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Synaptic Failure is a Flat Minima Optimizer
No full textSynaptic failure is a well-known phenomenon in which weaker synapses fail more frequently. Whether this has any purpose is still unknown. In this work, we modify Dropout to implement synaptic failure in artificial neural networks, through a novel activation function we call NormOut. NormOut sets a neuron's probability of successfully firing equal to the ratio of its activation to the maximum activation in some set of neurons. We propose variants inspired by lateral inhibition and firing thresholds, and show that they have hugely different effects on activation dynamics. We find that NormOut improves the performance of a baseline VGG-16 on CIFAR-10, with one variant even outperforming Dropout in achieving both better test accuracy and a significantly flatter minimum. In addition to the effect on overfitting, we explore NormOut's impact on adversarial robustness against a suite of white and black-box attacks. Intriguingly, we find that some variants of NormOut produce extreme gradient masking without obfuscation. Rather than masking through flattening, we find that these variants actually induc high curvature in the loss landscape, suggesting an as yet unknown form of gradient masking. Overall, we show that simply modelling synaptic failure in two layers has a significant impact on the topology of the loss landscape, with the best implementations of synaptic failure optimizing strongly for flat minima. We claim this as evidence that synaptic failure is a feature, and not a bug, of the brain.Computer Scienc
Characterization of silencer element-associated chromatin
No full textGene regulation is a carefully controlled process that is essential for development and cellular function.
Transcriptional enhancers increase the expression of target genes, while transcriptional silencers
decrease their expression. Until very recently, silencers have received much less attention than have
enhancers. Recently, thousands of silencers have been identified by large-scale reporter assays in
several species, but despite this large collection of examples, silencers as a class are difficult to predict
based on histone modifications or other chromatin signatures. They are largely unannotated by commonly
assayed histone marks and many do not contain known repressor binding sites. A subset are marked by
the polycomb repressive mark H3K27me3, but that constitutes only a small subset of silencers and the
mark is not specific to silencers. In chapter 2, I present my work on a system to isolate chromatin for
unbiased proteomic analysis. In chapter 3, I present a survey of many repressive histone marks in
Drosophila mesoderm and S2 cells and find that none are significantly enriched in silencers, disputing a
previously published report of H4K20me1 enrichment. In chapter 4, I explore future directions for
determining the chromatin state of silencers and possible models of silencer function. Overall, this
dissertation provides a comprehensive overview of known transcriptional silencers and their
characteristics and details the development of a locus-specific proteomic method.Biological and Biomedical Science
Postnatal Mandibular Growth in Alk2/Alk3 cKO Mice
No full textLigands of the TGFβ superfamily (including BMPs, Activins, TGFβ, and GDFs) are known to play a crucial role in bone biology with multiple studies highlighting their importance in skeletal development, homeostasis, and fracture repair.1,4 Previous studies have shown that alterations in signaling through the type I BMP receptors, Alk2, Alk3, and Alk6 alone or in combinations, result in bone and cartilage defects, and influence bone development and growth.4 Pertinent to this thesis, it has been reported that Alk2 and Alk3 are critical for mandibular condylar development.8,23 However, few studies exist that examine the effects of BMP type I receptors on postnatal mandibular growth, where anomalies lead to malocclusions that affect oral health, general health, and quality of life. We removed Alk2 and Alk3 in Gli1+ progenitor cells including those in the mandible from P0-P5 using the inducible Gli1-CRE-ER (Alk2/3 cKO mice). No differences in mandibular length were detected at P10 in Alk2/3 cKO mice in comparison to Alk2/3fl/fl mice. At one month of age, Alk2/3 cKO mice displayed a smaller overall body size, shorter mandibular length and height, and reduced mandibular bone volume in comparison to controls. Additionally, the mandibular molar roots were shorter in the Alk2/3 cKO mice at one month. Our results indicate that BMP signaling through Alk2 and Alk3 is required for postnatal growth of the murine mandible in length, height, bone volume, and molar root length. Future studies are needed to evaluate if the smaller body size of the Alk2/3 cKO mice is due to changes in the ability of the mice to feed or due to effects of removing Alk2 and Alk3 in Gli1+ cells, which are present in many body tissues including the long bones, craniofacial bones, cervical loop of the incisors, periodontal ligament, adrenal cortex, gastrointestinal tract, and hair follicles. 11,18,19 It is possible that mandibular phenotypes observed in P28 Alk2/3 cKO mice are due to a combination of direct effects on BMP signaling in Gli1+ cells resident in the mandible and indirect effects of the mice being smaller overall.Orthodontic
