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UNDERSTANDING THE ROLE OF SEX HORMONES ON HUMAN IMMUNODEFICIENCY VIRUS-1 (HIV-1) PATHOGENESIS AND LATENCY
Get PDFSex and gender differences in HIV-1 acquisition, pathogenesis, and latency have long been observed but are not fully understood as there are many contributing factors such as sex hormones, sex chromosomes, epigenetic regulation, socio-economic behaviors, microbiome, immune regulation, etc. More generally, a large body of work exists to show that immune responses vary by sex although the contributions of the above factors are not fully detangled. Here, the impact of sex and gender differences on immune system function will be more thoroughly explored with a specific interest in HIV-1 latency and pathogenesis.
The first study explores the impact of the sex hormone, 17β-estradiol (E2) and how E2’s signaling via estrogen receptor α (ERα) affects CD4+ T cell transcription and function as is related to important factors for HIV-1 latency. E2-ERα transcriptional signaling demonstrated a lack of canonical/nuclear signaling that was further confirmed with ERα protein isoform profiling. E2 cytoplasmic signaling was observed in CD4+ T cells and points to a new direction for the field that recognizes the variations seen in ERα in CD4+ T cells.
The second study more broadly explores the impact of sex hormones on immune cell function in transgender women living with HIV (TWLWH). Because many aspects of gender can impact immune responses, the study was designed to limit gender-based factors that may impact immune responses to fully evaluate the effect of sex hormones on immune responses in TW(LWH). Immunophenotyping revealed a consistent impact of sex hormones on markers of metabolism and activation in TWLWH. This work helps to better understand the impact of sex hormones on immune responses in TWLWH.
Collectively, this work enhances the understanding of how sex hormones regulate the immune system in the context of HIV and provide a new framework for future work investigating the role of sex and gender in people living with HIV (PLWH)
Three-dimensional and high temporal resolution whisker deformation during textured surface whisking
No full textPurpose: The aims of this dissertation are (1) to establish a method for high temporal resolution 3D tracking of the full mouse whisker during interaction with surfaces, (2) to characterize the whisker-surface interaction during undirected whisking against varying textures, and (3) to characterize the neuronal encoding of texture in whisker follicle innervating primary mechanosensory neurons of the trigeminal ganglion (TG).
Methods: We performed 3D reconstructions of the whisker and surface based on the calibrated epipolar geometry of the stereo imaging system, and adapted 2D methods for the quantification of whisker shape, whisker mechanics, and whisker-object interactions to 3D. Simultaneous electrophysiological recordings in the whisker trigeminal ganglion provided single-unit responses aligned in time to the videographic data.
Results: Surface material affected whisker deformation and the amplitudes of texture-related dynamic whisker events, and some TG neurons exhibited material selectivity.
Conclusions: Surface stickiness (i.e. material identity) information is available to the whisker somatosensory system at the levels of whisker mechanics and primary mechanosensory neuron response
Leveraging analytical tools to evaluate the behavior of nanoscale anthropogenic materials in environmental matrices
Get PDFThe impact of nanoscale materials in environmental matrices can be disproportionately large. Engineered nanomaterials have garnered attention as a promising tool for sustainable agriculture, as they have been demonstrated to deliver pesticides, nutrients, and other cargo of interest more efficiently than conventional methods. In plant systems, the interactions of engineered nanomaterials are influenced by many factors such as particle size, composition, surface charge and charge density, and plant composition. As more and more nanomaterials are being designed specifically for use in nano-enabled agriculture, it is important to understand the mechanisms behind their interactions. Model plant systems show promise in being a high-throughput tool to probe nanomaterial interactions with plant cell walls, which are the main barrier nanomaterials face in entering the plant cell. Using model systems to mimic the plant cell wall, we examined how nanoparticle charge, size, and solution chemistry regulate nanoparticle adsorption to and penetration through the plant cell wall. Our findings demonstrate that small, positively charged nanoparticles adsorb and penetrate most efficiently, and that calcium-induced crosslinking can selectively restrict or permit nanoparticle movement, highlighting the complexity of nanomaterial uptake in plant systems. These insights can inform the development of nano-enabled agricultural technologies while also guiding environmental risk assessments.
Beyond nanomaterials, micro- and nanoplastics (MNPs) are increasingly detected in the environment, raising concerns about their interactions with plants and potential for uptake into edible plants. MNPs can serve as vectors for plastic additives and organic pollutants, which may enter food chains through plant uptake. However, detecting and quantifying MNP movement within plant systems remains a challenge. To address this, we developed labeling strategies to track MNP accumulation in hydroponically grown plants. Our results indicate that MNP uptake is size-dependent, with preferential accumulation in roots, and that associated contaminants are also taken up into the plant and can undergo metabolic transformations.
