The persuasiveness of ambient intelligence

Ambient intelligence (AmI) is a novel concept for embedded computing that builds on the large-scale integration of electronic devices into peoples’ surroundings and the ubiquitous availability of digital information to the users of such environments. The concept however is not only concerned with the integration of computing in the background but, as a direct result of the disappearing computer and the corresponding interaction technologies, it calls for novel means of control that support the natural and intelligent use of such smart environments, emphasizing predominantly social aspects. As the familiar box-like devices are replaced by hidden functions embedded in the surroundings, the classical meaning and implication of security and trust needs to be revisited in the context of ambient intelligence. In this chapter, we briefly revisit the foundations of the AmI vision by addressing the role of AmIware, which refers to the basic and enabling AmI technologies, and by presenting some basic definitions of ambient intelligence. Next we discuss the meaning and role of persuasion on the basis of models and theories for motivation originating from cognitive science. Notions such as compliance and ambient journaling are used to develop an understanding of the concept of ambient persuasion. We also address the ethics of ambient intelligence from the point of view of a number of critical factors such as trust and faith, crossing boundaries, and changing realities. The chapter concludes with a summary of findings and some final remarks

Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development

Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia.

This is a pre-copyedited, author-produced version of an article accepted for publication in International Journal of Epidemiology, following peer review. The version of record: Cornelis Blauwendraat, Xylena Reed, Lynne Krohn et al., on behalf of the International Parkinson’s Disease Genomics Consortium (IPDGC), Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia, Brain, Volume 143, Issue 1, January 2020, Pages 234–248, https://doi.org/10.1093/brain/awz350 is available online at: https://doi.org/10.1093/brain/awz350.Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions

SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Neurological Motor Disorder

Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

Altres ajuts: Leonard Wolfson Foundation; United Kingdom Medical Research Council (MRC, MR/N008324/1); DRI Limited; UK Medical Research Council; Alzheimer's Society and Alzheimer's Research UK; Medical Research Council (MR/N026004/1); Wellcome Trust (202903/Z/16/Z); Dolby Family Fund; National Institute for Health Research; University College London; Fundación Séneca, Agencia de Ciencia y Tecnología de la Región de Murcia (00007/COVI/20).Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease