71446 research outputs found
Sort by
Evolution of Signals and Sensory Systems
No full textSensory systems allow organisms to detect relevant signals in the environment. Signals and sensory systems also connect organisms to each other, forming the foundation for all communication in both interspecific and intraspecific interactions. In this thesis, I explore the interplay between signals and senses through an evolutionary lens. In chapter 1, I survey sensory receptors across all major groups of animals to uncover emerging evolutionary patterns. Building on this characterization of receptors throughout animal evolution, I then investigate species that exemplify how conserved and lineage-specific sensory receptors shape novel organismal adaptations. In chapter 2, I show that infrared radiation is an ancient pollination signal used by cycads to attract their beetle pollinators. I then elucidate the molecular basis of both the signal and the sense: heat production by the plants and infrared detection by the beetles. In chapter 3, I trace the evolutionary trajectory of the cephalopod-chemotactile receptors (CRs), from their ancestral role as neurotransmitter receptors to sensory receptors expressed in octopus and squid arms. Finally, in chapter 4, I study pheromone-producing organs across a butterfly radiation to reveal a tradeoff in the evolution of male signals: getting too attractive is costly. These studies span levels of biological organization from molecular mechanisms to the complexity and wonder of behaviors, revealing fundamental insights into the coding logic of animals’ sensory worlds.Biology, Organismic and Evolutionar
Universal Dynamics of Metrologically Useful Entanglement in Strongly Interacting, Disordered Many-Body Systems
No full textControlling the dynamics of targeted quantum correlations is a central goal across many disciplines of quantum science. For applications in nanoscale quantum sensing, nitrogen-vacancy (NV) centers in diamond have recently emerged as a leading platform due to their atom-like nature, exquisite magnetic sensitivity and well-developed coherent control techniques under ambient conditions. However, harnessing the entanglement structure required to improve this sensitivity beyond the standard quantum limit (SQL) from the native dipolar interactions between NV centers is challenging due to their strong positional disorder, three-dimensional geometry and low-fidelity readout.
Coupled tightly to proof of principle experimental demonstrations, this thesis provides a theoretical blueprint to realize practical, entanglement-enhanced quantum sensing in the solid-state via far-from-equilibrium dynamics of dense ensembles of NV centers in diamond. Our most fundamental contribution is to identify a universal mechanism exploiting the thermalization of long-wavelength spin textures to generate scalable spin squeezing in the absence of finite temperature symmetry breaking. We further develop a novel sensing protocol based on asymmetric time-reversal capable of rapidly breaking the SQL without high-fidelity readout. Challenging long-standing beliefs in the field, these results open the door to a new era of entanglement-enhanced sensing under ambient conditions, with applications ranging from nanoscale imaging of biological structures to covariance magnetometry of exotic quantum materials.Physic
New Paradigms in Social Choice
Get PDFSeveral current preference aggregation challenges — ranging from aligning large language models to summarizing civic discussions — closely resemble classical questions in social choice theory. Yet they often fall outside the scope of traditional frameworks: the outputs may be unconventional, individuals may express preferences over only a tiny fraction of alternatives, or real-world instances may exhibit much richer structure. This thesis bridges that gap by developing new theoretical frameworks, formal analyses, and algorithms tailored to these settings, offering principled approaches to collective decision-making in modern, complex environments.
Part I addresses AI alignment. We introduce an axiomatic framework for evaluating alignment methods and show that widely-used loss-minimization techniques violate some of the most fundamental principles of preference aggregation. We further demonstrate that aligning a single model faces inherent limitations, regardless of the algorithm used. To overcome this challenge, we propose using an ensemble of models that collectively capture a broader range of human preferences and provide both theoretical and empirical evidence for the effectiveness of this approach.
Part II focuses on preference elicitation in settings where individuals can feasibly provide only limited feedback across a large space of alternatives, an increasingly common restriction in contexts such as civic participation platforms. We design algorithms that elicit the right information for meaningful aggregation, with provable guarantees, and develop theoretical tools to characterize the fundamental trade-offs imposed by such informational constraints.
Part III studies liquid democracy, a flexible voting system in which individuals may delegate their votes to others. While much of the literature emphasizes worst-case failures, we propose a semi-random model that better captures realistic delegation behavior. Under mild assumptions, we show that liquid democracy avoids many of the previously-identified pitfalls. These results are further supported by real-world experiments in classroom and corporate settings, offering empirical evidence of the paradigm’s practical viability.Engineering and Applied Sciences - Computer Scienc
Distinguished bases in the wrapped Floer cohomology of tropical Lagrangian surfaces
Get PDFHomological mirror symmetry implies a correspondence between Lagrangian Floer chain
complexes and corresponding Hom spaces in the category of coherent sheaves. One notable
aspect of studying chain complexes and their homology groups is that the methods for
calculation and their properties can vary significantly. For example, while there are vast
studies of canonical bases of the cohomology rings on the algebraic side, the descriptions of
Lagrangian Floer cohomology rings often fail to give a distinguished basis.
In this paper, we present a model for tropical Lagrangians in (C^∗)^2 that gives rise to distinguished
bases in their wrapped Floer cohomology. The main ingredient is the “argument
constraint,” which imposes a nontrivial geometric restriction on holomorphic disks bounded
by these special Lagrangians. As a model example, we consider a 1-family of Lagrangians
that are generically non-exact. Under mirror symmetry, this will also give distinguished
bases of the ring of functions on P^1 minus 4 points.Mathematic
The 969th Field Artillery Battalion and the “Historical Approach” at the International Military Tribunal (sample chapter)
No full textThe 969th Field Artillery Battalion and the “Historical Approach” at the International Military Tribunal constitutes a chapter in the monograph entitled Service in the Shadow of Justice: The Legacy of the Black American Military Court Guards in the Nuremberg Military Tribunals. This chapter documents the earliest attempt to assign Black troops to duty in Nuremberg at the start of the International Military Tribunal in 1945. It includes content from an interview with Junius Charles Heard, a descendant of a member of the 969th Field Artillery Battalion. It also examines the advocacy of Lieutenant General George S. Patton, Jr. on behalf of Black troops. The fuller work demonstrates that the assignment of Black troops to security details at the historic Nuremberg Trials was both symbolic and significant in the Long Civil Rights Movement and within the activism surrounding the desegregation of the U.S. military. Dim perceptions on the performance of the U.S. Army’s Black troops (pejoratively termed “the Negro Problem”) during WWII and the continuation of Jim Crow policies in the European Theater were factors in the exclusion of these servicemen from earlier duty at the Trials (1945-1949). By 1946, Nuremberg had become a symbol for the strivings of American racial justice while the verdicts delivered at the International Military Tribunal precipitated calls for anti-lynching legislation. A confluence of events, including slowly staged advocacy work by the Black press and by antiracists from within the U.S. military, eventually brought Black troops into courtroom duty while the service window and stakes in the Nuremberg legacy waned. America was at its finest postwar display in the Palace of Justice while simultaneously revealing a tension between its democratic ideals and actions. The Black U.S. military court guards of Nuremberg are situated in this complex and historic legacy.Author's Origina
Models of Human Decision-Making for Planning Digital Interventions Using Reinforcement Learning
No full textDigital interventions support people in sustaining effort toward their long-term goals, yet the user-level data available to personalize these interventions is scarce and noisy. This dissertation studies how reinforcement learning (RL) systems can make high-quality decisions under these data limitations by modeling the human user.
The first part of the thesis focuses on what human model to use. Drawing from behavioral science, I formalize Behavior Model RL (BMRL), a two-agent framework in which the human is represented as a sequential decision-maker with potentially maladapted Markov Decision Process (MDP) parameters, and the AI intervenes on these parameters to help reach their goal. BMRL requires us to specify how the AI agent models the other human agent. In practice, we must simplify our human models to support online learning for the AI, even knowing that these assumptions do not fully reflect real users. For instance, I introduce a simple, computationally tractable model of a user's goal-directed behavior in digital settings. I also point out that, as a field, RL simplifies its agents' discount models; we use exponential discounting to model agents (including human ones), despite evidence from psychology that humans discount hyperbolically. I examine how such modeling choices affect an AI’s ability to learn policies online, and I develop tools to understand whether these simplified models can generalize to more complex human behaviors.
The second part of the thesis examines how to learn human models online. I study the bias-variance trade-offs that arise when personalizing to individuals with limited data, and propose algorithms that manage model complexity over time. One method learns how model complexity should evolve by transferring "kernel evolution"' trajectories from prior users to new users, enabling rapid and stable online model selection in Gaussian Process regression. Another method increases the size of the AI's state space model of the human as more data is collected.
Together, these contributions provide a computational foundation for embedding behavioral insights into human models so that we can plan digital interventions using RL. They illustrate that the right inductive biases can enable AI systems to plan effective, interpretable, and personalized support for behavior change.Engineering and Applied Sciences - Computer Scienc
Expanding the toolbox for deubiquitylase pharmacology
No full textUbiquitylation is a posttranslational modification that governs protein cellular fate. Balanced ubiquitin signaling is vital for regulating cell function, replication, and survival, and its dysregulation is implicated in various indications such as neurodegeneration, cancer, autoimmunity, and neurodevelopmental disorders. Ubiquitin is covalently attached to substrates in a stepwise manner by an E1, E2, E3 enzymatic cascade, and is removed by a class of isopeptidases called deubiquitylases (DUBs). DUBs can stabilize both oncogenic drivers and tumor suppressors in cancer. Additionally, both loss-of-function and gain-of-function DUB mutations can cause or drive disease pathologies. Therefore, targeting DUBs with small-molecule tools offers direct and indirect therapeutic approaches for disease intervention.
The work in this thesis expands the available chemical toolbox for the interrogation of DUB biology in healthy and disease states, and provides starting points for DUB-targeted therapeutic development. I focus on two DUBs, USP7 and USP48. The potential for USP7-targeted therapeutics in cancer via the regulation of the p53/MDM2 pathway is well-documented. More recently, USP7 has emerged as a critical regulator in neurodevelopment, as mutations in the USP7 gene were identified as causal for the rare neurodevelopmental disorder, Hao-Fountain syndrome (HAFOUS). Our interest in USP48 arose from recent studies by Dana-Farber colleagues that identified USP48 knockout as a novel sensitizer to hypomethylating agents in acute myeloid leukemia and potentially other cancer types.
In Chapter 2, I describe the discovery and rigorous mechanistic characterization of MS-8, a first-in-class small-molecule DUB activator. I demonstrate that MS-8 allosterically engages ubiquitin-specific protease 7 (USP7) and induces enzymatic activation, similar to the mechanism of auto-activation by the C-terminal tail of USP7. We assess the therapeutic potential of our activator in vitro and in cells against a panel of HAFOUS patient-derived USP7 variants and identify a subset of mutations sensitive to MS-8 driven activation. Additionally, we provide an initial structure-activity relationship for MS-8 and highlight viable exit vectors on the scaffold for the development of heterobifunctional DUB recruiters. In Chapter 3, I introduce a next generation covalent inhibitor for USP7. Using a structure-guided approach, we elaborate the reported noncovalent Compound 41 into a covalent USP7 inhibitor. Through a focused medicinal chemistry campaign, we optimize our covalent series and validate its useability as a cellular probe in p53-wildtype and p53-mutant cell lines. Lastly, in Chapter 4, I describe the identification and validation of first-in-class selective inhibitors of USP48. I performed a USP48-focused high throughput screen then triaged screening actives in a series of orthogonal assays and counter screens to credential 3 novel scaffolds. We demonstrate the chemical tractability of one of our hits, MD-156, to support further medicinal elaboration. In this chapter, I additionally explore USP48 intramolecular regulation by its C-terminal ubiquitin-like (UBL) domain and define the consequences of UBL domain deletion to USP48 enzymatic activity and substrate-recognition.
Ultimately this thesis provides a novel USP7 activator and a framework for future DUB activator discovery, as well as two inhibitors for USP7 and USP48 with pharmacological potential for the treatment of cancers. These agents are important tools for studying the detailed mechanism of pathologies of the DUBs in their respective diseases. Moreover, these compounds and associated knowledgebases set the stage for future DUB-focused biological discovery and targeted therapies.Chemical Biolog
Investigating the spatiotemporal control of lipopolysaccharide transport to the outer membrane in Escherichia coli
No full textThe Gram-negative cell envelope consists of an inner membrane (IM), an outer membrane (OM)
and a thin layer of peptidoglycan (PG) in between the two membranes. The IM has phospholipids
in its inner and outer leaflets, whereas the OM is asymmetric with phospholipids (PL) in the inner
leaflet and lipopolysaccharide (LPS) in the outer leaflet. The bacterial cell envelope is essential
for the cell, as it gives the bacteria its shape and acts as a protective barrier inhibiting the entry of
external antimicrobial factors such as antibiotics and phages. Many of the proteins involved in cell
envelope biogenesis are known, however it is less well understood how synthesis of the different
cell envelope components is coordinated.
Here we investigated the transport of LPS to the OM and how it is regulated during cell division.
First, we showed that fluorescent wheat germ agglutinin (WGA) binds specifically to N-acetylglucosamine (GlcNAc)-modified LPS (GlcNAcLPS) in the model organism E. coli MG1655. Previous
studies showed that WGA binds to GlcNAc, but this sugar is present in different molecules in the
cell envelope. The binding site for fluorescently labeled WGA (FL-WGA) on cells therefore remained
unclear. We showed that in intact cells, FL-WGA does not bind to PG as previously
thought but instead labels GlcNAcLPS. We used this discovery to develop an E. coli strain in which
transport of newly synthesized GlcNAcLPS to the OM could be tracked. Using this tool, we showed
that nascent LPS is inserted into the OM at dispersed locations in the cell cylinder during cell
elongation and at the division site during cell division. A similar pattern of labeling was previously
observed for protein insertion into the OM and for new PG synthesis, indicating that LPS transport
is likely to be coordinated with these processes.
While studying the effect of different cell division inhibitors on LPS transport at the division site,
we discovered that the division-specific PG synthesis inhibitor cephalexin blocks LPS transport at
midcell. Such a block was not observed when assembly of the division machinery (divisome) was
blocked in cephalexin treated cells by expression of the division inhibitor SulA. Thus, inhibition of
LPS transport at the division site in cephalexin treated cells, requires assembly of the divisome.
We hypothesized that PL is used to expand the OM at midcell when LPS transport is blocked by
cephalexin treatment. Accordingly, cephalexin treatment rendered cells sensitive to the detergent
sodium dodecyl sulfate (SDS) to which cells with an intact OM are normally resistant. These results
reveal that beta-lactam antibiotics like cephalexin not only affect PG synthesis but also disrupt
the permeability barrier of the OM. Additionally, these findings indicate that LPS transport
requires proper PG synthesis at the division site and that the two processes are likely to be coordinated
by a mechanism that remains to be elucidated.Biological and Biomedical Science
Rigorous Loving: Black Women, Black Feminism, and Friendship, 1970-1996
No full text"Rigorous Loving: Black Women, Black Feminism, and Friendship, 1970-1996" is an interdisciplinary project that explores the multifaceted and mostly overlooked significance of Black women’s friendships to Black women’s cultural productions within the late 20th century United States. Applying methods from Black women’s history, Black feminist literary studies, transnational women of color feminist studies, and more, I unearth and analyze theories of friendship evident in the archival material, published interviews, and literary work of prominent activists, writers, and poets such as Audre Lorde, June Jordan, Alice Walker, Barbara Smith, and Lucille Clifton.
I return to these notable Black women political and literary figures to uplift what, I argue, is a neglected aspect (and influence on) their work: friendships. Friendships were significant to these writers’ lives and their cultural productions in a multitude of ways. First, my dissertation, reveals how friendships were vital to the existence and survival of many of their cultural productions. Second, through examining friendship beyond romanticized, heteronormative, and de-politicized framings, I reveal how these Black women writers theorized friendship (including the care and the conflict) as essential to their Black feminist praxis and as a site of political possibility that defied the normative expectations of friendship and Black womanhood within the Anglo-American patriarchal family. My dissertation centers four different cultural forms: retreats, letters, anthologies, and poetry. Each chapter is organized around one cultural production through which I investigate how friendships were manifested, deepened, or tested.
Ultimately, through this research, I propose that friendship appeared in at least three ways across these women’s work: (1) as a site of political theorizing, organizing, and knowledge production; (2) as a site of creative possibility and epistemological transgressions; and (3) as a space of refuge and survival. By “space of refuge,” I mean a spatial imaginary that is quite literally a “retreat,” outside of the domain of normative visions of cis-heterosexual womanhood, especially for Black women, Black feminists, and Black working-class lesbian feminists in a world that perpetually threatened their existence.American Studie
Precision Medicine: Biomarkers of Genome Integrity in Guiding Better Lung Cancer Outcomes
No full textLung cancer remains the leading cause of cancer mortality, and standard treatments such as radiotherapy (RT) and chemotherapy act through DNA damage. Yet patients show substantial variability in both treatment response and side effects. Because DNA repair is central to maintaining genome integrity and differs across individuals and life stages, assessing genome integrity could help identify which patients will benefit most from therapy while minimizing harmful outcomes. My dissertation focuses on developing and applying genome-integrity biomarkers to better understand treatment response and prognosis in lung cancer. I focused on three complementary domains: functional DNA repair capacity measured by fluorescence multiplex host cell reactivation (FM-HCR), telomere length dynamics during and after RT, and germline genetic variation. Across this work, I established strategies to adapt functional DNA repair assays for population studies, demonstrating that they capture meaningful inter-individual differences. I showed that changes in telomere length over the course of treatment provide stronger signals for predicting side effects than single, static measurements. And by integrating genetic data with functional measures, I found that certain genetic variants influence repair capacity and contribute to differences in treatment toxicity and prognosis. Together, these studies highlight the value of linking functional and genomic measures of genome integrity. By bringing these approaches together, my work provides a framework for using genome-integrity biomarkers to guide more personalized RT decisions and improve long-term outcomes in lung cancer patients.Population Health Science