71446 research outputs found
Sort by
Manipulation of urease within the gut microbiome using small-molecule inhibitors
No full textMicrobial urea metabolism plays a critical role in shaping gut microbial ecology and host nitrogen balance, yet its mechanistic underpinnings and therapeutic potential remain underexplored. In my thesis work, we sought to advance our understanding of urea metabolism within the gut microbiome and evaluate the therapeutic potential of small-molecule urease inhibitors to modulate host-microbe interaction. In my thesis work we sought to advance our understanding of urea metabolism within the gut microbiome and evaluate the therapeutic potential of small-molecule urease inhibitors to modulate host-microbe interactions. Using an interdisciplinary approach that integrated bioinformatics, chemical biology, organic synthesis, microbiome profiling, and in vivo physiology, we investigated microbial urease as a conserved and druggable enzyme within the gut microbiome. We identified and characterized urease homologs across human, ancient, and murine microbiomes, revealing broad phylogenetic distribution and active site conservation. We further evaluated benurestat, a hydroxamic acid-based inhibitor, through structure–activity relationship studies and demonstrated its potency, gut-restriction, and therapeutic efficacy in reducing ammonia levels and improving survival in murine models of acute liver injury. Altogether, my thesis establishes a mechanistic and translational framework for targeting microbial urease and supports the development of gut-restricted small-molecule inhibitors to modulate host-microbe interactions in disease
Chapter 2 presents a comprehensive bioinformatic and structural analysis of urease-encoding genes across human, murine, and ancient microbiomes. Using a sequence-structure-function pipeline developed in collaboration with the Huttenhower lab, we identified hundreds of microbial urease homologs, characterized the structural conservation of a selection of diverse sequences, and highlighted widespread preservation of active site residues across phylogenetically diverse taxa. These findings underscore the broad evolutionary conservation of urease and support its tractability as a microbiome-targeted enzyme. This chapter also addresses common challenges in urease annotation and emphasizes the need for integrated functional validation.
Chapter 3 focuses on the discovery and structure–activity relationship of hydroxamic acid-based urease inhibitors, with an emphasis on benurestat as the main scaffold. Comparative biochemical assays demonstrated that benurestat is a potent and selective inhibitor of bacterial urease, outperforming earlier compounds such as acetohydroxamic acid. Through synthetic modifications and docking-guided design, I characterized key structural determinants of inhibitor potency and selectivity. Notably, halogenated derivatives improved activity, while modifications to the α-amino acid motif reduced efficacy, pointing to structural constraints within the urease active site. These studies provide medicinal chemistry insights that guide further optimization of gut-restricted urease inhibitors.
Chapter 4 establishes the in vivo therapeutic potential of benurestat, a gut-restricted small-molecule urease inhibitor, in murine models of hyperammonemia and acute liver injury. Unlike less selective or systemically absorbed analogs, benurestat significantly reduced both fecal and serum ammonia levels, preserved gut microbial structure, and conferred complete protection against lethal thioacetamide-induced liver injury. Comparative studies with other known urease inhibitors, including AHA, flurofamide, and ebselen, demonstrated benurestat’s superior potency, gut localization, and therapeutic efficacy. Control experiments with an inactive analog (KRC40) confirmed that the observed effects were driven by specific inhibition of microbial urease. Metagenomic analysis further revealed that benurestat may be modulating the gut microbiome without inducing broad dysbiosis and supporting a distinct microbial signature under hepatic stress. Together, these findings validate microbial urease as a clinically relevant and tractable target and demonstrate that gut-restricted enzyme inhibition can yield meaningful host benefits by precisely modulating microbial metabolism in disease.
Collectively, this thesis defines a thorough mechanistic and translational framework for targeting gut microbial urease to modulate host-microbe interactions in disease. Through an integrated approach combining comparative genomics, structural bioinformatics, chemical biology, synthetic chemistry, and in vivo murine models, this work reveals that urease is a broadly conserved and druggable microbial enzyme across human-associated microbiomes. Detailed structure–activity relationship studies guided the identification and optimization of benurestat, a potent and gut-restricted urease inhibitor that effectively lowers systemic ammonia levels and protects against lethal liver injury in preclinical models. Rigorous experiments confirmed urease-specific mechanisms, while metagenomic profiling demonstrated that therapeutic efficacy can be achieved without inducing broad disruption of the gut microbiota. Altogether, this body of work not only establishes urease as a clinically relevant microbial target but also advances the broader concept of using small-molecule inhibitors to selectively modulate microbial metabolism with precision and translational potential.Chemistry and Chemical Biolog
Methods for visualizing a whole human chromosome in super resolution and distinguishing maternal and paternal homologs genome-wide
No full textChromatin is organized into discrete units called chromosomes, which form chromosome territories (CTs) in interphase cells. Chromatin and chromosome organization play a critical role in genome regulation and inheritance, with misfolding leading to diseases such as developmental disorders and cancers. Thus, these fundamental features of chromatin organization and their consequences are being intensely studied across genomic scales. The process, however, is complex and demanding. For example, at the single-cell level, the genome exhibits extensive structural variability, making it challenging to establish structure-function relationship. Furthermore, using allele-specific techniques, variability has been observed between homologs at known imprinted regions and between the two X chromosomes during X-chromosome inactivation. Yet, how sub-chromosomal regions fold across an entire chromosomal fiber to form CTs in single cells and how the paternal and maternal homologs differ remain challenging to address. In my dissertation, I describe the development of two in situ imaging technologies. The first method enables imaging of an entire chromosome in super-resolution using OligoSTORM single-molecule localization microscopy (SMLM). We applied this technology to capture human chromosome 19, revealing its 3D volumetric structure from a 1-Mb genomic resolution to the scale of an entire 56-Mb chromosome with nanometer precision. My goal was not only to reveal chromosome 19 in 3D super resolution, but also to capture its 3D volumetric features, including volume and ellipticity, among others. The second method extends the application of Homolog-specific Oligopaints (HOPs), a FISH-based technology, to identify the parent-of-origin (PO) of homologous chromosomes across the entire human genome. We demonstrated the scalability of HOPs by identifying the PO for all 22 pairs of homologous chromosomes, plus the sex chromosomes. Finally, we integrated chromosome-19 HOPs with whole chromosome-19 OligoSTORM imaging, offering a first look at the 3D structures of both the paternal and maternal chromosome 19 with super resolution in human cells. We envision that our OligoSTORM imaging approach could scale to whole-genome studies. Furthermore, these methods together could enhance studies of allelic regulation, such as X-chromosome inactivation and genomic imprinting, and how allelic regulation is linked to allelic chromatin organization at the single-cell level.Biological and Biomedical Science
Understanding pathological narcissism: Empirical explorations of clinical phenomena
No full textPathological narcissism is a controversial and poorly understood construct. The present
dissertation aims to advance the understanding of pathological narcissism with empirical
research motivated by clinical theory. In three papers, we examine cognitive, affective, and
behavioral components of pathological narcissism that can inform conceptualization and clinical
intervention. In Paper 1, we characterize self-bolstering cognitive tendencies in the memory
recall and future thinking of people scoring high in narcissistic grandiosity. These tendencies
may inform how people develop and maintain an enhanced sense of self. In Paper 2, we examine
the regulatory function of grandiose fantasizing. We demonstrate that grandiose fantasizing is
effectively used as an affect regulation strategy among participants scoring high in narcissism,
lending empirical support to a longstanding clinical theory. In Paper 3, we examine an
underexplored and harmful behavior associated with pathological narcissism – nonsuicidal self-injury
(NSSI). We identify strong associations between narcissistic grandiosity and engaging in
NSSI for interpersonal reasons (e.g., bonding with peers, seeking revenge), but not for
intrapersonal reasons (e.g., regulating affect). Together, these studies show consistent differences
across cognitive, affective, and behavioral domains between individuals scoring high and those
scoring low in pathological narcissism. We hope this work contributes to the growing body of
literature that is clarifying and destigmatizing this perplexing personality pathology.Psycholog
A New Field in Mind: A History of Interdisciplinarity in Early Brain Sciences
No full textAuthor's Origina
Prowess: Battling Cancer While Living
No full textProwess is novel about a woman's determination and survival in the face of adversity from
both within and without. Willow Adair faces not just external trials-- infidelity, neglect, a
family in disarray--but a second front as well in her rocky battle with cancer and recovery
from other accidents and illnesses. Through Willow's story, the novel explores the
resiliency and strength of the human spirit, offering a hopeful vision not only of survival
but also renewal
Women Who Cross Their Legs
No full textJade Porter knew her small-town life could be perfect, if absolutely everything about it was different. She didn’t want to have to lean on shopping carts to get through Walmart like her Nana and cousins. She wanted to be fit. She wanted to be fancy like the women on TV, like the women in fashion magazines - like women who crossed their legs.
