Group A streptococcal vaccine delivery by immunization with a self-adjuvanting M protein-based lipid core peptide construct

Background & objectives: To develop a broad strain coverage GAS vaccine, several strategies have been investigated which included multi-epitope approaches as well as targeting the M protein conserved C-region. These approaches, however, have relied on the use of adjuvants that are toxic for human application. The development of safe and effective adjuvants for human use is a key issue in the development of effective vaccines. In this study, we investigated the lipid polylysine core peptide (LCP) system as a self-adjuvanting GAS vaccine delivery approach. Methods: An LCP-GAS construct was synthesised incorporating multiple copies of a protective peptide epitope (J8) from the conserved carboxy terminal C-repeat region of the M protein. B10.BR mice were immunized parenterally with the LCP-J8 construct, with or without conventional adjuvant, prior to the assessment of immunogenicity and the induction of serum opsonic antibodies. Results: Our data demonstrated immunogenicity of LCP-J8 when coadministered in complete Freund's adjuvant (CFA), or administered in the absence of conventional adjuvant. In both cases, immunization led to the induction of high-titre J8 peptide-specific serum IgG antibody responses, and the induction of heterologous opsonic antibodies that did not cross-react with human heart tissue proteins. Interpretation & conclusion: These data indicated the potential of a novel self-adjuvanting LCP vaccine delivery system incorporating a synthetic GAS M protein C-region peptide immunogen in the induction of broadly protective immune responses, and pointed to the potential application of this system in human vaccine development against infectious diseases.

Synthesis and immunological evaluation of M protein targeted tetra-valent and tri-valent group A streptococcal vaccine candidates based on the lipid-core peptide system

Group A streptococcus (GAS) is responsible for causing many clinical complications including the relatively benign streptococcal pharyngitis and impetigo. However. if left untreated. these conditions may lead to more severe diseases such as rheumatic fever (RF) and rheumatic heart disease (RHD). These diseases exhibit high morbidity and mortality, Particularly in developing countries and in indigenous populations of affluent countries. Only ever occur following GAS infection, a vaccine offers Promise for their Prevention. As stich, we have investigated the Use of the lipid-core peptide (LCP) system for the development of multi-valent Prophylactic GAS vaccines. The current study has investigated the capacity of this system to adjuvant LIP to four different GAS peptide epitopes. Presented are the synthesis and immunological assessment of tetra-valent and tri-valent GAS LCP systems. We demonstrated their capacity to elicit systemic IgG antibody responses in B10.BR mice to all GAS peptide epitopes. The data also showed that the LCP systems Were self-adjuvanting. These findings are particularly encouraging for the development of multi-valent LCP-based GAS vaccines.

Synthesis of a highly pure lipid core peptide based self-adjuvanting triepitopic group A Streptococcal vaccine, and subsequent immunological evaluation

We have developed a highly pure, self-adjuvanting, triepitopic Group A Streptococcal vaccine based on the lipid core peptide system, a vaccine delivery system incorporating lipidic adjuvant, carrier, and peptide epitopes into a single molecular entity. Vaccine synthesis was performed using native chemical ligation. Due to the attachment of a highly lipophilic adjuvant, addition of 1% (w/v) sodium dodecyl sulfate was necessary to enhance peptide solubility in order to enable ligation. The vaccine was synthesized in three steps to yield a highly pure product (97.7% purity) with an excellent overall yield. Subcutaneous immunization of B10. BR (H-2(k)) mice with the synthesized vaccine, with or without the addition of complete Freund's adjuvant, elicited high serum IgG antibody titers against each of the incorporated peptide epitopes.

Lexical and nonlexical processing in developmental dyslexia: a case for different resources and different impairments

In a group of adult dyslexics word reading and, especially, word spelling are predicted more by what we have called lexical learning (tapped by a paired-associate task with pictures and written nonwords) than by phonological skills. Nonword reading and spelling, instead, are not associated with this task but they are predicted by phonological tasks. Consistently, surface and phonological dyslexics show opposite profiles on lexical learning and phonological tasks. The phonological dyslexics are more impaired on the phonological tasks, while the surface dyslexics are equally or more impaired on the lexical learning tasks. Finally, orthographic lexical learning explains more variation in spelling than in reading, and subtyping based on spelling returns more interpretable results than that based on reading. These results suggest that the quality of lexical representations is crucial to adult literacy skills. This is best measured by spelling and best predicted by a task of lexical learning. We hypothesize that lexical learning taps a uniquely human capacity to form new representations by recombining the units of a restricted set.

