Genetic implications of individual intervention and neuronal dysfunction in neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) are a group of conditions appearing in childhood, with developmental deficits that produce impairments of functioning. Autism spectrum disorder (ASD) is a common NDD with a high heritability affected by complex genetic factors, including both common and rare variants. Behavior interventions such as social skills group training (SSGT) have been widely used in school-aged autistic individuals to relieve social communication difficulties in a group setting. Studies have confirmed that intervention outcomes can be influenced by sex and age, but how the genetic risk contributes to the outcome variability remains elusive. Furthermore, although large population cohorts have been well studied and have found numerous genes associated with ASD and NDDs, the molecular and neuronal outcomes of risk variants and genes are unclear. Therefore, this thesis included four studies in which the effects of genetic factors on intervention outcomes and cellular level neuronal functions were investigated. Results from this thesis may provide a genetic perspective for further studies to explore potential individualized treatments for ASD and other NDDs. Specifically, In STUDY 1-3, exome sequencing and microarray were performed on individuals from a randomized controlled trial of SSGT (KONTAKT®). Common and rare variants, including copy number variations (CNVs) and exome variants, were tested for association effects with SSGT and standard care intervention outcomes. Polygenic risk scores (PRSs) were calculated from common variants, and clinically significant rare CNVs and rare exome variants were prioritized. Molecular diagnoses were identified in 12.6% of the autistic participants. PRSs and carrier status of clinically significant rare variants were associated with intervention outcomes, although with varied effects on both SSGT and standard care. In addition, genetic scores representing variant loads in specific gene sets were obtained from rare and common variants in ASD-related pathways. Outcomes of interventions were differentially associated with genetic scores for ASD-related gene sets including synaptic transmission and transcription regulation from RNA polymerase II. After combining genetic information and behavior measures, a machine learning model was able to select important features and confirm that the intervention outcomes were predictable. In STUDY 4, genetic variants affecting Calcium/Calmodulin Dependent Serine Protein Kinase (CASK) gene, a risk gene for NDDs, were examined using human induced pluripotent stem cell-derived neuronal models to identify the cellular effects of these mutation consequences. CASK protein was reduced in maturing neurons from mutation carriers. Bulk RNA sequencing results revealed that the global expression of genes from presynaptic development and CASK network were downregulated in CASK-deficient neurons compared to controls. Neuronal cells influenced by CASK mutations showed a decrease of inhibitory presynapse size and changed excitatory-inhibitory (E/I) balance in developing neural circuitries. In summary, this is the first study to investigate the association of genome-wide rare and common variants with ASD intervention outcomes. Differential variant effects were found for individuals receiving SSGT or standard care. Future studies should include genetic information at different levels to improve molecular genetic testing for diagnoses and intervention plans. Presynapses and E/I imbalance could be an option to be developed for the treatment of CASK-related disorders

Organ Donation, Trust and Reciprocity

This dissertation consists of three chapters that focus on topics in fields of experimental economics and health economics. The first chapter, “Do I Care if You Know I Betrayed You?” , examines how concern for others’ disutility from betrayal can affect the decision to repay trust in the trust game. We use a laboratory experiment to compare trustees’ behavior when betrayal is obfuscated to an identical monetary payoffs situation where betrayal is revealed. We find that more trustees choose to defect in our experiment when betrayal is obfuscated than when it is revealed. Our result suggests that concern for betrayal costs influences not only the decision to trust but also the decision to repay trust. The second chapter, “Increasing Organ Donation via Changes in the Default Choice or Allocation Rule”, utilizes a laboratory experiment to evaluate the effectiveness of alternative public policies targeted at increasing the rate of deceased donor organ donation. The experiment includes treatments across different default choices and organ allocation rules inspired by the donor registration systems applied in different countries. Our results indicate that the opt-out with priority rule system generates the largest increase in organ donation relative to an opt-in only program. However, sizeable gains are achievable using either a priority rule or opt-out program separately, with the opt-out rule generating approximately 80% of the benefits achieved under a priority rule program. The third chapter, “Improving the Approach to Organ Donor Registration”, proposes to improve organ donor registry by providing a persuasive message with the registration request. I designed a laboratory experiment to examine the impact of the persuasive message on donation decisions. The results indicate that the persuasive message has a positive impact on donation decisions in the early rounds of the experiment. Subjects were about 21 percent more likely to register as a donor in round 1 of the experiment when they were provided with a persuasive message. This behavioral difference across treatment decreased as subjects played more rounds, since subjects in the control treatment learned the information in the persuasive message through playing the game. We further find this treatment effect is mainly from subjects who are not organ donors in real life, while the treatment effect is very small for those who are self-reported organ donors