Investigating Dendritic Cell Migration: Insights From Tuning the Mechanical Properties of Collagen via Click Chemistry
No full textDendritic cells (DCs) are the primary antigen presenting cell capable of activating T cells, a group of immune cells widely used in cancer immunotherapy due to their ability to kill self-cells. However, outcomes have been varied, with one determinant factor emerging as the mechanical environment of the extracellular matrix (ECM). The increase in collagen crosslinking and ECM stiffness has been correlated with worse outcomes in many solid tumors, but the impact on the migration of DCs has not been extensively studied in 3D culture. This thesis created a highly tunable, well-characterized gel system by conjugating click chemistry groups (either norbornene or tetrazine) to collagen type I. Functionalized collagens were mixed together at differing ratios, thus varying the amount of crosslinking in each gel. The storage modulus, loss modulus, stress relaxation, and pore size of gels was quantified using rheometry and confocal microscopy. Human monocyte-derived DCs (moDCs) were embedded in the gels and their average speed and mean squared distance (MSD) analyzed using TrackMate following time-lapse confocal imaging. Crosslinking increases gel storage modulus (G’) and decreases loss modulus (G”), creating stiffer gels. Crosslinking also increases stress relaxation time, indicating less viscoelastic behavior, and decreases pore size. When embedded in 2 mg/mL gels, moDCs move significantly faster in uncrosslinked conditions. The maximum MSD of cells is also decreased in crosslinked 2 mg/mL gels, indicating increased cell confinement. The moDCs move significantly slower and are more confined in 4 mg/mL gels. These results suggest that collagen deposition and crosslinking occurring in the tumor ECM may negatively affect DC migration.Biomedical Engineering A
Structural Connectivity Changes and Prognosis in Comatose Patients Post-Cardiac Arrest
No full textAccurate neuroprognostication of cardiac arrest survivors who are initially comatose after restoration of spontaneous circulation is crucial for guiding patient management. Because hypoxic-ischemic injury is typically diffuse, damage to a network of brain regions is likely involved in the patient’s disorder of consciousness. To quantify these complex brain network changes, graph theoretical methods were applied. We hypothesize that structural connectivity metrics may provide additional insights into determining which patients will likely recover consciousness and those who will not.
Eighteen comatose patients and four community dwelling participants underwent multi-shell high angular diffusion MRI as part of a prospective study. Structural connectivity matrices were constructed using probabilistic tractography and parcellated with the Automated Anatomical Labels atlas. Network topology was analysed using clustering coefficient, global efficiency, and degree. Exploratory analysis extended for this thesis included analysis of the additional graph theory metrics: neighborhood overlap, Rentian scaling, modularity, assortativity, betweenness centrality, and eigenvector centrality. Hub index analysis was performed to explore the relation between structural disconnection of anatomical hubs and disorders of consciousness.
Patients demonstrated reduced clustering coefficient, decreased global efficiency, and lower degree than controls, reflecting diminished local and global network efficiencies. Significant trends were associated with all of the exploratory metrics except for assortativity. In general, these changes were most pronounced in patients with worse outcomes, whereas patients who experienced arousal recovery exhibited metrics closer to those of healthy controls. The hub index analysis based on nodal degree and betweenness revealed disproportionate damage to high-degree nodes such as the thalamus, putamen and precuneus, further linking topological disruption to the severity of outcomes.
This study highlights the potential of graph theoretical measures of structural connectivity to guide critical decisions in the care patients. By bridging structural connectivity with clinical outcomes, this research provides valuable insights into the neural mechanisms underlying consciousness and recovery after cardiac arrest.Applied Mathematic
The Effects of Payment Incentives, Benefit Design, and Provider Organization on the Value of Care
No full textThis dissertation explores how the design of health care payment systems and changes in the organization of providers affect the value, equity, and efficiency of care. The first two chapters investigate how the design of the Medicare Advantage (MA) payment system and recent supplemental benefit policies affect plan offerings and beneficiaries’ utilization of care. The third chapter assesses the effects of vertical consolidation between physicians and health systems on care quality and patient steering. The findings from these papers have important implications for policy to improve the value of the U.S. health care system.
