ASD: the Alternative Splicing Database

Alternative splicing is widespread in mammalian gene expression, and variant splice patterns are often specific to different stages of development, particular tissues or a disease state. There is a need to systematically collect data on alternatively spliced exons, introns and splice isoforms, and to annotate this data. The Alternative Splicing Database consortium has been addressing this need, and is committed to maintaining and developing a value-added database of alternative splice events, and of experimentally verified regulatory mechanisms that mediate splice variants. In this paper we present two of the products from this project: namely, a database of computationally delineated alternative splice events as seen in alignments of EST/cDNA sequences with genome sequences, and a database of alternatively spliced exons collected from literature. The reported splice events are from nine different organisms and are annotated for various biological features including expression states and cross-species conservation. The data are presented on our ASD web pages (http://www.ebi.ac.uk/asd).

Brain oscillations and connectivity in autism spectrum disorders (ASD):new approaches to methodology, measurement and modelling

Although atypical social behaviour remains a key characterisation of ASD, the presence ofsensory and perceptual abnormalities has been given a more central role in recentclassification changes. An understanding of the origins of such aberrations could thus prove afruitful focus for ASD research. Early neurocognitive models of ASD suggested that thestudy of high frequency activity in the brain as a measure of cortical connectivity mightprovide the key to understanding the neural correlates of sensory and perceptual deviations inASD. As our review shows, the findings from subsequent research have been inconsistent,with a lack of agreement about the nature of any high frequency disturbances in ASD brains.Based on the application of new techniques using more sophisticated measures of brainsynchronisation, direction of information flow, and invoking the coupling between high andlow frequency bands, we propose a framework which could reconcile apparently conflictingfindings in this area and would be consistent both with emerging neurocognitive models ofautism and with the heterogeneity of the condition.

The differential impact of oxytocin receptor (OXTR) genotypes on the risk of autism spectrum disorder (ASD) and resulting social communication deficits

Background: Autism spectrum disorder (ASD) is multifactorial and is likely the result of complex interactions between multiple environmental and genetic factors. Recently, it has been suggested that each symptom cluster of the disorder, such as poor social communication, may be mediated by different genetic influences. Genes in the oxytocin pathway, which mediates social behaviours in humans, have been studied with single nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) being implicated in ASD. This thesis examines the presence of different oxytocin receptor genotypes, and their associations with ASD and resulting social communication deficits. Methods: The relationship between four OXTR variants and ASD was evaluated in 607 ASD simplex (SPX) families. Cases were compared to their unaffected siblings using a conditional logistic approach. Odds ratios and associated 95 percent confidence intervals were obtained. A second sample of 235 individuals with a diagnosis of ASD was examined to evaluate whether these four OXTR variants were associated with social communication scores on the Autism Diagnostic Interview – Revised (ADI-R). Parameter estimates and associated 95 percent confidence intervals were generated using a linear regression approach. Multiple testing issues were addressed using false discovery adjustments. Results: The rs53576 AG genotype was significantly associated with a lower risk of ASD (OR = 0.707, 95% CI: 0.512-0.975). A single genotype (AG) provided by the rs2254298 marker was found to be significantly associated with higher social communication scores (Parameter estimate = 1.833, SE = 0.762, p = 0.0171). This association was also seen in a Caucasian only and mothers as the respondent samples. No association was significant following false discovery rate adjustments. Conclusion: The findings from these studies provide limited support for the role of OXTR SNPs in ASD, especially in social communication skills. The clinical significance of these associations remains unknown, however, it is likely that these associations do not play a role in the severity of symptoms associated with ASD. Rather, they may be important in the appearance of social deficits due to the rs2254298 markers association with enlarged amygdalas.

Characteristics of change triggered temper outbursts in children with PWS and ASD and how these may impact on the efficacy of behavioural intervention strategies.

Background
Temper outbursts are prevalent in individuals with PWS and are often triggered by unexpected changes to routines or plans. However, such outbursts are also common in individuals with several other neurodevelopmental disorders, including those with a diagnosis of autism spectrum disorder (ASD). We compared the profile of temper outbursts in children with PWS to that in children with ASD. We examined whether differences in the temper outburst profile predicted differences in the outcomes of two caregiver led intervention strategies aiming to reduce change triggered outbursts.
Methods and results
Thirteen 7-15 year olds with PWS – taking part in a larger study involving 60 children evidencing temper outbursts following changes – were individually matched for age to children with ASD (mean ages: 10.70; 10.76 yrs). Caregivers participated in a structured/semi-structured interview on children's outbursts; completed a web-based outburst diary over a 6 month baseline; and are currently using either a change signalling intervention to reliably warn children of forthcoming changes; or a planning ahead intervention to reduce children's exposure to unexpected changes.
As reported at interview, on average, children with PWS showed more frequent temper outbursts than those with ASD (closer to daily vs. weekly). For seven children with PWS and six with ASD, 60% or more of their temper outbursts were reported to be triggered by changes. Whilst outbursts had similar durations when triggered by changes or by other events in children with PWS; change triggered outbursts in children with ASD were generally shorter. The most commonly reported outburst components in children with PWS included indicators of heightened emotional arousal but this was not the case for children with ASD. Data on behavioural change associated with each of the intervention strategies will be discussed.
Conclusions
Change triggered temper outbursts can be a problem for children PWS and ASD, however subtle differences appear to exist in the profile of these outbursts. Some of these differences may be relevant for the expected efficacy of different behavioural intervention strategies that target outbursts.
Summary
Temper outbursts (tantrums) were compared in children with PWS or autism spectrum disorder before and during use of one of two helping strategies. Helping strategies were led by caregivers and aimed to reduce outbursts that follow changes to routines or plans by making such changes more predictable, or by reducing the quantity of changes. Characteristics of outbursts may be important to help us predict which helping strategies may be most effective.

