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Test Tubes in Teapots: Modern Medical Diagnostics Enter the Home
Get PDFHome diagnostic testing is a new phenomenon with old roots. This thesis traces the paths of three important diagnostic tests of the last century as they moved from the hospital and clinic into the home. In the early 20th century, home urine glucose testing became the mainstay of successful diabetes management and remained so for decades, forcing doctors and their patients into an uneasy new partnership of not-quite equals. In the 1970s, home pregnancy testing became a symbol of privacy, autonomy and the liberation of the healthy female body from the medicalized sphere of illness, promising somewhat more on all these fronts than it actually delivered. In the 1980s, home HIV testing became the focus of a tangled decades-long regulatory struggle, generating passionate debate about the proper handling of fraught medical information during a time of crisis. All these tests aimed to ease the experience of diagnosis and to expedite high-quality care. All of them also raised expectations that their use would improve not only the individual's but also the community's health. Not one of them proved to be a clearly effective public health tool. Their histories hold useful lessons for a future in which home diagnostic testing plays an increasingly prominent role
CHARACTERIZING INTRA- AND INTER-TUMOR HETEROGENEITY IN HIGH-GRADE SEROUS OVARIAN CANCER SUBTYPES USING SINGLE-CELL AND SPATIAL TRANSCRIPTOMICS
No full textHigh-grade serous ovarian cancer (HGSOC) is a prevalent and aggressive ovarian
cancer known for its heterogeneous tumor micro-environment (TME) and genetic
variation. Advances in single-cell RNA sequencing (scRNAseq) and spatially-resolved
transcriptomics have enabled the study of complex TME. Established molecular
subtyping methods that categorize HGSOC tumors into molecular subtypes also
provide the framework to explore distinct gene expression patterns associated with
clinical implications.
In this study, we explore connections between pseudo-bulk derived molecular
subtypes and spatial domains characterized by distinct gene expression in HGSOC
tissues and its variability between patients. We generated a new dataset of N =4
spatial replicates of 10x Visium Spatial Gene Expression from a single HGSOC tissue
to examine intra-tumor heterogeneity in space, and identified differing spatial patterns
of gene expression pertaining to immune pathway and vasculature development. We
further integrated our dataset with a previously published dataset to enable exploration
of inter-patient and inter-subtype tumor heterogeneity. For the purpose of performing
spatial sample de-convolution, we also generated an integrated single-cell dataset
incoporating N =7 newly sequenced HGSOC tissues and N =5 published scRNA
samples provided to use as reference. Functional characterization of tumor spaces
revealed potentially shared cell states across molecular subtypes, while correlation
analysis underscored subtype-specific spatial anti-colocalization between spots exhibiting
antigen presenting functions and B cell-mediated immunity. We also explored the cell
composition of fibroblast spatial domains. We also explored the association between
subtypes and the abundance of fibroblasts expressing the COL1A1 and STAR gene
markers and the total proportion of fibroblasts in spot
Investigating the Role of Mitochondria Remodeling Dynamics in Asymmetric Inheritance of Protein Aggregates in Budding Yeast
No full textMitochondrial dynamics are vital for mitochondrial and cellular health especially in quality control and asymmetric inheritance. This thesis investigates the role of mitochondrial dynamics in responding to proteotoxic stress in the budding yeast, Saccharomyces cerevisiae. Using innovative high-throughput image analysis tools developed during this study, we quantitatively examine the intricate behaviors of mitochondria under stress conditions.
Using the tools we developed, our research reveals that mitochondrial remodeling plays a critical role in managing proteotoxic stress by facilitating the asymmetric retention of protein aggregates. We identify specific remodeling adaptations essential for this process, including biased fission near protein aggregates which promotes their consolidation into fewer, larger masses. This adaptation significantly reduces the likelihood of passing these aggregates to progeny during cell division.
