach of Christian trauma theologians to cases of traumatic human suffering can be fruitfully extended and applied by ecotheologians in the context of the present ecological crisis. The category of trauma acknowledges the seemingly incomprehensible severity and scale of current ecological suffering, whilst also resisting the impulse to explain such suffering in terms of its origin or its solution. I argue that three defining characteristics of human trauma are identifiable in the ecological realm--namely, a rupture to communication, a rupture to flesh, and a rupture to time. But this ascription of trauma to nonhuman entities does not require envisaging the earth as conscious. Instead, I understand ecological trauma as an anthropomorphism of earth systems and processes that enables us to better relate to ecological suffering. Following existing work in trauma theology, I propose that the practice of bearing witness to ecological trauma constitutes a vital coping strategy. In response to the rupture of communication, I argue that Christ serves as a witness to traumas such as climate change and biodiversity loss. In response to the rupture of flesh, I expand this model of Christic witnessing by suggesting that Christ's incarnation in the flesh enables him to bear witness to the wounded flesh of the world. And in response to the rupture of time, I contend that Christ's recapitulation of creation, along with the persistence of the wounds on his resurrection and ascension flesh, allow him to witness the recurrence and permanence of contemporary ecological devastation. I conclude that a process of Christic witnessing forms one possible theology of ecological trauma. In short, Christ's permanently wounded flesh bears witness to a permanently wounded world

    Exceptional performance of room temperature sputtered flexible thermoelectric thin film using high target utilization sputtering technique

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    The High Target Utilisation Sputtering technique (HiTUS) is of interest for industrial processes, including in roll-to-roll manufacturing. This study marks the first application of HiTUS to thermoelectric materials, exemplified by bismuth telluride. The HiTUS technique separates the sputtering power into the plasma power and the target power, with additional kinetic energy in the sputtering particles from the applied electrical field, thus enabling a much wider sputter parameter space to modify the film performance. This study investigates how plasma power, target power, and substrate bias in HiTUS intricately influence crystal orientation/size, elemental composition, surface morphology, and other film properties. These factors subsequently affect carrier density/mobility, and consequently the thermoelectric performance of the bismuth telluride film. These deposited films reach a power factor of 6.5 × 10−4 W m−1 K−2 with a figure of merit ≈0.14 at room temperature, the highest value for room-temperature sputtered un-doped bismuth telluride. Subsequent post-deposition annealing significantly enhances the crystallinity of the film (highly polycrystalline), further improving the power factor to 23.5 × 10−4 W m−1 K-2, with a figure of merit ≈0.45 at room temperature. The excellent performance of the HiTUS fabricated thermoelectric film opens opportunities for the large-area manufacture of thin-film thermoelectric materials and devices

    Convergence of policy gradient methods for finite-horizon stochastic linear-quadratic control problems

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    We study the global linear convergence of policy gradient (PG) methods for finite-horizon continuous-time exploratory linear-quadratic control (LQC) problems. The setting includes stochastic LQC problems with indefinite costs and allows additional entropy regularisers in the objective. We consider a continuous-time Gaussian policy whose mean is linear in the state variable and whose covariance is stateindependent. Contrary to discrete-time problems, the cost is noncoercive in the policy and not all descent directions lead to bounded iterates. We propose geometry-aware gradient descents for the mean and covariance of the policy using the Fisher geometry and the Bures-Wasserstein geometry, respectively. The policy iterates are shown to satisfy an a-priori bound, and converge globally to the optimal policy with a linear rate. We further propose a novel PG method with discrete-time policies. The algorithm leverages the continuous-time analysis, and achieves a robust linear convergence across different action frequencies. A numerical experiment confirms the convergence and robustness of the proposed algorithm

    The role of lipid metabolising enzymes in CD1a-associated cutaneous inflammation

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    Atopic dermatitis (AD) and psoriasis (Ps) are common, relapsing-remitting inflammatory skin diseases that result in increased morbidity and reduced quality of life. CD1a contributes to AD and Ps pathogenesis via the presentation of activating neo-lipid antigens produced by endogenous and exogenous PLA2s (PLA2). In addition, very long chain sphingomyelins (SMs) have been shown to physically antagonise CD1a-T cell receptor (TCR) interactions. Interestingly, both mammals and bacteria can produce sphingomyelinases (SMases), a class of lipid metabolising enzymes, that digests SM into ceramide and phosphorylcholine. Therefore, we sought to establish whether CD1a neo-lipid antigen generation extends beyond the PLA2 superfamily, by examining the presence of SMase-specific CD1a-dependent T cell activation, which may help to explain the role of bacterial infection in AD. Here, we used a range of techniques including skin RNA sequencing, isoelectric focusing and functional T cell assays. Through bioinformatic analysis, we discovered the elevated expression of mammalian SMase genes, SMPD1 and SMPD3, in addition to PLA2s in AD and Ps lesional tissue. Following this, we identified the capacity for bacterial SMases to degrade CD1a-preferred SMs, with potentiation by the presence of cobalt and nickel, which are two frequently occurring allergic contact dermatitis (ACD) allergens. Additionally, we demonstrated the presence of bacterial SMase-reactive CD1a-dependent T cell responses via upregulation of cytokine production and CD69. In conclusion, bacterial SMases can effectively digest very long chain inhibitory SMs and stimulate the activation of CD1a-reactive T cells. Additionally, our results suggest that mammalian SMases may similarly contribute to CD1a neo-lipid antigen generation. This thesis expands upon our understanding of the involvement of lipid metabolising enzymes in CD1a-dependent T cell activation and provides support for a hitherto unknown pathway underlying the development skin inflammatory disorders. Therefore, here we present potential novel targets involved in disease initiation which may be amenable for therapeutic modulation

