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Oxygen-Regulating MEMS Devices for Cell Transplantation to Cure Type 1 Diabetes
No full textType 1 diabetes is an autoimmune disease in which immune cells specifically attack and destroy the insulin-producing beta cells in the pancreatic islets that regulate blood glucose levels. Traditionally managed with frequent injections of exogenous insulin, beta cell replacement therapy—also known as islet transplantation—has emerged as an alternative clinical option. Recently, the focus has shifted toward subcutaneous islet transplantation, offering a promising and minimally invasive therapy. However, the survival of transplanted islets has been shown to be significantly challenged by hypoxia-induced graft loss stemming from inadequate oxygen supply.
To address this issue, we have developed innovative hollow mesh devices that regulate oxygen. These devices can either bring oxygen from the adjacent oxygen-rich tissue or draw additional oxygen from ambient air to improve oxygen delivery to the hypoxic microenvironment of islet grafts. Fabricated using MEMS techniques and biocompatible materials, these devices feature a network of unobstructed air-containing microchannels. Utilizing the property that oxygen diffuses 10,000 times faster in air than in interstitial fluids, these devices effectively overcome oxygen supply barriers when co-transplanted with islet grafts. By integrating these hollow meshes with the islet grafts, oxygen can be rapidly redistributed throughout the graft, establishing local oxygen balance and regulation. This approach significantly reduces hypoxia-induced graft loss and improves the efficacy of post-transplant blood glucose regulation in recipients.
In this thesis, we first delved into the physiology of oxygen transport within an islet, establishing the critical oxygen threshold necessary for islet cell survival. We developed equivalent circuit models for oxygen diffusion and constructed oxygen-regulating hollow mesh MEMS devices based on these models. We investigated the effects of oxygenation through both computational models and benchtop experiments. Finally, using our device, we demonstrated enhanced survival of islet grafts in diabetic rodent models, successfully achieving a long-term cure for diabetes.
With the preclinical success of this oxygen-regulating hollow mesh in mitigating cellular oxygen deficiency, we also explored and proposed future pathways toward clinical effectiveness. Our device holds significant therapeutic potential to revolutionize clinical outcomes in islet transplantation with the ultimate goal of curing type 1 diabetes.</p
Probing the Higher Redshift Universe by Studying Strong Lensing of Gravitational Waves and Enhancing Search Sensitivity of the GstLAL Search Pipeline
Get PDFThe LIGO-Virgo-KAGRA (LVK) collaboration first observed gravitational waves in 2015, and more than gravitational-wave events have been observed, all coming from mergers of compact objects (black holes and neutron stars), known as compact binary coalescences (CBC). Studying and observing gravitational waves opens a new window for us to understand the nature of spacetime and the universe. Strain data from LVK's detectors are analyzed by search pipelines to identify weak gravitational-wave signals in noisy data. To maximize the potential of gravitational waves, it is essential to continue to improve search pipelines' sensitivity to probe GW sources with the broadest range of parameters and from the furthest distances. I will give a detailed overview of the GstLAL pipeline and present related development (ongoing) work for GstLAL to enhance its search effectiveness and efficiency.
In the second part of my thesis, I will focus on gravitational lensing of gravitational waves. As masses can produce curvature in spacetime, gravitational waves, like electromagnetic (EM) waves, are deflected when passing by massive intervening objects before reaching gravitational-wave detectors on Earth, an effect known as gravitational lensing. Observing lensed gravitational waves confirms another prediction in Einstein's general relativity and enables us to conduct cosmography studies, test general relativity, search for dark matter and other exotic phenomena, and deepen our understanding of the universe. I will give a detailed introduction to gravitational lensing of gravitational waves. We then introduce a Targeted subthreshold search for strongly-lensed gravitational wave pipeline called "TESLA". The TESLA pipeline is the flagship to look for sub-threshold lensed gravitational waves. Next, we present the results of the LVK collaboration-wide effort to search for lensing signatures in gravitational-wave data from the third observing run O3. Next, we introduce a significant update to the TESLA pipeline, now known as the TESLA-X pipeline, with enhanced search sensitivity towards lensed gravitational waves. We also introduce an alternative ranking statistic implemented into the TESLA-X pipeline that considers the signal's consistency with the assumed lens model. Finally, we end the thesis with a summary and an outline of possible future work.</p
Clearing the Air: A Chemical Approach to Understanding Secondary Organic Aerosol Formation From Volatile Chemical Products
No full textUnderstanding sources of air pollution is critically important as ~7 million premature deaths are associated with poor air quality. A key component of urban air quality is secondary organic aerosol (SOA), a type of particulate matter that contributes smog. SOA is formed via the reactive oxidation of volatile organic chemicals (VOCs), gas-phase compounds often emitted from anthropogenic sources. Historically, SOA formation and VOC emissions have been driven by on-road mobile sources. In recent years, however, other sources, such as consumer and industrial solvents - so called volatile chemical products (VCPs) - have become increasingly more important. SOA also impacts climate change, as particulate matter affects global radiative forcing.
