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Rapid Hydrogel Micropatterning and Cadherin Switching: Insights into Developmental Patterning and Mesendodermal Trajectories in Human Embryonic Stem Cells
No full textThis thesis comprises two parts, each contributing novel insights into self-organized patterning and differentiation in human pluripotent stem cells (hPSCs).
Self-organized patterning of mammalian pluripotent stem cells on micropatterned surfaces has been established as an in vitro platform for early developmental studies, complementary to in vivo animal models. The first project addressed the limitations of current micropatterning techniques, due to complex fabrication processes, such as micro-contact printing, preventing widespread usage in biological research. We developed a projection stereolithography-based micropatterning method that uses a digitally tunable photomask to rapidly print hydrogel with micro-features onto glass-bottomed-culture vessels. Combined with the laminin-521 (or LN521) extracellular matrix coating, this technology provides a surface suitable for hPSC attachment and growth with minimal non-specific cell adhesion. The study demonstrated the self-patterning results of hPSCs following gastrulation and ectodermal induction produced on our micropatterned surface are comparable with those obtained using commercially available micropatterned plates. This novel micropatterning approach enables customizable, rapid fabrication of micropatterned surfaces for cell study at a reduced cost, with potential application in developmental biology and regenerative medicine research.
The second project explores cadherin switching during the epithelial-mesenchymal transition (EMT) in the differentiation trajectory of hPSCs through the primitive streaks (PS) and into mesodendermal subtypes. We measured EMT, and cadherin switching (E-cadherin downregulation and N-cadherin upregulation) during hPSC differentiation to PS and subsequently to distinct mesendodermal subtypes using established protocols and variants in signaling modulation of the key pathways, i.e., Activin, BMP, and Wnt. The findings reveal that while early signaling perturbations largely affected the extent of cadherin switching, the differentiation potential of PS cells was unimpacted. Specifically, definitive endoderm progenitors retained the ability to differentiate into both endodermal and mesodermal fates, while PS cells in mid to posterior regions exhibited restricted potential toward definitive endoderm. Additionally, E-Cadherin knockout did not alter cell fate outcomes in mesendodermal differentiation. Overall, the project revealed the decoupling of cadherin dynamics from cell fate decisions in mesendodermal differentiation through PS coordinates, with translational potential for cancer and age-related degenerative disease studies, where modulating EMT and cadherin switching could support innovative therapy development
Neutron scattering studies of Sr(Co1−xNix)2As2, FeSn, CsV3Sb5, and YbMnBi2
No full textIn this thesis, we present several neutron scattering investigations on the complex magnetic and electronic properties of a series of quantum materials, including helical order in Sr(Co1-xNix)2As2, spin excitations in FeSn and CoSn, electron-phonon coupling in charge-density-wave state of CsV3Sb5, vortex lattice in Ta doped CsV3Sb5, and spin chirality in YbMnBi2.
Firstly, we investigate magnetic ordering and spin fluctuations in Sr(Co1-xNix)2As2, a quasi-two-dimensional planar magnet. Neutron scattering studies reveal a c-axis incommensurate helical magnetic structure in Sr(Co1-xNix)2As2, with enhanced quasi-2D ferromagnetic spin fluctuations induced by Ni doping. Band structure calculations suggest that this helical order arises from Ruderman-Kittel-Kasuya-Yosida (RKKY) interactions mediated by itinerant electrons, offering insight into the quantum order-by-disorder mechanism near a quantum critical point.
Next, we examine spin excitations in the metallic kagome lattice materials FeSn and CoSn. In these systems, destructive quantum interference of electronic hopping paths produces nearly localized electrons, resulting in flat electronic bands. Our neutron scattering measurements uncover well-defined spin waves in FeSn and paramagnetic scattering in CoSn, highlighting the delicate balance between geometric frustration and magnetic order in kagome systems. Furthermore, we observe anomalous non-dispersive excitations, attributed to the scattering from hydrocarbon contamination.
