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THE FUTURE OF SMALL MODULAR REACTORS IN A LOW-CARBON WORLD: ANALYSIS OF CURRENT TECHNOLOGIES
Get PDFThere are many challenges facing the implementation of nuclear energy as an energy source in the United States. Historically, the economics of nuclear energy, particularly capital costs and indirect expenses, have posed significant challenges to overcome. With the increase in data centers and the development of new technology, particularly the advancement of Small Modular Reactors (SMRs), there is potential for nuclear energy to become an economically viable source in the United States over the next several decades.
This capstone explores the types of SMR technology and compares and contrasts the various types and their ability to meet new and existing energy demands in the United States. The analysis and discussion provide evidence that there is a future for small modular reactors in a low-carbon world, consisting of smaller thermal nuclear reactors and/or fast neutron reactors.
The comparison of various SMR technologies shows that the short-term barriers are lower for smaller-scale versions of existing thermal reactors, such as the NuScale Power Modules. Data centers require large amounts of energy in the short term, and this timing has played, and will continue to play, a significant role in the success of SMRs in general. The immediate energy demands of data centers will also significantly influence which SMRs will be successful. While Pressurized Water Reactor SMRs, which are smaller versions of existing reactors, are well equipped to meet short-term energy demands, there are benefits to continuing to invest in more advanced reactors with different coolants and fast reactors with more efficient fuel use. There is a longer path to commercialization for these types of reactors. Still, the higher efficiency of these advanced reactors makes them strong candidates for fulfilling the long-term increasing energy demand. In general, SMRs are well suited to be a part of the United States’ energy mix due to their lower cost, faster builds, and location flexibility (including at refurbished/obsolete coal plants). Their range of storage applications also makes SMRs good candidates to help with renewable integration and provide electricity and heat to industrial processes.
To bolster the success of SMRs in the United States, five key recommendations are proposed: further development and streamlining of SMR-specific regulation, additional policy support for SMRs, investment in both developed (ex., NuScale) and more conceptual (ex., Em2) SMR technologies, development of domestic fuel enrichment and fabrication, and established nuclear fuel waste protocols. With these developments, SMRs can continue to emerge as a low-carbon baseload power source to support a low-carbon world
USING MULTIPLEX IMMUNOFLUORESCENCE TO EXPLORE THE CO-LOCALIZATION OF SENESCENCE MARKERS IN PANCREATIC TUMORS
Get PDFPancreatic ductal adenocarcinoma (PDAC), the most prevalent form of pancreatic cancer, is a significant clinical challenge due to its poor prognosis, late diagnosis, and resistance to therapy. Cellular senescence paradoxically contributes to tumor progression through various pathways. This study explores the role of senescence in PDAC by analyzing the markers p53, p21, p16, 53BP1, HMGB1, and Lamin B1, using multiplex immunofluorescence (MxIF) and tissue microarray (TMA) technologies.
MxIF allowed for the simultaneous visualization of multiple markers on single tissue sections, preserving tissue integrity and architecture, while TMAs provided high-throughput analysis of diverse patient samples. Colocalization of senescence markers revealed heterogeneity in their expression across tumor regions, reflecting senescence's dual role in suppressing and promoting tumorigenesis. Correlation analyses showed distinct marker patterns associated with tumor presence and progression, offering insights into the molecular complexity of PDAC.
This study underscores the utility of MxIF and TMAs in elucidating the spatial and molecular dynamics of senescence in PDAC. The findings advance our understanding of the connection between senescence and tumor progression, highlighting potential biomarkers for diagnosis and therapeutic targeting in one of the deadliest malignancies
Optimizing Implementation of Household Contact Tracing To Prevent Tuberculosis Epidemics in South Africa
No full textBackground: Tuberculosis (TB) remains a public health challenge in high-burden countries like South Africa. Household contact tracing (HHCT) offers a promising strategy to prevent TB transmission. However, implementation challenges require better understanding of underlying social and contextual determinants. Multidimensional poverty (MP), encompassing deprivations in health, education, and living standards, may influence HHCT implementation and help identify at-risk households to prioritize targeted strategies to more efficiently allocate constrained resources.
