Transcriptional profiling of HERV-K(HML-2) in amyotrophic lateral sclerosis and potential implications for expression of HML-2 proteins

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. About 90% of ALS cases are without a known genetic cause. The human endogenous retrovirus multi-copy HERV-K(HML-2) group was recently reported to potentially contribute to neurodegeneration and disease pathogenesis in ALS because of transcriptional upregulation and toxic effects of HML-2 Envelope (Env) protein. Env and other proteins are encoded by some transcriptionally active HML-2 loci. However, more detailed information is required regarding which HML-2 loci are transcribed in ALS, which of their proteins are expressed, and differences between the disease and non-disease states. Methods For brain and spinal cord tissue samples from ALS patients and controls, we identified transcribed HML-2 loci by generating and mapping HML-2-specific cDNA sequences. We predicted expression of HML-2 env gene-derived proteins based on the observed cDNA sequences. Furthermore, we determined overall HML-2 transcript levels by RT-qPCR and investigated presence of HML-2 Env protein in ALS and control tissue samples by Western blotting. Results We identified 24 different transcribed HML-2 loci. Some of those loci are transcribed at relatively high levels. However, significant differences in HML-2 loci transcriptional activities were not seen when comparing ALS and controls. Likewise, overall HML-2 transcript levels, as determined by RT-qPCR, were not significantly different between ALS and controls. Indeed, we were unable to detect full-length HML-2 Env protein in ALS and control tissue samples despite reasonable sensitivity. Rather our analyses suggest that a number of HML-2 protein variants other than full-length Env may potentially be expressed in ALS patients. Conclusions Our results expand and refine recent publications on HERV-K(HML-2) and ALS. Some of our results are in conflict with recent findings and call for further specific analyses. Our profiling of HML-2 transcription in ALS opens up the possibility that HML-2 proteins other than canonical full-length Env may have to be considered when studying the role of HML-2 in ALS disease

DEVELOPING STIMULUS CONTROL OF THE HIGH-RATE SOCIAL-APPROACH RESPONSES OF AN ADULT WITH MENTAL RETARDATION: A MULTIPLE-SCHEDULE EVALUATION

We evaluated a multiple schedule in which the extinction (S−) components were signaled overtly by a black lanyard and the reinforcement (S+) components were not correlated with any programmed stimuli in developing stimulus control over the high-rate social-approach responses of an adult with mental retardation. Responding was consistently low in the presence of the S− and consistently high when the lanyard was absent (i.e., the S+ condition). Component durations were thinned successfully to a level that was manageable for caregivers

Deviations from Prescribed Prompting Procedures: Implications for Treatment Integrity

Abstract The acquisition of new skills may be hindered when teaching procedures vary from previously validated approaches or contain errors. In the present study, we compared the acquisition and maintenance of response chains taught using a perfectly implemented system of least prompts and a multiple verbal prompts procedure (i.e., addition of multiple verbal prompts and failure to follow through with more intrusive prompts). Four children, aged 6-9, participated in the study. An adapted alternating treatments design was used to compare the effectiveness and efficiency of learning during the system of least prompts and the alternative system of least prompts. Results were consistent with those obtained in previous studies in that the perfectly implemented and alternative prompting procedures were effective in teaching new skills for all participants. However, the perfectly implemented treatment required fewer trials to mastery for 4 of the 5 evaluations. Response chains taught under the multiple verbal prompts condition had poorer maintenance for 2 of the 5 evaluations. The results of the current study suggest that deviations from empirically identified teaching procedures may reduce the speed with which new skills are acquired

Preference for Reinforcers Under Progressive- and Fixed-Ratio Schedules: A Comparison of Single and Concurrent Arrangements

