Strain-dependent and distinctive T-cell responses to HIV antigens following immunisation of mice with differing chimpanzee adenovirus vaccine vectors

In vivo vaccination studies are conventionally conducted in a single mouse strain with results, only reflecting responses to a single immunogenetic background. We decided to examine the immune response to an HIV transgene (gag, pol and nef fusion protein) in 3 strains of mice (CBA, C57BL/6 and BALB/c) to determine the spectrum of responses and in addition to determine whether the serotype of the adenoviral vector used (ChAd3 and ChAd63) impacted the outcome of response. Our results demonstrated that all three strains of mice responded to the transgene and that the magnitude of responses were different between the strains. The C57BL/6 strain showed the lowest range of responses compared to the other strains and, very few responses were seen to the same peptide pool in all three strains of mice. In CBA and BALB/c mice there were significant differences in IFNγ production dependent on the adenoviral vector used. Our results suggest that employing a single strain of mouse may underestimate the efficacy and efficiency of vaccine products

Dopamine modulates dynamic decision-making during foraging

The mesolimbic dopaminergic system exerts a crucial influence on incentive processing. However, the contribution of dopamine in dynamic, ecological situations where reward rates vary, and decisions evolve over time, remains unclear. In such circumstances, current (foreground) reward accrual needs to be compared continuously with potential rewards that could be obtained by travelling elsewhere (background reward rate), in order to determine the opportunity cost of staying versus leaving. We hypothesised that dopamine specifically modulates the influence of background – but not foreground – reward information when making a dynamic comparison of these variables for optimal behaviour. On a novel foraging task based on an ecological account of animal behaviour (marginal value theorem), human participants of either sex decided when to leave locations in situations where foreground rewards depleted at different rates, either in rich or poor environments with high or low background rates. In line with theoretical accounts, people’s decisions to move from current locations were independently modulated by changes in both foreground and background reward rates. Pharmacological manipulation of dopamine D2 receptor activity using the agonist cabergoline significantly affected decisions to move on, specifically modulating the effect of background reward rates. In particular, when on cabergoline, people left patches in poor environments much earlier. These results demonstrate a role of dopamine in signalling the opportunity cost of rewards, not value per se. Using this ecologically derived framework we uncover a specific mechanism by which D2 dopamine receptor activity modulates decision-making when foreground and background reward rates are dynamically compared

A eukaryote assemblage intercalated with Marinoan glacial deposits in South Australia

Video of digital X-ray tomographs (µCT) in longitudinal plane through cylinder of siltstone, maximum diameter seen (left to right when viewing movie) is 5.4m

The climatic significance of Late Ordovician-early Silurian black

The Ordovician-Silurian transition (455-430 Ma) is characterized by repeated climatic perturbations, concomitant with major changes in the global oceanic redox state best exemplified by the periodic deposition of black shales. The relationship between the climatic evolution and the oceanic redox cycles, however, remains largely debated. Here, using an ocean-atmosphere general circulation model accounting for ocean biogeochemistry (MITgcm), we investigate the mechanisms responsible for the burial of organic carbon immediately before, during and right after the latest Ordovician Hirnantian (445-444 Ma) glacial peak. Our results are compared with recent sedimentological and geochemical data. We show that the late Katian time slice (445 Ma), typified by the deposition of black shales at tropical latitudes, represents an unperturbed oceanic state, with regional organic carbon burial driven by the surface primary productivity. During the Hirnantian, our experiments predict a global oxygenation event, in agreement with the disappearance of the black shales in the sedimentary record. This suggests that deep-water burial of organic matter may not be a tenable triggering factor for the positive carbon excursion reported at that time. Our simulations indicate that the perturbation of the ocean circulation induced by the release of freshwater, in the context of the post-Hirnantian deglaciation, does not sustain over sufficiently long geological periods to cause the Rhuddanian (444 Ma) oceanic anoxic event. Input of nutrients to the ocean, through increased continental weathering and the leaching of newly-exposed glaciogenic sediments, may instead constitute the dominant control on the spread of anoxia in the early Silurian

Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles

In preclinical models for Duchenne muscular dystrophy, dystrophin restoration during adeno-associated virus (AAV)-U7-mediated exon-skipping therapy was shown to decrease drastically after six months in treated muscles. This decline in efficacy is strongly correlated with the loss of the therapeutic AAV genomes, probably due to alterations of the dystrophic myofiber membranes. To improve the membrane integrity of the dystrophic myofibers at the time of AAV-U7 injection, mdx muscles were pre-treated with a single dose of the peptide-phosphorodiamidate morpholino (PPMO) antisense oligonucleotides that induced temporary dystrophin expression at the sarcolemma. The PPMO pre-treatment allowed efficient maintenance of AAV genomes in mdx muscles and enhanced the AAV-U7 therapy effect with a ten-fold increase of the protein level after 6 months. PPMO pre-treatment was also beneficial to AAV-mediated gene therapy with transfer of micro-dystrophin cDNA into muscles. Therefore, avoiding vector genome loss after AAV injection by PPMO pre-treatment would allow efficient long-term restoration of dystrophin and the use of lower and thus safer vector doses for Duchenne patients

