Using an emergent system concept in designing interactive games for autistic children

This paper features the design process, the outcome, and preliminary tests of an interactive toy that expresses emergent behavior and can be used for behavioral training of autistic children, as well as for an engaging toy for every child. We exploit the interest of the autistic children in regular patterns and order to stimulate their motivational, explorative and social skills. As a result we have developed a toy that consists of undefined number of cubes that express emergent behavior by communicating with each other and changing their colors as a result of how they have been positioned by the players. The user tests have shown increased time of engagement of the children with the toy in comparison with their usual play routines, pronounced explorative behavior and encouraging results with improvement of turn taking interaction

昆虫の生理および行動の統合性におけるセロトニン受容体の機能

博士（学術）神戸大

Epigenetic alteration at the DLK1-GTL2 imprinted domain in human neoplasia: analysis of neuroblastoma, phaeochromocytoma and Wilms' tumour

Epigenetic alterations in the 11p15.5 imprinted gene cluster are frequent in human cancers and are associated with disordered imprinting of insulin-like growth factor (IGF)2 and H19. Recently, an imprinted gene cluster at 14q32 has been defined and includes two closely linked but reciprocally imprinted genes, DLK1 and GTL2, that have similarities to IGF2 and H19, respectively. Both GTL2 and H19 are maternally expressed RNAs with no protein product and display paternal allele promoter region methylation, and DLK1 and IGF2 are both paternally expressed. To determine whether methylation alterations within the 14q32 imprinted domain occur in human tumorigenesis, we investigated the status of the GTL2 promoter differentially methylated region (DMR) in 20 neuroblastoma tumours, 20 phaeochromocytomas and, 40 Wilms' tumours. Hypermethylation of the GTL2 promoter DMR was detected in 25% of neuroblastomas, 10% of phaeochromocytoma and 2.5% of Wilms' tumours. Tumours with GTL2 promoter DMR hypermethylation also demonstrated hypermethylation at an upstream intergenic DMR thought to represent a germline imprinting control element. Analysis of neuroblastoma cell lines revealed that GTL2 DMR hypermethylation was associated with transcriptional repression of GTL2. These epigenetic findings are similar to those reported in Wilms' tumours in which H19 repression and DMR hypermethylation is associated with loss of imprinting (LOI, biallelic expression) of IGF2. However, a neuroblastoma cell line with hypermethylation of the GTL2 promoter and intergenic DMR did not show LOI of DLK1 and although treatment with a demethylating agent restored GTL2 expression and reduced DLK1 expression. As described for IGF2/H19, epigenetic changes at DLK1/GTL2 occur in human cancers. However, these changes are not associated with DLK1 LOI highlighting differences in the imprinting control mechanisms operating in the IGF2-H19 and DLK1-GTL2 domains. GTL2 promoter and intergenic DMR hypermethylation is associated with the loss of GTL2 expression and this may contribute to tumorigenesis in a subset of human cancers

Improved Detection of Bifidobacteria with Optimised 16S rRNA-Gene Based Pyrosequencing

The 16S rRNA gene is conserved across all bacteria and as such is routinely targeted in PCR surveys of bacterial diversity. PCR primer design aims to amplify as many different 16S rRNA gene sequences from as wide a range of organisms as possible, though there are no suitable 100% conserved regions of the gene, leading to bias. In the gastrointestinal tract, bifidobacteria are a key genus, but are often under-represented in 16S rRNA surveys of diversity. We have designed modified, ‘bifidobacteria-optimised’ universal primers, which we have demonstrated detection of bifidobacterial sequence present in DNA mixtures at 2% abundance, the lowest proportion tested. Optimisation did not compromise the detection of other organisms in infant faecal samples. Separate validation using fluorescence in situ hybridisation (FISH) shows that the proportions of bifidobacteria detected in faecal samples were in agreement with those obtained using 16S rRNA based pyrosequencing. For future studies looking at faecal microbiota, careful selection of primers will be key in order to ensure effective detection of bifidobacteria

Results from recent detachment experiments in alternative divertor configurations on TCV

