Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants

Coordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2−/− lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis

Reflection and the art of coaching: fostering high-performance in olympic ski cross

In preparation for the 2010 Vancouver Winter Olympic Games, the lead author engaged in systematic reflection in an attempt to implement coaching behaviours and create practice environments that promoted athlete development (psycho-social and physical performance). The research was carried out in relation to his work as head Ski Cross coach working with (primarily) three athletes in their quest for Olympic qualification and subsequent performance success in the Olympic Games. This project sought to examine coach-athlete interactions. Of particular interest were coach and athlete responses regarding the implementation of autonomy supportive coaching behaviours in a high context. Autonomy supportive coaching behaviours have previously been strongly associated with positive athlete psycho-social and performance outcomes, however, a paucity of research has examined its implementation in high-performance contexts. Through the use of participant ethnography, it was possible to gain considerable insights regarding athletes' perceptions of choice, implications of perceived athletic hierarchies, as well as cultural and experience-related influences on training and performance expectations

Global trends in biodiversity and ecosystem services from 1900 to 2050

Despite the scientific consensus on the extinction crisis and its anthropogenic origin, the quantification of historical trends and of future scenarios of biodiversity and ecosystem services has been limited, due to the lack of inter-model comparisons and harmonized scenarios. Here, we present a multi-model analysis to assess the impacts of land-use and climate change from 1900 to 2050. During the 20th century provisioning services increased, but biodiversity and regulating services decreased. Similar trade-offs are projected for the coming decades, but they may be attenuated in a sustainability scenario. Future biodiversity loss from land-use change is projected to keep up with historical rates or reduce slightly, whereas losses due to climate change are projected to increase greatly. Renewed efforts are needed by governments to meet the 2050 vision of the Convention on Biological Diversity

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Bending the curve of terrestrial biodiversity needs an integrated strategy

Increased efforts are required to prevent further losses to terrestrial biodiversity and the ecosystem services that it provides1,2. Ambitious targets have been proposed, such as reversing the declining trends in biodiversity3; however, just feeding the growing human population will make this a challenge4. Here we use an ensemble of land-use and biodiversity models to assess whether—and how—humanity can reverse the declines in terrestrial biodiversity caused by habitat conversion, which is a major threat to biodiversity5. We show that immediate efforts, consistent with the broader sustainability agenda but of unprecedented ambition and coordination, could enable the provision of food for the growing human population while reversing the global terrestrial biodiversity trends caused by habitat conversion. If we decide to increase the extent of land under conservation management, restore degraded land and generalize landscape-level conservation planning, biodiversity trends from habitat conversion could become positive by the mid-twenty-first century on average across models (confidence interval, 2042–2061), but this was not the case for all models. Food prices could increase and, on average across models, almost half (confidence interval, 34–50%) of the future biodiversity losses could not be avoided. However, additionally tackling the drivers of land-use change could avoid conflict with affordable food provision and reduces the environmental effects of the food-provision system. Through further sustainable intensification and trade, reduced food waste and more plant-based human diets, more than two thirds of future biodiversity losses are avoided and the biodiversity trends from habitat conversion are reversed by 2050 for almost all of the models. Although limiting further loss will remain challenging in several biodiversity-rich regions, and other threats—such as climate change—must be addressed to truly reverse the declines in biodiversity, our results show that ambitious conservation efforts and food system transformation are central to an effective post-2020 biodiversity strategy

Options for the sustainable management of discrete seal populations as part of a site-based conservation strategy

SIGLEAvailable from British Library Document Supply Centre-DSC:8313.905(45) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Getting beneath the surface of marine mammal – fisheries competition

<p>1: In systems where marine mammals are perceived to compete with fisheries, the priorities of conservationists and wildlife managers can come into conflict. Resolution of these conflicts requires quantitative information on the intensity of competition, i.e. the expected reduction in resource acquisition by one competitor as a result of a given increase in resource acquisition by the other.</p> <p>2: The intensity of competition will depend on the extent to which marine mammals and fisheries overlap in space and time with their shared resource, and the way in which individual competitors' preferences for particular prey or target species vary in response to variations in the population composition of these prey and the abundance of other components of the system.</p> <p>3: We use two examples of marine mammals, Steller sea lions Eumetopias jubatus in Alaska and grey seals Halichoerus grypus in the UK, to illustrate these points and to challenge some intuitive notions about the nature of marine mammal–fisheries interactions.</p> <p>4: We conclude that the four main sources of ecological complexity (spatial heterogeneity, individual variation, multi-species interactions and long-term dynamics) can have a substantial effect on scientific predictions of the likely outcome of different management actions.</p> <p>5: We argue that a pragmatic approach, which considers the effect of ecological complexity while avoiding the indiscriminate addition of detail to mathematical models of competition, is the best way to provide scientific advice on issues that require urgent action.</p&gt

Synaptic protein DLG2 controls neurogenic transcriptional programs disrupted in schizophrenia and related disorders

Genetic studies robustly implicate perturbation of DLG2-scaffolded mature postsynaptic signalling complexes in schizophrenia. Here we study in vitro cortical differentiation of DLG2-/- human embryonic stem cells via integrated phenotypic, gene expression and disease genetic analyses. This uncovers a developmental role for DLG2 in the regulation of neural stem cell proliferation and adhesion, and the activation of transcriptional programs during early excitatory corticoneurogenesis. Down-regulation of these programs in DLG2-/- lines delays expression of cell-type identity and causes marked deficits in neuronal migration, morphology and active properties. Genetic risk factors for neuropsychiatric and neurodevelopmental disorders converge on these neurogenic programs, each disorder displaying a distinct pattern of enrichment. These data unveil an intimate link between neurodevelopmental and mature signalling deficits contributing to disease - suggesting a dual role for known synaptic risk genes - and reveal a common pathophysiological framework for studying the neurodevelopmental origins of Mendelian and genetically complex mental disorders

Oxidation contributes to low glutathione in the airways of children with cystic fibrosis

Glutathione is an important antioxidant in the lungs but its concentration is low in the airways of patients with cystic fibrosis. Whether this deficit occurs from an early age or how oxidative stress contributes to lowering glutathione is unknown. We measured glutathione, its oxidation products, myeloperoxidase, and biomarkers of hypochlorous acid in bronchoalveolar lavage from children with cystic fibrosis and disease controls using mass spectrometry and immunological techniques. The concentration of glutathione was lower in bronchoalveolar lavage from children with cystic fibrosis, whereas glutathione sulfonamide, a specific oxidation product of hypochlorous acid, was higher. Oxidised glutathione and glutathione sulfonamide correlated with myeloperoxidase and a biomarker of hypochlorous acid. The percentage of glutathione attached to proteins was higher in children with cystic fibrosis than controls. Pulmonary infections in cystic fibrosis resulted in lower levels of glutathione but higher levels of oxidised glutathione and glutathione sulfonamide in bronchoalveolar lavage. The concentration of glutathione is low in the airways of patients with cystic fibrosis from an early age. Increased oxidation of glutathione by hypochlorous acid and its attachment to proteins contribute to this deficiency. Therapies targeted against myeloperoxidase may boost antioxidant defence and slow the onset and progression of lung disease in cystic fibrosis