The payment system establishes incentives for MA plans to attract and retain beneficiaries from minoritized racial and ethnic groups and those dually eligible for Medicaid (duals) by offering these groups additional benefits. In Chapter 1, with coauthors J. Michael McWilliams and Vilsa E. Curto, we examine how payment incentives in the MA program resulted in differential plan offerings to groups of historically underserved beneficiaries after a 2020 policy change granted MA plans broader flexibility in benefit design (Special Supplemental Benefits for the Chronically Ill [SSBCI]). We found that plans with higher shares of patients from these groups were more likely to offer SSBCI benefits: a 1 standard deviation increase in a plan’s non-white share was associated with a 20.8 percentage point (p .010) increase in the probability that the plan offered any SSBCI benefit. We found stronger associations in more competitive markets and for groups that can be more easily targeted with additional benefit offerings. These findings are consistent with the potential for population-based payment systems to redistribute resources to underserved groups in ways that could mitigate health care disparities; they also highlight the challenges and tradeoffs involved.
In Chapter 2 with coauthors J. Michael McWilliams and Michael E. Chernew, we investigate the value of supplemental benefits delivered through MA. The availability and type of supplemental benefits offered in the MA program has increased over time, driven by growing rebates and recent policies expanding the benefits plans can provide. Some supplemental benefits may be more highly valued by beneficiaries than others. For example, direct health services such as dental, vision, and hearing are likely essential for most enrollees. An example of a benefit that is not a medical service, but can provide additional health-related value, is non-emergency medical transportation (NEMT). NEMT may serve as a complement for medical care to expand access to and use of services by providing rides to doctors’ appointments. Therefore, NEMT has the potential to increase utilization of routine outpatient care and in turn reduce emergency care. In this study, we investigate the value of supplemental transportation by examining the impact of MA plans offering NEMT on enrollees’ utilization of care. To do so, we leverage the 2019 expansion of the definition of “primarily health related” supplemental benefits. We found that the offering of NEMT led to a decrease in ambulance use days of 0.008 days (95% CI, -0.016 - -0.001; p=0.037), representing a 5% decrease from the pre-period treatment group mean of 0.16 use days per beneficiary per year. We did not find strong evidence of increased value, measured by changes in care utilization, associated with the offering of NEMT for evaluation and management, imaging, procedure, emergency room, or annual wellness visits. Future research should investigate the impact of other supplemental benefits or combinations of benefits that are frequently offered together to understand the value of MA benefit packages overall. This knowledge is needed to make decisions regarding MA payment rates, allowable benefits, and how to efficiently provide high-value coverage in the Medicare program.
In Chapter 3 with coauthors Anna D. Sinaiko, Vilsa E. Curto, Mark Soto, and Meredith B. Rosenthal, we investigate the effects of vertical consolidation in health care delivery. Vertical relationships (ownership, affiliations, joint contracting) between physicians and health systems are increasing in the US. Many proponents of vertical relationships argue that increased spending associated with consolidation is accompanied by improvements in quality of care. In this study, we used stacked difference-in-differences to estimate the effect of vertical relationships between primary care physicians (PCPs) and large health systems on use of low-value care, post-hospitalization follow-up, utilization among patients with ambulatory care-sensitive conditions (ACSC), and timeliness of specialty care for commercially insured individuals in Massachusetts over the period 2013-2017. A patient’s PCP entering a vertical relationship had no association with the probability of follow-up within 90 days of cancer diagnosis with any oncologist but led to a 7.34–percentage point (pp) (95% CI, 2.28-12.40; p=0.010) increase in the probability of follow-up with an oncologist in the health system. PCP–health system vertical relationships led to a significant decrease in fragmentation of practice site visits of −1.05 pp (95% CI, −2.05 to 0.05; p=0.040). We found no effect of PCP-health system vertical relationships on patients’ low-value care or ACSC utilization. These results should be considered by policymakers when assessing the potential benefits against the demonstrated harms (spending increases) of vertical consolidation.Health Polic
Teamwork Makes The Dream Work: The Role of Team Functionality in Improving Organizational Performance in Public K-12 Districts
No full textThis capstone examines how enhancing team functionality within a school district’s Communications Department can support improved organizational performance. Using the Oakland Unified School District (OUSD) as a case study, the project explores how formal systems and structured collaboration within the communications team can lead to more effective and coherent messaging aligned with the district’s strategic initiatives. In a context of declining enrollment, budget deficits, and intense scrutiny from stakeholders, OUSD’s ability to clearly communicate its mission, priorities, and successes is essential to building trust and supporting student achievement.
