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Toward general world models
No full textWhat do we study in neuroscience? Recent advances in our understanding of both non-neuronal cells within the nervous system and contemporary machine learning models necessitate a renewed focus on answering this foundational question in sufficient generality to be able to capture a wide array of phenomena whose deep resonances may escape more restrictive starting points. Here, I present two investigations that both tug at tensions within traditional conceptions.First, I explore calcium activity in the astrocyte network, where tantalizing results have suggested the possibility that these neglected cells carry wide-reaching consequences for the functioning of brains and organisms. The results of these investigations reveal not only that astrocytes' bidirectional interactions with neurons carry a remarkable amount of structure in relation to a core physiological state (sleep), but also suggest that astrocytes may perform sophisticated spatial and temporal integration of their proximal neuronal inputs, implementing a form of combinatorial logic.Second, I explore the structure of how language models respond when placed in relationship with highly-evocative naturalistic text. In the early stages of the explosion of interest around language models, a common argument levied against them was that, because they were trained to solve the task of next-token prediction (that is, of learning syntax), language models lacked actual understanding of the meaning of the tokens they were predicting (that is, of semantics). The results here—generating a rich and highly-structured portrait of human emotional life, through simple prompt-based impersonation and question-answering geared toward the practical task of hypothesis generation and symptom annotation in psychiatry—add to a growing body of work suggesting that, on the contrary, by solving the problem of generating language syntax, these models do (and, as implied by recent theoretical work, perhaps must) learn a latent structural image of semantics.Finally, I draw the threads of these investigations together toward an answer of that foundational question: in neuroscience, we study the dynamics of interacting world models. I sketch a framework, the postmodern synthesis, of how the mechanics of these changing minds---when viewed as consisting solely of their relational structure---might be rigorously modeled using the mathematical language of double categories. This framework touches formal resonances with both quantum field theory and classical genetics. By framing our science the other way 'round, from the perspective of the mental content, rather than its material implementation, we may be able to ask new questions
Fatty Fortifications: Blood-Brain Barrier Lipids in Neurodegeneration and Neuroinflammation
No full textThe aim of this dissertation is to increase the understanding of how the cerebral vasculature (CV) becomes dysregulated in neurological disease, with a focus on the blood-brain barrier (BBB). I begin this dissertation with a literature review on the topics of the BBB in health and disease, the complex pathology of sporadic Alzheimer’s disease (AD), the importance of lipids in neuroinflammatory contexts such as AD, evidence of CV dysfunction in AD, and a brief overview of the key findings of my dissertation research establishing a connection between these topics. A large body of literature implicates CV dysfunction, including avascularity, reduced cerebral blood flow (CBF), hemorrhage, and BBB permeability, as a common feature of AD pathology; however, the molecular nature of this dysfunction had never been explored. To address this knowledge gap, I employed a multi-omic approach, leveraging both proteomics and lipidomics, to identify the molecular changes to the CV in post-mortem sporadic AD patients. This multi-omic strategy revealed a loss of sphingolipid (SL) and ceramide (CER) biosynthetic machinery at the protein level, and a distinct loss of CERs at the lipid level. To understand the functional importance of these changes to the CV, I used mouse genetics to conditionally inhibit SL biosynthesis specifically