The correct function of cardiac sarcomeric proteins allow for people to maintain quality of life. However, mutations of the cardiac sarcomeric proteins can result in remodeling of the heart which typically results in death. I present a full atomistic cardiac thin filament model that I have developed and three studies that I conducted while at the University of Arizona, while pursuing my doctoral degree in chemistry The goal was to develop the model to be able to study the effects of the mutations on the thin filament proteins. First, I present the long process of developing the model that is still evolving as new information is available. Second, I present the study of two mutants, the troponin T R92L mutant and the tropomyosin D230N mutant. Molecular dynamics was used to simulate the wild–type and mutant versions of the model which resulted in a visualization of the change of interaction between the tropomyosin and troponin, specifically at the overlap region. Third, I present the study of calcium release which is the "gatekeeper" to cardiac contraction. Steered molecular dynamics was utilized to find a previously unseen molecular mechanism that alters the rate of calcium release depending on the mutant. Fourth, I present the study of the mechanism of the tropomyosin transition across the actin filament, in which a longitudinal transition is favored. The studies helped to provide an atomistic level understanding of the cardiac thin filament as well as the methodology to which the mutations disrupt the natural functions of the sarcomeric proteins. The new results of the research can provide new insight into how the effects of the disease causing mutations can be mitigated, potentially extending the life of people with the conditions.

La dysautonomie familiale (FD) est une neuropathie causée par une mutation du gène IKBKAP induisant un épissage alternatif du pré-ARNm et une déficience de la protéine IKAP/hELP1. La compréhension des mécanismes moléculaires à l'origine de la spécificité tissulaire et le développement de thérapies curatives nous ont amené à identifier une signature des microARN caractéristique de la FD reliée au facteur d'épissage neurone-spécifique NOVA1, à partir de cellules souches olfactives humaines ecto-mésenchymateuses d'individus sains ou de patients FD. De plus, nous avons identifié le protéasome 26S comme étant suractivé chez les patients et dont le blocage corrige l'épissage aberrant du pré-ARNm d'IKBKAP tout en augmentant l’expression d’IKAP/hELP1. Ainsi, l'ensemble de ce travail apporte des perspectives de recherche novatrices pour de nombreuses pathologies neurodégénératives.Nous avons mené un projet de recherche secondaire concernant l’identification de biomarqueurs sanguins pour une maladie très fréquente, la dépression. Nous avons conduit une étude translationnelle à l'aide d'un modèle animal de stress chronique (UCMS) et identifié des signatures transcriptionnelles communes entre le sang et deux régions cérébrales, le gyrus cingulaire et le gyrus dentelé. Plusieurs biomarqueurs candidats ont été validés sur des échantillons sanguins chez la Souris et l'Homme, avec une corrélation entre la variation d'expression d'ACSL1, RALGPS1 et MPP1 et l'évolution du score clinique des patients. En conclusion, ce travail identifie de nouveaux biomarqueurs potentiels de la dépression et renforce la légitimité d'analyser des tissus périphériques dans le cadre d'une pathologie mentale. / Familial dysautonomia (FD) is a neuropathy caused by a mutation in the IKBKAP gene inducing an alternative pre-mRNA splicing and a deficiency of the protein IKAP/hELP1. The understanding of molecular mechanisms underlying tissue specificity and the development of curative therapies led us to identify a particular microRNA signature in FD associated to the neuron-spécific splicing factor NOVA1, from human olfactory ecto-mesenchymal stem cells of control individuals and FD patients. Moreover, we identified the 26S proteasome as being overactived in patients and whose inhibition corrects aberrant IKBKAP pre-mRNA splicing concomitantly to an increase of IKAP/hELP1 expression level. Taken together, these results bring innovative research perspectives for many neurodegenerative diseases.We conducted a secondary project concerning the identification of blood biomarker for a very prevalent disease, major depression. We conducted a translational study using animal model of chronic stress (UCMS) and identified common transcriptional signatures between blood and two brain regions, cingulate gyrus and dentate gyrus. Several candidate biomarkers were validated as similarly dysregulated in blood of mice and men, with correlation of expression variation of ACSL1, RALGPS1 and MPP1 in relation to clinical score evolution. In conclusion, this work identifies new potential biomarkers for depression and reinforces the legitimacy to analyze peripheral tissues in the context of mental disorders.