Characterizing the chemistry and SOA formation from VCPs can elucidate our understanding of modern urban air pollution, particularly as we try to uncover recent stagnation in air quality. Because VCPs are comprised of hundreds of individual chemical compounds, it is exceedingly difficult to study and characterize each one individually. By contrast, understanding these compounds through a chemistry lens can help to make broader generalizations about larger classes of compounds.
This dissertation looks at the chemistry leading to SOA formation from several chemicals that make up VCPs. Specifically, this work looks at benzyl alcohol and ethoxyethanol. These compounds are used in personal care products, cleaning products, architectural coatings and adhesives. Understanding the reactivity of these compounds can help us understand more broadly the chemistry and SOA potential of other chemicals in VCPs that have similar chemical structures
From the Sun to the Stars: A Solar Calibrator for the Keck Planet Finder and New Frontiers in Exoplanet Obliquities
Get PDFThe galactic census is underway. In the thirty years since the discovery of 51-Pegasi b, the first extrasolar planet discovered orbiting a main sequence star, over 5,600 more have been tallied. The known exoplanet population is diverse, yet no extrasolar system observed to date resembles our own. The radial velocity (RV) technique, which works by measuring the reflex motion of a star from a perturbing planet, remains the most capable method for discovering exo-Earths. An exo-Earth would accelerate its star up to 9 cm/s, Doppler-shifting stellar absorption lines across the detector of a modern spectrograph by 1/10,000th the width of a typical CCD pixel. At this level of precision, every component of the instrument becomes critical to the overall stability. Yet, despite many instruments reaching <30 cm/s precision (such as the Keck Planet Finder; KPF), exoplanet discovery has stalled around the 1 m/s level. The primary limitation is now correlated noise introduced by physical processes on the stellar surface, dubbed "stellar activity," which manifests RV variability up to many m/s on timescales from minutes to decades.
This thesis has two primary themes. The first is concerned with addressing the stellar activity problem and improving RV instrument performance. Both are well-probed using "Sun-as-a-star" observations, as the Sun is the only star in the universe with all orbiting planets accounted for and its surface resolved at all timescales, wavelengths, and spatial scales. Chapter 3 presents the Solar Calibrator (SoCal), an autonomous system that feeds stable, disc-integrated sunlight to KPF at the W. M. Keck Observatory. With SoCal, KPF acquires 200–800 daily high-resolution (R = 98,000) optical (445-–870 nm) solar spectra up to a signal-to-noise of 2400, providing a rich and unmatched dataset for developing novel methods for mitigating stellar activity. We also leveraged SoCal to discover, diagnose, and fix a detector issue in KPF, and to develop and optimize the data reduction pipeline. We compared SoCal RVs to solar RVs from the NEID solar feed and found excellent agreement on intra-day timescales at the single-measurement photon-noise level (30—40 cm/s).
The second theme of this thesis is the precise characterization of extrasolar planets in extremely close-in orbits. These most extreme exoplanets often constrain planet formation theories the most. Chapter 2 presents the discovery and characterization of TOI-1347 b, the most massive rocky ultra-short-period exoplanet discovered to date. We found tentative evidence for a high mean-molecular-weight atmosphere on the planet, which orbits its star in just 20 hours. An atmosphere on such a highly irradiated world would be unusual, but not impossible, though JWST follow-up measurements are needed to confirm. Chapters 4, 5, 6, and 7 probe the mysterious formation pathways of hot Jupiters from four unique angles. Archeological clues to their dynamical histories remain in their present-day stellar obliquity, the angle between the star’s rotation axis and the planet’s orbital plane. The first is WASP-107 b, a super-Neptune that must have migrated to explain its ultra-low density and escaping atmosphere. We measured WASP-107 b to be on a polar orbit, an indicator of a history of dynamics with its outer planetary companion WASP-107 c. The second is KELT-18 b, an ultra-hot Jupiter we also found to be on a polar orbit. The mutually misaligned stellar companion in the system may be to blame. The third, Kepler-1656 b, is a highly eccentric sub-Saturn that could plausibly be undergoing migration kick-started by its outer planetary companion. Its orbit may be aligned, atypical of the traditional picture of high-eccentricity migration. The fourth, Kepler-1658 b, is actively experiencing tidal orbital decay around an evolved star, two aspects that strongly constrain orbital realignment timescales. The system either retains its primordial configuration or constrains tidal efficiencies. Unfortunately, our transit observations are contaminated by a massive starspot, which preclude the direct measurement of the obliquity. This chapter instead explores new methods for directly modeling starspots in EPRV spectra.</p
Exploring Thermal Photonics for Sustainability: From Selective Solar Absorbers to Terrestrial Radiative Cooling
Get PDFPhotonic materials for thermal emission control have attracted much attention in sustainable technologies where energy and heat management are highly desirable. Controlling the frequency dependency of emissivity enables passive suppression or enhancement of thermal emission which can be used to exploit thermodynamically favorable conditions.
