Reward devaluation in autistic and adolescents with complex needs: a feasibility study

Rewards act as a motivator for positive behaviour and learning. Although compounding evidence indicates that reward processing operates differently in autistic individuals who do not have co-occurring learning disabilities, little is known about individuals who have such difficulties or other complex needs. This study aimed first to assess the feasibility of using an adapted reward devaluation paradigm to examine basic reward processes in this underrepresented population, and second to investigate whether autistic children and adolescents with complex needs would show dynamic behavioural changes in response to changes in the motivational value of a reward. 27 autistic children and adolescents with complex needs and 20 typically-developing 5-year-old children took part in the study. Participants were presented with two visual cues on a touchscreen laptop which triggered the delivery of a video, music or physical reward. One of the rewards was then presented in abundance to decrease its motivational value. Participants showed decreased interest in the video and music rewards after devaluation. The experimental setup was found to be suitable to test individuals with complex needs, although recommendations are made for the use of physical rewards. The results suggest that autistic participants with complex needs demonstrate goal-directed behaviour and that it is feasible to develop experimental paradigms that can shed important light on learning processes that are fundamental to many education and intervention strategies for this population

IdeS: A Bacterial Proteolytic Enzyme with Therapeutic Potential

Background: IdeS, a proteinase from Streptococcus pyogenes, cleaves immunoglobulin (Ig)G antibodies with a unique degree of specificity. Pathogenic IgG antibodies constitute an important clinical problem contributing to the pathogenesis of a number of autoimmune conditions and acute transplant rejection. To be able to effectively remove such antibodies is therefore an important clinical challenge. Methodology/Principal Findings: IdeS was found to specifically and efficiently cleave IgG in human blood in vitro (20 mg of IdeS caused a complete degradation of IgG in one ml of human whole blood in 15 minutes) and to clear IgG from the blood stream of rabbits in vivo (no IgG was detected six hours following an intravenous injection of 5 mg of IdeS) without any side effects. In a mouse model of immune thrombocytopenic purpura (ITP), polyclonal IgG antibodies against platelet surface antigens were used to induce a lethal disease. These profoundly thrombocytopenic animals were treated and cured by a single injection of IdeS. Conclusions/Significance: Novel information is provided concerning the IgG-cleaving activity of IdeS in vitro and in vivo. The highly specific and rapid elimination of IgG in vivo, the dramatic effect in a mouse model of ITP, and the lack of sid

Limits to the muon flux from WIMP annihilation in the center of the Earth with the AMANDA detector

A search for nearly vertical up-going muon-neutrinos from neutralino annihilations in the center of the Earth has been performed with the AMANDA-B10 neutrino detector. The data sample collected in 130.1 days of live-time in 1997, ~10^9 events, has been analyzed for this search. No excess over the expected atmospheric neutrino background is oberved. An upper limit at 90% confidence level on the annihilation rate of neutralinos in the center of the Earth is obtained as a function of the neutralino mass in the range 100 GeV-5000 GeV, as well as the corresponding muon flux limit.Comment: 14 pages, 11 figures. Version accepted for publication in Physical Review

Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells

Celiac disease is an auto-immune disease in which an immune response to dietary gluten leads to inflammation and subsequent atrophy of small intestinal villi, causing severe bowel discomfort and malabsorption of nutrients. The major instigating factor for the immune response in celiac disease is the activation of gluten-specific CD4+ T cells expressing T cell receptors that recognize gluten peptides presented in the context of HLA-DQ2 and DQ8. Here we provide an in-depth characterization of 28 gluten-specific T cell clones. We assess their transcriptional and epigenetic response to T cell receptor stimulation and link this to genetic factors associated with celiac disease. Gluten-specific T cells have a distinct transcriptional profile that mostly resembles that of Th1 cells but also express cytokines characteristic of other types of T-helper cells. This transcriptional response appears not to be regulated by changes in chromatin state, but rather by early upregulation of transcription factors and non-coding RNAs that likely orchestrate the subsequent activation of genes that play a role in immune pathways. Finally, integration of chromatin and transcription factor binding profiles suggest that genes activated by T cell receptor stimulation of gluten‑specific T cells may be impacted by genetic variation at several genetic loci associated with celiac disease.</p