In addition to their impact on food systems, plastic-derived chemicals also pose risks to drinking water quality. Phthalates, widely used as plasticizers in drinking water distribution systems, can leach from polyvinyl chloride (PVC) pipes and react with free chlorine present in the drinking water as a disinfectant. These reactions can generate disinfection byproducts, altering the composition of contaminants in drinking water. Understanding these processes is essential for evaluating potential human exposure and developing safer materials for water distribution.
Together, these studies highlight the complex interactions between nanomaterials, plastics, and environmental systems. By improving our ability to track material movement and transformations in environmental and agricultural contexts, we can better assess risks and design safer, more sustainable technologies
Embodying Intelligence in 3D Microfabricated Devices for Soft Robotics and Engineered Living Materials
No full textEmbodying intelligence into materials involves creating systems that autonomously sense, adapt, and respond to environmental stimuli and biological cues, mimicking the dynamic behaviors of natural organisms. Incorporating these concepts to build devices is one of the scientific ‘Grand challenges’ directly impacting soft robotics and bioengineering. Previously, researchers have done so by building bioinspired devices with stimuli-responsive materials like hydrogels or interfacing materials directly with biology to create intelligent biological hybrids that can sense and actuate. However, these structures and devices often only work in certain conditions; they are tethered and lack complexity. My dissertation advances this by developing untethered robots that autonomously navigate unstructured environments and designing systems for large-scale organoid culture, offering more adaptable, scalable solutions for bioengineering and robotics.
In the first part of the research, I developed a bio-inspired, untethered, unidirectional bilayer gelbot that mimics the inchworm's locomotion. By adjusting linker stiffness, morphology, and segment count, I demonstrated precise control over the robot's displacement, with movement biased toward the direction of asymmetry. These thermoresponsive soft robots autonomously navigate unpatterned surfaces, showing promising potential for applications in targeted drug delivery and bio-actuation.
The second focus of my work is on interfacing synthetic materials and devices with biology to create devices to sustain engineered living materials (ELMs) like neural organoids (NO). NOs derived from human-induced pluripotent stem cells model neurodevelopment and disease. However, they are limited by core necrosis from diffusion constraints beyond 500 µm, hindering their complexity and effectiveness as disease models. Based on inputs from the computational modeling of necrosis in a NO, I designed, and fabricated multimodal 3D microfluidic platforms, integrating synthetic vasculature and embedded electrodes, to support long-term culture of organoids. These systems enable the growth of NOs up to 10 mm while maintaining organoid viability and long-term electrophysiological monitoring. I also tested the robustness of my platform across 3D culture systems with a long-term GFP-producing bacterial culture.
The findings presented in this dissertation contribute to the advancement of intelligent material systems that can sense, adapt, and actuate within dynamic environments. These bio-inspired robots and culture platforms pave the way for innovations in soft robotics, drug delivery, disease modeling, and tissue engineering, bridging synthetic and biological systems, and laying the foundation for scalable, intelligent systems in future applications
Psychometric Evaluation of brightwheel’s Experience Assessment
Get PDFThe purpose of this psychometric evaluation was to assess the validity and reliability of
brightwheel’s Experience Assessment. The assessment was designed to be used by
early learning center educators to obtain a comprehensive and multidimensional view of
a child’s learning journey across eight domains of development. The primary focus of
this report is on the evidence for the assessment’s reliability and validity as
demonstrated by indicators of domain score distributions, internal consistency reliability,
measurement invariance, and item-test correlations.
● The present study used a purposive sample of 593 students 0-5 years of age in
10 early learning centers across eight U.S. states.
● Trained educators used the assessment to rate students, collecting data during a
5-week period in the spring of 2025.
● The assessment measure consisted of eight domains divided into 73 sub-skills.
On each sub-skill, students could be rated from benchmark 1 (infants) to 8
(primary grades).
● Results showed that domain score distributions were generally normally
distributed and moved in the expected direction across student ages (i.e., higher
scores for older children), suggesting that the assessment produces scores that
align with the developmental progress expected.
● Sub-skills within each domain were highly inter-correlated. For all domains,
Cronbach’s alpha was >.90, indicating excellent internal consistency reliability
and providing evidence that sub-skills within a domain measure the same
underlying concept.
● Internal consistency patterns were sustained when comparing subgroups of
students in centers that used brightwheel’s broader Experience Curriculum to
students in centers that did not, as well as when disaggregated by curriculum
product lines (i.e., Preschool, Toddler, Baby). The assessment’s similar
performance across groups provided evidence of measurement invariance.
