Switching on the Lights for Gene Therapy

Strategies for non-invasive and quantitative imaging of gene expression in vivo have been developed over the past decade. Non-invasive assessment of the dynamics of gene regulation is of interest for the detection of endogenous disease-specific biological alterations (e.g., signal transduction) and for monitoring the induction and regulation of therapeutic genes (e.g., gene therapy). To demonstrate that non-invasive imaging of regulated expression of any type of gene after in vivo transduction by versatile vectors is feasible, we generated regulatable herpes simplex virus type 1 (HSV-1) amplicon vectors carrying hormone (mifepristone) or antibiotic (tetracycline) regulated promoters driving the proportional co-expression of two marker genes. Regulated gene expression was monitored by fluorescence microscopy in culture and by positron emission tomography (PET) or bioluminescence (BLI) in vivo. The induction levels evaluated in glioma models varied depending on the dose of inductor. With fluorescence microscopy and BLI being the tools for assessing gene expression in culture and animal models, and with PET being the technology for possible application in humans, the generated vectors may serve to non-invasively monitor the dynamics of any gene of interest which is proportionally co-expressed with the respective imaging marker gene in research applications aiming towards translation into clinical application

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes(1). Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel(2)) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants

Effects of benefit finding, social support and caregiving on youth adjustment in a parental illness context

Social support and benefit finding are two related processes that may protect youth from the adverse effects of caring for an ill parent. The primary purpose of this study was to test a mediational model proposal that benefit finding mediates the effects of social support and caregiving on youth adjustment in the context of parental illness. Given the dearth of research on benefit finding in the youth caregiving field, an additional aim was to further clarify the benefit finding construct in the parental illness context. A total of 428 Australian youth (mean age 12.77 years) who had a parent with a serious health problem completed a questionnaire. Exploration of the benefit finding construct showed that it was unidimensional, relevant to youth caregivers, unrelated to measured demographics, but highly linked to caregiving demands and engagement. Results from path modelling analysis supported the mediational model proposal that benefit finding mediates the effects of social support and caregiving on youth adjustment. While caregiving responsibilities in general has a detrimental effect on adjustment, a small counter-balancing indirect effect was detected via the role of increased benefit finding due to caregiving responsibilities. Most of the benefit finding research in youth has been conducted in the context of trauma, where parental support is a significant protective factor. This study makes an important contribution to understanding benefit finding and social support processes in the context of a chronic stressor where one of the usual sources (parents) of significant coping support is limited

Explanation and Levels in Cognitive Neuroscience

Talk of levels is widespread in the life sciences including neuroscience. This chapter explores some of the most common characterizations of levels found in neuroscience, with a specific focus on how levels of organization are invoked in explanations.21 page(s