Binding-site purification of actives (B-SPA) enables efficient large-scale progression of fragment hits by combining multi-step array synthesis with HT crystallography

Fragment approaches are long-established in target-based ligand discovery yet their full transformative potential lies dormant, because progressing hits to potency remains underserved by methodological work. The only credible progression paradigm is multiple cycles of costly conventional design-make-test-analyse (DMTA) medicinal chemistry, necessitating picking winners early and discarding others.  It is effective to cheaply parallelize large numbers of non-uniform multi-step reactions, because, even without compound purification, a high-quality readout of binding is available, viz. crystallography. This can detect low-level binding of slightly active compounds, which the targeted binding site extracts directly from crude reaction mixtures (CRMs). In this proof-of-concept study, we expand a fragment hit from a crystal-based screen of the bromodomain PHIP2, using array synthesis on low-cost robotics to implement 6 independent multi-step reaction routes of up to 5 steps, attempting the synthesis of 1876 diverse expansions,  designs entirely driven by synthetic tractability. The expected product was present in 1108 (59%) CRMs, detected by automated mass spectrometry, 22 individual products were resolved in crystal structures of CRMs added to crystals, providing an initial SAR map, pose stability in 19 and instability in 3 products and resolved stereochemical preference. One compound showed biochemical potency (IC50=34 μM) and affinity (Kd=50 μM) after resynthesis.</p

High prevalence of veterinary drugs in bird's nests.

The environmental impact of insecticides used as ectoparasitic treatments for companion animals is not well understood, since they are not subject to detailed environmental risk assessment. Many of these treatments include active ingredients such as fipronil and imidacloprid that are banned from agricultural use in the EU. These treatments are applied topically and can remain on the animal's fur for an extended period of time. Birds (adults, eggs, and nestlings) using fur as an inner layer for their nests have the potential of being exposed dermally to these chemicals. In this study, we collected 103 nests from blue and great tits, which were lined with fur. Using UHPLC-MS/MS, we detected 17 out of the 20 insecticides we screened for, with the number of insecticides detected per nest ranging from 2 to 11. Fipronil, imidacloprid, and permethrin were detected in 100 %, 89.1 %, and 89.1 % of samples, respectively. The average concentration of fipronil, imidacloprid and permethrin were respectively 115.5 ppb, 376.3 ppb, and 231.1 ppb. Dinotefuran was found at the highest concentration of 7198 ppb in a single sample. Overall, a higher number of either dead offspring or unhatched eggs was found in nests containing a higher number of insecticides, higher total concentration of insecticides or a higher concentration of fipronil, imidacloprid or permethrin, suggesting that contact exposure of eggs to insecticides in nest lining may lead to mortality and lower reproductive success. This highlights the need for a re-evaluation of the environmental risks associated with use of these potent and persistent insecticides on companion animals.</p

Design and fashion: Procrustean metaphors in intellectual property law

The call for a definition of the regulation of fashion design develops from multiple influences and theories which interpret expressions and contributions communicated by designers, investors, trend-setters, observers, consumers and many others. For each participant, there could be a different definition of fashion design. Conversely, legal metaphors for fashion often do not reflect its variety, diversity and evolution as conveyed through the experience of apparel and accessories by stakeholders. This chapter challenges the current justifications and paradigms that apply to design law for fashion. It does so by way of an analysis of legal disputes emerging from disruptive societal and technological changes affecting the market and value of goods and services within the relevant industry. The chapter questions and rephrases the notions of scarcity and authenticity associated with exclusive intellectual property rights systems. It proposes that any legal recognition of fashion design should effectively accommodate a rigorous understanding of non-conscious design as experienced by creators, audiences and consumers.</p

Convalescent COVID-19 monocytes exhibit altered steady-state gene expression and reduced TLR2, TLR4 and RIG-I induced cytokine expression

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, can induce trained immunity in monocytes. Trained immunity is the result of metabolic and epigenetic reprogramming of progenitor cells leading to an altered inflammatory response to subsequent activation. To investigate the monocyte response 3-6 months post SARS-CoV-2 infection, steady-state gene expression and innate immune receptor stimulation were investigated in monocytes from unvaccinated SARS-CoV-2 naïve individuals and convalescent COVID-19 participants. The differentially expressed genes (DEGs) identified were involved in the regulation of innate immune signalling pathways associated with anti-viral defence. COVID-19 participants who had experienced severe symptoms exhibited a larger number of DEGs than participants that had mild symptoms. Interestingly, genes encoding receptors that recognise SARS-CoV-2 RNA were downregulated. DDX58 encoding retinoic-acid inducible gene I (RIG-I), was downregulated which corresponded with a reduced response to RIG-I activation. Furthermore, toll-like receptor (TLR)1/2 and TLR4 activation also exhibited reduced cytokine secretion from convalescent COVID-19 monocytes. These data suggest that following SARS-CoV-2 infection, monocytes exhibit altered steady-state gene expression and reduced responsiveness to innate immune receptor activation. As both RIG-I and TLRs recognise components of SARS-CoV-2, this may lead to a moderated inflammatory response to SARS-CoV-2 reinfection in the months following the initial infection.</p

Integrating ePROMs: a key opportunity for England’s national cancer plan

No description supplied</p

Managing the disorderly woman: the witch in mainstream American film and television

