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THE INFLUENCE OF SOCIAL INTEGRATION ON THE HEALTH OUTCOMES OF INTERNAL MIGRANT POPULATIONS IN CHINA
No full textChina’s internal migrant population, now nearly 380 million, plays a pivotal role in the country’s urbanization and economic progress. However, these migrants face profound health disparities driven by socioeconomic inequalities, limited healthcare access, and varied levels of social integration. This dissertation investigates the association between social integration and health outcomes among internal migrants, focusing on noncommunicable disease (NCD), self-reported health (SRH), and healthcare service utilization.
Cross-sectional data of 154,579 participants from the 2017 China Migrant Dynamic Survey was obtained. The survey collected data on demographic and socio-economic characteristics, migrant status, health awareness, access to health and public service, social integration status, and key disease conditions of China’s internal migrant population. Statistical analyses including multivariable logistic regression, stratified analysis, and cluster analysis were performed to explore how social integration and its various dimensions impact health outcomes of the internal migrant populations.
The study revealed that moderate levels of social integration were associated with lower chronic disease prevalence, whereas both the lowest and highest levels of integration increased disease prevalence. In addition, the results indicated positive associations between a sense of belonging and social participation with SRH, while acculturation showed a negative relationship. Cluster analysis classified internal migrants into three distinctive integration groups: Adaptive, Balanced and Rooted Individuals, with the Rooted Individuals exhibited the highest SRH scores, showing the protective effects of community ties and cultural preservation. Moreover, specific subgroups experience varying health risks based on their integration level.
Together, these studies reveal a complex dynamic between social integration and health among internal migrants. These findings highlight the protective effect of balanced social integration levels on health, while both low and excessive integration levels can have adverse effects. Furthermore, it is crucial to foster community ties and preserve cultural identity to mitigate the stress of acculturation while enhancing access to resources and support networks through active social participation. Tailored public health policies and interventions, designed to address the unique needs of the internal migrants and especially the vulnerable subgroups, are essential for promoting health equity and integration among the internal migrant populations in China
SIGNIFICANT BARRIERS TO INCORPORATING ADVANCED NUCLEAR ENERGY INTO THE U.S. ENERGY PORTFOLIO
Get PDFAdvanced nuclear reactors, particularly small modular reactors and micro-reactors are a recognized aspect of meeting future global energy demand. To better understand the advanced nuclear industry in the United States, this paper seeks to define the top barriers facing the industry today and summarize the current state of each of the top three barriers in the United States. Through initial AI-supported research, literature review, and interviews with industry experts, significant barriers to advanced nuclear technology deployment in the United States are identified. With high levels of financial risk realized in new and near-memory nuclear power plant construction as well as new risks introduced through first-of-a-kind designs, identifying and securing sufficient funding for advanced nuclear technologies is a challenge. The infrastructure required to streamline construction and operation of advanced nuclear reactors, including built structures, experienced workforce, and a materials supply chain can only grow relative to the deployment of new designs. Despite efforts to streamline regulations and licensing, domestic policy continues to be a complicated and slow process for new technologies to comply with. The United States is poised to lead the world into a future of reliable, accessible, and clean energy through the new nuclear technologies developed by American scientists and engineers – IF barriers to deployment are addressed in time
Characterization of 2023-2024 H3N2 influenza viruses
Get PDFDuring the 2023-2024 flu season in the Northern Hemisphere, the influenza A virus (IAV) H3N2 dominated from Feb 2024 to May 2024. Seasonal IAV can accumulate mutations on antigenic sites of the hemagglutinin (HA) protein, leading to escape from preexisting immunity and launching annual epidemics. Therefore, surveillance of emerging IAV clades is important for
identifying and understanding the viral adaptations that allow for escape from vaccine induced immunity. The H3N2 subclades found during the 2023-2024 flu season are J.2, J.1, J, and G.2
with J.2 being dominant. A J.2 subclade H3N2 virus
(A/Baltimore/JH23641/2024) was isolated from an infected person and its amino acid sequence was compared with the H3 vaccine strain
(A/Darwin/9/2021-subclade G.2). I used RT-PCR to extract both HA sequences and align them together. There are fifteen mutations between the H3 vaccine and seasonal strains, with three located at antigenic sites. Mutations include I156K, M184I, and N202D, which could be important factors facilitating the H3N2 subclade J.2 dominance in circulation.
To assess the escape from vaccine induced immunity, neutralization assays were performed on sera acquired from healthcare workers pre- and post-vaccination during the 2023-
2024 season. Post-vaccination sera have a higher neutralization titer against both vaccine and circulating H3N2 strains, indicating three mutations on HA antigenic sites do not adversely affect neutralizing antibody titers. We also investigated H3 seasonal virus replication kinetics using low multiplicity of infection (MOI) growth curves in human Nasal Epithelial Cells (hNECs) cultures
under different physiological temperatures. The physiological temperatures did not affect total
infectious virus production but did change the kinetics, with less virus being produced early after
infection and more virus produced late after infection at 33C compared to 37C. The 2023-24 H3N2 J.2 subclade doesn’t have antigenic drift compared with the vaccine strain and no specific
viral replication changes under different physiological temperatures
Engineering Molecular Platforms for the Development and Characterization of Cellular Therapeutics
No full textMeticulous characterization of immune function is critical to expanding our understanding of the immune system, and the application of this knowledge has been instrumental in developing effective cellular therapeutics. Here, molecular engineering techniques are combined with protein and cellular engineering to both create new methodology to assay immune cells at the single-cell level and to advance natural killer (NK) cell therapeutic development for hematologic malignancies.
In one example, a microparticle-based technology (termed nanovials) is employed to simultaneously assess the cell surface expression profiles and protein secretion behavior of stimulated T cells at single-cell resolution. The capacity to stimulate primary mouse CD8+ T cells directly loaded on protein-conjugated nanovials in both nonspecific and antigen-specific fashion is shown. Additionally, it is shown that nanovials can simultaneously capture multiple different secreted cytokines on the single-cell scale, and that viable T cells contained within the nanovials can be sorted based on cytokine secretion levels. This platform is further applied to characterize the phenotypic profile of resting T cells that secrete interferon gamma (IFNγ) following activation by staining cells for surface marker expression prior to on-particle stimulation. Overall, the nanovial platform and assays developed herein offer previously inaccessible insights into the functional properties of T cells, which will inform the design of future cell therapies.
In another example, protein engineering is used to generate a repertoire of chimeric antigen receptor (CAR)-expressing natural killer (NK) cell formulations that target the CD123 antigen on the surface of acute myeloid leukemia (AML) cells with varying affinity. Each formulation employed a distinct CAR variant based on antibodies that target two unique epitopes on CD123, allowing for study of the effects target antigen epitope and affinity, as well as target antigen expression, influences CAR-NK cell function. Specifically, variants of the anti-CD123 antibody single-chain variable fragment (scFv) 26292 were discovered through directed evolution of an error-prone mutagenic library, and previously reported variants of the anti-CD123 antibody scFv 7G3 f are investigated. CARs were introduced into immortalized NK-92 cells as well as primary NK cells for characterization of the resulting engineered immune cells through in vitro binding, activation, and cytotoxicity studies and mouse xenograft models. Antigen-specific CAR NK cell activation and cytotoxicity against AML is noted across a broad panel of affinity –variants derived from both the 26292 and 7G3 scFvs. Moreover, affinity-based differences in functional activation are noted, and show dependence on experimental time course and are target epitope of the scFv.
Overall, the work herein aims to engineer molecular platforms to expand our knowledge of immune cell function and modulation, especially as related to the design of effective cellular therapeutics
DETERMINANTS OF CERVICAL ADENOCARCINOMA IN A STATE-OF-THE-ART CERVICAL CANCER SCREENING PROGRAM
Get PDFIntroduction: Cervical cancer incidence in the U.S. has declined following the introduction of screening to detect and treat cervical precancerous lesions, but rates of cervical adenocarcinoma (ADC) have increased. The Kaiser Permanente Northern California (KPNC) integrated health system has adopted a robust cervical cancer screening program to provide real-world evidence for the efficacy of co-testing in clinical practice. Calendar period trends in cervical cancer show that despite the introduction of co-testing with HPV, cases of ADC are now nearly as common as cases of cervical squamous cell carcinoma (SCC) at KPNC. Reasons for the high incidence of cervical ADC in a well-screened population of women are not well-understood.
Methods: A cohort of over 1,000,000 women were enrolled in co-testing at KPNC between 2003-2015 to assess risk of cervical cancer and have been followed over time. Programmatic determinants of incident cervical cancer cases were determined through review of patient case reports. Poisson regression models with robust variance were used to calculate prevalence ratios with 95% confidence intervals for the association between programmatic determinants and subtype. Multivariate models were adjusted for age at diagnosis, stage at diagnosis and body mass index (BMI). A time to event analysis was conducted using Kaplan Meier methods to assess differences in time from first co-test to cancer diagnosis by race/ethnicity and subtype; differences were assessed with log-rank tests.
Results: A total of 683 cancers were classified as incident cervical cancers (SCC: n=362, 53.0%; and ADC: n=312, 47.0%). Compared to SCC, those with ADC had a higher prevalence of false-negative colposcopy (aPR: 1.30, 95% CI: 1.07-1.57) and false-negative screen (aPR: 1.17, 95% CI: 0.96-1.42). Those with ADC had a lower prevalence of non-compliance (aPR: 0.63, 95% CI: 0.45-0.87) and treatment failures (aPR: 0.53, 0.35-0.80) compared to those with SCC. Log-rank tests revealed no significant difference in time to diagnosis by race and histology (^2 (7)=3.69; p=0.81).
Conclusion: Detection failures were more strongly associated with ADC, while treatment failures and non-compliance were more associated with SCC, highlighting the limitations of current screening methods for detecting ADC. Future research is needed to improve screening and early detection for ADC
Developing a Hybrid Thymus: Integrating Bioengineered Approaches for Immune System Regeneration
Get PDFThe thymus is key to immune tolerance, guiding T cell development via thymic selection. Thymic epithelial cells (TECs) shape T cells by presenting self-signals, allowing survival of self-recognizing T cells and removal of self-reacting ones, preventing self-attack. This process also creates regulatory T cells (Tregs) that balance immunity. The Hybrid-Thymus Project uses this to improve transplant acceptance.
In transplantation, the recipient's immune system recognizes donor tissue as foreign, causing rejection. Current treatments use immunosuppressants with risks. The Hybrid-Thymus Project offers an alternative: modifying thymic selection to induce acceptance. This involves transplanting donor TECs into the recipient's thymus, creating a mixed environment where donor TECs present foreign signals. These signals help donor-specific Tregs develop and reduce rejection-causing T cells.
Our experiments track transplanted TEC behavior using imaging (IVIS) and to see their settlement and persistence in the thymus. This non-invasive imaging shows their integration and impact on the recipient's immune cells. Blood tests assess overall immune responses, including Treg and aggressive T cell numbers. We aim to link thymic changes to systemic immunity, understanding how central tolerance affects the whole immune system.
This work advances transplant science by using the thymus's natural ability to create tolerance, the Hybrid-Thymus Project hopes for lasting, specific transplant acceptance, potentially removing the need for long-term immunosuppressants. Beyond transplants, this could help autoimmune diseases and other overactive immune conditions, advancing both treatments and basic immunology
FUNCTIONAL REGROWTH OF NOREPINEPHRINE AXONS IN THE ADULT MOUSE BRAIN FOLLOWING INJURY
Get PDFIt is widely believed that axons in the central nervous system of adult mammals do not regrow following injury. This failure contributes to the limited recovery of function following injury to the brain or spinal cord. Some studies of fixed tissue have suggested that, counter to dogma, neurons that express monoamine neurotransmitters regrow following injury. While suggestive, these studies were limited in their scope and unable to determine if the reappearance of axon density was indeed due to regrowth of damaged axons, as opposed to sprouted collaterals from the shafts of surviving axons, or if these newly grown axon are competent to release neurotransmitter in physiologically relevant contexts. Previous work in the Linden Lab demonstrated that serotonin neurons are capable of regrowth following injury but was unable to establish whether these regrown axons were competent to release neurotransmitter in a physiologically relevant context.
In this thesis, I tested the hypothesis that norepinephrine (NE) neurons have the ability to regrow axons functional to release neurotransmitter in response to external stimuli following injury. I used in vivo two-photon microscopy in layer 1 of the primary somatosensory cortex in transgenic mice harboring a fluorophore selectively expressed in NE neurons. This protocol allowed me to explore the dynamic nature of NE axons following injury with the selective NE axon toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). Following DSP4 treatment, NE axons were massively depleted and then slowly and partially recovered their density over a period of weeks. This regrowth was dominated by new axons entering the imaged volume. There was almost no contribution from local sprouting from spared NE axons. Regrown axons did not appear to use either the paths of previously lesioned NE axons nor NE axons that were spared and survived DSP4 treatment as a guide. To measure NE release, GCaMP8s was selectively expressed in neocortical astrocytes and startle-evoked, NE receptor-mediated Ca2+ transients were measured. These Ca2+ transients were abolished soon after DSP4 lesion but returned to pre-lesion values after 3-5 weeks, roughly coincident with NE axon regrowth, suggesting that the regrown NE axons are competent to release NE in response to a physiological stimulus in the awake mouse.
Both NE and serotonin axons have very similar dynamic properties. Both are thin, unmyelinated, and predominantly signal through volume transmission rather than synaptic transmission. These shared dynamic properties indicate that the molecular machinery enabling this unusual capacity for regrowth may also be shared. Here, we provide initial evidence supporting the hypothesis of an existing mechanistic pathway to enable axon regeneration in the adult mammalian brain, the elucidation of which could provide the foundation for novel therapies to promote axon regeneration and functional recovery within the CNS
Enhancing Power System and Market Operations through Stochastic Modeling, Inverse Optimization, and Machine Learning
Get PDFModern power system and market operations are characterized by both challenges and opportunities, often in paradoxical ways. First, the increasing integration of renewable energy sources (RES) and distributed energy resources (DERs) introduces stochasticity, which can reduce system efficiency but also provide additional flexibility to support operations. Second, while information asymmetry among power market participants continues to hinder operational efficiency, advancements in data availability and data mining create opportunities for information recovery. Third, while machine learning offers promising solutions to manage the complexity of operational models, it may also compromise their explainability. This dissertation explores these paradoxes, aiming to leverage emerging opportunities while addressing critical challenges in power system and market operations.
The research begins by tackling challenges in power transmission systems and wholesale markets. First, to efficiently use flexible resources like energy storage, a chance-constrained stochastic market framework is proposed, enabling the co-optimization and pricing of energy, reserves, and a new service called virtual inertia provision. This framework mitigates high uncertainty and inertia shortages in RES-dominated systems. Second, to address information asymmetry among power producers and improve market participant strategy design, a data-driven inverse optimization model is developed to recover private offer prices from public market-clearing results. This method is computationally efficient, robust, and offers strong performance guarantees for information recovery. Additionally, an operational-adversarial conditional generative adversarial network is introduced to enhance grid-awareness in scenario generation for extreme operational conditions. By integrating feedback from downstream operational models through modified gradient descent, this model identifies critical scenarios for system operations, enabling effective scenario-based reserve scheduling.
The focus then shifts to power distribution systems, examining incentive-based voltage regulation using grid-edge DERs in environments with uncertainty and partial information. A distributionally robust incentive design model with online learning is introduced, enabling the distribution system operator (DSO) to effectively incentivize DER aggregators to participate in voltage regulation. Aggregators respond to these incentives by adjusting their DER settings, while the DSO dynamically adjusts its conservativeness level based on aggregator responses. This work highlights the potential of combining stochastic modeling, inverse optimization, and machine learning to tackle diverse challenges in power system and market operations
Two-Eyed Seeing: Weaving Bioethics with Deep, Social, and Indigenous Ecologies
Get PDFThis thesis proposes Etuaptmumk, or "Two-Eyed Seeing" (TES), as a methodological framework for reimagining bioethical principles in environmental contexts. While canonical bioethics—founded on respect for autonomy, non-maleficence, beneficence, and justice—has provided valuable guidance in medical and research ethics, these principles prove inadequate for addressing complex ecological challenges. Drawing from deep ecology's biospheric egalitarianism, social ecology's critique of hierarchical systems, and Indigenous ecological knowledge, this paper reconceptualizes bioethical principles as: (1) relational autonomy and agency, (2) resilience and defense, (3) solidarity, and (4) holistic justice. Additionally, this work advocates for "weaving" these principles together rather than merely weighing them against each other—thereby constructing ethical tapestries that honor the interconnectedness of all life forms. Applied to a case study of Indigenous food sovereignty, these reimagined principles reveal pathways toward addressing complex socio-ecological challenges that extend beyond health maximization. By integrating Indigenous and non-Indigenous knowledges, this framework offers bioethicists a more comprehensive approach to environmental issues that acknowledges our embeddedness in ecological systems while recognizing the inherent value of nonhuman communities. The proposed framework does not supplant traditional bioethics, but rather enriches it through dialogue with marginalized perspectives, ultimately fostering more sustainable and just relationships with the biosphere in an era of unprecedented ecological crisis
Cellular Fractionation and Reconstitution of Immune Subcellular Vesicles for Synthetic Biology
No full textOrganelles are essential for the survival, proliferation, and differentiation of eukaryotic cells and carry out cell-specific functions that influence phenotype. Cell phenotype is reflected in the abundance and activity of organelles; for instance, energy-intensive cells such as skeletal muscle fibers have greater mitochondrial density and activity due to their metabolic requirements. Despite the importance of organelles for determining cell function and phenotype, relatively little attention has been devoted to isolating and repurposing organelles as a tool for synthetic biology and cellular engineering. The top-down approach of isolating organelles from biological cells and reconstituting them to form synthetic cells dates back to the early 1970s, but this field has seen little development and attention since the late 1990s. To enable the generation of reconstituted synthetic cells, whole cells can be split into cytoplasts (enucleated cells) and karyoplasts (membrane-wrapped vesicles containing the nucleus and a small volume of cytoplasm) through density gradient centrifugation in the presence of cytochalasin B, an agent that destabilizes the cellular cytoskeleton and prevents actin polymerization. Cytoplasts from one cell type can be fused to whole cells or karyoplasts from another cell type to generate cybrids (cytoplast-whole cell) or reconstituted cell (cytoplast-karyoplast) hybrids that exhibit different characteristics depending on the donor cells. Cybrids and reconstituted cell hybrids have unexplored potential as research tools and therapeutics for diseases including metabolic disorders and cancer. For example, cybrids could be used to treat mitochondrial disorders by fusing cytoplasts containing healthy mitochondria to patient hematopoietic stem cells to generate cybrids with enhanced mitochondrial function. Prior studies have successfully generated cybrids and reconstituted cells with hybrid phenotypes via more rudimentary methods and performed initial characterization, including proliferation and gene expression assays. However, rigorous functional characterization of these products is lacking and the protocols used to generate cytoplasts, karyoplasts, and reconstituted cells vary significantly in their methods and results, warranting further investigation. In this thesis, a streamlined method to generate cytoplasts, karyoplasts, and reconstituted cybrids or cell hybrids is presented. Initial optimization experiments were performed to facilitate improved fractionation product yield, identification and staining, storage conditions, and characterization of reconstituted cell products