The findings contribute significant new insights into mitochondrial function, revealing complex cellular strategies for managing mitochondrial health. These discoveries open potential therapeutic avenues for diseases characterized by mitochondrial dysfunction and proteotoxic stress. Future research should expand these studies to mammalian systems to explore the broader applicability of the findings
Impact Evaluation of Flashlight360 in Mountain View Public Schools: Year 2
Get PDFThis study examined the effectiveness of Flashlight360 by continuing a retrospective, mixed-methods quasi-experimental design of ELLs in Grades 1-12 during the 2023-24 school year in a large western state school district. Outcome measures included composite, speaking, and writing achievement gains on the WIDA ACCESS assessment administered to students in schools that implemented Flashlight360, relative to those of students in schools that did not implement the program. Impact analyses showed significant positive impacts of Flashlight360 on WIDA ACCESS composite score and proficiency levels, both for two-year and one-year student participants. Additional analyses showed significant positive impacts of Flashlight360 on WIDA ACCESS Speaking and Writing subscale scores for one-year students, as well as directionally positive impacts for two-year students. Digital usage variables were not significantly associated with WIDA ACCESS scores or proficiency levels.Flashlight Learnin
Tuning microstructure and reactive properties of titanium dioxide based thermites using Al-Zr composite fuels
Get PDFThermites are a class of energetic materials widely used for welding, breaching, and enhancing pyrotechnics and explosives. A great deal of research has been conducted with thermites focused on generating higher heats of reaction, faster reaction speeds, and larger pressure rises via gas generation. However, little work has focused on thermite formulations that produce no gas and do not expand. Enabling such behavior will allow for new applications of thermite powders such as sustained heating within sealed vessels and space applications where sustained reactions with low gas generation and minimal expansion are required to reduce mechanical stresses or additional pressure generation.
In this project I focused on fabricating composite aluminum-zirconium (Al-Zr) fuel powders and their subsequent combination with titanium dioxide (TiO2) powders to produce novel thermite formulations via arrested reactive milling (ARM). The microstructure and ignition properties of loose Al-Zr and Al-Zr-TiO2 powders were characterized and then they were compacted to study burn properties as moderately dense solids. The most suitable non-expanding thermite formulation was identified and then it was incorporated as a heat source for decontamination in a sealed vessel. The effectiveness of the thermite as a biological decontamination method was tested against Bacillus atrophaeus spores. The resulting data showed complete inactivation of all spores, with no destruction of the sealed vessel during reaction
EVALUATING THE EFFECT OF BASELINE ON THE RATE OF RECOVERY FROM A STRESSOR IN SINGLE-ARM STUDIES OF RESILIENCE
Get PDFMany older adults encounter some significant stressors during their lifetime. The capacity to recover well following such stressors is termed resilience. Resilience is an ongoing and dynamic process, and usually lasts over a long term. In geriatric studies, a key objective is to evaluate how baseline functional levels of patients influence resilience after experiencing the stressors. Typically, research on resilience in older adults involves a single-arm setup where all participants undergo the stressors. The straightforward method of regressing change on baseline treats resilience as difference between pre and post-stressor measurements, which instead is a long term process. It yields biased results due to mathematical coupling and regression to the mean (RTM). To solve these issues, we develop a corrective approach to address the bias in evaluating baseline effect on the rate of recovery from stressors for longitudinal single-arm studies of resilience. Assuming the overall trajectory of resilience is roughly linear, our approach involves fitting a linear regression model with time-baseline interaction, considers a counterfactual control group and uses sensitivity analysis to determine the possible range of an unidentifiable parameter. Only minimal distributional assumptions are required. Simulation studies under multiple different scenarios demonstrate the validity of the method. We illustrate our method by applying it to a large-scale prospective longitudinal study comprising older adults (N=7,239) who received total knee replacement (TKR) surgery. We showcase how external data can be employed as counterfactual control group to refine the sensitivity analysis. Naive analyses demonstrate that patients with higher baseline functional levels recover more slowly after experiencing the surgery. However, the corrected analyses reveal that there is a slight positive relationship between baseline function and the rate of recovery due to TKR. It is of extreme importance to correct biases brought by mathematical coupling and regression to the mean (RTM) when deducing the impact of baseline status on the rate of recovery after experiencing stressors. Our approach offers a simple estimator to achieve this objective
THE ROLE OF INTRA-TUMORAL MICROBIOME IN MODULATING MUCOSAL-ASSOCIATED INVARIANT T CELL (MAIT) FUNCTION IN LUNG CANCER
Get PDFMucosal-associated invariant T cells (MAITs) represent a subset of innate-like unconventional T cells pivotal in safeguarding mucosal immunity. MAIT cells possess unique features, which recognize bacterial-derived metabolites presented on nonclassical MHC-related molecule 1 (MR1). The role of MAIT cells in anti-tumoral immunity and in immune checkpoint blockade (ICB) therapy remains poorly understood.
We hypothesize that a finely tuned equilibrium among MAIT cells, the microbiome, and tumor cells within the tumor microenvironment (TME) significantly influences the immune response to cancer and the treatment outcomes. To explore this hypothesis, we analyzed the composition of the lung microbiome in a cohort of non-small cell lung cancer (NSCLC) patients and investigated the in vitro recognition of microbial antigens by MAIT TCR. We also developed a gene profiling pipeline to elucidate potential correlations between microbial riboflavin biosynthesis capacity and their ability to activate MAITs.
