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Persistent Cerebellar Molecular Layer Interneuron Activity Facilitates Anticipatory Tongue Movements in Mice
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyPrecise, anticipatory movements depend on the brain’s ability to generate motor commands in advance of immediate sensory input. Although the cerebellar cortex receives abundant sensory input via the mossy-fiber pathway, the mechanisms by which continuous sensory signals are transformed remain poorly understood. I co-developed a targeted lick-interception task and investigated the role of molecular layer interneurons during motor learning using wide-field Ca2+ imaging in Crus I and II. Mice either adjusted their lick onset timing (anticipatory) or tongue projection speed (reactive), allowing me to study neural dynamics underlying different adaptive behaviors. My results reveal a sensorimotor division in the left cerebellar hemisphere: Crus I Ca2+ activity increases in response to sensory aspects of the task, while Crus II is engaged during orofacial movements, such as licking and chewing. Over the course of learning, molecular layer interneurons in Crus I acquire persistent sensory-related activity in mice that develop anticipatory behavior. Crus I exhibits enhanced activity up to five seconds before movement onset locked to the spatial position of a continuously moving target independent of body movement. In more anticipatory mice, movement onset becomes linked to the dynamics of this persistent activity, whereas less anticipatory mice adjust their movements based on immediate sensory-related input. Moreover, chemogenetic inhibition of Crus I, but not Crus II, impairs behavioral performance and delays lick onset without altering overall lick parameters. My results indicate that anticipatory behavior in dynamic sensorimotor tasks relies on sensory representations encoded by molecular layer interneurons
Molecular Crowding and Enzyme Dynamics: Unraveling the Complex Interactions in Cellular Environments
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyEnzymes are ubiquitously involved in cellular processes. The enzyme environment conditions greatly affect enzyme specificity, folding and activity. These facts suggest a pivotal role of the cytosolic milieu on enzyme behavior. On the other hand, enzymes could also affect the cytosolic biophysical properties, suggesting an intricated interplay between enzyme catalysis and the cellular milieu. However, this interplay has been poorly studied due to the paramount challenges in mimicking the cellular complexity in vitro and the interdisciplinary nature of these mechanisms. Here, we utilized a liquid-liquid phase separation system to generate membraneless protein droplets, simulating cytosolic protein crowding in vitro. These droplets allow the study of enzyme kinetics in a cytosol-mimicking environment. By using an interdisciplinary approach spanning from biochemistry, rheology and fluid dynamics, we characterized the interplay between enzyme activity and a cytosolic-mimicking droplets. Specifically, we showed how enzymatic activity is affected by the cytosolic features and environmental stress in protein-crowded conditions. Moreover, we discovered that enzyme can generate emerging phenomena when localized in a protein-crowded environment such as droplets migration and viscosity modulation. This study highlights the interconnection between enzymes and the cytosolic environment and the underestimated role of enzyme activity in triggering complex cellular phenomena
The Diversification of Brain Structure in Ants
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyAnts, as an example of complex social cooperation and ecological dominance, represent one of the most successful groups among animals. Their complex eusociality, cooperative behaviors, and adaptability to diverse environments is inextricably linked to the evolution of their organ systems. The brain, as a pivotal organ mediating organism-environment interactions, plays a critical role in these adaptive strategies. While the basic neuroanatomical scheme is conserved, natural selection has shaped relative sizes of neuropils and the overall brain size to generate diversity across the ants. While a rich body of literature has advanced our understanding of the vertebrate brain size evolution, broad scaled comparative neuroanatomy for insects has only gained more traction in recent decades. Here, I take the comparative neuroanatomical approach to unravel the general principles and processes driving the macroevolution of the ant brain. To do so, in the first chapter I take a broader phylogenetic view and explore the evolution of odorant receptor (OR) repertoires across a broad range of hymenopteran species, revealing that in contrast to a widely held hypothesis, eusociality did not drive an expansion in the OR repertoire. Instead, my results suggested that factors such as the loss of flight may have played a role in shaping some of this variation. Subsequently, in the second chapter I examined brain and neuropil size variation of 9 distinct neuropils from 75 ant species, uncovering divergent body size scaling patterns of different brain regions. While visual neuropils displayed hyper-allometric scaling, olfactory regions showed more constrained isometry. Additionally, I showed that the evolution of miniaturized sterile workers was associated with dramatic reductions in brain regions forming a “visual module”, leading to the reduction in the overall brain size, contributing to an energy-efficient "cheaper worker" phenotype. Together, these findings elucidate the intricate interplay between sensory, social, and ecological factors that make the brain of an ant “the most marvellous atoms of matter in the world…” (Darwin, “The descent of man”; 1871, p.145