    A genome-wide association study based on the China Kadoorie Biobank identifies genetic associations between snoring and cardiometabolic traits

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    Despite the high prevalence of snoring in Asia, little is known about the genetic etiology of snoring and its causal relationships with cardiometabolic traits. Based on 100,626 Chinese individuals, a genome-wide association study on snoring was conducted. Four novel loci were identified for snoring traits mapped on SLC25A21, the intergenic region of WDR11 and FGFR, NAA25, ALDH2, and VTI1A, respectively. The novel loci highlighted the roles of structural abnormality of the upper airway and craniofacial region and dysfunction of metabolic and transport systems in the development of snoring. In the two-sample bi-directional Mendelian randomization analysis, higher body mass index, weight, and elevated blood pressure were causal for snoring, and a reverse causal effect was observed between snoring and diastolic blood pressure. Altogether, our results revealed the possible etiology of snoring in China and indicated that managing cardiometabolic health was essential to snoring prevention, and hypertension should be considered among snorers

    The isolation of VCAM-1+ endothelial cell-derived extracellular vesicles using microfluidics

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    Background: Vascular cell adhesion molecule-1 (VCAM-1+) endothelial cell-derived extracellular vesicles (EC-EVs) are augmented in cardiovascular disease, where they can signal the deployment of immune cells from the splenic reserve. Endothelial cells in culture activated with pro-inflammatory tumor necrosis factor-α (TNF-a) also release VCAM-1+ EC-EVs. However, isolating VCAM-1+ EC-EVs from conditioned cell culture media for subsequent in-depth analysis remains challenging. Aim: We utilized the extracellular vesicles (EV) microfluidics herringbone chip (EVHB-Chip), coated with anti-VCAM-1 antibodies, for selective capture of VCAM-1+ cells and EC-EVs. Methods and Results: Engineered EA.hy926 endothelial cells overexpressing VCAM-1 (P < 0.001 versus control) showed increased binding to the VCAM-1- EVHB-Chip versus an IgG device. TNF-α-stimulated human umbilical cord vein endothelial cells (HUVECs) exhibited elevated VCAM-1 protein levels (P < 0.001) and preferential binding to the VCAM-1- EVHB-Chip versus the IgG device. HUVECs stimulated with TNF-α showed differential gene expression of intercellular adhesion molecule-1 (ICAM-1) (P < 0.001) and VCAM-1 (P < 0.001) by digital droplet PCR versus control cells. HUVEC-derived EC-EVs were positive for CD9, CD63, HSP70, and ALIX and had a modal size of 83.5 nm. Control and TNF-α-stimulated HUVEC-derived EC-EV cultures were captured on the VCAM-1- EVHB-Chip, demonstrating selective capture. VCAM-1+ EC-EV were significantly enriched for ICAM-1 (P < 0.001) mRNA transcripts. Conclusion: This study presents a novel approach using the EVHB-Chip, coated with anti-VCAM-1 antibodies and digital droplet PCR for the study of VCAM-1+ EC-EVs. Isolation of VCAM-1+ EC-EV from heterogeneous sources such as conditioned cell culture media holds promise for subsequent detailed characterization, and may facilitate the study of VCAM-1+ EC-EVs in cardiovascular and metabolic diseases, for disease monitoring and therapeutic insights

    Aftersound: Mhamad Safa in conversation with Gascia Ouzounian

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    This conversation, which took place at The Showroom, London, on March 8, 2022, brings together the sound producer and architect Mhamad Safa and the sonic theorist Gascia Ouzounian in exploring Safa’s work on sound, trauma, and acoustic jurisprudence, with a focus on Beirut and Lebanon. The conversation covers a range of topics, from the differential policing of noise along lines of social difference; to earwitnessing war and conflict; to the long-term unfolding of auditory forms of trauma and “sonic aftershocks.” Safa and Ouzounian discuss the need for better legal frameworks for confronting the harms of sound; what “collateral damage” might constitute in the context of listening to warfare; and what justice would mean for survivors of sonic violence

    Creativity, artificial intelligence, and God

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    In response to the rise of generative artificial intelligence (AI), many question the value of human creativity. What’s the point of human creativity if computers can out-create in both speed and caliber? Against such pessimism, this chapter offers hope from the Christian tradition. In particular, it offers a theological framework for understanding what creativity is. It argues that creativity is not a merely technical ability, a faint echo of God’s capacity to create ex nihilo, but rather a fundamentally moral phenomenon that reflects creativity in imago—that is, God’s wise ordering, loving care, and transformation of all created things. This is a hopeful paradigm that tempers AI-hysteria with scriptural realism. The chapter proceeds in five parts: Part 1 follows the example of AI philosopher Margaret Boden who uses analogy to understand what creativity is. Part 2 utilizes analogy to understand human creativity in light of Old Testament descriptions of God’s creative, moral action: the part distinguishes creativity ex nihilo from creativity in imago and defines creativity writ large with respect to the latter. Parts 3 and 4 use analogy to differentiate divine and human creativity from their computational counterpart: the parts stress the moral difference that transformation in Christ makes. Part 5 concludes by emphasizing the moral responsibility of God’s image-bearers to question their use and development of AI: the part looks to scriptural exemplars who fail and succeed in questioning astonishing, non-human intelligences

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