Divertor detachment is explored on the TCV tokamak in alternative magnetic geometries. Starting from typical TCV single-null shapes, the poloidal flux expansion at the outer strikepoint is varied by a factor of 10 to investigate the X-divertor characteristics, and the total flux expansion is varied by 70% to study the properties of the super-X divertor. The effect of an additional X-point near the target is investigated in X-point target divertors. Detachment of the outer target is studied in these plasmas during Ohmic density ramps and with the ion ∇B drift away from the primary X-point. The detachment threshold, depth of detachment, and the stability of the radiation location are investigated using target measurements from the wall-embedded Langmuir probes and two-dimensional CIII line emissivity profiles across the divertor region, obtained from inverted, toroidally-integrated camera data. It is found that increasing poloidal flux expansion results in a deeper detachment for a given line-averaged density and a reduction in the radiation location sensitivity to core density, while no large effect on the detachment threshold is observed. The total flux expansion, contrary to expectations, does not show a significant influence on any detachment characteristics in these experiments. In X-point target geometries, no evidence is found for a reduced detachment threshold despite a 2-3 fold increase in connection length. A reduced radiation location sensitivity to core plasma density in the vicinity of the target X-point is suggested by the measurements

DLK1 Is a Somato-Dendritic Protein Expressed in Hypothalamic Arginine-Vasopressin and Oxytocin Neurons

Delta-Like 1 Homolog, Dlk1, is a paternally imprinted gene encoding a transmembrane protein involved in the differentiation of several cell types. After birth, Dlk1 expression decreases substantially in all tissues except endocrine glands. Dlk1 deletion in mice results in pre-natal and post-natal growth deficiency, mild obesity, facial abnormalities, and abnormal skeletal development, suggesting involvement of Dlk1 in perinatal survival, normal growth and homeostasis of fat deposition. A neuroendocrine function has also been suggested for DLK1 but never characterised. To evaluate the neuroendocrine function of DLK1, we first characterised Dlk1 expression in mouse hypothalamus and then studied post-natal variations of the hypothalamic expression. Western Blot analysis of adult mouse hypothalamus protein extracts showed that Dlk1 was expressed almost exclusively as a soluble protein produced by cleavage of the extracellular domain. Immunohistochemistry showed neuronal DLK1 expression in the suprachiasmatic (SCN), supraoptic (SON), paraventricular (PVN), arcuate (ARC), dorsomedial (DMN) and lateral hypothalamic (LH) nuclei. DLK1 was expressed in the dendrites and perikarya of arginine-vasopressin neurons in PVN, SCN and SON and in oxytocin neurons in PVN and SON. These findings suggest a role for DLK1 in the post-natal development of hypothalamic functions, most notably those regulated by the arginine-vasopressin and oxytocin systems

CADM1 is a strong neuroblastoma candidate gene that maps within a 3.72 Mb critical region of loss on 11q23

<p>Abstract</p> <p>Background</p> <p>Recurrent loss of part of the long arm of chromosome 11 is a well established hallmark of a subtype of aggressive neuroblastomas. Despite intensive mapping efforts to localize the culprit 11q tumour suppressor gene, this search has been unsuccessful thus far as no sufficiently small critical region could be delineated for selection of candidate genes.</p> <p>Methods</p> <p>To refine the critical region of 11q loss, the chromosome 11 status of 100 primary neuroblastoma tumours and 29 cell lines was analyzed using a BAC array containing a chromosome 11 tiling path. For the genes mapping within our refined region of loss, meta-analysis on published neuroblastoma mRNA gene expression datasets was performed for candidate gene selection. The DNA methylation status of the resulting candidate gene was determined using re-expression experiments by treatment of neuroblastoma cells with the demethylating agent 5-aza-2'-deoxycytidine and bisulphite sequencing.</p> <p>Results</p> <p>Two small critical regions of loss within 11q23 at chromosomal band 11q23.1-q23.2 (1.79 Mb) and 11q23.2-q23.3 (3.72 Mb) were identified. In a first step towards further selection of candidate neuroblastoma tumour suppressor genes, we performed a meta-analysis on published expression profiles of 692 neuroblastoma tumours. Integration of the resulting candidate gene list with expression data of neuroblastoma progenitor cells pinpointed <it>CADM1 </it>as a compelling candidate gene. Meta-analysis indicated that <it>CADM1 </it>expression has prognostic significance and differential expression for the gene was noted in unfavourable neuroblastoma versus normal neuroblasts. Methylation analysis provided no evidence for a two-hit mechanism in 11q deleted cell lines.</p> <p>Conclusion</p> <p>Our study puts <it>CADM1 </it>forward as a strong candidate neuroblastoma suppressor gene. Further functional studies are warranted to elucidate the role of <it>CADM1 </it>in neuroblastoma development and to investigate the possibility of <it>CADM1 </it>haploinsufficiency in neuroblastoma.</p

Using an emergent system concept in designing interactive games for autistic children

This paper features the design process, the outcome, and preliminary tests of an interactive toy that expresses emergent behavior and can be used for behavioral training of autistic children, as well as for an engaging toy for every child. We exploit the interest of the autistic children in regular patterns and order to stimulate their motivational, explorative and social skills. As a result we have developed a toy that consists of undefined number of cubes that express emergent behavior by communicating with each other and changing their colors as a result of how they have been positioned by the players. The user tests have shown increased time of engagement of the children with the toy in comparison with their usual play routines, pronounced explorative behavior and encouraging results with improvement of turn taking interaction

