Historical child sexual abuse in England and Wales: the role of historians

This article reflects on methodological and ethical issues that have shaped a collaborative project which aims to chart social, legal and political responses to child sexual abuse in England and Wales across the twentieth century. The etymological problem of searching for child sexual abuse in the historical archive is discussed, given that the term itself is a relatively recent one. Acknowledging that research tools will always be partial, it then focuses on the gaps and silences in the archive, most problematically in relation to the voices and experiences of victims and survivors themselves. Finally it discusses ethical issues relating to the naming or anonymising of those accused and convicted (as well as victims and survivors) in the writing up of research findings. The discussion focuses on two key periods – the 1920s and 1950s – and on education policy, including regulatory procedures for teachers in state and fee-paying schools.ESRCThis is the final version of the article. It first appeared from Taylor & Francis via http://dx.doi.org/10.1080/0046760X.2016.117712

Flexibility and intrinsic disorder are conserved features of hepatitis C virus E2 glycoprotein

The glycoproteins of hepatitis C virus, E1E2, are unlike any other viral fusion machinery yet described, and are the current focus of immunogen design in HCV vaccine development; thus, making E1E2 both scientifically and medically important. We used pre-existing, but fragmentary, structures to model a complete ectodomain of the major glycoprotein E2 from three strains of HCV. We then performed molecular dynamic simulations to explore the conformational landscape of E2, revealing a number of important features. Despite high sequence divergence, and subtle differences in the models, E2 from different strains behave similarly, possessing a stable core flanked by highly flexible regions, some of which perform essential functions such as receptor binding. Comparison with sequence data suggest that this consistent behaviour is conferred by a network of conserved residues that act as hinge and anchor points throughout E2. The variable regions (HVR-1, HVR-2 and VR-3) exhibit particularly high flexibility, and bioinformatic analysis suggests that HVR-1 is a putative intrinsically disordered protein region. Dynamic cross-correlation analyses demonstrate intramolecular communication and suggest that specific regions, such as HVR-1, can exert influence throughout E2. To support our computational approach we performed small-angle X-ray scattering with purified E2 ectodomain; this data was consistent with our MD experiments, suggesting a compact globular core with peripheral flexible regions. This work captures the dynamic behaviour of E2 and has direct relevance to the interaction of HCV with cell-surface receptors and neutralising antibodies

Structural and functional analysis of the tandem β-zipper interaction of a streptococcal protein with human fibronectin

Bacterial fibronectin-binding proteins (FnBPs) contain a large intrinsically disordered region (IDR) that mediates adhesion of bacteria to host tissues, and invasion of host cells, through binding to fibronectin (Fn). These FnBP IDRs consist of Fn-binding repeats (FnBRs) that form a highly extended tandem β-zipper interaction on binding to the N-terminal domain of Fn. Several FnBR residues are highly conserved across bacterial species, and here we investigate their contribution to the interaction. Mutation of these residues to alanine in SfbI-5 (a disordered FnBR from the human pathogen Streptococcus pyogenes) reduced binding, but for each residue the change in free energy of binding was <2 kcal/mol. The structure of an SfbI-5 peptide in complex with the second and third F1 modules from Fn confirms that the conserved FnBR residues play equivalent functional roles across bacterial species. Thus, in SfbI-5, the binding energy for the tandem β-zipper interaction with Fn is distributed across the interface rather than concentrated in a small number of "hot spot" residues that are frequently observed in the interactions of folded proteins. We propose that this might be a common feature of the interactions of IDRs and is likely to pose a challenge for the development of small molecule inhibitors of FnBP-mediated adhesion to and invasion of host cells

