Why is it so hard to enact responsible change?: Scientists need to work more closely with other social groups to implement sustainable innovation

This is the final version. Available on open access from EMBO Press via the DOI in this record. Biotechnology and Biological Sciences Research Council (BBSRC)UK Research and Innovation | Engineering and Physical Sciences Research Council (EPSRC)Wellcome Trus

Genomic Risk Profiling of Ischemic Stroke: Results of an International Genome-Wide Association Meta-Analysis

Introduction: Familial aggregation of ischemic stroke derives from shared genetic and environmental factors. We present a meta-analysis of genome-wide association scans (GWAS) from 3 cohorts to identify the contribution of common variants to ischemic stroke risk.Methods: This study involved 1464 ischemic stroke cases and 1932 controls. Cases were genotyped using the Illumina 610 or 660 genotyping arrays; controls, with Illumina HumanHap 550Kv1 or 550Kv3 genotyping arrays. Imputation was performed with the 1000 Genomes European ancestry haplotypes (August 2010 release) as a reference. A total of 5,156,597 single-nucleotide polymorphisms (SNPs) were incorporated into the fixed effects meta-analysis. All SNPs associated with ischemic stroke (P < 1 x 10(-5)) were incorporated into a multivariate risk profile model.Results: No SNP reached genome-wide significance for ischemic stroke (P < 5 x 10(-8)). Secondary analysis identified a significant cumulative effect for age at onset of stroke (first versus fifth quintile of cumulative profiles based on SNPs associated with late onset, beta = 14.77 [10.85, 18.68], P = 5.5 x 10(-12)), as well as a strong effect showing increased risk across samples with a high propensity for stroke among samples with enriched counts of suggestive risk alleles (P < 5 x 10(-6)). Risk profile scores based only on genomic information offered little incremental prediction.Discussion: There is little evidence of a common genetic variant contributing to moderate risk of ischemic stroke. Quintiles based on genetic loading of alleles associated with a younger age at onset of ischemic stroke revealed a significant difference in age at onset between those in the upper and lower quintiles. Using common variants from GWAS and imputation, genomic profiling remains inferior to family history of stroke for defining risk. Inclusion of genomic (rare variant) information may be required to improve clinical risk profiling

<i>C-elegans</i> model identifies genetic modifiers of alpha-synuclein inclusion formation during aging

Inclusions in the brain containing alpha-synuclein are the pathological hallmark of Parkinson's disease, but how these inclusions are formed and how this links to disease is poorly understood. We have developed a &lt;i&gt;C-elegans&lt;/i&gt; model that makes it possible to monitor, in living animals, the formation of alpha-synuclein inclusions. In worms of old age, inclusions contain aggregated alpha-synuclein, resembling a critical pathological feature. We used genome-wide RNA interference to identify processes involved in inclusion formation, and identified 80 genes that, when knocked down, resulted in a premature increase in the number of inclusions. Quality control and vesicle-trafficking genes expressed in the ER/Golgi complex and vesicular compartments were overrepresented, indicating a specific role for these processes in alpha-synuclein inclusion formation. Suppressors include aging-associated genes, such as sir-2.1/SIRT1 and lagr-1/LASS2. Altogether, our data suggest a link between alpha-synuclein inclusion formation and cellular aging, likely through an endomembrane-related mechanism. The processes and genes identified here present a framework for further study of the disease mechanism and provide candidate susceptibility genes and drug targets for Parkinson's disease and other alpha-synuclein related disorders

Stroke genetics: prospects for personalized medicine.

Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice

Influence of coding variability in APP-Aβ metabolism genes in sporadic Alzheimer’s disease

This is the final version of the article. Available from the publisher via the DOI in this record.The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4<p-value<0.05), were found to be rare coding variants (0.009%<MAF<1.4%) with moderate to strong effect size (1.84<OR<Inf) that map to genes mainly involved in Aβ extracellular degradation (TTR, ACE), clearance (LRP1) and APP trafficking and recycling (SORL1). These results were partially replicated in the gene-based analysis (c-alpha and SKAT tests), that reports ECE1, LYZ and TTR as nominally associated to AD (1.7e-3 <p-value <0.05). In concert with previous studies, we suggest that 1) common coding variability in APP-Aβ genes is not a critical factor for AD development and 2) Aβ degradation and clearance, rather than Aβ production, may play a key role in the etiology of sporadic AD.This study was supported by the Alzheimer's Research UK, the Medical Research Council (MRC), the Wellcome Trust/MRC Joint Call in Neurodegeneration Award (WT089698) to the UK Parkinson's Disease Consortium (whose members are from the University College London Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee), grants (P50 AG016574, U01 AG006786, and R01 AG18023), the National Institute for Health Research Biomedical Research Unit in Dementia at University College London Hospitals, University College London; the Big Lottery (to Dr. Morgan); a fellowship from Alzheimer's Research UK (to Dr. Guerreiro); and the Intramural Research Programs of the National Institute on Aging and the National Institute of Neurological Disease and Stroke, National Institutes of Health (Department of Health and Human Services Project number, ZO1 AG000950-10). The MRC London Neurodegenerative Diseases Brain Bank and the Manchester Brain Bank from Brains for Dementia Research are jointly funded from ARUK and AS. Tissue samples were supplied by The London Neurodegenerative Diseases Brain Bank, which receives funding from the MRC and as part of the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and Alzheimer’s Society