Methods: We analyzed the Kharituwe-TB cluster randomized trial of 4,417 individuals diagnosed with TB and their 6,150 household contacts in urban Soshanguve and rural Limpopo. We performed multilevel mixed-effects modeling to examine associations between MP deprivation and HHCT acceptability by individuals diagnosed with TB. We used Bayesian modeling to examine associations between acceptability and implementation reach. Using compartmental mathematical modeling, we projected the long-term impact of HHCT as change in TB incidence, burden of TB averted using disability-adjusted life years (DALY), and maximum cost per TB case that justifies cost-effectiveness.
Results: We found greater household MP deprivation to be significantly associated with lower odds of HHCT acceptability. Each 10% greater MP deprivation was associated with 23% lower odds of acceptability (95% CI: 11%, 34%) with stronger impact in urban households versus rural. Among all households, finding HHCT to be acceptable was associated with 65% lower odds of no reach (95% CI: 27%, 85%). Among households with some reach, finding HHCT to be acceptable was associated with 4.5 times greater odds of complete reach (95% CI: 2.18, 10.42). We projected enhanced and high-intensity HHCT to reduce TB incidence on average annually by 1.78% (1.47%, 2.07%) and 5.25% (4.40%, 6.06%), respectively, while also averting annual DALYs by 4.32% (3.74%, 4.93%) and 12.53% (10.95%, 14.18%). Using a willingness-to-pay of 377 (497) for enhanced and 838, $1,484) for high-intensity HHCT.
Conclusion: Multidimensional poverty is an important upstream determinant of HHCT implementation and may be used as a tool to identify at-risk households. Optimizing HHCT implementation by prioritizing targeted, context-specific strategies offers long-term epidemiologic impact to prevent TB epidemics in South Africa
Insights into Pancreatic Cancer Immunology and Cell-Cell Communication through Single-Cell and Spatial Genomics
No full textCancers often utilize cell-cell communication to avoid detection and eradication by the immune system through immunosuppression. Cancer immunotherapies that alter dysregulated signaling, including immune checkpoint inhibitors (ICI), have improved outcomes for many cancers. However, Pancreatic Ductal Adenocarcinoma (PDAC) remains deadly due to its complex, suppressive tumor microenvironment (TME). Combination immunotherapies have led to increased T cell infiltration, but tumors persist. This dissertation seeks to identify immune cell states and communication signals between cells within the PDAC TME for modulation by immunotherapy using single-cell and spatial genomics as well as novel statistical approaches to identifying signaling alterations induced by therapy.
To identify cells exhibiting interactions with non-neoplastic cells in PDAC and pancreatic intraductal neoplasm (PanIN) that may develop into PDAC, transcriptional states of human PanIN lesions were assayed by spatial transcriptomics. PanIN carcinogenesis exhibited a switch from immune response signature to proliferation associated with change to fibroblast phenotypes in the ductal stroma. To further investigate cell-cell communication in the PDAC TME and the role of immunotherapy in altering communication networks, primary tumors from patients in a platform study of cancer neoadjuvant immunotherapy consisting of the GVAX allogeneic PDAC vaccine, PD-1 checkpoint inhibition, and CD137-agonist co-stimulation underwent single-cell RNA-seq. Treatment with vaccine alone was associated with greater T cell receipt of signals associated with T cell naivety and CD137-agonist was found to induce TREM2 signaling associated with scavenging response in macrophages. The novel approach to statistical assessment of differential cell signaling was developed into the cell-cell communication inference (CCI) software dominoSignal. Accurate detection of differential cell signaling was assessed on simulated data, establishing minimum sample sizes and cell numbers for accurate results and a bootstrapping approach for applications in data sets with few biological replicates. The differential cell signaling test was applied to investigate effects of neoplastic cell phenotypes on communication networks in PDAC, mechanisms of tumor resistance to cancer vaccine therapy in a murine Panc02 tumors, and alterations to intracellular signaling outcomes in response to histone deacetylase inhibition in murine breast cancer. This software is available as an open-source package from Bioconductor for application with any single-cell RNA-seq data set
SUBZERO PRESERVATION OF KIDNEY CELLS USING AN ANTIFREEZE PEPTOID-BASED PRESERVATION MEDIA
Get PDFBackground: Kidney transplant is an important procedure for end-stage renal failure. However, the high organ discard rate has contributed to the organ shortage crisis. This is partially driven by the limitation of the current organ preservation method involving storage in the University of Wisconsin (UW) preservation solution at 4°C. To address this gap, one possible solution is the usage of XT-ViVo (XTV), a preservation solution that utilizes antifreeze proteins to overcome the damaging effects of ice crystal formation of subzero preservation (below 0°C). Such low temperatures can increase organ preservation times by decreasing metabolic activity, though further investigation is needed to determine the efficacy of this new solution.
