Salience strategy: connectivity, aesthetics and the learning mind

This dissertation adds to the many arguments already made for the value of art (cultural artifact) in teaching and learning. The special approach developed here concludes with the articulation of Salience Strategy. The argument firstly questions the value of seeing intelligence as a problem-solving faculty. It continues by examining consciousness, memory and the imagination as both the ground and substance of intellection. It argues that, amongst other things, interconnectedness, reiterative pathways and networks are central to the operation of consciousness and therefore, are central to its epiphenomenal attributes like intelligence. As education should strive for greater intellectual functioning so it should, therefore, strive to harness the paradigms of interconnectedness, reiterative pathways and networks. The art object, (device, gesture, statement), it is proposed, is valuable when deployed as hubs in networks of ideas allowing learners to form patterns of unexpected and creative linkages enhancing both memory, curiosity and a capacity for imaginative and associative thinking. Learning becomes movement through a landscape of complex objects and outgrowths. Two salience itineraries are explored in this dissertation. The first in relation to concepts overheard during learner conversations over the duration of a school week, and a second, exploiting my own work as an artist, selected work by the British artist Richard Long, and some of the issues raised in the theoretical discussion of consciousness and networks

Effects of recency of habituation of varied auditory, visual, and audio-visual stimuli on the perceptual investigatory responses of kindergarten children

The purpose of the experiment was to determine and compare the effects of recency of habituation of varied auditory, visual, and audio-visual stimuli on the perceptual investigatory responses of kindergarten children. Two delay intervals (5-minutes and 5-days) and three types of habituation (auditory, visual, and audio-visual) were studied. Factorial analysis of variance made it possible to analyze the independent and interactive effects of these variables on the investigatory responses of the children during 5-minutes of testing. The population of the study consisted of 144 children drawn from three church-related kindergartens in Greensboro, North Carolina. Thirty six of these children, with an equal distribution of boys and girls, were randomly selected from each kindergarten. Within each of these groups, subjects were assigned to six experimental conditions: (1) Short delay auditory habituation (SA); (2) Short delay audio-visual habituation (SAV); (3) Short delay visual habituation (SV); (4) Long delay auditory habituation (LA); (5) Long delay audio-visual habituation (LAV); and (6) Long delay visual habituation (LV). The remaining 36 children, with an equal number of boys and girls, were assigned to a "replacement" group. Children were randomly selected from the latter group to replace experimental subjects, who, for various reasons were unable to complete the experiment. The stimuli, varied sounds and color-pictures, were presented with a simple motor task in which pressing manipulanda (rubber bulbs) produced auditory and visual stimuli. Prior to testing sessions, subjects in the SA and LA groups were exposed to auditory stimuli; subjects in the SAV and LAV groups were exposed to auditory and visual stimuli; and subjects in the SV and LV groups were exposed to visual stimuli. Subjects in the SA, SAV, and SV groups had a 5-minute delay interval between the preliminary (habituation) sessions and testing sessions, whereas subjects in the LA, LAV, and LV groups had a 5-day delay between preliminary and testing sessions. All sessions were conducted in a cubicle, where the children were seated at a small table in front of a clown's face made of plywood. The number of bulb-pressing responses were recorded separately for each child during each minute of testing. These responses were designated auditory responses if they resulted in the presentation of sounds or visual responses if they resulted in the presentation of color-pictures. The original scores were transformed to visual preference scores by the following formula: VP = V j where VP is the visual preference score of a subject, V is the (V + A) frequency of his visual responses, and A is the frequency of his auditory responses. An analysis of variance for a 2 x 3 x 5 factorial design was performed on the visual preference (VP) scores of the 18 subjects in each of the experimental groups. The results of the analysis indicated: (a) there were differences in subjects' mean VP scores resulting from varied types of habituation; (b) there were differences in subjects' mean VP scores resulting from the interaction of amount of delay and type of habituation; (c) there were differences in subjects' mean VP scores resulting from the interaction of type of habituation and minutes of testing; (d) there were differences in subjects' mean VP scores resulting from the interaction of amount of delay, type of habituation, and minutes of testing. Additionally, single factor analyses of variance indicated that: (a) mean VP scores were greatest for subjects in the SA group, next greatest for subjects in the SAV group, and least for subjects in the SV group; (b) mean VP scores were greatest for subjects in the LA group, next greatest for subjects in the LAV group, and least for subjects in the LV group; (c) mean VP scores were greater for subjects in the SA group than for subjects in the LA group; (d) mean VP scores were greater for subjects in the LV group than for subjects in the SV group

