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Dynamics of Complex Quantum Systems - Engineering and Control in Cold Atomic Systems
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyIn this thesis, I study the dynamics of cold atoms, with a focus on two aspects: impurity dynamics in supersolid Bose-Einstein condensates (BECs) and quantum control through employing shortcuts to adiabaticity (STA) techniques. In the first project, I study the interplay between an impurity and a supersolid phase of the BEC. Through theoretical analyses and numerical simulations, I explore the diverse ways in which the impurity atom influences the condensate and vice versa, revealing the emergence and decay of Bloch oscillations known from solid-state systems. In the second project, I study the concept of shortcuts to adiabaticity, introducing a unique perspective on dynamically controlling quantum many-body systems. By designing shortcuts for various external geometries, I demonstrate how effective adiabatic dynamics can be achieved in systems with complex spectra, to facilitate faster and more efficient state transitions. I derive an analytical expression for an STA using a mean-field approach for the BEC and establish connections to strongly interacting bosonic systems. I show that for various potentials unit fidelity for the desired target state can be achieved in very short times. The achieved results pave the way for enhanced quantum control of cold atomic systems, offering opportunities for further exploration and application in related areas of research
Development of a Human Midbrain Organoid Model Containing Microglia for Investigating the Role of Glucocerebrosidase in Alpha-Synuclein Pathology
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyMicroglia, as the intrinsic immune cells of the brain, play a pivotal role in maintaining the delicate equilibrium of the central nervous system. Any disturbance in the fine-tuned balance of microglial function can result in neuroinflammation. Under conditions of neurodegeneration, microglial dysfunction can exacerbate neuroinflammation and pathological mechanisms, contributing to the disease progression. This project investigates the involvement of microglia in the clearance of the Parkinson’s disease (PD)-associated pathological protein, alpha-synuclein (a-syn). In particular, this thesis project aims to test the hypothesis that microglia with impaired glucocerebrosidase (GCase) function, resulting in lysosomal dysfunction, can phagocytose but not degrade a-syn, leading to its accumulation in lysosomes and subsequent cellular dysfunction. This investigation is carried out using a human midbrain organoid (hMO) model, offering a physiologically relevant platform to study PD pathogenesis.
A novel human reporter cell line, incorporating enhanced green fluorescent protein (EGFP) tagging of the TMEM119 protein, was generated using CRISPR/Cas9 technology. TMEM119 is a microglia specific gene, thus, this reporter cell line will facilitate the visualisation and tracking of microglial cells within the organoid model.
To investigate the role of GCase in microglia under PD pathogenesis, we targeted the TMEM119-EGFP cell line (wildtype) to create a GBA1 knockout (GBA1-/-) cell line, TMEM119-EGFP::GBA1-/-. Human embryonic stem cells were then differentiated into microglia, and both wildtype and GBA1-/- microglia were assessed for characteristic properties, including their ability to phagocytose a-syn. Transcriptomic profiling was conducted to gain insight into the molecular mechanisms occurring in lysosomally affected microglia. Notable differences were observed between WT and GBA1-/- haematopoietic progenitor cells (HPCs). In particular, biological processes associated with immune response and cellular components including lysosomes, were suppressed in the GBA1-/- HPCs. GBA1-/- a-syn pre-formed fibril (PFF) treated human microglia (hMG) samples exhibited a distinct transcriptional profile compared to WT PFF treated hMGs, with a number of DEGs involved in endocytosis and endosome recycling.
Expanding beyond the cellular level, several co-culture strategies were tested to integrate microglia into hMOs in order to provide a physiologically relevant and three-dimensional model for the study of PD. This model combines newly generated cell lines – H9 TMEM119-EGFP and H9 TMEM119-EGFP::GBA1-/- – with previously established lines, including H9 SNCA-mKO2 overexpression and H9 GBA1-/-. HPCs and midbrain progenitor cells were combined in a defined ratio to form a neural spheroid which enhanced microglial integration and resulted in hMOs containing hMG. This approach provides a unique platform for disease modelling and will facilitate a deeper understanding of the complex interactions between microglia and a-syn in Parkinson’s pathology.
In summary, this research represents a multifaceted approach, combining genetic engineering techniques, with advanced cellular and organoid models, to unravel the intricacies of microglia involvement in a-syn clearance. Understanding the molecular and functional aspects of this process will provide valuable insights and lead to the development of targeted therapeutic interventions for Parkinson’s disease and related neurodegenerative conditions
Aging Effects on Murine Adoptive T cell Therapy for Solid Tumor
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyAging is associated with reduction in diversity of antigen-specificity and activity of T cells. This might be related to an increased prevalence of cancers in people over 65 years old. Accordingly, adoptive T cell therapy (ACT) may be useful to treat cancers in elderly individuals, but the efficacy of ACT in elderly patients remains unclear. In this study, I found that intrinsic aging of CD8+ T cells impairs their anti-tumor activity in a mouse model of ACT with engineered T cells expressing TCR specific to tumor or antigens (TCR-T cells), although it does not affect cytotoxicity of CD8+ TCR-T cells in vitro. Single-cell RNA-sequencing (scRNA-seq) analysis revealed a significant increase in proportion of terminally exhausted cells and a decrease in progenitor exhausted cells in tumor-infiltrating aged TCR-T cells in ACT. Moreover, expression of endothelial PAS domain-containing protein 1 (Epas1) is significantly decreased in aged CD8+ T cells. Crispr-mediated ablation of Epas1 in young CD8+ T cells results in reduction in their anti-tumor activity and accumulation in the tumor in ACT. Moreover, Epas1-deficient tumor-infiltrating cells tend to exhibit the phenotype of terminally exhausted cells. These findings suggest that aging decreases Epas1 expression in CD8+ T cells, which in turn promotes cell exhaustion and decreases their anti-tumor activity. Enhancing Epas1 expression may therefore be a therapeutic strategy to improve the efficacy of ACT in the elderly
Prolonged mitosis: A key indicator for detecting stressed and damaged cells
Full text linkDuring mitosis, chromosomes condense, align to form a metaphase plate and segregate to the two daughter cells. Mitosis is one of the most complex recurring transformations in the life of a cell and requires a high degree of reliability to ensure the error-free transmission of genetic information to the next cell generation. An abnormally prolonged mitosis indicates potential defects that compromise genomic integrity. The mitotic stopwatch pathway detects even moderately prolonged mitoses by integrating memories of mitotic durations, ultimately leading to p53-mediated cell cycle arrest or death. This mechanism competes with mitogen signaling to stop the proliferation of damaged and potentially dangerous cells at a pre-oncogenic stage. Mitosis is a highly vulnerable phase, which is affected by multiple types of cellular damages and diverse stresses. We discuss the hypothesis that the duration of mitosis serves as an indicator of cell health
Analogues of Light and Gravity in the Collective Excitations of Quantum Magnets and Cold Atoms
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyAnalogies are fundamental for human reasoning. In condensed matter, analogies with high-energy phenomenology have led to new insights, as exemplified by the Anderson Higgs mechanism, which led to the electroweak unification. Other extreme-scale phe nomena beyond the realm of experiment or observation can nevertheless be embodied by condensed matter analogues, at least in part. These analogues, such as the Hawking radiation emitted from the horizons of classical flowing fluids, can provide new avenues for empirically-driven inquiry. In this Thesis, I identify connections between two of nature’s fundamental force carrying Bosons and the Goldstone modes found in ordered phases of quantum mag nets and cold atoms. Specifically, I show how the long-wavelength spin waves in a collinear antiferromagnet—known to be massless, spin-1 excitations—correspond to pho tons. Building on this framework, I then establish that the long-wavelength excitations of a ferroquadrupolar, quantum spin-nematic are massless, spin-2 excitations, which corre spond to gravitons, i.e. quantized gravitational waves, in flat spacetime. Since quantum spin nematics can be realized in spinor condensates, I argue that these results offer an avenue for realizing a one-to-one analogue of gravitational waves in experiment. This con nection is further illustrated through simulation of a ferroquadrupolar spin-nematic phase, as realized in the spin-1 Bilinear-Biquadratic model on a triangular lattice. Working in a U(3) representation which captures both dipolar and quadrupolar degrees of freedom, I simulate both the thermodynamic and dynamical properties of this model. Within Clas sical Monte Carlo simulation, I find results consistent with a topological phase transition into the spin nematic phase, mediated by the unbinding of vortices. Using Molecular Dynamics simulations, I then elaborate on the dynamical properties of these vortices, and demonstrate how the annihilation of pairs of vortices could be used to generate analogue gravitational waves in spin nematics, suggesting a route to realization in spinor conden sates. I qualitatively extend the analogue to the profile of waves emitted by vortex pairs in the spin nematic, as compared to the characteristic profile measured by LIGO originating from binary mergers of massive objects
The Role of JunB in Exhausted CD8 T Cell Populations in Tumors
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyPrecursor exhausted T (Tpex) cells are sustained in the lymph nodes and tumor tissues, giving rise to terminally exhausted T (Ttex) cells for tumor control. Moreover, they are responsible for enhanced anti-tumor responses in immune checkpoint therapy. However, the mechanism underlying the maintenance of Tpex cells remains largely unknown. In this study, using a B16 mouse melanoma model, I demonstrate that the AP-1 transcription factor JunB is essential for persistence of tumor-resident Tpex and Ttex cells. I found that expression of JunB is enhanced when Tpex cells adapt to tumor tissues. Junb-deficient CD8 T cells can differentiate into Tpex cells in the tumor draining lymph nodes (TdLNs), but they cannot accumulate in the tumor, thus failing to control tumor growth. Junbdeficient tumor-specific CD8 T cells in TdLNs or intra-tumoral Tpex cells with dTAGmediated JunB degradation impairs maintenance of Tpex phenotypes, including loss of Ly108, upon ex vivo stimulation with tumor-infiltrating dendritic cells. Moreover, dTAGmediated JunB degradation in intra-tumoral Ttex cells significantly reduces cell viability and ability to express effector molecules. Transcriptomic and chromatin landscape analyses revealed that JunB promotes chromatin accessibility and expression of Myb, which is critical for Tpex maintenance. Importantly, overexpression of JunB enhances antitumor CD8 T cell responses. These results suggest that JunB is required for adaptation of Tpex cells to tumor environment and maintain balance between Tpex and Ttex cells. These JunB functions might be a target to improve CD8 T cell-dependent cancer therapy
Analysis of the Function of JunB in Regulation of CD8+ T Cell Response
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyCD8+ T cells are essential for adaptive immune responses to eliminate virus-infected and cancer cells. T cell receptor (TCR)-stimulated naïve CD8+ T cells differentiate into cytotoxic effector CD8+ T cells. TCR-induced activator protein-1 (AP-1) subunit, BATF, and its interacting protein, IRF4, are required for clonal expansion of effector CD8+ T cell cells in response to acute infection of pathogens. BATF function is dependent on AP-1 dimeric partners, such as JunB. However, whether and how JunB regulates CD8+ T cell responses remains unknown. In this study, I found that JunB is induced upon TCR stimulation and essential for the clonal expansion of effector CD8+ T cells in response to Listeria Monocytogenes infection. JunB is required for survival and metabolic reprogramming to glycolysis in effector CD8+ T cells. Furthermore, JunB promotes the expression of genes required for CD8+ T cell responses, such as Tcf7 and Runx3, while inhibiting the expression of a proapoptotic gene, Bcl2l11 (encoding Bim), and coinhibitory receptor genes, Pdcd1 and Havcr2 (encoding PD-1 and TIM3, respectively). JunB controls chromatin accessibility at genomic regions related to a subset of its target genes, including an enhancer region of Pdcd1. These results demonstrate that JunB is critical for transcriptional and epigenetic regulation for clonal expansion of effector CD8+ T cells
Control of Cold Atomic Systems for Quantum Heat Engines
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyIn this thesis, I present the work I did in my PhD in the field of quantum thermodynamics. The aim of this work is to explore quantum engines that can exploit the great tunability of cold atomic systems as the working medium. The thesis is divided into two parts. In the first part, I study the thermodynamics of one-dimensional interacting systems to use them for designing quantum engines. It consists of two research projects. In the first project, I explore anomalous heat flows between two strongly correlated particles and discuss the perspective of using it to realize a quantum fridge. In the second project, I study a quantum heat engine where the work extraction is assisted by changing the interaction within the working medium. In the second part of my thesis, I focus on controlling open quantum systems for optimizing the performance of quantum engines. The quantum Brownian motion has been used to test the different methods. This part consists of two projects, where in the first one, I realize a shortcut to equilibration protocol in a driven open quantum system. For that I propose two different methods. The first one consists of mapping the dynamics of the quantum Brownian motion to an effective stochastic dynamics of an isolated particle. The second methods consists of doing the shortcut protocol by reverse engineering a time-dependent master equation, which was derived by using the Lewis-Riesenfeld invariant. Finally in the second project, I use optimal control methods to speed up the thermalization in isochoric strokes. I also derive a speed limit that predicts the timescale at which the optimal control fails. All projects significantly contribute to the understanding and control of quantum engines
Unveiling the Genomic and Transcriptomic Landscape of Anemones and Corals: Key Players in the Mutualistic Symbiosis with Algae and Anemonefish
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyThe mutualistic symbiosis between giant sea anemones, Symbiodiniaceae algae, and anemonefish is a classic example of mutualism in coral reef ecosystems. Despite its significance, the mechanisms involved remain incompletely understood. This is due to our limited knowledge regarding giant sea anemone taxonomy, the different contributions to symbiosis, and the roles of the three widely dissimilar partners. To address these gaps, I conducted a transcriptome study of giant anemones in Okinawa, revealing molecular similarities, phylogenetic relationships, and anemonefish host preferences. The study identified three distinct groups within giant sea anemones (Entacmaea, Heteractis, and Stichodactyla) with symbiotic dinoflagellates. Additionally, E. quadricolor was found to have four cryptic lineages among which two, quite divergent, live in sympatry and are associated with different anemonefish species, suggesting they may correspond to cryptic species. Investigating global gene expression changes due to the photosymbiotic relationship in S. gigantea in the presence/absence of anemonefish revealed elevated expression of nitrogen assimilation related genes, suggesting the delivery of CO2 and ammonia waste from anemonefish to anemone’s symbiosome membrane. Draft genomes of three giant sea anemones were successfully obtained, contributing to the understanding of genomic novelties in symbiotic adaptation. Taken together, these data provide solid foundations for the genomic analysis of giant sea anemones, the iconic hosts of anemonefish
Population Dynamics of Microorganisms in Spatially Structured Environments
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyMicrobial populations live and grow in spatially structured environments. These structures lead to spatial patterns in populations and alter the course of their natural evolution. Such phenomena are theoretically studied using spatially explicit models. However, these models are still poorly understood due to their analytical and numerical complexity. In this thesis, we study two systems of microorganisms living and proliferating in different spatially structured environments. The first system consists of populations of Escherichia coli growing in rectangular microchannels with two open ends. We study such populations with a lattice model in which cells shift each other along lanes as they reproduce. The model predicts rapid diversity loss along the lanes, with neutral mutations appearing in the middle of the channel being the most likely to fixate. These theoretical predictions are in agreement with our experimental observations. The second system is constituted by planktonic microorganisms that are transported by chaotic oceanic currents. To replicate their dynamics, we employ an individual-based coalescence model. The model predicts the effect of oceanic currents on the biodiversity of planktonic communities, as observed in metabarcoding data sampled from oceans and lakes around the world