Methods: Digested mouse kidney cells were stored at 4°C or –5°C in either complete media (CM), UW, or XTV for one of the following durations: 24H, 48H, 72H, 96H, or 120H. Cells were rewarmed following storage, and recovery of metabolic activity was assessed through the measurement of total ATP levels. All statistical analysis was performed at the significance level of 0.05.
Results: Relative to the baseline, there was a significant decrease in metabolic activity recovery following storage at 4°C for 24H in CM, 96H in UW, and 72H in XTV, as well as at –5°C for 24H in CM, 96H in UW, and 96H in XTV. Cells stored in CM showed statistically significant lower relative metabolic activity than UW or XTV cells during all timepoints of storage at both 4°C and –5°C. UW cells showed significantly lower metabolic activity than XTV cells at –5°C at 48H (p < 0.0013), 72H (p < 0.0006), and 120H (0.013), but not for the 24H and 96H timepoints. No significant difference was found when comparing cells stored in UW at 4°C to XTV at 4°C, UW at 4°C to UW at –5°C, or UW at 4°C to XTV at –5°C.
Conclusions: Following storage, cells showed a delay in the decrease of metabolic activity recovery in UW or XTV than compared to CM. Storage in XTV at –5°C showed significantly higher recovery of metabolic activity than UW at –5°C, and similar recovery to UW at 4°C
Mechanisms of endocycling during cancer evolution
No full textWhole-Genome Doubling (WGD) occurs in about 40% of all cancers and is a chromosomally unstable intermediate that promotes aneuploidy. The mechanisms that drive WGD are poorly understood, but one proposed model is endoreplication – two rounds of DNA replication without cell division. However, cell cycle entry is thought to be an irreversible commitment to cell division. To address this apparent contradiction, we developed a new biosensor to study cell cycle at the single-cell level. Multiplexing this reporter with existing biosensors enabled us to holistically quantify cell cycle regulation at high temporal resolution.
Using these tools, I studied how cell cycle dynamics change when cells experience stress. Unexpectedly, I found that cells frequently bypass mitosis and exit the cell cycle directly from G2 in response to diverse cellular stresses. In the context of cell cycle commitment, the dogma has been that cells initiate a positive feedback loop that ensures cell cycle completion independently of exogenous signals. The work presented here challenges this dogma by demonstrating that even beyond the restriction point, mitogen signaling and the classic CDK4/6-Rb-E2F pathway are required to maintain cell cycle commitment during times of cellular stress. When this G2 commitment fails, cells bypass mitosis altogether and become competent to reinitiate DNA replication with 4C DNA content. These findings provide insight into cancer development and reveal important considerations for cancer therapies that inhibit the Ras-MAPK pathway and CDK4/6
AEROSOL EXPOSURES: INDOOR AIR, NICOTINE USE, AND IMPLICATIONS FOR HEALTH
No full textAccurate exposure assessment that incorporates both behaviors and the surrounding environment is of vital importance to understanding health risks, especially in vulnerable populations. This dissertation contains results from two studies: two papers that investigate exposures related to electronic cigarette (e-cigarette) use in the “Exposure to Metals from Electronic Cigarettes” (EMIT) Study and three papers that investigated nicotine use, indoor air contaminants, and stress in the “COVID-19 Wayakta He? (“Are you on guard against COVID-19”)” Study.
