SIRT1 Activity Is Linked to Its Brain Region-Specific Phosphorylation and Is Impaired in Huntington’s Disease Mice

Huntingtons disease (HD) is a neurodegenerative disorder for which there are no disease-modifying treatments. SIRT1 is a NAD+-dependent protein deacetylase that is implicated in maintaining neuronal health during development, differentiation and ageing. Previous studies suggested that the modulation of SIRT1 activity is neuroprotective in HD mouse models, however, the mechanisms controlling SIRT1 activity are unknown. We have identified a striatum-specific phosphorylation-dependent regulatory mechanism of SIRT1 induction under normal physiological conditions, which is impaired in HD. We demonstrate that SIRT1 activity is down-regulated in the brains of two complementary HD mouse models, which correlated with altered SIRT1 phosphorylation levels. This SIRT1 impairment could not be rescued by the ablation of DBC1, a negative regulator of SIRT1, but was linked to changes in the sub-cellular distribution of AMPK-α1, a positive regulator of SIRT1 function. This work provides insights into the regulation of SIRT1 activity with the potential for the development of novel therapeutic strategies

Acoustic transmission through compound subwavelength slit arrays

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.The angular dependence of the transmission of sound in air through four types of 2D slit-arrays formed of aluminium slats is explored, both experimentally and numerically. For a simple, subwavelength periodic slit-array, it is well known that Fabry-Perot-like wave-guide resonances, supported by the slit-cavities, hybridising with bound acoustic surface waves, result in ‘Enhanced Acoustic Transmission’ at frequencies determined by the length, width and separation of each slit-cavity. We demonstrate that altering the spacing or width of some of the slits to form a compound array (i.e. an array having a basis comprised of more than one slit) results in sharp dips in the transmission spectra, that may have a strong angular dependence. These features correspond to ‘phase resonances’, which have been studied extensively in the electromagnetic case. This geometry allows for additional near-field configurations compared to the simple array, whereby the field in adjacent cavities can be out-of-phase. Several types of compound slit-array are investigated; one such structure is optimised to minimise the effect of boundary-layer loss mechanisms present in each slit cavity, thereby achieving a deep, sharp transmission minimum in a broad maximumThe authors would like to thank the UK Ministry of Defence’s Defence Science and Technology Laboratorty (DSTL) for their financial support and permission to publis

Stable isotope evidence for crustal recycling as recorded by superdeep diamonds

© 2015 Elsevier B.V. Sub-lithospheric diamonds from the Juina-5 and Collier-4 kimberlites and the Machado River alluvial deposit in Brazil have carbon isotopic compositions that co-vary with the oxygen isotopic compositions of their inclusions, which implies that they formed by a mixing process. The proposed model for this mixing process, based on interaction of slab-derived carbonate melt with reduced (carbide- or metal-bearing) ambient mantle, explains these isotopic observations. It is also consistent with the observed trace element chemistries of diamond inclusions from these localities and with the experimental phase relations of carbonated subducted crust. The 18O-enriched nature of the inclusions demonstrates that they incorporate material from crustal protoliths that previously interacted with seawater, thus confirming the subduction-related origin of superdeep diamonds. These samples also provide direct evidence of an isotopically anomalous reservoir in the deep (≥350 km) mantle

Reaching peak emissions

Rapid growth in global CO2 emissions from fossil fuels and industry ceased in the past two years, despite continued economic growth. Decreased coal use in China was largely responsible, coupled with slower global growth in petroleum and faster growth in renewables

Gene expression and matrix turnover in overused and damaged tendons

Chronic, painful conditions affecting tendons, frequently known as tendinopathy, are very common types of sporting injury. The tendon extracellular matrix is substantially altered in tendinopathy, and these changes are thought to precede and underlie the clinical condition. The tendon cell response to repeated minor injuries or “overuse” is thought to be a major factor in the development of tendinopathy. Changes in matrix turnover may also be effected by the cellular response to physical load, altering the balance of matrix turnover and changing the structure and composition of the tendon. Matrix turnover is relatively high in tendons exposed to high mechanical demands, such as the supraspinatus and Achilles, and this is thought to represent either a repair or tissue maintenance function. Metalloproteinases are a large family of enzymes capable of degrading all of the tendon matrix components, and these are thought to play a major role in the degradation of matrix during development, adaptation and repair. It is proposed that some metalloproteinase enzymes are required for the health of the tendon, and others may be damaging, leading to degeneration of the tissue. Further research is required to investigate how these enzyme activities are regulated in tendon and altered in tendinopathy. A profile of all the metalloproteinases expressed and active in healthy and degenerate tendon is required and may lead to the development of new drug therapies for these common and debilitating sports injuries