Lexical learning and dysgraphia in a group of adults with developmental dyslexia

We investigated the ability to learn new words in a group of 22 adults with developmental dyslexia/dysgraphia and the relationship between their learning and spelling problems. We identified a deficit that affected the ability to learn both spoken and written new words (lexical learning deficit). There were no comparable problems in learning other kinds of representations (lexical/semantic and visual) and the deficit could not be explained in terms of more traditional phonological deficits associated with dyslexia (phonological awareness, phonological STM). Written new word learning accounted for further variance in the severity of the dysgraphia after phonological abilities had been partialled out. We suggest that lexical learning may be an independent ability needed to create lexical/formal representations from a series of independent units. Theoretical and clinical implications are discussed. © 2005 Psychology Press Ltd.

A magnetoencephalographic study of low-level auditory processing in developmental dyslexia

The possibility that developmental dyslexia results from low-level sensory processing deficits has received renewed interest in recent years. Opponents of such sensory-based explanations argue that dyslexia arises primarily from phonological impairments. However, many behavioural correlates of dyslexia cannot be explained sufficiently by cognitive-level accounts and there is anatomical, psychometric and physiological evidence of sensory deficits in the dyslexic population. This thesis aims to determine whether the low-level (pre-attentive) processing of simple auditory stimuli is disrupted in compensated adult dyslexics. Using psychometric and neurophysiological measures, the nature of auditory processing abnormalities is investigated. Group comparisons are supported by analysis of individual data in order to address the issue of heterogeneity in dyslexia. The participant pool consisted of seven compensated dyslexic adults and seven age and IQ matched controls. The dyslexic group were impaired, relative to the control group, on measures of literacy, phonological awareness, working memory and processing speed. Magnetoencephalographic recordings were conducted during processing of simple, non-speech, auditory stimuli. Results confirm that low-level auditory processing deficits are present in compensated dyslexic adults. The amplitude of N1m responses to tone pair stimuli were reduced in the dyslexic group. However, there was no evidence that manipulating either the silent interval or the frequency separation between the tones had a greater detrimental effect on dyslexic participants specifically. Abnormal MMNm responses were recorded in response to frequency deviant stimuli in the dyslexic group. In addition, complete stimulus omissions, which evoked MMNm responses in all control participants, failed to elicit significant MMNm responses in all but one of the dyslexic individuals. The data indicate both a deficit of frequency resolution at a local level of auditory processing and a higher-level deficit relating to the grouping of auditory stimuli, relevant for auditory scene analysis. Implications and directions for future research are outlined.

Probing the neurocognitive trajectories of children's reading skills

Emerging evidence of the high variability in the cognitive skills and deficits associated with reading achievement and dysfunction promotes both a more dimensional view of the risk factors involved, and the importance of discriminating between trajectories of impairment. Here we examined reading and component orthographic and phonological skills alongside measures of cognitive ability and auditory and visual sensory processing in a large group of primary school children between the ages of 7 and 12 years. We identified clusters of children with pseudoword or exception word reading scores at the 10th percentile or below relative to their age group, and a group with poor skills on both tasks. Compared to age-matched and reading-level controls, groups of children with more impaired exception word reading were best described by a trajectory of developmental delay, whereas readers with more impaired pseudoword reading or combined deficits corresponded more with a pattern of atypical development. Sensory processing deficits clustered within both of the groups with putative atypical development: auditory discrimination deficits with poor phonological awareness skills; impairments of visual motion processing in readers with broader and more severe patterns of reading and cognitive impairments. Sensory deficits have been variably associated with developmental impairments of literacy and language; these results suggest that such deficits are also likely to cluster in children with particular patterns of reading difficulty. © 2012 Elsevier Ltd.

The neural correlates of reading impairment in adults with developmental dyslexia:evidence from fMRI between group analyses and an fMRI multiple-case study

