Mapping training and development provision for early years practitioners

Final report for Creativity, Culture and Educatio

Review of research and evaluation on improving adult literacy and numeracy skills

The purposes of this literature review are threefold. First, this review summarises findings of the research from the last decade in six fields identified by the Department for Business, Innovation and Skills (BIS) as critical to its forward planning: (1) the economic, personal and social returns to learning; (2) the quality and effectiveness of provision; (3) the number of learning hours needed for skills gain; (4) learner persistence; (5) the retention and loss of skills over time; (6) the literacy and numeracy skills that are needed. Second, this review assesses this evidence base in terms of its quality and robustness, identifying gaps and recommending ways in which the evidence base can be extended and improved. Thirdly, this review attempts to interpret the evidence base to suggest, where possible, how returns to ALN learning for individuals, employers and wider society might be increased through effective and cost-effective interventions

Identification and control of subglacial water networks under Dome A, Antarctica

Subglacial water in continental Antarctica forms by melting of basal ice due to geothermal or frictional heating. Subglacial networks transport the water from melting areas and can facilitate sliding by the ice sheet over its bed. Subglacial water flow is driven mainly by gradients in overburden pressure and bed elevation. We identify small (median 850 m) water bodies within the Gamburtsev Subglacial Mountains in East Antarctica organized into long (20–103 km) coherent drainage networks using a dense (5 km) grid of airborne radar data. The individual water bodies are smaller on average than the water bodies contained in existing inventories of Antarctic subglacial water and most are smaller than the mean ice thickness of 2.5 km, reflecting a focusing of basal water by rugged topography. The water system in the Gamburtsev Subglacial Mountains reoccupies a system of alpine overdeepenings created by valley glaciers in the early growth phase of the East Antarctic Ice Sheet. The networks follow valley floors either uphill or downhill depending on the gradient of the ice sheet surface. In cases where the networks follow valley floors uphill they terminate in or near plumes of freeze-on ice, indicating source to sink transport within the basal hydrologic system. Because the ice surface determines drainage direction within the bed-constrained network, the system is bed-routed but surface-directed. Along-flow variability in the structure of the freeze-on plumes suggests variability in the networks on long (10s of ka) timescales, possibly indicating changes in the basal thermal state

An evaluation of Minor Groove Binders as anti- Trypanosoma brucei brucei therapeutics

A series of 32 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for activity against Trypanosoma brucei brucei. Four compounds have been found to possess significant activity, in the nanomolar range, and represent hits for further optimisation towards novel treatments for Human and Animal African Trypanosomiases. Moreover, SAR indicates that the head group linking moiety is a significant modulator of biological activit

Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine

In recent years, the neglected diseases drug discovery community has elected phenotypic screening as the key approach for the identification of novel hit compounds. However, when this approach is applied, important questions related to the mode of action for these compounds remain unanswered. One of such questions is related to the rate of action, a useful piece of information when facing the challenge of prioritising the most promising hit compounds. In the present work, compounds of the "Leishmania donovani box" were evaluated using a rate of action assay adapted from a replicative intracellular high content assay recently developed. The potency of each compound was determined every 24 hours up to 96 hours, and standard drugs amphotericin B and miltefosine were used as references to group these compounds according to their rate of action. Independently of this biological assessment, compounds were also clustered according to their minimal chemical scaffold. Comparison of the results showed a complete correlation between the chemical scaffold and the biological group for the vast majority of compounds, demonstrating how the assay was able to bring information on the rate of action for each chemical series, a property directly linked to the mode of action. Overall, the assay here described permitted us to evaluate the rate of action of the "Leishmania donovani box" using two of the currently available drugs as references and, also, to propose a number of fast-acting chemical scaffolds present in the box as starting points for future drug discovery projects to the wider scientific community. The results here presented validate the use of this assay for the determination of the rate of action early in the discovery process, to assist in the prioritisation of hit compounds

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification

Freezing of ridges and water networks preserves the Gamburtsev Subglacial Mountains for millions of years

Once an ice sheet grows beyond a critical thickness, the basal thermal regime favors melting and development of subglacial water networks. Subglacial water is necessary for bedrock erosion, but the exact mechanisms that lead to preservation of subglacial topography are unclear. Here we resolve the freezing mechanisms that lead to long-term, high-altitude preservation across the Gamburtsev Subglacial Mountains in East Antarctica. Analyses of a comprehensive geophysical data set reveal a large-scale water network along valley floors. The ice sheet often drives subglacial water up steep topography where it freezes along high ridges beneath thinner ice. Statistical tests of hypsometry show the Gamburtsevs resemble younger midlatitude mountains, indicating exceptional preservation. We conclude that the Gamburtsevs have been shielded from erosion since the latest Eocene (∼34 Ma). These freezing mechanisms likely account for the spatial and temporal patterns of erosion and preservation seen in other glaciated mountain ranges

Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy

The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development