http://www.rssboard.org/rss-specification 720 https://escholarship.org/uc/ucsf_etd/rss Recent eScholarship items from UC San Francisco Electronic Theses and Dissertations Sun, 30 Aug 2026 02:34:19 +0000 https://escholarship.org/uc/item/3br5r472 Deep mutational scanning (DMS) experiments have been successfully leveraged to understand genotype to phenotype mapping. However, the overwhelming majority of DMS have focused on amino acid substitutions. Thus, it remains unclear how indels differentially shape the fitness landscape relative to substitutions. In order to further our understanding of the relationship between substitutions and deletions, we leveraged a protein language model to analyze every single amino acid deletion in the human proteome. We discovered hundreds of thousands of sites that display opposing behavior for deletions versus substitutions: sites that can tolerate being substituted but not deleted, or vice versa. We identified secondary structural elements and sequence context to be important mediators of differential tolerance. Our results underscore the value of deletion-substitution comparisons at the genome-wide scale, provide novel insights into how substitutions could systematically differ from deletions,... https://escholarship.org/uc/item/3br5r472 Wed, 5 Aug 2026 00:00:00 +0000 Goldman, Grant https://orcid.org/0000-0002-1158-6065 https://escholarship.org/uc/item/5z10z7tj Aging is defined by a progressive deterioration of tissue and organ functionality during adulthood. Across species from invertebrates to mammals, the female reproductive system has consistently been found to be one of the first organs to lose functionality with age. While oocytes have long been assumed to be the primary cells affected by aging, growing evidence points to ovarian somatic cells as key contributors, though the molecular mechanisms driving their aging remain poorly understood. In the Drosophila ovary, a layer of somatic follicle cells surrounds each germ-cell cyst. These follicle cells are essential for guiding and supporting germ-cell cyst development into a mature oocyte. We found that aging is characterized by an accumulation of phenotypes in the somatic compartment, including failure of the follicle cells to encapsulate germ-cell cysts, an extended S phase, and increased DNA damage. These follicle encapsulation defects are associated with the lack of a germ-cell... https://escholarship.org/uc/item/5z10z7tj Wed, 10 Jun 2026 00:00:00 +0000 Wolfgram, Emily Allyson https://orcid.org/0000-0003-1073-7981 https://escholarship.org/uc/item/98d9b89k Purpose/Background: Moral distress among registered nurses (RNs) has been extensively examined in acute care settings, drawing increased attention during the COVID-19 pandemic. However, research has been limited for certified nursing assistants (CNAs) who comprise approximately 60% of the nursing home workforce and provide most of the direct care. Moral distress is a significant contributor to burnout and turnover. CNAs differ from RNs in education, training, and scope of practice and are predominantly women and individuals from racially and ethnically diverse, often immigrant, backgrounds, factors that may shape their professional positioning and experiences of moral distress in nursing home settings. This study aimed to explore the lived experience of moral distress among CNAs who work in nursing homes and to give voice to this population.Method: Guided by an interpretive phenomenological approach, semi-structured interviews were conducted with CNAs who currently work in, or... https://escholarship.org/uc/item/98d9b89k Thu, 4 Jun 2026 00:00:00 +0000 Toivanen-Atilla, Kirsi https://orcid.org/0000-0002-2431-8385 https://escholarship.org/uc/item/9892z9cn ATP-dependent chromatin remodelers are essential regulators of genome function. By altering histone–DNA contacts, these enzymes reposition nucleosomes, change nucleosome accessibility, and catalyze histone exchange during transcription, replication, and DNA repair. A central challenge in chromatin biology is to understand how remodelers that share a conserved Snf2-family ATPase motor nevertheless generate distinct remodeling outcomes in different chromatin contexts. This thesis investigates that question with a focus on how nucleosomal cues and family-specific regulatory elements govern remodeler specificity, with particular emphasis on the INO80 family.The first part of this thesis focuses on the mechanism by which INO80 positions nucleosomes. Precise nucleosome positioning is essential for controlling the sites of transcription and replication initiation, and INO80 is uniquely required in vivo to establish such positioning. This role can be explained by the observation that... https://escholarship.org/uc/item/9892z9cn Thu, 4 Jun 2026 00:00:00 +0000 Kaur, Upneet https://orcid.org/0000-0002-1894-3563 https://escholarship.org/uc/item/8q08r9fx Runt-related transcription factors 1 and 3 (Runx1 and Runx3) have been shown to orchestrate various developmental and cellular processes in numerous cell types and are critical for proper proliferation, differentiation, and cell lineage commitment. Using a conditional knockout mouse line, we specifically deleted Runx1 and Runx3 in the thymic epithelial compartment. Our findings reveal that Runx1 and Runx3 play critical, yet unique roles in controlling the development