Structural and functional studies of mannose binding lectin (MBL) and the lectin pathway of complement in children with cancer.

Infection remains a major cause of morbidity and hospitalisation in children receiving chemotherapy treatment for cancer. Among patients with the same diagnosis and treatment regimen, not all suffer equally from infectious complications. This suggests that as yet unidentified host factors may contribute to increased susceptibility to infection. Deficiency of mannose binding lectin (MBL), a pattern recognition receptor of the innate immune system, has been proposed as one such factor but clinical studies have been inconclusive. MBL works in concert with MBL associated serine proteases (MASPs) to activate the lectin pathway of complement. Functional activity of the pathway has not been investigated in children with cancer to date. Children undergoing chemotherapy were recruited to cross sectional observational and longitudinal studies with details of febrile neutropenia (FN) episodes recorded prospectively. MBL gene polymorphisms were characterized by heteroduplexing and reverse hybridization. MBL protein and MASP levels were measured and functional activity of the lectin pathway was quantified. High oligomer structure of MBL was analysed by Western blotting. Transcriptional regulation of MBL in response to infection and inflammation was studied. The MBL promoter was cloned and its activity investigated using luciferase assays. A major finding is that individuals in possession of MBL variant alleles suffered from more frequent and longer episodes of FN over the study period compared to wildtype individuals. Functional analysis enabled identification of specific deficiencies within the pathway in patients deemed MBL sufficient by their genotype and protein level. Changes in MASP levels were noted in response to chemotherapy and complement function was observed to increase during FN episodes. Structural analysis revealed variability in MBL higher order oligomer structure during the acute phase of FN and promoter studies further highlighted the complexity of MBL regulation. The results presented in this thesis provide further evidence that MBL deficiency increases the frequency and the duration of FN in the largest paediatric cancer cohort studied to date. The complex interplay between other pathway components appears crucial to MBL function but their influence on clinical outcome is not yet fully understood

How Inter- and Intramolecular Processes Dictate Aggregation-Induced Emission in Crystals Undergoing Excited-State Proton Transfer

Aggregation-induced emission (AIE) offers a route for the development of luminescent technologies with high quantum efficiencies. Excited-state intramolecular proton transfer (ESIPT) coupled to AIE can produce devices with emission across the visible spectrum. We use a combination of theoretical models to determine the factors that mediate fluorescence in molecular crystals undergoing ESIPT. Using two materials based on 2′-hydroxychalcone as exemplar cases, we analyze how inter- and intramolecular processes determine the emissive properties in the crystal environment. This systematic investigation extends the current interpretation of AIE to polar chromophores with multiple decay pathways. We find that population of nonradiative pathways is dictated by the electronic effects of the substituents and the degree of distortion allowed in the crystal environment. Localization of the electron density is crucial to maximize fluorescence via ESIPT. Our conclusions offer design strategies for the development of luminescent molecular crystals

ONIOM(QM:QM') Electrostatic Embedding Schemes for Photochemistry in Molecular Crystals.

Understanding photoinduced processes in molecular crystals is central to the design of highly emissive materials such as organic lasers and organic light-emitting diodes. The modelling of such processes is, however, hindered by the lack of excited state methodologies tailored for these systems. Embedding approaches based on the Ewald sum can be used in conjunction with excited state electronic structure methods to model the localised excitations which characterise these materials. In this article, we describe the implementation of a two-level ONIOM(QM:QM') point charge embedding approach based on the Ewald method, the Ewald Embedded Cluster (EEC) model. An alternative self-consistent method is also considered to simulate the response of the environment to the excitation. Two molecular crystals with opposing photochemical behaviour were used to benchmark the results with single reference and multireference methods. We observed that the inclusion of an explicit ground state cluster surrounding the QM region was imperative for the exploration of the excited state potential energy surfaces. Using EEC, accurate absorption and emission energies as well as S1-S0 conical intersections were obtained for both crystals. We discuss the implications of the use of these embedding schemes considering the degree of localisation of the excitation. The methods discussed herein are implemented in an open source platform (forage, https://github.com/Crespo-Otero-group/fromage) which acts as an interface between popular electronic structure codes (Gaussian, Turbomole and Molcas)

Advocating for platform data access : challenges and opportunities for academics seeking policy change

