Care Planning and Review for Looked After Children: Fifteen Years of Slow Progress?

This Critical Commentary reviews progress in research into planning and reviewing for children in care in England and Wales since the publication of two major studies in the late 1990s (roughly coinciding with the New Labour period). It briefly considers the changing context of law, regulation and guidance and the aims and objectives of the care planning and review system. It then reviews the limited research literature available, in relation to a series of key topics. Consideration is also given to guides for children and practitioners on the subject. The commentary concludes by suggesting that this is an area in which research has failed to keep pace with changes in policy and practice, and recommends a more systematic approach

Glycogen and its metabolism: some new developments and old themes

Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been the subject of extensive investigation and much is known about its regulation by hormones such as insulin, glucagon and adrenaline (epinephrine). There has been debate over the relative importance of allosteric compared with covalent control of the key biosynthetic enzyme, glycogen synthase, as well as the relative importance of glucose entry into cells compared with glycogen synthase regulation in determining glycogen accumulation. Significant new developments in eukaryotic glycogen metabolism over the last decade or so include: (i) three-dimensional structures of the biosynthetic enzymes glycogenin and glycogen synthase, with associated implications for mechanism and control; (ii) analyses of several genetically engineered mice with altered glycogen metabolism that shed light on the mechanism of control; (iii) greater appreciation of the spatial aspects of glycogen metabolism, including more focus on the lysosomal degradation of glycogen; and (iv) glycogen phosphorylation and advances in the study of Lafora disease, which is emerging as a glycogen storage disease

Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation

Glycogen synthase (GS) is the rate limiting enzyme in the synthesis of glycogen. Eukaryotic GS is negatively regulated by covalent phosphorylation and allosterically activated by glucose-6-phosphate (G6P). To gain structural insights into the inhibited state of the enzyme, we solved the crystal structure of yGsy2-R589A/R592A to a resolution of 3.3 Å. The double mutant has an activity ratio similar to the phosphorylated enzyme and also retains the ability to be activated by G6P. When compared to the 2.88 Å structure of the wild-type G-6-P activated enzyme, the crystal structure of the low-activity mutant showed that the N-terminal domain of the inhibited state is tightly held against the dimer-related interface thereby hindering acceptor access to the catalytic cleft. Based on these two structural observations, we developed a reversible redox regulatory feature in yeast GS by substituting cysteine residues for two highly conserved arginine residues. When oxidized, the cysteine mutant enzyme exhibits activity levels similar to the phosphorylated enzyme, but cannot be activated by G-6-P. Upon reduction, the cysteine mutant enzyme regains normal activity levels and regulatory response to G-6-P activation

Decision Making Methods for Water Resources Management Under Deep Uncertainty

Substantial anthropogenic change of the Earth’s climate is modifying patterns of rainfall, river flow, glacial melt and groundwater recharge rates across the planet, undermining many of the stationarity assumptions upon which water resources infrastructure has been historically managed. This hydrological uncertainty is creating a potentially vast range of possible futures that could threaten the dependability of vital regional water supplies. This, combined with increased urbanisation and rapidly growing regional populations, is putting pressures on finite water resources. One of the greatest international challenges facing decision makers in the water industry is the increasing influences of these “deep” climate change and population growth uncertainties affecting the long-term balance of supply and demand and necessitating the need for adaptive action. Water companies and utilities worldwide are now under pressure to modernise their management frameworks and approaches to decision making in order to identify more sustainable and cost-effective water management adaptations that are reliable in the face of uncertainty. The aim of this thesis is to compare and contrast a range of existing Decision Making Methods (DMMs) for possible application to Water Resources Management (WRM) problems, critically analyse on real-life case studies their suitability for handling uncertainties relating to climate change and population growth and then use the knowledge generated this way to develop a new, resilience-based WRM planning methodology. This involves a critical evaluation of the advantages and disadvantages of a range of methods and metrics developed to improve on current engineering practice, to ultimately compile a list of suitable recommendations for a future framework for WRM adaptation planning under deep uncertainty. This thesis contributes to the growing vital research and literature in this area in several distinct ways. Firstly, it qualitatively reviews a range of DMMs for potential application to WRM adaptation problems using a set of developed criteria. Secondly, it quantitatively assesses two promising and contrasting DMMs on two suitable real-world case studies to compare highlighted aspects derived from the qualitative review and evaluate the adaptation outputs on a practical engineering level. Thirdly, it develops and reviews a range of new potential performance metrics that could be used to quantitatively define system resilience to help answer the water industries question of how best to build in more resilience in future water resource adaptation planning. This leads to the creation and testing of a novel resilience driven methodology for optimal water resource planning, combining optimal aspects derived from the quantitative case study work with the optimal metric derived from the resilience metric investigation. Ultimately, based on the results obtained, a list of suitable recommendations is compiled on how to improve the existing methodologies for future WRM planning under deep uncertainty. These recommendations include the incorporation of more complex simulation models into the planning process, utilisation of multi-objective optimisation algorithms, improved uncertainty characterisation and assessments, an explicit robustness examination and the incorporation of additional performance metrics to increase the clarity of the strategy assessment process.HR Wallingford LtdEngineering and Physical Sciences Research Council (EPSRC