Linear plasma experiment for non-linear microwave interaction experiments

As a non-linear medium, plasma can exhibit diverse dynamics when excited bymultiple EM waves. Electromagnetic waves are vital to the introduction of energyin laser plasma interactions and the heating of magnetically confined fusion reactors.In laser plasma applications Raman coupling via a Langmuir oscillation or Brillouinscattering mediated by ion-acoustic waves are of interest. Signals with normalisedintensities approaching those used in some recent laser plasma interactions can begenerated using powerful and flexible microwave amplifiers, interacting in relativelytenuous, cool and accessible plasma. Other multi-wave interactions are interesting formagnetic confinement fusion plasmas, for example beat-wave interactions betweentwo microwave signals coupling to cyclotron motion of the ions and electrons or thelower hybrid oscillations may be useful in heating the plasmas or for driving currents.A linear plasma experiment is being built to test such multifrequency microwaveinteraction in plasma, based on prior research on geophysical cyclotron wave emissionand propagation [1,2]. The main section of the plasma will be magnetised at up to0.05T, with the plasma created by an RF helicon source to generate a dense, large,cool plasma with a high ionisation fraction. A range of frequency-flexible sources willprovide microwave beams to enable multi-wave coupling experiments. The paper willpresent progress on this apparatus and experiments.The authors gratefully acknowledge support from the EPSRC, MBDA UK Ltd andTMD Technologies Ltd.[1] Ronald K., Speirs D.C., McConville S.L., Phelps A.D.R., Robertson C.W., WhyteC.G., He W., Gillespie K.M., Cross A.W., Bingham R., 2008, Phys. Plasmas, 15,art.056503[2] Speirs, D.C., Bingham, R., Cairns, R.A., Vorgul, I., Kellett, B.J., Phelps, A.D.R.,Ronald, K, 2014, Phys. Rev. Lett., 113, art 15500

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

OBJECTIVES: ‘Persistent cloaca’ is a severe malformation affecting females in which the urinary, genital and alimentary tracts share a single conduit. Previously, a Uroplakin IIIA (UPIIIA) mutation was reported in one individual with persistent cloaca, and UPIIIA, Sonic Hedgehog (SHH), Ephrin B2 (EFNB2) and Hepatocyte Nuclear Factor 1β (HNF1β) are expressed during the normal development of organs that are affected in this condition. HNF1β mutations have been associated with uterine malformations in humans, and mutations of genes homologous to human SHH or EFNB2 cause persistent cloaca in mice. PATIENTS AND METHODS: We sought mutations of coding regions of UPIIIA, SHH, EFNB2 and HNF1β genes by direct sequencing in a group of 20 patients with persistent cloaca. Most had associated malformations of the upper renal tract and over half had impaired renal excretory function. The majority of patients had congenital anomalies outside the renal/genital tracts and two had the VACTERL association. RESULTS: Apart from a previously described index case, we failed to find UPIIIA mutations, and no patient had a SHH, EFNB2 or HNF1β mutation. CONCLUSION: Persistent cloaca is only rarely associated with UPIIIA mutation. Despite the fact that SHH and EFNB2 are appealing candidate genes, based on their expression patterns and mutant mice phenotypes, they were not mutated in these humans with persistent cloaca. Although HNF1β mutations can perturb paramesonephric duct fusion in humans, HNF1β was not mutated in persistent cloaca

Photoswitchable paclitaxel-based microtubule stabilisers allow optical control over the microtubule cytoskeleton

Small molecule inhibitors are prime reagents for studies in microtubule cytoskeleton research, being applicable across a range of biological models and not requiring genetic engineering. However, traditional chemical inhibitors cannot be experimentally applied with spatiotemporal precision suiting the length and time scales inherent to microtubule-dependent cellular processes. We have synthesised photoswitchable paclitaxel-based microtubule stabilisers, whose binding is induced by photoisomerisation to their metastable state. Photoisomerising these reagents in living cells allows optical control over microtubule network integrity and dynamics, cell division and survival, with biological response on the timescale of seconds and spatial precision to the level of individual cells within a population. In primary neurons, they enable regulation of microtubule dynamics resolved to subcellular regions within individual neurites. These azobenzene-based microtubule stabilisers thus enable non-invasive, spatiotemporally precise modulation of the microtubule cytoskeleton in living cells, and promise new possibilities for studying intracellular transport, cell motility, and neuronal physiology