In Part I, we present the development of a selective solar absorber which suppresses thermal emission for efficient conversion of solar energy into thermal energy. Our absorber uses an ultrathin metal layer and an antireflective coating to suppress thermal emission and enhance solar absorption, respectively. Furthermore, we constructed a novel scalable photothermal reactor which utilizes the selective solar absorber for thermocatalytic processes. Thermochemical processes provide a sustainable alternative for fuel synthesis compared to traditional industrial methods, and catalyzed processes operate at reduced temperatures and pressures allowing them to be powered solely by direct solar thermal energy. Using sunlight, we synthesized C₆ – C₂₄ carbon chain length olefins from ethylene gas with Ni-catalyzed ethylene oligomerization, demonstrating a vital step for direct CO₂ to sustainable aviation fuel synthesis.
In Part II, we present silicon oxide and silicon nitride bilayer laminate nanoparticle films as scalable efficient daytime terrestrial radiative coolers which couple enhanced thermal emission with the cold background of space. We show experimentally that laminate nanoparticle films deposited from a nonthermal plasma are well described by effective medium mixing models, and their fill fraction tunability enables them to spectrally match more efficiently to the atmospheric transmission window than conventional dense laminate thin films. During this process, we realized a need for directly measuring thermal emission in a controlled ambient to facilitate inter-comparisons between radiative cooling performances. In response, we constructed a new instrument for direct spectrally and angularly resolved radiative emission measurements, providing a new avenue to study the thermal emission behavior of photonic materials.</p
Higher-Order Chromatin States and Nuclear Structures Regulating Gene Expression
Get PDFAlthough the same genome is present in every cell, each cell type orchestrates a distinct gene expression program, which can be rapidly adapted in response to stimuli. Accordingly, gene regulation is a highly complex, context-specific process that involves the dynamic interplay between numerous regulatory factors. Most methods to study these regulatory factors only measure pairwise interactions between molecules and are limited to mapping one regulatory protein at a time. Consequently, the combinatorial complexity of gene regulation at individual genomic loci and the functional consequence of many regulatory factors remain underexplored. To address this, we have developed new sequencing-based approaches and computational analyses to comprehensively profile, at unprecedented scale, the diverse gene regulatory landscape and directly establish the link between regulatory factors and transcriptional outcomes. In Chapter 2, we present Chromatin Immunoprecipitation Done-In-Parallel (ChIP-DIP), a highly multiplexed method for mapping hundreds of proteins to DNA within a single sample. ChIP-DIP increases the throughput of existing methods by > 100-fold and enables the production of consortium-scale, cell type-specific data within a single lab. Capitalizing on the scale and diversity provided by ChIP-DIP, we uncover unique quantitative combinations of histone modifications that define distinctive classes of regulatory elements. Specifically, we find features distinguishing classes of promoters that correspond to different polymerase activity, transcriptional levels, and gene types and find acetylation patterns distinguishing classes of enhancers that exhibit distinct activity states, induction potential, and regulatory potential. Next, in Chapter 3, we apply RNA-DNA SPRITE (RD-SPRITE), a method for simultaneous measurement of RNA and DNA organization, to investigate the functional relationship between genome structure and transcription. We demonstrate that RD-SPRITE precisely detects individual, nascent pre-mRNAs at their transcriptional locus and, as a result, can be used to assess the 3D genome structure present during active transcription. We find that RNA polymerase II transcription occurs within genomic structures previously thought to be inactive, such as the B compartment and DNA regions near the nucleolus. This suggests that active transcription can occur throughout the nucleus and argues against structural domains that preclude transcription. Overall, our findings highlight the ability of RD-SPRITE to establish a structure-function link. Finally, in Chapter 4, we apply RD-SPRITE to study the transcriptional dependence of nuclear organization. We demonstrate that transcriptional inhibition leads to the loss of high-order structure around multiple RNA-processing bodies — the nucleolus, the scaRNA hub and the histone locus body — that are responsible for essential nuclear functions such as RNA processing and gene regulation. These findings suggest a role for RNA and nascent transcription in the formation and maintenance of long-range 3D contacts and critical nuclear compartments. In summary, we have developed new approaches to explore epigenomic and organizational complexity within the mammalian nucleus and have uncovered genome-wide principles of gene regulation.</p
Control of Unknown Dynamical Systems: Robustness and Online Learning of Feedback Control
Get PDFOver the past few decades, our physical and digital worlds have become increasingly intertwined and reliant on each other. Advancements in areas such as machine learning, online optimization, and control theory, along with ubiquitous access to computational power, have played a crucial role in this technological evolution. As a result, we are now moving towards a future where complex and intelligent dynamical systems, with humans in the loop, govern our daily lives.
