Washington University Medical Center
Washington University St. Louis: Open ScholarshipNot a member yet
26344 research outputs found
Sort by
Elucidating the Role of PBAF Chromatin Remodeling Subunit Arid2 in B Cell Development
No full textB cells are key components of the adaptive immune system that mediate humoral immunity through the production of antigen-specific antibodies. The generation of functional B cells involves multiple stages of differentiation across distinct anatomical niches, requiring precise regulation of microenvironmental signals and intrinsic transcriptional networks. SWI/SNF chromatin remodeling complexes have emerged as key regulators of B cell lineage commitment by modulating the accessibility of transcriptional programs required for differentiation and maturation. However, the specific roles of individual SWI/SNF subunits and distinct complexes within early B cell differentiation remain poorly understood. In this thesis, I investigated the function of Arid2, an essential subunit of the PBAF chromatin remodeling complex, in murine B cell development. Using conditional knockout models generated with Mb1-Cre and CD19-Cre mice, I demonstrate that Arid2 regulates the differentiation of progenitor B cells into mature Follicular B cells. Mb1-cre mediated deletion resulted in a more pronounced reduction of splenic and circulating Follicular B cells compared to CD19-Cre deletion, indicating that earlier loss of Arid2 disrupts B cell maturation. Transcriptomic profiling of isolated pro-B, pre-B, and Follicular B cells revealed that Arid2 regulates stage-specific gene expression programs throughout B cell development, progressively affecting lineage specification, B cell receptor signaling, and immune response pathways. Functionally, Arid2-deficient B cells exhibited intrinsic defects in T-cell dependent immune responses, including reduced germinal center formation and impaired IgG antibody production. Together, these findings define a critical function for Arid2 in early B cell differentiation and humoral immunity. Ultimately, this work advances our understanding of chromatin remodeling dynamics during B cell development and establishes a foundation for future studies of Arid2-mediated regulatory mechanisms in both normal and disease contexts
Understanding Outer Membrane Vesicle Biogenesis in Bacteroides thetaiotaomicron
No full textOuter membrane vesicles (OMVs) are small proteoliposomes generated by active protrusion of the outer membrane (OM) in Gram-negative bacteria during growth. Over 60 years of experimentation has ascribed numerous functions to OMVs produced by different bacteria. However, the mechanism(s) by which OMVs are produced is poorly understood. Due to this, the field remains controversial because many regard OMVs as byproducts of cell lysis and question their physiological relevance. Previous studies in Pseudomonas aeruginosa and related species confirmed that these microbes undergo programmed cell death that results in the stochastic release of vesicles and cellular contents. On the contrary, Bacteroides spp. have been shown to produce large quantities of OMVs that contain select protein cargo in the absence of cell lysis. This discrepancy indicates that OMV production may not be a universal process amongst Gram-negative bacteria. In this work, we aim to better our understanding of OMV biogenesis and regulation Bacteroides thetaiotaomicron VPI-5482 (Bt). We developed a novel molecular toolkit to enable the visualization and quantification of OMVs in vitro. To identify genes that impact OMV biogenesis and regulation, we adapted these tools to enable the high-throughput screening of a transposon mutant library. Genes uncovered during our screen were found to regulate OMV production, alter cargo selection, and even preclude OMV biogenesis. Many of these genes exhibit unique characteristics and are only found in Bacteroidota. Our investigations center the role of a new family of dual membrane-spanning anti-sigma factors (Dma) that modulate OMV biogenesis and are important for in vivo fitness of Bt. These studies represent the first systematic analyses to identify and characterize genetic factors involved in OMV biogenesis in Bt. Our results greatly improve the field’s understanding of OMV biology and will guide future studies regarding their role and importance in these organisms
Combining Code Analysis and Pedagogical Guidance: Automated Tools for Teaching Debugging in Introductory Programming
No full textThe ability to debug code is critical to being a programmer and represents a distinct skill from writing code. Yet debugging is rarely explicitly taught in introductory programming and Computer Science courses. Instead, novices typically develop their own debugging habits and strategies when they encounter bugs in their code, which are often less effective than those of expert programmers. When students do seek help with debugging, they traditionally turn to office hours conducted by Teaching Assistants (TAs) or, increasingly, to Large Language Models such as ChatGPT. However, both sources of assistance have limitations. TAs are often students themselves with limited teaching experience, yet little has been studied about how this inexperience manifests in actual interactions with students. And general LLM assistants can quickly identify and fix bugs, but are not designed as pedagogical tools and may not help students learn effective debugging strategies. This dissertation addresses these limitations by first filling the gap in our understanding of TA-student interactions during office hours, then developing tools designed to improve debugging assistance more broadly. We conduct observational studies which show that TAs often struggle with both debugging student code and providing pedagogically sound guidance, and identify specific TA debugging strategies that predict tutoring quality. We develop a core algorithm which analyzes buggy student code, generates corrections that preserve the student\u27s intended approach, and produces runtime data explaining how fixes change program behavior. We then design and evaluate tools which present this algorithmic analysis to an intermediary --- a Teaching Assistant or, in later iterations, a Large Language Model --- and guide the intermediary through interpreting the analysis for the student, in a way that can help the student learn an effective debugging process. Our evaluation demonstrates that algorithm-driven assistance can significantly improve both debugging accuracy and speed for TAs, potentially enabling them to focus on providing sound guidance to the student; while LLM-mediated interfaces show promise for providing consistent, pedagogically sound guidance directly to students
Over 30 Million and Growing: Child Development Accounts Around the World
No full textThis report discusses the global reach and origins of Child Development Account policies, documenting impacts on approximately 32 million children worldwide. The policies range from Singapore’s comprehensive asset-building framework to Kazakhstan’s pioneering National Fund for Children. The seven policies highlighted here represent growing efforts to provide structured and lifelong asset-building across the full population, beginning as early as birth
The Original Function Of Tax Apportionment
No full textThe Constitution’s requirement that direct taxes be apportioned by state population is both confounding and important. At best, tax apportionment is regarded as reflecting the unique federalism concerns of the Founding; at worst, it is viewed as a tainted product of the constitutional compromise over slavery. And, in light of the Supreme Court’s decision in Moore v. United States (2024)—which refused to rule out that apportionment might be required for taxes on unrealized gains—tax apportionment is the subject of renewed legal and scholarly interest.
We consider one historical dimension of tax apportionment that has not been developed elsewhere: its original function. Today, apportionment can feel puzzling. But it emerged and persisted across hundreds of years of English, British, and American colonial practice because it was useful. We argue that the original function of tax apportionment was to solve a set of incentive problems that emerges when a central authority (like the crown) must rely on local authorities (like town and county officials) for tax gathering. In the context of this principal-agent problem, apportionment preserves the benefits of local flexibility—the local community can raise its allotment however it sees fit—but imposes a quota that limits flexibility and protects the central fisc. But we do not offer this theory to rationalize apportionment today. Indeed, understanding the original function of tax apportionment helps us understand exactly how far the Constitution’s use of tax apportionment strayed from its original purpose
Racial and Ethnic Differences in Experiencing Administrative Burdens in Public Benefit Programs
No full textComplex program rules can make it difficult to enroll and stay in public programs. These barriers are administrative burdens, the difficulties program applicants and participants face in accessing the benefits to which they are entitled under law. Drawing upon data from the Workforce Economic Inclusion and Mobility Survey of a nationally representative sample of 2,511 low-wage U.S. workers, this brief examines whether the experience of administrative burdens in the Supplemental Nutrition Assistance Program and Medicaid vary by the race and ethnicity of the individual interacting with the program
“They Not Like Us” - Who Actually Won the Drake vs. Kendrick Beef?
No full textIn the spring of 2024, two of hip-hop\u27s biggest names, Drake and Kendrick Lamar, ignited a rap battle that dominated headlines, playlists, and streaming platforms. What started as humorous lyrical jabs quickly escalated into character defamation and conspiracy theories within three swift weeks. Fans quickly picked sides as streams skyrocketed, and media platforms blew up. Yet beneath the hype, this was not just another clash of egos; it was a cultural spectacle between two influential giants. This paper argues that while Drake and Lamar have been cast as the central figures of this lyrical war, neither of them truly comes out more victorious than the other. The real loser of this beef is Black culture and identity, which gets reduced to content that is monetized, consumed, and recycled for clicks and streams. In addition, both artists lack authenticity, though in different ways, as they exploit hip-hop\u27s cultural impact for their own personal gain: Drake by selectively leaning into his Blackness when it benefits his commercial image, and Lamar by presenting himself as the righteous underdog while still using the very system he critiques to advance his career. What was once a language of liberation has become a product to be sold to mainstream America. Instead of challenging systemic structures, both artists reinforce it, packaging Black struggle, creativity, and authenticity as entertainment for mass consumption
Financial Well-Being Among Self-Employed Older Americans
No full textAs people live longer, there has been growing attention in recent years on extending working lives. Although many older adults fully retire, those who continue to work often turn to self-employment—a broad category that includes entrepreneurs, small business owners, consultants, contractors, gig workers, and people who take on side jobs. Rates of self-employment rise sharply with age, with nearly 30 percent of employed adults in their 70s working for themselves—approximately twice the share of those in their 60s
Predicting 72-hours Mortality for MIMIC-Ⅲ Patients: An Ensemble Learning Approach Using XGboost
No full textThe condition of ICU patients can change rapidly, sometimes leading to critical deterioration. However, little changes in vital signs such as heart rate and blood pressure often precede these rapid declines. By applying time series analysis and machine learning models, we hope to detect these early signals and implement interventions in advance to save more lives
Being a Caregiver for a Friend or Family Member
No full textInformal caregivers give assistance to family and friends who have functional limitations that challenge self-care. Most often, caregivers assist younger adults living with a disability and older people with age- associated chronic conditions. Family caregivers are the backbone of our long-term care system in this country, delivering 80% of care. Caregiving is increasing as people live longer with more chronic conditions. Indeed, caregiving is the new norm in our older society. As Roselyn Carter said: There are only four kinds of people in the world. Those who have been caregivers, those who are currently caregivers, those who will be caregivers, and those who will need a caregiver