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Parkinson’s disease (PD) is a devastating neurodegenerative disease and the second most prevalent after Alzheimer’s disease. The most characteristic hallmark of Parkinson’s is the presence of Lewy Bodies, clumps of aggregated α-synuclein protein, in the Substantia Nigra. While much has been said and theorized about α-synuclein, mitochondrial dysregulation in neurons of Parkinson’s patients is an equally important consideration due to the role that the mitochondria plays in supplying neurons with their energy needs through ATP. C. elegans is a non-vertebrate animal often used to study aging and neurodegenerative disease due to its simple, well characterized genome. This literature review aims to outline the genetic and some environmental factors that cause mitochondrial dysregulation leading to the progressive neurodegeneration witnessed in Parkinson’s, as modeled in C. elegans. Through a select review of studies done on C. elegans homolog of genes associated with mitochondrial function, this review aims to elucidate the mechanism by which each mutation not only causes the deficits seen in PD on its own but also how it interacts with other genes to worsen or alleviate symptoms. Ultimately, understanding these pathways and mechanism will be crucial to discovering and creating new therapeutic treatments and targets.

T cells are critical for the control of viral infections and T cell responses are regulated by a dynamic network of non-coding RNAs, including microRNAs (miR) and long non-coding RNAs (lncRNA). Here we show that an activation-induced decline of lncRNA growth arrest-specific transcript 5 (GAS5) activates DNA damage response (DDR), and regulates cellular functions and apoptosis in CD4 T cells derived from people living with HIV (PLHIV) via upregulation of miR-21. Notably, GAS5-miR21-mediated DDR and T cell dysfunction are observed in PLHIV on antiretroviral therapy (ART), who often exhibit immune activation due to low-grade inflammation despite robust virologic control. We found that GAS5 negatively regulates miR-21 expression, which in turn controls critical signaling pathways involved in DNA damage and cellular response. The sustained stimulation of T cells decreased GAS5, increased miR-21 and, as a result, caused dysfunction and apoptosis in CD4 T cells. Importantly, this inflammation-driven T cell over-activation and aberrant apoptosis in ART-controlled PLHIV and healthy subjects (HS) could be reversed by antagonizing the GAS5-miR-21 axis. Also, mutation of the miR-21 binding site on exon 4 of GAS5 gene to generate a GAS5 mutant abolished its ability to regulate miR-21 expression as well as T cell activation and apoptosis markers compared to the wild-type GAS5 transcript. Our data suggest that GAS5 regulates TCR-mediated activation and apoptosis in CD4 T cells during HIV infection through miR-21-mediated signaling. However, GAS5 effects on T cell exhaustion during HIV infection may be mediated by a mechanism beyond the GAS5-miR-21-mediated signaling. These results indicate that targeting the GAS5-miR-21 axis may improve activity and longevity of CD4 T cells in ART-treated PLHIV. This approach may also be useful for targeting other infectious or inflammatory diseases associated with T cell over-activation, exhaustion, and premature immune aging.

HCV infection is associated with immune dysregulation and B cell Non-Hodgkins lymphoma (HCV-NHL). We have previously shown in vitro that HCV core protein differentially regulates T and B cell functions through two negative signaling pathways, programmed death-1 (PD-1) and suppressor of cytokine signaling-1 (SOCS-1). In this report, we performed a detailed immunologic analysis of T and B cell functions in the setting of HCV-NHL. We observed that T cells isolated from patients with HCV-NHL exhibited an exhausted phenotype including decreased expression of viral-specific and non-specific activation markers; whereas B cells exhibited an activated phenotype including over-expression of cell activation markers and immunoglobulins compared to healthy subjects. Individuals with HCV alone or NHL alone exhibited abnormal T and B cell phenotypes, but to a lesser extent compared to HCV-NHL. This differential activation of T and B lymphocytes was inversely associated with the expression of PD-1 and SOCS-1. Interestingly, blocking PD-1 during TCR activation inhibited SOCS-1 gene expression, suggesting that these regulatory pathways are linked in T cells. Importantly, blocking PD-1 also restored the impaired T cell functions observed in the setting of HCV-NHL. These results support a coordinated mechanism by which HCV might cause immune dysregulation that is associated to HCV-NHL.

