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Modeling Human Axial Patterning and Segmentation
No full textDuring embryonic development, the body plan is established through the precise coordination of cell signaling, fate specification, and morphogenesis across space and time. In vertebrates, this is exemplified by somitogenesis—the sequential formation of somites during axial development—which segments the body and relies on tightly regulated differentiation and morphogenesis. While the molecular players and signaling mechanisms of somitogenesis vary across model organisms, our understanding of human axial morphogenesis has been limited by the inaccessibility of early human embryos. Here, we overcome these challenges by generating axially elongating organoids through the induction of anteroposterior symmetry breaking in spatially coupled epithelial cysts derived from human pluripotent stem cells. These organoids reproducibly recapitulate the formation of a neural tube flanked by presomitic mesoderm that is sequentially and periodically segmented into anteroposteriorly polarized somites. Using a combination of chemical and genetic perturbations, single-cell transcriptomics, and live fluorescent microscopy, we investigate the principles linking the spatiotemporal dynamics of signaling, patterning, and morphogenesis during human axial development. By generating and perturbing organoids that robustly recapitulate the architecture of multiple axial tissues found in human embryos, this work provides a platform to dissect the mechanisms driving human development.Engineering and Applied Sciences - Applied Physic
Environmental factors and immune related outcomes in the United States
No full textEnvironmental factors have been found to be important risk factors of human health. Previous studies
suggested that PM2.5 could perturb the immune system. PM2.5 is complex mixture of multiple
constituents, and each of these constituents could have varying impact on health. However, most existing
studies treated PM2.5 as a single exposure. How each of the constituents affects the immune system is
less clear. Non-optimal temperature is another environmental factor that could potentially impair the
immune function of human body. While the effects of mean temperature have been extensively studied,
the influence of temperature variability—particularly over longer time periods—remains insufficiently
explored.
In this dissertation, we attempted to address these gaps. We began by studying the association between
long-term exposure to PM2.5, PM2.5 constituents, source-specific PM2.5 and hospital admissions from
non-respiratory infections among the Medicare beneficiaries in the US between 2000-2016. We found that
PM2.5 was associated with increased risk of hospital admissions from total non-respiratory infections and
its subtypes including intestinal infections, urinary tract infections and septicemia. Sulfate, nickel and
copper contributed the largest weights in the association between PM2.5 and non-respiratory infections.
Anthropogenic sources of PM2.5 were found to have the largest impact on the exposure-outcome
associations.
In chapter II, we studied the association between seasonal temperature variability, seasonal temperature
and hospital admissions from infections using an adapted difference-in-difference analysis among the
Medicare beneficiaries. We found that increased temperature variability in both warm and cold season,
higher mean temperature in warm season and lower mean temperature in cold season were associated
with increased admissions from infections.
In the last chapter, we shifted our focus from the older population to an immunocompromised group—
kidney transplant recipients. Here we investigated the association between exposure to PM2.5
constituents prior to kidney transplant (KT) and post-KT outcomes including acute rejection, delayed graft
function, graft failure and mortality. We found that sulfate contributed the larges weight in the
association between the PM2.5 mixture and long-term post-KT outcomes (graft failure and mortality)
while lead, organic carbon and nickel contributed the largest weights in the short-term outcomes (delayed
graft function and acute rejection).
This dissertation contributes to the growing body of evidence on the impact of environmental exposures
on the immune system. It further demonstrates that the health effects of PM2.5 can vary depending on its
chemical constituents and specific sources. Overall, this work provides important insights into the broader
health implications of air pollution and climate change on human populations.Population Health Science
Morphological analysis of glia-neuron interactions during cochlea wiring
No full textCochlea hair cells, the sensory receptors for hearing, transduce auditory input to electrical signal relayed to the brain via bipolar spiral ganglion neurons (SGNs). SGNs extend a peripheral process (SGNpp) to target one hair cell, and their central processes coalesce with vestibular axons and brainstem efferents to form the eighth cranial nerve. In the mature cochlea, SGN cell bodies are myelinated by satellite glia while SGN peripheral and central axons are myelinated by Schwann cells. SGNpps exit the spiral ganglion at the same time as neural crest-derived glia precursors (GPs) and, after reaching the hair cell region, SGNpps of similar characteristic sound frequency will fasciculate into radial bundles intertwined with GPs. It is not known how radial bundles are formed nor if the tightly associated GPs contribute to SGNpp outgrowth organization during cochlear wiring.