Topological Properties of Degenerate Quantum Gases in Kronig-Penney Like Potentials
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyIn this thesis I study the topological properties exhibited in cold atom systems trapped in periodic and finite-size one-dimensional potentials. Ultracold atoms provide an excellent platform for exploring various many-body quantum models that are challenging to identify in traditional condensed matter systems. In particular, recent advancements in experimental cold atom physics have enabled the creation of subwavelength nanoscale potentials, making it possible to realize the Kronig-Penney model and its variations. One of these considers shifting a regular lattice of point-like barriers within a finite-sized box, which allows topologically protected edge states to emerge as a function of the shift parameter. The continuous shift parameter then provides a virtual dimension and the system becomes effectively two-dimensional, allowing topological states to be explored over a large and flexible parameter space. In my work I go beyond the standard singleparticle treatment of topological system and analyze the equilibrium and non-equilibrium physics of fermionic and bosonic many-body systems. The first project I present focuses on the non-equilibrium dynamics of a ground-state fermionic many-body gas following a quench between different lattice shift parameters that allow for edge states with different chirality. I examine the role of the single-particle chiral edge states in the non-equilibrium dynamics of the system and demonstrate that the usual monotonic decay associated with the orthogonality catastrophe, typically observed with increasing system size, is significantly altered. The second study explores the topological characteristics of a system of two interacting particles in the Kronig-Penney-type nanoscale potential and examines the appearance of two-particle topological states within the spectrum. This investigation is extended to the Rice-Mele model, where similar topological features are observed. Finally, the third study considers the optical realization of a height-modulated nanoscale potential, which generates a complex potential landscape. To probe the many-body properties of such a system, I examined the spectral function of a Tonks–Girardeau gas in a quasiperiodically modulated KP potential. By varying the modulation amplitude and frequency, I identified a transition between delocalized and localized single-particle eigenstates. In the localized regime, the spectral function shows flat, non-dispersive modes that reflect localized states, whereas in the delocalized regime it becomes continuous and dispersive
Epigenetic Dynamics of Plant Aging: Nuclear Envelope Dysfunction and the Spatiotemporal Modulation of DNA Methylation in Arabidopsis
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyAging is a multifactorial biological process characterized by a progressive decline in physiological function, accompanied by widespread molecular and epigenomic alterations. While disruption of nuclear envelope components causes premature aging syndromes such as progeria in humans, the evolutionary conservation and broader implications of nuclear architectural dysfunction during whole-plant aging remain largely unresolved. In particular, epigenetic drift—genome-wide alterations in chromatin organization, DNA methylation, and heterochromatin integrity—is a conserved hallmark of aging and progeroid conditions, yet its chromatin-state specificity, spatial distribution, and reversibility are poorly characterized in plants.
In this thesis, I use Arabidopsis thaliana to dissect the molecular architecture of epigenomic aging, focusing on how nuclear envelope dysfunction—particularly loss of KAKU4 and CRWNs—accelerates age-associated phenotypes and drives genome-wide epigenetic instability. Through lifespan phenotyping and multi-omics profiling, I show that nuclear envelope defects promote transcriptional drift and impair heterochromatin maintenance, abolishing the normal age-linked accumulation of CHH methylation at transposable elements and across pericentromeric heterochromatin.
To resolve methylation dynamics within individual plants, I establish a spatially resolved aerial rosette system induced by photoperiod reactivation and extend this analysis to the perennial-like soc1 ful mutant. I demonstrate that age-related CHH methylation at transposable elements is dependent on organ age and leaf developmental order, accumulating in basal rosettes but remaining attenuated in newly formed distal rosettes. Parallel analysis of dedifferentiated callus reveals sustained CHH hypomethylation and a failure to acquire age-linked methylation over time, recapitulating the epigenomic resilience of meristematic progenitors even under prolonged in vitro culture.