● All individual items were positively and highly (r >.80) correlated with their
respective total domain scores, and thus no items were recommended for
exclusion from the assessment.
● Overall, the findings provided strong evidence regarding the reliability and validity
of the Experience Assessment across all assessment domains and curriculum
product lines, contributing initial support for the assessment as a tool to measure
early learning milestones
Sumerian Texts on Prisms in the Old Babylonian Period
No full textScholars studying how scribes were trained to read and write in the Old Babylonian period (ca. 1,900-1,600 BC) in Mesopotamia have long realized that school texts come in a variety of different shapes and sizes, and that these differences reflect different pedagogical functions within the context of the ancient scribal school. Early work on scribal education classified these school texts into one of five categories, based on their physical shape: Type I tablets, Type II tablets, Type III tablets, Type IV tablets, and prisms.
Previous scholarship has suggested the pedagogical function of Type II, Type III, and
Type IV tablets, based on a comprehensive study of their physical form, the compositions inscribed on them, the types of errors they contain, and their archaeological context. Yet such studies are lacking for both Type I tablets and for prisms, and the present dissertation aims to comprehensively treat this latter category.
This dissertation’s examination of the distribution of prisms reveals that they are much more frequent at the elementary level of scribal education; at the advanced level, their use is restricted to a small group of compositions. Moreover, the errors contained in the texts inscribed on prisms at the elementary level suggest that copying from another source played a prominent role in the creation of these objects at that level; by contrast, at the advanced level, the primary method of production was, as with advanced tablet sources, memorization.
The dissertation also argues that, in most cases, to produce a longer text, scribes did not use a prism with a higher number of faces, but either increased the number of columns or increased the size of the object. There is some evidence, particularly from the prism HS 1501 examined in chapter iv, that scribes did not plan out the distribution of lines beforehand, and that they therefore often accidentally ran behind and needed to catch up by increasing the number of lines per face.
Finally, the dissertation provides a complete catalogue of prisms from Old Babylonian
Nippur and a new translation and philological commentary of the composition Lipit-Eštar A
CONSTRUCTION OF ARTIFICIAL RNA GENOMES IN YEAST
No full textWhile most of the living organisms have evolved to use DNA molecules as the carriers of genetic information, it is widely accepted that before the emergence of DNA, RNA molecules served as the genetic material in the primordial RNA world. Constructing RNA-based genomes using a synthetic biology approach provides a unique opportunity to investigate the fundamental principles of early life. However, our current understanding of RNA genome design, particularly the structure-function relationships governing RNA genome stability and replication, is largely limited to a few well-characterized structural elements.
In this dissertation, I explored the design principles of RNA genomes by analyzing the global secondary structures of natural ScNV20S and ScNV23S RNA genomes in Saccharomyces cerevisiae, demonstrating that the pervasive RNA folding plays an essential role in RNA genome maintenance. To enable the engineering of viable RNA replicons, I developed SCfold, a structure-constrained coding sequence (CDS) inverse folding algorithm, for manipulating RNA genomes towards desired secondary structures while preserving their protein-coding capacity. Furthermore, I established a two-vector launching system for RNA replicons in yeast, facilitating the construction of extended RNA genomes with increased gene content and larger sizes than the natural narnavirus genomes.
Through these approaches, I found that the pervasive internal structures of narnavirus-based RNA genomes are not required for RNA-dependent RNA polymerase (RdRp) recognition and replication but instead contribute to RNA genome stability. The results of this thesis provide valuable insights into the feasibility of using RNA as a self-sustaining genetic material. The computational and experimental methodologies developed enable the rational design of viable RNA genomes, paving the way for creation of synthetic RNA-based lifeforms. These tools could be applied beyond studies of RNA genomes, with broad potential applications in RNA biology and synthetic biology
Diet and Early Childhood Caries in Colombia: A Cross-Sectional Analysis of ENSAB-IV
Get PDFBackground: Early Childhood Caries (ECC) is a highly prevalent condition in Colombia, and its association with diet is well established. However, dietary patterns are shaped by complex contextual factors, and the correlation between diet and ECC at the national level has not yet been analyzed in Colombia. This study aimed to examine the association between dietary intake and ECC among preschool-aged children using nationally representative data.
Methods: We conducted a secondary analysis of the IV National Oral Health Study (ENSAB IV), Colombia’s latest cross-sectional survey from 2013–2014, which included a nationally representative sample of children aged 1, 3, and 5 years. ECC experience was defined as a dmft-ICDAS Epi score ≥1, with an additional classification for severe ECC. We evaluated associations between ECC and nine food groups. Poisson regression models with robust variance were used to estimate adjusted prevalence ratios.
