Solvent exposure of Tyr10 as a probe of structural differences between monomeric and aggregated forms of the amyloid-β peptide.

Aggregation of amyloid-β (Aβ) peptides is a characteristic pathological feature of Alzheimer's disease. We have exploited the relationship between solvent exposure and intrinsic fluorescence of a single tyrosine residue, Tyr10, in the Aβ sequence to probe structural features of the monomeric, oligomeric and fibrillar forms of the 42-residue Aβ1-42. By monitoring the quenching of Tyr10 fluorescence upon addition of water-soluble acrylamide, we show that in Aβ1-42 oligomers this residue is solvent-exposed to a similar extent to that found in the unfolded monomer. By contrast, Tyr10 is significantly shielded from acrylamide quenching in Aβ1-42 fibrils, consistent with its proximity to the fibrillar cross-β core. Furthermore, circular dichroism measurements reveal that Aβ1-42 oligomers have a considerably lower β-sheet content than the Aβ1-42 fibrils, indicative of a less ordered molecular arrangement in the former. Taken together these findings suggest significant differences in the structural assembly of oligomers and fibrils that are consistent with differences in their biological effects.This work was funded by grants to E.K.E from the Wenner-Gren Foundations, the Hasselblad Foundation, and the Swedish Innovation Agency (Vinnova) and to C.M.D from the Wellcome Trust. The TEM imaging was carried out in the Multi-Imaging Unit in the Department of Physiology, Development and Neuroscience, University of Cambridge, UK and quantitative amino acid analysis was carried out at the Protein and Nucleic Acid Chemistry Facility, Department of Biochemistry, University of Cambridge, UK.This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.bbrc.2015.11.01

Clustering of supernova Ia host galaxies

For the first time the cross-correlation between type Ia supernova host galaxies and surrounding field galaxies is measured using the Supernova Legacy Survey sample. Over the z=0.2 to 0.9 redshift range we find that supernova hosts are correlated an average of 60% more strongly than similarly selected field galaxies over the 3-100 arcsec range and about a factor of 3 more strongly below 10 arcsec. The correlation errors are empirically established with a jackknife analysis of the four SNLS fields. The hosts are more correlated than the field at a significance of 99% in the fitted amplitude and slope, with the point-by-point difference of the two correlation functions having a reduced $\chi^2$ for 8 degrees of freedom of 4.3, which has a probability of random occurrence of less than 3x10^{-5}. The correlation angle is 1.5+/-0.5 arcsec, which deprojects to a fixed co-moving correlation length of approximately 6.5+/- 2/h mpc. Weighting the field galaxies with the mass and star formation rate supernova frequencies of the simple A+B model produces good agreement with the observed clustering. We conclude that these supernova clustering differences are primarily the expected outcome of the dependence of supernova rates on galaxy masses and stellar populations with their clustering environment.Comment: ApJ (Letts) accepte

Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity

AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energy homeostasis which achieves this through the phosphorylation of a myriad of downstream targets. One target is TBC1D1 a Rab-GTPase-activating protein that regulates glucose uptake in muscle cells by integrating insulin signalling with that promoted by muscle contraction. Ser237 in TBC1D1 is a target for phosphorylation by AMPK, an event which may be important in regulating glucose uptake. Here, we show AMPK heterotrimers containing the α1, but not the α2, isoform of the catalytic subunit form an unusual and stable association with TBC1D1, but not its paralogue AS160. The interaction between the two proteins is direct, involves a dual interaction mechanism employing both phosphotyrosinebinding (PTB) domains of TBC1D1 and is increased by two different pharmacological activators of AMPK (AICAR and A769962). The interaction enhances the efficiency by which AMPK phosphorylates TBC1D1 on its key regulatory site, Ser237. Furthermore, the interaction is reduced by a naturally occurring R125W mutation in the PTB1 domain of TBC1D1, previously found to be associated with severe familial obesity in females, with a concomitant reduction in Ser237 phosphorylation. Our observations provide evidence for a functional difference between AMPK α-subunits and extend the repertoire of protein kinases that interact with substrates via stabilisation mechanisms that modify the efficacy of substrate phosphorylation

How Abnormal Is the Behaviour of Captive, Zoo-Living Chimpanzees?