Planning for the Unseen and Unheard: the child with ASD

“Children are a kind of indicator species.
If we can build a successful city for children,
we will have a successful city for all people.”

Enrique Peñalosa (former mayor of Bogotá)

Should society be judged by how they treat their weakest members, the concept of the Child Friendly City offers more than ample scope for critiquing the genuine health and inclusivity of our urban environments. If we accept childhood as a crucial human development phase that demands inclusive and welcoming places for play, exploration and growth, many cities today are becoming increasingly barren habitats, arguably full of nothing but empty childhoods. (Raven-Ellison 2015) With children today less able to roam and explore our streets than those of yesteryear, (Bird 2007) the situation is now developing where our young are becoming increasingly socially and spatially excluded from our supposedly shared Built Environment. That progressively restrictive urban realm is particularly pronounced for those with Autism Spectrum Disorder, for whom our cities can be disorientating, difficult and even frightening places.

As a profession we have a responsibility to provide inclusive built environments that do not preclude the presence of the most vulnerable in society, among them those with ASD. Accordingly this paper seeks to introduce emerging research into the current challenges facing these young urban stakeholders before discussing how planning processes and design interventions might make our cities more accessible to those with ASD.

References:

Bird, W. (2007) Natural Thinking, Sandy, Bedfordshire: RSPB.

Raven-Ellison, D. (2015) “London’s Empty Childhoods” in London Essays – Green Spaces, Issue 3 – found at: http://essays.centreforlondon.org/issues/green/londons-empty-childhoods/ accessed 9th May 2016.

Increased frequency of the autism broader phenotype in mothers transmitting etiological CNVs to sons affected by Autism Spectrum Disorder (ASD)

Autism Spectrum Disorder (ASD) is a frequent and complex neurodevelopmental disorder, characterized by impairments in social communication and repetitive behaviors and with a high male to female ratio: ~4:1. Genetic factors, including rare Copy Number Variants (CNVs), have a substantial impact in ASD risk1, and are associated with specific phenotypic manifestations2. Recent studies reported that rare inherited CNVs are enriched in mothers of ASD children compared with mothers of controls and are preferentially transmitted from mothers to ASD children suggesting a sex bias in CNV transmission; further, the imbalanced transmission of small pathogenic CNVs from unaffected mothers to their sons with ASD has been described3,4. An increased prevalence of autism-like personality traits is found in unaffected relatives of ASD children, suggesting a genetic liability of a broader autism phenotype (BAP)5. The BAP in parents of autistic children can be assessed by the Social Responsiveness Scale (SRS)6 and Broad Autism Phenotype Questionnaire (BAPQ)7 reports. The SRS is 65-item questionnaire to identify sub-clinical social impairments and interpersonal behaviour in individuals. The BAPQ is a 36-item questionnaire measures social aloofness, rigid personality, and pragmatic language deficits in both parents and children.

Gene-environment interactions in Autism Spectrum Disorders (ASD)

Spectrum Disorder (ASD), is a heterogeneous neurodevelopmental disorder with na estimated global prevalence rate of 17:10000, and a male to female ratio of 4:1. Patients with ASD presente language and communication difficulties and stereotyped behaviours. Comorbidity with other disorders, such as Intelectual Disability, Fragile-X syndrome (FXS) epilepsy and tuberous sclerosis frequently occurs. ASD presents amultifactorial etiopathology, and genetic factos alone are not suficiente to explain how the syndrome arises, with recente studies establishing ASD heritability at approximately 50%. Pre-, peri- and post-natal exposure to toxic environmental factos has been implicated in the development of ASD. Involvement of epigenetic regulatory mechanisms has been suggested, supported by the occurrence of autistic symptoms in patients with disorders aris ing from epigenetic mutations, such as FXS. A polygenic and epistatic model is a strong hypothesis to explain ASD. The main goal of this project is to identify specific exposure patterns to environmental toxicants in children diagnosed with ASD and integrate the results with genetic and epigenetic data.