Building advanced control systems is a critical step in this journey, as they enable swift and data-informed decision-making. However, as we aim to create even more sophisticated closed-loop systems, we must proceed with a careful balance of ambition and caution. While the benefits of these interconnected systems are abundant and our dependence on them deepens, ensuring the actual reliability and safety of the systems becomes increasingly challenging due to the growing complexity of their dynamics. This challenge is particularly prominent in safety-critical applications involving physical systems, which often have strict and non-negotiable safety and performance requirements. To establish a harmonious relationship between our physical and digital worlds, it is crucial to develop intelligent closed-loop control systems that are not only fast and efficient, but also reliable and fault-tolerant.
The title of this thesis, "Control of Unknown Dynamical Systems: Robustness and Online Learning of Feedback Control," reflects the central focus of this work on addressing this pressing challenge. The thesis aims to develop theoretical frameworks and tools that provide insights and contribute new approaches to the design of control systems capable of handling the inherent uncertainty in real-world dynamical systems.
The first part of the thesis focuses on the design of closed-loop systems that are robust to dynamic uncertainty, particularly in settings involving nonlinear dynamics and complex control constraints. The second part introduces a general framework for learning-to-control algorithms that provide worst-case guarantees, even in scenarios where the dynamic uncertainty is arbitrarily large. By addressing these key aspects, this work aims to advance our understanding and capabilities in designing control systems that can effectively deal with uncertainty.</p
Development and Applications of Imaginary Time Path Integral Methods
Get PDFRecent engineering advances have opened up avenues to novel technologies that bridge the gap between the quantum and the classical. In order to understand large-scale quantum systems, a variety of approximate theoretical treatments have been proposed. This thesis focuses on development and applications of path-integral methods, which have enjoyed broad applicability in recent years for exploring nuclear quantum effects in the domains that span physical, bio-, geo-, and materials chemistry.
Feynman's path-integral formulation of quantum statistical mechanics offers powerful and widely used strategies for including nuclear quantum effects in complex chemical systems. These strategies are based on the observation that the quantum Boltzmann statistical mechanics of a quantum system is exactly reproduced by the classical Boltzmann statistical mechanics of an isomorphic ring-polymer system. For the numerically exact calculation of quantum Boltzmann statistical properties, the classical Boltzmann distribution of the ring-polymer system can be sampled using Monte Carlo (i.e., path-integral Monte Carlo, or PIMC) or molecular dynamics (PIMD).
Chapters 1 and 2 of this thesis identify and — with no computational overhead — eliminate the issues in virtually all previous numerical implementations of PIMD that stem from time discretization. The resultant integration scheme requires only a small modification to existing PIMD algorithms and provides accurate statistical and dynamical data in a single-shot simulation with an up to 3-fold increase in the timestep duration.
Chapter 3 transitions from the PIMD method development to the applications of the related PIMC method to understand equilibrium of stable heavy isotopes (D, 13C, 17, and 18O in small gaseous molecules. We present a collaborative experiment-theory calibration of the temperature dependence of the clumped isotope effect in methane in Chapter 4. We continue in Chapter 5, adding the study of isotopic fractionation between methane, water, and molecular hydrogen. Here we present the first concrete example of the effect of Born-Oppenheimer approximation on PI calculations. Finally, Chapter 6 extends our treatment to ethane and propane. For propane, in addition to multiple clumped isotope effects, there is also a strong site preference for the heavy isotopes to occupy the central (methylene) group.
