Exploring leadership in early childhood practice: summary of original research

This is a summary of the research undertaken for this project. The results of our research project are presented within the book ‘Leading in Early Childhood’, published by Sage, 2016, and are being prepared for presentation in early childhood journal articles and at academic and practitioner conferences

Young children as citizens: Learning from practice in the early childhood setting

This paper examines enactments of young children’s citizenship in early childhood settings in England, which is an under researched area, in this study young children are positioned as social actors, competent and capable of making decisions and enacting citizenship. Values, child rights and citizenship are interconnected and often inseparable in practice. A mixed methods multiple-case study was conducted in England across several early childhood settings in the private and independent sector. Our findings indicate that young children enact citizenship through micro acts embedded into their day-to-day activities; such acts are often spontaneous in response to events or interactions. These are often pro-social in nature comprised as behaviours such as helping or showing concern for others. Our findings give visibility to the distinctive ways in which young children may enact citizenship including, for example, physical expressions

Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration

Acknowledgements We are indebted to Jim Humphries, JennyCorrigan, LizDarley, Elizabeth Joynson, Natalie Walters, Sara Wells and the whole necropsy, histology, genotyping and MLC ward 6 teams at MRC Harwell for excellent technical assistance. We thank the staff of the WTSI Illumina Bespoke Team for the RNA-seq data, the Sanger Mouse Genetics Project for the initial mouse characterization and Dr David Adams for critical reading of the manuscript. We also thank KOMP for the mouse embryonic stem cells carrying the knockout first promoter-less allele (tm1a(KOMP)Wtsi) within Zfp016. Conflict of Interest statement. None declared. Funding This work was funded by the UK Medical Research Council (MRC) to A.A.-A. and a Motor Neurone Disease Association (MNDA) project grant to A.A.-A. and EMCF. D.L.H.B. is a Wellcome Trust Senior Clinical Scientist Fellow and P.F. is a MRC/MNDA Lady Edith Wolfson Clinician Scientist Fellow. Funding to pay the Open Access publication charges for this article was provided by the MRC grant number: MC_UP_A390_1106.Peer reviewedPublisher PD

Rapid-response radio observations of short GRB 181123B with the Australia Telescope Compact Array

We introduce the Australia Telescope Compact Array (ATCA) rapid-response mode by presenting the first successful trigger on the short-duration gamma-ray burst (GRB) 181123B. Early-time radio observations of short GRBs may provide vital insights into the radio afterglow properties of Advanced LIGO- and Virgo-detected gravitational wave events, which will in turn inform follow-up strategies to search for counterparts within their large positional uncertainties. The ATCA was on target within 12.6 hr post-burst, when the source had risen above the horizon. While no radio afterglow was detected during the 8.3 hr observation, we obtained force-fitted flux densities of $7 \pm 12$ and $15 \pm 11~\mu$Jy at 5.5 and 9 GHz, respectively. Afterglow modelling of GRB 181123B showed that the addition of the ATCA force-fitted radio flux densities to the Swift X-ray Telescope detections provided more stringent constraints on the fraction of thermal energy in the electrons (log$\epsilon_e = -0.75^{+0.39}_{-0.40}$ rather than log$\epsilon_e = -1.13^{+0.82}_{-1.2}$ derived without the inclusion of the ATCA values), which is consistent with the range of typical $\epsilon_e$ derived from GRB afterglow modelling. This allowed us to predict that the forward shock may have peaked in the radio band $\sim10$ days post-burst, producing detectable radio emission $\gtrsim3-4$ days post-burst. Overall, we demonstrate the potential for extremely rapid radio follow-up of transients and the importance of triggered radio observations for constraining GRB blast wave properties, regardless of whether there is a detection, via the inclusion of force-fitted radio flux densities in afterglow modelling efforts

AT 2017gbl: A dust obscured TDE candidate in a luminous infrared galaxy

We present the discovery with Keck of the extremely infrared (IR) luminous transient AT 2017gbl, coincident with the Northern nucleus of the luminous infrared galaxy (LIRG) IRAS 23436+5257. Our extensive multiwavelength follow-up spans ∼900 d, including photometry and spectroscopy in the optical and IR, and (very long baseline interferometry) radio and X-ray observations. Radiative transfer modelling of the host galaxy spectral energy distribution and long-term pre-outburst variability in the mid-IR indicate the presence of a hitherto undetected dust obscured active galactic nucleus (AGN). The optical and near-IR spectra show broad ∼2000 km s-1 hydrogen, He i, and O i emission features that decrease in flux over time. Radio imaging shows a fast evolving compact source of synchrotron emission spatially coincident with AT 2017gbl. We infer a lower limit for the radiated energy of 7.3 × 1050 erg from the IR photometry. An extremely energetic supernova would satisfy this budget, but is ruled out by the radio counterpart evolution. Instead, we propose AT 2017gbl is related to an accretion event by the central supermassive black hole, where the spectral signatures originate in the AGN broad line region and the IR photometry is consistent with re-radiation by polar dust. Given the fast evolution of AT 2017gbl, we deem a tidal disruption event (TDE) of a star a more plausible scenario than a dramatic change in the AGN accretion rate. This makes AT 2017gbl the third TDE candidate to be hosted by a LIRG, in contrast to the so far considered TDE population discovered at optical wavelengths and hosted preferably by post-starburst galaxies

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured rodent myotubes

Aims/hypothesis: Impaired glucose uptake in skeletal muscle is an important contributor to glucose intolerance in type 2 diabetes. The aspartate protease, beta-site APP-cleaving enzyme 1 (BACE1), a critical regulator of amyloid precursor protein (APP) processing, modulates in vivo glucose disposal and insulin sensitivity in mice. Insulin-independent pathways to stimulate glucose uptake and GLUT4 translocation may offer alternative therapeutic avenues for the treatment of diabetes. We therefore addressed whether BACE1 activity, via APP processing, in skeletal muscle modifies glucose uptake and oxidation independently of insulin. Methods: Skeletal muscle cell lines were used to investigate the effects of BACE1 and α-secretase inhibition and BACE1 and APP overexpression on glucose uptake, GLUT4 cell surface translocation, glucose oxidation and cellular respiration. Results: In the absence of insulin, reduction of BACE1 activity increased glucose uptake and oxidation, GLUT4myc cell surface translocation, and basal rate of oxygen consumption. In contrast, overexpressing BACE1 in C2C12 myotubes decreased glucose uptake, glucose oxidation and oxygen consumption rate. APP overexpression increased and α-secretase inhibition decreased glucose uptake in C2C12 myotubes. The increase in glucose uptake elicited by BACE1 inhibition is dependent on phosphoinositide 3-kinase (PI3K) and mimicked by soluble APPα (sAPPα). Conclusions/interpretation: Inhibition of muscle BACE1 activity increases insulin-independent, PI3K-dependent glucose uptake and cell surface translocation of GLUT4. As APP overexpression raises basal glucose uptake, and direct application of sAPPα increases PI3K–protein kinase B signalling and glucose uptake in myotubes, we suggest that α-secretasedependent shedding of sAPPα regulates insulin-independent glucose uptake in skeletal muscle