VictorJuiz/thesis huggingface dataset:
Molecular dynamics of supercritical fluids

Supercritical fluids have received renewed interest in the past few decades because of their industrial applications. Underlying many of these applications is the high tunability of the fluid properties in the near-critical region, which is not captured by the widely held notion of the supercritical state as a single broad continuum. In fact, recent works show that the supercritical region can be divided into liquid-like and gas-like states based on thermodynamic and transport properties with a rapid crossover at the Widom line. However, the picture is less clear when it comes to the microscopic dynamics due to a lack of experimental data and physical understanding of the molecular-scale dynamics in the supercritical state. This dissertation focuses on this problem and contains two main parts. In the first part, a combination of inelastic X-ray scattering measurements and molecular dynamics (MD) simulations is used to study supercritical water. The results show that, contrary to commonly used models, there exist two components in the intermolecular dynamics, and it is the ratio between them that changes rapidly at the Widom line and drives the liquid-like to gas-like transition. In the second part, three additional systems—silicon, tellurium, and the Lennard-Jones fluid—are investigated via MD simulations, and the two-component behavior is found to be universal among these systems. The fraction of the liquid-like component is quantified and found to correlate with the degree of intermolecular bonding. The consequences of the two-component phenomenon for modeling supercritical fluid properties will be discussed

Keywords: Physics.
Advisor: Doniach S.
Hastings Jerome
Reis David A.
The molecular forces shaping enzyme function and evolution : from hydrogen bonds to enzyme temperature adaptation

For billions of years, organisms and their enzymes have been evolving and adapting in response to selection pressures and opportunities presented by their environments. The mechanisms that underly enzyme adaptation are fundamental to our understanding of how enzymes work and the process of molecular evolution. Enzyme adaptation occurs through changes in the molecular interactions that specify enzyme structure and function. In particular, hydrogen bonds are central to how enzymes have evolved and are ubiquitous in enzyme structures, where they are often found in extended networks. Given the ubiquity and importance of hydrogen bonds, this dissertation seeks to understand the physical principles that govern hydrogen bond structure and energetics and their contribution to enzyme function and adaptation. I first define the physical principles that determine hydrogen bond lengths and energies. I then investigate the extent that hydrogen bonds in networks are coupled, structurally an energetically, to one another, improving our understanding of hydrogen bonds and the local and collective structural dynamics that exist within proteins and providing quantitative benchmarks for the design of hydrogen bonds and their networks. Second, to address the interplay between hydrogen bonds and other molecular interactions and enzyme evolution, I investigated enzyme temperature adaptation, as temperature profoundly influences enzyme stabilities and activities, providing a direct link between an environmental selection pressure and enzyme function. Performing deep mechanistic and structural studies and broad phylogenetic and sequence analyses, I identify new molecular mechanisms of enzyme temperature adaptation, test and revise nearly all prior proposals for enzyme adaptation to increased temperature, provide evidence that enzymes frequently adapt to temperature at sites of low epistasis, favoring parallel adaptation. This work improves our understanding of the molecular and evolutionary mechanisms underly enzyme evolution and suggests design principles that can be applied to enzyme engineering

Keywords: Biochemistry.
Advisor: Herschlag Daniel
Fordyce Polly
Krasnow Mark
Yeh Ellen
Molecular mechanism of pathogenic LRRK2 membrane recruitment

Activating mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) cause Parkinson's disease and we showed previously that activated LRRK2 phosphorylates a subset of Rab GTPases. Moreover, Golgi-associated Rab29 can recruit LRRK2 to the surface of the Golgi and activate it there for both auto- and Rab substrate phosphorylation. Here we define the Rab29 binding region of the LRRK2 Armadillo domain and show that it can also bind additional LRRK2 substrates, Rab8A and 10. Moreover, we identify a distinct and higher affinity interaction interface between phosphorylated Rab8 and Rab10 within LRRK2's N-terminus that can retain LRRK2 on membranes in cells to catalyze multiple phosphorylation events. These findings reveal a feed-forward pathway that provides spatial control and apparent membrane activation of LRRK2 kinase activity

Keywords: Biochemistry.
Advisor: Pfeffer Suzanne
Harbury Pehr
Straight Aaron
Molecular mechanisms of membrane fusion at the synapse

Membrane fusion is a fundamental biophysical process that facilitates synaptic transmission in both the pre- and postsynaptic terminals. Neurotransmitters are released from the presynaptic terminal via synaptic vesicle (SV) fusion with the presynaptic plasma membrane, while postsynaptically, neurotransmitter receptors are inserted via fusion of trafficking vesicles with the postsynaptic membrane. While the key molecules involved in SV fusion, including neuronal SNARES, the calcium sensors synaptotagmins, Munc13, Munc18, complexin, NSF, SNAPs, and many other synaptic proteins have been identified and atomic-resolution structures of some of their complexes determined, much is yet unknown about the architecture of the synaptic proteins in their native environment at the SV docking site. Recently some of the SV fusion proteins have also been found to be important for the insertion of the ionotropic, glutamatergic AMPA receptors (AMPARs) via AMPAR trafficking vesicle (ATV) fusion. However, at present, understanding of the regulation of AMPAR insertion is much more limited compared to SV fusion. In this this, I investigate the mechanisms of membrane fusion both pre- and postsynaptically

Advisor: Brünger Axel T.
Chen Lu (Professor of neurosurgery)
Ding Jun (Jun B.)
Malenka Robert C.
Molecular Mechanisms of Neuronal Activity Mediated NF1 Optic Glioma Initiation

In pediatric brain tumors, a permissive tumor microenvironment is known to be central for promoting the proliferation of cancerous cells. While a great variety of cell types may occupy the tumor microenvironment, neurons have been shown to be essential components, where their activity increases growth of high-grade glioma tumors (Venkatesh et al., 2015). However, the relationship between neural activity and initiation of the tumor is not well understood. Currently, many forms of pediatric brain cancers are unamenable to many classes of therapeutics and current treatment strategies remain unsatisfactory. Neurofibromatosis Type 1 (NF1), a tumor predisposition syndrome, causes small tumors to develop which associate with nerves. Patients may also develop low-grade gliomas of the optic pathway, optic pathway gliomas (OPG), where retinal ganglion cells (RGCs) constitute the sole neuronal component. Using a mouse model of these NF1-OPGs as a platform, we can interrogate the mechanisms of initiation of these gliomas, as they relate to neural activity. By manipulating the light-induced activity of this visual pathway, this project helps characterize the relationship between neuronal activity and glioma initiation. Mice possessing mutations in Nf1 were sacrificed after tumor initiation and their optic chiasms were analyzed for tumor volume, cellular proliferation, among other molecular markers. We demonstrated that neuronal activity plays a central role in the initiation of these gliomas and that this initiation is mediated through the ADAM10/neuroligin-3 molecular pathway. This demonstrates a novel characterization of the mechanisms of glioma initiation, which could yield novel therapeutic strategies for these pediatric low-grade gliomas along with other neuroligin-3 mediated adult high-grade gliomas.

Keywords:  Department of Biology
Biology
pediatric brain tumor
neurofibromatosis type 1
optic pathway glioma
glioma
NF1
cancer
Neuroligin-3
Text
Thesis
Advisor: Monje Michelle
McConnell Susan
Molecular mechanisms of STING signaling

The innate immune STING pathway exists at a unique tipping point in cell signaling: not enough STING activation leaves cells vulnerable to cancer or viral infection, while too much STING signaling causes inflammation and autoimmunity. It is therefore paramount that we understand the complete molecular mechanism of how STING is activated and regulated. Here I describe the use of structural and biochemical techniques to elucidate a more complete molecular picture of STING activation. l explain how these findings have led us toward a molecular tool for inhibiting STING activation, which may prove valuable for the future treatment of autoimmune and inflammatory syndromes. Finally, I discuss how STING is activated and regulated in the context of the cell, which gives us clues into how it delivers an effective and robust immune response without causing harmful inflammatory effects

Keywords: Biochemistry.
Advisor: Li Lingyin
Harbury Pehr
Rohatgi Rajat
Yeh Ellen
Molecular mechanisms of synaptic vesicle biogenesis

Synaptic vesicles (SVs) are secretory vesicles crucial to neuronal communication. Here we investigated the molecular mechanisms underlying somatic SV biogenesis. In C. elegans, we showed that the conserved ARF-like small GTPase ARL-8/Arl8 serves as a master regulator in SV proteins' journey from the Golgi to axonally transported SVs. ARL-8 facilitates SV biogenesis by promoting the sorting of SV proteins into SVs. In strong loss-of-function arl-8 mutants, SV proteins were mis-sorted to degradative compartments, and fewer SVs were generated. We further demonstrated that ARL-8 is localized to membranes and activated by part of the BLOC-1-related complex (BORC), with the SAM-4/Myrlysin subunit displaying GEF activity towards ARL-8. In addition to ARL-8, we present one of the first evidence to implicate sorting nexins 1 (SNX-1/SNX1) and 6 (SNX-6/SNX6) in synaptic protein sorting and function. Both SNXs localized to early endosomes in the soma. Loss of the SNXs decreased synaptic localization of the SV protein SNB-1 as well as endosomal localization of the early endosome protein RAB-5. Functionally, SNX-6 is required for normal synaptic transmission, as its loss-of-function mutant demonstrated aldicarb resistance. Together, our results establish ARL-8 as well as SNX-1 and SNX-6 to be novel regulators of SV biogenesis and implicate a model in which they inhibit non-SV fate and promote SV fate for SV cargoes, respectively

Advisor: Shen Kang
McConnell Susan K.
Pfeffer Suzanne
Wang Xinnan
Molecular modeling of mechanically reliable hybrid organosilicate materials

Hybrid organosilicate glass materials have unique properties and functionalities due to combining characteristics of organic and inorganic species which renders them a very appealing material choice for a wide range of current and emerging nanotechnologies in microelectronics, protective and antireflective coatings, flexible electronics, solar cell applications and many more. However, material innovations are needed to enhance the mechanical reliability of hybrid organosilicate materials which are inherently very brittle and fragile for their reliable use and integration in these device technologies. The focus of this thesis dissertation is to elucidate the fundamental structure-property relationships in hybrid organosilicate glasses through computational techniques; and ultimately establish a computational design space where the elastic and fracture properties of these materials are tuned through the proper exploitation of several of their structural features to enhance their mechanical reliability, which is evaluated in terms of elastic stiffness and fracture energy. Remarkably, it is shown that ultrastiff low density hybrid organosilicate networks with fracture energies comparable to fully dense silica can be generated with the use of hyperconnected hybrid organosilicate glass networks derived from cyclic and molecularly planar precursors. Furthermore, the structural features that lead to increased elastic and fracture properties help improve the mechanical reliability of hybrid organosilicate glasses under extreme temperature regimes, in the presence moisture and under nanoscale confinement, which is a significant step for the reliable service use and integration of hybrid organosilicate materials in next generation device technologies

Keywords: Mechanical Engineering.
Advisor: Cai Wei
Dauskardt R. H. (Reinhold H.)
Gu Wendy (Professor of mechanical engineering)
Molecular tools to modulate voltage-gated sodium channels

Voltage-gated sodium channels (NaVs) are responsible for sodium influx upon cellular depolarization and, as such, are fundamental to action potential initiation and propagation. There are nine voltage-sensing channel subtypes, NaV1.1--1.9, which are differentially distributed throughout the body. NaV dysfunction—whether in terms of channel activity, expression, or localization—is implicated in a host of diseases, including epilepsy, multiple sclerosis, and neuropathic pain. Efforts to fully elucidate the mechanisms of NaV-dependent pathogenesis are limited by a lack of rapid, efficient, and selective methods for the manipulation of NaV subpopulations (Chapter 1). Accordingly, we have developed tools for subtype-selective (Chapter 2) and location-specific (Chapters 3--4) channel inhibition. Toward the goal of subtype-selective channel inhibition, we designed a mutant NaV-electrophile pair for the covalent labelling of individual NaV subtypes. Building off work from Drs. William Parsons and Darren Finkelstein, we determined that a reactive saxitoxin (STX) derived probe, saxitoxin ethyl maleimide, selectively and irreversibly inhibits engineered NaVs expressing appropriately positioned cysteine point mutations. Labelling occurs rapidly and efficiently at low probe concentrations—i.e., up to 40% irreversible inhibition after 6-minute application of 500 nM toxin. Modification of STX ethyl maleimide with a biotin moiety or 'clickable' tetrazine tag should enable live cell imaging of target NaV subtypes. The efficacy of NaV labelling by such trifunctional probes has been demonstrated by patch clamp electrophysiology; efforts continue to translate these results to channel visualization with confocal microscopy and immunoblotting. Toward the goal of location-specific channel inhibition, one-photon (Chapter 3) and two-photon (Chapter 4) photocleavable groups were appended to saxitoxin. Derivatization of the photocage with carboxylate groups destabilized STX binding to the NaV. As such, inert photocaged STX compounds (STX PCs) could be applied to cells prior to selective, light-induced, focal release. Several rounds of optimization yielded STX PCs with large differences in potency pre- vs. post-uncaging—5.2 µM vs. 90 nM against rat hippocampal neurons for the optimal one-photon STX PC; 2.1 µM vs. 100 nM for the analogous two-photon STX PC—following exposure to only 5 ms of 130 mW UV light. These large differences in potency enable precise control of action potential firing in hippocampal neurons, with tandem laser--STX PC application acting as a molecular switch for electrical activity. Collaborations using these STX PCs to examine the role of NaVs in epilepsy are ongoing. The precise control of NaV function, whether through the modulation of a single channel subtype or a localized subpopulation, will help disentangle the complex biochemistry underlying electrogenesis and ectopic excitability, thereby aiding efforts to develop better treatments for electrical signaling disorders

Keywords: Chemistry.
Advisor: Du Bois Justin
Khosla Chaitan
Wender Paul A.
Momentum Subspaces in Gapped Relativistic Quantum Field Theories as Codespaces for Quantum Error Correction

This thesis reports a study of the quantum error correction properties of quantum field theory through the investigation of codespaces comprising momentum states subject to the error of spatial erasure. A formulation of code quality that measures state distinguishability using expectation values of localized operators is proposed, after which it is evaluated in the context of gapped relativistic theories under the limit of a small erasure region. An analytic bound on the code quality is derived for free theory as a function of the size of erasure and momentum, while an estimate of the code quality is provided for general interacting theories, with substantial progress towards a precise bound. A discussion of relations with the information structure of quantum field theory and possible directions for further research is provided.

Keywords:  Department of Physics
Quantum error correction
Quantum field theory
Thesis
Advisor: Hayden Patrick
Qi Xiaoliang
A morphology framework for understanding fungal-bacterial interactions in soil

Soils are physically, chemically, and morphologically complex at microscopic scales. Bacterial and fungal communities in soils, likewise, display extreme micro-heterogeneity. This dissertation explores deeper consideration of microscale soil context in studying microbial biogeography. I begin with the assumption that microbial communities are structured by their physical habitats -- microscale soil pores -- and that soil conditions that influence pore size, shape, and connectivity may be significant predictors of microbial communities and interactions at landscape scale. Further, that consideration of microbial traits related to the way they physically navigate soil pores (filamentous growth form, flagellate motility) may predict their individual and collective responses to changes in the soil environment. In my first chapter, I surveyed bacterial and fungal biomass and communities across a landscape with diverse soil characteristics and plant communities. I found that community structures of unicellular and filamentous fungi and bacteria were correlated with distinct soil and plant factors. These communities were sampled from pooled, sieved soils, as is common in microbial ecology. In my second chapter, I investigated the effect of sieving soil samples on patterns of bacterial and fungal biogeography, and the detection and strength of microbial interactions. Sampling microbial communities in individual aggregates revealed distinct distance-decay relationships between fungi and bacteria, and between different bacterial genera. Further, network analysis of soil aggregates revealed distinct positive associations between members of specific fungal genera and putative fungal-mutualist bacteria from genus Burkholderia compared to sieved soil. These bacterial-fungal interactions might be mediated by environmental context, especially degree and frequency of soil saturation. Specifically, flagellate soil bacteria may move along water films surrounding fungal hyphae, exploiting 'fungal highways' to bypass air-filled pores. In my third chapter, I tested the fungal highway mechanism by culturing diverse flagellate bacteria and filamentous fungi from sediment, co-culturing a selected pair in saturated and unsaturated sand, and measuring their distribution and biomass in relationship to each other. The bacterium benefited from exploitation of fungal highways in unsaturated -- but not saturated -- soil media. By investigating the impact of soil morphology on microbial biogeography and interactions, my dissertation shows the potential utility of soil pore-scale considerations in reducing the noise of a seemingly intractably complex system

Keywords: Biology.
Advisor: Peay Kabir
Dekas Anne
Fendorf Scott
Fukami Tadashi
Mordecai Erin
Multimodal representations for vision, language, and embodied AI

Recent years have seen incredible growth and advances in artificial intelligence research. Much of this progress has primarily been made on three fronts: computer vision, natural language processing, and robotics. For example, image recognition is widely considered the holy grail of computer vision, whereas language modeling and translation have been fundamental tasks in natural language processing. However, many practical applications and tasks require going beyond solving these domain-specific problems and instead require solving problems which involve all three of the domains together. An autonomous system not only needs to be able to recognize objects in an image, but also interpret natural language descriptions or commands and understand how they might relate to its perceived visual observations. Furthermore, a robot needs to utilize this information for decision-making and determining which physical actions to take in order to complete a task. In the first part of this dissertation, I present a method for learning how to relate natural language and 3D shapes such that the system can draw connections about words like "round" described in a text description with the geometric attributes of round in a 3D object. To relate the two modalities, we rely a cross-modal embedding space for multimodal reasoning and learn this space without fine-grained, attribute-level categorical annotations. By learning how to relate these two modalities, we can perform tasks such as text-to-shape retrieval and shape manipulation, and also enable new tasks such as text-to-shape generation. In the second part of this dissertation, we allow the agent to be embodied and explore a task which relies on all three domains (computer vision, natural language, and robotics): robot navigation by following natural language instructions. Rather than relying on a fixed dataset of images or 3D objects, the agent is now situated in a physical environment and captures its own visual observations of the space using an onboard camera. To draw connections between vision, language, and robot physical state, we propose a system that performs planning and control using a topological map. This fundamental abstraction allows the agent to relate parts of the language instruction with relevant spatial regions of the environment and to relate a stream of visual observations with physical movements and actions

Keywords: Electrical Engineering.
Advisor: Sadigh Dorsa
Savarese Silvio
Guibas Leonidas J.