Collimated, single-pass atom source from a pulsed alkali metal dispenser for laser-cooling experiments

We have developed an improved scheme for loading atoms into a magneto-optical trap (MOT) from a directed alkali metal dispenser in < 10^-10 torr ultra-high vacuum conditions. A current-driven dispenser was surrounded with a cold absorbing "shroud" held at < 0 C, pumping rubidium atoms not directed into the MOT. This nearly eliminates background alkali atoms and reduces the detrimental rise in pressure normally associated with these devices. The system can be well-described as a current-controlled, rapidly-switched, two-temperature thermal beam, and was used to load a MOT with 3 x 10^8 atoms.Comment: 5 pages, 4 figure

Reply to: Punctuated transgression (?): Comment on Oliver, T.S.N., Donaldson, P., Sharples, C., Roach, M., and Woodroffe, C.D. Punctuated progradation of the Seven Mile Beach Holocene barrier system, southeastern Tasmania

Our interpretation of the depositional history of the prograded barrier at Seven Mile Beach in Tasmania, described in Oliver et al. (2017a), was based on the morphology of ridges apparent in the LiDAR-based digital elevation data and a sample of 14 optically-stimulated luminescence (OSL) ages. Dougherty (2018) has identified gaps in the chronology and speculated that progradation may have occurred as sea level fell from a mid-Holocene highstand inappropriately applying sea-level curves from mainland Australia. Despite a highstand being inferred by early research in Tasmania, glacio-isostatic modelling and recent sea-level studies adopted a prevailing view that excluded a highstand. Our observations led us to question this prevailing view and to suggest that it might be appropriate to reopen the debate on Holocene sea-level change in Tasmania. We welcome the renewed interest in the chronology and sea-level history of this prograded barrier, and look forward to further clarification based on new evidence. The site may have the potential to become one of the more continuous and better-constrained sea-level records in southern Australia

Incorporation of phosphate into glycogen by glycogen synthase

The storage polymer glycogen normally contains small amounts of covalently attached phosphate as phosphomonoesters at C2, C3 and C6 atoms of glucose residues. In the absence of the laforin phosphatase, as in the rare childhood epilepsy Lafora disease, the phosphorylation level is elevated and is associated with abnormal glycogen structure that contributes to the pathology. Laforin therefore likely functions in vivo as a glycogen phosphatase. The mechanism of glycogen phosphorylation is less well-understood. We have reported that glycogen synthase incorporates phosphate into glycogen via a rare side reaction in which glucose-phosphate rather than glucose is transferred to a growing polyglucose chain (Tagliabracci et al. (2011) Cell Metab13, 274-282). We proposed a mechanism to account for phosphorylation at C2 and possibly at C3. Our results have since been challenged (Nitschke et al. (2013) Cell Metab17, 756-767). Here we extend the evidence supporting our conclusion, validating the assay used for the detection of glycogen phosphorylation, measurement of the transfer of (32)P from [β-(32)P]UDP-glucose to glycogen by glycogen synthase. The (32)P associated with the glycogen fraction was stable to ethanol precipitation, SDS-PAGE and gel filtration on Sephadex G50. The (32)P-signal was not affected by inclusion of excess unlabeled UDP before analysis or by treatment with a UDPase, arguing against the signal being due to contaminating [β-(32)P]UDP generated in the reaction. Furthermore, [(32)P]UDP did not bind non-covalently to glycogen. The (32)P associated with glycogen was released by laforin treatment, suggesting that it was present as a phosphomonoester. The conclusion is that glycogen synthase can mediate the introduction of phosphate into glycogen, thereby providing a possible mechanism for C2, and perhaps C3, phosphorylation