Si l’étiologie de l’autisme reste mal identifiée, ce trouble est caractérisé par des déficits de la communication sociale, notamment de l’attention conjointe, une importante difficulté à comprendre autrui comme agent intentionnel, un manque d’empathie et des déficits d’imitation. Cette recherche a pour objectifs d’étudier d’une part le lien entre la dysrégulation d’attention conjointe et le développement ultérieur de la communication sociale et d’autre part l’impact d’un programme d’intervention individuelle centrée sur l’hétérorégulation de l’attention conjointe chez de jeunes enfants avec autisme. Il s’agit d’une étude à la fois longitudinale (12 mois) et transversale qui porte sur 10 jeunes enfants avec autisme appariés par âge de développement à 10 jeunes enfants avec trisomie 21 et 10 enfants tout-venants. Le développement psychologique des enfants de ces trois groupes est évalué à l’aide de tests psychométriques validés et étalonnés (Brunet-Lézine, BECS, EDEI-R). L’évaluation de la dysrégulation de l’activité d’attention conjointe et de la communication sociale est réalisée au cours de séances d’activités ludiques au moyen d’outils cliniques originaux. L’analyse comparative des résultats met en évidence une dysrégulation dans les processus d’attention conjointe (désynchronisation, persévérations, ruptures, variabilité, lenteur) contribuant au développement atypique de la communication sociale dans l’autisme notamment pour ce qui concerne la fonction directive et la production de gestes conventionnels et pourrait expliquer les difficultés des enfants avec autisme à s’adapter dans une situation sociale. Par ailleurs, l’évolution différentielle des enfants avec autisme bénéficiant de l’intervention montre que les variabilités interindividuelles dans les profils développementaux cognitifs et socio-communicatifs des enfants de notre étude correspondent aux variabilités interindividuelles de dysrégulation d’attention conjointe. Notre modèle de recherche est donc bien confirmé, et met en évidence l’intérêt de l’évaluation de la dysrégulation d’attention conjointe comme pronostic du développement de la communication sociale. Ces résultats nous incitent à proposer des interventions centrées sur l’hétérorégulation d’attention conjointe et de la communication sociale chez de jeunes enfants avec autisme. / The etiology of autism remains poorly identified, however it has been established that this disorder is characterized by deficits in social communication, in particular in joint attention, which involves major difficulties in understanding others as intentional agents, a lack of empathy and deficits in imitation. The objectives of this research are to study, on one hand, the link between joint attention dysregulation and later social communication development, and on the other hand, the impact of an intervention program based on the hetero-regulation of joint attention for young children with autism. It is both a longitudinal (12 months) and transversal study concerning 10 young children with autism, matched by developmental age to 10 young children with Down’s syndrome and to 10 young typically developing children. The development of the children comprising these three groups is assessed with appropriate clinical tools (Brunet-Lézine, BECS, EDEI-R). The assessment of dysregulation (in the domains of activity, joint attention and social communication skills) is realized during play sessions using original clinical tools. The results show dysregulation in processes of joint attention (desynchronization, perseverations, breaking off, instability, slowness) contributing to atypical development of social communication in autism, in particular with regard to producing imperative function and conventional gestures, which could explain the difficulties that children with autism exhibit when learning to socialize. However, differential evolution in children with autism benefiting from intervention shows that inter- individual instabilities in cognitive profiles and in the development of social communication skills correspond to interindividual instabilities in the dysregulation of joint attention. Our model is thus supported by the data, underlining therefore the interest of using joint attention dysregulation as a predictor of social communication development. These results also emphasize the value of therapies based on the hetero-regulation of joint attention and of social communication for young children with autism.

Social networking has become an integral part of daily communication and information sharing. Although researchers continue to explore the fields of social networking and emotion regulation separately, there is a lack of research bridging these areas of interest, particularly in the adolescent population. The purpose of this study was to examine the predictive relationship between the environmental and social variables of Facebook use, online social connectedness, and quality of parent-child relationship with adolescent emotion regulation. Fogel's social process theory of emotion provided the framework for this study and allowed for examination of the social networking environment. Research questions addressed independent variables of Facebook use, online social connectedness, and quality of parent-child relationship as well as interactions. Hypotheses were directed at different facets of emotion regulation including emotional control, emotional self-awareness, and situational responsiveness. A sample of 80 adolescents 13- to 18-years old was gathered through snowball sampling of Facebook groups and pages targeting parents of adolescents. Individual multiple regressions were used to examine prediction and interaction among variables. Results showed greater Facebook use predicted decreased emotional self-awareness and greater quality of parent-child relationship predicted improved emotional control in adolescents. The findings of this study promote positive social change by implicating the role of social networking use in predicting maladaptive adolescent emotional development and well-being. Future research will benefit from a larger sample size and include various social networking platforms along with gender and age-specific data.

