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Single-Cell Analysis of Normal and Perturbed Early T-Cell Developmental Processes
Get PDFEarly T-cell development converts multipotent precursors to committed pro-T cells, silencing progenitor genes while inducing T-cell genes. However, both the underlying steps of developmental progression and the regulations involved have remained obscure. Although some of the expressions of important regulators in early T-cell development have been studied in bulk populations, the nature of heterogeneity in this constantly refreshed developmental continuum makes it difficult to understand the developmental trajectories that the cells have undergone using bulk analysis, both in natural conditions and under gene perturbations.
Combining droplet-based single cell RNA sequencing (scRNA-seq), deep-sequenced whole-transcript scRNA-seq, and seqFISH for key regulatory genes, we established regulatory phenotypes of sequential ETP subsets; confirmed initial co-expression of progenitor- with T-cell specification genes; defined stage-specific relationships between cell-cycle and differentiation; and generated a pseudotime model from ETP to T-lineage commitment, supported by RNA velocity and transcription factor perturbations. This model was validated by developmental kinetics of ETP subsets at population and clonal levels. The results imply that multilineage priming is integral to T-cell specification in natural developing pro-T cells in the thymus.
Moreover, we examined the functional implications of some of the transcription factors (TFs) through bone marrow (BM) derived ex-vivo differentiation systems. Using scRNA-seq, Cell Hashing, and a pool-based CRISPR/Cas9 perturbation system, we established the normal and perturbed developmental trajectories before and after the T-lineage commitment stages. Our analysis revealed that, without the essential lineage commitment TF, Bcl11b, the developing early T cells immediately realized the lack of the essential regulator around the proliferating late DN2a stage. But instead of pushing the developmental path backwards to resemble the earlier stage of uncommitted cells, cells lacking Bcl11b underwent a diverging route of accumulation of 'non-T' genes that are not naturally expressed in earlier stages, potentially leading to the eventual loss of Notch responses. Our results also revealed the complex regulations by TFs that set up the earliest T-lineage progression and commitment conditions. The SCENIC analysis suggested that Gata3 and Tcf7, despite both being important regulatory factors for T-lineage progression, have very different regulatory roles in controlling proliferation and suppressing myeloid lineages. Furthermore, pseudotime analysis also showed that some of the stem and progenitor genes and 'multilineage' associated genes expressed by early pro-T cells potentially hold back the T-lineage differentiation speed. In summary, our study leveraged both in vivo thymic pro-T cells' developmental trajectory obtained through single-cell analysis and ex-vivo derived T cells for internal-controlled perturbations, and revealed some profound roles of TFs in regulating early T-cell differentiation processes.</p
Large-Scale Photonics Integration: Data Communications to Optical Beamforming
Get PDFIntegrated photonics is an emerging technology that has begun to transform our way of life with the same amount of impact that integrated CMOS electronics has. Currently, photonics integration is orders of magnitude less complicated than its electronics counterparts. Nonetheless, it serves as one of the main driving forces to meet the exponentially increasing demand for high-speed and low-cost data transfer in the Information Age. It also promises to provide solutions for next-generation high-sensitivity image sensors and precision metrology and spectroscopy instruments. In this thesis, integrated photonics architectures for solid-state photonic beamforming and processing are investigated for high-resolution and high sensitivity lens-free transceiver applications. Furthermore, high-efficiency integrated electro-optical modulators aiming to meet the demand of high-density photonic integration with improved modulation efficiency, small footprint, and lower insertion loss are investigated.
Two integrated photonic solid-state beamforming architectures incorporating two-dimensional apertures are explored. First, a novel transceiver architecture for remote sensing, coherent imaging, and ranging applications is demonstrated. It reduces system implementation complexity and offers a methodology for very-large-scale coherent transceiver beamforming applications. Next, a transmitter beamforming architecture inspired by the diffraction pattern of the slit annular ring is analyzed and demonstrated. This transceiver architecture can be used for coherent beamforming applications such as imaging and point-to-point optical communication. Finally, a coherent imager architecture for high-sensitivity three-dimensional imaging and remote-sensing applications is present. This novel architecture can suppress undesired phase fluctuations of the optical carrier signal in the illumination and reference paths, providing higher resolution and higher acquisition speed than previous implementations.