Dynamics of Income Distribution

In this paper, we have obtained closed-form solutions in Cass-Koopmans growth models with heterogeneous agents. The relationship between the form of production function and the dynamics of income distribution is made explicit. We then use this relationship to determine what production structure is simultaneously consistent with facts on growth and income inequality. Our empirical findings give support to models with decreasing returns in the reproducible factor.Income Distribution, Economic Growth

A Metaphor Analysis of Love Allusions in A Dream of Red Mansions

The paper explores two love allusions, ‘the pledge between plant and stone’ and ‘Jin’s marriage’ in the Chinese literary classics A Dream of Red Mansions written by Cao Xueqin and provides new explanations to the theme of the novel. Nearly 20 metaphorical expressions in the novel are selected through Critical Metaphor Analysis with 6 specifically representational examples analyzed in the paper by building integration networks based on Conceptual Integration Theory (CIT). The findings are as follow: 1) the counterculture of ‘plant and stone’ is embodied in the mythological stories at the beginning of the novel. 2) a ‘nested integrational network’, originally proposed by the researchers, links the mythological narrative space and the fictional human world space. 3) the comparison between integration networks of the two love allusions shows anti-feudalism of the author Cao Xueqin. This paper offers an interpretation of the novel from the aspect of cognitive linguistics, which, in turn, could promote the development of CIT within this field

Increasing Organ Donation via Changes in the Default Choice or Allocation Rule

The supply of deceased donor organs is a limiting factor for transplantation based therapies. This research utilizes a laboratory experiment to evaluate the effectiveness of alternative public policies targeted at increasing the rate of deceased donor organ donation. The experiment includes treatments across different default choices (opt-in versus opt-out) and organ allocation rules (without versus with priority rule) inspired by the donor registration systems applied in different countries. Furthermore, the experiment includes a controlled treatment to measure the effects of a neutral versus descriptive framing of the decision task. Our results indicate that the opt-out system with priority rule generates the largest increase in organ donation relative to an opt-in only program. However, sizeable gains are achievable using either a priority rule or optout program separately, with the opt-out rule generating approximately 80% of the benefits achieved under a priority rule program

Cationic Polymer Brush Coated Nanoparticles for Gene Delivery

PhDPolymer brushes generated via “grafting-from” approach emerged as an attractive surface modification tool offering chemical stability, synthetic flexibility and unprecedented control over the polymer grafting density, thickness, chemical composition and functionality. They display interesting features to many applications in regenerative medicine including cell culture, tissue engineering and as delivery systems due to exquisite control of physicochemical and biological properties. Cationic polymer brushes are particularly attractive in the field of designing effective vectors for gene delivery as polymer brush allows the design and coating of a variety of particles with well-defined core-shell architecture and chemistry to efficiently condense and deliver nucleic acids. This thesis concentrates on designing safe and efficient gene delivery vectors based on ‘graft from’ cationic polymer brush and understanding the interaction of nucleic acids with polymer brush. Chapter one presented fundamental knowledge of polymer brush and its biomedical application. The first part of this chapter describes the definition of polymer brush, the preparation strategies, mechanism of atom transfer radical polymerisation and the responsiveness of polymer brush including solvent, pH and ionic strength. The second part discusses the state-of-art applications of polymer brush in regenerative medicine including protein resistant polymer brush for tissue engineering and as drug/gene delivery systems.Chinese Scholarship Counci