Results: Dietary intake was differentially associated with ECC. Children who consumed vegetables eight or more times per week had a 6% lower prevalence of ECC compared to non-consumers. In contrast, high consumption of soda, juice, and fats was associated with a 17%, 7.5%, and 6% higher prevalence of ECC, respectively. No statistically significant associations were found for other food groups. Dietary patterns varied by age and region, and intake of free sugars exceeded recommended guidelines.
Conclusions: Regional variability in dietary patterns should be considered in the implementation of national public health policies on childhood nutrition and oral health. The high consumption of sugar-sweetened beverages and sweets underscores the urgent need for population-level interventions to promote healthy dietary behaviors
Sympathetic innervation as a negative regulator in islet plasticity during pregnancy in mice
Get PDFPancreatic islets of Langerhans are essential for glucose homeostasis, and the loss of insulin-producing beta-cells in islets or their dysfunction causes diabetes. Pregnancy is a unique physiological condition during which islets show striking morphological and functional plasticity during adulthood. During pregnancy, increased islet mass, elevated proliferation of insulin-producing beta-cells, and enhanced insulin secretion to compensate for increased insulin resistance. Failure of these islet adaptive responses to the increased metabolic demand during pregnancy has been proposed to contribute to gestational diabetes. Thus, it is critical to understand the molecular mechanisms that underlie islet plasticity during pregnancy. Many of the mechanisms that contribute to islet plasticity during development and in times of pathological metabolic stress have also been explored during pregnancy; however, one of the pathways that has remained unexplored is neuronal input from sympathetic nerves. This input is important for controlling hormone secretion and maintaining glucose homeostasis, but their effect during pregnancy has not yet been studied.
Using iDISCO-based tissue clearing and 3D imaging, we found that sympathetic nerves undergo structural changes as the islet mass expands during pregnancy in mice. Furthermore, chemical ablation of nerves using 6-OHDA revealed that denervation results in increased islet area and cell proliferation in pregnant mice compared to pregnant mice with intact nerves. Pregnant mice injected with 6-OHDA also exhibit increased insulin secretion in response to a glucose challenge; they also displayed improved glucose tolerance and insulin sensitivity at gestational day 16, compared to vehicle-treated pregnant mice.
Islet plasticity during pregnancy is a tightly regulated process in which negative regulatory pathways are likely to be as important as positive regulatory pathways to prevent unrestricted beta-cell proliferation, islet expansion, and insulin secretion. Our results suggest a previously uncharacterized role for sympathetic nerves in acting as a ‘brake’ to prevent excessive islet growth and insulin secretion during pregnancy
ASSESSING PROTEIN FOLDING ACROSS SCALES AND DOMAINS OF LIFE
No full textProteins are the workhorses of our cells- performing many functions essential for life. To execute their designated tasks, most proteins must fold into their native conformations efficiently. Protein folding has been studied extensively for small proteins. However, extant proteomes are primarily composed of large multidomain proteins which follow more complicated folding pathways. This increased complexity leads to an increased propensity to aggregate, making them more challenging to study by traditional methods. In this thesis, I developed two methods that enable the study of larger, more complex proteins: in vitro experiments with optical tweezers and reporter assays in living mammalian cells.
Optical tweezers are a powerful single-molecule technique to study protein folding. As with most single-molecule methods, optical tweezers require small amounts of sample to collect data. However, the technique is limited to proteins that can be readily purified. In chapter 2, I describe a method I developed to overcome this constraint. By relying on a highly efficient and specific tethering system, I can directly pull-out proteins of interest from bacterial and mammalian cell lysates with minimal purification. This approach facilitates efficient screening of proteins. It is especially useful for large multidomain proteins and eukaryotic proteins which are often difficult to express and purify.
In chapter 3, I describe a method I developed using arrest peptides to detect co-translational folding and chaperone binding in cultured human cells. Arrest peptides (APs) are protein sequences that, once translated, cause the ribosome to stall. It has been demonstrated that co-translational protein folding leads to arrest release in bacteria, but the human system is much less well understood. My results suggest that AP translation stalling can be released by binding of chaperones near the exit tunnel in human cells. Chapter 4 outlines preliminary work aimed at expanding this assay to explore human proteins and enhance throughput, enabling parallel screening of multiple proteins.
Overall, the methods developed in this thesis enhance our ability to study the folding of complex proteins in vitro and in vivo. This knowledge is crucial for addressing the causes of protein misfolding linked to diseases such as Parkinson’s and Alzheimer’s