Sandra L. Harris

The p53 pathway: positive and negative feedback loops

The p53 pathway responds to stresses that can disrupt the fidelity of DNA replication and cell division. A stress signal is transmitted to the p53 protein by post-translational modifications. This results in the activation of the p53 protein as a transcription factor that initiates a program of cell cycle arrest, cellular senescence or apoptosis. The transcriptional network of p53-responsive genes produces proteins that interact with a large number of other signal transduction pathways in the cell and a number of positive and negative autoregulatory feedback loops act upon the p53 response. There are at least seven negative and three positive feedback loops described here, and of these, six act through the MDM-2 protein to regulate p53 activity. The p53 circuit communicates with the Wnt-beta-catenin, IGF-1-AKT, Rb-E2F, p38 MAP kinase, cyclin-cdk, p14/19 ARF pathways and the cyclin G-PP2A, and p73 gene products. There are at least three different ubiquitin ligases that can regulate p53 in an autoregulatory manner: MDM-2, Cop-1 and Pirh-2. The meaning of this redundancy and the relative activity of each of these feedback loops in different cell types or stages of development remains to be elucidated. The interconnections between signal transduction pathways will play a central role in our understanding of cancer.

Age and IQ at intake as predictors of placement for young children with autism: a four- to six-year follow-up.

The predictive power of age and IQ at time of admission to an intensive treatment program using applied behavior analysis were examined in a 4- to 6-year follow-up of educational placement. Twenty-seven children with autistic disorder who were between the ages of 31 and 65 months and had IQs on the Stanford Binet between 35 and 109 at time of admission to the Douglass Developmental Disabilities Center were followed up 4 to 6 years after they left the preschool. The results showed that having a higher IQ at intake (M = 78) and being of younger age (M = 42 months) were both predictive of being in a regular education class after discharge, whereas having a lower IQ (M = 46) and being older at intake (M = 54 months) were closely related to placement in a special education classroom. The results are interpreted as pointing to the need for very early intervention for children with Autistic Disorder. It is also emphasized that older children and those with lower IQs in the present study showed measurable gains in IQ from treatment. The data should not be taken to suggest that children older than 4 years of age do not merit high quality treatment.

The regulation of exosome secretion : a novel function of the p53 protein

The p53 protein responds to stress signals by regulating the transcription of a variety of genes. Some of these genes encode secreted proteins that may be involved in the communication between adjacent cells. In this study, a proteomics approach was employed to identify proteins secreted by cells in a p53-dependent manner after DNA damage. In addition to the known transcriptional targets of p53, a set of proteins encoded by genes that are not transcriptional targets of p53 were found to increase in the culture medium after p53 activation. These proteins exit the cell via small, secreted vesicles called exosomes and exosome production by cells was found to be regulated by the p53 response. A p53-regulated gene product, TSAP6, was shown to enhance exosome production in cells undergoing a p53 response to stress. Thus, the p53 pathway regulates the production of exosomes into the medium and these vesicles can communicate with adjacent cells and even cells of the immune system.

Teaching Social Skills to People with Autism

The treatment of social skills deficits remains one of the most challenging areas in meeting the needs of people with autism. Difficulties in understanding social stimuli, in initiating and responding to social bids, and in appreciating the affect that is intrinsic to social interactions can be baffling for people with autism. Researchers and practitioners of applied behavior analysis have tried a variety of strategies for teaching social skills. This article examines a range of useful procedures for teaching social skills to people with autism, including skills that are adult mediated, peer mediated, and child-with-autism mediated. The authors also consider the potential of classwide interventions in inclusive settings, pivotal response training, and the use of scripts to teach social initiations.

Changes in cognitive and language functioning of preschool children with autism.

Preschool children with autism and their normally developing peers were compared on the Stanford-Binet IV and Preschool Language Scale before and after 1 school year. Both measures showed that although the children with autism functioned at a lower level than their normally developing peers, the children with autism had narrowed this gap after treatment, making a nearly 19-point increase in IQ and an 8-point gain in language quotient. The IQ measure remained stable for the normally developing peers while their language showed a 7.73-point increase. The data support the notion that young children with autism can make very significant developmental gains.

Commitment to Philosophy, Teacher Efficacy, and Burnout Among Teachers of Children with Autism

Variables that may be related to burnout in teachers of students with autism, including commitment to an underlying philosophy of a treatment and professional self-efficacy, were explored. Teachers using one of two different treatment approaches to autism participated: those using Applied Behavior Analysis (n = 34), and those using TEACCH (Treatment and Education of Autistic and Related Communication-Related Handicapped Children) (n = 30). Participants completed the Autism Treatment Philosophy Questionnaire, developed by the authors to differentiate between the philosophy of the approaches; Teacher Efficacy Scale, and Maslach Burnout Inventory. Results indicate a significant difference in philosophical commitment between the groups, but no differences in teaching efficacy or burnout. The relationship between a commitment to ones teaching approach and certain dimensions of teaching efficacy and burnout was found to be significant. Implications include the need for adequate training of teachers of students with autism.

Changes in language development among autistic and peer children in segregated and integrated preschool settings

Five young children with autism enrolled in a segregated class, five other children with autism in an integrated class, and four normally developing peer children in the integrated class were compared for developmental changes in language ability as measured by the Preschool Language Scale before and after training. The results, based on Mann- Whitney U tests, showed that (a) all of the children as a group made better than normative progress in rate of language development, (b) the scores of the autistic children were significantly lower than the peers before and after treatment, and (c) there were no significant differences in changes in language ability between the autistic children in the segregated and integrated classes.

Treating self-injurious behavior of a retarded child by overcorrection

Overcorrection procedures applied to chronic self-injurious behavior of an 8-year-old rubella syndrome boy produced rapid suppression of self-injury. The procedure was implemented at school and at home with control maintained 24 hr a day. The results suggest that overcorrection may be useful in certain cases of self-injurious behavior and is a procedure that can be consistently applied by staff and parents.

Teaching children with autism to respond to joint attention initiations

ABSTRACT Children with autism fail to develop joint attention skills appropriate to developmental age. Joint attention is a predictor of ability in several core domains of autism including language, social development, affective sharing, and theory of mind capacity, thus establishing the significance of teaching joint attention. However, there is limited research to assist clinicians with methods to teach this skill. The present study used a multiple baseline with reversal design across three children to examine the effectiveness of a training program to teach children with autism to respond to successively more demanding joint attention initiations given by adults. Consistent with previous research, during baseline, all participants demonstrated low levels of joint attention skills. Following intervention, independent responses to joint attention bids were observed for all three participants. These findings support previous reports suggesting that behavioral intervention may facilitate the development of joint attention skills. An assessment before baseline and following treatment indicated no change in initiating joint attention skills, indicating that clinicians may have to teach these skills independently.

The acquisition of language skills by autistic children: Can parents do the job?

The mothers and fathers of 11 preschool autistic children were taught operant procedures used in teaching speech to nonverbal children. The childrens speech skills were assessed twice before and once after their parents were trained. At posttreatment, the children showed significant gains in prespeech and speech skills as measured by a 21-step hierarchy of speech behaviors. Those children who had acquired at least verbal imitative skill after training made greater progress than those who had not. Although children maintained their gains in a 1-year follow-up assessment, there was no evidence of significant improvement beyond that achieved at the end of training. The importance of support for parents in continuing to do formal “teaching” after the training program ends was stressed.