Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein

Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin precursor protein (MstnPP) has been shown to associate with large molecular weight filamentous inclusions containing the Alzheimer's amyloid beta peptide in sIBM tissue, and MstnPP is upregulated following ER stress. The mechanism for how MstnPP contributes to disease pathogenesis is unknown. Here, we show for the first time that MstnPP is capable of forming amyloid fibrils in vitro. When MstnPP-containing Escherichia coli inclusion bodies are refolded and purified, a proportion of MstnPP spontaneously misfolds into amyloid-like aggregates as characterised by electron microscopy and binding of the amyloid-specific dye thioflavin T. When subjected to a slightly acidic pH and elevated temperature, the aggregates form straight and unbranched amyloid fibrils 15 nm in diameter and also exhibit higher order amyloid structures. Circular dichroism spectroscopy reveals that the amyloid fibrils are dominated by β-sheet and that their formation occurs via a conformational change that occurs at a physiologically relevant temperature. Importantly, MstnPP aggregates and protofibrils have a negative effect on the viability of myoblasts. These novel results show that the myostatin precursor protein is capable of forming amyloid structures in vitro with implications for a role in sIBM pathogenesis

Replication of the association of HLA-B7 with Alzheimer's disease: a role for homozygosity?

BACKGROUND: There are reasons to expect an association with Alzheimer's disease (AD) within the HLA region. The HLA-B & C genes have, however, been relatively understudied. A geographically specific association with HLA-B7 & HLA-Cw*0702 had been suggested by our previous, small study. METHODS: We studied the HLA-B & C alleles in 196 cases of 'definite' or 'probable' AD and 199 elderly controls of the OPTIMA cohort, the largest full study of these alleles in AD to date. RESULTS: We replicated the association of HLA-B7 with AD (overall, adjusted odds ratio = 2.3, 95% confidence interval = 1.4–3.7, p = 0.001), but not the previously suggested interaction with the ε4 allele of apolipoprotein E. Results for HLA-Cw*0702, which is in tight linkage disequilibrium with HLA-B7, were consistent with those for the latter. Homozygotes of both alleles appeared to be at particularly high risk of AD. CONCLUSION: HLA-B7 and HLA-Cw*0702 are associated with AD in the Oxford population. Because of the contradictions between cohorts in our previous study, we suggest that these results may be geographically specific. This might be because of differences between populations in the structure of linkage disequilibrium or in interactions with environmental, genetic or epigenetic factors. A much larger study will be needed to clarify the role of homozygosity of HLA alleles in AD risk

Reducing publication delay to improve the efficiency and impact of conservation science.

Evidence-based decision-making is most effective with comprehensive access to scientific studies. If studies face significant publication delays or barriers, the useful information they contain may not reach decision-makers in a timely manner. This represents a potential problem for mission-oriented disciplines where access to the latest data is required to ensure effective actions are undertaken. We sought to analyse the severity of publication delay in conservation science-a field that requires urgent action to prevent the loss of biodiversity. We used the Conservation Evidence database to assess the length of publication delay (time from finishing data collection to publication) in the literature that tests the effectiveness of conservation interventions. From 7,447 peer-reviewed and non-peer-reviewed studies of conservation interventions published over eleven decades, we find that the raw mean publication delay was 3.2 years (±2SD = 0.1) and varied by conservation subject. A significantly shorter delay was observed for studies focused on Bee Conservation, Sustainable Aquaculture, Management of Captive Animals, Amphibian Conservation, and Control of Freshwater Invasive Species (Estimated Marginal Mean range from 1.4-1.9 years). Publication delay was significantly shorter for the non-peer-reviewed literature (Estimated Marginal Mean delay of 1.9 years ± 0.2) compared to the peer-reviewed literature (i.e., scientific journals; Estimated Marginal Mean delay of 3.0 years ± 0.1). We found publication delay has significantly increased over time (an increase of ~1.2 years from 1912 (1.4 years ± 0.2) to 2020 (2.6 years ± 0.1)), but this change was much weaker and non-significant post-2000s; we found no evidence for any decline. There was also no evidence that studies on more threatened species were subject to a shorter delay-indeed, the contrary was true for mammals, and to a lesser extent for birds. We suggest a range of possible ways in which scientists, funders, publishers, and practitioners can work together to reduce delays at each stage of the publication process

Protostellar Outflow Evolution in Turbulent Environments

The link between turbulence in star formatting environments and protostellar jets remains controversial. To explore issues of turbulence and fossil cavities driven by young stellar outflows we present a series of numerical simulations tracking the evolution of transient protostellar jets driven into a turbulent medium. Our simulations show both the effect of turbulence on outflow structures and, conversely, the effect of outflows on the ambient turbulence. We demonstrate how turbulence will lead to strong modifications in jet morphology. More importantly, we demonstrate that individual transient outflows have the capacity to re-energize decaying turbulence. Our simulations support a scenario in which the directed energy/momentum associated with cavities is randomized as the cavities are disrupted by dynamical instabilities seeded by the ambient turbulence. Consideration of the energy power spectra of the simulations reveals that the disruption of the cavities powers an energy cascade consistent with Burgers'-type turbulence and produces a driving scale-length associated with the cavity propagation length. We conclude that fossil cavities interacting either with a turbulent medium or with other cavities have the capacity to sustain or create turbulent flows in star forming environments. In the last section we contrast our work and its conclusions with previous studies which claim that jets can not be the source of turbulence.Comment: 24 pages, submitted to the Astrophysical Journa