Rapid Accumulation of CD14+CD11c+ Dendritic Cells in Gut Mucosa of Celiac Disease after in vivo Gluten Challenge

Of antigen-presenting cells (APCs) expressing HLA-DQ molecules in the celiac disease (CD) lesion, CD11c(+) dendritic cells (DCs) co-expressing the monocyte marker CD14 are increased, whereas other DC subsets (CD1c(+) or CD103(+)) and CD163(+)CD11c(-) macrophages are all decreased. It is unclear whether these changes result from chronic inflammation or whether they represent early events in the gluten response. We have addressed this in a model of in vivo gluten challenge.Treated HLA-DQ2(+) CD patients (n = 12) and HLA-DQ2(+) gluten-sensitive control subjects (n = 12) on a gluten-free diet (GFD) were orally challenged with gluten for three days. Duodenal biopsies obtained before and after gluten challenge were subjected to immunohistochemistry. Single cell digests of duodenal biopsies from healthy controls (n = 4), treated CD (n = 3) and untreated CD (n = 3) patients were analyzed by flow cytometry.In treated CD patients, the gluten challenge increased the density of CD14(+)CD11c(+) DCs, whereas the density of CD103(+)CD11c(+) DCs and CD163(+)CD11c(-) macrophages decreased, and the density of CD1c(+)CD11c(+) DCs remained unchanged. Most CD14(+)CD11c(+) DCs co-expressed CCR2. The density of neutrophils also increased in the challenged mucosa, but in most patients no architectural changes or increase of CD3(+) intraepithelial lymphocytes (IELs) were found. In control tissue no significant changes were observed.Rapid accumulation of CD14(+)CD11c(+) DCs is specific to CD and precedes changes in mucosal architecture, indicating that this DC subset may be directly involved in the immunopathology of the disease. The expression of CCR2 and CD14 on the accumulating CD11c(+) DCs indicates that these cells are newly recruited monocytes

Scoliosis and dental occlusion: a review of the literature

<p>Abstract</p> <p>Background</p> <p>Idiopathic scoliosis is a deformity without clear etiology. It is unclear wether there is an association between malocclusion and scoliosis. Several types of occlusion were described in subjects with scoliosis, mostly case-reports.</p> <p>Objectives</p> <p>The aim of this review was to evaluate the type of occluslins more prevalent in subjects with scoliosis</p> <p>Search strategy</p> <p>All randomised and controlled clinical trials identified from the Cochrane Oral Health Group Trials Register, a MEDLINE search using the Mesh term scoliosis, malocclusion, and relevant free text words, and the bibliographies of papers and review articles which reported the outcome of orthodontic treatment in subjects with scoliosis that were published as abstracts or papers between 1970 and 2010.</p> <p>Selection criteria</p> <p>All randomised and controlled clinical trials published as full papers or abstracts which reported quantitative data on the outcomes malocclusion in subjects with scoliosis.</p> <p>Data collection and analysis</p> <p>Data were extracted without blinding to the authors, age of patients or type of occlusion.</p> <p>Main results</p> <p>Using the search strategy eleven observational longitudinal studies were identified. No randomized clinical trials were recorded. Twenty-three cross-sectional studies were recorderd, and the others studies were reviews, editorials, case-reports, or opinions. The clinical trials were often not controlled and were about the cephalometric evaluation after treatment with the modified Milwuakee brace, followed by the orthodontic treatment of the class II relationship with a functional appliance. Clinical trials also included the study of the associations between scoliosis and unilateral crossbite, in children with asymmetry of the upper cervical spine. This association was also investigated in rats, pigs and rabbits in clinical trials. The other associations between scoliosis and occlusion seems to be based only on cross-sectional studies, case-reports, opinions.</p> <p>Authors' conclusions</p> <p>Based on selected studies, this review concludes that there is plausible evidence for an increased prevalence of unilateral Angle Class II malocclusions associated with scoliosis, and an increased risk of lateral crossbite, midline deviation in children affected by scoliosis. Also, documentation of associations between reduced range of lateral movements and scoliosis seem convincing. Data are also mentioned about the association between plagiocephaly and scoliosis.</p

Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules

Celiac disease is caused by an abnormal intestinal T-cell response to gluten proteins of wheat, barley and rye. Over the last few years, a number of gluten T-cell epitopes restricted by celiac disease associated HLA-DQ molecules have been characterized. In this work, we give an overview of these epitopes and suggest a comprehensive, new nomenclature

An Imperfect Dopaminergic Error Signal Can Drive Temporal-Difference Learning

An open problem in the field of computational neuroscience is how to link synaptic plasticity to system-level learning. A promising framework in this context is temporal-difference (TD) learning. Experimental evidence that supports the hypothesis that the mammalian brain performs temporal-difference learning includes the resemblance of the phasic activity of the midbrain dopaminergic neurons to the TD error and the discovery that cortico-striatal synaptic plasticity is modulated by dopamine. However, as the phasic dopaminergic signal does not reproduce all the properties of the theoretical TD error, it is unclear whether it is capable of driving behavior adaptation in complex tasks. Here, we present a spiking temporal-difference learning model based on the actor-critic architecture. The model dynamically generates a dopaminergic signal with realistic firing rates and exploits this signal to modulate the plasticity of synapses as a third factor. The predictions of our proposed plasticity dynamics are in good agreement with experimental results with respect to dopamine, pre- and post-synaptic activity. An analytical mapping from the parameters of our proposed plasticity dynamics to those of the classical discrete-time TD algorithm reveals that the biological constraints of the dopaminergic signal entail a modified TD algorithm with self-adapting learning parameters and an adapting offset. We show that the neuronal network is able to learn a task with sparse positive rewards as fast as the corresponding classical discrete-time TD algorithm. However, the performance of the neuronal network is impaired with respect to the traditional algorithm on a task with both positive and negative rewards and breaks down entirely on a task with purely negative rewards. Our model demonstrates that the asymmetry of a realistic dopaminergic signal enables TD learning when learning is driven by positive rewards but not when driven by negative rewards

Temporal-Difference Reinforcement Learning with Distributed Representations

Temporal-difference (TD) algorithms have been proposed as models of reinforcement learning (RL). We examine two issues of distributed representation in these TD algorithms: distributed representations of belief and distributed discounting factors. Distributed representation of belief allows the believed state of the world to distribute across sets of equivalent states. Distributed exponential discounting factors produce hyperbolic discounting in the behavior of the agent itself. We examine these issues in the context of a TD RL model in which state-belief is distributed over a set of exponentially-discounting “micro-Agents”, each of which has a separate discounting factor (γ). Each µAgent maintains an independent hypothesis about the state of the world, and a separate value-estimate of taking actions within that hypothesized state. The overall agent thus instantiates a flexible representation of an evolving world-state. As with other TD models, the value-error (δ) signal within the model matches dopamine signals recorded from animals in standard conditioning reward-paradigms. The distributed representation of belief provides an explanation for the decrease in dopamine at the conditioned stimulus seen in overtrained animals, for the differences between trace and delay conditioning, and for transient bursts of dopamine seen at movement initiation. Because each µAgent also includes its own exponential discounting factor, the overall agent shows hyperbolic discounting, consistent with behavioral experiments

The IceCube Data Acquisition System: Signal Capture, Digitization, and Timestamping

IceCube is a km-scale neutrino observatory under construction at the South Pole with sensors both in the deep ice (InIce) and on the surface (IceTop). The sensors, called Digital Optical Modules (DOMs), detect, digitize and timestamp the signals from optical Cherenkov-radiation photons. The DOM Main Board (MB) data acquisition subsystem is connected to the central DAQ in the IceCube Laboratory (ICL) by a single twisted copper wire-pair and transmits packetized data on demand. Time calibration is maintained throughout the array by regular transmission to the DOMs of precisely timed analog signals, synchronized to a central GPS-disciplined clock. The design goals and consequent features, functional capabilities, and initial performance of the DOM MB, and the operation of a combined array of DOMs as a system, are described here. Experience with the first InIce strings and the IceTop stations indicates that the system design and performance goals have been achieved.Comment: 42 pages, 20 figures, submitted to Nuclear Instruments and Methods