in endothelial cells (ECs), the BBB-containing cells lining the lumen of the CV. In doing so, I found that loss of EC SL biosynthesis promotes BBB permeability in healthy adult mice and inhibits angiogenesis capacity promoting hemorrhage in response to a hypoxic environment; all of which have been shown to occur in AD patients. In this process, I noticed a fatty acid (FA) elongase enzyme, Elovl7, to be downregulated in the AD CV at the protein and transcript level. Further, I found that Elovl7 is uniquely expressed in brain ECs in both humans and mice and becomes dysregulated in several mouse models of neurological disease. To clarify the role of Elovl7 in brain ECs, I used mouse genetics to conditionally delete Elovl7 from brain ECs of adult mice. In doing so, I discovered that Elovl7 generates phosphatidylcholines (PCs) and lyso-PCs (LPCs) for the CV, and its absence results in decreased levels of docosapentaenoic acid (DPA), an anti-inflammatory FA, in the brain. When confronted with a systemic inflammatory stimulus, loss of Elovl7 exacerbated hemorrhage and drove persistent reactivity in astrocytes and microglia. Together, these findings show that lipids synthesized within brain ECs are important in maintaining CV integrity and modulating neuroinflammation. This body of work reveals multiple novel targetable therapeutic avenues to fortify the brain vasculature across a broad spectrum of neurological disorders
This Time, It’s Personal: Biography as a Generative Force in Sound Practice
Full text linkIn this thesis, I explore how proximity between play-texts and personal texts forms the foundation of my sound design process. I investigate how my sound design process intersects with dramatic literature, other design elements, and personal experience to create a cohesive and purposeful theatrical environment. Furthermore, I juxtapose accounts of my creative process on two case studies with biographical anecdotes and original proposals for new works
Structural Insights into Acyl Carrier Protein-based Pathways
No full textAcyl carrier proteins (ACPs) are the central players in many important and interesting biosynthetic pathways. These include fatty acid synthases (FASs) from primary metabolism as well as polyketide synthases (PKSs) from secondary metabolism. In all examples, ACP interacts with partner proteins (PPs), either as standalone enzymes (type II) or as enzymatic domains (type I), to faithfully and efficiently build the product in a stepwise fashion. Understanding the structural basis of ACPs and their interactions with PPs is principal in employing these pathways for applicable benefits, including the development of protein-protein interaction (PPI) modulators as therapeutics and the engineering of pathways to produce new useful molecules such as material monomers. To facilitate the elucidation of ACP-based structures, we utilize mechanism-based crosslinking using chemical probes derived from the natural post-translational phosphopantetheine modification of ACP. Crosslinking serves to trap PPIs and restrict dynamic motions, enabling structural studies by X-ray crystallography and cryo-electron microscopy (EM). In chapter 1, the thioesterase (TE)-catalyzed termination of type II fatty acid biosynthesis (FAB) in model green algae Chlamydomonas reinhardtii (Cr) was studied by X-ray crystallography and computationally-generated models. Activity assays coupled with mutational studies laid the groundwork for engineered production of polymer building blocks in green algae.
In chapter 2, a cerulenin-based crosslinker was developed to specifically target ketosynthases (KSs). Its validation by a crystal structure of an ACP-crosslinked complex provides a new tool in the ACP structural biology toolbox. Then in chapter 3, a hitherto unseen inhibition mechanism by cerulenin is elucidated using isotopically-labeled analogs and nuclear magnetic resonance (NMR).
In chapter 4, multi-domain type I PKS mycocerosic acid synthase (MAS) from Mycobacterium tuberculosis (Mtb) was captured in four states using crosslinking and single-particle cryo-EM. These revealed key differences between type II and type I interactions, as well as insights into higher-order regulation.
Finally in chapter 5, a novel approach to type I structural studies was developed using split intein fusions in conjunction with crosslinking. This was applied to MAS and type I PKS 6-methylsalicylic acid synthase (6MSAS). Single-particle cryo-EM produced a high-resolution structure of a MAS compartment, validating a new tool for type I structural biology
Unintentional Fentanyl Use Detected in Hair of People With HIV Risk Using Methamphetamine
Full text linkThis study assessed hair samples to detect fentanyl exposure among people with or at risk of HIV reporting methamphetamine use without intention to use opioids concomitantly
A semantic strength and neural correlates in developmental dyslexia
Full text linkIntroductionMost studies of dyslexia focus on domains of impairment (e.g., reading and phonology, among others), but few examine possible strengths. In the present study, we investigated semantic fluency as a cognitive strength in English-speaking children with dyslexia aged 8-13.MethodsNinety-seven children with dyslexia completed tests of letter and semantic verbal fluency, standardized measures of reading and cognitive functions, and task-free resting-state functional magnetic resonance imaging (rs-fMRI). First, we adjusted performance on semantic fluency by letter fluency and created a residual score that was used to separate participants into high (residual >0) or average (residual <0) semantic performance groups. We then employed a psycholinguistic clustering and switching approach to the semantic fluency task and performed dynamic task-free rs-fMRI connectivity analysis to reveal group differences in brain dynamics.ResultsHigh and average semantic fluency groups were well-matched on demographics and letter fluency but differed on their psycholinguistic patterns on the semantic fluency task. The high semantic fluency group, compared to the average semantic fluency group, produced a higher number of words within each cluster, a higher max cluster size, and a higher number of switches. Differential dynamic rs-fMRI connectivity (shorter average dwell time and greater brain state switches) was observed between the high and average groups in a large-scale bilateral frontal-temporal-occipital network.DiscussionThese data demonstrate that a subgroup of children with dyslexia perform above average on semantic fluency tasks and their performance is strongly linked to distinct psycholinguistic patterns and differences in a task-free resting-state brain network, which includes regions previously implicated in semantic processing. This work highlights that inter-individual differences should be taken into account in dyslexia and reveals a cognitive area of strength for some children with dyslexia that could be leveraged for reading interventions
Material characterization and biocompatibility of polycarbonate-based polyurethane for biomedical implant applications
Full text linkPolycarbonate polyurethane (PCU) resins are widely used in biomedical applications due to their excellent mechanical properties, biocompatibility, and resistance to degradation. The performance of these materials in implantable devices depends on factors such as hardness, molecular weight, and their interactions with cells and tissues. Understanding the relationship between material properties and biological outcomes is essential for optimizing their use in medical devices. In this study, three PCU resins were selected for evaluation as potential polymer implant materials: Chronoflex (CF) 65D, and two Carbothane (CB) samples 95A with different molecular weights. Dynamic mechanical analysis (DMA) revealed that the storage modulus was primarily influenced by the hard domain content, with greater elasticity observed at higher frequencies and lower temperatures. Tensile hysteresis behavior at room temperature was strongly correlated with hardness, with lower hardness samples demonstrating improved strain recovery. Cytotoxicity testing indicated cell viability above 70% for both CF and CB films. Normal Human Lung Fibroblasts (NHLF) grown on CF films exhibited a more homogeneous distribution across the surface, adopting an elongated morphology that conformed closely to the underlying topography. In contrast, cells on CB films tend to aggregate, forming clustered structures. This study demonstrates that the mechanical and biological performance of PCU resins is closely linked to their hardness, molecular weight, and structural composition. The results highlight that a morphology with a higher proportion of hard domains produces a more uniform and favorable environment for cell adhesion and organization
Blue Carbon Stocks Along the Pacific Coast of North America Are Mainly Driven by Local Rather Than Regional Factors
No full textAbstract:
Coastal wetlands, including seagrass meadows, emergent marshes, mangroves, and temperate tidal swamps, can efficiently sequester and store large quantities of sediment organic carbon (SOC). However, SOC stocks may vary by ecosystem type and along environmental or climate gradients at different scales. Quantifying such variability is needed to improve blue carbon accounting, conservation effectiveness, and restoration planning. We analyzed SOC stocks in 1,284 sediment cores along >6,500 km of the Pacific coast of North America that included large environmental gradients and multiple ecosystem types. Tidal wetlands with woody vegetation (mangroves and swamps) had the highest mean stocks to 1 m depth (357 and 355 Mg ha−1, respectively), 45% higher than marshes (245 Mg ha−1), and more than 500% higher than seagrass (68 Mg ha−1). Unvegetated tideflats, though not often considered a blue carbon ecosystem, had noteworthy stocks (148 Mg ha−1). Stocks increased with tidal elevation and with fine (<63 μm) sediment content in several ecosystems. Stocks also varied by dominant plant species within individual ecosystem types. At larger scales, marsh stocks were lowest in the Sonoran Desert region of Mexico, and swamp stocks differed among climate zones; otherwise stocks showed little correlation with ecoregion or latitude. More variability in SOC occurred among ecosystem types, and at smaller spatial scales (such as individual estuaries), than across regional climate gradients. These patterns can inform coastal conservation and restoration priorities across scales where preserving stored carbon and enhancing sequestration helps avert greenhouse gas emissions and maintains other vital ecosystem services
Understanding early ontogeny and whisker growth dynamics of Weddell seal (Leptonychotes weddellii) pups through stable isotope analysis
Full text linkAbstract:
Stable isotope analysis of animal tissues is a valuable tool for understanding foraging ecology, habitat use, and developmental changes throughout an animal's life. Stable isotope values of whisker segments offer long‐term data on mammalian foraging, as whisker growth incorporates isotopic signals from the diet and reflects dietary shifts during events like birth and weaning. We estimated birth dates of 7‐week‐old Weddell seal (Leptonychotes weddellii) pups (n = 17) by analyzing stable carbon (δ13C) and nitrogen (δ15N) isotope values measured from sequentially sampled whisker segments to evaluate the technique's accuracy in predicting early developmental events. We also estimated prenatal and postnatal whisker growth rates to construct a timeline for each pup using the stable isotope values measured longitudinally along each whisker. All pups showed consistent trends in δ13C and δ15N values along the length of their whiskers, with no evidence of a weaning signal. Post‐birth, δ15N values across the sequentially sampled segments of vibrissae steadily increased, likely reflecting the pups' dependence on maternal milk. The δ13C values remained mostly constant, suggesting that mothers did not forage far from their breeding colonies, and the δ15N values were similar across individual timelines, indicating that mothers occupied a narrow trophic range
Supercritical Fluids in the System Albite-Water: Phase Relations and Properties
Full text linkIn this dissertation, I have conducted physical experiments to investigate the phase relations in the NaAlSi2O6 −SiO2 −H2O system above the critical conditions and the changes in the compositions of the supercritical fluids. I have also conducted a series of molecular dynamics simulations to study the stability fields of the supercritical fluids and their physical properties under subduction zone conditions. The NaAlSi3O8 − H2O system is a simple system for fluids liberating from subducting slabs and triggering mantle melting in subduction zones. The change in the mineral phases and the associated fluids can significantly affect the rheological properties of the crust and mantle in subduction zones, which are responsible for geological processes such as volcanic eruptions and deep earthquakes. The presence of fluids complicates phase diagrams by shifting phase boundaries and dissolving otherwise stable minerals compared to dry systems. Boettcher and Wyllie [1969] first studied the phase relations of NaAlSi3O8 − H2O up to 35 kilobars and provided an overview of mineral reactions and phase transitions. However, they failed to identify supercritical fluids and thus misinterpreted key phase relations. In my experimental approach, I revisited the phase relations of NaAlSi2O6 (jadeite)-H2O, NaAlSi3O8 (albite)-H2O, and NaAlSi3O8 (albite)-H2O-NaCl at 1.7-3 GPa, 600-900 °C, and 10-15 wt% H2O. The run products were carefully examined with X-ray diffraction, binocular microscopy, scanning electron microscopy (SEM), and electron probe microanalysis (EPMA). My results provide comprehensive phase relations in these systems above the critical pressures and constrain compositional changes of the associated supercritical fluids. In my computational approach, I mainly focused on supercritical fluids in the NaAlSi3O8 (albite)-H2O system above the critical conditions. I applied machine learning molecular dynamics to study the viscosities and electrical conductivities of the fluids. My results challenge the previous viscosity model, support the existence of water-rich subduction zones (∼20 wt% H2O), and rapid ascent of fluids from the subducting slab to the thermal maximum of the mantle wedge. Future work aims to expand the compositions of the fluids with phase changes, the stability fields of the fluids, and how the physical properties of the fluids change under subduction zone conditions