Synthesis of novel fluorinated building blocks and α-helix peptidomimetics

At its heart, the present PhD thesis is based on the premise of two important areas in modern organic chemistry: firstly, the development of new methodologies to incorporate fluorine into organic molecules; and secondly, the design and synthesis of small molecules with high therapeutic potential. The work presented in the first three chapters will therefore focus on the incorporation of fluorine into organic molecules and the synthesis of fluorinated building blocks. In each chapter, we aim to obtain biologically relevant small molecules containing fluorine atoms or fluorinated groupings. The introduction of fluorine is a commonly used method in drug discovery to fine-tune the properties of drug candidates and therefore, given the scarcity of fluorine-containing molecules in natural sources, new synthetic methods towards new fluorinated scaffolds represent an important goal for organic chemists. On the other hand, the fourth and final chapter will explore the possibilities of novel p-terphenyl structures as peptidomimetics to exploit important biological targets. In this context, the present PhD thesis will have the following structure: Chapter 1. Synthesis of enantioenriched 1-amino-1,2-dihydronaphthalenes. This work builds upon past efforts in our research group in the area of diversity oriented synthesis, utilising ortho-bromobenzaldehyde as a common precursor. In this study, we will synthesise an unprecedented fluorinated scaffold containing a trifluoromethyl group, during which we will explore the effect of fluorinated groups during the ring-closing metathesis reaction (RCM). Chapter 2. Synthesis of 1,2-fluorohydrins via 1,2-difunctionalisation of olefins. This chapter focuses on simplicity and practicality. Fluorohydrins are an important class of fluorinated organic molecules; fludrocortisone was the first fluorinated drug to obtain FDA approval. Their synthesis has traditionally relied on the opening of epoxides, but in this chapter we will bypass this intermediate to form fluorohydrins directly from olefins, one of the most widely available and inexpensive classes of chemical. Chapter 3. Synthesis and reactivity of β-fluorovinyl sulfones. In this chapter we will develop methodologies for the stereodivergent synthesis of both (E)- and (Z)-β-fluorovinyl sulfones, a scarcely studied structure with potential as a fluorinated building block. We will also explore the reactivity of these structures. Finally, the hydrogenation reaction of fluorovinyl sulfones will be explored more in depth, as well as preliminary studies into the asymmetric hydrogenation of other vinyl fluorides. Chapter 4. Synthesis and biological evaluation of novel p-terphenyls as α-helix mimetics. The work described in this chapter is part of a long-term project within our research group, in collaboration with J. Gallego (UCV) and J. Alcamí (ISCIII). We found that p-terphenyls can be used to mimic the α-helix in the Rev protein of HIV-1. In this way, these small molecules are able to inhibit the replication of the virus. This chapter will build upon this work, exploring different structures and substitution patterns in order to learn more about the structure-activity relationship of these compounds, as well as designing a new derivative to tackle a protein-protein interaction that is key in the parasitic cycle of malaria. In conclusion to this chapter, 18+ new terphenyl structures will be synthesised and biologically tested against these important interactions present in HIV and malaria, all bearing structural modifications to the lead compound. It's worth noting that this represents the first development of a terphenyl scaffold active against the MyoA-MTIP protein-protein interaction in the malaria infection

Transfer Learning Bayesian Optimization to Design Competitor DNA Molecules for Use in Diagnostic Assays

With the rise in engineered biomolecular devices, there is an increased need for tailor-made biological sequences. Often, many similar biological sequences need to be made for a specific application meaning numerous, sometimes prohibitively expensive, lab experiments are necessary for their optimization. This paper presents a transfer learning design of experiments workflow to make this development feasible. By combining a transfer learning surrogate model with Bayesian optimization, we show how the total number of experiments can be reduced by sharing information between optimization tasks. We demonstrate the reduction in the number of experiments using data from the development of DNA competitors for use in an amplification-based diagnostic assay. We use cross-validation to compare the predictive accuracy of different transfer learning models, and then compare the performance of the models for both single objective and penalized optimization tasks