Finally, by integrating tissue- and genotype-specific methylation trajectories, I define cytosine-level changes that consistently vary with age and remain comparatively stable in regenerative contexts. Although preliminary, these loci provide candidate markers for assessing epigenetic age in Arabidopsis and suggest that nuclear integrity and developmental state shape the balance between methylation drift and maintenance
Nonequilibrium Properties of Strongly Correlated One-dimensional Quantum Gases
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyUnderstanding and controlling nonequilibrium quantum systems offers promising routes to applications unattainable in equilibrium systems. While equilibrium physics benefits from well-established approaches, such as minimizing free energy and obtaining various thermodynamic quantities, nonequilibrium systems possess less general guiding principles and approaches. Furthermore, strong correlations plays a crucial role in various quantum phenomena, such as high-temperature superconductors or superfluid helium, yet analyzing strongly correlated quantum systems remains exceedingly challenging. This is because these systems often require rigorous analysis beyond the standard perturbation theory, leading to the necessity of dealing with the large Hilbert space dimensions, which makes theoretical analysis difficult. However, in the case of a one-dimensional strongly interacting Bose gas called Tonks–Girardeau (TG) gas, an exact mapping to a noninteracting fermions is possible, providing a unique platform to study a strongly correlated many-body systems. This thesis aims to advance the theoretical understanding of nonequilibrium strongly correlated quantum systems from two distinct perspectives: integrability and Floquet physics. First, I investigate the nonequilibrium dynamics of strongly correlated TG bosons immersed in a weakly correlated Bose–Einstein condensate. I show that the TG bosons form an integrable soliton-train supported by the condensate. Moreover, since a gas of the noninteracting fermions follows the same governing equations, the quantum statistical nature of the soliton-train can be addressed, leading to the notion of a quantum soliton-trains. Next, I study the TG gas under a strong external time-periodic drive. By computing the nonequilibrium Green’s function exactly, I reveal the excitation spectrum of this Floquet-engineered material. Employing Floquet spectral function theory and the Bose–Fermi mapping theorem, I uncover the existence of nonequilibrium Lieb excitations when the underlying mapped fermions form a Floquet–Fermi sea
Of Movement and Mice: A Study of Movement Variability Using Marker-based 3D Motion Capture and Mathematical Representations of Locomotion on a Treadmill
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyLocomotion is an important output of the central nervous system (CNS) and an essential component of many behaviours. The inherent variability of animal locomotory movements is the key to understanding how living things move so well. Most studies asses mouse locomotion using central metrics such as step-length, speed, angular excursions, and phase differences of limbs. The limitation of such approaches is that by describing variability as just the degree of spread around some measure of centrality we lose the ability to look at the dynamics. Additionally, there is mounting evidence that variability encodes dynamic signatures that are key to understanding both the function and dysfunction of the CNS. Few studies examine the whole body of the animal as it moves, particularly in tasks that involve more natural movements. Fewer still, that do this in all three spatial dimensions (3D). However, locomotion is a whole bodied movement, and most organisms move in 3D. Therefore, there is a need to study whole bodied movements in 3D, with sufficient spatio-temporal resolution to analyse their inherent variability. This entails using observational methods capable of capturing natural movements alongside analytical methods to interpret the data. In this thesis, I present my work on obtaining mathematical representations of voluntary treadmill locomotion of mice. I use a novel marker assisted 3D motion capture system, adapted for mice, to obtain a 30 dimensional trajectory of the whole body as they run unrestrained on a treadmill set at different speeds. I use principal component analysis to get a basis set of vectors that represent the changes in the body configuration of the mice during treadmill locomotion. Additionally, I use delay embedding techniques to untangle non-stationarities in the data to uncover the different classes of body movement cycles. This approach enables the characterisation of the whole body of the mouse as it locomotes on a treadmill and sets the stage for systematically studying the effect of pharmacological perturbations and different neurological conditions on movement
Controlled Evolutions between Antiferromagnetism and Spin Glass
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyThe control over chemical disorder in crystalline matter can be considered as a tool for developing technologically and fundamentally important materials. For example, the technological importance of disorders is recognized in studies of energy materials and microelectronics. The fundamental importance is also exemplified by the discovery of Fractional Quantum Hall Effect at extremely clean interfaces of single crystals of GaAs. While many magnetic systems exhibit long-range magnetic order, certain combinations of spin type, spin interaction and geometry can create spin frustrations leading to disordered spin states; this contrast between ordered and disordered states is exemplified by antiferromagnetism (AFM) and spin glass (SG). While these two states can originate from the same chemical platform but with different levels of chemical disorder, which can be both intriguing and technically challenging, the realization and understanding of this evolution should provide both new perspectives to materials science and the advancement of measurement technology.