This thesis interrogates the representation of woman as witch in mainstream American film and television. I conceive of the witch as an incarnation of the disorderly woman, embodying the patriarchal myth of woman as leaky, volatile, abject body that must be controlled. At the same time, I draw on theories of the carnivalesque to position the witch as a polysemic figure, capable of expressing celebratory fantasies of liberation from hegemonic order alongside hetero-patriarchal fears of its disruption. Indeed, I emphasise that the witch has been appropriated by feminists as an affirmative figure of unruly womanhood at various points in history, in ways that have altered and added to her excess of meanings. Conceiving of the witch as a polysemic figure, this thesis is concerned with how her multiple meanings are deployed and negotiated in twentieth and twenty-first century American film and television to symbolically manage changing approaches to women, power, and feminisms. I argue that the witch proliferates in American popular media in ‘waves’, re-emerging in moments of socio-cultural turmoil to re-negotiate the boundaries around womanhood and its relationship to power. As such, while previous studies have focused on how the witch functions in specific time periods, this thesis examines how, and to what ends, the dominant image of the witch in American popular media changes over time. Specifically, I consider the implications of the horror hag’s popularity in the Sixties giving way to the emergence of the glamorous, benignly empowered domestic witch in the ‘postfeminist’ 1990s, and of the domestic witch’s replacement by the confident teenage witch protagonists of recent popular Gothic media. My analysis thus investigates the ways in which ideas of female power – intimately linked with the gains of feminist movements – have shifted over time, particularly as they have been subject to the co-optation and management of hegemonic discourses. As such, this thesis provides a contribution to work on the historic construction and re-construction of the category ‘woman’ in popular media, including the ways in which strategies of negotiation are currently at work in a Western cultural climate wherein an idea of feminism has gained new mainstream popularity. </p

Equity, inclusion, intersectionality, and the institution: holding change in tension at the Bush and the Globe

This chapter examines what it means to work within a contemporary theatre institution for change, and specifically toward equitable access, social justice, anti-racism, and decolonisation. It focuses on white, Black, and brown women’s leadership on these issues across two very different London theatres – Shakespeare’s Globe and The Bush – and it culminates in an intersectional reading of Adjua Andoh and Lynette Linton’s Richard II at Shakespeare’s Globe (2019).</p

Empowering quality education through sustainable and equitable electricity access in African schools

Africa's schools will educate the majority of the 21st century's working population, influencing the global economy. Through combined spatial analysis techniques on over 500,000 schools, we estimate a 2 billion EUR cost to power unelectrified schools with decentralized solar photovoltaic systems. Given the positive effect on children's food security and the growing need for digitalization, ensuring clean electricity access includes both electricity demand for internet connectivity and electric cooking. Our analysis reveals that 32% of African school-aged children live near unelectrified schools, with the nearest electrified school often too far away. The electrification of these facilities would reduce education-seeking trips by an average 45 min by motorized transport or 6 h on foot. This significant time savings, combined with the broader benefits of decentralized energy, can significantly enhance educational access, economic development, and environmental sustainability in Africa.</p

Techno-nationalism and capability development in the global pharmaceuticals industry, 1918–1970

Techno-nationalism intensifies deglobalisation and so presents new risks in international business, with government policy increasing multinational corporation (MNC) costs through targeting their technology inflows and outflows in various ways. However, recent scholarship in international business has focused exclusively on the current geopolitical tensions between the US and China. We adopt a longer-term perspective that permits us to offer a revised definition of techno-nationalism less embedded in the present-day context. We then review three episodes of historical techno-nationalism by the U.S. and U.K. governments targeting the acquisition of pharmaceuticals technological capabilities from the then-technological leaders between 1918 and 1970. This review suggests that the success of techno-nationalist policies was less associated with the absolute level of costs imposed on MNCs and more associated with: the absorptive capacities of the host economies’ domestic industries; the ease with which the targeted MNCs were able to develop mitigation strategies; and, our main contribution, the different mechanisms used and targets focused on by governments. We develop a typology of successful techno-nationalist policies from this historic survey to highlight that government policies might vary between those that differentiate between either technology-push or demand-pull mechanisms and those that focus on either firm-based or location-based targets.</p

Consumers as regulators of global value chains’ conduct? A consumer-inclusive framework of change

Inadequate conduct of global value chains (GVCs) has given rise to serious concerns by academics and policymakers but efforts to improve it have made minimal progress, jeopardizing global wealth distribution and accentuating inequality. We advance a novel analytical framework for addressing this concern, underpinned by the trust of including the consumers as an important constituency that could bring about the desired change. Blending insights of governmentality, social movements, and ethical consumerism theories with those of ethical conduct in GVCs and combining them with lessons of a comparative analysis of ethical conduct in the coffee and fashion GVCs, we develop a framework for change that is driven by consumer agency and their power to ‘regulate’ global brands’ conduct via their consumption behavior. We identify a range of private- and public-sector constituencies that could mobilize the consumers towards this end and explicate the mechanisms to bring about this outcome. This framework supplements the top-down approach proposed by extant research with a bottom-up, grassroot approach. In doing this it directs the debate regarding GVC conduct to new directions based on a different logic. The framework guides policy intervention by extending the role of governments from that of regulators of global brands to facilitators of consumers’ mobilization and societal change.</p