Background. Many captive chimpanzees (Pan troglodytes) show a variety of serious behavioural abnormalities, some of which have been considered as possible signs of compromised mental health. The provision of environmental enrichments aimed at reducing the performance of abnormal behaviours is increasing the norm, with the housing of individuals in (semi-)natural social groups thought to be the most successful of these. Only a few quantitative studies of abnormal behaviour have been conducted, however, particularly for the captive population held in zoological collections. Consequently, a clear picture of the level of abnormal behaviour in zoo-living chimpanzees is lacking. Methods. We present preliminary findings from a detailed observational study of the behaviour of 40 socially-housed zoo-living chimpanzees from six collections in the United States of America and the United Kingdom. We determined the prevalence, diversity, frequency, and duration of abnormal behaviour from 1200 hours of continuous behavioural data collected by focal animal sampling. Results, conclusion, and significance. Our overall finding was that abnormal behaviour was present in all sampled individuals across six independent groups of zoo-living chimpanzees, despite the differences between these groups in size, composition, housing, etc. We found substantial variation between individuals in the frequency and duration of abnormal behaviour, but all individuals engaged in at least some abnormal behaviour and variation across individuals could not be explained by sex, age, rearing history or background (defined as prior housing conditions). Our data support a conclusion that, while most behaviour of zoo-living chimpanzees is ‘normal’ in that it is typical of their wild counterparts, abnormal behaviour is endemic in this population despite enrichment efforts. We suggest there is an urgent need to understand how the chimpanzee mind copes with captivity, an issue with both scientific and welfare implications

The interplay of protein aggregates, microglia and neuroinflammation in neurodegenerative disease

Neurodegenerative diseases such as Alzheimer\u27s disease, Parkinson\u27s disease and amyotrophic lateral sclerosis are characterized by the deposition of insoluble protein aggregates. In addition, neuro-inflammatory processes, in particular microglial activation, are key pathological features of these disorders. While microglial activation is a necessary and neuroprotective response to tissue damage, it has been proposed that chronic neuroinflammation is detrimental to neurons and may contribute to the progression of disease. One potential mechanism by which microglia may be continuously activated is through contact with protein aggregates. Protein aggregates, such as amyloid fibrils, are protease-resistant and possess repetitive structures that may be immunologically mistaken for patterns found in bacterial cell walls. In this review, we will explore the downstream consequences of the interaction of protein aggregates with microglia, and how this has potential to shape the inflammatory landscape

Next generation sequence analysis of the transcriptome of Sydney rock oysters (Saccostrea glomerata) exposed to a range of environmental stressors

Sydney rock oysters (Saccostrea glomerata) were exposed to environmental stressors at contaminated field sites or in a controlled laboratory setting. RNA seq transcriptome data were generated for the gill and digestive gland using Roche's 454 pyrosequencing technology. 28,685 contigs were de novo assembled which encoded 11,671 different protein products. The data will act as a reference for future studies in ecology, immunology and environmental toxicology.3 page(s

Design of orthogonal genetic switches based on a crosstalk map of σs, anti-σs, and promoters

Cells react to their environment through gene regulatory networks. Network integrity requires minimization of undesired crosstalk between their biomolecules. Similar constraints also limit the use of regulators when building synthetic circuits for engineering applications. Here, we mapped the promoter specificities of extracytoplasmic function (ECF) σs as well as the specificity of their interaction with anti‐σs. DNA synthesis was used to build 86 ECF σs (two from every subgroup), their promoters, and 62 anti‐σs identified from the genomes of diverse bacteria. A subset of 20 σs and promoters were found to be highly orthogonal to each other. This set can be increased by combining the −35 and −10 binding domains from different subgroups to build chimeras that target sequences unrepresented in any subgroup. The orthogonal σs, anti‐σs, and promoters were used to build synthetic genetic switches in Escherichia coli. This represents a genome‐scale resource of the properties of ECF σs and a resource for synthetic biology, where this set of well‐characterized regulatory parts will enable the construction of sophisticated gene expression programs.Life Technologies, Inc.United States. Defense Advanced Research Projects Agency (Chronicle of Lineage Indicative of Origins N66001-12-C-4018)United States. Office of Naval Research (N00014-10-1-0245)National Institutes of Health (U.S.) (NIH AI067699)National Science Foundation (U.S.). Synthetic Biology Engineering Research Center (SA5284-11210)American Society for Engineering Education. National Defense Science and Engineering Graduate FellowshipHertz Foundation (Fellowship