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

Hepatic transcriptomic profiles from barramundi, Lates calcarifer, as a means of assessing organism health and identifying stressors in rivers in northern Queensland

Resource managers need to differentiate between sites with and without contaminants and those where contaminants cause impacts. Potentially, transcriptomes could be used to evaluate sites where contaminant-induced effects may occur, to identify causative stressors of effects and potential adverse outcomes. To test this hypothesis, the hepatic transcriptomes in Barramundi, a perciforme teleost fish, (Lates calcarifer) from two reference sites, two agriculturally impacted sites sampled during the dry season, and an impacted site sampled during the wet season were compared. The hepatic transcriptome was profiled using RNA-Seq. Multivariate analysis showed that transcriptomes were clustered based on site and by inference water quality, but not sampling time. The largest differences in transcriptomic profile were between reference sites and a site sampled during high run-off, showing that impacted sites can be identified via RNA-Seq. Transcripts with altered abundance were linked to xenobiotic metabolism, peroxisome proliferation and stress responses, indicating putative stressors with the potential for adverse outcomes in barramundi

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

Combined strong and weak lensing analysis of 28 clusters from the Sloan Giant Arcs Survey

We study the mass distribution of a sample of 28 galaxy clusters using strong and weak lensing observations. The clusters are selected via their strong lensing properties as part of the Sloan Giant Arcs Survey (SGAS) from the Sloan Digital Sky Survey (SDSS). Mass modelling of the strong lensing information from the giant arcs is combined with weak lensing measurements from deep Subaru/Suprime-cam images to primarily obtain robust constraints on the concentration parameter and the shape of the mass distribution. We find that the concentration c_vir is a steep function of the mass, c_vir \propto M_vir^-0.59\pm0.12, with the value roughly consistent with the lensing-bias-corrected theoretical expectation for high mass (10^15 h^-1 M_sun) clusters. However, the observationally inferred concentration parameters appear to be much higher at lower masses (10^14 h^-1 M_sun), possibly a consequence of the modification to the inner density profiles provided by baryon cooling. The steep mass-concentration relation is also supported from direct stacking analysis of the tangential shear profiles. In addition, we explore the two-dimensional shape of the projected mass distribution by stacking weak lensing shear maps of individual clusters with prior information on the position angle from strong lens modelling, and find significant evidence for a large mean ellipticity with the best-fit value of e = 0.47 \pm 0.06 for the mass distribution of the stacked sample. We find that the luminous cluster member galaxy distribution traces the overall mass distribution very well, although the distribution of fainter cluster galaxies appears to be more extended than the total mass.Comment: 29 pages, 15+9 figures, 7 tables, accepted for publication in MNRA

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

The impact of the initial COVID-19 outbreak on young adults’ mental health: a longitudinal study of risk and resilience factors

Few studies assessing the effects of COVID-19 on mental health include prospective markers of risk and resilience necessary to understand and mitigate the combined impacts of the pandemic, lockdowns, and other societal responses. This population-based study of young adults includes individuals from the Neuroscience in Psychiatry Network (n = 2403) recruited from English primary care services and schools in 2012–2013 when aged 14–24. Participants were followed up three times thereafter, most recently during the initial outbreak of the COVID-19 outbreak when they were aged between 19 and 34. Repeated measures of psychological distress (K6) and mental wellbeing (SWEMWBS) were supplemented at the latest assessment by clinical measures of depression (PHQ-9) and anxiety (GAD-7). A total of 1000 participants, 42% of the original cohort, returned to take part in the COVID-19 follow-up; 737 completed all four assessments [mean age (SD), 25.6 (3.2) years; 65.4% female; 79.1% White]. Our findings show that the pandemic led to pronounced deviations from existing mental health-related trajectories compared to expected levels over approximately seven years. About three-in-ten young adults reported clinically significant depression (28.8%) or anxiety (27.6%) under current NHS guidelines; two-in-ten met clinical cut-offs for both. About 9% reported levels of psychological distress likely to be associated with serious functional impairments that substantially interfere with major life activities; an increase by 3% compared to pre-pandemic levels. Deviations from personal trajectories were not necessarily restricted to conventional risk factors; however, individuals with pre-existing health conditions suffered disproportionately during the initial outbreak of the COVID-19 pandemic. Resilience factors known to support mental health, particularly in response to adverse events, were at best mildly protective of individual psychological responses to the pandemic. Our findings underline the importance of monitoring the long-term effects of the ongoing pandemic on young adults’ mental health, an age group at particular risk for the emergence of psychopathologies. Our findings further suggest that maintaining access to mental health care services during future waves, or potential new pandemics, is particularly crucial for those with pre-existing health conditions. Even though resilience factors known to support mental health were only mildly protective during the initial outbreak of the COVID-19 pandemic, it remains to be seen whether these factors facilitate mental health in the long term

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