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ACTIVATION OF THE ARCUATE NUCLEUS CORRELATES WITH MECHANICAL LOADING-ENHANCED BONE FORMATION
No full textBone continuously undergoes remodeling throughout life to maintain structural integrity and mineral homeostasis. Mechanical loading is one of the most important physiological stimuli for bone formation and maintenance. While the local cellular mechanisms have been well studied, the systemic regulation of bone in response to mechanical loading is less well understood. In this study, we investigated neuronal activation in the arcuate nucleus (ARC) of the hypothalamus and its correlation with systemic bone formation in response to tibial mechanical loading in mice. Daily tibial loading was administered to the left limb of 12-week-old male mice over three consecutive days, using the contralateral limb as a control. Immunohistochemical analysis revealed significant elevation of c-Fos expression, a marker of neuronal activation, in ARC neurons, accompanied by enhanced phosphorylated STAT3 signaling, indicative of JAK-STAT pathway activation. Micro-CT assessments demonstrated significant increases in bone volume fraction (BV/TV) in the loaded tibia and distant skeletal regions, including the femur, talus, and lumbar spine (L4-L5), suggesting systemic skeletal responses. No significant changes were observed in the calcaneus. These findings support the presence of a bone-brain axis mediating skeletal responses to mechanical stimuli. Understanding this neural regulation may provide novel therapeutic approaches for skeletal disorders related to reduced mechanical loading, such as osteoporosis or immobilization-induced bone loss
Random Forest for Hypothesis Testing: Development and Application to Cancer Detection
Get PDFHypothesis testing is the foundation of scientific inquiry. Contemporary data for hypothesis testing includes thousands of variables collected on a cohort composed of a small number of samples. From these data, machine learning technologies are employed to evaluate various hypotheses and statistics about an outcome, such as the presence or absence of a disease. We here ask a question that has been challenging to answer: does a set of variables provide enough relevant information about an outcome? We answer this question in this thesis by: (1) reducing this question (also known as the k-sample testing problem) to the well-known independence testing problem, (2) using a kernel decision forests, which are popular tools for classification and regression, to develop a new hypothesis test, and (3) estimate information-theoretic quantities directly from random forest which allows us to quantify uncertainty within the data set. We show the value of these approaches through extensive mathematical theory, simulated experiments, and applications to cancer detection. Specifically, when developing cancer detection models, we find that combinations of variable sets often decrease rather than increase sensitivity over the optimal single variable set. Based on these results, we suggest that our algorithms can more efficiently and reliably answer this question than existing approaches
Optimization of Electrolytes for Low Temperature Zinc-ion Battery
No full textThe rapid growth of electric vehicle (EV) adoption has significantly increased global demand for advanced energy storage systems. While lithium-ion batteries dominate the current market, the high production costs, raw material supply risks, and safety concerns have urged the exploration of alternative chemistries. Zinc-ion batteries (ZIBs) have emerged as a promising candidate due to zinc's abundance, low cost, and compatibility with aqueous electrolytes, enhancing safety and environmental sustainability. However, zinc-ion batteries performance at sub-zero temperatures remains a critical challenge due to electrolyte freezing and degraded interfacial kinetics. To address these issues, the bonding between solvated water molecules and zinc ions needs to be weakened. One of the strategies is combining several different anions or cations to form a high entropy electrolyte (HEE) to reduce the water molecule in the solvation structure.
Here, we develop a self-driving electrochemical testing platform integrated with Bayesian optimization to autonomously explore and optimize low-temperature zinc electrolyte formulations. The platform enables automated formulation, real-time conductivity analysis with high accuracy, and iterative optimization. The optimized electrolyte demonstrates superior ionic conductivity (92.59 mS/cm at –20 °C) and prolonged cycle life in Zn | Zn symmetric cells compared to conventional ZnSO4 electrolytes. Additionally, it achieves stable coulombic efficiency in Zn | Cu half-cell at room temperature and enhanced rate capability in Zn | NaV3O8 full cells under –20 ℃. Furthermore, the self-driving electrochemical testing platform can be applied to other system for optimizing ionic conductivity, potential window, and other properties that can be measured by electrochemical methods
Approximating and Showing the Existence of Closed Orbits in Planar Differential Systems
Get PDFThis thesis investigates the finding of closed orbits and limit cycles in
continuous-time dynamical systems within the plane. The first part of the
work uses a geometric approach to understanding possible regions of space
in which a closed-orbit trajectory is possible. This analysis is applied to
quadratic systems that have been proven to have three or four limit cycles.
Then, aspects of this geometric approach applied numerically create an
algorithm that utilizes Poincar´e maps sequentially to find closed orbits of
several known systems. The results of this analysis and algorithm give
valuable tools that can be applied to find closed orbits within a certain
level of tolerance and could be extended in the future to find small regions
of the plane where closed orbits and limit cycles could be found
SUBJECT TO REVISION: CONFRONTING PRECONCEIVED NOTIONS, SCIENTIFICALLY
No full textAt many moments during this program, my research into a new subject of fascination forced me to reconsider a long-held assumption about myself or about the world. I look forward to those moments of reckoning, especially when they help me to become a more caring and well-informed member of my local and global communities. Through science communication, I am eager to help others find joy in confronting their own preconceived notions. The following articles and essays tackle my own assumptions about subjects like birth control side effects, natural beauty products, trauma responses, and more
Investigating Alphavirus Host-Protein Interactions as Determinants of Neurovirulence
Get PDFChikungunya virus (CHIKV) is an emergent, yet neglected, member of the Alphavirus genus and Togaviridae family. Historically viewed as a predominantly arithrogenic virus, CHIKV has increasingly been associated with neurological manifestations such as meningitis and encephalitis, as well as chronic sequelae involving hand inflexibility, general immobility, and depression. However, CHIKV central nervous system (CNS) infections remain ill-studied and overlooked, in part due to CHIKV misdiagnosis as dengue virus or Zika virus infection. Furthermore, of the CHIKV CNS studies available, most focus on neuronal infection, even though astrocytes are the known major CNS target. Studies within this thesis are the first to identify heterogeneous ribonucleoprotein K (hnRNP K) as a CHIKV host factor that regulates viral replication via modulation of subgenomic RNA translation, and thus structural protein synthesis. These in vitro experiments further identified the CHIKV hnRNPK-viral RNA binding site through genomic cross-alignment, RNA co-immunoprecipitation, and RT-qPCR analyses. Site-directed mutagenesis of this binding site to modify RNA secondary structure significantly attenuated viral replication and hindered both viral transcription and translation. Deeper mechanistic studies indicated that hnRNP K is mono-ADP-ribosylated, a post-translational modification that regulates hnRNP K affinity to bind RNA. Furthermore, these mono-ADP-ribose (MAR) residues appear to be cleaved by the CHIKV non-structural protein 3 (nsP3) macrodomain (MD), as demonstrated by protein co-immunoprecipitation and Western blotting experiments. Studies within this thesis therefore demonstrate that interaction between nsP3 and hnRNP K positively regulates CHIKV replication, E2 synthesis, and hnRNPK–vRNA binding affinity in astrocytes in vitro. In addition, investigations into alphavirus defective interfering particles (DIPs) as determinants of neurovirulence are furthermore explored. Through nanopore sequencing, we were able to identify novel alphavirus open-reading frame (ORF) products that appear to impact both viral replication and cell survival in a cell type-dependent manner. Future directions are subsequently explored and detailed
Disentangling Retest Effects in Cognitive Aging: Findings From ACHIEVE Study
Get PDFBackground: The ACHIEVE study, a multicenter randomized controlled trial, investigated the effect of hearing intervention on cognitive decline in older adults. However, retest effects - improvements in cognitive performance due to repeated testing – could potentially bias estimates of cognitive trajectories. Our study aimed to evaluate the magnitude of retest effects within ACHIEVE and examine whether retest effects varied by baseline hearing levels (30≤PTA<40 vs. 40≤PTA<70), trial interventions (health education vs. hearing aids), and population sources (ARIC vs. de novo).
Methods: We used data from 977 participants within ACHIEVE who completed in-person cognitive tests at baseline, year 1, and year 3, excluding year 2 due to COVID-19 disruptions. The primary outcome was the global cognitive factor score derived from a neurocognitive battery excluding auditory-dependent tests (Digit Span Backwards and Logical Memory Test). Secondary outcomes include domain-specific factor scores for language, executive function, and memory. The primary exposure was the retest effect, modeled as a binary indicator (0 for baseline test and 1 for subsequent tests). Linear mixed effect models were fitted to estimate the retest effects and longitudinal changes in cognitive scores, adjusting for demographic factors. Interaction terms were incorporated to assess whether the retest effect varied by features of interest.
Results: Significant retest effects emerged for global cognition, executive function, and memory, equating approximately to one year of cognitive decline, but was not observed for language. Participants with poorer baseline hearing exhibited smaller retest effects, while the de novo population showed stronger retest effects compared to ARIC population. Although the hearing intervention did not universally modify retest effects, it notably enhanced retest effects on global cognition and memory within the ARIC subcohort only.
Conclusions: Our findings highlight substantial retest effects in global cognition, executive function, and memory, emphasizing the importance of accounting for them in longitudinal cognitive studies. Tailored analytic strategies are recommended in studies using repeated neuropsychological testing
Structural Basis of Autoregulation in Diverse CRISPR Systems
No full textCRISPR-Cas systems are adaptive immune systems that provide bacteria and archaea with a heritable memory of past infection by invasive mobile genetic elements such as bacteriophage and plasmids. During infection, small fragments of foreign DNA, known as spacers, are inserted into CRISPR arrays within the host genome. These spacers are transcribed into guide RNAs, which are processed and assembled into CRISPR effector complexes. During reinfection, sequence complementarity between crRNA and the invading genome directs effector complexes to bind and destroy foreign DNA. CRISPR-Cas systems must be tightly regulated to prevent the acquisition of spacers from the host genome, which results in autoimmunity. In recent years, our understanding of CRISPR regulation has grown rapidly. While prior research has primarily explored transcriptional regulation by host factors, recent discoveries reveal that some CRISPR loci encode autoregulatory RNAs with partial complementarity to cas promoters. These RNAs guide effector complexes to bind but not cleave their own promoters, thereby repressing transcription. This thesis presents high-resolution cryo-electron microscopy structures of autoregulatory effector complexes from S. pyogenes and E. coli, both in the presence and absence of target DNA. Our findings demonstrate that these regulatory RNAs structurally mimic guide RNAs, and that limited complementarity with the target induces a conformational state in effector complexes that precludes DNA cleavage. These results highlight a conserved autoregulatory strategy that balances CRISPR immunity while safeguarding host genomic integrity
The impact of tobacco product use and dual/poly-tobacco use on depressive symptoms among cancer survivors: Evidence from the National Health and Nutrition Examination and Survey (NHANES) 2005-2018
Get PDFBackground: Depression is a more common experience among cancer survivors compared to the general population. Tobacco use is linked to depression in the general population, but its impact among cancer survivors remains underexplored, especially those using multiple tobacco products. This study investigates the association between tobacco use and depressive symptoms among U.S. cancer survivors.
Methods: We studied 3,366 adult cancer survivors who participated in the 2005 – 2018 National Health and Nutrition Examination Survey (NHANES) . Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), with scores ≥ 10 indicating clinically relevant depressive symptoms. Information on smoking status and use of specific combustible and smokeless tobacco products during the past five days was assessed using a self-reported questionnaire. Cancer survivors were categorized based on their tobacco use pattern as: non-user, mono-tobacco user (use of only one type of tobacco product), and dual/poly-tobacco user (use of ≥2 types of tobacco products). We evaluated odds ratios (OR, 95% confidence interval [CI]) for the presence of depressive symptoms comparing tobacco use patterns using logistic regression models, adjusted for sociodemographic characteristics and lifestyle factors. Sensitivity analyses were conducted using a broader depressive symptom threshold (PHQ-9 ≥ 5).
Results: Among participants, 81.5% were non-users, 17.3% were mono-users, and 1.1% were dual/poly-users. Depressive symptoms were present in 17.3% of cancer survivors. Compared to non-users, mono-users (OR = 2.04, 95% CI: 1.36 - 3.05), and dual/poly-users (OR = 3.00, 95% CI: 1.02 - 8.85) had significantly increased odds of depressive symptoms. Furthermore, sensitivity analyses using a lower PHQ-9 threshold (≥ 5) showed similar but attenuated associations. Conclusions: Tobacco use, particularly involving multiple products, was strongly associated with elevated depressive symptoms among cancer survivors in the U.S. This highlights the need for integrated approaches in survivorship care addressing both tobacco cessation and mental health interventions
Future Attachments: Women, Historical Narrative, and Politics, 1792-1856
No full textThis dissertation studies the melancholy futurism of three British feminists of the first half of the long nineteenth-century, Mary Wollstonecraft (1759-97), Mary Shelley (1797-1851), and Elizabeth Barrett Browning (1806-61). Each felt the loss of a progressive model of history, and thus of the possibility of such thing as the progressive public intellectual. Committed to thinking of women as historical subjects, and indeed privileged historical subjects, they were also committed to thinking through humankind’s embodiment as a material creature—priorities they struggled to harmonize. For each, that is, embodiment is a historical problem. Together, they thus offer a counterpoint to the tendency in Romantic and Victorian studies of the last few decades to hold up materiality as aperture onto the onward flow of history and/or as evidence and guarantor of critical agency. Instead, they approach an encounter with materiality as an opportunity to confront their own normative assumptions about which subjects get to count as historically exceptional and which do not