Child sexual abuse is a worldwide problem throughout the history of mankind. Under the influence of Freud in the 1890’s, an impression was established that claims of sexual abuse were the result of hysterical symptoms in women. His theory of the oedipus complex, depicted girls as fantasizing about sexual attention of their fathers. Children were blamed for their own sexual abuse. In the 1960’s, activists for children’s rights brought the plight of children to the foreground. Despite the fact that child sexual abuse is declared as a crime today, in the public opinion children are not beyond suspicion of having initiated or contributed to their own sexual abuse. Child sexual abuse ravages childhood. The effect of sexual abuse on children and their families can not be underestimated. Child sexual abuse affects the child, the parents of the child, and the support system of the child by intense feelings of guilt, anger, blame and mistrust associated with the abuse. Role confusion and transgression of interpersonal boundaries before, during, and after the sexual abuse might occur in families affected by child sexual abuse. It is indicated that the victim, parents and the family system need to undergo a healings process after the ordeal of child sexual abuse. Even though professionals agree that sexual abuse of children has an initial and a long-term negative impact on a person’s life, the cause of this harm is not always agreed on. It appears if harm to the child is caused by the incident of the sexual abuse itself, as well as through the reaction of important others to the abused child. In this study, the researcher explored through a qualitative, applied study, the experiences of adolescents’ of the parental reaction after child sexual abuse. During the literature review, the researcher found that children might hesitate to disclose their sexual abuse to adults as a result of fear. Some children fear that adults will not believe them, blame them for being abused or they fear to cause harm to the family system by the disclosure. Empirical evidence in this study added the observation that children also might not disclose their abuse to parents because they could fear possible parental anger violently expressed towards the offender after disclosure. For the respondents this might lead to the removal of the parent out of the family system, and would implicate according to them, the breaking up of the known family system. Empirical evidence in this study confirms the opinion of literature that the way in which the parental structure responds to the sexual abuse of the adolescent, may be of major importance in predicting the adolescents’ ability to come to terms with the experience. Parents not validating the incident and conjugating effect of child sexual abuse on their child, might cause re-traumatization of the child and they could have a severe negative impact on the healing process of the child. As time goes by, parents might alter their negative response to the disclosure of the abuse, but respondents in this study were not always able to accept or benefit from the changed parental reaction. / Dissertation (MSD)--University of Pretoria, 2008. / Social Work and Criminology / unrestricted

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22327号 / 医博第4568号 / 新制||医||1041(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 江藤 浩之, 教授 生田 宏一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This study examined familial regulation of young children's TV viewing in Ghana. Participants were families with young children four through eight years enrolled at a school in the south of Ghana. An online survey of TV regulation practices of families (restrictive, coviewing, and instructive), TV viewing hours of young children, and families' perception of TV influence on their children was completed by 158 family members (mostly parents). Results showed that restrictive regulation is the most predominately used strategy in Ghana, although all 3 regulation styles were used. College educated families were significantly more likely to use restrictive regulation than families with a primary school education. Further, over 70% of the young children exceeded the World Health Organization (2019), and the American Academy of Pediatrics (2016) recommended two hours of young children’s TV viewing. Results are discussed in terms of policy suggestions and future research.

Broad personality or global traits are unlikely to assist in solving capital crimes, so forensic psychologists have begun to focus on characteristics of the crime to create differentiating profiles. The purpose of this study was to determine if offender and victim characteristics and method of murder could provide cluster profiles differentiating familial relationship between offender and victim. Guided by classical conditioning theory and social learning theory, an archival database of 147 capital offenders responsible for 506 victims was analyzed. Cluster analysis yielded 3 distinct profiles. Compared to other clusters, Cluster 1 offenders tended to be Black and unfamiliar with their victims, who tended to be male between 20 and 50 years old that were typically shot. Cluster 2 offenders tended to be White and familiar with their typically female victims under the age of 20 who they typically murdered by use of blunt force or strangulation. Cluster 3 offenders were distinguished from the other 2 clusters only by having accounted for 90.6% of all victims who were stabbed, but no other associations with variables in the data set were discovered to explain this finding. Though limited in sample size, range of variables, and supplemental insights that could have been gained from case files or interviews, the results contribute to positive social change with offender-victim characteristics and method of murder profiles that begin to differentiate the familial offender-victim relationship and that future research can prospectively build on to create retrospective profiling models, which could potentially lead to resolving unsolved serial murder cases.