The strategic project focused on strengthening the Communications Department by developing systems—such as formal meeting agendas, individual work plans, a data dashboard, and a monthly review protocol—to improve internal collaboration and alignment with senior leadership priorities. These tools were designed not only to enhance team functionality, but also to ensure that the department’s messaging consistently reflected the mission and vision of OUSD, and supported its core initiatives, such as creating a joyful learning environment, ensuring literacy by third grade, empowering graduates, and recruiting and retaining a diverse and stable workforce.
Furthermore, coherence across key departments—especially among partners aligned in purpose—is essential to improving the district’s ability to communicate strategically and effectively, even as some teams already work collaboratively. The project demonstrated that by building and implementing systems that promote collaboration and cross-department partnerships, the Communications Department can serve as a model for how functional teams contribute to district-wide coherence and, ultimately, better organizational performance.
Drawing on John Kotter's 8-Step Change Model, J. R. Hackman’s framework for cross-level analysis and team effectiveness, the PELP Coherence Framework, and Monica Higgins’ Career Imprints theory, this capstone underscores that when teams operate with alignment, clarity and shared purpose, they are better positioned to amplify student success stories, engage stakeholders, and support district-wide goals.Educatio
IMPACT OF APOE GENOTYPE AND CSF BIOMARKERS OF AD CO-PATHOLOGY ON COGNITIVE DECLINE AND MOTOR PROGRESSION IN SPORADIC, GBA, AND LRRK2 PARKINSON'S DISEASE
No full textParkinson’s disease (PD) is emerging as rapidly escalating global health problem. As of 2019, an estimated 8.5 million individuals worldwide are affected, with prevalence doubling over 25 years. Disability-adjusted life years (DALYs) linked to PD have risen, alongside a 100% mortality increase since 2000. This growing burden—marked by rising incidence, prevalence, morbidity, and mortality—necessitates refining our understanding of PD clinical heterogeneity, especially in genetic subtypes, which account for 10–15% of cases.
Emerging evidence underscores the significance of Alzheimer’s disease (AD) co-pathology in PD, raising questions about its impact on progression. The APOE genotype, particularly the APOE4 allele, a known AD risk factor, may also influence PD progression. While cognitive decline is a key non-motor PD feature, the role of APOE4 in motor deterioration is underexplored, and its effect on cognitive decline shows mixed results. Additionally, whether APOE4 affects sporadic and genetic PD subtypes differently, especially LRRK2-associated PD, is a critical gap.
The role of AD-associated CSF biomarkers in PD also needs further study. The classical AD signature—low Aβ42 and elevated phosphorylated tau (pTau) in CSF —may be linked to worsened cognitive decline in PD. However, it is unclear if this biomarker profile affects all PD subtypes or shows subtype-specific effects.
Understanding these factors is crucial for enrichment strategies in disease-modifying trials. Identifying biomarker-defined subgroups with accelerated progression can better enrich trials for patients likely to benefit from targeted interventions. This approach is essential, as PD remains incurable, and precision-based therapeutic strategies are urgently needed.
Using longitudinal multicenter data, in manuscript 1, we studied the impact of APOE polymorphism and CSF AD biomarkers on the cognitive trajectories of sporadic, genetic PD and Healthy control groups and in manuscript 2, we analyzed the impact of APOE polymorphism on the motor decline in sporadic and genetic PD groups.
This body of work, based on two longitudinal cohort studies, highlights the differential impact of APOE polymorphisms and AD co-pathology markers on cognitive decline and motor progression in sporadic and genetic PD (GBA-PD, LRRK2-PD).