MicroRNAs and immunomodulation by vitamin D

The active form of vitamin D, 1,25(OH)$_2$D3, plays well-established roles in calcium regulation and bone formation. 1,25(OH)$_2$D3 is also thought to exert immunoregulatory effects upon cells of the innate (dendritic cell) and adaptive (T cell) immune systems, that may impact health and disease. In recent years, the role of 1,25(OH)$_2$D3 has been implicated in autoimmune diseases such as rheumatoid arthritis (RA). 1,25(OH)$_2$D3 brings about genetic and epigenetic changes within immune cells, the latter which may include effects of microRNAs (miRNAs); small non-coding RNAs with an important regulatory role. To study the role of 1,25(OH)$_2$D3 on miRNAs in RA, we utilised n=20 (RA) and n=7 (reactive arthritis, ReA) matched patient serum and synovial fluid (SF) samples to derive measurements of vitamin D metabolite concentrations by LC-MS/MS, vitamin D binding protein abundance by ELISA, and circulating miRNA expression by qPCR. To study the role of 1,25(OH)$_2$D3 on miRNAs in healthy immune cells, we also generated $in$ $vitro$ models of dendritic cells (DC) and CD4+ T cells, treated with 1,25(OH)$_2$D3 or vehicle at different stages of development. An unbiased array approach was then used to screen 372 miRNAs closely related to inflammation in the DC and T cell models. Bioinformatic analyses were used to identify predicted gene targets of significantly regulated miRNAs in both DC and T cells. Results showed that 1,25(OH)$_2$D3 in SF was low or undetectable in 13/20 RA and 4/7 ReA samples. MiR-146a and miR-155 was up-regulated in RA SF compared to serum, but did not significantly correlate with RA disease markers. In DC, miR-155 but not miR-146a was up-regulated by LPS-induced cell maturation in the presence or absence of 1,25(OH)$_2$D3. Global down-regulation of miRNAs was observed after either short or long-term treatment of DC with 1,25(OH)$_2$D3. This was due, in part, to suppression of expression for miRNA processing genes. In contrast to DC, global miRNA down-regulation was not observed in T cells treated with 1,25(OH)$_2$D3. Notably, MiR-155 was up-regulated by cell activation but not 1,25(OH)$_2$D3, and miR-212-3p was up-regulated by activation and 1,25(OH)$_2$D3. Together, these results suggest that any 1,25(OH)$_2$D3 generated within the synovial microenvironment may be restricted to the cells involved in immunoregulation within this tissue. The role of miR-146a and miR-155 in immune cells is still unclear; it is unlikely that these miRNAs are actively mediating gene silencing to cause inflammation within the local environment, but rather they are maintained as a reserve of miRNAs not associated with their target gene. Global down-regulation of miRNAs following 1,25(OH)$_2$D3 in DC, but not T cells, suggests a role for 1,25(OH)$_2$D3-mediated miRNA down-regulation as opposed to decreased miRNA synthesis. Coupled with bioinformatic tools and gene ontology analysis, there is potential to identify novel roles for 1,25(OH)$_2$D3-responsive miRNAs in the prediction and pathogenesis of inflammatory disease

Li Hanjun and the early Communist movement in China

This thesis explores the role Li Hanjun played in the initial stage of the Communist movement in China. It describes Li’s early life, including his family background, his upbringing, his schooling and the environment he grew up in. It analyses some of Li’s early writings to demonstrate his philosophical predispositions and political orientation, as well as his character and temperament. It examines Li’s understanding of Marxism and his endeavours to disseminate it and to introduce various socialist theories into China. It describes his contacts with socialists of other countries and his cooperation with Korean socialists and Soviet agents in China, which helped open up the Communist movement in East Asia. The research focuses on Li Hanjun’s activities in establishing the Chinese Communist Party (CCP) and the opinions he expressed at the Party’s founding congress. It also deals with his ideas and actions in directing labour movements in China. Li Hanjun was a dissident within the CCP and later left the Party. This study clarifies the divergence of views between him and other Party leaders, and shows that his rejection of the Bolshevik doctrines of centralism and dictatorship and of unconditional receipt of financial aid and orders from the Communist International (Comintern) were the main causes of the conflicts and his expulsion. The thesis discusses Li’s vision of socialism, and shows that his ideal socialist society was not one in which a centralist government and the dictatorship of a Communist élite should control and intervene in everything but a collectivity of associations of free and autonomous working people organised in cooperatives. The thesis ends with a critical assessment of Li as a historical figure. It recovers historical facts that have sunk into oblivion, and thus differs from comparable studies published both in China and abroad. It fills important gaps in the history of the early Communist movement in China

Education distillation:getting student models to learn in shcools

Knowledge distillation is one of the methods for model compression, and existing knowledge distillation techniques focus on how to improve the distillation algorithm so as to enhance the distillation efficiency. This paper introduces dynamic incremental learning into knowledge distillation and proposes a distillation strategy for education distillation. Specifically, it is proposed to take fragmented student models divided from the complete student model as lower-grade models. As the grade level rises, fragmented student models deepen in conjunction with designed teaching reference layers, while learning and distilling from more teacher models. By moving from lower to higher grades, fragmented student models were gradually integrated into a complete target student model, and the performance of the student models gradually improved from lower to higher grades of the stage. Education distillation strategies combined with distillation algorithms outperform the results of single distillation algorithms on the public dataset CIFAR100,Caltech256, Food-101 dataset