We also investigate the electron-phonon coupling in CsV3Sb5, a kagome lattice material exhibiting intertwined CDW and superconductivity. Neutron scattering experiments demonstrate that the CDW in CsV3Sb5 is associated with a static lattice distortion and a sudden hardening of a longitudinal optical phonon mode. This finding underscores the critical role of wave vector-dependent electron-phonon interactions in the CDW order, contributing to our understanding of its coupling with superconductivity in kagome metals.
The fourth study focuses on the superconductivity in Ta-doped CsV3Sb5, which exhibits enhanced superconductivity upon suppression of CDW order. Through Small-Angle Neutron Scattering (SANS), we probe the vortex lattice structure and its evolution in the superconducting state of Cs(V0.86Ta0.14)3Sb5. Our results show that the vortex lattice exhibits a strikingly conventional behavior, including a triangular symmetry, conventional 2e pairing, and a field dependent scattering intensity that follows a London model. Our results suggest that optimal bulk superconductivity in Cs(V0.86Ta0.14)3Sb5 arises from a conventional Bardeen-Cooper-Schrieffer electron-lattice coupling.
Finally, we investigate the giant anomalous Nernst effect (ANE) and anomalous Hall effect (AHE) in the canted antiferromagnet YbMnBi2. The ab-plane spin canting in YbMnBi2 is believed to break time-reversal symmetry, generating a non-zero Berry curvature that gives rise to the giant ANE and AHE. However, direct evidence for this mechanism has remained elusive, as earlier unpolarized neutron measurements excluded significant moment canting. By leveraging the unique advantages of polarized neutron scattering, which can differentiate magnetic scattering from nuclear scattering, we have uncovered clear evidence of spin chirality persisting at temperatures well above room temperature. Additionally, further neutron scattering measurements have revealed inversion-symmetry breaking and anisotropic spin fluctuations, indicating the presence of Dzyaloshinsky-Moriya interactions that likely drive the observed spin chirality, which in turn underlies the ANE and AHE. Our findings provide a detailed mechanism that directly explains the origins of the giant ANE and AHE in YbMnBi2.
Overall, the combination of these works advances the understanding of quantum materials by revealing new insights into the magnetic, electronic, and lattice dynamics of these complex systems. The results presented herein pave the way for future studies on quantum magnetism, unconventional superconductivity, and the development of new materials with novel electronic and magnetic properties
Towards Fine-Grained Isolation Mechanisms for Intraprocess Isolation
No full textMemory safety has long been a significant challenge in computer software security.
In this thesis, we propose a set of methods to mitigate memory safety issues. Our
approach allows for isolation of different functions and modules within an application
at the granularity of individual functions, thereby preventing the spread of memory
safety issues between these modules.
With our thread-safe security monitor, developers can specify untrusted code and
data requiring extra protection, thereby restricting access to sensitive information in
two key ways. The first, called a sandbox, isolates error-prone components, such as
those used for computation, protocol state machines, and parsers. The second, called
a safebox, protects sensitive data or security-critical elements, including privilege
flags, access tokens, and ACLs. This model enhances data protection and supports
the incremental isolation of critical parts at minimal cost.
We introduce an innovative combination of memory safety with contextual re-
sources, allowing the allocation of isolation contexts for temporarily created resources.
For instance, this enables the isolation of communication contents between connec-
tions from different users, with sharing permitted only through securely isolated mod-
ules. A typical example is a chat server where each client has its own context for
handling user connections and encryption keys, preventing attackers from accessing
other users’ information. The received data is shared among receiving users through
a shared memory within a safe module which include sufficiently small TCB code
(containing only the minimal code required for memory copying). Finally, develop-
ers can set additional system resource policies for these contexts, thus limiting their
access to file systems, networks, and other resources.
By utilizing alias mapping, we map the same physical memory to multiple vir-
tual memory addresses, allowing different modules to share data structures without
frequent copying. We embed this alias into the higher bits of the virtual address,
which enables efficient address translation across domains with minimal overhead
and facilitates the seamless use of shared memory across function calls.