Immunogeniciteit en veiligheid van monovalent RIVM meningococcen B OMP vesicle F91 vaccin toegediend aan kinderen die 2,5 jaar geleden zijn gevaccineerd met hexavalent meningococcen B vaccin

This report describes the results with respect to immunogenicity as well as reactogenicity of a monovalent P1.7h,4 OMV vaccine (MonoMen) used as booster vaccination in children previously vaccinated with a hexavalent MenB vaccine. The participants in this study were immunised in 1995-1996 with hexavalent MenB vesicle vaccine or with hepatitis B vaccine (control group). The booster vaccination with MonoMen was well tolerated. No serious adverse events occurred during the study. Most systemic adverse reactions were observed during day 2 and 3. Local reactions, which generally lasted for three days, were more common than systemic reactions. The rise of the GMT of bactericidal antibodies against P1.7h,4 in children primed with MenB was much higher as compared to children who received the HepB vaccine. About 80% of the children with an immune response after the primary series with the hexavalent vaccine, also showed an immune response after the booster vaccination with MonoMen which indicates the presence of an immunological memory for these children. Remarkably, immune responses against strains not present in MonoMen were also observed. Cross-reacting antibodies possibly cause these responses. In spite of the somewhat weak response against P1.7h,4 after the primary vaccination series with the hexavalent vaccine, an adequate response against this strain was found after boosting with MonoMen. Based on these results in combination with the results of the phase II trial with MonoMen in toddlers MonoMen seems a safe and highly immunogenic vaccine.Dit rapport beschrijft een follow-up studie naar veiligheid en immunogeniciteit van monovalent P1.7h,4 OMV vaccin (MonoMen) gebruikt als boostervaccinatie in kinderen eerder gevaccineerd met hexavalent MenB vaccin. De deelnemers aan deze studie zijn in het kader van een eerdere studie gevaccineerd met hexavalent MenB vesicle vaccin of met HepB vaccin (controle groep). Tijdens de studie traden geen ernstige bijwerkingen op. Systemische bijwerkingen werden vooral gerapporteerd tijdens de 2e en 3e dag na vaccinatie Lokale bijwerkingen, die over het algemeen 3 dagen duurden, kwamen vaker voor. De stijging van de GMT van bactericide antistoffen tegen P1.7h,4 in kinderen geprimed met hexavalent MenB was aanzienlijk hoger dan die in kinderen die HepB ontvingen. Ongeveer 80% van de kinderen die een immuunrespons tegen P1.7h,4 vertoonden na de primaire serie met hexavalent MenB vaccin, reageerde ook met een immuunrespons op de boostervaccinatie met MonoMen, hetgeen wijst op de aanwezigheid van een immunologisch geheugen. Opmerkelijke titerstijgingen tegen stammen niet aanwezig in het monovalente vaccin werden waargenomen, deze worden waarschijnlijk veroorzaakt door kruisreagerende antistoffen. Ondanks een wat lagere respons tegen het subtype P1.7h,4 na primaire vaccinatie serie met het hexavalente vaccin, wordt een adequate respons tegen deze stam gezien na de booster met MonoMen. Op grond van deze resultaten in combinatie met de resultaten van de fase II trial met MonoMen in peuters lijkt MonoMen een veilig en zeer immunogeen vaccin

Intestinal microbiology in early life: specific prebiotics can have similar functionalities as human-milk oligosaccharides

Human milk is generally accepted as the best nutrition for newborns and has been shown to support the optimal growth and development of infants. On the basis of scientific insights from human-milk research, a specific mixture of nondigestible oligosaccharides has been developed, with the aim to improve the intestinal microbiota in early life. The mixture has been extensively studied and has been shown to be safe and to have potential health benefits that are similar to those of human milk. The specific mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides has been found to affect the development of early microbiota and to increase the Bifidobacterium amounts as observed in human-milk-fed infants. The resulting gut ecophysiology is characterized by high concentrations of lactate, a slightly acidic pH, and specific short-chain fatty acid profiles, which are high in acetate and low in butyrate and propionate. Here, we have summarized the main findings of dietary interventions with these specific oligosaccharides on the gut microbiota in early life. The gut ecophysiology in early life may have consequences for the metabolic, immunologic, and even neurologic development of the child because reports increasingly substantiate the important function of gut microbes in human health. This review highlights major findings in the field of early gut colonization and the potential impact of early nutrition in healthy growth and development