Neuropsychiatric disease (NPD) clustering in families with Autism Spectrum Disorder (ASD): genetic, epigenetic and environmental issues

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication/interaction and by unusual repetitive and restricted behaviors and interests. ASD often co-occurs in the same families with other neuropsychiatric diseases (NPD), such as intellectual disability, schizophrenia, epilepsy, depression and attention deficit hyperactivity disorder. Genetic factors have an important role in ASD etiology. Multiple copy number variants (CNVs) and single nucleotide variants (SNVs) in candidate genes have been associated with an increased risk to develop ASD. Nevertheless, recent heritability estimates and the high genotypic and phenotypic heterogeneity characteristic of ASD indicate a role of environmental and epigenetic factors, such as long noncoding RNA (lncRNA) and microRNA (miRNA), as modulators of genetic expression and further clinical presentation. Both miRNA and lncRNA are functional RNA molecules that are transcribed from DNA but not translated into proteins, instead they act as powerful regulators of gene expression. While miRNA are small noncoding RNAs with 22-25 nucleotides in length that act at the post-transcriptional level of gene expression, the lncRNA are bigger molecules (>200 nucleotides in length) that are capped, spliced, and polyadenylated, similar to messenger RNA. Although few lncRNA were well characterized until date, there is a great evidence that they are implicated in several levels of gene expression (transcription/post-transcription/post-translation, organization of protein complexes, cell– cell signaling as well as recombination) as shown in figure 1.

Maternal Copy Number Variants (CNV) transmission to their Autism Spectrum Disorder (ASD) sons correlates with phenotypic traits

Background: Common neurodevelopmental disorder, global prevalence ~1 %; Persistent deficits in social communication and social interaction; restricted and repetitive behavior, interests, or activities; Highly heterogeneous clinical presentation; Male to female ratio ~4:1.

The Autistic Behavioural Indicators Instrument (ABII) : development and instrument utility in discriminating autistic disorder from speech and language impairment and typical development

The Autistic Behavioural Indicators Instrument (ABII) is an 18-item instrument developed to identify children with Autistic Disorder (AD) based on the presence of unique autistic behavioural indicators. The ABII was administered to 20 children with AD, 20 children with speech and language impairment (SLI) and 20 typically developing (TD) children aged 2-6 years. Results indicated that the ABII discriminated children diagnosed with AD from those diagnosed with SLI and those who were TD, based on the presence of specific social attention, sensory, and behavioural symptoms. A combination of symptomology across these domains correctly classified 100% of children with and without AD. The paper concludes that the ABII shows considerable promise as an instrument for the early identification of AD.

Effect of selected feed meals and starches on diet digestibility in the mud crab, Scylla serrata

The present study examined the capacity of the mud crab, Scylla serrata to digest experimental diets that contained different animal and plant-based feed meals or different levels or types of starch. The apparent dry matter digestibility (ADMD) coefficients for all feed meals tested in the first part of this study, except meat meal, were similar (78–88%). Crude protein digestibility (ACPD) coefficients for all feed meals were relatively high, with values ranging from 86% to 96%. Cotton seed meal, poultry meal, canola meal, fishmeal, soybean meal and lupin meal had similar gross energy digestibility (AGED) values (P>0.05) ranging from 84% to 89%. In the second part of this study, the impact of selected starches on the digestibility of fishmeal-based formulated diets was assessed. The apparent starch digestibility (ASD) of wheat starch decreased significantly as the inclusion level was increased from 15% to 60%, however, there was no significant effect on ACPD values. At a 30% inclusion level, the ASD of diets containing different starches decreased in the order corn>wheat>potato=rice. Moreover, ACPD values were significantly higher (P<0.05) in the diets containing corn or rice starch than in those containing wheat or potato starches.

Theory-of-Mind Continuum Model: Why Mind Matters in Philosophy, Psychology and Education

Theory-of-Mind has been defined as the ability to explain and predict human behaviour by imputing mental states, such as attention, intention, desire, emotion, perception and belief, to the self and others (Astington & Barriault, 2001). Theory-of-Mind study began with Piaget and continued through a tradition of meta-cognitive research projects (Flavell, 2004). A study by Baron-Cohen, Leslie and Frith (1985) of Theory-of-Mind abilities in atypically developing children reported major difficulties experienced by children with autism spectrum disorder (ASD) in imputing mental states to others. Since then, a wide range of follow-up research has been conducted to confirm these results. Traditional Theory-of-Mind research on ASD has been based on an either-or assumption that Theory-of-Mind is something one either possesses or does not. However, this approach fails to take account of how the ASD population themselves experience Theory-of-Mind. This paper suggests an alternative approach, Theory-of-Mind continuum model, to understand the Theory-of-Mind experience of people with ASD. The Theory-of-Mind continuum model will be developed through a comparison of subjective and objective aspects of mind, and phenomenal and psychological concepts of mind. This paper will demonstrate the importance of balancing qualitative and quantitative research methods in investigating the minds of people with ASD. It will enrich our theoretical understanding of Theory-of-Mind, as well as contain methodological implications for further studies in Theory-of-Mind