Acidification effects on biofouling communities: winners and losers

How ocean acidification affects marine life is a major concern for science and society. However, its impacts on encrusting biofouling communities, that are both the initial colonizers of hard substrata and of great economic importance, are almost unknown. We showed that community composition changed significantly, from 92% spirorbids, 3% ascidians and 4% sponges initially to 47% spirorbids, 23% ascidians and 29% sponges after 100days in acidified conditions (pH 7.7). In low pH, numbers of the spirorbid Neodexiospira pseudocorrugata were reduced x5 compared to controls. The two ascidians present behaved differently with Aplidium sp. decreasing x10 in pH 7.7, whereas Molgula sp. numbers were x4 higher in low pH than controls. Calcareous sponge (Leucosolenia sp.) numbers increased x2.5 in pH 7.7 over controls. The diatom and filamentous algal community was also more poorly developed in the low pH treatments compared to controls. Colonization of new surfaces likewise showed large decreases in spirorbid numbers, but numbers of sponges and Molgula sp. increased. Spirorbid losses appeared due to both recruitment failure and loss of existing tubes. Spirorbid tubes are comprised of a loose prismatic fabric of calcite crystals. Loss of tube materials appeared due to changes in the binding matrix and not crystal dissolution, as SEM analyses showed crystal surfaces were not pitted or dissolved in low pH conditions. Biofouling communities face dramatic future changes with reductions in groups with hard exposed exoskeletons and domination by soft-bodied ascidians and sponges.EU [227799, 00415/2010]; Natural Environment Research Council [bas0100036, bas0100025

Boundary-layer effects on acoustic transmission through narrow slit cavities

PublishedJournal ArticleWe explore the slit-width dependence of the resonant transmission of sound in air through both a slit array formed of aluminum slats and a single open-ended slit cavity in an aluminum plate. Our experimental results accord well with Lord Rayleigh's theory concerning how thin viscous and thermal boundary layers at a slit's walls affect the acoustic wave across the whole slit cavity. By measuring accurately the frequencies of the Fabry-Perot-like cavity resonances, we find a significant 5% reduction in the effective speed of sound through the slits when an individual viscous boundary layer occupies only 5% of the total slit width. Importantly, this effect is true for any airborne slit cavity, with the reduction being achieved despite the slit width being on a far larger scale than an individual boundary layer's thickness. This work demonstrates that the recent prevalent loss-free treatment of narrow slit cavities within acoustic metamaterials is unrealistic.The authors would like to thank DSTL for their financial support

Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4<sup>+</sup> T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system <i>in</i> <i>vivo</i>. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation

The Herschel Exploitation of Local Galaxy Andromeda (HELGA) II: Dust and Gas in Andromeda

We present an analysis of the dust and gas in Andromeda, using Herschel images sampling the entire far-infrared peak. We fit a modified-blackbody model to ~4000 quasi-independent pixels with spatial resolution of ~140pc and find that a variable dust-emissivity index (beta) is required to fit the data. We find no significant long-wavelength excess above this model suggesting there is no cold dust component. We show that the gas-to-dust ratio varies radially, increasing from ~20 in the center to ~70 in the star-forming ring at 10kpc, consistent with the metallicity gradient. In the 10kpc ring the average beta is ~1.9, in good agreement with values determined for the Milky Way (MW). However, in contrast to the MW, we find significant radial variations in beta, which increases from 1.9 at 10kpc to ~2.5 at a radius of 3.1kpc and then decreases to 1.7 in the center. The dust temperature is fairly constant in the 10kpc ring (ranging from 17-20K), but increases strongly in the bulge to ~30K. Within 3.1kpc we find the dust temperature is highly correlated with the 3.6 micron flux, suggesting the general stellar population in the bulge is the dominant source of dust heating there. At larger radii, there is a weak correlation between the star formation rate and dust temperature. We find no evidence for 'dark gas' in M31 in contrast to recent results for the MW. Finally, we obtained an estimate of the CO X-factor by minimising the dispersion in the gas-to-dust ratio, obtaining a value of (1.9+/-0.4)x10^20 cm^-2 [K kms^-1]^-1.Comment: 19 pages, 18 figures. Submitted to ApJ April 2012; Accepted July 201