Effect of synthetic hormones on reproduction in Mastomys natalensis

Rodent pest management traditionally relies on some form of lethal control. Developing effective fertility control for pest rodent species could be a major breakthrough particularly in the context of managing rodent population outbreaks. This laboratory-based study is the first to report on the effects of using fertility compounds on an outbreaking rodent pest species found throughout sub-Saharan Africa. Mastomys natalensis were fed bait containing the synthetic steroid hormones quinestrol and levonorgestrel, both singly and in combination, at three concentrations (10, 50, 100 ppm) for seven days. Consumption of the bait and animal body mass was mostly the same between treatments when analysed by sex, day and treatment. However, a repeated measures ANOVA indicated that quinestrol and quinestrol+levonorgestrel treatments reduced consumption by up to 45%, particularly at the higher concentrations of 50 and 100 ppm. Although there was no clear concentration effect on animal body mass, quinestrol and quinestrol+levonorgestrel lowered body mass by up to 20% compared to the untreated and levonorgestrel treatments. Quinestrol and quinestrol+levonorgestrel reduced the weight of male rat testes, epididymis and seminal vesicles by 60-80%, and sperm concentration and motility were reduced by more than 95%. No weight changes were observed to uterine and ovarian tissue; however, high uterine oedema was observed among all female rats consuming treated bait at 8 days and 40 days from trial start. Trials with mate pairing showed there were significant differences in the pregnancy rate with all treatments when compared to the untreated control group of rodents

Modelling ranging behaviour of female orang-utans: a case study in Tuanan, Central Kalimantan, Indonesia

Quantification of the spatial needs of individuals and populations is vitally important for management and conservation. Geographic information systems (GIS) have recently become important analytical tools in wildlife biology, improving our ability to understand animal movement patterns, especially when very large data sets are collected. This study aims at combining the field of GIS with primatology to model and analyse space-use patterns of wild orang-utans. Home ranges of female orang-utans in the Tuanan Mawas forest reserve in Central Kalimantan, Indonesia were modelled with kernel density estimation methods. Kernel results were compared with minimum convex polygon estimates, and were found to perform better, because they were less sensitive to sample size and produced more reliable estimates. Furthermore, daily travel paths were calculated from 970 complete follow days. Annual ranges for the resident females were approximately 200 ha and remained stable over several years; total home range size was estimated to be 275 ha. On average, each female shared a third of her home range with each neighbouring female. Orang-utan females in Tuanan built their night nest on average 414 m away from the morning nest, whereas average daily travel path length was 777 m. A significant effect of fruit availability on day path length was found. Sexually active females covered longer distances per day and may also temporarily expand their ranges

Domestication Syndrome in Caimito (Chrysophyllum cainito L.): Fruit and Seed Characteristics

Domestication Syndrome in Caimito (Chrysophyllum cainitoL.): Fruit and Seed Characteristics: The process of domestication is understudied and poorly known for many tropical fruit tree crops. The star apple or caimito tree (Chrysophyllum cainito L., Sapotaceae) is cultivated throughout the New World tropics for its edible fruits. We studied this species in central Panama, where it grows wild in tropical moist forests and is also commonly cultivated in backyard gardens. Using fruits collected over two harvest seasons, we tested the hypothesis that cultivated individuals of C. cainito show distinctive fruit and seed characteristics associated with domestication relative to wild types. We found that cultivated fruits were significantly and substantially larger and allocated more to pulp and less to exocarp than wild fruits. The pulp of cultivated fruits was less acidic; also, the pulp had lower concentrations of phenolics and higher concentrations of sugar. The seeds were larger and more numerous and were less defended with phenolics in cultivated than in wild fruits. Discriminant Analysis showed that, among the many significant differences, fruit size and sugar concentration drove the great majority of the variance distinguishing wild from cultivated classes. Variance of pulp phenolics among individuals was significantly higher among wild trees than among cultivated trees, while variance of fruit mass and seed number was significantly higher among cultivated trees. Most traits showed strong correlations between years. Overall, we found a clear signature of a domestication syndrome in the fruits of cultivated caimito in Panama

Critical reflections on evidence, ethics and effectiveness in the management of tuberculosis: public health and global perspectives

BACKGROUND: Tuberculosis is a major cause of morbidity and mortality globally. Recent scholarly attention to public health ethics provides an opportunity to analyze several ethical issues raised by the global tuberculosis pandemic. DISCUSSION: Recently articulated frameworks for public health ethics emphasize the importance of effectiveness in the justification of public health action. This paper critically reviews the relationship between these frameworks and the published evidence of effectiveness of tuberculosis interventions, with a specific focus on the controversies engendered by the endorsement of programs of service delivery that emphasize direct observation of therapy. The role of global economic inequities in perpetuating the tuberculosis pandemic is also discussed. SUMMARY: Tuberculosis is a complex but well understood disease that raises important ethical challenges for emerging frameworks in public health ethics. The exact role of effectiveness as a criterion for judging the ethics of interventions needs greater discussion and analysis. Emerging frameworks are silent about the economic conditions contributing to the global burden of illness associated with tuberculosis and this requires remediation