In the first study, APOE ε4 carriers in sPD experienced significantly faster cognitive decline compared to ε3 and ε2 carriers, a pattern not observed in GBA-PD, LRRK2-PD, or healthy controls. Regarding CSF biomarkers of AD co-pathology, lower Aβ42 levels universally predicted cognitive decline across all groups, whereas higher baseline p-tau levels were linked to worse cognitive outcomes in sPD and LRRK2-PD, but not in GBA-PD or HC.
The second study assessed motor progression in relation to APOE polymorphisms across PD subtypes, revealing that APOE ε4 carriers in sPD exhibited faster motor decline compared to ε3 carriers, while no such association was found in genetic PD subtypes.
These findings emphasize the importance of genotyping PD patients not only for GBA and LRRK2 variants but also for APOE polymorphisms, as APOE’s impact on disease progression differs between sporadic and genetic PD. With growing recognition of AD co-pathology in PD and PD-related changes in AD, it is essential to understand how these overlapping pathologies shape the clinical trajectory. This knowledge is critical for designing future clinical trials on disease-modifying therapies and calls for large-scale, longitudinal studies to further validate these differential effects.Graduate Educatio
Engineering Functional Microcapsules for Controlled Cargo Delivery
No full textMicrocapsules are a tiny container on the order of 100 with a typical structure made of an aqueous core and a solid shell. They are widely used in cargo delivery application because of its unique core-shell structure. Some fragile or expensive cargo molecules can be encapsulated inside the core of the capsules while being protected by the shell during transfer. And after these capsules are transferred to the target positions, some channels on the capsules shell will be triggered open by external signals to release the encapsulated cargo into the surrounding environment. Because of its characteristics of allowing for controlled release, protection of active ingredients as well as targeted delivery, microcapsules have applications in many different fields such as pharmaceuticals, food industry, cosmetics, and agriculture. One major application of microcapsules is for drug delivery. As an example, polysaccharide based microcapsules are developed for biomedical applications. Microcapsules with different tailored structures can be fabricated to encapsulate specific drugs. And after encapsulation, the surface of the capsules are being modified with specific ligands to target specific receptors on cellular membranes. The ligands on the microcapsules bind to the targeted receptors on the cells to ensure that the drug is delivered specifically to the intended site/position. And for the drug release step, the microcapsules can be designed to respond to specific conditions in the microenvironment, such as reactive oxygen species (ROS), glutathione (GSH), and pH levels, to trigger the release of the drug by external stimuli like ultrasound, light, or magnetic fields. Other applications of microcapsules include encapsulation and controlled release of flavors and vitamins in food industry, moisturizers and anti0aging compounds in cosmetics or pesticides and fertilizers in agriculture.
In this dissertation, I'll present my PhD work on designing different core-shell structures as delivery vehicles from many different aspects such as the structural properties of capsule shell, adaptive response and versatility for different cargo sizes.Engineering and Applied Sciences - Applied Physic
Optimizing Public School Teacher Salary Schedules
No full textThe structure of public school teacher salary schedules has a significant impact on teacher retention, recruitment, and student outcomes in the United States. While traditional step-and-lane salary structures provide incremental pay increases based on experience and educational attainment, they often lack strategic alignment with teacher effectiveness. This thesis introduces an optimization-based framework for designing teacher salary schedules aimed at maximizing cumulative teacher effectiveness within existing budget constraints. By using synthetic data based on publicly available metrics from Michigan public schools, we model various salary functional forms—linear, logarithmic, and power—and explore their implications for teacher retention and effectiveness.
Our findings suggest that a concave power function, which prioritizes higher salary increases in the early career stages, aligns best with district-level goals of fostering retention and improving educational outcomes. Through comparative analysis across Michigan’s statewide data and district-specific data from Detroit and Bloomfield Hills, we demonstrate that the power model yields more consistent and realistic salary distributions, particularly in districts facing high turnover rates or early-career attrition. Additionally, this framework provides a practical approach for districts to adapt salary schedules to their unique profiles without requiring policy overhauls.
This work contributes to the literature on teacher compensation by offering a scalable, data-driven method that bridges the gap between traditional pay structures and optimized salary schedules. The model serves as a foundation for further research and policy development aimed at enhancing teacher effectiveness and educational equity through more intentional salary design.Computer Scienc