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Heterozygous mutations cause genetic instability in a yeast model of cancer evolution
No full textGenetic instability, a heritable increase in the mutation rate, accelerates evolutionary adaptation1 and is widespread in cancer2,3. In mammals, instability can arise from damaging both copies of genes involved in DNA metabolism and cell cycle regulation4 or from inactivating one copy of a gene whose product is present in limiting amounts (haploinsufficiency5), but determining the relative importance of these two mechanisms is difficult. In E. coli6, applying repeated, strong selection enriches for genetic instability. We used this approach to evolve genetic instability in diploid cells of the budding yeast, Saccharomyces cerevisiae and isolated clones with increased rates of point mutation, mitotic recombination, and chromosome loss. We identified candidate, heterozygous, instability-causing mutations and engineering these mutations, as heterozygotes, into the ancestral diploid strain caused genetic instability. Mutations that inactivate one copy of haploinsufficient genes are more common than those that dominantly alter the function of the mutated gene copy. The mutated genes are enriched for genes functioning in transport, protein quality control, and DNA metabolism, and reveal new targets for genetic instability7-11, including essential genes. Although only a minority (10 out of 57 genes with orthologs or close homologs) of the targets we identified have homologous human genes implicated in cancer2, the remainder are candidates to contribute to human genetic instability. To test this hypothesis, we inactivated six examples in a near haploid human cell line: five of these mutations increased instability. We conclude that single genetic events cause genetic instability in diploid yeast cells, and propose that similar, heterozygous mutations in mammalian homologs initiate genetic instability in cancer.Molecular and Cellular BiologyAccepted Manuscrip
SHARD: Spatio-Hierarchical Architectures for RNA Data
No full textWe present a novel hierarchical transformer architecture for integrating morphological features with gene expression data in spatial single-cell analysis. Unlike existing approaches that either process bulk tissue regions or analyze modalities separately, our framework is the first to directly pair individual segmented cell images with their corresponding gene expression vectors through a cross-modal attention mechanism and incorporate information from neighboring cells. Our framework processes both individual cells and their microenvironments (niches) through a multimodal, multi-scale approach that preserves cell-level granularity while capturing tissue context.
We constructed a system with three components: a cell image encoder for morphological features, a gene expression encoder based on the pre-trained scGPT model, and a cross-modal attention transformer that aligns these data types. Together, this model is trained on 17.5 million cells from 20 tissue samples using the 10X Xenium platform, applying masked gene expression modeling with negative binomial distribution loss.
As a result, it improves over existing methods, with superior clustering results, with higher silhouette scores (0.49 vs. 0.32) and cell classification performance comparable to cutting-edge methods.
This thesis establishes a foundation for cell analysis that connects segmented morphological data and gene expression while representing tissue context at multiple scales. These embeddings create more generalizable understandings of cell function and have applications across disease classification, cell type identification, and spatial context analysis.Computer Scienc
Essays in Finance, Technology, and Behavior
No full textThis dissertation consists of three essays that study how patterns in human behavior inform models of finance and technology. The first essay develops methods to measure economic representations from language, and uses these representations to study how the market values firms. It finds that firms can be misvalued when they are misperceived, including during waves of investor attention to new technologies. The second essay, co-authored with Keyon Vafa, builds a framework to evaluate lookahead bias in pretrained language models, and finds evidence of the bias in applications to finance and political economy. It describes how to prevent lookahead bias by using time-indexed language models in forecasting analyses. The third essay, co-authored with Johnny Tang, analyzes how partisanship relates to economic beliefs, and finds partisan differences in optimism, attention to economic topics, and interpretation of economic shocks. It discusses how these differences in stated beliefs can help to interpret partisan differences in economic decisions.Economic
Death and Destruction at the Bridal Shop
No full textThe work is set in New Orleans in the apocalyptic conditions after Hurricane Katrina and is best characterized as commercially-accessible literary fiction with set in an era of climate change and explores deep themes of love, loss and meaning in a humorous way. It is almost finished and is currently at 137,560 words. It is told from the perspective of multiple narrators as I found that the best way to both approximate life as we experience it and to capture the struggles of a community.
My book tells the story of Chrissy, a drug-addicted stripper, who has a wild and unlikely spiritual experience and struggles to retain that miraculous sense of purpose in her life but, nevertheless, ends up in the suburbs of New Orleans married to an orthodontist. Chrissy's search for meaning plays out against the backdrop of hurricane winds and driving rain and flood waters drowning the world, forcing ordinary people to find meaning in the most difficult of circumstances
Critical quantum liquids and the cuprate high temperature superconductors
No full textPhysicsAuthor's Origina
Different Ways of Returning the Gaze: Indian Travel Writers on Victorian and Edwardian England
No full textThis thesis examines writings about English society and culture by Indian travel writers during the Victorian and Edwardian periods, focusing on two key texts: Journal of a Residence of Two Years and a Half in Great Britain (1841) by Parsi cousins Jehangeer Nowrojee and Hirjeebhoy Merwanjee, and the article series “The Heart of Things” by Olive Christian Malvery, published in Pearson’s Magazine (1904–1905). The analysis explores how these Indian writers, during their travels in London, engaged with the society they encountered, and compares their perspectives to the European Orientalist gaze. It investigates how factors such as gender and racial identity shaped their observations and how these influenced their ability to ‘return the gaze’ towards imperialist travelers to the East. The thesis argues that although all three writers were Indian by birth, their confidence in their cultural identities varied significantly, as did their gendered experiences, influencing their critiques and reflections on British society. Both Nowrojee and Merwanjee’s journal and Malvery’s articles reveal the complexities of navigating identity within the British Empire while observing and, at times, challenging or reinforcing Orientalist narratives. This work highlights how Indian voices actively engaged with the dominant cultural forces of Victorian and Edwardian England, offering nuanced insights into cross-cultural encounters that enrich our understanding of this period
Social Response to Mindfulness in Azerbaijan: The Impact of Skepticism and Stigma on Interest in and Willingness to Practice Mindfulness Among Azerbaijani Adults.
No full textMindfulness practices are known for their effectiveness in improving people’s subjective well-being on both physiological and psychological levels. Research on this topic is gaining popularity. The psychological research in Azerbaijan, on the other hand, is not well-developed, and many gaps in existing research need to be addressed to gain a better understanding of the psychological mechanisms of this culture. To address the question of whether skepticism and stigma around psychology and mental health present in Azerbaijan would serve as a barrier to people’s perceptions of mindfulness practices, I conducted a pilot study that aimed at measuring Azerbaijani adults’ interest in and willingness to practice mindfulness. I examined whether informational triggers regarding physical versus mental health benefits of mindfulness would influence their responses. I hypothesized that because of skepticism and stigmatization that create negative beliefs and expectations around psychology and mental health, with the presence of informational trigger in the context of mental health, there would be a barrier to being open-minded and willing to participate in mindfulness-related activities and practices, despite them being beneficial. The responses of 91 participants were analyzed by performing a one-way ANOVA. The hypothesis was supported by the results of the study that suggest that people in the “mental health” information group demonstrated lower levels of interest in and willingness to practice mindfulness. Implications, limitations, and future directions arising from these findings are also discussed in this paper
Mechanical Controllers for Robotic Grippers
No full textThis thesis explores the definition, design, prototyping, testing, and analysis of a mechanical controller, which is a mechanical system designed to control a robotic gripper without the use of digital or electrical systems. The intention of developing such a system is to either 1) act in parallel with conventional digital systems that coordinate the movements of a robotic gripper to provide complementary control and safety features, or 2) serve as an alternative method for manipulation in scenarios where conventional systems may be limited. This task was accomplished through the development of a ”Force-Activated Clutch” that is able to simultaneously measure the forces acting on a gripper, monitor the gripper’s position, and manipulate the gripper’s degrees of freedom to achieve a desired movement. Two complete prototypes were developed over the course of this thesis, with the second prototype serving as the basis for all testing and verification. To accompany the second prototype, a computational optimization structure was built in MATLAB to constrain and define the mechanical system’s dimensions by processing 413,343 possible designs. In the end, the prototype did not meet the technical specifications; however, the theoretical design and the exercise of the mechanism in testing affirm the viability of a mechanical controller in robotic grippers.Mechanical Engineering S