Independent researchers’ access to digital platform data is critical for our understanding of the online world; yet recent reflections have shown that data are not always readily available (Asbjørn Møller & Bechmann, 2019; Bruns, 2018; Tromble, 2021). In the face of platform power to determine data accessibility, academics can often feel powerless, but opportunities and openings can emerge for scholars to shape practice. In this article, we examine the potential for academics to engage with non-academic audiences in debates around increased data access. Adopting an autoethnographic approach, we draw on our personal experiences working with policymakers and digital platforms to offer advice for academics seeking to shape debates and advocate for change. Presenting vignettes that detail our experiences and drawing on existing scholarship on how to engage with non-academic audiences, we outline the opportunities and challenges in this kind of engagement with a view to guiding other scholars interested in engaging in this space

Just what is data-driven campaigning? A systematic review

Discussions of data-driven campaigning have gained increased prominence in recent years. Often associated with the practices of Cambridge Analytica and linked to debates about the health of modern democracy, scholars have devoted considerable attention to the rise of data-driven politics. However, most studies to date have focused solely on practice in the US, and few scholars have made efforts to define the precise meaning of ‘data-driven campaigning’. With growing recognition that data-driven campaigning can take different forms dependent on context and available resource, new questions have emerged as to exactly what features are indicative of this phenomena. In this piece we systematically review existing discussions of data-driven campaigning to unpack the components of this idea. Identifying areas of convergence and divergence in existing discussions of ‘data’, ‘driven’, and ‘campaigning’, we classify existing debate to highlight integral features and variable practices. This article accordingly provides the first comprehensive definition of data-driven campaigning, and aims to facilitate international study of this activity

The regulatory ecosystem of data driven campaigning in the UK

Political campaigns are increasingly described as data-driven, as parties collect and analyse large quantities of voter data to target their campaign messages in ever more granular ways, particularly online. These practices have increasingly been facing calls for greater regulation due to the range of harms they are seen to pose for citizens and democracy more generally. Such harms include the intrusions on voter privacy, reduced transparency in how messages are constructed and targeted at voters and exposure to increasingly divisive and polarizing political content. Given that data-driven campaigning (DDC) encompasses a range of different practices that are likely to fall under the remit of multiple agencies, it is not evident how suitable current regulatory frameworks are for addressing the harms associated with the growth of DDC. This paper takes a first step toward addressing that question by mapping an emergent regulatory “ecosystem” for DDC in the particular case of the UK. Specifically, we collect and analyse interview data from a range of regulators working directly or indirectly in the election campaigns and communication arena. Our analysis shows that while privacy violations associated with DDC are seen by regulators to be largely well covered by current legislation, other potential harms are given lesser to no priority. These gaps appear to be due to regulators lacking either the powers or the incentives to intervene

Altered visual processing in a rodent model of Attention-Deficit Hyperactivity Disorder

A central component of Attention-Deficit Hyperactivity Disorder (ADHD) is increased distractibility, which is linked to the superior colliculus (SC) in a range of species, including humans. Furthermore, there is now mounting evidence of altered collicular functioning in ADHD and it is proposed that a hyper-responsive SC could mediate the main symptoms of ADHD, including distractibility. In the present study we have provided a systematic characterization of the SC in the most commonly used and well-validated animal model of ADHD, the spontaneously hypertensive rat (SHR). We examined collicular-dependent orienting behavior, local field potential (LFP) and multiunit responses to visual stimuli in the anesthetized rat and morphological measures in the SHR in comparison to the Wistar Kyoto (WKY) and Wistar (WIS). We found that SHRs remain responsive to a repeated visual stimulus for more presentations than control strains and have a longer response duration. In addition, LFP and multiunit activity within the visually responsive superficial layers of the SC showed the SHR to have a hyper-responsive SC relative to control strains, which could not be explained by altered functioning of the retinocollicular pathway. Finally, examination of collicular volume, neuron and glia densities and glia:neuron ratio revealed that the SHR had a reduced ratio relative to the WKY which could explain the increased responsiveness. In conclusion, this study demonstrates strain-specific changes in the functioning and structure of the SC in the SHR, providing convergent evidence that the SC might be dysfunctional in ADHD

Rotaxane Co-II Complexes as Field-Induced Single-Ion Magnets

Mechanically chelating ligands have untapped potential for the engineering of metal ion properties. Here we demonstrate this principle in the context of CoII-based single-ion magnets. Using multi-frequency EPR, susceptibility and magnetization measurements we found that these complexes show some of the highest zero field splittings reported for five-coordinate CoII complexes to date. The predictable coordination behaviour of the interlocked ligands allowed the magnetic properties of their CoII complexes to be evaluated computationally a priori and our combined experimental and theoretical approach enabled us to rationalize the observed trends. The predictable magnetic behaviour of the rotaxane CoII complexes demonstrates that interlocked ligands offer a new strategy to design metal complexes with interesting functionality