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Sökning: WFRF:(Graham Hilary)

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1.
  • Klionsky, Daniel J., et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • Ingår i: Autophagy. - : Landes Bioscience. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • Forskningsöversikt (refereegranskat)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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2.
  • Jiang, X., et al. (författare)
  • Shared heritability and functional enrichment across six solid cancers
  • 2019
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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3.
  • Power, Chris, et al. (författare)
  • The contribution of childhood and adult socioeconomic position to adult obesity and smoking behaviour : an international comparison
  • 2005
  • Ingår i: International Journal of Epidemiology. - 0300-5771 .- 1464-3685. ; 34:2, s. 335-344
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND:Our objective was to investigate the contribution of childhood and adult socioeconomic position (SEP) to adult obesity and smoking behaviour, in particular to establish the role of childhood circumstances across different studies in Europe and the US.METHODS:Seven population-based surveys in six Western countries (Britain, Denmark, Finland, Netherlands, Sweden, US) were examined, with participants aged 30-50 yr and born between 1910 and 1960. Adult smoking was analysed using three outcomes (ever, current, or ex-) and adult obesity was defined as body mass index (kg/m(2)) > or =30.RESULTS:A strong effect of adult social position was observed for smoking outcomes and obesity. For example, manual SEP in adulthood increased the risk of ever smoking (adjusted odds ratio (OR) 1.47-2.00 for men; 0.94-1.81 for women), and obesity (adjusted OR 1.06-2.24 for men, 1.21-3.26 for women). In most studies, childhood position was not associated with ever-smoking. For current smoking, manual childhood position was associated among women (adjusted OR 1.09-1.54), but no consistent pattern was seen for men. For ex-smoking, manual childhood origins lowered the chance of quitting among women (adjusted OR 0.64-0.81) except in the US (OR = 1.17); among men this association was seen in fewer studies (adjusted OR 0.74-1.09). For obesity, manual origins increased the risk for women (adjusted OR 0.96-2.50); effects were weaker among men but mostly in the same direction (adjusted OR 0.79-1.42).CONCLUSIONS:As expected, adult SEP was an important influence on smoking behaviour and obesity. In addition, factors related to disadvantaged social origins appeared to increase the risk of obesity and reduce the probability of quitting smoking in adulthood, particularly in women.
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4.
  • Anney, Richard, et al. (författare)
  • Individual common variants exert weak effects on the risk for autism spectrum disorders.
  • 2012
  • Ingår i: Human Molecular Genetics. - 0964-6906. ; 21:21, s. 4781-92
  • Tidskriftsartikel (refereegranskat)abstract
    • While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASD), the contribution of common variation to ASD risk is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating association of individual SNPs, we also sought evidence that common variants, en masse, might affect risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest p-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. By contrast, allele-scores derived from the transmission of common alleles to Stage 1 cases significantly predict case-status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele-score results, it is reasonable to conclude that common variants affect ASD risk but their individual effects are modest.
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5.
  • Bird, Philippa K, et al. (författare)
  • Income inequality and social gradients in children's height : a comparison of cohort studies from five high-income countries.
  • 2019
  • Ingår i: BMJ paediatrics open. - 2399-9772. ; 3:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Health and well-being are better, on average, in countries that are more equal, but less is known about how this benefit is distributed across society. Height is a widely used, objective indicator of child health and predictor of lifelong well-being. We compared the level and slope of social gradients in children's height in high-income countries with different levels of income inequality, in order to investigate whether children growing up in all socioeconomic circumstances are healthier in more equal countries.Methods: We conducted a coordinated analysis of data from five cohort studies from countries selected to represent different levels of income inequality (the USA, UK, Australia, the Netherlands and Sweden). We used standardised methods to compare social gradients in children's height at age 4-6 years, by parent education status and household income. We used linear regression models and predicted height for children with the same age, sex and socioeconomic circumstances in each cohort.Results: The total analytic sample was 37 063 children aged 4-6 years. Gradients by parent education and household income varied between cohorts and outcomes. After adjusting for differences in age and sex, children in more equal countries (Sweden, the Netherlands) were taller at all levels of parent education and household income than children in less equal countries (USA, UK and Australia), with the greatest between-country differences among children with less educated parents and lowest household incomes.Conclusions: The study provides preliminary evidence that children across society do better in more equal countries, with greatest benefit among children from the most disadvantaged socioeconomic groups.
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6.
  • Fazey, Ioan, et al. (författare)
  • Transforming knowledge systems for life on Earth: Visions of future systems and how to get there
  • 2020
  • Ingår i: Energy Research and Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 70
  • Tidskriftsartikel (refereegranskat)abstract
    • Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.
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7.
  • Michailidou, Kyriaki, et al. (författare)
  • Association analysis identifies 65 new breast cancer risk loci.
  • 2017
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 551:7678, s. 92-94
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
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9.
  • Pinto, Dalila, et al. (författare)
  • Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.
  • 2014
  • Ingår i: American journal of human genetics. - 1537-6605. ; 94:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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10.
  • Watts, Nick, et al. (författare)
  • Health and climate change : policy responses to protect public health
  • 2015
  • Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 386:10006, s. 1861-1914
  • Forskningsöversikt (refereegranskat)abstract
    • The 2015 Lancet Commission on Health and Climate Change has been formed to map out the impacts of climate change, and the necessary policy responses, in order to ensure the highest attainable standards of health for populations worldwide. This Commission is multidisciplinary and international in nature, with strong collaboration between academic centres in Europe and China. The central finding from the Commission's work is that tackling climate change could be the greatest global health opportunity of the 21st century. The key messages from the Commission are summarised below, accompanied by ten underlying recommendations to accelerate action in the next 5 years.
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