Moreover, several compact, high-speed CMOS compatible modulators that enable high-density photonic integration are explored. Ultra-compact and low insertion loss silicon-organic-hybrid modulators are designed and implemented for high-speed beamforming and high-efficiency complex signal modulation applications. Finally, a novel integrated nested-ring assisted modulator topology is analyzed and implemented for high-density and high modulation efficiency applications.</p
Hybrid Si/III-V Lasers for Next-generation Coherent Optical Communication
Get PDFThe most important application of semiconductor lasers is, without doubt, optical communication, the backbone of the information age. In the past few decades, incoherent optical communication with conventional semiconductor lasers, the III-V distributed feedback (DFB) lasers, has successfully fulfilled the global demand for the data rate. However, in order to support the rapidly growing Internet traffic of the 21st century, the transition from incoherent to coherent optical communication is inevitable, requiring new types of lasers, as the conventional III-V DFB lasers lack the phase coherence needed to serve as the light sources in coherent optical communication. The existent alternatives with high phase coherence are external cavity lasers (ECLs) and fiber lasers, whose high price and bulky size effectively thwart the upgrade of the current communication networks. This is the main motivation for us to develop high-coherence semiconductor lasers.
To achieve the goal, we shall rethink and redesign semiconductor lasers. Advanced modern fabrication technology helps us to turn bold ideas into reality. Not only do we build semiconductor lasers on hybrid platforms, but also engineer elaborately the optical mode to enhance the lasers’ phase coherence. The newly developed semiconductor lasers, hybrid Si/III-V lasers, are the core of the entire thesis. Their design principles, fabrication process, properties and performance in the coherent optical communication system will be presented and discussed. The experimental results show the Si/III-V lasers' superiority to their conventional counterparts.
Aside from possessing high phase coherence, the Si/III-V lasers have great potential to be the light sources on the integrated photonic platforms. The fundamental obstacle thwarting photonic integration is optical feedback, to which the conventional semiconductor lasers are very sensitive. Without the protection provided by optical isolators, which unfortunately cannot be fabricated on chip, the performance of the conventional III-V DFB lasers could get significantly degraded by optical feedback. The Si/III-V lasers, with their built-in high-Q resonators, are very robust against optical feedback and can function properly in the isolator-free coherent optical communication systems. Thus, the cost of future optical networks can be further reduced by monolithically integrating passive photonic devices such as modulators and demodulators with the Si/III-V lasers.
Finally, all the studies centered on laser coherence trigger us to think deeply about the underlying relation between different means of characterizing laser coherence. A rigorous mathematical relation, the Central Relation, has been derived here, which not only unveils the fundamental relation between laser lineshape and frequency noise power spectral density (PSD) but also provides new methods of frequency noise controlling like optical filtering.</p
From Bipedal to Quadrupedal Locomotion, Experimental Realization of Lyapunov Approaches
Get PDFPossibly one of the most significant innovations of the past decade is the hybrid zero dynamics (HZD) framework, which formally and rigorously designs a control algorithm for robotic walking. In this methodology, Lyapunov stability, which is often used to certificate a dynamical system's stability, was introduced to the control law design for a hybrid control system. However, the prerequisites of precise modeling to apply the HZD methodology can often be too restrictive to design controllers for uncertain and complex real-world hardware experiments. This thesis addresses the problem raised by noisy measurements and the intricate hybrid structure of locomotion dynamics.
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First, the HZD methodology's construction is based on the full-order, hybrid dynamics of legged locomotion, which can be intractable for control synthesis for high-dimensional systems. This thesis studies the general structure of hybrid control systems for walking systems, ranging from 1D hopping, 2D walking, 2D running, and 3D quadrupedal locomotion on rough terrains. Further, we characterize a walking behavior--gait--as a solution (execution) to a hybrid control system. To find these solutions, which represent a "gait," we employed advanced numerical methods such as collocation methods to parse the solution-finding problem into the open- and closed-loop trajectory optimization problems. The result is that we can find versatile gaits for ten different robotic platforms efficiently. This includes bipedal running, bipedal walking on slippery surfaces, and quadrupedal robots walking on sloped terrains. The numerous solution-finding examples expand the applicability of the HZD framework towards more complex dynamical systems.
Further, for the uncertain and noisy real-world implementation, the exponential stability of the continuous dynamics is an ideal but restrictive condition for hybrid stability. This condition is especially challenging to satisfy for highly dynamical behaviors such as bipedal running, which loses ground support for a short period. This thesis observes the destabilizing effect of the noisy measurements of the phasing variable. By reformulating the traditional input-to-state stability (ISS) concept into phase-uncertainty to state stability, we are able to synthesize a robust controller for bipedal running on DURUS-2D. This time+state-based controller formally guarantees stability under noisy measurements and stabilizes the 1.75 m/s running experiments.
