VictorJuiz/thesis huggingface dataset:
Rett Syndrome Induced Pluripotent Stem Cell-derived Neurons Exhibit Electrophysiological Aberrations

Induced pluripotent stem (iPS) cells generated from patients hold great promise for studying diseases that affect the central nervous system, as differentiation into the neuronal lineage creates a limitless supply of affected cells for disease study. Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder primarily caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Due to the inaccessibility of patient neurons, most of what is known about underlying phenotypes has been described using mouse models. iPS cells provide a potential solution, but reprogramming of patient cells is hampered by low efficiency, and early methods of identifying iPS cells involve transgenic techniques that are not translatable to human patient samples. The first part of this thesis describes the generation and characterization of a pluripotency reporter to address this issue. The EOS lentiviral reporter allows real-time observation of pluripotency changes during reprogramming, and is a useful tool for more efficient isolation of reprogrammed cell lines. Further, the EOS selection system can be used in a disease context to reproducibly mark and maintain disease-specific iPS cell lines for future use in disease modelling. Though iPS cells have been used to study RTT in vitro, extensive assessments of neuron function and electrophysiology have not yet been performed. In the second part of this thesis, iPS cell lines generated from a RTT mouse model were tested for their ability to model disease in vitro. Directed differentiation of multiple Mecp2-deficient and wild-type iPS cell lines to glutamatergic neurons revealed neurons that lack Mecp2 have a smaller soma size, diminished sodium currents, and are less excitable, firing fewer, prolonged action potentials that are smaller in magnitude. This deficiency in intrinsic excitability was accompanied by a dysfunction at excitatory glutamatergic synapses, which together recapitulate changes previously observed in the Mecp2-deficient mouse brain. Having accumulated counts and recordings from hundreds of neurons with consistent responses among lines, the iPS cell system is a representative model of the neuronal and synaptic defects in RTT. These results illustrate the requirement of MeCP2 in normal neuronal function, and suggest altered neuronal homeostasis or aberrant network circuitry may underlie RTT pathogenesis.

Keywords: Rett syndrome
Induced pluripotent stem cells
Neuronal differentiation
Neuron electrophysiology
Autism spectrum disorders
Disease modelling
Advisor: Ellis, James
Restoring Local Spiritual and Cultural Values in Science Education: The Case of Ethiopia

It has been repeatedly observed that home and local context matter in the education of children. A smooth transition between home and classroom prepares children for enjoyable and meaningful life-long learning. Knowledge building in children is influenced by previous experience, values, beliefs and sociocultural factors associated with community. Against this theoretical background, the thesis examined the integration of local spiritual and cultural values to improve science education in Ethiopia. This autoethnographic research used in-depth interviews, supplementary observations and focus group discussion and my biography to identify the perception and practice of common and unique spiritual and cultural values. The study examined whether these values were included and/or excluded in the school curriculum and explored the possibilities for incorporating values in science education and the anticipated tensions resulting from their inclusion. Students, science teachers, parents, employers, curriculum experts, policymakers, elders, and religious leaders participated in the research, conducted in a randomly selected secondary school in Addis Ababa. The sampling followed a kind of snowball method, with a total of twenty key informants participating in interviews, fifteen classroom observations, and one focus group discussion. The data collection aimed at generating stories, which underlie the autoethnography methodology. Findings indicated that belief in and fear of God animated and sustained the Ethiopian way of life. Although spiritual teachings derived from sacred writings were the initial foundation for Ethiopian cultural norms, the two merged together later, creating a mosaic pervading every aspect of life in Ethiopia. Education was sustained on this merger of spiritual and cultural norms and values. It was also shown that the now century-old system of formal education did not incorporate those local spiritual and cultural values. Current science education also has little relationship to Ethiopian spiritual and cultural norms and is, therefore, in need of restoration. Findings showed that efforts to recapture local spiritual and cultural values in the curriculum may encounter obstacles and tensions. Clearly, the future of a more prosperous Ethiopia depends on the extent to which curriculum stakeholders can overcome these obstacles and put in place a relevant, contextual, and holistic education.