In the EMIT chapters, we describe user preferences, self-reported health outcomes according to the e-cigarette device type used, and we compare blood metal levels. This was done in a cohort recruited from April 2019 to March 2020 in Maryland, USA. In total, N = 91 participants were recruited and administered a comprehensive questionnaire. Blood metals were analyzed by inductively coupled plasma - mass spectrometry. E-cigarette users reported more shortness of breath, headaches, and fatigue compared to non-users. We found significant differences in blood levels of Chromium, Nickel, Antimony, Selenium, and Zinc between e-cigarette users and non-users. Our results show that device type and behaviors impact self-reported health outcomes and exposure to certain metals. This indicates potential differential health risks for e-cig users given what we know about chronic, low-dose metal inhalation. This information can help inform public health interventions and harm reduction strategies.
In the COVID-19 Wayakta He? Chapters, we assess nicotine use, indoor air pollution from air nicotine (AN) and nitrogen dioxide (NO2), and self-reported stress with COVID-19 infection outcomes. We recruited 562 participants who filled out a 97-item survey. Households deployed passive AN and NO2 air monitors in their homes for one week. Each participant provided saliva samples for COVID-19 serological testing and cortisol analysis. Prevalence of nicotine use among participants was 53%. The proportional odds were higher for nicotine users for longer COVID-19 recovery time and lower for more severe COVID-19 infection. The odds of COVID-19 infection were higher for those exposed to AN and the odds of long COVID-19 higher for those exposed to NO2. Working adults were more likely to report that health concerns, impact on their children, and their work were their greatest sources of stress than non-working adults. Salivary cortisol was negatively associated with age, female gender, and employment. This study provided critical data on COVID-19 in a rural, indigenous population. Results will help understand the role those environmental exposures played on increased COVID-19 mortality, help target public health interventions and inform Tribal public health policies on emergency preparedness and exposure analyses
The impact of Influenza A virus on cell polarity in human nasal epithelial cell cultures
No full textInfluenza virus circulates seasonally continuing to cause significant levels of morbidity and mortality every year. It infects the epithelial cells of the respiratory tract which has a temperature gradient of 33°C to 37°C progressing from the upper to lower respiratory tract. Lower respiratory tract infection and extensive damage to epithelial cells are associated both with severe influenza disease and susceptibility to bacterial co and secondary infections. Epithelial cells are polarized cells that form cell to cell junctional complexes, including tight junctions which are a key physical barrier to pathogen entry. Understanding damage to epithelial cell polarity and barrier integrity and if this differs by physiological ranges of temperature provides information about disease pathology. MDCK-SIAT cells were used to establish a new method of studying epithelial cell polarity in the laboratory. When grown on Transwells, MDCK-SIATs will polarize at both 37°C and 33°C as measured by transepithelial electrical resistance and tight junction integrity. Influenza infection results in loss of barrier integrity at both temperatures, but the disruption is greater and earlier at 37°C than 33°C. Once established in immortal cells, the method was applied in the primary cell system of human nasal epithelial cell cultures. Circulating H1N1 and H3N2 viruses from the 2023-2024 influenza season were selected for comparison. H1N1 showed greater cell to cell spread than H3N2 at both 37°C and 33°C in MDCK plaque assays. In hNEC cultures there was no difference between viral induction of apoptosis. H1N1 infected cells had higher levels of apoptosis at 33°C than 37°C at 96hpi. H1N1 did demonstrate greater disruption of tight junctions than H3N2 at 37°C, but there was no difference between viruses impact on tight junctions at 33°C. Both viruses showed greater barrier disruption at 33°C than 37°C at a portion of timepoints
Tuning Post-Translational Modifications in Mammalian Cells: Exploring Media Optimization and Gene Editing Strategies
No full textThe production of biologics has revolutionized the treatment of numerous diseases, offering targeted high-efficacy therapeutics for conditions ranging from cancer to autoimmune disorders. These biologics are typically produced using mammalian cells, requiring carefully optimized manufacturing processes to ensure high yields and product quality attributes that meet regulatory standards.