Here we find that GPs extend radially ordered “sawtooth-like” protrusions at the early stage of SGNpp extension. Most SGNpps can be found growing along or behind the glia protrusions, within the same radial domain. This suggests that GPs may play a role in early SGNpp pathfinding. From sparse labeling of GPs early in development, we identified four morphological classes of GPs across the cochlea. These morphologies hint at multiple modes of interaction with SGNpps, other migrating GPs and otic mesenchyme cells that may foster cochlea wiring fidelity. Furthermore, changing interactions between GPs and SGNpps during development may promote radial bundling of SGNpps underlying cochlear tonotopy.Medical Science
Simulation and Analysis of Electrochemical Systems
No full textPorous electrodes are essential components in redox flow batteries, a promising technology for long duration, grid-scale energy storage, which will be a vital part of the clean energy transition. Carbon capture and storage (CCS) can mitigate and eventually reverse global warming. In this thesis I present four works, in which a porous electrode and a CCS system are each subject to one simulation and one analysis. First, I show a 3D digital twin for porous electrodes that uses direct numerical solution of the governing Navier-Stokes and Nernst-Plank equations for incompressible flow and electrochemical mass transport with Butler-Volmer reaction kinetics. Our performant, open source code handles systems approaching a billion cells at 1.25 μm resolution on a single workstation, and will scale well on modern scientific supercomputers. This work also includes a novel reformulation of the steady state concentration problem, and introduces a figure of merit, the mass-transport limiting utilization of an electrode Umt. Second, I simulate the steady state concentrations in an electrochemical acid-base generator that was experimentally characterized by my collaborators and is suitable for CCS. Third, I solve for the equilibrium concentrations in another experimental CCS system, in which aqueous quinones capture CO2 via both pH-swing and nucleophilicity swing mechanisms. Finally, I perform an elaborate nonlinear iterative calibration to measure the state of charge of an operating porous electrode given experimental image intensity and electrochemical data obtained by fluorescence microscopy.Engineering and Applied Sciences - Applied Mat
The Kremlin’s Conundrum: Telegram as Russia’s Information Battlefield
No full textThe project of this thesis is to investigate the dynamics of communication within Russian on a popular online social media platform, in the context of the Ukraine- Russia war. The investigation is structured around three directions: (1) influence, (2) communities, and (3) assessing the causal impact of a government intervention in the informational space.
The individuals that make up our dataset are generally well-established actors in the Russian informational space, with their identity ranging from public figures, to members of the government, to anonymous individuals who have amassed a significant online following.Applied Mathematic
Novel mechanisms of gene regulation driving aggressive leukemias
No full textAcute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases coopting stem cell gene regulatory programs, yet the mechanisms through which this occurs remain poorly understood. Increased expression of the stem cell transcription factor, MECOM, underlies one key driver mechanism in largely incurable AMLs. How MECOM results in such aggressive AML phenotypes remains unknown. To address existing experimental limitations, I engineered and applied targeted protein degradation with functional genomic readouts to demonstrate that MECOM promotes malignant stem cell-like states by directly repressing prodifferentiation gene regulatory programs. Remarkably and unexpectedly, a single node in this network, a MECOM-bound cis-regulatory element located 42 kb downstream of the myeloid differentiation regulator CEBPA, is both necessary and sufficient for maintaining MECOM-driven leukemias. Importantly, targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden in vivo. In an effort to translate these biological insights into a therapeutic strategy, this work also explored the use of heterobifunctional small molecules and chemically induced proximity to rewire MECOM transcriptional activity. While efficacy was limited, this portion of the study revealed key principles to consider when aiming to therapeutically engineer and reprogram transcription in this manner. In sum, these findings suggest a broadly applicable approach for functionally dissecting oncogenic gene regulatory networks to inform improved therapeutic strategies.Biological and Biomedical Science