Progressive-ratio (PR) schedules were used to identify the break point (i.e., the last schedule value completed) for 2 reinforcers under single and concurrent schedules. After the respective break points were established, the same reinforcers were presented under concurrent fixed-ratio (FR) schedules that were yoked to the break points obtained with the PR schedules. Results suggested that the participants responded more for the high-preference item than for the low-preference item, regardless of the presentation arrangement (single or concurrent presentations). This pattern of responding was maintained when the reinforcers were presented under dissimilar FR schedules. The results suggest that responding for differentially preferred stimuli may vary as a function of differences in schedule requirements

MANDS FOR INFORMATION GENERALIZE ACROSS ESTABLISHING OPERATIONS

The current study extends the literature on teaching mands for information by assessing whether mands generalize across different establishing operations (EOs). Three children with autism were taught to perform multiple behavior chains, 3 of which included a common response (e.g., “Where is the spoon?”) used for different purposes. An interrupted-behavior-chain procedure was used to contrive the EO for each mand. After teaching a mand for information under 1 EO, the remaining chains were interrupted to determine whether the mand had generalized to different EOs. For all participants, mands for information generalized across EOs. For 2 participants, a new mand-for-information topography emerged after training

Utility of Extinction-induced Response Variability for the Selection of Mands

Functional communication training (FCT; Carr & Durand, 1985) is a commonly used differential reinforcement procedure for replacing problem behavior with socially acceptable alternative responses. Most studies in the FCT literature consist of demonstrations of the maintenance of responding when various treatment components (e.g., extinction, punishment) are present and absent (e.g., Fisher et al., 1993; Wacker et al., 1990). Relatively little research on FCT has (a) evaluated the conditions under which alternative responses are acquired or (b) described procedures with technological precision. Thus, additional research on a cogent technology for response acquisition appears to be warranted. In the current study, we evaluated the efficacy of exposing problem behavior to extinction for inducing response variability as a tool for selecting an alternative response during FCT. Once participants engaged in appropriate alternative responses, the reinforcer identified in the functional analysis as maintaining problem behavior was delivered contingent on the alternative behavior. Results showed that exposing problem behavior to extinction was a useful method for producing alternative behaviors during FCT

A COMPARISON OF METHODS FOR TEACHING RECEPTIVE LABELING TO CHILDREN WITH AUTISM SPECTRUM DISORDERS

Many early intervention curricular manuals recommend teaching auditory-visual conditional discriminations (i.e., receptive labeling) using the simple-conditional method in which component simple discriminations are taught in isolation and in the presence of a distracter stimulus before the learner is required to respond conditionally. Some have argued that this procedure might be susceptible to faulty stimulus control such as stimulus overselectivity (Green, 2001). Consequently, there has been a call for the use of alternative teaching procedures such as the conditional-only method, which involves conditional discrimination training from the onset of intervention. The purpose of the present study was to compare the simple-conditional and conditional-only methods for teaching receptive labeling to 3 young children diagnosed with autism spectrum disorders. The data indicated that the conditional-only method was a more reliable and efficient teaching procedure. In addition, several error patterns emerged during training using the simple-conditional method. The implications of the results with respect to current teaching practices in early intervention programs are discussed

EVALUATION OF AN ENHANCED STIMULUS–STIMULUS PAIRING PROCEDURE TO INCREASE EARLY VOCALIZATIONS OF CHILDREN WITH AUTISM

Evidence to support stimulus–stimulus pairing (SSP) in speech acquisition is less than robust, calling into question the ability of SSP to reliably establish automatically reinforcing properties of speech and limiting the procedure's clinical utility for increasing vocalizations. We evaluated the effects of a modified SSP procedure on low-frequency within-session vocalizations that were further strengthened through programmed reinforcement. Procedural modifications (e.g., interspersed paired and unpaired trials) were designed to increase stimulus salience during SSP. All 3 participants, preschoolers with autism, showed differential increases of target over nontarget vocal responses during SSP. Results suggested an automatic reinforcement effect of SSP, although alternative interpretations are discussed, and suggestions are made for future research to determine the utility of SSP as a clinical intervention for speech-delayed children