The purpose of this study is to explore the processes of family resilience within a grandmother-headed household, caring for orphaned grandchildren, in a low socio-economic South African community. To do so, the researcher posed questions relating to the existing family processes, resources and how those are utilised to grow from adverse situations. A qualitative methodological design was followed to allow the accounts of the sample to emerge. A single grandmother-headed household was chosen to take part in a focus group. The transcriptions from the focus group was analysed using an in-depth inductive thematic analyses in order to induce themes that emerged from their experiences. These themes were then analysed in relation to the current literature on family resilience in grandmother-headed households. This study forms part of a larger longitudinal project headed by Dr R. Mampane, namely: Building resilience in families: The role of care workers in mitigating family risk factors. The themes that emerged as a result of the inductive thematic analysis were: spirituality; family resilience processes (communication, problem solving, roles and role reversal, emotional attachment, involvement, managing behaviour, and knowledge and respect of the individual); resources (inter-familial resources and external resources); the family’s perceptions (definition of the family and definition of adversity); and finally adversities (males, physical impairments, and inter- and intra-familial conflict, amongst others less pronounced). These findings answered questions regarding the process and support structures utilised by a grandmother-headed household to overcome and grow from their adversities. A conceptual model for family resilience was suggested. A better understanding of how a grandmother-headed household engages in resilient processes could assist various professionals and community healthcare workers identify processes of strength and the lack thereof in grandmotherheaded household who look after their orphaned grandchildren. / Mini-dissertation (MEd)--University of Pretoria, 2014. / tm2015 / Educational Psychology / MEd / Unrestricted

Identifying individuals with hereditary cancer predisposition can improve health outcomes for patients and their family members through early cancer detection and prevention strategies. Prior research about family sharing of genetic test results among those with hereditary breast cancer has overwhelmingly been limited to the BRCA1 and BRCA2 genes. The present study sought to compare family sharing behaviors in women with pathogenic BRCA variants to women with pathogenic variants in the more recently identified and characterized PALB2 gene. A total of 18 BRCA carriers and 13 PALB2 carriers were interviewed about family sharing practices using a semi-structured guide based on the Integrated Behavioral Model. Barriers and facilitators to family sharing were similar for both BRCA and PALB2 carriers, with logistical difficulties and emotional struggles related to anticipated negative reactions from relatives being the most salient barriers. The most important facilitators were: attitude that sharing enables health protection, provider recommendation, strong family relationships, confidence in sharing basic information, knowledge of what to share and how to share, and belief that sharing is highly important. Given similar attitudes, norms, and control beliefs related to family sharing, similar, but tailored interventions may be effective at increasing family disclosures among both groups. Such interventions should involve a discussion of patients’ attitudes towards sharing with healthcare providers to strengthen motivations and address barriers and provision of informational resources to increase confidence and knowledge. Family sharing resources should clearly specify which relatives need to be informed, why sharing is important, and how at-risk relatives may benefit.

LDL-apheresis and haemorheopheresis are the most frequent methods of extracorporeal ellimination methods used for lowering the LDL cholesterol in patients with familial hypercholesterolaemia (FH). In case of failure of conservative therapy (represented by pharmacotherapy and/or dietary regime) these methods reprensent the effective and accessible solution for the clinical status characterized by high morbidity and mortality as well. The lipid components are the most frequent observed markers for the effeciveness of intervention. However, immunity with its effector molecules plays also essential role and there is suppose, that could also reflect the state and progress of atherosclerosis in FH patients. The aim of this thesis was to evaluate the levels of selected immunological markers (plasmatic glykoprotein α-2-macroglobulin, IL-10, soluble endoglin, soluble apoptotic factor sAPO-Fas and soluble form of adhesive P-selectin) and their changes after LDL-apheresis and haemorheopheresis employing enzyme immunoanalysis and immuno nephelometry. Totally, 12 patients were involved in this study, 3 were treated by haemorheopheresis, the rest 9 received LDL-apheresis. As a results, significant decreases in serum levels of α-2- macroglobulin, soluble endoglin and sAPO-1/Fas were recorded. Observed changes of...

Symptomatic sinus bradycardia, due to either sick sinus syndrome or vagotonia, can be familial, affecting several members of a family. We report an 18-year-old male patient with palpitations and limited exercise capacity who was noted to have severe sinus bradycardia. His resting heart rate was 40/min, with normal PR and corrected QT intervals, and sinus pauses up to 6 seconds during sleep. Exercise treadmill test and pharmacologic autonomic blockade during electrophysiologic studies abolished the bradycardia, suggestive of vagotonia rather than intrinsic sinus node dysfunction. This patient's father and a female cousin had a similar clinical history but associated with syncope and severe sinus bradycardia. The mode of transmission appeared to be autosomal dominant. All three have permanent demand pacemakers implanted and are asymptomatic.