An Essential Role for Tumor Necrosis Factor in Natural Killer Cell–mediated Tumor Rejection in the Peritoneum

Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I− variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I− RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3− NK1.1+ cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I− prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte–mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I− tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum

Psychopolitics: Peter Sedgwick’s legacy for mental health movements

This paper re-considers the relevance of Peter Sedgwick's Psychopolitics (1982) for a politics of mental health. Psychopolitics offered an indictment of ‘anti-psychiatry’ the failure of which, Sedgwick argued, lay in its deconstruction of the category of ‘mental illness’, a gesture that resulted in a politics of nihilism. ‘The radical who is only a radical nihilist’, Sedgwick observed, ‘is for all practical purposes the most adamant of conservatives’. Sedgwick argued, rather, that the concept of ‘mental illness’ could be a truly critical concept if it was deployed ‘to make demands upon the health service facilities of the society in which we live’. The paper contextualizes Psychopolitics within the ‘crisis tendencies’ of its time, surveying the shifting welfare landscape of the subsequent 25 years alongside Sedgwick's continuing relevance. It considers the dilemma that the discourse of ‘mental illness’ – Sedgwick's critical concept – has fallen out of favour with radical mental health movements yet remains paradigmatic within psychiatry itself. Finally, the paper endorses a contemporary perspective that, while necessarily updating Psychopolitics, remains nonetheless ‘Sedgwickian’

Psychiatric Survivors & Experiential Rights

Human rights may be categorised as belonging to ‘three generations’: political, social and ‘solidarity’ rights. This paper considers this schema theoretically, deploying the example of the ‘psychiatric survivor’ movement in Britain in support of its central claims. Psychiatric survivors comprise groups of psychiatric patients who have campaigned both for political and social rights in addition to a singular form of ‘right’, which is referred to here as ‘experiential’. The paper clarifies the meaning of the ‘experiential right’ and, drawing upon aspects of social theory, considers how it is to be understood in the context of the ‘three generations’ schema

Anmeldelser

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Broadband repeatable <0.025 dB average loss rapid adiabatic based 3-dB coupler in a 45 nm SOI CMOS process

We demonstrate a 75 µm-long rapid adiabatic coupler (RAC) with an average insertion loss <0.025 dB/coupler and an average power splitting ratio of 50±1.09% over 40 nm bandwidth and 68 reticles across a 300 mm 45 nm SOI CMOS wafer.Accepted manuscrip

Leadership and charisma: a desire that cannot speak its name?

Leadership has proved impossible to define, despite decades of research and a huge number of publications. This article explores managers’ accounts of leadership, and shows that they find it difficult to talk about the topic, offering brief definitions but very little narrative. That which was said/sayable provides insights into what was unsaid/ unsayable. Queer theory facilitates exploration of that which is difficult to talk about, and applying it to the managers’ talk allows articulation of their lay theory of leadership. This is that leaders evoke a homoerotic desire in followers such that followers are seduced into achieving organizational goals. The leader’s body, however, is absent from the scene of seduction, so organizational heteronormativity remains unchallenged. The article concludes by arguing that queer and critical leadership theorists together could turn leadership into a reverse discourse and towards a politics of pleasure at work

The Decreasing Significance of Stigma in the Lives of Bisexual Men: Keynote Address, Bisexual Research Convention, London

This article is constructed around a keynote address given at the Bisexual Research Convention, held in London 2010. The keynote was delivered by sociologist Eric Anderson, on behalf of himself and the other authors of this article. The keynote reflected upon a body of ongoing research, funded by the American Institute of Bisexuality and collected by this team of researchers, into the changing relationship between men and homophobia. It first contextualizes 20th-century attitudes toward homo/bisexuality before showing a declining significance of biphobia and homophobia in men's lives today. In accordance with the keynote, this article draws from preliminary findings of multiple ongoing studies of bisexual men in the United States and the United Kingdom