In this dissertation I explore the relation between magnetic properties and chemical disorder, using AB2O4 spinel structure, more specifically ZnFe2O4, as the platform. The B-site of the structure accommodates a pyrochlore sublattice consisting of a network of corner-sharing tetrahedra, which can support spin frustration. On the other hand, the real material can be affected by chemical disorders such as site-occupancy mixing due to similarity of cation sizes and off-stoichiometry.
ZnFe2O4 spinel has been assigned as a magnetically long-range ordered system. However, neutron diffraction studies in the literature have demonstrated only short-range correlation, which raises speculations about spin frustration and possible spin glass (SG) or spin liquid states in this system. We used a high-temperature solution growth technique and magnetic probes to establish a feedback loop between synthesis parameters and crystal quality. Our methodology allows us to distinguish between off-stoichiometry and site occupancy mixing, and also allows us to control it. We show that, unlike commonly produced low-quality crystals, our stoichiometric ZnFe2O4 crystal demonstrates the longrange AFM ground state with no signature of SG in the clean limit of inversion disorder. Although the pyrochlore lattice has a large degree of freedom for its spins in the unit cell, the AFM structure can be fully refined using neutron elastic diffraction. This unique spin structure is composed of FM and AFM local clusters on individual tetrahedrons, arranged in a checkerboard pattern which is strongly correlated with the lattice being distorted into a breathing pyrochlore structure.
With our technical understanding of disorder control, we specifically induce the disorder in the system by replacing Fe3+ on the B-site with nonmagnetic Ga3+ ions in the Zn(Fe,Ga)2O4 spinel, but keep other types of disorder at the minimum. This allows us to create a finely stepped transition from AFM to SG and capture the intermediate states in between. This pathway from AFM to SG allows a clear revelation of the disparity between characteristic temperatures of magnetic heat capacity and magnetic susceptibility, which remains an unresolved issue in the spin glass literature. Using neutron magnetic diffuse scattering of characteristic compositions along the evolution pathway, we can correlate the critical fluctuations and dynamic slowdown with AFM and SG respectively. Furthermore, we reveal a correlation between the onset of spin correlation length and the characteristic temperature of the heat capacity. The onset of short-range correlation in SG thus is similar to that in the long-range AFM order of a thermodynamic phase.