Remediation strategies of shaft and common mode voltages in adjustable speed drive systems

AC motors are largely used in a wide range of modern systems, from household appliances to automated industry applications such as: ventilations systems, fans, pumps, conveyors and machine tool drives. Inverters are widely used in industrial and commercial applications due to the growing need for speed control in ASD systems. Fast switching transients and the common mode voltage, in interaction with parasitic capacitive couplings, may cause many unwanted problems in the ASD applications. These include shaft voltage and leakage currents. One of the inherent characteristics of Pulse Width Modulation (PWM) techniques is the generation of the common mode voltage, which is defined as the voltage between the electrical neutral of the inverter output and the ground. Shaft voltage can cause bearing currents when it exceeds the amount of breakdown voltage level of the thin lubricant film between the inner and outer rings of the bearing. This phenomenon is the main reason for early bearing failures. A rapid development in power switches technology has lead to a drastic decrement of switching rise and fall times. Because there is considerable capacitance between the stator windings and the frame, there can be a significant capacitive current (ground current escaping to earth through stray capacitors inside a motor) if the common mode voltage has high frequency components. This current leads to noises and Electromagnetic Interferences (EMI) issues in motor drive systems. These problems have been dealt with using a variety of methods which have been reported in the literature. However, cost and maintenance issues have prevented these methods from being widely accepted. Extra cost or rating of the inverter switches is usually the price to pay for such approaches. Thus, the determination of cost-effective techniques for shaft and common mode voltage reduction in ASD systems, with the focus on the first step of the design process, is the targeted scope of this thesis. An introduction to this research – including a description of the research problem, the literature review and an account of the research progress linking the research papers – is presented in Chapter 1. Electrical power generation from renewable energy sources, such as wind energy systems, has become a crucial issue because of environmental problems and a predicted future shortage of traditional energy sources. Thus, Chapter 2 focuses on the shaft voltage analysis of stator-fed induction generators (IG) and Doubly Fed Induction Generators DFIGs in wind turbine applications. This shaft voltage analysis includes: topologies, high frequency modelling, calculation and mitigation techniques. A back-to-back AC-DC-AC converter is investigated in terms of shaft voltage generation in a DFIG. Different topologies of LC filter placement are analysed in an effort to eliminate the shaft voltage. Different capacitive couplings exist in the motor/generator structure and any change in design parameters affects the capacitive couplings. Thus, an appropriate design for AC motors should lead to the smallest possible shaft voltage. Calculation of the shaft voltage based on different capacitive couplings, and an investigation of the effects of different design parameters are discussed in Chapter 3. This is achieved through 2-D and 3-D finite element simulation and experimental analysis. End-winding parameters of the motor are also effective factors in the calculation of the shaft voltage and have not been taken into account in previous reported studies. Calculation of the end-winding capacitances is rather complex because of the diversity of end winding shapes and the complexity of their geometry. A comprehensive analysis of these capacitances has been carried out with 3-D finite element simulations and experimental studies to determine their effective design parameters. These are documented in Chapter 4. Results of this analysis show that, by choosing appropriate design parameters, it is possible to decrease the shaft voltage and resultant bearing current in the primary stage of generator/motor design without using any additional active and passive filter-based techniques. The common mode voltage is defined by a switching pattern and, by using the appropriate pattern; the common mode voltage level can be controlled. Therefore, any PWM pattern which eliminates or minimizes the common mode voltage will be an effective shaft voltage reduction technique. Thus, common mode voltage reduction of a three-phase AC motor supplied with a single-phase diode rectifier is the focus of Chapter 5. The proposed strategy is mainly based on proper utilization of the zero vectors. Multilevel inverters are also used in ASD systems which have more voltage levels and switching states, and can provide more possibilities to reduce common mode voltage. A description of common mode voltage of multilevel inverters is investigated in Chapter 6. Chapter 7 investigates the elimination techniques of the shaft voltage in a DFIG based on the methods presented in the literature by the use of simulation results. However, it could be shown that every solution to reduce the shaft voltage in DFIG systems has its own characteristics, and these have to be taken into account in determining the most effective strategy. Calculation of the capacitive coupling and electric fields between the outer and inner races and the balls at different motor speeds in symmetrical and asymmetrical shaft and balls positions is discussed in Chapter 8. The analysis is carried out using finite element simulations to determine the conditions which will increase the probability of high rates of bearing failure due to current discharges through the balls and races.