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UNDERSTANDING RESISTANCE AND PERSISTENCE OF MYCOBACTERIUM ABCESSUS TO COMMON CLINICAL DRUGS TO PROPOSE AN OPTIMIZED TREATMENT REGIMENT
No full textBacterial diseases are treated with antibiotics. Historically, only two criteria are prioritized to select antibiotics for treatment of bacterial infections. These criteria are efficacy and lack of adverse events. Another critical aspect that is often overlooked is how often bacteria become resistant to these antibiotics. Antimicrobial resistance (AMR) is a major public health concern and being able to understand how often bacteria become resistant to these treatments may help us develop novel regimens to minimize AMR emergence and allow us to use current antimicrobial tools for longer. Current literature and drug development practice focuses on the efficacy of and the adverse events (side effects) of the drug, but rarely do they consider how frequently these infections develop resistance or persistence to these drugs.
Mycobacterium abcessus is an emerging pathogen whose infection is difficult to treat partly due to rapid AMR emergence against existing antibiotics. Understanding how M. abcessus reacts to clinically used drugs in vitro based on current clinical knowledge will allow us to develop new testing protocols to see if these drugs have synergistic or antagonistic effects when used together, since M. abcessus disease is treated with a multi-drug regimen. This research utilizes a “Bedside to Benchside” process where we take the knowledge of the clinic (bedside) and combine it with lab techniques (benchside) to generate new information that can fill in any knowledge gaps in the clinical practice and more effectively treat M. abcessus infection.
This thesis is organized into three different sections that build on one another to generate insight into how frequently M. abcessus mutates to gain resistance against the commonly used drugs in clinical settings to treat M. abcessus infections. These findings, as mentioned in the previous paragraph, will allow us to understand how often and how much we can use our current tools and for how long, a vital part of minimizing AMR from overtaking a population and causing patient morbidity and mortality, therefore providing a novel multi-drug regimen from our current tools based on how frequently we see AMR mutations
ASSOCIATION OF CARDIOVASCULAR-KIDNEY-METABOLIC SYNDROME SEVERITY WITH LOW BONE MINERAL DENSITY: NHANES 2005–2018
No full textAbstract
Background:
Cardiovascular-Kidney-Metabolic (CKM) syndrome is a recently defined framework capturing the interconnected pathophysiology of obesity, metabolic dysfunction, kidney disease, and cardiovascular complications. CKM syndrome may impair bone health through chronic inflammation, insulin resistance, and adipokine dysregulation. Low bone mineral density (BMD) is a major risk factor for fractures, which increase healthcare costs due to complications such as impaired mobility, venous thromboembolism, and hospital-acquired infections. Despite the high prevalence of CKM syndrome, its relationship with bone health remains unclear. Understanding this association could enhance fracture risk assessment and early intervention strategies.
Methods:
We conducted a cross-sectional analysis of 9,186 adults aged ≥40 years from the National Health and Nutrition Examination Survey (NHANES) 2005–2018. Participants were classified into CKM stages (0–4) based on American Heart Association criteria. BMD was measured at the femoral neck, lumbar spine, and total hip using dual-energy X-ray absorptiometry. Multivariable logistic regression models assessed associations between CKM stages and BMD categories (normal, osteopenia, osteoporosis), adjusting for demographics, socioeconomic status, lifestyle factors, laboratory measures, and glucocorticoid use.
Results:
Among U.S. adults ≥40 years, 93.9% had CKM syndrome, with 26.8% at advanced stages (3–4). A non-linear relationship was observed between CKM stages and BMD. Stage 1 (overweight/obesity or prediabetes) was associated with the highest prevalence of normal BMD (64%; 95% CI, 60.8%–67.3%) and the lowest prevalence of osteoporosis (5%; 95% CI, 3.5%–6.5%). Advanced stages showed higher osteopenia (46.8% and 44.7%) and osteoporosis (13.9% and 12.0%) rates compared to Stage 1. Stage 0 (metabolically healthy, normal weight) also had high osteopenia (49.5%) and osteoporosis (10.8%) prevalence. Site-specific analyses indicated that femoral neck BMD was most affected, while hip BMD remained relatively preserved. However, associations with bone loss were no longer significant after adjusting for age.
Conclusions:
CKM syndrome severity is linked to bone health deterioration, especially at the femoral neck. The early increase in BMD associated with obesity diminishes with advanced CKM stages. These findings underscore the importance of bone health monitoring in patients with CKM syndrome, particularly at advanced stages
GENETIC VARIATION IN ENTPD1 IS ASSOCIATED WITH CD39+ CD120b+ REGULATORY T CELL PROPORTIONS IN MEN WITH AND WITHOUT HIV
No full textBackground: People living with HIV are at increased risk of coronary artery disease (CAD), even with effective antiretroviral therapy. Chronic inflammation is thought to play a role in this increased risk. Regulatory T cells (Tregs), particularly those expressing CD39 and CD120b, may help regulate inflammation. Previous studies have shown that Treg proportions are under strong genetic control, but the genetic determinants of functionally distinct Treg subsets in people living with HIV remain unclear.
Methods: We measured proportions of CD4+ T cells, Tregs (CD4+ CD25+ FOXP3+), and a Treg subset co-expressing CD39 and CD120b using flow cytometry in 347 men from the Multicenter AIDS Cohort Study (MACS). We performed a genome wide association studies for assocations with CD4+ T cell proportions, Treg cell proportions, and CD39+ CD120b+ Treg cell proportions in a liner mixed model using the Illumina MEGA array. We further evaluated effect modification by HIV status and genetic ancestry.
Results: We did not observe any genome-wide significant associations for total CD4+ or bulk Treg proportions. However, we identified a genome-wide significant association for CD39+ CD120b+ Treg proportions on chromosome 10 at the ENTDP1 gene. The most significant SNP, rs4917714, was associated with a 0.96 standard deviation increase on the inverse-normal transformed scale, which corresponds to an estimated 20 percentage point increase in raw CD39+ CD120b+ Treg proportions per effect allele (p = 1.1 x 10-31). This association was consistent across HIV status and ancestry groups, with no significant interactions observed.
Conclusion: Genetic variation in ENTPD1 is strongly associated with the proportion of CD39+ CD120b+ Tregs, independent of HIV status. These findings extend previous reports linking ENTPD1 to CD39 expression and highlight a potential mechanism contributing to inflammation and CAD risk. Future analyses will assess whether Treg variation predicts plaque progression in this cohort
IOPs to SNARKs: Security from Practice to Theory
Get PDFInteractive Oracle Proofs (IOPs) are a powerful proof system model that combines features of probabilistically checkable proofs and interactive proofs. While IOPs have enabled remarkable advances in zero-knowledge proofs, verifiable computation, and other cryptographic applications, their security properties when transformed into non-interactive proofs remained partially understood. This transformation pathway - from IOPs to Succinct Non-interactive ARguments of Knowledge (SNARKs) via the Fiat-Shamir transform - has become the foundation for many deployed proof systems. Understanding the security of this transformation is crucial as these SNARKs secure millions of dollars in blockchain transactions daily.
This dissertation begins with a focused analysis of the Fiat-Shamir security of the FRI (Fast Reed-Solomon Interactive Oracle Proof of Proximity) protocol. This analysis was motivated by FRI serving as a critical component in several deployed proof systems securing hundreds of millions of dollars of assets on various blockchains. The second part of this analysis examines the concrete security of the deployed, non-interactive FRI implementations. This quantifies a previously expected, but significant gap between FRI's provable security parameters in the random oracle model and the conjectured bounds assumed in implementations.
The second part of this dissertation takes a deeper look at soundness notions in IOPs. Building upon recent advances in understanding Fiat-Shamir security, we expanded the existing frameworks that establish relationships between various soundness notions. Our work extends multiple pathways to proving the soundness of IOPs, contributing to a comprehensive understanding of their security properties
COLORING OUTSIDE THE LINES: A LIBERATORY DESIGN FRAMEWORK FOR DEI LEARNING AND EXPLORATION
Get PDFColoring Outside the Lines: A Liberatory Design Framework for DEI Learning and Exploration disrupts the one-size-fits-all approach to traditional diversity training, advocating for a human-centered, equity-driven model tailored for teachers in alternative licensure programs.
Chapter 1 examines how race shapes educational experiences and outcomes, particularly through the lens of White dominant culture (WDC). It highlights the systemic barriers that reinforce racial inequities in education, emphasizing the reciprocal influence of socialization, identity development, and institutional policies on teacher-student interactions. Chapter 2 outlines a needs assessment examining teacher perceptions of diversity training at ALTPRP, an alternative licensure program. Findings revealed variances in participant perceptions of the training across racial identities. These findings raise critical concerns about the effectiveness, inclusivity, and broader socio-ecological factors influencing participant engagement in diversity training programs. Chapter 3 expands on the social ecology of diversity training, framing diversity training spaces as interpersonal interactions embedded within educational and organizational systems. The social ecological model is introduced to highlight the interconnected relationships between participants, training design, cultural influences, and training contexts. Chapter 4 outlines a liberatory design process for DEI learning and exploration, leveraging design science research to create a human-centered approach that centers on the voices of participants. In Chapter 5, I introduce A Guide to Facilitating Liberatory DEI Learning & Exploration and reflect on my experience creating a resource to help facilitators design and lead DEI learning using the Coloring Outside the Lines framework
Deciphering Mitochondrial Roles of XIAP During Sublethal and Lethal Cellular Stress
No full textMitochondria play central roles in determining cell fate, balancing between support of survival and triggering of apoptosis in response to cellular stress. The X-linked inhibitor of apoptosis (XIAP) is best known for suppressing caspase activity, yet emerging evidence suggests it also directly regulates mitochondrial stress responses. This thesis sought to investigate how XIAP influences the decision between cell death and survival across varying severities of cellular insults that are sensed by mitochondria. Using immunoblotting and fluorescence microscopy I compared mitochondrial integrity, and apoptosis- and autophagy-related parameters in wild-type and XIAP-deficient cancer cells subjected to controlled stress conditions. My findings reveal insult- and time-dependent differential effects of XIAP deficiency on cellular survival and apoptotic signaling cascades in cancer cells and support a model in which XIAP acts as a molecular switch, sensing the level of mitochondrial damage and steering cells toward apoptosis or survival accordingly. Overall, this work highlights a previously underappreciated dimension of XIAP function, offering new insights into how cells integrate mitochondrial damage signals
The Neuronal Heat Shock Response
No full textHeat shock, which refers to abrupt increases in environmental temperature, induces a cascade of cellular stress responses called the heat shock response (HSR). The HSR is an ancient and highly conserved mechanism used by prokaryotes and eukaryotes and involves the downregulation of global translation and concomitant upregulation of canonical heat shock protein 70 (Hspa1a; Hsp70). Although the HSR is well-characterized, the mechanism of translation regulation remains controversial and may be cell-type specific. In our study of cultured neurons we found that in response to heat shock, neurons rapidly upregulate global ubiquitination and downregulate global translation, which is regulated at the phase of elongation. As opposed to other cell types studied, mammalian neurons do not exhibit the conserved HSR because they do not upregulate the cytoprotective protein, Hsp70, during heat shock. Here, we reveal that neuronal adaptation to heat shock involves a brake on protein translation, with slowed elongating ribosomes, phosphorylation of eukaryotic elongation factor-2 (p-eEF2), increased global ubiquitination, and suppressed integrated stress response (ISR) translation of ATF4. RNA-sequencing analysis and ribosome profiling revealed heat shock induced transcriptional changes and significantly altered ribosome-associated transcripts, with the most highly upregulated transcript being Hspa1a, despite undetectable Hsp70 protein during heat shock. We found that pre-existing and newly synthesized transcripts during heat shock were loaded with ribosomes and translated during recovery following heat shock. Heat shocked neurons had to be returned to baseline temperature within one hour to survive and restore translation, which required de-phosphorylation of eEF2. Within 15 minutes of recovery following heat shock, there was a brief activation of the ISR and ATF4 protein expression, during which time ISRIB enhanced protein synthesis and survival. Hsp70 protein was also finally expressed after nearly two hours of recovery following heat shock and was associated with increased cellular viability. The results of these studies support a model that in response to heat shock, ribosomes are loaded and move slowly on transcripts so that they are poised to be rapidly translated during recovery. Our work elucidates the neuronal HSR and provides insight into translational regulation and the relationship between HSR and the ISR
Characterization of Recombinant SARS-CoV-2 BA.5 Reporter Gene Viruses
Get PDFThe emergence of SARS-CoV-2 caused a global pandemic, and its continued impact highlight the need to study viral replication dynamics and immune escape mechanisms. Bacterial artificial chromosomes (BAC) are a well-established platform to generate SARS-CoV-2 infectious cDNA clones, providing a powerful tool to investigate functional mutations that trigger adaptive phenotypic changes, determine virus replication kinetics, and screen compounds for antiviral activity.
In this study, I developed and characterized an infectious cDNA clone to rescue recombinant SARS-CoV-2 Omicron BA.5 viruses engineered to express either a fluorescent (mCherry) or chemiluminescent (Nluc) reporter gene. Using a BAC-based approach, I inserted the reporter genes as an independent transcriptional unit upstream of the N gene to preserve viral integrity and ensure stable expression during infection. The rescued reporter viruses replicated efficiently in VeroE6/TMPRSS2 cells and produced strong, quantifiable reporter gene signals that correlated well with viral spread and cytopathic effects. Interestingly, we observed temperature-dependent replication differences between the two constructs, with rBA.5 Nluc performing better at 37°C and rBA.5 mCherry showing greater efficiency at 33°C. Both reporter viruses exhibited slightly faster replication kinetics compared to the wild-type (WT) isolate, likely due to adaptation during the cloning or rescuing process. Importantly, neutralization assays using human sera demonstrated the utility of these constructs for antiviral screening. I also generated a Nluc encoding recombinant SARS-CoV-2 in the Mu variant background which will be used to investigate features of long COVID in a mouse model system. This recombinant infectious clone system could provide a flexible and powerful tool for studying SARS-CoV-2 replication and pathogenesis, allowing rapid testing of antiviral agents and vaccines in a high-throughput format
Systems Pharmacology Model of Type 2 Diabetes Pathogenesis Driven by Cellular Senescence and Inflammation
Get PDFType 2 diabetes mellitus is a chronic metabolic disorder whose prevalence is increasing, affecting individuals across all age groups. Despite advancements in treatment—primarily lifestyle changes, insulin therapies, and oral medications, current interventions fail to target the root causes of the disease: insulin resistance and pancreatic beta cell dysfunction. Emerging research suggests that cellular senescence, a state of irreversible cell cycle arrest, plays a critical role in the pathogenesis of type 2 diabetes. Senescent cells secrete pro-inflammatory factors known as senescence-associated secretory phenotypes (SASPs), which contribute to systemic inflammation, metabolic dysfunction, and insulin resistance.
This research explores the interaction between inflammation, senescence, and type 2 diabetes through the development of a systems pharmacology model. The model maps the pathways by which aging, oxidative stress, and inflammatory markers initiate and reinforce cellular senescence, creating an autocatalytic cycle that impairs glucose regulation and reduces beta cell mass. Based on this framework, the study proposes targeted therapeutic strategies, such as exercise-induced anti-inflammatory cytokines and antioxidants like vitamin B12, selenium, and hesperetin—to disrupt this cycle and mitigate disease progression.
The model serves as both a conceptual tool and a foundation for future computational studies, therapeutic development, and biomarker discovery. By addressing the underlying pathophysiology rather than just the symptoms, this approach offers the potential for long-term, disease-modifying treatments that could substantially reduce the global burden of type 2 diabetes
INTERVENTIONS FOR DECLINING STUDENT WELL-BEING IN THE CONTEXT OF A HIGH-ACHIEVING SCHOOL
No full textAdolescents in high-achieving schools (HAS) frequently experience elevated risks for stress, anxiety, and maladaptive perfectionism, despite socioeconomic advantages and access to high-quality educational opportunities. This paradox highlights a growing concern in adolescent development and well-being: that privilege does not uniformly translate to thriving. Instead, students in HAS often encounter a constellation of stressors, including peer comparison and competition and high parental achievement expectations, that undermine both hedonic and eudaimonic well-being. The purpose of this dissertation was to investigate how contextual factors shape adolescent well-being in HAS environments and to evaluate a pilot intervention designed to mitigate risks through the combined use of socioemotional learning (SEL) strategies for students and autonomy-supportive workshops for parents.
This mixed-method study was guided by Bronfenbrenner’s (1977) Ecological Systems Theory and Spencer’s (2007) Phenomenological Variant of Ecological Systems Theory. Quantitative data were collected at two time points by an instrument anchored by the EPOCH Measure of Adolescent Well-being. Qualitative data was drawn from semi-structured interviews with students and parents and guardians.
Findings revealed modest improvements in adolescent well-being, with the most notable gains in the domains of connectedness and perseverance. Qualitative analyses suggested that students demonstrated increased self-compassion, while parents reported greater awareness of autonomy-supportive communication practices. However, persistent challenges remain as students described ongoing stress from academic demands, fear of falling behind peers, and cultural narratives equating worth with achievement. Parents acknowledged tension between supporting autonomy and maintaining high achievement expectations.
This study contributes to the literature by documenting both the promise and limitations of school-based well-being interventions situated in high-achieving settings. It likewise advances understanding of how contextual influences intersect in adolescent well-being and highlights the need for systemic multi-level approaches. Implications for practice include aligning student and parent supports and designing sustainable interventions that promote socioemotional flourishing as an essential outcome for students