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Predictive Processing, Hierarchical Predictive Coding, and Multi-Modal Evidence from Local/Global Oddball Paradigms
No full textPrediction is thought to be a fundamental function of the cortex. Before the adoption of predictive frameworks and invention of predictive paradigms in psychological and neuroscientific research, many studies in the field addressed concepts related to prediction. These include habituation, conditioning, and attention. The discovery of mismatch negativity marked the advent of many predictive paradigms, most prominently “oddball paradigms”. On the side of computational modeling, many have drawn inferences from neuronal mechanisms and the hierarchical and recurrent (i.e. involving feedforward/feedback streams) nature of the brain to successfully simulate neuronal behavior when it comes to prediction and prediction error. This also inspired theoretical works such as the Bayesian brain hypothesis and the free energy principle, which mathematically formalized the brain’s mechanism to minimize prediction error. An important paradigm that arose from the study of hierarchy and predictive processing was the local/global oddball paradigm. In this paradigm, repetition-driven predictions are orthogonalized with pattern-driven predictions, allowing for the delineation of brain areas and mechanisms of two different levels of predictive processing. Studies using fMRI, EEG, and LFP somewhat consistently found that local oddball effects occur earlier, are found in sensory and higher order cortical areas, and are related to gamma power increase. Global oddball effects, on the other hand, occur later, are found predominantly in frontal areas, and are associated with alpha/beta power decrease. However, studies examining single-unit spiking were inconsistent in showing significant global oddball encoding in the cortex. This may be due to the anesthetized state of subjects, lack of learning, and under-sampling of brain areas and/or neurons in a cortical column. Further studies using multi-area high-density recording methods in awake, behaving subjects are needed to elucidate cellular level predictive mechanisms
Things That Were, Things That Are, and Some Things That Have Not Yet Come To Pass: Investigations in Galactic Archaeology via Asteroseismology, Spectroscopy, and Astrometry of Evolved Stars to Unlock the Secrets of the Milky Way in the Past, Present, and Future
No full textStellar Galactic Archaeology is the study of the stars in the Milky Way as artifacts to determine the formation and evolution of our home Galaxy. With a rapid increase in space-borne telescopes and ground-based counterparts that can collect considerable amounts of precise data, we can perform Galactic Archaeology for enormous selections of evolved stars through the multiple methods of asteroseismology, spectroscopy, and astrometry. Using the APO-K2 sample of ~7,500 stars, precision values are calculated and used to investigate various stellar parameter spaces for the sample, including the evolutionary states of the stars, the galactic kinematic profiles, and the identification of halo and stream stars. A well-understood selection function is determined to consider the APO-K2 sample on a Galactic scale. Further investigations include shedding light on a possible cause of overestimated asteroseismic masses in low-metallicity halo stars and the effect of Galactic chemical evolution on the future creation and habitability of planets in the Milky Way, based on their assumed ability to form plate tectonics with the elements available from their host stars.
Also included is an in-depth investigation specific to the asteroseismic parameters of Milky Way stars. The investigation involves the observation of a sample of Kepler stars in search of binary companions, which may inhibit our observations of asteroseismic oscillations in Kepler light curves by introducing spurious flux. Of the two investigations performed in this vein, amplitude dilution, or the reduction of observable asteroseismic oscillations, is found to at least in part be caused by stellar companions. However, it is not the only cause of non-detections in sample stars. As an extension of this work, the script designed to determine secondary star contamination in large Kepler and TESS data samples underwent a redesign to create a web tool for students, allowing them to access space telescope data
Understanding Employee Retention in a Life Plan Community
No full textLeadership and Learning in Organizations capstone projectLife plan communities are a type of senior living community that offers tiered lifestyle and healthcare options on one campus. The life plan community we studied has over 300 residents and is a nonprofit organization with a staff of approximately 250 employees, in addition to volunteers and interns. High employee turnover exists at both the staff and leadership levels. We utilized a mixed-methods approach to data collection, analyzing termination report data provided by the organization’s human resources department, employee interviews, and biannual professional association survey data. Findings revealed key challenges related to early employee retention and satisfaction driven by gaps in communication, training, and clarity of expectations. Strong commitment to the work was demonstrated by medium- and long-term employees
Characterization of the Calcium-Mediated Tetramerization of Human Calprotectin
