Proteomic analysis reveals GIT1 as a novel mTOR complex component critical for mediating astrocyte survival

As a critical regulator of cell growth, the mechanistic target of rapamycin (mTOR) protein operates as part of two molecularly and functionally distinct complexes. Herein, we demonstrate that mTOR complex molecular composition varies in different somatic tissues. In astrocytes and neural stem cells, we identified G-protein-coupled receptor kinase-interacting protein 1 (GIT1) as a novel mTOR-binding protein, creating a unique mTOR complex lacking Raptor and Rictor. Moreover, GIT1 binding to mTOR is regulated by AKT activation and is essential for mTOR-mediated astrocyte survival. Together, these data reveal that mTOR complex function is partly dictated by its molecuflar composition in different cell types

Chemical genetics of \u3ci\u3ePlasmodium falciparum\u3c/i\u3e

Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library—many of which showed potent in vitro activity against drug-resistant P. falciparum strains—and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery

Directors of public health as ‘a protected species’: qualitative study of the changing role of public health professionals in England following the 2013 reforms

Background: The Health and Social Care Act 2012 gave councils in England responsibility for improving the health of their populations. Public health teams were transferred from the NHS, accompanied by a ring-fenced public health grant. This study examines the changing role of these teams within local government. Methods: In-depth case study research was conducted within 10 heterogeneous councils. Initial interviews (n=90) were carried out between October 2015 and March 2016, with follow-up interviews (n=21) 12 months later. Interviewees included elected members, directors of public health (DsPH) and other local authority officers, plus representatives from NHS commissioners, the voluntary sector and Healthwatch. Results: Councils welcomed the contribution of public health professionals, but this was balanced against competing demands for financial resources and democratic leverage. DsPH – seen by some as a ‘protected species’ – were relying increasingly on negotiating and networking skills to fulfil their role. Both the development of the existing specialist public health workforce and recruitment to, and development of, the future workforce were uncertain. This poses both threats and opportunities. Conclusions: Currently the need for staff to retain specialist skills and maintain UKPH registration is respected. However, action is needed to address how future public health professionals operating within local government will be recruited and developed

Early Mississippian sandy siltstones preserve rare vertebrate fossils in seasonal flooding episodes

Flood-generated sandy siltstones are under-recognised deposits that preserve key vertebrate (actinopterygians, rhizodonts, and rarer lungfish, chondrichthyans and tetrapods), invertebrate and plant fossils. Recorded for the first time from the lower Mississippian Ballagan Formation of Scotland, more than 140 beds occur throughout a 490 m thick core succession charac-terised by fluvial sandstones, palaeosols, siltstones, dolostone ‘cementstones’ and gypsum from a coastal–alluvial plain setting. Sandy siltstones are described as a unique taphofacies of the Ballagan Formation (Scotland, UK);they are matrix-supported siltstones with millimetre-sized siltstone and very fine sandstone lithic clasts. Common bioclasts include plants and mega-spores, fish, ostracods, eurypterids and bivalves. Fossils have a high degree of articulation compared with those found in other fossil-bearing deposits, such as conglomerate lags at the base of fluvial channel sandstones. Bed thickness and distribution varies throughout the formation, with no stratigraphic trend. The matrix sediment and clasts are sourced from the reworking of floodplain sediments including desiccated surfaces and palaeosols. Secondary pedogenic modification affects 30% of the sandy siltstone beds and most (71%) overlie palaeosols or desiccation cracks. Sandy siltstones are interpreted as cohesive debris flow deposits that originated by the over-bank flooding of rivers and due to localised floodplain sediment transport at times of high rainfall; their association with palaeosols and desiccation cracks indicates seasonally wet to dry cycles throughout the Tournaisian. Tetrapod and fish fossils derived from floodplain lakes and land surfaces are concentrated by local erosion and reworking, and are preserved by deposition into temporary lakes on the floodplain; their distribution indicates a local origin, with sediment transported across the floodplain in seasonal rainfall episodes. These deposits are significant new sites that can be explored for the preservation of rare non-marine fossil material and provide unique insights into the evolution of early terrestrial ecosystems

A new Mississippian tetrapod from Fife, Scotland, and its environmental context

The Visean stage of the Mississippian was a time of rapid tetrapod diversification which marks the earliest appearance of temnospondyls, microsaurs and the limbless aïstopods. Tetrapod finds from this stage are very rare and only a dozen sites are known worldwide. Here we announce the discovery of a new Visean site in Fife, Scotland, of Asbian age, and from it describe a new species of the baphetoid Spathicephalus. These specimens represent the oldest known baphetoid by three million years, yet belong to the most specialized members of the clade. Unlike typical baphetoids with large marginal teeth and palatal fangs characteristic of early tetrapods, spathicephalids had very broad flattened heads with a dentition consisting of a large number of small, uniform teeth. Spathicephalids were probably one of the earliest tetrapod groups to use suction feeding on small, aquatic prey. Palynological and sedimentological analysis indicates that the new fossil bed was deposited in a large, stratified, freshwater lake that became increasingly saline

Reinterpreting the age of the uppermost ‘Old Red Sandstone’ and Early Carboniferous in Scotland

In Scotland, the base of the Ballagan Formation has traditionally been placed at the first grey mudstone within a contiguous Late Devonian to Carboniferous succession. This convention places the Devonian–Carboniferous boundary within the Old Red Sandstone (ORS) Kinnesswood Formation. The consequences of this placement are that tetrapods from the Ballagan Formation were dated as late Tournaisian in age and that the ranges of typically Devonian fish found in the Kinnesswood Formation continued into the Carboniferous. The Pease Bay specimen of the fish Remigolepis is from the Kinnesswood Formation. Comparisons with its range in Greenland, calibrated against spores, show it was Famennian in age. Detailed palynological sampling at Burnmouth from the base of the Ballagan Formation proves that the early Tournaisian spore zones (VI and HD plus Cl 1) are present. The Schopfites species that occurs through most of the succession is Schopfites delicatus rather than Schopfites claviger. The latter species defines the late Tournaisian CM spore zone. The first spore assemblage that has been found in Upper ‘ORS' strata underlying the Ballagan Formation (Preston, Whiteadder Water), contains Retispora lepidophyta and is from the early latest Famennian LL spore zone. The spore samples are interbedded with volcaniclastic debris, which shows that the Kelso Volcanic Formation is, in part, early latest Famennian in age. These findings demonstrate that the Ballagan Formation includes most of the Tournaisian with the Devonian–Carboniferous boundary positioned close to the top of the Kinnesswood Formation. The Stage 6 calcrete at Pease Bay can be correlated to the equivalent section at Carham, showing that it represents a time gap equivalent to the latest Famennian glaciation(s). Importantly, some of the recently described Ballagan Formation tetrapods are older than previously dated and now fill the key early part of Romer's Gap