We simplify the process by allowing developers to express intentions rather than
operations through code annotations, improving maintainability. This information
can coexist with regular software code and be dynamically enabled or disabled through
our tools, optimizing the use of limited hardware resources while balancing security
and performance.
Our system demonstrated 95% compatibility in LTP testing, indicating its ca-
pability to support most applications developed for the Linux platform, including
those that utilize signals and multithreading, without requiring additional porting.
We conducted several micro-benchmarks for the implementation mechanisms our sys-
tem relies on, better illustrating the system’s overhead sources and providing clearer
guidance for users.
We implemented module isolation in real applications like NGINX and Redis and
created separate isolation contexts for user connections. These evaluations demon-
strate that our system can be easily and progressively applied in practical software.
Our overhead for individual module isolation ranged from 3% to 10%. When isola-
tion was performed on both dimensions simultaneously, our overhead reached 10% to 40
New perspectives on local k-mer sampling schemes and improvements to genome alignment
No full textThe thesis is split into two parts. First, we develop new techniques for improving the speed and accuracy of genome alignment. Afterwards, we prove a near-tight lower bound for local k-mer sampling methods and show that existing sampling schemes are much closer to being optimal than previously anticipated.
Core-genome alignment, the process of identifying and aligning genomic regions highly-conserved across all members of a population, is often used to enhance signal for phylogeny inference and identify essential functions. However, as the input size grows, the probability of any region being highly conserved across all members drops substantially, leading to a loss in recall for core-genome alignment methods. We ameliorate this issue by proposing a divide & conquer framework which can work with any strict core-genome alignment method. By applying this framework to Parsnp, a method released in 2014, we show that it can outperform state-of-the-art methods for core-genome alignment in 2024.
We then turn our attention to pairwise homology mapping, the problem of identifying homologous regions between pairs of genomes and predicting their level of similarity. MashMap2 is a widely used method for this task, however it has been shown to have significant bias at high levels of similarity and also suffers from poor performance at lower levels of similarity. We address both of these issues through the use of a novel k-mer sampling scheme and multiple probabilistic shortcuts, reducing the runtime by over 10x and eliminating the bias.
In the second part, we prove a near-tight lower bound on the density of a widely used class of k-mer sampling schemes and in the process, show that existing schemes are much closer to achieving minimum density than previously anticipated. For small w and k where k ≡ 1 (mod w), we show that the lower bound is empirically tight and conjecture that it is tight for all k ≡ 1 (mod w). This marks the first time there is an analytical description for the density of any minimum density k-mer sampling scheme
Some Geometric Aspects of Higher-Rank Teichmüller Theory
No full textWe study qualitative aspects of the geometry of Hitchin representations of surface groups in PSL(n,R). The thematic core of this thesis is on Thurston-Klein geometric structures with distinguished foliations that are associated to Hitchin representations in SL(3,R) and PSL(4,R). This direction was initiated by Guichard-Wienhard’s work on PSL(4,R)-Hitchin representations.
We establish the following results on these foliated structures. First, we prove a rigidity theorem for the projective geometry of leaves of Guichard-Wienhard’s codimension-1 foliation associated to a PSL(4,R)-Hitchin representation. We then classify all foliations of domains of discontinuity in RP(3) for PSL(4,R)-Hitchin representations that are geometrically similar to those studied by Guichard and Wienhard. Finally, we give a parallel framework to Guichard-Wienhard’s work in PSL(4,R) for geometric structures modeled on the space of full flags in R^3 for SL(3,R)-Hitchin representations.
We give a number of applications of our results and the surrounding circle of ideas.