After a college hazing incident left her behind bars and covered in the blood of three volleyball teammates – Jade’s wish came true. Suddenly, she wasn’t a white co-ed in a Confederate-leaning family from Georgia. Jade became the oldest by minutes, of three sisters with her same face . . . but different skin tones. Who are you when everything you thought you knew about yourself was a lie? And why had so many hands spent millions to keep the sisters separated
Assessing Teachers' Mathematical Knowledge: What Knowledge Matters and What Evidence Counts?
No full textAccepted Manuscrip
Timed chromatin invasion during mitosis governs prototype foamy virus integration site selection and infectivity
No full textSelection of a suitable chromatin environment during retroviral integration is a tightly
regulated and multilayered process that involves interplay between viral and host factors.
However, whether intrinsic chromatin dynamics during mitosis modulate retroviral
genome invasion is currently poorly described. Direct interaction between the
spumaretrovirus prototype foamy virus (PFV) Gag protein and cellular chromatin has
been described as a major determinant for integration site selection. A previous Gag
chromatin-binding site (CBS)–nucleosome co-crystal structure revealed an interaction
with the histone H2A-H2B acidic patch via a highly conserved arginine anchor residue.
Yet, the molecular mechanisms regulating Gag-chromatin capture during PFV infection
remain obscure. Here, we investigated the kinetics of Gag-chromatin interactions during
mitosis and proviral integration of PFV-infected synchronized cells. Using Gag CBS variant
viruses, we showed that alteration of Gag affinity for nucleosome binding induced
untimely chromatin tethering during mitosis, decreased infectivity and redistributed viral
integration sites to markers associated with late replication timing of host chromosomes.
Mutant Gag proteins were moreover defective in their ability to displace the histone H4
tail from the nucleosome acidic patch of highly condensed mitotic chromatin. These data
indicate that the mitotic chromatin landscape during Gag–nucleosome interactions hosts
PFV integration site selection determinants and that spumaretroviruses evolved high-
affinity chromatin binding to overcome early mitosis chromatin condensation for optimal
viral DNA tethering, integration and infection.Author's Origina
Patriots for Profits: An Investigation into the Crimes and Mismanagement of American Manufacturing Corporations during the First World War Era
No full textAmerica’s military-industrial complex suffered from widespread profiteering that severely hindered its efficiency and performance during the nation’s involvement in World War I. Of all American industries that suffered the most from corruption and theft, aircraft production suffered the most. This thesis explores the extent of the damage caused by profiteering by individuals and companies on the American aeronautic industry along with case studies exploring the effect of profiteering on lumber and copper production. This research argues that profiteering led to the widespread inefficiencies, reduced quality, and shortages experienced by the American military-industrial complex in the First World War. With over one billion dollars spent on building a modern air service between 1917 and 1918, unadjusted for inflation, the Americans failed to produce more than one type of operational combat plane and never produced a pursuit plane. The Aircraft Production Board and War Department only issued contracts for the mass production of a single airplane motor, the Liberty Motor, which proved too large and powerful to be used in any small pursuit fighter planes forcing them to be utilized in the large and unpopular DH-4 type. The favoritism of the Liberty Motor along with certain manufacturing companies had its origin not in ignorance exclusively, but in corrupt profiteering