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STRUCTURE AND ELECTROCATALYTIC PERFORMANCE CORRELATION STUDY USING NANO INTERMETALLIC MATERIALS AS MODEL SYSTEMS
No full textElectrocatalysts play a vital role in renewable energy technologies, particularly in the effort to combat climate change. Noble metals are widely utilized in catalytic reactions due to their exceptional activity and stability; however, their high cost drives the need for methods to minimize the use of these precious materials. One effective approach is alloying noble metals with more abundant and less expensive metals. These resulting alloys, classified into solid solutions and ordered intermetallic compounds (OICs), can significantly enhance catalytic performance. Although solid-solution alloys have demonstrated improved catalytic activity, their heterogeneous atomic distributions complicate the identification of active sites on nanoparticle surfaces. Conversely, OICs allow for precise control over crystal structure and active site distribution, thereby facilitating structure-property correlations.
To develop cost-effective and high-performance electrocatalysts, researchers have turned to transition metals combined with oxophilic elements such as Sn, Sb, and Bi. Despite considerable efforts to create new bimetallic materials with superior electrocatalytic properties, there have been limited systematic investigations into the structure-property relationships that govern their performance. Difficulties in controlling particle size, chemical composition, and testing environments have posed significant challenges, hindering the comprehensive evaluation of how structural factors impact electrocatalytic efficiency.
In this thesis, we summarize the previous investigation on intermetallic nanoparticles used to elucidate how atomic structure influences electrocatalytic performance. We focus on the hydrogen oxidation reaction (HOR) and methanol electro-oxidation reaction (MeOR) as model reactions. By synthesizing uniform nanoparticles of targeted OIC phases (e.g., PtSb, PtSb2; Pd3Bi ordered phase, solid solution phase, and partially ordered phase), we explore their electrocatalytic performance for the selected reactions. Our findings reveal that surface strain-modified core-shell structured PtSb and PtSb2 nanoparticles (denoted as Pt@Pt-Sb) exhibit distinct reactivity towards HOR in alkaline solutions. Additionally, we observe the reactivity of MeOR can be varied significantly by altering the size of Pd ensembles, with some configurations even switching the reaction on and off.
Through advanced characterizations, we elucidate the underlying reaction mechanisms, demonstrating the effects of strain modulation on the electronic structure and kinetics of Pt@Pt-Sb materials, as well as the ensemble effect on Pd3Bi materials in alkaline solutions. Moving forward, we advocate for integrating experimental data with computational models to further validate our findings and improve the precision of electrochemical reaction simulations.
In summary, our research on Pt/Pt-Sb and Pd-Bi materials highlights the utility of ordered intermetallic materials as a platform for understanding the structure, electrocatalytic performance, kinetics, and fundamental mechanisms of catalytic reactions. We believe that this research approach can facilitate the rational design of electrocatalyst materials by revealing underlying scientific principles
OCCUPATIONAL HEAT EXPOSURE IN HAZARDOUS MATERIALS WORKERS
Get PDFFully encapsulated chemical protective ensembles such as Level A suits expose workers to elevated levels of heat stress due to the extreme conditions created within the suit. While general guidelines exist for core temperature, few studies have evaluated the exposure of workers operating in this posture. This retrospective observational study explores the physiological response of prolonged heat exposure experienced by a specialized Hazardous Materials (HAZMAT) Team, trained in the characterization and identification of unknown toxic substances and equipped for extended operational durations. Unlike traditional HAZMAT workers limited to 45-minute operations using a self-contained breathing apparatus (SCBA), these teams often operate in Level A suits for durations exceeding two hours utilizing specialized breathing apparatuses. This group frequently employs the Draeger BG4 rebreather. The BG4 rebreather is designed for up to four hours of continuous use. It is more commonly found in mining operations, but seldom seen in encapsulated suit applications. This extended usage provides a rare look into the effects of extended exposure and the potential for occupational heat-related illness.
The study uses retrospective data from Physiological Status Monitors (PSM) measuring heart rate, respirations, skin temperature, and estimated core temperature. Initially monitored in real-time for heat exposure, the data was archived without context. This paper summarizes the analysis of these datasets utilizing over 35 work events, to assess prolonged heat exposure impacts. The lack of contextual data necessitated establishing exertion zones for data categorization and evaluation. Descriptive statistics, survival data, and regression analysis focusing on core temperature data were used for analysis.
Key findings indicate that heat exposure levels can quickly escalate beyond critical thresholds, significantly increasing the risk of injuries and performance decrements. On average, workers entered exertion zones classified as critical within 90 minutes, with regression analyses suggesting escalation to severe exposures within two hours. While the sample group had the advantage of real-time monitoring, most teams within the same workforce do not employ PSM devices, relying instead on subjective measures such as personal comfort, tolerance, and coworker assessments to gauge heat exposure risks. This study emphasizes the potential dangers and vulnerabilities of such practices
Integrating Managed Care for Dual-Eligible Beneficiaries: Evidence from Dual-Eligible Special Needs Plans
Get PDFThis dissertation contains three papers; in each I examine a different facet of Medicare managed care for individuals dually eligible for Medicare and Medicaid in the U.S., a vulnerable population historically receiving fragmented health care. Focusing on Dual-Eligible Special-Needs Plans (D-SNPs) in Medicare Advantage, in the following chapters I study whether and how D-SNP integration with Medicaid can achieve higher quality care for dual-eligibles. I identify important heterogenous effects across beneficiaries, by focusing on a group whose care is most likely affected by incentives resulting from integration: beneficiaries who use long-term services and supports (LTSS).
In chapter 2, I study potentially avoidable hospitalizations and find that state policies requiring alignment and integration with Medicaid can increase the delivery of efficient care by D-SNPs, but only in settings where insurers have the most financial interest at stake. Integration—when the insurer is responsible for both Medicare and Medicaid spending— is associated with decreasing potentially avoidable hospital utilization for long-term nursing home residents by 22%, but absent these incentives, most D-SNPs act similarly relative to other MA plans.
In chapter 3, I compare enrollment and disenrollment from D-SNPs relative to other MA plans and traditional Medicare based on integration status and LTSS use. Encouragingly, I find that LTSS users display preferences for integration, suggesting that decreases in utilization do not appear to come at the expense of enrollee satisfaction and that integration remains an important federal and state policy lever in the design of the public insurance landscape for dual-eligibles.
In chapter 4, I assess structural changes in nursing home provider networks associated with integration that can influence access, plan choice, and quality of care. Developing new methodology to define these networks, I find that integration is associated with increases in network breadth (approximately 10 p.p. in 2019 and 5 p.p. in 2022) as well as some changes in network composition with regards to quality and orientation toward Medicaid.
In chapter 5, I discuss conclusions and recommendations for state and federal policy, as well as areas of future research
Characterizing the diversity of the pre-core region of the hepatitis B virus
No full textAs per the World Health Organization (WHO), the global burden of chronic hepatitis B is estimated to be 300 million, with predominance in the Western Pacific and African regions. One of WHO’s goals set in 2016 is the elimination of viral hepatitis public health threat by 2030. Despite the availability of a robust vaccine and oral antivirals, many challenges still exist towards the elimination of hepatitis B. To reach the goal, set up by WHO, widespread vaccination efforts along with multiple cure avenues must be in place. The persistence of the viral genome in the liver tissues is a barrier to sterilizing cure. To design better therapeutics, understanding the viral genome and its dynamics in-vivo may be useful. The current project aims to understand viral diversity with respect to the pre-core region of the hepatitis B genome. The pre-core region gives rise to HBeAg which is one of the serological markers of hepatitis B infection. Some mutations in the region lead to negative diagnostic results for HBeAg. Specific mutations have also been associated with progression towards hepatocellular carcinoma and fulminant hepatitis. To understand viral diversity of the pre-core, two types of data were interrogated across three different patient samples. In one method to understand the single hepatocyte level diversity of the virus, single cells were isolated from flash frozen liver tissue, and PCR was carried out to amplify the pre-core region, followed by Sanger sequencing. A multiple sequence alignment was carried out to check for intracellular diversity, but no diversity was found. A second exploration was carried out with hepatitis B virus sequences from plasma using next-generation sequencing. It was aligned to the pre-core region and the quasi-species complexity was measured with the bioinformatics tool quasi-tools. The measures across the two samples differed considerably, with one patient sample showing more diversity than the other. The investigation of the reason for this difference along with the effect of mutations are some of the future goals of this project
IMPAIRED ENDOTHELIAL CELL MECHANOTRANSDUCTION IN AN ENGINEERED IN VITRO MODEL OF FBN1 DEFICIENCY
No full textThe cardiovascular system plays an integral role in the functioning of every organ system in the human body by providing a transportation vehicle for the delivery of nutrients, regulators of metabolism, growth, and immune effector populations. This system is highly vulnerable to catastrophic failure in the connective tissue disorder Marfan Syndrome (MFS) due to mutations in the Fibrillin-1 (FBN1) gene; a critical extracellular matrix (ECM) protein. Clinical and murine studies of MFS have revealed significant pathological contributions of the aortic media to the degeneration of aortic architecture; however, a role for the aortic intima in MFS disease progression remains largely unexplored. The intima, composed primarily of endothelial cells (EC), fulfills a significant role in maintaining the health and function of the aorta through regulation of vascular tone, hemostasis, inflammation, and aortic medial vascular smooth muscle cell (vSMC) phenotype. Thus, new models are needed to elucidate a plausible role for FBN1 mutations in disrupting endothelium function.
Towards generating an in vitro model to elucidate potential impacts of FBN1-deficiency on EC (structure and function), we first confirmed the replication of well characterized markers of dysfunction, observed both in vivo and in vitro, in vascular smooth muscle cells (vSMC) derived from an hiPS Cell line, MFS 766, harboring a pathogenic FBN1 variant. Our findings, specifically the deficit in vSMC extracellularly deposited FBN1, motivated further studies using MFS 766 in hiPS Cell-derived EC. Although we did not observe differences in the differentiation capacity of MFS 766 hiPS Cells towards EC, we did confirm a significant decrease in the abundance of extracellularly deposited FBN1 compared to control hiPS Cell-derived EC, homozygous for the WT FBN1 allele. To address the potential impacts of interline-variability in our observations of FBN1 deficiency in MFS 766 EC, we generated and fully characterized two new hiPS Cell lines from patient dermal fibroblasts and used next generation sequencing to confirm the presence of two novel intronic splice variants; one of which (HFD2) was located proximal to the point mutation found in the MFS 766 line. Utilizing an additional control hiPS Cell line to confirm differences between normal and FBN1-deficient cell progeny, we compared FBN1 deposition in MFS 766 EC and newly generated HFD2 EC and found significant decreases in extracellular FBN1 abundance in both hiPS Cell lines harboring FBN1 mutations compared to controls. Qualitatively, we also observed properly localized but porous and abnormally wide vascular endothelial cadherin containing junctions in EC harboring FBN1 mutations. Due to VECad’s role in the transduction of tensional force and maintenance of the intimal barrier, we exposed EC to physiologic cyclic stretch at timepoints which corresponded to FBN1-deficits. In EC cultured on ECM naturally deficient in FBN1 and exposed to uniaxial cyclic stretch, we observed severely diminished cytoskeletal dynamics, and an absence of change to both nuclear shape and nuclear orientation; characteristic of impaired mechanotransduction. Notably, we also observed maladaptive changes to VECad and ZO-1 proteins including abnormal junctional morphology and delocalization from cell-cell junctions. Collectively, the impaired sensitivity to mechanical force and the observations of endothelial monolayer fracture were indicative of diminished barrier function in FBN1-deficient contexts. Using an established MFS mouse model harboring a missense FBN1 mutation and reduced extracellular FBN1, we observed increased permeability of the aortic intima to the large protein albumin, normally localized to the sera. Altogether, these data implicate dysfunction of EC mechanosensitive responses in the possible onset or progression of MFS
VIRTUAL STAIN CONVERSION BETWEEN IMMUNOHISTOCHEMISTRY AND HEMATOXYLIN & EOSIN IMAGES USING DEEP GENERATIVE MODELS FOR INFERENCE OF PANCREATIC ISLET CELLULAR COMPOSITION IN TYPE 1 DIABETES
Get PDFIn Type 1 diabetes (T1D) patients, insulin-producing β-cells residing in the islets of Langerhans are selectively destroyed due to autoimmunity. This is mostly due to the complex interplay between the islets of Langerhans and nearby structures of the pancreas, which is yet to be deciphered. An effective and long-lasting therapeutic for globally increasing T1D patients has not been developed yet due to the knowledge voids in the pathophysiology of T1D. Specifically, researchers have been struggling to determine if β-cell destruction is caused by the immune system or is self-inflicted. In order to analyze this, pancreatic tissue blocks were sectioned to slides and stained with immunohistochemistry (IHC) and hematoxylin & eosin (H&E) stains to identify the spatial correlation between the islets and the nearby structures. However, IHC and H&E stains cannot be stained concurrently on the same slide of the tissue block, leading to the classic intra-slide variation problem. Therefore, this study utilized several deep generative models, including a new class of conditional diffusion models called Image-to-Image Schrödinger Bridge (I2SB), to virtually stain between IHC and H&E slides of the tissue block. Since most, if not all, of the previous virtual staining works utilized Generative Adversarial Networks (GANs), GANs and I2SB models were trained and evaluated in their ability to generate a virtual H&E image of high perceptual quality. By utilizing segmentation model-based and model-free evaluation methods, it was shown that a “conditional” variant of I2SB model, I2SB-cond, performed the best in the generation of virtual H&E images, but was not utilized due to its conditioned tissue map suffering from the intra-slide variation problem. The state-of-the-art GAN model for virtual staining and the vanilla I2SB model performed similarly, and was utilized to generate virtual WSIs, showing that these models can indeed be utilized to resolve the intra-slide variation problem. Lastly, the dominant performance of I2SB-cond model hints at its future potential for virtually staining the islets, or generation of virtual IHC images
Investigations of How Cancer Cells Respond to Stress
Get PDFMetastatic cancer is incurable and causes millions of deaths each year. Cancer cells can evade stressful conditions such as hypoxia and chemotherapy exposure through various mechanisms. These stressful conditions that cancer cells are exposed to cause an increase in their already elevated reactive oxygen species (ROS) levels. In turn, the DNA damage response (DDR) of cancer cells becomes activated and arrestation of cell growth in the canonical mammalian cell cycle may occur. If the arrested cells have exited the cell cycle after S phase but before mitotic division, they can overcome exposure to chemotherapy as cancer cells in the poly-aneuploid cancer cell (PACC) state. Cancer cells in the PACC state are protected from further DNA damage and from undergoing programmed cell death. They can later undergo depolyploidization and repopulate a tumor cell population with chemotherapy-resistant progeny. Cancer cells in the PACC state are physically larger than the parental cancer cells that they arise from and undergo endocycling, causing their genomic content to be greater than these parental cancer cells as well; these two characteristics of the PACC state can be predicted to require the support of microtubules. Given the role of ROS, DDR and potentially, microtubules, in the PACC state, I decided to investigate these aspects of cancer cells of the PACC state. I studied BRCC3, CAT and SOD1 gene expression through RT-qPCR, and investigated microtubules through IF staining of -tubulin, in untreated cancer cells and cancer cells in the PACC state at various time points post-chemotherapy treatment. The results of these experiments did not show significant differences in gene expression of BRCC3, CAT or SOD1, nor in the average ⍺-tubulin quantities, between parental untreated cells and cancer cells in the PACC state post-treatment. However, the quantity of ⍺-tubulin present surrounding the perinuclear space was greater in cancer cells in the PACC state 10 days post-treatment, compared to all other cells. Due to heterogeneity within and between biological replicates in each of these experiments, further studies are needed to define the roles of ROS, DDR and microtubules in the response of cancer cells to stress, through the PACC state
ENCLOSURE WITH CHINESE CHARACTERISTICS: AGRARIAN CAPITALISM AND UNEVEN DEVELOPMENT IN RURAL CHINA
Get PDFThis dissertation examines China’s ongoing rural capitalist transformation, tracing the macro-historical origins, diverse local trajectories, and socioeconomic impacts of the Chinese state’s land transfer policy, which has transformed farmland into a rentable commodity and concentrated land for large-scale commercial agriculture. It makes the following arguments:
The expansion of capitalist social relations into the countryside is the Chinese state’s response to an overaccumulation crisis, exposed by the 2008 Global Financial Crisis. Through land transfer, the state sought to create new internal frontiers for capital investment, increase domestic demand, and reduce rural poverty and spatial inequality. Thus, this transformation is best understood through Harvey’s concept of “spatial fix.”
Institutionally, land transfer follows a clear “innovation—emulation" process. It was first a bottom-up policy experiment in early-industrialized, coastal regions in the early 1990s. In fostering this innovation, local cadres formed weak despotic, but strong infrastructural power through institutionalized cooperation with agricultural entrepreneurs. This created a thriving farming sector. However, in inland regions, where rural households still largely rely on subsistence farming, the emulation of land transfer mostly depended on local-state despotic power and top-down campaigns. Local cadres often coerced peasants to rent their lands to large-scale commercial farms’, but did not have institutional incentives to ensure farms’ viability after campaigns ended. This has led to widespread agribusiness failures and has worsened old villagers’ livelihood crises, caused by a breakdown of filial support under increasingly commodified social reproduction.
Interactions between institutional models and local political economies have formed different types of state power and trajectories of agrarian change. These dynamics may prevent the state’s attempt at engineering a spatial fix from reaching its intended objectives of creating sustained agrarian capital accumulation and reducing spatial inequality.
These findings contribute to theories of spatial fix by explaining the institutional, political dynamics that may lead to its failures. They challenge scholarship about the political economy of development by revealing the limits of experiment-based policymaking in reducing spatial inequality.
The dissertation draws on 19 months of comparative ethnography in two counties, over 150 interviews with academics, officials, villager households, and large-scale commercial farmers, and extensive archival research
ApoE isoforms modulate SARS-CoV-2 neurological infection and confer differential risks for infection-driven early AD pathogenesis through vascular injury
Get PDFGiven the pronounced disparities of clinical spectrum upon SARS-CoV-2 infection, a multitude of epidemiological studies have been conducted to pinpoint the potential contributors that implicate the different degrees of susceptibility to SARS-CoV-2 and heterogeneity in COVID-19 outcomes, while the underlying mechanisms are still insufficiently understood. In particular, there are growing concerns about the long-term cognitive sequela, as more than one-third of the hospitalized COVID-19 patients exhibited neurological manifestation. In this study, we showcased that apolipoprotein E (APOE), a well-known risk gene for Alzheimer’s disease, confers to variant-dependent host susceptibility to SARS-CoV-2 in APOE isogenic brain cell culture. Through quantitative PCR, we observed that APOE2/2 and APOE 4/4 bearing brain cells were more susceptible to SARS-CoV-2 infection, as they exhibited higher viral loads relative to APOE3/3. These findings align with the result of UK Biobank epidemiological study. Notably, APOE2/2 exhibited even higher viral loads compared to APOE4/4, suggesting that not only the neuroprotective role commonly associated with APOE2/2 is circumvented upon SARS-CoV-2 infection, but APOE2/2 also heightened the SARS-CoV-2 infection susceptibility. Based on RNAseq analysis and literature screening, we identified a list of genes as the potential targets of the APOE-variant dependent differential susceptibility, which were further validated on the transcriptomic level and protein level using in vitro assays. We speculated that genes related to SARS-CoV-2 viral entry and receptor were co-expressed with APOE2/2 at a higher level compared to APOE3/3 and APOE4/4, respectively. Such augmented susceptibility among APOE2/2 was manifested as the abnormal angiogenesis signaling and exacerbation of the vascular injury in the brain cell cultures, quantified by the cytokine and chemokine levels using MSD panel, implying an increased risk of hemorrhage and stroke among APOE 2/2 COVID-19 patients. Our findings bridge the gap between different APOE genotypes and the heterogeneity of SARS-CoV-2 clinical outcomes, further suggesting that personalized treatments and preventative interventions could be beneficial for COVID-19 patients with different APOE genotypes. Altogether, the results warrant future investigation of whether SARS-CoV-2 infection predisposes patients with different APOE isoforms to neuropathogenesis to varying extents
STUDY OF EARLY ACUTE PHTHALATE EXPOSURE USING A 3D HUMAN IPSC-DERIVED BRAIN MICROPHYSIOLOGICAL SYSTEM
No full textThis study aimed to explore the developmental neurotoxicity of endocrine-disrupting chemicals (EDC), using a human induced pluripotent stem cell (hiPSC)-derived 3D brain microphysiological system (bMPS). Phthalates (PAEs) are known ubiquitous EDCs with a pervasive presence in groundwater, maternal breast milk, and amniotic fluid. Di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate (MEHP), known endocrine disrupting chemicals, were used to model EDC exposure in this study.
This thesis focused on analysis of the effects of early acute PAE exposure by investigating cell viability and neurotoxic impacts measured by neurite outgrowth assay. bMPS, derived from neurotypical female and male iPS cells, were exposed to series of concentrations of DEHP and/or MEHP for 72 or 96 hrs at 2,4 or 8 weeks of bMPS differentiation. Overall cell viability/metabolic capacity was measured via resazurin assay and neurotoxic impacts were measured by quantification of neurite outgrowth. Both female and male bMPS exposed for 72 hours exhibited minimal effects when investigating cell viability whereas 96-hour exposure exhibited stronger effects on cell viability for both cell lines. Female bMPS analyzed 2W after differentiation exposed for 96 hours were vulnerable to the highest concentrations of MEHP (mean viability of 78% for 1.5 µg/mL, 60% for 4.5 µg/mL and 46% for 13.5 µg/mL compared to controls| n=4) whereas 2W male bMPS were vulnerable to DEHP at the lowest concentrations (mean viability of 58% for 0.625 µg/mL and 55% for 1.25 µg/mL compared to controls| n=4). bMPS analyzed at 4W after differentiation exposed for 96 hours were vulnerable to MEHP (mean viability of 69% at 2.5 µg/mL in female bMPS and 63% at 0.625 µg/mL in male bMPS | n=4). There was no impact at the 8W timepoint.
Looking at neurite outgrowth, there were no impacts to growth for bMPS after 72-hour PAE exposure and slight effects to 96-hour DEHP exposure in female bMPS (61% average reduction in growth at 5 µg/mL DEHP compared to controls | n=4).
This preliminary data suggests that exposure time is critical, but the impact by acute exposure to environmentally relevant doses of DEHP and MEHP is minimal. Further research is needed to explore the impact of chronic exposures to these chemicals on neural development, especially in the models genetically relevant to ASD. The end goal being to investigate the hypothesis that gene and environmental interactions impact people with certain genetic backgrounds more strongly after introduction of environmental stressors