First, we resolve a question asked by Benzécri in 1960 on the point-set topology of the space of projective equivalence classes of properly convex domains in RP(n) for n at least 2. Next, we give explicit geometric constructions of flows constructed in the dynamical study of Hitchin representations. Finally, we construct asymmetric metrics on PSL(n,R)-Hitchin components for n at least 4 and give a new formulation of Thurston’s asymmetric metric on Teichmüller space.
Finally, we study degree-n complex structures in the sense of Fock and Thomas. These are extensions of complex structures on surfaces whose deformation space T(n,S) is conjectured to be canonically homeomorphic to the PSL(n,R)-Hitchin component. Our main result in this direction is the construction of a canonical homeomorphism from Fock-Thomas spaces T(n,S) of higher complex structures to a bundle B(n,S) of harmonic tensors over Teichmüller space
Investigations of remote peroxin homologs: characterizing PEX8 in Arabidopsis thaliana
No full textPeroxisomes are organelles specialized to sequester diverse metabolic functions, including β-oxidation and detoxification of reactive oxygen species, and are essential for life in both plants and mammals. In plants, peroxisomes are the sole site of fatty acid β-oxidation and house key enzymes in the glyoxylate cycle, photorespiration, and phytohormone biosynthesis. The biogenesis of these organelles is orchestrated by a set of proteins called peroxins (PEX proteins). Although most peroxins display sequence conservation across eukaryotes, several peroxins appear to be rapidly evolving and have eluded discovery outside of the fungal lineage. In this work, I utilized structural homology to seek these elusive “fungi-specific” peroxins in plants. I discovered that a previously uncharacterized Arabidopsis thaliana (At) gene is an ortholog of yeast PEX8. Like yeast Pex8, At PEX8 is a Huntingtin, EF3, a-PP2A, TOR1 (HEAT) repeat protein with two predicted peroxisomal targeting signals. I found that insertional and frameshift mutations in PEX8 confer embryonic lethality with additional defects in gametogenesis. An artificial microRNA targeted to PEX8 impaired lumenal protein import, delayed degradation of lipid droplet components, and conferred physiological defects diagnostic of peroxisome dysfunction. I found that fluorescent reporters fused to PEX8 localized in puncta within peroxisomes and associated with peroxisome inner and outer membranes, providing new insight into PEX8 dynamics. These data are consistent with accumulating evidence that peroxisome protein import occurs through nuclear-pore-like protein condensates. Identifying PEX8 outside of fungi will enable future investigations of PEX8 function, exploiting the advantages of a different and multicellular model. Furthermore, the identification of plant PEX8 reveals broader conservation of peroxisome import machinery and raises the intriguing possibility that other peroxins with low sequence conservation may yet be identified across eukaryotes by utilizing advances in protein structural computation
4.1 Safeguarding the Benefits of Synthetic Cell Engineering
Full text linkThis entreaty was created as part of The Spirit of Asilomar and the Future of Biotechnology summit (February 23-26, 2025) in Pacific Grove, CA.The report outlines the transformative potential of synthetic cells in addressing global challenges through innovation in fields like medicine, energy, and education, while emphasizing their role as safe, accessible models for biological research. It advocates for responsible development through global collaboration, inclusive education, open science practices, and harmonized international governance to ensure equitable and secure deployment
Computational Perspectives on Complex Gene Relationships and Disease: From Cancer Networks to Gene Embeddings
No full textThe rapid proliferation of omics datasets driven by advances in high-throughput sequencing and molecular profiling has created unprecedented opportunities for understanding biological systems. However, the sheer complexity and scale of these data require computational frameworks for effective analysis and interpretation. In this thesis, we explore two complementary computational approaches centered on genes: network-based analyses of patient-specific protein-protein interaction (PPI) rewiring in cancer, and a benchmarking study comparing diverse gene embedding methods for functional gene prediction tasks.
First, using a previously developed method, Splitpea, we systematically analyze exon skipping-driven network rewiring across 7,949 samples spanning 28 cancer types from The Cancer Genome Atlas. Our analysis identifies conserved, cancer-specific, and subtype-specific splicing-induced PPI network alterations, highlighting core sets of rewired genes and revealing significant associations between extreme rewiring patterns and poor prognosis. This shows the potential of splicing-driven network disruptions as a novel framework for understanding cancer through the lens of splicing alterations.