However, the manufacturing of these complex therapeutics is challenged by the need for finely tuned cell culture conditions to ensure optimal product yield and quality. Small changes in cell culture conditions can significantly impact cell metabolism and protein quality attributes, potentially rendering the final product unsuitable for therapeutic use.
This thesis looks to address the challenge of modulating product quality attributes by employing gene editing techniques to develop cell lines tailored for producing recombinant proteins with desirable quality attributes and refining cell culture media formulations to control the availability of key components in media.
First, as a model case, we demonstrate the impact of product quality on therapeutic efficacy using butyrylcholinesterase (HuBChE), a human enzyme of significant value as a medical countermeasure against organophosphate poisoning. Given the scarcity of HuBChE in human plasma, recombinant production in mammalian cells is necessary to meet therapeutic demands. Through gene editing, we established a mammalian production platform that generates recombinant HuBChE with product quality attributes closely resembling the native human enzyme.
Next, we explored the regulation of metal availability in cell culture media, focusing on copper as a critical trace element that affects cell growth and protein PTMs. Using copper-specific chelating agents, we developed copper-buffered systems to maintain stable and bioavailable copper levels throughout the culture process. This controlled environment mitigates the adverse effects of copper fluctuations, supporting consistent cell performance and ensuring predictable quality attributes in the produced therapeutics.
Next, we seek to elucidate solubility interactions between different amino acids in aqueous solutions. By studying combinations of two amino acids in water, we identified negative, neutral, and positive interactions between amino acids. These experiments were also extended to see how amino acid solubilities were affected as a function of salt concentrations in solution as well, to ultimately guide more efficient cell growth media design
Computational Studies of Three-Phase Suspensions with Applications to Froth Flotation
Get PDFThree-phase multiphase flows are found in numerous industrial applications, including those involving the separation of different materials. Often these involve a liquid phase and a gas phase, with either solid particles or liquid drops as a third phase to be separated. Gas flotation removes oil droplets or fat from water in wastewater treatment, while froth flotation separates valuable hydrophobic particles from hydrophilic materials in mineral processing and plastic recycling. Although the contact angle between a solid, or a drop, and an air-liquid interface determines whether bubbles and particles/drops attach, predicting separation efficiency directly from the contact angle remains challenging, due to the complex interplay of many factors, such as the collision rate of bubbles and solid particles or drops, the turbulence level in the liquid, and the draining of the liquid film between bubbles and particles or drops.
This dissertation aims to enhance the fundamental understanding of three-phase flows through comprehensive numerical simulations. An extended front tracking method is developed, where the interface between two fluid phases is followed using connected marker points, to simulate the motion of triple contact lines for both three fluid systems and systems containing two fluids and suspended solid particles. After developing a method applicable to a wide range of three-phase systems, we examine gas-liquid-solid flows, as found in froth flotation. Key objectives include investigating bubble-particle interactions by conducting fully resolved numerical simulations of single and multiple bubbles rising through particle suspensions. The effects of the particle size, bubble deformability, contact angle, and particle concentration on capture rates are examined and used to gain insight into the process. To consolidate the simulation results, simple analytical models are also developed for the coarse flow, both for a single bubble and a layer containing several bubbles. The models contain adjustable parameters that are determined by matching the predictions with the simulation results for variables, such as the bubble Reynolds numbers and particle capture rates. The work demonstrates the feasibility of studying three-phase fluid systems, including those containing solids, using fully resolved numerical simulations