The goal of this project was to investigate the neural correlates of reading impairment in dyslexia as hypothesised by the main theories – the phonological deficit, visual magnocellular deficit and cerebellar deficit theories, with emphasis on individual differences. This research took a novel approach by: 1) contrasting the predictions in one sample of participants with dyslexia (DPs); 2) using a multiple-case study (and between-group comparisons) to investigate differences in BOLD between each DP and the controls (CPs); 3) demonstrating a possible relationship between reading impairment and its hypothesised neural correlates by using fMRI and a reading task. The multiple-case study revealed that the neural correlates of reading in dyslexia in all cases are not in agreement with the predictions of a single theory. The results show striking individual differences - even, where the neural correlates of reading in two DPs are consistent with the same theory, the areas can differ. A DP can exhibit under-engagement in an area in word, but not in pseudoword reading and vice versa, demonstrating that underactivation in that area cannot be interpreted as a ‘developmental lesion’. Additional analyses revealed complex results. Within-group analyses between behavioural measures and BOLD showed correlations in the predicted regions, areas outside ROI, and lack of correlations in some predicted areas. Comparisons of subgroups which differed on Orthography Composite supported the MDT, but only for Words. The results suggest that phonological scores are not a sufficient predictor of the under-engagement of phonological areas during reading. DPs and CPs exhibited correlations between Purdue Pegboard Composite and BOLD in cerebellar areas only for Pseudowords. Future research into reading in dyslexia should use a more holistic approach, involving genetic and environmental factors, gene by environment interaction, and comorbidity with other disorders. It is argued that multidisciplinary research, within the multiple-deficit model holds significant promise here.

An incentivized auction based group-selling approach for demand response management in V2G systems

Vehicle-to-Grid (V2G) system with efficient Demand Response Management (DRM) is critical to solve the problem of supplying electricity by utilizing surplus electricity available at EVs. An incentivilized DRM approach is studied to reduce the system cost and maintain the system stability. EVs are motivated with dynamic pricing determined by the group-selling based auction. In the proposed approach, a number of aggregators sit on the first level auction responsible to communicate with a group of EVs. EVs as bidders consider Quality of Energy (QoE) requirements and report interests and decisions on the bidding process coordinated by the associated aggregator. Auction winners are determined based on the bidding prices and the amount of electricity sold by the EV bidders. We investigate the impact of the proposed mechanism on the system performance with maximum feedback power constraints of aggregators. The designed mechanism is proven to have essential economic properties. Simulation results indicate the proposed mechanism can reduce the system cost and offer EVs significant incentives to participate in the V2G DRM operation.

The exploration enhancement workshop: An exploration-based approach to facilitating identity formation in young adults

This dissertation reports an investigation of the utility of two intervention programs to facilitate identity formation by way of exploration, one designed from an explicitly self-construction point of view and the other designed from an explicitly self-discovery point of view. The self-construction program was implemented using cognitive skills and orientations derived from Berzonsky (1989), Grotevant (1987), and Kurtines (1999). The self-discovery program was implemented using affective insight development strategies derived from Csikszentmihalyi (1990), Maslow (1968), and Waterman (1990). Three sets of measures were used: (a) cognitive identity measures, (b) affective identity measures, and (c) overall identity measures. Ninety undergraduates from Florida International University completed the intervention. Participants were assigned to one of three intervention conditions (Cognitive, Affective, and Control) and were pretested and posttested on cognitive, affective, and overall identity measures. Intervention strategies were introduced and discussed in the context of specific goals and choices that participants brought to group. Intervention results were then analyzed in terms of the effectiveness of the intervention conditions in promoting their respective developmental domains. The intervention was effective in promoting identity development in comparison to the control condition, with the cognitive condition facilitating cognitive competence and the affective condition facilitating affective insight. Results are discussed in the context of the constructivist and discovery perspectives, as well as in light of the broadened view of exploration offered in this paper. ^

Predictors of developmental gains in children enrolled in an early intervention setting

The purpose of this research was to determine whether initial developmental delay, site of intervention, frequency of intervention, age of the child, socio-economic status (SES), gender and ethnicity significantly predict developmental gains in a group of children enrolled in an early intervention setting. The records of 134 children enrolled in an inner-city program in Miami, Florida were reviewed for inclusion in this study. ^ Demographic variables, site placement and treatment frequencies were collected during a retrospective chart review. Level of delay was expressed using the developmental quotient and developmental gain was calculated using the mean gain on age equivalent scores or developmental tests. A multiple regression analysis was performed to determine which of the above variables significantly predicted developmental gains. Multivariate analysis compared developmental gains for all the developmental domains based on intervention site (center versus home-based) while controlling for developmental delay. ^ Children made greater developmental gains if they had higher developmental quotients and if they were younger at the time services were initiated. Frequency of intervention significantly improved developmental outcomes in children attending center-based programs. Children attending center-based programs also made significantly greater gains in gross motor skills compared to children attending home-based programs. ^ These findings emphasize the importance of early screening and referral of children with developmental delay and adjusting intervention for the child's developmental quotient. Children should receive intense treatment to maximize results. Decisions regarding program placement should be individualized according to the child's unique developmental pattern. Policy and program decisions affecting the curriculum of a child in early intervention need to reflect these multivariate considerations. ^