No full textCalprotectin (CP) is an S100 protein that plays a role in the inflammatory response by acting as a ligand for the receptor for advanced glycation end-products (RAGE) and Toll-like receptor 4 (TLR-4). Activation of these receptors leads to upregulation of inflammatory cytokines, chemokines, and CP through the NF-κB pathway. In the case of people with irritable bowel disease (IBD) these pathways are stimulated which leads to damage of the gastrointestinal tract and disease symptoms. CP is a heterodimer of the S100A8 and S100A9 EF-hand calcium binding proteins. Like all S100 proteins, calcium-induced conformational changes in CP are required for binding to partner proteins. However, in the case of CP, the addition of calcium correlates with self-association and the formation of a dimer of heterodimers (heterotetramer). Ligand induced receptor oligomerization has been proposed as a mechanism of receptor activation. Conversely, it has also been suggested that CP tetramerization can inhibit binding to receptors and serve as an autoinhibitory mechanism to modulate the inflammatory response. In order to investigate the functional relevance of CP tetramerization and facilitate in-depth biophysical and structural analysis, I prepared single-site mutations of two hydrophobic residues mediating the tetramer interface (Ile60, Ile73) and a double-site mutant (I160K,170K). With the goal of maximally destabilizing the tetramer interface, these Ile residues were mutated to Lys (I60K, I73K). This work reports biophysical characterization of the three tetramer-deficient mutants using calorimetric, scattering, and structural approaches. Dynamic light scattering, small-angle x-ray scattering, and nuclear magnetic resonance show that the CP tetramer-deficient mutants remain as dimers in solution even in the presence of 40-fold excess calcium. The crystal structure of CP I73K mutant was determined to atomic level resolution and confirms there are virtually no differences in the structure of the heterodimer. Together, these results indicate that the mutants will be useful reagents for discerning the functional role of CP oligomerization in activation of cell-surface receptors. The implications of these results are discussed in the context of the complexity of CP receptor signaling
SRSF2P95H splicing factor mutations impair emergency hematopoiesis and elicit context-specific splicing programs
No full textSRSF2P95H (P95H) splicing factor mutations are initiating mutations in myelodysplastic syndromes (MDS) that are associated with myeloid-biased hematopoiesis in both mouse models and human disease. Mechanistically, P95H substitutions induce transcriptome-wide alterations in RNA splicing that vary by cell type and context. The relationship between physiologic, context-specific P95H splicing and the characteristics of P95H-associated hematopoietic disease is poorly understood. This study characterizes P95H-directed splicing and hematopoiesis in two different physiologically relevant contexts: myeloid differentiation and inflammation. To evaluate splicing changes, we performed bulk RNA-seq of purified bone marrow promyelocyte, myelocytes, and neutrophil populations from Vav-Cre Srsf2P95H/+ (P95H) and Srsf2+/+ (WT) mice. Cluster-based differential splicing analysis was applied to these data, RNA-seq of P95mut MDS, and P95H mouse progenitors. To evaluate changes associated with acute inflammation, we induced emergency hematopoiesis in P95H mice. P95H splicing varied by cell type, differentiation state, and inflammatory status. The most prominent conserved event across myelopoiesis, in human MDS, and during inflammatory hematopoiesis impacted Csf3r, encoding the G-CSF receptor. Notably, P95H mouse bone marrow exhibited impaired activation of G-CSFR-dependent pathways (STAT3/5) that are G-CSFR specific in myelocytes and neutrophils. Human P95mut CMML also exhibited impaired G-CSF dependent activation. During short-term inflammatory hematopoiesis, P95H mutant myelo/erythro hematopoietic progenitor marrow cells fail to expand. This inflammatory hematopoiesis program is complemented by inflammation-specific P95H directed differential splicing within the marrow affecting TNF production, regulation of mRNA stability, and neutrophil function . Our findings implicate acute inflammation as a key driver of P95H hematopoietic dysfunction which impacts both hematopoiesis and splicing
Progress Towards Bringing the Gap Between Noninvasive Bioelectromagnetic Physiological Measurements and Microphysiological Systems to Detect, Characterize, and Treat Functional Gastrointestinal Disorders
No full textThe electrical gastric slow wave mediates neuromuscular interactions in the gastrointestinal syncytium, thus determining the functional status of peristalsis and digestion. It is regulated by interstitial cells of Cajal (ICC) and the enteric nervous system, which influences gastrointestinal motility and is affected by the gut-brain axis. Dysrhythmias of the gastric syncytium have been linked to functional GI motility disorders, which are characterized by overlapping symptomologies relating to dysfunction of the gastrointestinal system and lacking a physical, histological abnormality. There is a critical need for the development of diagnostic criteria that provide objective quantification of functional gastrointestinal abnormalities and dysrhythmia in order to improve patient outcomes. The central hypothesis for this work is that High-Resolution Electrogastrogram (HR-EGG) and Magnetogastrogram (MGG) can noninvasively distinguish the dysrhythmic slow wave patterns of pediatric functional nausea patients from the homeostatic slow wave of healthy pediatric controls. The overall objective is to utilize these tools to develop noninvasive objective markers of disease and severity to direct and inform clinical decision-making. Determining the optimal definition of normogastria that amplifies and does not inhibit the spatiotemporal characterization of slow wave propagation could lead to an enhanced characterization of gastrointestinal propagation dynamics, thus leading to greater clinical applicability of noninvasive bioelectromagnetic techniques. My research combines traditional approaches of measuring whole-body physiology with cell biology to create a multi-modal approach to understanding pathological processes of functional gastric activity.
Our clinical investigations have identified spatial and temporal clinical features crucial for diagnosing dysrhythmias in diseased states by assessing frequency and its power distribution. As revealed by power spectral analysis, patients exhibit significantly decreased normogastria, alongside notable differences in propagation velocities and directions. My results indicate that HR-EGG shows sufficient sensitivity and may represent an effective, low-cost, and portable tool for the noninvasive clinical detection of key pathological signatures of pediatric functional nausea. Future investigations encompassing the proposed microphysiological systems coupled to patient-derived duodenal organoid development could ascertain personalized treatment options in vitro by recapitulating the complex structure and function of the patient’s disordered environment, allowing an opportunity to explore the potential impact of myriad therapeutic interventions simultaneously
Direct observation of bidirectional motility by the cellobiohydrolase TfCel6B
No full textCellulose, the world’s most abundant biopolymer, is a primary structural component of plants. Its enzymatic breakdown in nature is catalyzed by cellulases, which hold potential to be utilized in bioreactors to convert cellulosic materials such as cultivated grasses, paper waste, and agricultural residues into soluble sugars for fermentation into liquid biofuels. However, crystalline cellulose is highly resistant to hydrolysis and current cellulases lack the efficiency needed to make large-scale biofuel production economically viable. A deeper understanding of the mechanisms by which cellulases degrade cellulose is essential for engineering improved enzymes for industrial applications.
The cellulase Thermobifida fusca Cel6B (TfCel6B) is of particular interest due to its retained activity at a wide range of temperatures and pH, yet its hydrolysis mechanism remains poorly understood. This dissertation investigates the molecular-scale activity of TfCel6B to address critical knowledge gaps. Optical tweezers were employed to directly observe individual TfCel6B molecules traversing cellulose microfibrils during processive hydrolysis. Enzyme motility was characterized across multiple cellulose isoforms to examine the influence of cellulose source on enzyme activity. The catalytic core of TfCel6B was also isolated and studied to elucidate the roles of individual domains in cellulose degradation.
Single-molecule assays revealed that after binding, TfCel6B frequently reverses its direction of movement—contrary to prior models suggesting unidirectional catalysis. Several hypotheses were proposed to explain this bidirectional motility, with evidence suggesting it is caused by irregularities in the ultrastructure of the cellulose substrate. These findings provide novel insights into cellulase function and pave the way for further mechanistic studies.
Optical tweezers-based cellulase motility assays are incredibly sensitive to noise in the form of mechanical drift of the sample plane. To address this, two video-based drift correction methods are employed and their performance is compared. In addition, this dissertation discusses relevant parameters for implementing effective drift correction methodology in an optical tweezers workflow
The China Embargo and the Trade War: A Legacy of Economic Ideological Containment
No full textDepartment of Asian Studies Honors Thesi
Evaluation of Supervised Learning Approaches for Assessing Heterogeneity of Treatment Effect in Clinical Trials
No full textInferring heterogeneity of treatment effect is a popular secondary aim of clinical trials. While there are several methods available to estimate conditional average treatment effects (CATEs) in clinical trials, they are often applied in settings with lower sample sizes than were included in corresponding seminal methodological work, making the validity of inference in these settings unclear. To provide practical guidance, we conducted a simulation study to evaluate the performance of different estimators for the CATE, including ordinary least squares (OLS) and causal forests, in a variety of settings. We evaluated 95% confidence interval (CI) coverage, bias, and variance under linear and non-linear data generating mechanisms (DGM) in the presence of 0-40 nuisance covariates and 0-16 effect modifying covariates. We found that while tree-based ensembles like causal forests can be quite flexible to linear or nonlinear settings, they can have meaningfully impaired coverage in many settings at sample sizes which constitute most trial applications. As expected, OLS has superior performance under linear DGMs but poor performance under nonlinear DGMs. We conclude with recommendations
Shearing interferometric fluorescence tomography for depth and spectrally resolved volumetric imaging
No full textWe introduce shearing interferometric fluorescence tomography (SIFT), a novel imaging technique that uses self-interference of fluorescent wavefronts to achieve axial localization of fluorophores. A shearing interferometer encodes wavefront curvature within spatial frequencies that vary with origin-fluorophore depth. This depth-multiplexed approach enables simultaneous acquisition of the entire axial fluorescence profile at each lateral excitation point. We present theory and experimental validation demonstrating axial sectioning and the feasibility of volumetric spectroscopic fluorescence imaging using SIFT. The depth-multiplexing capability of SIFT enables high-speed z-stack acquisition, with potential to improve fluorescent imaging for the study of degenerative retinal diseases and regenerative therapies.