Lastly, robotic dynamics have long been characterized as the interconnection of rigid-body dynamics. We take this perspective one step further and incorporate controller design into the formulation of coupled control systems (CCS). We first view a quadrupedal robot as two bipedal robots connected via some holonomic constraints. In a dimensional reduction manner, we develop a novel optimization framework, and the computational performance is reduced to a few seconds for gait generation. Furthermore, we can design local controllers for each bipedal subsystem and still guarantee the overall system's stability. This is done by combining the HZD framework and the ISS properties to contain the disturbance induced by the other subsystems' inputs. Utilizing the proposed CCS methods, we will experimentally realize quadrupedal walking on various outdoor rough terrains.</p
Investigating Sand Transport and Landslides, and Implications for Past and Present Environments on Mars and Earth
Get PDFWind-driven movement of sand and landslide activity are among the most important processes driving modern-day change on planetary surfaces. This thesis uses novel techniques and datasets to investigate the forces driving these processes on the surface of Mars, and also considers possible applications of the techniques described to Earth. Chapter 1 introduces past work done to understand these processes, and outstanding questions our work aims to answer. Chapter 2 presents and tests a new technique which aims to improve predictions of sand transport driven by wind on planetary surfaces by correcting coarse-resolution GCM predictions for the short-timescale fluctuations they miss. Chapter 3 presents new multiyear measurements of ripple migration at two dune fields on the surface of Mars, and applies these measurements, in conjunction with the new techniques described in Chapter 2, to investigate the dynamics of the Martian atmosphere, and test the accuracy of predictions made by Martian climate models. In Chapter 4, we study a large-scale natural sand trap in the Meroe Patera dune field on Mars, and estimate its trapped volume of sand in comparison to the volume of "missing" sand in a dune-free shadow zone downwind of the crater. The volume of trapped sand is far less than the missing volume, suggesting past escape of sand from the crater, despite a lack of obvious evidence for such escape in the present day. In Chapter 5, we change focus from sand transport to introduce an analysis of controls on the global distribution of Martian landslides. Chapter 6 discusses the limitations of applying the techniques of satellite image and climate model analysis described in Chapters 2-4 to terrestrial settings, as well as the possible utility of Chapter 5’s method on other planets.</p
Applications of Convex Analysis to Signomial and Polynomial Nonnegativity Problems
Get PDFHere is a question that is easy to state, but often hard to answer:
Is this function nonnegative on this set?
When faced with such a question, one often makes appeals to known inequalities. One crafts arguments that are sufficient to establish the nonnegativity of the function, rather than determining the function's precise range of values. This thesis studies sufficient conditions for nonnegativity of signomials and polynomials. Conceptually, signomials may be viewed as generalized polynomials that feature arbitrary real exponents, but with variables restricted to the positive orthant.
Our methods leverage efficient algorithms for a type of convex optimization known as relative entropy programming (REP). By virtue of this integration with REP, our methods can help answer questions like the following:
Is there some function, in this particular space of functions, that is nonnegative on this set?
The ability to answer such questions is extremely useful in applied mathematics.
Alternative approaches in this same vein (e.g., methods for polynomials based on semidefinite programming)
have been used successfully as convex relaxation frameworks for nonconvex optimization, as mechanisms for analyzing dynamical systems, and even as tools for solving nonlinear partial differential equations.
This thesis builds from the sums of arithmetic-geometric exponentials or SAGE approach to signomial nonnegativity. The term "exponential" appears in the SAGE acronym because SAGE parameterizes signomials in terms of exponential functions.
Our first round of contributions concern the original SAGE approach. We employ basic techniques in convex analysis and convex geometry to derive structural results for spaces of SAGE signomials and exactness results for SAGE-based REP relaxations of nonconvex signomial optimization problems.
We frame our analysis primarily in terms of the coefficients of a signomial's basis expansion rather than in terms of signomials themselves.
The effect of this framing is that our results for signomials readily transfer to polynomials. In particular, we are led to define a new concept of SAGE polynomials. For sparse polynomials, this method offers an exponential efficiency improvement relative to certificates of nonnegativity obtained through semidefinite programming.
We go on to create the conditional SAGE methodology for exploiting convex substructure in constrained signomial nonnegativity problems.
The basic insight here is that since the standard relative entropy representation of SAGE signomials is obtained by a suitable application of convex duality, we are free to add additional convex constraints into the duality argument. In the course of explaining this idea we provide some illustrative examples in signomial optimization and analysis of chemical dynamics.
The majority of this thesis is dedicated to exploring fundamental questions surrounding conditional SAGE signomials. We approach these questions through analysis frameworks of sublinear circuits and signomial rings. These sublinear circuits generalize simplicial circuits of affine-linear matroids, and lead to rich modes of analysis for sets that are simultaneously convex in the usual sense and convex under a logarithmic transformation. The concept of signomial rings lets us develop a powerful signomial Positivstellensatz and an elementary signomial moment theory. The Positivstellensatz provides for an effective hierarchy of REP relaxations for approaching the value of a nonconvex signomial minimization problem from below, as well as a first-of-its-kind hierarchy for approaching the same value from above.