Social-ecological connections across land, water, and sea demand a reprioritization of environmental management

Despite many sectors of society striving for sustainability in environmental management, humans often fail to identify and act on the connections and processes responsible for social-ecological tipping points. Part of the problem is the fracturing of environmental management and social-ecological research into ecosystem domains (land, freshwater, and sea), each with different scales and resolution of data acquisition and distinct management approaches. We present a perspective on the social-ecological connections across ecosystem domains that emphasize the need for management reprioritization to effectively connect these domains. We identify critical nexus points related to the drivers of tipping points, scales of governance, and the spatial and temporal dimensions of social-ecological processes. We combine real-world examples and a simple dynamic model to illustrate the implications of slow management responses to environmental impacts that traverse ecosystem domains. We end with guidance on management and research opportunities that arise from this cross-domain lens to foster greater opportunity to achieve environmental and sustainability goals.Peer reviewe

A clinical and cost effectiveness trial of a parent group intervention to manage challenging restricted and repetitive behaviours in young children with autism spectrum disorder: study protocol for a randomized controlled trial

Background Restricted and repetitive behaviours vary greatly across the autism spectrum, and although not all are problematic some can cause distress and interfere with learning and social opportunities. We have, alongside parents, developed a parent group based intervention for families of young children with autism, which aims to offer support to parents and carers; helping them to recognise, understand and learn how to respond to their child’s challenging restricted repetitive behaviours. Methods The study is a clinical and cost-effectiveness, multi-site randomised controlled trial of the Managing Repetitive Behaviours (MRB) parent group intervention versus a psychoeducation parent group Learning About Autism (LAA) (n = 250; 125 intervention/125 psychoeducation; ~ 83/site) for parents of young children aged 3–9 years 11 months with a diagnosis of autism. All analyses will be done under intention-to-treat principle. The primary outcome at 24 weeks will use generalised estimating equation (GEE) to compare proportion of children with improved RRB between the MRB group and the LAA group. The GEE model will account for the clustering of children by parent groups using exchangeable working correlation. All secondary outcomes will be analysed in a similar way using appropriate distribution and link function. The economic evaluation will be conducted from the perspective of both NHS costs and family access to local community services. A ‘within trial’ cost-effectiveness analysis with results reported as the incremental cost per additional child achieving at least the target improvement in CGI-I scale at 24 weeks. Discussion This is an efficacy trial to investigate the clinical and cost-effectiveness of a parent group based intervention designed to help parents understand and manage their child’s challenging RRB. If found to be effective, this intervention has the potential to improve the well-being of children and their families, reduce parental stress, greatly enhance community participation and potential for learning, and improve longer-term outcomes. Trial registration Trial ID: ISRCTN15550611 Date registered: 07/08/2018. Sponsor and Monitor: Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust R&D Manager Lyndsey Dixon, Address: St Nicholas Hospital, Jubliee Road, Gosforth, Newcastle upon Tyne NE3 3XT, [email protected], Tel: 0191 246 722

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

Orbitally forced ice sheet fluctuations during the Marinoan Snowball Earth glaciation

Two global glaciations occurred during the Neoproterozoic. Snowball Earth theory posits that these were terminated after millions of years of frigidity when initial warming from rising atmospheric CO2 concentrations was amplified by the reduction of ice cover and hence a reduction in planetary albedo. This scenario implies that most of the geological record of ice cover was deposited in a brief period of melt-back. However, deposits in low palaeo-latitudes show evidence of glacial–interglacial cycles. Here we analyse the sedimentology and oxygen and sulphur isotopic signatures of Marinoan Snowball glaciation deposits from Svalbard, in the Norwegian High Arctic. The deposits preserve a record of oscillations in glacier extent and hydrologic conditions under uniformly high atmospheric CO2 concentrations. We use simulations from a coupled three-dimensional ice sheet and atmospheric general circulation model to show that such oscillations can be explained by orbital forcing in the late stages of a Snowball glaciation. The simulations suggest that while atmospheric CO2 concentrations were rising, but not yet at the threshold required for complete melt-back, the ice sheets would have been sensitive to orbital forcing. We conclude that a similar dynamic can potentially explain the complex successions observed at other localities