Our investigation revealed that bacterial riboflavin biosynthesis within tumors elicits MAIT cell activation via the induction of MR1 expression on tumor cells. Surprisingly, we also observed that a non-riboflavin producing bacterial isolate, Enterococcus faecalis, augmented MR1-mediated recognition of tumor cells by tumor-infiltrating MAIT cells. This finding suggests a plausible role for the microbiome in modulating the innate immunosurveillance of NSCLC
Hypothalamic Sympathetic Activity Regulates Bone and Fat Metabolism During Lactation
No full textThe skeletal system, which approximately accounts for 20% of our total body weight, plays several critical functions. Including functioning as an endocrine organ implicated in whole-body metabolism. Several prospective studies show us the rate of bone loss and bone mineral density, in women, are strongly correlated with fat mass, rate of change of body weight and rate of change of fat mass, however similar correlations are either weaker or absent in men. Suggesting that the energy required for bone remodeling and maintenance of bone homeostasis must be derived from fat metabolism with an impact from sex-dependent mechanisms, since the mentioned correlations are subject to gender disparity. Emerging evidence into skeletal interoception, places hypothalamus at the center of regulating bone homeostasis. Specifically, ascending skeletal interoception signals are processed in Arcuate nucleus and the descending signals stem from activity within Paraventricular nucleus. Prolactin receptors are abundant in the mentioned nucleuses of hypothalamus, and the elevated level of the hormone is a determinant of decreasing bone mineral density and risk of bone fractures. In the current study, we investigated the role of prolactin hormone in regulating the hypothalamic sympathetic tone, its relationship with bone homeostasis, fat metabolism and possible link to neuropeptide Y - a most potent orexigenic peptide synthesized by neurons in arcuate nucleus which project towards the paraventricular nucleus
OPTIMIZATION OF ROCKET AND SIGNATURE TECHNIQUES USING SYNTHETIC PATIENT DATA TO PREDICT TYPE 2 DIABETES
Get PDFThis thesis explores the application of Time Series Classification (TSC) methods, specifically ROCKET and Signature Method, for predicting Type 2 Diabetes from synthetic patient data. The project attempts to enhance the predictability of Diabetes diagnoses by analyzing medical observation data through advanced mathematical and programming techniques.
Initial TSC analysis using both ROCKET and the Signature Method with an initial set of 19 features yielded underwhelming yet statistically significant results, showing improved accuracy over random chance. Further analysis and experimentation led to a refined set of nine features, further improving predictive accuracy. The best predictive accuracy was achieved using a random forest classifier on the normalized interpolated observational data combined with signatures drawn from the same normalized set of interpolated data. This measure of 0.6189 compares to the score of 0.6095 resulting from direct random forest classification on the normalized set of interpolated data without including the signatures, and this difference was shown to be statistically significant with p-value of 5.29 × 10−6 by comparison of means.
Having confirmed the potential of these TSC methods to improve diagnostic predictions in the case of Type 2 Diabetes, the research identifies the need for further exploration in an attempt to reach clinically useful levels of predictive accuracy. The thesis concludes with many suggestions for future research that would build on these findings
Magnetic Order in Candidate Topological Materials
Get PDFIn recent years, the discovery of topologically nontrivial electronic states has precipitated a large body of work to identify, synthesize, and probe crystals with topological physics. These materials can display robust and technologically useful properties, such as dissipationless conducting surface states, that are "protected" by the topology of the electronic band structure. While early three dimensional topological insulators were time-reversal invariant systems, a variety of magnetic topological materials that break time-reversal symmetry have begun to emerge. Increasingly, research has focused on the influence of magnetic order on topological electronic states. Neutron scattering offers a direct experimental probe of the magnetic order and its constituent interactions. It is an essential technique for understanding magnetism in topological materials.
This thesis describes neutron scattering results on three compounds: axion insulator candidate Eu5In2Sb6, double Dirac candidate EuPd3S4, and Weyl candidate Mn3Ga. We experimentally resolve the magnetic order in Eu5In2Sb6 and EuPd3S4, exploring theoretically its consequences for the electronic properties. For Mn3Ga, we provide the first inelastic neutron scattering data, revealing the magnetic interactions mediating the antichiral antiferromagnetic order.
This work is the result of strong collaboration between experiment, synthesis, and theory. It offers insight into both the magnetic and electronic properties of candidate topological materials