Identifying the science and technology dimensions of emerging public policy issues through horizon scanning

Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security.Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security

Terrestrial Mammal Conservation

"Terrestrial Mammal Conservation provides a thorough summary of the available scientific evidence of what is known, or not known, about the effectiveness of all of the conservation actions for wild terrestrial mammals across the world (excluding bats and primates, which are covered in separate synopses). Actions are organized into categories based on the International Union for Conservation of Nature classifications of direct threats and conservation actions. Over the course of fifteen chapters, the authors consider interventions as wide ranging as creating uncultivated margins around fields, prescribed burning, setting hunting quotas and removing non-native mammals. This book is written in an accessible style and is designed to be an invaluable resource for anyone concerned with the practical conservation of terrestrial mammals. The authors consulted an international group of terrestrial mammal experts and conservationists to produce this synopsis. Funding was provided by the MAVA Foundation, Arcadia and National Geographic Big Cats Initiative. Terrestrial Mammal Conservation is the seventeenth publication in the Conservation Evidence Series, linked to the online resource www.ConservationEvidence.com. Conservation Evidence Synopses are designed to promote a more evidence-based approach to biodiversity conservation. Others in the series include Bat Conservation, Primate Conservation, Bird Conservation and Forest Conservation and more are in preparation. Expert assessment of the evidence summarised within synopses is provided online and within the annual publication What Works in Conservation.

Switching the stereochemical outcome of 6-endo-trig cyclizations; Synthesis of 2,6-Cis-6-substituted 4-oxopipecolic acids

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6- substituted-4-oxo-L-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-L-pipecolic acids to the corresponding 4-hydroxy-L-pipecolic acids was also performed

GAMA: towards a physical understanding of galaxy formation

The Galaxy And Mass Assembly (GAMA) project is the latest in a tradition of large galaxy redshift surveys, and is now underway on the 3.9m Anglo-Australian Telescope at Siding Spring Observatory. GAMA is designed to map extragalactic structures on scales of 1kpc - 1Mpc in complete detail to a redshift of z~0.2, and to trace the distribution of luminous galaxies out to z~0.5. The principal science aim is to test the standard hierarchical structure formation paradigm of Cold Dark Matter (CDM) on scales of galaxy groups, pairs, discs, bulges and bars. We will measure (1) the Dark Matter Halo Mass Function (as inferred from galaxy group velocity dispersions); (2) baryonic processes, such as star formation and galaxy formation efficiency (as derived from Galaxy Stellar Mass Functions); and (3) the evolution of galaxy merger rates (via galaxy close pairs and galaxy asymmetries). Additionally, GAMA will form the central part of a new galaxy database, which aims to contain 275,000 galaxies with multi-wavelength coverage from coordinated observations with the latest international ground- and space-based facilities: GALEX, VST, VISTA, WISE, HERSCHEL, GMRT and ASKAP. Together, these data will provide increased depth (over 2 magnitudes), doubled spatial resolution (0.7"), and significantly extended wavelength coverage (UV through Far-IR to radio) over the main SDSS spectroscopic survey for five regions, each of around 50 deg^2. This database will permit detailed investigations of the structural, chemical, and dynamical properties of all galaxy types, across all environments, and over a 5 billion year timeline.Comment: GAMA overview which appeared in the October 2009 issue of Astronomy & Geophysics, ref: Astron.Geophys. 50 (2009) 5.1

Efficient Gene Targeting by Homologous Recombination in Rat Embryonic Stem Cells

The rat is the preferred experimental animal in many biological studies. With the recent derivation of authentic rat embryonic stem (ES) cells it is now feasible to apply state-of-the art genetic engineering in this species using homologous recombination. To establish whether rat ES cells are amenable to in vivo recombination, we tested targeted disruption of the hypoxanthine phosphoribosyltransferase (hprt) locus in ES cells derived from both inbred and outbred strains of rats. Targeting vectors that replace exons 7 and 8 of the hprt gene with neomycinR/thymidine kinase selection cassettes were electroporated into male Fisher F344 and Sprague Dawley rat ES cells. Approximately 2% of the G418 resistant colonies also tolerated selection with 6-thioguanine, indicating inactivation of the hprt gene. PCR and Southern blot analysis confirmed correct site-specific targeting of the hprt locus in these clones. Embryoid body and monolayer differentiation of targeted cell lines established that they retained differentiation potential following targeting and selection. This report demonstrates that gene modification via homologous recombination in rat ES cells is efficient, and should facilitate implementation of targeted, genetic manipulation in the rat

Plasma-photonic spatiotemporal synchronization of relativistic electron and laser beams

Modern particle accelerators and their applications increasingly rely on precisely coordinated interactions of intense charged particle and laser beams. Femtosecond-scale synchronization alongside micrometre-scale spatial precision are essential e.g. for pump-probe experiments, seeding and diagnostics of advanced light sources and for plasma-based accelerators. State-of-the-art temporal or spatial diagnostics typically operate with low-intensity beams to avoid material damage at high intensity. As such, we present a plasma-based approach, which allows measurement of both temporal and spatial overlap of high-intensity beams directly at their interaction point. It exploits amplification of plasma afterglow arising from the passage of an electron beam through a laser-generated plasma filament. The corresponding photon yield carries the spatiotemporal signature of the femtosecond-scale dynamics, yet can be observed as a visible light signal on microsecond-millimetre scales