In parallel with our mathematical work, we have developed the sageopt python package. Sageopt drives all the examples and experiments used throughout this thesis, and has been used by engineers to solve high-degree polynomial optimization problems at scales unattainable by alternative methods.
We conclude this thesis with an explanation of how our theoretical results affected sageopt's design.</p
Experimental and Theoretical Investigation of a Reductant-Activated Methodology for Covalent Functionalization of 1T' Transition Metal Dichalcogenides MoS₂ and WS₂
Get PDFChemically exfoliated MoS₂ (ceMoS₂) is a two-dimensional layered transition metal dichalcogenide in the 1T' phase that can be synthesized by intercalating and exfoliating MoS₂ of the thermodynamically stable and relatively inert 2H phase. Several functionalization techniques have emerged in the past decade to functionalize both the 2H and 1T' phases, with growing interest given the array of applications for MoS₂ in optoelectronics, catalysis, sensing, bioimaging, drug delivery, and photothermal treatment. To aid in this effort, we expanded upon a recently reported covalent functionalization method by developing a reduction-activated methodology to functionalize ceMoS₂ using one-electron metallocenes and showed that the coverage of a functional group increases as the reduction potential increases, allowing for greater control of the coverage. Using density functional theory (DFT), we found that the coverage of the smallest functional group, a methyl, is expected to be limited to ~64% per MoS₂ due to the steric hinderance associated with the methylation of sulfur sites that are adjacent to more than one methyl group. We also found that a similar coverage trend can be observed when applying reduction-activated functionalization to ceWS₂, albeit with a lower coverage at every potential that can be explained using DFT calculations as a difference in the thermodynamic favorability of the reaction. Reductant-activated functionalization provides a driving force that enables ceMoS₂ and 2H-MoS₂ to be functionalized when it is otherwise unreactive with electrophiles. Conceptualizing the work herein as part of a redox-activated functionalization method, there is an abundance of opportunity to explore oxidant- and reductant-activated functionalization on other chalcogenides, pnictides, and materials in the carbon and boron groups using both solution oxidants and reductants, as well as electrode-based electrochemical methods. Further exploration of redox-activated techniques expands the functionalization toolbox and enables researchers to develop application-specific functional materials.</p
Representation Theory of Real Reductive Groups
Get PDFThe representation theory of Lie groups has connections to various fields in mathematics and physics. In this thesis, we are interested in the classification of irreducible admissible complex representations of real reductive groups. We introduce two approaches through the local Langlands correspondence and the Beilinson-Bernstein localization respectively. Then we investigate the connection between these two classifications for the group GL(2, R)
Manganese Through Time and Other Stories Concerning Cyanobacteria and the World Around Them
Get PDFThis thesis is a collection of investigations concerning the interplay between Cyanobacteria and the inorganic/physical world. Chapters II-VI focus on manganese, an element Cyanobacteria have been
intimately entangled with for billions of years. Chapter II is a review/perspective paper on the dynamics of
manganese in the environment through time and the many ways manganese interfaces with dioxygen.
Chapter III deciphers environmental and biological signatures recorded in ancient rocks from the pivotal
moment in Earth history when oxygenic photosynthesis first evolved. Chapter IV explores the ecology of
desert varnish, and provides an adaptive physiological mechanism underpinning manganese enrichment.
Chapter V examines the ability of modern Cyanobacteria to catalyze manganese oxidation. Chapter VI
explains as kindly as possible that the field of manganese aquatic chemistry has fundamentally
misunderstood the chemistry of Mn(III) and highlights how the current methods being used are
problematic because of this misunderstanding. Chapters VII and VIII are not about manganese and instead
concern other aspects of the physical world and their interface with Cyanobacteria. Chapter VII is about the
impact of Hurricane Irma on a cyanobacterial mat ecosystem. Chapter VIII is about the use of ooids as an
environmentally friendly replacement for plastic microbeads in facial scrubs, in which Cyanobacteria
make a cameo as endoliths that facilitate ooid dissolution.</p
Paleomagnetism and Geochemistry of Basalts in the North American Cordillera, Davis Strait, and Antarctica
Get PDFChapter 1 is an introduction to the thesis and contains a brief summary on how the chapters relate to each other. In Chapter 2, we present new whole-rock geochemical data from the Brooks Range Ophiolite (BRO) together with new mineral chemistry data from the BRO, South Sandwich forearc, Izu-Bonin forearc, and Hess Deep. In Chapter 3, we use a combination of paleomagnetic data and thermal modeling to create a magnetic geothermometer (MGT) that can constrain the active transport lifetime of magmatic conduits and igneous intrusions. In Chapter 4, we present new stratigraphic and paleomagnetic data from Paleocene flood basalts on Baffin Island. In Chapter 5, we present new paleomagnetic and paleointensity data from the James Ross Island volcanic group, located on the Antarctic Peninsula.</p