Keywords: spiritual values
science education
cultural values
Ethiopia
Advisor: Wallace, John
Experiences Labelled Psychotic: A Settler’s Autoethnography beyond Psychosic Narrative

This autoethnography uses narrative inquiry within an anticolonial theoretical framework. As a White Italian male settler living on Turtle Island, I bring survivor experience to psychiatric definitions of “psychosis,” or what I call psychosic narrative, and to broader literatures for the purpose of decolonizing “mental” relations. Using reflexive critiques, including feminist antiracism, I question my own privileges as I consider the possibilities of Mad culture to disturb authorizations of practices like forced electroshock and drugging. Using journals, salient themes of experience are identified, including “delusion,” “psychosis,” “madness,” and “illness,” especially as they appear in texts about politics, culture, and theory. A temporally rigorous narrative approach to my readings allows for a self-reflexive writing on such themes in relation with antiracist anticolonial resistance. Thus a White psychiatric survivor resistance to psychiatry and its social (local) history is related to the problematic of global Western neoliberal heteropatriarchy in psychological institutional texts. Survivor testimonies bring critical madness and disability theories as they pertain to racialization and constructions of sex/uality and gender. Rather than present a comprehensive analysis, this narrative inquiry is generated from the process of research as it was experienced in order to represent and question its epistemological grounds.

Keywords: psychosis
delusion
madness
psychologization
psychiatric survivor
sanism
disability
decolonizing
autoethnography
narrative inquiry
temporality
Mad culture
Advisor: Wane, Njoki
Control and Protection of Multi-DER Microgrids

This dissertation proposes a power management and control strategy for islanded microgrids, which consist of multiple electronically-interfaced distributed energy resource (DER) units, to achieve a prescribed load sharing scheme. This strategy provides i) a power management system to specify voltage set points based on a classical power flow analysis; 2) DER local controllers, designed based on a robust, decentralized, servomechanism approach, to track the set points; and 3) a frequency control and synchronization scheme. This strategy is then generalized to incorporate both power-controlled and voltage-controlled DER units. Since the voltage-controlled DER units do not use inner current control loops, they are vulnerable to overcurrent/overload transients subsequent to system severe disturbances, e.g., faults and overloading conditions. To prevent DER unit trip-out or damage under these conditions, an overcurrent/overload protection scheme is proposed that detects microgrid abnormal conditions, modifies the terminal voltage of the corresponding VSC to limit DER unit output current/power within the permissible range, and restores voltage controllers subsequently. Under certain circumstances, e.g., microgrid islanding and communication failure, there is a need to switch from an active to a latent microgrid controller. To minimize the resultant transients, control transition should be performed smoothly. For the aforementioned two circumstances, two smooth control transition techniques, based on 1) an observer and 2) an auxiliary tracking controller, are proposed to achieve a smooth control transition. A typical microgrid system that adopts the proposed strategy is investigated. The microgrid dynamics are investigated based on eigenvalue sensitivity and robust analysis studies to evaluate the performance of the closed-loop linearized microgrid. Extensive case studies, based on time-domain simulations in the PSCAD/EMTDC platform, are performed to evaluate performance of the proposed controllers when the microgrid is subject to various disturbances, e.g., load change, DER abrupt outage, configuration change, faults, and overloading conditions. Real-time hardware-in-the-loop case studies, using an RTDS system and NI-cRIO industrial controllers, are also conducted to demonstrate ease of hardware implementation, validate controller performance, and demonstrate its insensitivity to hardware implementation issues, e.g., noise, PWM nonidealities, A/D and D/A conversion errors and delays.

Keywords: microgrid
distributed energy resource
protection
robust control
Advisor: Iravani, Mohammad Reza
Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors

The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non-transport permissive and intact BBB, we also assessed the role of magnetic resonance imaging (MRI) guided focused ultrasound (MRgFUS) disruption of the BBB in enhancing permeation of AuNPs across the intact BBB and tumor BBB in vivo. MRgFUS is a novel technique that can transiently increase BBB permeability thereby allowing delivery of therapeutics into the CNS. We demonstrated enhanced delivery of AuNPs with therapeutic potential into the CNS via MRgFUS. Our study was the first to establish a definitive role for MRgFUS in delivering AuNPs into the CNS. In summary, this thesis describes results from a series of research projects that have contributed to our understanding of the influence of design features on AuNP permeation through the BBB and also the potential role of MRgFUS in AuNP permeation across the BBB.

