Synthesis and Biological Evaluation of a Novel C8-Pyrrolobenzodiazepine (PBD) Adenosine Conjugate. A Study on the Role of the PBD Ring in the Biological Activity of PBD-Conjugates

Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN) moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge, this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments. Molecular dynamics simulations revealed that the PBD–ADN conjugate was poorly accommodated in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine amino group of the DNA duplex. These interesting findings shed further light on the ability of the substituents attached at the C8 position of PBDs to a ect and modulate the biological and biophysical properties of PBD hybrids

Cold Light Lite

Cold Light Lite is a new installation by Keith Sargent and Lindsay Seers. It represents a fragment of a larger work which included two robots, a scaffold structure and VR headsets placed in constructed pods. The exhibition here at FRAC is shaped by the artists' research into the life and work of Nikola Tesla, the title drawing on historic references to the first electric lights. No longer reliant on fire for illumination, the new electric light bulbs were referred to as 'Cold Light.' Tesla was an inventor, engineer and futurist who performed scientific experiments theatrically, as a showman. He is best known for his contributions to the design of the Alternating Current electrical system. Cold Light takes inspiration from Tesla's visionary revelations in science, his extraordinary consciousness and his non-normative brain. He considered himself to be an automaton reacting to internal and external stimuli. He aspired to give free energy to the world and to raise the level of human consciousness. Cold Light takes a complex stand on how time exists in the brain and the significance of electromagnetism in all things. The work displays a desire to edit images, objects and sounds in a relational way. It follows the associative way the brain functions as described in neuroscience, rather than the historic theatrical and filmic techniques that create seemingly coherent stories that resolve themselves. Potentially we revise our narratives endlessly. There is an intensity in the unfolding of the work that relates to a neurodivergent state of consciousness – in this case autism and attention deficit hyperactivity disorder. Human life appears to make very little sense. Slippages and repetitions weave between real and virtual elements – sculptural and architectural forms recur, rendered and recombined physically and digitally, calling into question distinctions between materiality and dream states and their interchangeable possibilities. Research on these subjects has been sustained over many years and developed through dialogues with scientists including Chris Frith, FRS FBA, professor emeritus at the Wellcome Trust Centre for Neuroimaging at University College London; Anil Seth, professor of Cognitive and Computational Neuroscience at the University of Sussex; Paul Fletcher, Bernard Wolfe Professor of Health Neuroscience, University of Cambridge; and science writer Philip Ball

A “halfway house” for improving captive welfare

It is certainly time to aim for higher quality management strategies for Thailand’s captive elephants, and to engage with sustainable livelihoods for traditional mahouts. Baker & Winkler’s proposal to rewild Thai elephants by placing them under the guardianship of Karen mahouts is recognized as not “wild” since it remains a form of management requiring elephants to live under the control of human caregivers. We applaud the positive welfare aims of this proposal; however, we caution that few of the long-term consequences for elephants or habitats can be known, and further considerations of elephant population dynamics and forest ecosystems are required if these proposals are to be successful for conservation and elephant welfare

SMASHfestUK: Exploring approaches for widening participation and increasing diversity in STEM through the Arts

Recent studies show that there is a known lack of gender, ethnic and socio-economic diversity in STEM education and careers. The Warwick Commission has again highlighted that this imbalance also exists in access to Culture and the Arts. The CASE Campaign for Science and Engineering, ‘Improving Diversity in STEM’ from May 2014 revealed that only “9% of STEM jobs (outside of Medicine) are held by women” and “BME men are 28% less likely to work in STEM than white men”. Many initiatives nominally seek to address this imbalance, but often suffer from institutional centrism, narrow-focus and community disconnectedness. The Warwick Commission states “The role of cultural organisations as partners in the fundamental place shaping role, building and moulding local communities and identities, remains underdeveloped”. SMASHfestUK – www.smashfestuk.com - is a science and arts festival that has recently completed its pilot run. It was conceived to explore new approaches to widening participation and improving diversity in STEM through the Arts. Key principles include: • Participatory authorship • Immersive entertainment • Narrative led • Trans-media delivery • Embedded and delivered in, and by, local communities The paper will discuss the principles, practice and audited impact of this approach. SMASHfestUK was funded by: The Wellcome Trust, The Arts Council, Middlesex University, The Physiological Society and L&Q Housing