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Past research shows that weight-related teasing is linked to binge eating, but little is known about the individual risk factors that render certain people more vulnerable than others. The current study examined three potential risk factors for binge eating in response to weight-related teasing: weight stigmatization experiences, weight bias internalization, and emotion dysregulation. The current study empirically investigated how these factors interacted to predict concurrent binge eating behavior through a self-report questionnaire and eating behavior in a laboratory following exposure to a weight stigma vignette. First, it was hypothesized that higher levels of weight stigmatization and emotion dysregulation would be associated with higher levels of binge eating, which was consistent with the results of a multiple linear regression analysis. Second, it was predicted that higher levels of weight stigmatization and emotion dysregulation would predict greater quantities of cookie consumption during a bogus taste test following exposure to a weight stigma vignette. The hypothesis was not supported by a multiple linear regression. Third, we posited that weight bias internalization would moderate the relationship between weight stigmatization and emotion dysregulation on disordered eating, such that higher levels of weight bias internalization would be associated with higher levels of binge eating. This was not supported by a hierarchical regression analysis. Overall, the results highlight variables pertinent to the relationship between weight stigma and binge eating. Future research should test the model in clinical samples to see if it is more relevant to people with more severe levels of eating pathology.

Theoretical models specify that anxiety aggregates in families. Research confirmed maternal anxiety as a predictor of childhood anxiety; however, very little evidence exists in support of paternal anxiety's role in child anxiety as well as about potentially reciprocal relationships between parental and child anxiety. The parent-child anxiety transmission mechanisms are also not fully understood; the majority of previous research focuses on the child's acquisition of anxiety symptoms from a parent via cognitive processes. Recent integrative theoretical models propose that child emotion regulation processes might be involved in parent-child anxiety transmission. The current dissertation aimed to address these gaps in literature. Both studies utilized data from over 800 mothers, 400 fathers, and their children drawn from the longitudinal NICHD Study of Early Childcare and Youth Development. Measures of maternal anxiety, paternal anxiety, child anxiety, and child emotion dysregulation were collected over a nine-year period when children were between the ages of 6 and 15 years. Study I provided evidence of significant indirect effects from parental anxiety to child anxiety through child emotion dysregulation for both mother-child and the father-child relationships. Child emotion dysregulation was non-significant in the father-child path of a family model, despite significant direct effects. The results provide evidence for child emotion dysregulation as an underlying process of parent-child anxiety transmission. Study II provided evidence of significant bidirectional predictive links of maternal anxiety and child anxiety across ages 6, 8, 10, and 15 years tested in a mother-child cross-lagged path model. Significant predictive paths from paternal anxiety to child anxiety were found from ages 6 to 8 and a significant predictive path from child anxiety to paternal anxiety was found from age 10 to age 15 in a father-child cross-lagged model. Additional tests of family models confirmed that there were unique effects of both maternal and paternal anxiety on child anxiety over time. The results show the long-term impact of both maternal anxiety and paternal anxiety on child anxiety as well as child anxiety's reciprocal effects on parental anxiety. Both studies demonstrate the importance of both mothers and fathers in childhood anxiety etiology. / Doctor of Philosophy / Research has shown that anxiety might run in families, and that parental and child anxieties might reinforce each other. In research, most attention is paid to mothers and how their anxiety influences child anxiety, including how children learn their anxious experiencing from their mothers. Very little research has been dedicated to studying fathers and how their anxiety might impact their children. The current two studies of this dissertation wanted to better understand how maternal and paternal anxiety shape child anxiety over the years. Study I tested whether the way how children regulate their emotions is influenced by parental anxiety and whether it contributes to their own anxiety. The evidence shows both mother and father anxiety influence children's regulation of their emotions, and in turn, this contributes to child anxiety. Therefore, how children control their emotions impacts how parental anxiety shapes child anxiety. Study II tested whether parental anxiety influences child anxiety consistently over time as children become adolescents. Study II also tested whether child anxiety contributes to parental anxiety over the years. Results showed that maternal and child anxiety consistently foretold each other when children were at 8, 10, and 15 years old. The results for fathers were more complicated and showed that father anxiety likely influences child anxiety when children are younger, while child anxiety influences paternal anxiety when children are older, during their teenage years. Both studies highlighted showed the importance of both mother and father anxiety to better understand child anxiety.