Keywords: Brain Tumor
Nanotechnology
Gold Nanoparticles
Blood Brain Barrier
Advisor: Rutka, James T.
Using Eye Movements to Investigate Insight Problem Solving

In four experiments on insight problem solving, we investigated the time course of the development of solution knowledge prior to response, as well as the impact of stimulus familiarity on task performance and eye movement measures. In each experiment, participants solved anagram problems while their eye movements were monitored. In Experiments 1a and 1b, each anagram problem consisted of a circular array of letters: a scrambled four-letter solution word containing three consonants and one vowel, and an additional randomly-placed distractor consonant. Viewing times on the distractor consonant compared to the solution consonants provided an online measure of knowledge of the solution. Viewing times on the distractor consonant and the solution consonants were indistinguishable early in the trial. In contrast, several seconds prior to the response, viewing times on the distractor consonant decreased in a gradual manner compared to viewing times on the solution consonants. Importantly, this pattern was obtained across both trials in which participants reported the subjective experience of insight and trials in which they did not. These findings are consistent with the availability of partial knowledge of the solution prior to such information being accessible to subjective phenomenal awareness. In Experiments 2 and 3, each anagram problem consisted of a centrally located three-letter string plus three additional individual letters located above and to the side of the central letter string. All the letters in the central letter string were members of the five-letter solution word, while one of the individual letters was a randomly placed distractor. In Experiment 2, we replicated our findings of the gradual development of solution knowledge using this more complex stimulus display. In Experiment 3, we manipulated the familiarity of the central letter string by presenting it either in the form of a three-letter word, or as a meaningless string of letters. Behavioural measures showed an overall negative impact of familiarity on task performance, while eye movement measures revealed a more complex pattern of effects, including both interference and facilitation. Critically, the effects of familiarity on problem solving did not interact with the development of solution knowledge prior to response.

Keywords: eye movements
problem solving
insight
anagrams
Advisor: Reingold, Eyal M.
The Significance of the Evolutionary Relationship of Prion Proteins and ZIP Transporters in Health and Disease

The cellular prion protein (PrPC) is unique amongst mammalian proteins in that it not only has the capacity to aggregate (in the form of scrapie PrP; PrPSc) and cause neuronal degeneration, but can also act as an independent vector for the transmission of disease from one individual to another of the same or, in some instances, other species. Since the discovery of PrPC nearly thirty years ago, two salient questions have remained largely unanswered, namely, (i) what is the normal function of the cellular protein in the central nervous system, and (ii) what is/are the factor(s) involved in the misfolding of PrPC into PrPSc? To shed light on aspects of these questions, we undertook a discovery-based interactome investigation of PrPC in mouse neuroblastoma cells (Chapter 2), and among the candidate interactors, identified two members of the ZIP family of zinc transporters (ZIP6 and ZIP10) as possessing a PrP-like domain. Detailed analyses revealed that the LIV-1 subfamily of ZIP transporters (to which ZIPs 6 and 10 belong) are in fact the evolutionary ancestors of prions (Chapter 3). We were further able to demonstrate that PrPC likely emerged from a ZIP ancestor molecule nearly half-a-billion years ago via a retrotransposition event (Chapter 4). Moreover, biochemical investigations on ZIP10, as a model LIV-1 ZIP transporter, demonstrated that the ectodomain shedding of ZIP10 observed in prion-infected mice resembles a cellular response to transition metal starvation and suggested that prion disease in mice might phenocopy a transition metal starvation status (Chapter 5). These studies have opened a new angle to study prion biology in health and disease. Biochemical investigations on other LIV-1 ZIPs and attempts at the structural elucidation of the PrP-like domain of LIV-1 ZIP proteins are ongoing and have not been included in this thesis.

Keywords: Prion protein
ZIP transporters
Zinc
Metal biology
Advisor: Schmitt-Ulms, Gerold
Dynamics of Holomorphic Maps: Resurgence of Fatou coordinates, and Poly-time Computability of Julia Sets