SMASHfestUK : A participatory action research programme resulting in the development of a novel model, ‘SCENE’ for inclusive public engagement with research

Keith developed an innovative science/technology/engineering/arts/maths (STEAM) festival (SMASHfestUK) based on community-based participatory-action-research using inclusive, co-design approach methods. SMASHfestUK explored the under-representation of white working-class and Black, Asian and BAME people in arts/cultural spaces and informal science learning, creating, prototyping and testing solutions. Keith developed the dynamic model, “SCENE,” for inclusive public-engagement. SCENE uses narratives, community-co-design, enquiry, entertainment and hyper-local approaches to engage publics. This pioneering model was developed dynamically over annual iteration

Marine Biogeochemical Modeling: Recent Advances and Future Challenges

One of the central objectives of the Joint Global Ocean Flux Study (JGOFS) is to use data from the extensive field programs to evaluate and improve numerical ocean carbon-cycle models. Substantial improvements are required if we are to achieve a better understanding of present-day biogeochemical properties and processes in the ocean and to predict potential future responses to perturbations resulting from human activities. We have made significant progress in this regard and expect even greater strides over the next decade as the synthesis of JGOFS data sets is completed and disseminated to the broader scientific community

‘Do we know if we need to reduce head impact exposure?’: A mixed-methods study highlighting the varied understanding of the longterm risk and consequence of head impact exposure across all stakeholders at the highest level of rugby union

Background: One strategy to prevent and manage concussion is to reduce head impacts, both those resulting in concussion and those that do not. Because objective data on the frequency and intensity of head impacts in rugby union (rugby) are sparse, stakeholders resort to individual perceptions to guide contact training. It is unknown whether there is a level of contact training that is protective in preparing elite players for contact during matches.  Objectives: This study aimed to describe how contact training is managed in elite male rugby, and how staff and players perceive contact training load and head impact load. Methods: This was a sequential explanatory mixed-methods study. Forty-four directors of rugby, defence coaches, medical and strength/conditioning staff and 23 players across all 13 English Premiership Rugby Union clubs and the National senior team participated in semi-structured focus groups and completed two bespoke questionnaires. Results: The study identified the varied understanding of what constitutes head impact exposure across all stakeholder groups, resulting in different interpretations and a range of management strategies. The findings suggest that elite clubsconduct low levels of contact training; however, participants believe that some exposure is required to prepare players andthat efforts to reduce head impact exposure must allow for individualised contact training prescription. Conclusion: There is a need for objective data, possibly from instrumented mouthguards to identify activities with a high risk for head impact and possible unintended consequences of reduced exposure to these activities. As data on head impact exposure develop, this must be accompanied with knowledge exchange within the rugby community.

SCENE: A novel model for engaging underserved and under-represented audiences in informal science learning activities

Inequitable access to science, technology, engineering, arts and mathematics (STEAM) has been explored by multiple studies which have shown that some publics are underserved by existing informal educational and cultural provision, and under-represented in related study choices and careers. Informal science learning (ISL) and public engagement with research activities (such as science festivals) tend to attract audiences which are largely white, middle class and already engaged with STEM (science, technology, engineering and mathematics). This article describes the development of an engagement approach and model through a story-based festival (SMASHfestUK) which was specifically designed to attract new and diverse audiences, including Black and mixed-heritage families, and families living with socio-economic disadvantage. The festival was delivered on five annual occasions, each co-designed with a wide selection of stakeholders, including audiences, researchers, performers, institutions and organizations, and considered as an iterative prototype. Key messages • Engagement with STEM can be tailored to under-represented audiences by co-designing a festival format and content that resonates with those audiences. • Enquiry-based learning with participants immersed in a meaningful story provides an opportunity for participants to experience STEM with agency. • Success was built on the SCENE model (STEAM, community, enquiry, narrative, entertainment), co-designed hyperlocally, leading with free entertainment and an overarching narrativ