Sheffield Submission to the CHiC Ineractive Task: Exploring Digital Cultural Heritage

The Cultural Heritage in CLEF 2013 (CHiC) interactive task focused on acquiring and analysing interactive information retrieval (IIR)behaviour in a Digital Cultural Heritage collection. The University of Sheffield contributed 120 on-line and 20 in-lab participants to this task. The results of both the on-line and in-lab experiments strongly indicate that when faced with a new, unfamiliar collection and an open-ended task, participants will spend more time using the category hierarchy for exploration, than the search box. However, analysis of the the number of items the on-line participants view in detail and then saved to their workspace indicates that the two access methods fulfil different functions. From this we conclude that the categories are seemingly there to support the development of an initial overview over the collection, while the search is used to locate things in a more focused manner

Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects

The tumor suppressor liver kinase B1 (LKB1) is an important regulator of pancreatic β cell biology. LKB1-dependent phosphorylation of distinct AMPK (adenosine monophosphate-activated protein kinase) family members determines proper β cell polarity and restricts β cell size, total β cell mass, and glucose-stimulated insulin secretion (GSIS). However, the full spectrum of LKB1 effects and the mechanisms involved in the secretory phenotype remain incompletely understood. We report here that in the absence of LKB1 in β cells, GSIS is dramatically and persistently improved. The enhancement is seen both in vivo and in vitro and cannot be explained by altered cell polarity, increased β cell number, or increased insulin content. Increased secretion does require membrane depolarization and calcium influx but appears to rely mostly on a distal step in the secretion pathway. Surprisingly, enhanced GSIS is seen despite profound defects in mitochondrial structure and function in LKB1-deficient β cells, expected to greatly diminish insulin secretion via the classic triggering pathway. Thus LKB1 is essential for mitochondrial homeostasis in β cells and in parallel is a powerful negative regulator of insulin secretion. This study shows that β cells can be manipulated to enhance GSIS to supra-normal levels even in the face of defective mitochondria and without deterioration over months

Remote control of glucose homeostasis in vivo using photopharmacology

Photopharmacology describes the use of light to precisely deliver drug activity in space and time. Such approaches promise to improve drug specificity by reducing off-target effects. As a proof-of-concept, we have subjected the fourth generation photoswitchable sulfonylurea JB253 to comprehensive toxicology assessment, including mutagenicity and maximum/repeated tolerated dose studies, as well as in vivo testing in rodents. Here, we show that JB253 is well-tolerated with minimal mutagenicity and can be used to optically-control glucose homeostasis in anesthetized mice following delivery of blue light to the pancreas. These studies provide the first demonstration that photopharmacology may one day be applicable to the light-guided treatment of type 2 diabetes and other metabolic disease states in vivo in humans

Glucose in the hypothalamic paraventricular nucleus regulates GLP-1 release.

Glucokinase (GK) is highly expressed in the hypothalamic paraventricular nucleus (PVN); however, its role is currently unknown. We found that GK in the PVN acts as part of a glucose-sensing mechanism within the PVN that regulates glucose homeostasis by controlling glucagon-like peptide 1 (GLP-1) release. GLP-1 is released from enteroendocrine L cells in response to oral glucose. Here we identify a brain mechanism critical to the release of GLP-1 in response to oral glucose. We show that increasing expression of GK or injection of glucose into the PVN increases GLP-1 release in response to oral glucose. On the contrary, decreasing expression of GK or injection of nonmetabolizable glucose into the PVN prevents GLP-1 release. Our results demonstrate that gluco-sensitive GK neurons in the PVN are critical to the response to oral glucose and subsequent release of GLP-1

Externalizing behaviors in preadolescents: familial risk to externalizing behaviors and perceived parenting styles

The aim was to investigate the contribution of familial risk to externalizing behaviors (FR-EXT), perceived parenting styles, and their interactions to the prediction of externalizing behaviors in preadolescents. Participants were preadolescents aged 10–12 years who participated in TRAILS, a large prospective population-based cohort study in the Netherlands (N = 2,230). Regression analyses were used to determine the relative contribution of FR-EXT and perceived parenting styles to parent and teacher ratings of externalizing behaviors. FR-EXT was based on lifetime parental externalizing psychopathology and the different parenting styles (emotional warmth, rejection, and overprotection) were based on the child’s perspective. We also investigated whether different dimensions of perceived parenting styles had different effects on subdomains of externalizing behavior. We found main effects for FR-EXT (vs. no FR-EXT), emotional warmth, rejection, and overprotection that were fairly consistent across rater and outcome measures. More specific, emotional warmth was the most consistent predictor of all outcome measures, and rejection was a stronger predictor of aggression and delinquency than of inattention. Interaction effects were found for FR-EXT and perceived parental rejection and overprotection; other interactions between FR-EXT and parenting styles were not significant. Correlations between FR-EXT and perceived parenting styles were absent or very low and were without clinical significance. Predominantly main effects of FR-EXT and perceived parenting styles independently contribute to externalizing behaviors in preadolescents, suggesting FR-EXT and parenting styles to be two separate areas of causality. The relative lack of gene–environment interactions may be due to the epidemiological nature of the study, the preadolescent age of the subjects, the measurement level of parenting and the measurement level of FR-EXT, which might be a consequence of both genetic and environmental factors

The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans

Aims: To investigate the effect of kisspeptin on glucose-stimulated insulin secretion and appetite in humans. Materials and methods: In 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose-stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose-stimulated insulin secretion in vitro in human pancreatic islets and a human β-cell line (EndoC-βH1 cells). Results: Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose-stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. Conclusions: Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin-based therapies for reproductive and potentially metabolic conditions

Brief Report: Testing the Psychometric Properties of the Spence Children’s Anxiety Scale (SCAS) and the Screen for Child Anxiety Related Emotional Disorders (SCARED) in Autism Spectrum Disorder

Anxiety is a prevalent and impairing co-morbidity among individuals with autism spectrum disorder (ASD), yet assessment measures, including screening tools, are seldom validated with autism samples. We explored the psychometric properties of the child and parent reports of the Spence Children’s Anxiety Scale (SCAS) and the Screen for Anxiety Related Disorder-71 (SCARED-71) with 49 males with ASD (10–16 years, 63% co-occurring anxiety). Both measures had excellent internal consistency and fair-good parent–child agreement. The SCAS has a higher proportion of items evaluating observable behaviors. Predictive power of the measures did not differ. Higher cut-points in the parent reports (SCARED only) and lower cut-points in the child reports may enhance prediction in this sample. Choice of measure and cut-points should be considered alongside intended purpose

Refining trait resilience: identifying engineering, ecological, and adaptive facets from extant measures of resilience

The current paper presents a new measure of trait resilience derived from three common mechanisms identified in ecological theory: Engineering, Ecological and Adaptive (EEA) resilience. Exploratory and confirmatory factor analyses of five existing resilience scales suggest that the three trait resilience facets emerge, and can be reduced to a 12-item scale. The conceptualization and value of EEA resilience within the wider trait and well-being psychology is illustrated in terms of differing relationships with adaptive expressions of the traits of the five-factor personality model and the contribution to well-being after controlling for personality and coping, or over time. The current findings suggest that EEA resilience is a useful and parsimonious model and measure of trait resilience that can readily be placed within wider trait psychology and that is found to contribute to individual well-bein

Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease