Dartmouth Institute for Health Policy and Clinical Practice
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Precision Without Invasion: The Path to Biopsy-Free Cervical Diagnostics
No full textThis study explores a non-invasive, biopsy-free method for diagnosing cervical cancer using two-photon excitation fluorescence imaging and AI-driven image analysis. Researchers trained a custom Cellpose model to automatically annotate single-cell metabolic data from optical sections of cervical tissue based on redox ratios derived from NADH and FAD autofluorescence. Results showed that the custom model outperformed generalist alternatives in identifying cellular structures and that cancerous and healthy tissues exhibit distinct redox ratio distributions and depth-dependent metabolic trends. These findings underscore the potential of metabolic imaging and automated analysis to reveal intra-lesion heterogeneity and improve diagnostic precision.https://digitalcommons.dartmouth.edu/wetterhahn_2025/1002/thumbnail.jp
Comparing approaches to transmitted light image analysis in mouse oocyte masses
No full textThis project explores a dataset of transmitted light microscopy images quantifying the impact of a knockout Moloney sarcoma oncogene (MOS) mutation in ovarian mouse models. MOS is highly expressed in oocytes undergoing meiotic division, and encodes a serine/threonine kinase protein which activates the MAP kinase cascade. Absence of MOS expression has been noted to coincide with loss of meiotic arrest, which impedes fertilization, as well as germline tumor growth. Oocytes were cultured from MOS-/- and wildtype mice, as well as wildtype oocytes activated with strontium chloride. Oocytes were cultured to develop masses and then imaged with transmitted light microscopy. Comparative analyses were performed between three analytical softwares—Cellpose, CellProfiler, and ImageJ—to determine the relative efficacy of these approaches in identifying mass boundaries, size, and abundance. ImageJ enables the most accurate identification of mass boundaries regardless of image preprocessing or quality. Cellpose is able to identify the boundaries of masses with similar accuracy to ImageJ in cells where masses and nuclei are of comparable size, but struggles to identify differentially-sized masses and introduces artifact measurements. CellProfiler analysis is performed through two modified pre-generated pipelines and through a custom pipeline; all three pipelines are able to preprocess and segment images based on value but perform poorly in the presence of stark value gradients, leading to under- or over-segmentation of mass boundaries. The necessity of pre-generating data on mass diameter to run CellProfiler decreases the accessibility of this approach due to the inherently large variation in mass size within this dataset.https://digitalcommons.dartmouth.edu/wetterhahn_2025/1004/thumbnail.jp
Does Bilingualism on Resumes Affect Callback Rates?
Full text linkI study the influence of bilingualism in Spanish on the likelihood of receiving a callback for female customer service positions in the Chicago area. Data are collected from sixteen unique resumes submitted to 131 different job postings in an audit study, with applicants differing in bilingual ability. Bilingualism in Spanish significantly in- creases the likelihood of a callback by 17.86%-25.4%, implying bilingualism is valued in customer service roles. This suggests that bilingualism in Spanish may increase job prospects. While previous research studies this using observational and survey data, I use an audit study design with resumes to obtain causal results. Future research should explore more occupations over a longer period to see how bilingualism affects other occupations in a sample more representative of the labor market
TerrainCraft: Automated Land-Cover–Driven Terrain Generation for Marine Robot Simulations
Full text linkFrom self-driving cars navigating city streets to all-terrain vehicles tackling rugged landscapes, recent leaps in robotic autonomy due to fast pace development in deep learning are reshaping how machines interact with the real world. However, autonomy in the aquatic environment is still limited, due to difficulty in testing and unavailability of realistic simulation environments.
In this project, we aim to create an automated system that simplifies the processes of creating synthetic datasets for marine robots navigation training tasks. We achieved this through a land cover map controlled terrain generation. Our goal is to provide an automatic terrain generation system that includes multiple terrain types, give users a certain level of customizability and reach a realistic level for simulation.
Currently, obtaining real-world datasets for marine robots is high-cost and difficult. Datasets that are currently in use are either hand captured by humans or specific types of robots, which will restrict the usability to limited sensor types. Additionally, the equipment used in the capturing process is expensive and subject to risk of damage. Finally, the time consuming nature of such tasks also limited the creation of large datasets.
To generate synthetic, but realistic datasets, we propose an approach that follows two steps: 1) generate the topology of the environment and 2) create a real 3D world asset that can be simulated with a realistic physics game engine. For generating the topology of the environment, we provide the environment topology generation in two modes: a) given an input map, we trained U-net model to output a classified land-cover map; b) without any map, for generating random terrains that are realistic, we propose a diffusion-model. The Diffusion-model will output a randomly generated map which is similar to the land-cover map. The user can use either map as input to generate a terrain.
For generating realistic 3D worlds, we propose a PCG system that takes as input the land-cover at the previous step and generates terrains in a game engine. We chose UE5 as our main tool given its realism, available in literature, and the availability of routines that can be used for PCG
On Losing Oneself: Reflections on a Performance Practice
No full textThis thesis is a reflection on a performance practice shaped by presence, process, and the unseen. Through the lens of three original works, (a)temporalities, TechniTerra, and What I Couldn’t Say Out Loud, I explore the act of performance as a devotional offering, a site of transcendence, and a method of attunement. I write from within: inside rehearsal, inside sensation, inside the unknowable. Each work serves as a record of inquiry, not asking “what can I make of this,” but “what begins to unfold when we tune ourselves to something larger?” In these pages, I share rehearsals that felt like portals, moments where sound arrived when I left, and vocal practices that led me beyond thought and into the wilderness.
This is a traceback, a reflection of a voice unfolding– intuitive, embodied, and in ongoing relationship with the sacred and the strange. The language here attempts to honor the process more than the product. What emerges is less a theory and more a way of being: a devotion to creating from the edge of knowing, and to performing as a way of remembering what we never fully forgot
Progress towards the asymmetric de novo synthesis of tetracyclic triterpenoids: cucurbitanes, lanostanes, and cardiotonic steroids
Full text linkThe complex molecular scaffolds of tetracyclic triterpenoid natural products continue to inspire novel chemical reactions. Steroid-based drugs have contributed significantly to human health in the past century, demonstrating a broad range of therapeutic applications including anti-viral, anti-inflammatory, and anti-cancer activities. However, the efficient and flexible synthesis of tetracyclic triterpenoids remains an unsolved problem. Despite numerous reports of medically relevant bioactivity associated with cucurbitanes, lanostanes, and cardenolides, exploration of their pharmaceutical promise has been limited by a lack of access to molecules bearing their requisite carbon frameworks. Prior to the initiation of my doctoral research, there were no reported syntheses of any cucurbitane natural product and only three reported syntheses of lanostanes. Our efforts to establish robust chemical methods to populate this pharmaceutically privileged chemical space has culminated in the following progress: (1) the first total synthesis of a cucurbitane natural product, octanorcucurbitacin B; (2) a novel cucurbitane-to-lanostane rearrangement affording an enantiomeric lanostane system; and (3) efforts towards the first asymmetric total synthesis of sarmentogenin, a cardenolide
MECHANISMS THAT CONTRIBUTE TO AGE-DEPENDENT SEGREGATION ERRORS IN DROSOPHILA OOCYTES
Full text linkMeiotic chromosome segregation errors in human oocytes are the leading cause of miscarriages and aneuploid pregnancies, and these errors increase dramatically as women age. Using Drosophila oocytes as a model system, this dissertation identifies the NAD⁺-dependent deacetylase Sirt1 as a key regulator of chromosome segregation and meiotic arm cohesion. Loss of Sirt1 activity during meiotic prophase leads to premature loss of arm cohesion and increased segregation errors in Drosophila oocytes. In addition, elevated acetylation of its substrate, histone H4K16, indicates that Sirt1 activity declines in oocytes during aging. Strikingly, dietary administration of the Sirt1 activator SRT1720 preserves Sirt1 deacetylase activity on oocyte chromosomes during aging and significantly suppresses age-dependent segregation errors.
In addition to describing an essential role for Sirt1 in the accurate segregation of meiotic chromosome segregation, this dissertation also identifies proteins that suffer oxidative damage during oocyte aging. A biochemical approach identified BubR1 as one of several proteins that sustain significant aging-induced oxidation. Moreover, functional analysis of flies harboring a mutation in the kinase domain of BubR1 supports the model that BubR1 kinase activity is required to promote meiotic cohesion. Together, these findings deepen our understanding of the molecular drivers of age-related meiotic errors and may inform novel intervention strategies to improve reproductive outcomes in aging oocytes
Multi-spectral paired-agent imaging for dynamic visualization and quantification of the PDL1 axis
No full textImmune checkpoint inhibitors (ICIs) have transformed the cancer treatment landscape, yet their clinical efficacy remains limited to a subset of patients. Existing biomarkers used to select patients for ICIs are imperfect predictors of therapeutic response and offer static snapshots of highly dynamic tumor-immune interactions. To address this limitation, this thesis develops and validates a novel technique – multi- spectral paired-agent imaging of receptors (mPAIR) – to quantify immune checkpoint proteins in vivo. Focusing on the PDL1 axis, this work integrates receptor-binding studies, molecular imaging, and optical engineering to develop a multiplexed in vivo imaging technique. First, a panel of targeted imaging agents and near-infrared fluorophores was systematically selected and optimized for mPAIR. Liquid and tumor-mimicking phantoms were used to validate fluorophore spectral distinction and diffusion dynamics, confirming multi-target quantification of PDL1, PD1, and CD80. In an in vivo syngeneic murine lymphoma model, receptor concentrations of PDL1, PD1, and CD80 calculated from mPAIR strongly correlated with quantitative flow cytometry-derived receptor counts, despite challenges associated with bound residual imaging agents. Collectively, these findings establish mPAIR as a promising tool for quantitative and real-time profiling of immune checkpoint availability in tumor models. Overall, this work lays the foundation for utilizing optical imaging biomarkers to improve patient selection and therapeutic monitoring for ICI therapies
How’s it growing? Tools for observing snow and sea ice in a changing Arctic Ocean
Full text linkSeptember Arctic sea ice extent has diminished by roughly 50% in the 45 years since satellite observations began. The Arctic Ocean may experience ice-free summers within the next decade, with implications for habitat, resource extraction, geopolitics, and local and global climate change. To predict how Arctic sea ice will change in the future, we need to understand its behavior in the present. In situ sea ice mass balance measurements (snow accumulation, ice growth, snow and ice surface melt, and bottom melt) are essential for studying the processes driving rapid changes in the ice pack, and for validating remote sensing measurements and climate models. Here, we evaluate sea ice mass balance observations from the 2019-2020 MOSAiC expedition in the central Arctic, highlighting significant changes in sea ice growth and melt processes over the past several decades. Our results indicate that snow depth and its heterogeneity are powerful controls on winter ice growth in the younger, thinner ice pack of the modern Arctic. Yet we lack the precise, spatially dense snow depth measurements needed to fully understand and model the role of snow in the sea ice system. We developed a distributed, autonomous snow depth observation system that is ~95% less expensive than existing systems to fill this gap. Finally, while this system is a leap forward in low-cost snow observation, budget and resource constraints continue to limit the scope of autonomous snow depth sampling efforts. We conducted a study to investigate how sample size and arrangement influence parameter estimation errors in order to determine efficient snow sampling strategies. We found that the current practice of using a single autonomous station to estimate mean snow depth produces estimation error on the order of ±0.10 m. Increasing the sample size to just 16 stations decreases estimation uncertainty for the mean to roughly ±0.02 m and enables standard deviation estimation to the same uncertainty. This uncertainty metric represents a ~50% improvement over using a single station and is adequate for most use-cases. Collectively, this thesis provides critical insight into processes dictating ice mass balance in the contemporary Arctic, and delivers a new toolkit for obtaining urgently needed observations of snow on Arctic sea ice
Biochemical and Structural Insights into the Yersinia Effector YopM and its Negative Regulation of the Pyrin Inflammasome
No full textBacteria utilize sophisticated secretion systems to inject effectors into host cells in order to facilitate their survival and replication in the host. Some pathogenic species of Gram-negative bacteria use a conserved contact-dependent T3SS to inject a wide array of effectors. While the effectors diverge in their structures, functions and cell-localization, the T3SS is well conserved. Several effectors discussed in this thesis target key host inflammasome responses. The focus of this work is how the Yersinia effector YopM inhibits the pyrin inflammasome. During Yersinia infection, two effectors, YopE and YopT inadvertently activate the pyrin inflammasome while targeting RhoA to avoid phagocytosis. Pyrin acts as a guard, sensing bacterial modifications to RhoA and assembles a caspase-1 inflammasome. When activated, pyrin is dephosphorylated and interacts with the inflammasome adaptor ASC through homotypic PYD-PYD interactions. However, YopM counteracts this YopE/T-triggered assembly of the pyrin inflammasome by hijacking host kinases RSK and PRK to phosphorylate pyrin, locking it in an inactive state. Here, I determined that YopM specifically binds to the N-terminal PYD of human pyrin using x-ray crystallography. I identified key residues in both YopM and the hPYD involved in their interactions. I also show that mutation of key residues on YopM abolishes its binding to the hPYD and inhibition of the human pyrin inflammasome in THP-1 cells. Interestingly, YopM does not bind to the mouse PYD and seems to target the mouse pyrin inflammasome using a different pathway. The YopM-hPYD complex presented here is the first, to my knowledge, of a virulence factor targeting a member of the DDF of proteins. I expand on current knowledge of protein-protein interactions of the PYD subfamily by identifying a role for electrostatic patches and key residues discussed herein. The complex structure identifies the central LRRs 5-6 on YopM as the key binding site for hPYD. I also provide insights on YopM by solving the structure of the 13-LRR YopMPestA isoform. Additional biochemical analyses of YopMPestA determined that YopM is monomeric under neutral pH conditions, and that low pH acts as a conformational switch, triggering tetramer formation