Impulsivity and Rapid Decision-Making for Reward

Impulsivity is a feature of many brain disorders. Although often defined as the predisposition to act with an inadequate degree of deliberation, forethought, or control, it has proven difficult to measure. This may in part be due to the fact that it is a multifaceted construct, with impulsive decisions potentially arising as a result of a number of underlying mechanisms. Indeed, a “functional” degree of impulsivity may even promote effective behavior in healthy participants in a way that can be advantageous under certain circumstances. Although many tasks have been developed to study impulsivity, few examine decisions made rapidly, for time-sensitive rewards. In the current study we examine behavior in 59 adults on a manual “Traffic Light” task which requires participants to take risks under time pressure, if they are to maximize reward. We show that behavioral variables that index rapid anticipatory responding in this paradigm are correlated with one, specific self-report measure of impulsivity: “lack of premeditation” on the UPPS Impulsive Behavior Scale. Participants who scored more highly on this subscale performed better on the task. Moreover, anticipatory behavior reduced significantly with age (18–79 years), an effect that continued to be upheld after correction for potential age differences in the ability to judge the timing of responses. Based on these findings, we argue that the Traffic Light task provides a parametric method to study one aspect of impulsivity in health and disease: namely, rapid decision-making in pursuit of risky, time-sensitive rewards

<i>In vivo</i> gene silencing following non-invasive siRNA delivery into the skin using a novel topical formulation

AbstractTherapeutics based on short interfering RNAs (siRNAs), which act by inhibiting the expression of target transcripts, represent a novel class of potent and highly specific next-generation treatments for human skin diseases. Unfortunately, the intrinsic barrier properties of the skin combined with the large size and negative charge of siRNAs make epidermal delivery of these macromolecules quite challenging. To help evaluate the in vivo activity of these therapeutics and refine delivery strategies we generated an innovative reporter mouse model that predominantly expresses firefly luciferase (luc2p) in the paw epidermis — the region of murine epidermis that most closely models the tissue architecture of human skin. Combining this animal model with state-of-the-art live animal imaging techniques, we have developed a real-time in vivo analysis work-flow that has allowed us to compare and contrast the efficacies of a wide range nucleic acid-based gene silencing reagents in the skin of live animals. While inhibition was achieved with all of the reagents tested, only the commercially available “self-delivery” modified Accell-siRNAs (Dharmacon) produced potent and sustained in vivo gene silencing. Together, these findings highlight just how informative reliable reporter mouse models can be when assessing novel therapeutics in vivo. Using this work-flow, we developed a novel clinically-relevant topical formulation that facilitates non-invasive epidermal delivery of unmodified and “self-delivery” siRNAs. Remarkably, a sustained >40% luc2p inhibition was observed after two 1-hour treatments with Accell-siRNAs in our topical formulation. Importantly, our ability to successfully deliver siRNA molecules topically brings these novel RNAi-based therapeutics one-step closer to clinical use

Investigation of the utility of the 1.1B4 cell as a model human beta cell line for study of persistent enteroviral infection.

This is the final version. Available on open access from Nature Research via the DOI in this record. Data availability: The research data supporting this publication are provided within this paper.The generation of a human pancreatic beta cell line which reproduces the responses seen in primary beta cells, but is amenable to propagation in culture, has long been an important goal in diabetes research. This is particularly true for studies focussing on the role of enteroviral infection as a potential cause of beta-cell autoimmunity in type 1 diabetes. In the present work we made use of a clonal beta cell line (1.1B4) available from the European Collection of Authenticated Cell Cultures, which had been generated by the fusion of primary human beta-cells with a pancreatic ductal carcinoma cell, PANC-1. Our goal was to study the factors allowing the development and persistence of a chronic enteroviral infection in human beta-cells. Since PANC-1 cells have been reported to support persistent enteroviral infection, the hybrid 1.1B4 cells appeared to offer an ideal vehicle for our studies. In support of this, infection of the cells with a Coxsackie virus isolated originally from the pancreas of a child with type 1 diabetes, CVB4.E2, at a low multiplicity of infection, resulted in the development of a state of persistent infection. Investigation of the molecular mechanisms suggested that this response was facilitated by a number of unexpected outcomes including an apparent failure of the cells to up-regulate certain anti-viral response gene products in response to interferons. However, more detailed exploration revealed that this lack of response was restricted to molecular targets that were either activated by, or detected with, human-selective reagents. By contrast, and to our surprise, the cells were much more responsive to rodent-selective reagents. Using multiple approaches, we then established that populations of 1.1B4 cells are not homogeneous but that they contain a mixture of rodent and human cells. This was true both of our own cell stocks and those held by the European Collection of Authenticated Cell Cultures. In view of this unexpected finding, we developed a strategy to harvest, isolate and expand single cell clones from the heterogeneous population, which allowed us to establish colonies of 1.1B4 cells that were uniquely human (h1.1.B4). However, extensive analysis of the gene expression profiles, immunoreactive insulin content, regulated secretory pathways and the electrophysiological properties of these cells demonstrated that they did not retain the principal characteristics expected of human beta cells. Our data suggest that stocks of 1.1B4 cells should be evaluated carefully prior to their use as a model human beta-cell since they may not retain the phenotype expected of human beta-cells.JDRFJDRFMedical Research Council (MRC)Diabetes UKNorman Family TrustEuropean Foundation for the Study of Diabete

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention