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Measuring and Manipulating the Mechanics of Epithelial Cells and Tissues
Get PDFMechanical forces are largely responsible for shaping sheets of epithelial cells into tissues and organs. During epithelial morphogenesis, cells dynamically tune their mechanical forces to locally promote or resist shape changes. Our current understanding of how these mechanical forces coordinate and drive tissue shape changes is lacking. In particular, it is not well understood why some epithelial cell sheets remodel and flow like fluids, while others stretch and bend like elastic solids, or at what length scale mechanical behaviors of individual cells give rise to tissue-level behaviors. In this work, I develop a framework to analyze tissue structure and dynamics through quantification of cell packings and protein localization patterns. I then combine this framework with optogenetic perturbations and nanoengineering techniques to measure and manipulate the mechanical properties and forces of cultured cells with high spatiotemporal precision.
In chapter 2, I address these challenges by studying how cells respond to different mechanical cues in the fruit fly, Drosophila melanogaster, during early development. Specifically, I quantify global system disorder arising from internal and external stresses by using order parameters that describe the area and stretch distortion between the center of cells. Using these order parameters, we find that structural disorder is synchronized with internal and external stresses imposed on the germband. Furthermore, we dissect the contribution of each stress on the embryo using different mutants that inhibit one or more of these stresses.
In chapter 3, I refine this analysis to identify the cellular and supracellular myosin networks that tune cellular mechanics and forces, connect them to local cell packings, and determine their overall impact on tissue movement. Using cell geometries to infer mechanical properties, I analyze the cell packings during the active processes of fluid-like germband extension (GBE) and the solid-like bending during ventral furrow formation (VFF). We find that the local cell packings match the global cell packings in the ventral furrow, while the local cell packings match the regional behavior in the germband when averaging over N = 3 nearest neighbors.
In chapter 4, I investigate how the mechanical forces of epithelial tissue sheets can be altered using an in vitro culture system. Using optogenetic tools, I manipulate myosin activity in cultured cells and quantify the induced forces by measuring the deflection of an array of micropillars on which the tissue is grown. I show that the traction forces resulting from activation of the optogenetic tool are increased up to 3-fold higher than baseline during activation and decrease to near-baseline levels 30 minutes after activation is stopped.
These studies improve our understanding of the mechanisms and mechanics underlying cellular self-organization and clarify how perturbations of these mechanisms can lead to disease states like congenital anomalies and cancer
Will AI Revolutionize Transport?
No full textArtificial intelligence is revolutionizing the way we work, the way we stay informed, the way we interact with others. It is also set to transform the way we move around in cities. In the air, electric vertical take-off and landing vehicles – eVTOLs – (or air taxis) are already being tested, promising to take passengers from one end to a city to another at record speeds, while relieving traffic. On the ground, self-driving cars have been making the news for several years now, holding up the hope of safer, greener journeys in major cities around the world. This transport revolution also raises several challenges: How can we guarantee passengers’ safety? What new liability issues arise from the widespread use of autonomous vehicles? Will these new modes of transportation really help cut down pollution and green-house gases? Will they improve urban transport and the quality of our lives? To help us navigate these questions, we are honored to welcome to Vis A Vis two experts who are mobilizing AI in support of the transport revolution
At the Limits of Catalan: Alguerese as a Contact Language
No full textThe Alguerese dialect of Catalan, spoken since the 14th century in the Sardinian town of Alghero, presents a unique problem within the subfield of Catalan dialectology: namely, that its idiosyncrasies cannot be explained by comparing it solely to other Catalan dialects. Rather, Alguerese is better understood as a contact language situated between general Catalan, Logudorese Sardinian, and Sassarese. Building on prior work which considers the phonology, lexicon, and semantics of Alguerese from a contact perspective, this thesis is the first work which so considers the grammar. Relying on descriptive grammars of the dialect by Palomba (1906) and Pais (1970), this thesis proposes novel syntactic analyses of Alguerese polar questions and possessive noun phrases, as well as novel morphological analyses of the past perfective, imperfect subjunctive, and adjective iteration in order to conclude that the grammar of Alguerese demonstrates evidence of contact between Catalan and Sardinian.
Keywords: Lingustics, Alguerese, Alghero, Catalan, Sardinian, Sassarese, Romance Lingustics, Dialectology, Sardini
GRID3 COD - Health Facilities v5.0
No full textThe GRID3 COD - Health Facilities v5.0 dataset consists of health facility points with name, location, health zone, and health area, among other attributes, for fifteen provinces in the Democratic Republic of the Congo (COD).
Province group 1: Haut-Katanga, Kasaï, Kasaï-Oriental, Kinshasa, and Lomami
Province group 2: Haut-Lomami and Tanganyika
Province group 3: Ituri and Kwilu
Province group 4: Maniema
Province group 5: Kasaï-Central
Province group 6: Tshopo and Mongala
Province group 7: Sankuru
Province group 8: Kongo-Central
This operational dataset has not been fully validated by government officials or ministries.
This current version supersedes the GRID3 COD - Health Facilities v4.0 ( https://doi.org/10.7916/szwf-gb16 ). The following changes were made:
Updated data for Haut-Lomami Province
Added data Kongo-Central Province
Keywords: Health Facilitie
GRID3 COD - Health Zones v5.0
No full textThe GRID3 COD - Health Zones v5.0 dataset consists of health zone boundaries with name, location, and other related attributes for fifteen provinces in the Democratic Republic of the Congo (COD).
Province group 1: Haut-Katanga, Kasaï, Kasaï-Oriental, Kinshasa, and Lomami
Province group 2: Haut-Lomami and Tanganyika
Province group 3: Ituri and Kwilu
Province group 4: Maniema
Province group 5: Kasaï-Central
Province group 6: Tshopo and Mongala
Province group 7: Sankuru
Province group 8: Kongo-Central
This operational dataset has not been fully validated by government officials or ministries.
This current version supersedes the GRID3 COD - Health Zones v4.0 ( https://doi.org/10.7916/d8rn-6e24 ). The following changes were made:
Updated data for Haut-Lomami Province
Added data Kongo-Central Province
Keywords: Health Zone
“I’m Already Channeled Out by the World, Lemme Go Ahead and Get Drinking”: Sex Offender Registration and Notification Policies as Social Determinants of Behavioral Health
No full textAs of 2017, there were approximately 861,000 people in the U.S. required to register under sexual offender registration and notification policies. While evidence indicates that these policies do not deter sexual offending or prevent recidivism, these policies do have significant effects on the wellbeing of registrants and their communities. Registrants face numerous policy and legal proscriptions, such as residency restrictions that prohibit them from living in proximity to schools or public spaces, exclusion from public housing and shelters, and ineligibility for federal funds directed towards reentry, vocational, or social services. Moreover, they experience intense stigma and alienation, which often manifest as abandonment by social networks, exclusion from community spaces, and overt discrimination and harassment.
Many of the severely destabilizing collateral consequences of sex offender registration policies are also known risk factors for substance use. These policies and restrictions may therefore create or exacerbate a substance use risk environment and increase the likelihood of substance-use-related harms, including interpersonal harms. However, no public health research has directly examined relationships between sex offender registration policies and substance use related harms. This dissertation identifies and addresses this gap in knowledge through a rapid review of the collateral consequences literature, followed by studies based on 44 qualitative interviews with people required to register in Philadelphia and the 20 qualitative interviews with professional stakeholders who work with them.
The rapid review yielded 42 peer reviewed studies and governmental reports documenting the collateral consequences of sex offender registration and notification policies. Consequences typically fell into the categories of housing, employment, education, relationships, mental health, criminal justice, stigma, and safety. Housing was the most frequently reported barrier, closely followed by employment and stigma. Only one study alluded to substance use, and no studies focused their attention on substance use related harms. Most studies were published in criminal justice and/or forensic psychology journals, and no literature was published in public health journals.
Six key themes emerged from 20 qualitative semi-structured interviews with criminal legal, substance use, and forensic stakeholders who work with people required to register in Philadelphia. These themes described how 1) “sex offender” is an extremely stigmatized and villainized identity, 2 & 3) how sex offender registration related restrictions transform the social and material context of reentry, 4) how both the formal restrictions and the labeling have detrimental impacts on mental health and self-concept, 5) how these material and psychosocial consequences of SORN increase substance use risk and restrict access to court-referred drug treatment, and 6) how the overall landscape has dangerous and destructive implications, especially for overdose risk.
Forty-four interviews with adult men required to register in Philadelphia yielded similar themes that broadly illustrated the challenging reentry landscape faced by people required to register, as well as the impacts of sex offender registration policies on health and wellbeing. These themes documented how 1) sex offender registration policies enact formal barriers—such as residency restrictions--that cultivate a restricted reentry landscape, 2) how registration policies and the sex offender label have wide ranging and significant interpersonal effects, 3) how both the formal and informal barriers impact the mental health of people required to register, and 4) how all of these consequences impact substance use related harms.
Results suggest that sex offender registration and notification laws operate as social determinants of poor health for registrants and are previously unstudied collateral consequences of sex offender criminalization. These findings provide evidence for social service providers, funders, policy advocates, and officials on the need to reform harmful and ineffective policies and improve access to treatment services for people required to register
Horror as Multimedia Genre
No full textNew music, the horror film genre, and science fiction have a lot in common. This relationship has been cultivated and explored by many artists in the last seventy years. The horror boom of the 1980s introduced audiences to the music of modernists such as Ligeti, Penderecki, and Takemitsu, resulting in the popular notion that “contemporary music sounds like horror music.” This phenomenon led me to explore how and why sounds may make us experience fear, uneasiness, and thrill, triggering emotional responses.
In the past seven years, I have written pieces exploring this fascination: Yuggoth (2018), The Final Girl (2018), on the other side (2018), Zansei (2020), Restless (2022), and Polka is a Czech Dance (2023). What I discovered through this artistic research is that the audiovisual works inspired by horror often dealt with collective fears and social taboos about femininity, body, and otherness.
Film theoreticians have been very productive in the past fifteen years in providing feminist, queer, black study and postcolonial analyses of countless films belonging to the horror genre (Lerner 2010; Doherty 2015; Hawkins 2020; Paszkiewicz and Rusnak 2020; Lowenstein 2022; McCollum and Clarke 2022; Creed 2023). However, not much has been written from a similar perspective in music, especially audiovisual compositions. Most scholars focus on the relationship between sound and image (Cook 1998; Cohen 2011; Chion 2019), whether in film or concert music; however, the research often omits a broader cultural and sociological context.
My intention with this dissertation is to find a new approach to a cultural and socio-political analysis of multimedia works relating to themes of horror and otherness. I will examine the works of two composers who have been practicing engaged and relational (Lehmann 2015) music: Jennifer Walshe and Natacha Diels, and their respective pieces, AN GLÉACHT (2015) and Second Nightmare, for KIKU (2013). I argue that the sonic and visual spheres in these works cannot be separated and, along with musical analysis, can be fruitfully examined through a lens of film theory, psychology in film and music, and the overall cultural context. This dissertation aims to go beyond traditional sound and musical analysis methods to address the rarely investigated horror-inspired works in art music
From pole to shoreline: constraining mantle structure and flow to understand past sea-level change
No full textAccurately predicting the magnitude, timing, and spatial distribution of sea-level change over the coming centuries is crucial for understanding its impact on coastal communities around the world. As the climate continues to warm, efforts to model and predict the response of Earth’s ice sheets to climate warming requires deep knowledge of how ice sheets and sea level interact with the solid Earth. Reconstructing sea level during past warm periods can provide unique constraints on ice sheet processes during warming but requires the correction of paleo shorelines for solid Earth deformation.
Chapters 2 and 3 of this thesis focus on reconstructing sea level during Pliocene warm periods from paleo shorelines by understanding their geomorphology and deformation history. The solid Earth also directly affects ice sheets since it provides important boundary conditions (e.g., heat flow) and feedback mechanisms (e.g., glacial isostatic adjustment). Chapter 4 of this thesis provides a new model of seismic attenuation below Antarctica, which is an important constraint for temperature and viscosity that govern the state of the Antarctic mantle.
In Chapter 2, I present an estimate of early Pliocene (~5 Ma) global mean sea level inferred from three paleo shorelines in Patagonian Argentina. Despite their similar age (~5 Ma), these shorelines are observed today at elevations that vary by >50 m. They archive not only sea level millions of years in the past but also dynamic changes in Earth’s topography arising from glacial isostatic adjustment and thermally driven mantle convection. We model and correct for both processes and infer that global mean sea level during the early Pliocene peaked at 17.5 6.4 m (1). This implies significant sectors of West Antarctica and parts of East Antarctica were likely ice free during this time, a constraint which ice sheet models can leverage to improve the parameterization of ice sheet instability mechanisms. Our simulations further elucidate patterns of mantle flow through the Patagonian slab window.
In Chapter 3, I apply a similar approach, expanding to a global dataset of ten wave cut escarpments that formed during mid-Pliocene times (~3 Ma). In addition to better constraining -mid-Pliocene sea level using direct inferences from paleo shorelines corrected for geodynamic deformation, this study provides an observational dataset for benchmarking convection models. We include Pliocene scarps from the US East Coast, Nome (Alaska), De Hoop (South Africa), Mahafaly (Madagascar), Kongo Central (DRC), Benghazi (Libya), Al Wusta (Oman), Socotra (Yemen), Darling (Australia), and Roe Plain (Australia), constrain their elevations with high-resolution remote sensing, and correct for talus deposition on the surface. This reveals short wavelength patterns of topographic change, which we compare against geodynamic predictions.
Our best estimate of mid-Pliocene global mean sea level, after correcting for paleo shoreline deformation, comes from De Hoop, South Africa from which we use to infer a peak GMSL of 11.6 ± 5.2 m (1). This estimate is lower than our early Pliocene inference, which is in line with cooling over the course of the Pliocene and provides further constraints on Antarctic ice sheet change. Lastly, our data-model comparison informs future model development and highlights the need for robust parameterization of compositional and thermal anomalies in the mantle.
The final chapter aims to constrain lateral variations in attenuation in the Antarctic upper mantle. Attenuation is a critical geophysical observable that informs inferences of mantle properties, such as temperature and viscosity, from seismic tomography models, enabling better parameterization of glacial isostatic adjustment, which can stabilize or slow ice sheet retreat. Rock mechanics experiments have characterized the anelastic processes that drive a nonlinear relationship between slow seismic waves speeds and high mantle temperatures. This relationship includes 7 free parameters that can be constrained using various geophysical constraints. Here we use full wavefield simulations and waveform amplitude measurements to constraint these parameters. This results in a new high-resolution 3-D upper mantle attenuation model computed using seismic wave speeds and the laboratory-based anelastic parameterization. The preferred model reduces the total amplitude misfit relative to a 1-D reference model by 13.1% and 0.4% on the 25 – 60 and 50 – 150 second period bands, respectively.
From pole to shoreline, this thesis connects topographic change driven by slab window mantle flow beneath Argentina to millions-years old escarpments around the world to ice sheet-ice shelf collapse processes in Antarctica and the mantle properties underneath. The results highlight the important role that the mantle below coastlines and ice sheets plays in improving our understanding of past, present, and future ice sheet variability and sea-level change
Hydrodynamic limits and fluctuations for interacting particle systems
No full textIn this thesis, we study the limiting behavior of several different models in the KPZ universality class.
In Chapters 1 and 2, we study the hydrodynamic limits of the -PNG model and the inhomogeneous stochastic six-vertex model with periodic weights using soft techniques. We show that the height functions of both models converge almost surely to a deterministic limit shape. The key element of the proofs is the construction of colored versions of both models, which allows us to apply the superadditive ergodic theorem. Along the way, we also construct the stationary -PNG model and prove a version of Burke's theorem for it.
In Chapter 3, we consider the stochastic six-vertex model with step initial conditions and a single second-class particle at the origin. We show almost sure convergence of the speed of the second-class particle to a random limit. This allows us to define the stochastic six-vertex model speed process, whose law we show to be ergodic and stationary for the dynamics of the multi-class stochastic six-vertex process. The proof requires the development of precise bounds on the fluctuations of the height function of the stochastic six-vertex model around its limit shape using methods from integrable probability. As part of the proof, we also obtain a novel geometric stochastic domination result that states that a second-class particle to the right of any number of third-class particles will at any fixed time be overtaken by at most a geometric number of third-class particles.
In Chapters 4 and 5, we show that under a certain moderate deviation scaling, the multiplicative-noise stochastic heat equation describes the fluctuations of the quenched density of two different models of diffusion in a time-dependent random environment. The first model is the motion of a particle under a continuum random environment whose distribution is given by the Howitt-Warren flow. The second model is a 1D nearest-neighbor random walk in a space-time random environment. The proofs rely on certain Girsanov transforms and showing that the quenched density solves a prelimiting SPDE that resembles the stochastic heat equation. For the random walk model, we also show that independent noise is generated in the limit, in the sense that the prelimiting noise field does not converge to the driving noise of the limiting SPDE
Investigating the contributions of eIF3 subunits to translation initiation
No full textThe transfer of genetic information is a necessity for all life on earth. The final step in this information flow is the translation of messenger RNA (mRNA) into protein by the ribosome. The molecular machinery responsible for translation includes the ribosome itself and a suite of factors responsible for getting the ribosome onto the mRNA at the correct time in a process called translation initiation. In addition to correct timing, translation initiation must also both be highly accurate and begin at the correct location (called the start codon), otherwise the incorrect protein product will be made.
This process involves several factors across all domains of life. In eukaryotes, these factors are called eukaryotic initiation factors (eIFs). There are over a dozen eIFs that are all required for the process of translation initiation. The primary focus of this thesis is on the molecular mechanisms used by one of these factors, a protein complex called eIF3. However, because eIF3 makes extensive functional and/or physical interactions with other eIFs and functions throughout many of the mechanistic steps of translation initiation, the insights gained into eIF3 function inform the understanding of the process of translation initiation broadly.
Generally, when studying molecular mechanism, it is often necessary and always desired to have the most control of the system under study as possible. In the case of eIF3, a large fraction of our knowledge about its function over the previous decades has come from in vivo genetic or cell-extract-based studies, which inherently lack precise control over components. While these studies have provided immense information regarding the impact of eIF3 across translation initiation and are the foundation for all future work, they lack information regarding the molecular mechanisms eIF3 employs.
Therefore, to develop a system capable of interrogating such mechanisms, Chapter 2 of this thesis presents a recombinantly reconstituted eIF3 complex that is functional in vitro and is used as a basis for site-specific fluorophore labeling of an individual eIF3 subunit. This biochemically active, reconstituted eIF3 is used throughout the rest of the thesis as it allows for enhanced control over the composition and identity of the eIF3 species under investigation.
In Chapter 3, the mRNA-binding activity of eIF3 is explored. The mRNA-binding activity ascribed to eIF3 is shown to be largely driven by a single eIF3 subunit, with the other subunits modulating this activity. Specifically, the largest eIF3 subunit, eIF3a, is shown to be the primary driver of mRNA-binding by eIF3 and the interactions of other subunits are shown to alter the observed binding. Following up on the study of mRNA-binding by individual eIF3 subunits, Chapter 4 expands to the study of eIF3 subunits and their coordination in additional biochemical activities, including the ability to bind to the ribosome itself. Lastly, the involvement of eIF3 in the attachment of mRNA to the ribosome is investigated. Specifically, Chapter 5 investigates the role of eIF3 in the process of loading the mRNA into the ribosome, a process that necessitates the handoff of the mRNA from the eIFs responsible for initial recognition of the mRNA to the ribosome.
Collectively, this thesis establishes a toolkit for studying the mechanistic roles of individual eIF3 subunits throughout translation initiation and uses this toolkit to describe how a single factor can accomplish such a wide range of biochemical activities