All the isotopic equilibrium calculations utilize accurate potential energy surfaces and are validated against experimental data in close collaboration with Daniel Stolper's experimental group at Berkeley, representing (to the best of our knowledge) the most accurate reference data available to date.</p
Gravitational Wave Exotica - Advancing the Search for Signatures of Exotic Compact Objects and Gravitational Lensing from Data-Analysis and Theoretical Perspectives
Get PDFIn this thesis, I explore two new arenas of gravitational-wave physics and advance them from both data-analysis and theoretical perspectives. I probe the nature of the remnant of a compact binary merger and study the strong gravitational lensing of gravitational waves. For probing the nature of a merger remnant, I first describe recipes of computing radiation emitted by a perturbed Kerr black hole, and in particular using the Generalized Sasaki-Nakamura formalism. Using a modified Kerr black hole spacetime as a model of a generic compact object, I then describe a prescription to compute waveforms of the repeating bursts of gravitational waves, referred to as gravitational-wave echoes, that are theorized to be emitted when a compact object with a reflective surface is formed as the remnant of a merger. Equipped with a waveform model for these echoes, I present a Bayesian model selection approach to look for echoes in data while inferring properties of the potential exotic compact object. I apply this approach to search for echoes in the data covering the first, the second, and the first half of the third observing run of the LIGO-Virgo-KAGRA network. For the strong lensing of gravitational waves, I first develop a Bayesian statistical framework that is capable of computing the probability of a given set of gravitational-wave events being the strongly-lensed counterparts of the same source or simply coming from distinct sources. If they are truly lensed, the framework can also infer the properties of the lensed source in a way unaffected by lensing. I apply this framework to search for signatures of strongly-lensed binary black hole systems in the data covering the third observing run. While we did not find any statistically significant evidence in the search for gravitational-wave echoes and strongly-lensed binary black holes, we can still place limits using the null results. Admittedly the existence of exotic compact objects is speculative and the observing rate of strongly-lensed gravitational waves is rare; however, the scientific impacts that they can bring are profound if they are proven to exist
Atomic Dynamics in Solids and Liquids from Inelastic Neutron Scattering
Get PDFAs temperature increases, atomic scale disorder, or entropy, drives the thermophysical properties of materials. One way it does this is by passing heat through materials in the form of vibrations. In solids, vibrational motions are called phonons, and their behaviors are used to predict macroscopic properties such as thermal expansion and thermal conductivity. Vibrational dynamics also exist in liquids but are traditionally less studied. Other forms of entropy include configurational and electronic entropy, which also evolve with temperature. Configurational changes in solids are often small, but in liquids, the prominence of diffusion makes this contribution significant. This dissertation addresses these atomistic components of entropy in two studies, one on bcc chromium and the other on the melting of monatomic systems.
In the first study, phonon densities of states (DOS) of body-centered cubic chromium were measured by time-of-flight inelastic neutron scattering (INS) at temperatures up to 1493 K. Density functional theory calculations with both quasi-harmonic (QH) and anharmonic (AH) methods were performed at temperatures above the Neel temperature. Features in the phonon DOS decrease in energy (soften) substantially with temperature. A Born-von Karman analysis using fits to the experimental DOS reveals a softening of almost 17% of the high transverse phonon branch between 330 and 1493 K. The low transverse branch changes by approximately half this amount. The AH calculations capture the observed behavior of the two transverse phonon branches, but the QH calculations give some inverted trends. Vibrational entropies from phonons and electrons are obtained, and their sum is in excellent agreement with the entropy of chromium obtained by calorimetry, indicating that above 330 K, no explicit temperature-dependent magnetic contributions are necessary.
The second investigation delves into the latent heat of melting, defined as TmΔSfus where Tm is the melting temperature and ΔSfus is the entropy of fusion. At the scale of atoms and electrons, ΔSfus has components from changes of atom configurations, atom vibrations, and thermal excitations of electrons. New data analyses were developed for inelastic neutron scattering to obtain changes in vibrational spectra upon melting. Combining these INS experiments with computational work using thermodynamic integration and molecular dynamics, components of ΔSfus were obtained for a total of six elements, Ge, Si, Bi, Sn, Pb, Li. Upon melting, there is always a positive change of configurational entropy, ΔSconfig. A baseline value of ΔSconfig=1.2kB/atom, approximately the value for Richard's rule, corresponds to zero change in the vibrational part of the entropy of fusion, ΔSvib. Elements having values of ΔSfus
that depart from this value of Richard's rule have both an additional ΔSvib and an additional ΔSconfig. Surprisingly, the extra ΔSconfig is close to 77% of ΔSvib, for both positive and negative deviations from Richard's rule. This implies a correlation between the change in the number of basins in a potential energy landscape and the change in the inverse of their curvature upon melting.</p