Our work thus provides a new perspective into the nature of spin glass in real materials. Advancements of new sciences using real crystalline materials can be greatly dependent on their quality. Successful differentiations can reveal magnetic behavior hidden beneath excessive chemical disorder. In the field of quantum magnetism, differentiating between spin frustration and chemical disorders is likely to be a long-lasting challenge for many subjects, including exotic topics such as quantum spin liquids. The approach to fine tune the type and amount of chemical disorder opens a road for new materials and facilitates the improvement of the characterization techniques
The Genomic Landscape of Multi-trait Phenotypic Convergence in Strumigenys Trap-jaw Ants
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyPhenotypic convergence – the independent evolution of similar traits in separate lineages – is widespread across the tree of life, involving some of the most remarkable adaptations. Recent advances in sequencing methods and computational tools allow us to harness such natural experiments of replicated evolution, providing a window into the genotype-phenotype link for biodiversity at large. In this thesis, I focus on trap-jaw mandibles, an ultrafast biomechanical innovation comprising a suite of morphological, neurological, and behavioral adaptations that have evolved several times independently in the hyperdiverse ant genus Strumigenys. To determine whether genome-wide sequence convergence underlies the convergent evolution of the trap-jaw phenotype, I newly sequenced and analyzed highly accurate, chromosome-scale genome assemblies for 17 ant species, including 13 Strumigenys species representing three independent origins of the trap-jaw mechanism in Asia, Africa, and South America. Analyses of protein-coding genes revealed limited evidence for widespread convergence at the sequence level; however, one notable gene, Obsc, which encodes Obscurin—a protein crucial for muscle structure and function, particularly in organizing sarcomeres essential for rapid muscle contractions—exhibited convergent amino acid substitutions among trap-jaw clades, suggesting that adaptive changes in muscle proteins may have contributed to the evolution of the ultrafast mandible closure characteristic of trapjaw ants. In contrast, analyses of ∼255,000 conserved non-exonic elements (CNEs) revealed that trap-jaw lineages experienced a significant excess of accelerated CNEs compared to an empirical null distribution, identifying ∼680-900 elements specifically accelerated in trap-jaws (TRAP aCNEs). Functional annotation of genes associated with TRAP aCNEs revealed enrichment in biological processes related predominantly to nervous system function and development, as well as morphogenesis. I discuss how convergence in the regulatory regions of these genes might explain the evolution of a suite of adaptations involved in the trap-jaw phenotype, highlighting that convergence in regulatory regions, more so than in protein-coding genes, is more strongly associated with phenotypic convergence in Strumigenys. Overall, this work presents a new high-quality resource of chromosome-level ant genomes and provides insights into the genomic landscape associated with the convergent evolution of a fascinating phenotype
The Role of the CNOT3 Subunit of the CCR4-NOT Complex in Cellular Senescence
Full text linkOkinawa Institute of Science and Technology Graduate UniversityDoctor of PhilosophyCellular senescence is a fundamentally irreversible cell cycle arrest associated with upregulated inflammatory responses. Cellular senescence is involved in numerous biological processes, including tumor suppression and organismal aging. Uncovering its mechanism will contribute to the development of novel therapeutic strategies for age-associated diseases as well as cancer. However, the molecular regulators involved in senescence are not fully elucidated. The CCR4- NOT complex, known for its role in gene expression and mRNA decay, is one such regulator. Despite its broad functions, the specific function of the CCR4-NOT complex, particularly the CNOT3 subunit, in cellular senescence remains unknown. In this thesis work, I studied the role of the CCR4-NOT deadenylase complex in cellular senescence, focusing on the regulatory interplay between the CNOT3 subunit and long non-coding RNA (lncRNA). LncRNAs were chosen for their emerging role in regulating gene expression and senescence. Here, I show that the downregulation of CNOT3 is sufficient for cellular senescence induction in A549 human non-small cell lung cancer cells. Knockdown of CNOT3 causes the upregulation of multiple cellular senescence hallmarks, such as CDKN1A, TP53, the senescence-associated secretory phenotype (SASP) (IL6, IL8, and STC1), and senescence-associated β-galactosidase activity. Moreover, these senescence hallmarks are more significantly upregulated when CNOT3 downregulation is combined with PLK-1 inhibitor (BI2536), which reduces the dividing cell population. These results suggest that CNOT3 downregulation could enhance the susceptibility of lung cancer cells to chemotherapy. I also explored the regulatory network involving CNOT3 and lncRNA. Previously, it has been reported that lncRNA can interact with RNA and RNAbinding proteins to regulate gene expression at the post-transcriptional level by determining the fate of target molecules. To investigate the relationship between CNOT3 and lncRNAs, I analyzed microarray RNA-seq data from CNOT3 knockdown in A549 cells and identified a subset of lncRNAs that were upregulated upon CNOT3 depletion. Among them, the lncRNA MAGI2-AS3 was found to influence the cellular senescence pathway, suggesting that CNOT3 and lncRNAs collaboratively regulate cellular senescence. This thesis highlights the multilayered regulatory roles of CNOT3 and its lncRNA partners, offering a novel perspective on enhancing chemotherapy efficacy