The present thesis is dedicated to two topics in Dynamics of Holomorphic maps. The first topic is dynamics of simple parabolic germs at the origin. The second topic is Polynomial-time Computability of Julia sets. Dynamics of simple parabolic germs. Let F be a germ with a simple parabolic fixed point at the origin: F( w) = w + w2 + O(w3). It is convenient to apply the change of coordinates z = −1/w and consider the germ at infinity [special characters omitted] The dynamics of a germ f can be described using Fatou coordinates. Fatou coordinates are analytic solutions of the equation &phis;( f(z)) = &phis;(z) + 1. This equation has a formal solution [special characters omitted]where ∑bjz–j is a divergent power series. Using Écalle's Resurgence Theory we show that [special characters omitted] can be interpreted as the asymptotic expansion of the Fatou coordinates at infinity. Moreover, the Fatou coordinates can be obtained from [special characters omitted] using Borel-Laplace summation. J. Écalle and S. Voronin independently constructed a complete set of invariants of analytic conjugacy classes of germs with a parabolic fixed point. We give a new proof of validity of Écalle's construction. Computability of Julia sets. Informally, a compact subset of the complex plane is called computable if it can be visualized on a computer screen with an arbitrarily high precision. One of the natural open questions of computational complexity of Julia sets is how large is the class of rational functions (in a sense of Lebesgue measure on the parameter space) whose Julia set can be computed in a polynomial time. The main result of Chapter II is the following: Theorem. Let f be a rational function of degree d ≥ 2. Assume that for each critical point c ∈ Jf the ω-limit set ω(c) does not contain either a critical point or a parabolic periodic point of f. Then the Julia set Jf is computable in a polynomial time.

Keywords: Holomorphic dynamics
Resurgence Theory
Computability and Computational Complexity
Simple Parabolic Germs
Advisor: Yampolsky, Michael
Synthesis and Reactivity of Allylic Amines in Palladium Catalysis

Reaction of unsymmetrical allylic electrophiles with amines gives rise to regioisomeric allylamines. It was found that linear products result from the thermodynamically controlled isomerization of the corresponding branched products, which form initially. The isomerization was found to be promoted by the presence of acid and active palladium catalyst. The use of base shut down the isomerization pathway and allowed for the preparation and isolation of branched allylamines. This methodology provides a powerful control element, which allows for the installation of quaternary and chiral centres next to nitrogen. Later, the isomerization was combined with ring-closing metathesis to afford the synthesis of exocyclic allylamines from their thermodynamically less-stable endocyclic precursors. This rearrangement became feasible as a result of the electrophilic nature of a C – N bond in allylamines. When compared to the conventional intramolecular allylic amination, such approach escapes chemoselectivity issues, which makes it attractive attractive for late-stage synthetic modifications.

Keywords: palladium catalysis
allylic amine
Advisor: Yudin, Andrei
Tumor-specific Expression of Versican G3 Domain Promotes Breast Cancer Cell Invasion and Bone Metastasis

Increased local tumor tissue expression of versican in breast cancer patients is predictive of relapse and has a negative impact on survival rates. It is recognized that bone is a common anatomic site of breast cancer metastasis. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. We exogenously expressed a G3 construct in mouse breast cancer cell line 66c14, and found that G3 expression enhanced breast cancer cell proliferation and migration, and spontaneous metastasis to bone in an orthotopic model by upregulating the EGFR-mediated signaling pathway. Possessing anti-apoptotic and drug resistant properties, overexpression of versican was accompanied by selective sensitization to several chemotherapeutic agents. The dual roles of G3 in modulating breast cancer cell resistance to chemotherapeutic agents may, in part, explain breast cancer cell resistance to chemotherapy and EGFR therapy. The apoptotic effects of chemotherapeutics depend upon the activation and balance of down stream signals in the EGFR pathway. New knowledge gained by our experiments includes the understanding that GSK-3β (S9P) appears to function as a key check-point in this balance. In addition, versican G3 enhanced breast cancer cell self-renewal in vitro and in vivo. Versican was expressed at high levels in breast cancer mammosphere cells, which contained a high percentage of SP cells. Reduction of versican’s functionality through anti-versican shRNA or knocking out the EGF-like motifs using G3ΔEGF reduced the effect of versican on enhancing mammosphere and colony formation. Versican promoted breast cancer cell self-renew appears to play a role in enhanced chemotherapeutic drug resistance (including Docetaxel, Doxorubicin, and Epirubicin), which relates partly to its upregulated expression of EGFR signaling. Versican enhances breast cancer bone metastasis not only by enhancing tumor cell mobility, invasion, and survival in bone tissues, but also through mechanisms inhibiting osteoblast cell growth and differentiation, affording favorable microenvironments for tumor metastasis.

Keywords: Versican
Invasion
Metastasis
Advisor: Yee, Albert
Yang, Burton B.