Second, recognizing the importance of effective data representation, we benchmark 38 gene embedding methods across various functional prediction tasks involving single genes and one or more gene pairs. Our findings demonstrate that embedding performance is primarily influenced by the type of training data rather than specific computational algorithms or embedding size. Notably, biomedical literature-based embeddings consistently excel across general tasks, whereas embeddings derived from gene expression data, amino acid sequences, and protein-protein interactions show superior performance in specific functional contexts.
Collectively, these two distinct yet complementary computational perspectives enhance our understanding of gene function in health and disease, providing valuable insights for leveraging computational tools to uncover molecular mechanisms in biological research
Recording and stimulation of spinal interneurons in freely moving mouse using ultraflexible electrodes
No full textIntra-spinal microstimulation (ISMS) is a valuable tool for both scientists and engineers,
offering mechanistic studies of the response characteristics of local spinal cord neurons
and circuits in-vivo as well as potentials for high-resolution stimulation treatments of
spinal cord injuries and other motor deficits. However, due to technological limitations,
previous studies have mostly been conducted in anesthetized or highly constrained animals.
This approach overlooks the dynamics of motor behaviors, which are integral to these
applications and may influence the effect of ISMS on local spinal circuit. In this study, we
investigate the effect of temporally synchronizing ISMS with natural behavioral states on
the neural activation and behavioral outcome in the mouse lumbar cord. This study also
contributes to understanding the spinal cord interneuron population dynamics from an
electrophysiological point of view. We leverage ultraflexible intraspinal electrodes, the na-
noelectronic threads (NETs), for concurrent recording and stimulation during unrestrained
motor behaviors.
We find that single pulse stimulation no greater than 2nC/phase elicited robust neu-
ral activation. Stimulation of different channels along the dorsal-ventral axis yielded
distinctive activation pattern and well-separated neuron-populational trajectories after
dimensionality reduction of single-unit spiking activities, with mild day-to-day fluctua-
tions and overall stability. Preliminary results suggest that the strength of modulation is
dependent on the site of stimulation. Pulse-train stimulations elicited a spectrum of hind
limb movements including stepping, limb flapping and muscle contraction at low currents
with considerable trial-to-trial variability. In order to mitigate variability in pre-stimulation
baseline neural state, we implement closed-loop stimulation using real-time behavioral
markers, controlling the behavioral state for each stimulation. This paradigm will help
reveal how the spinal cord neural circuitry along the dorsal-ventral axis reacts and adapts
to perturbation during rhythmic activity. These ongoing efforts underscore the critical
interplay between ISMS and behavior. Our study holds implications for advancing the
stimulation paradigm for both basic scientific investigation and potential translational
applications
Nineteenth-Century Virtuosic Transcriptions of Vocal Music: A New Typology
Full text linkThe development of the piano into a highly virtuosic instrument in nineteenth-century Europe led to a proliferation of repertoire exploiting its new mechanical capabilities. A significant portion of the repertoire comprises works that transform existing music into solo piano compositions. Vocal music like art song, oratorio, and opera frequently provided source material for these works. Since the nineteenth century, terms like “transcription,” “fantasy,” “arrangement,” and “paraphrase” have been used to refer to works of this sort, but they are often used imprecisely, inconsistently, and interchangeably. To address the categorical difficulty, a new typology is proposed in this document. The proposed types are based on the qualities and traits of existing repertoire, as revealed by analysis of representative pieces. Aspects of compositional design and various pianistic idioms are among many characteristics which contribute to the transformation of source material, and which will serve as a basis for study. As a final demonstration of the proposed types, three newly composed solo piano works are included as an appendix, the final chapter serving as an explanation of their methodology and connection to the existing repertoire