of medullary thymic epithelial cells (mTECs). ScRNA-sequencing (scRNA-seq) analysis on Runx1 conditional knockout mice reveal alterations in mTEC cell types, with a remarkable expansion of alveolar type 2 epithelial cells (AT2), a previously unknown mimetic cell type within the thymus. Conversely our findings show Runx3 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator+ (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Consequently, TEC-specific... https://escholarship.org/uc/item/8q08r9fx Thu, 4 Jun 2026 00:00:00 +0000 Sin, Jun Hyung https://orcid.org/0009-0002-7338-3877 https://escholarship.org/uc/item/8852v3x4 The ability to alter our behavior based on sensory inputs, such as odors or textures, is a necessity for adaptation. The medial prefrontal cortex (mPFC), important for cognitive function(Miller et al., 2001), produces gamma synchrony that is necessary for this behavioral flexibility tested in mice(Cho et al., 2015; Cho et al., 2020; Cho et al., 2023). It is unclear what contributes to this necessary gamma synchrony. The insula is also known to be necessary for proper cognitive function (Gehrlach et al., 2020; Menon et al., 2010; Kayyal et al., 2021), and also has bidirectional connectivity with the mPFC (Gehrlach et al., 2020). Here we apply optogenetic inhibition on the medial insular cortex (mIC) to mPFC projecting (mIC-mPFC) cell bodies and terminals during a Rule-Shifting task in mice to show that this projection is necessary for texture to odor cue rule shifts. We further determine the existence of gamma synchrony between mIC and mPFC parvalbumin interneurons (PVIs) during... https://escholarship.org/uc/item/8852v3x4 Thu, 4 Jun 2026 00:00:00 +0000 Hagopian, Lara Louise https://orcid.org/0000-0003-0481-301X https://escholarship.org/uc/item/7ts2z0ff Background: There is a lack of research focusing exclusively on the sexual and reproductive healthcare of lesbian-identified Black women compared to studies with samples of heterosexual-identified and bisexual-identified Black women. Lesbian-identified Black women are likely to have different sexual and reproductive healthcare needs and concerns than heterosexual-identified Black women. An example of such needs includes the need for tailored safer sex options and education on alternative ways of achieving pregnancy, as well as other cultural considerations.Objectives: This dissertation sought to 1) examine and interpret how lesbian-identified Black women navigate accessing sexual and reproductive healthcare, 2) identify and interpret barriers and facilitators to accessing sexual and reproductive healthcare among lesbian-identified Black women, and 3) examine resiliency and protective factors employed by lesbian-identified Black women when navigating sexual and reproductive healthcare.Method:... https://escholarship.org/uc/item/7ts2z0ff Thu, 4 Jun 2026 00:00:00 +0000 Scott-Henderson, Daphne https://orcid.org/0000-0003-4439-3697 https://escholarship.org/uc/item/7h97w8r9 Cardiac MRI encodes rich spatiotemporal information about cardiac structure and function, yet standard analysis pipelines reduce this signal to scalar phenotypes derived from segmentation, discarding temporal dynamics and constraining discovery to predefined traits. To address this, we fine-tuned a pretrained VideoMAE model on 4-chamber cardiac MRI videos from 60,498 UK Biobank participants using a masked autoencoding objective, generating high-dimensional embeddings without label supervision. Attention analysis revealed preferential weighting of high-motion intra-cardiac regions, consistent with the spatiotemporal reconstruction objective. The embeddings predicted sex with 95.2% accuracy and body surface area with r = 0.85, showed biologically coherent correlations with blood biomarkers including testosterone, SHBG, and HDL cholesterol, and were broadly associated with segmentation-derived cardiac phenotypes, explaining substantial variance across chamber volumes (adjusted R2... https://escholarship.org/uc/item/7h97w8r9 Thu, 4 Jun 2026 00:00:00 +0000 Saylor, Wren https://orcid.org/0000-0002-6806-7469 https://escholarship.org/uc/item/71r8f9vs Presurgical dental decompensation is a critical step in combined orthodontic–orthognathic treatment, as it systematically reverses natural dentoalveolar compensations across the sagittal, vertical, and transverse planes to fully unmask the underlying skeletal discrepancy. This preparatory phase enables precise surgical repositioning of the jaws, stable postoperative occlusion, and harmonious facial esthetics. Despite its importance, the direct influence of decompensation adequacy on postoperative facial profile attractiveness has remained relatively understudied. The present retrospective investigation tested the central hypothesis that greater achievement of three-dimensional ideal dental decompensation from T1 (initial records) to T2 (presurgical) would correlate with higher postoperative attractiveness ratings at T3 (postsurgical).The study included sixty-two adult patients (34 female, 28 male; mean age 26.4 ± 8.1 years) with skeletal Class III (61.3 %), Class II (25.8 %),... https://escholarship.org/uc/item/71r8f9vs Thu, 4 Jun 2026 00:00:00 +0000 Ricupito, Michael Eaton https://orcid.org/0009-0008-8976-9436 https://escholarship.org/uc/item/6w51r8dw Animals must continuously update internal representations of the external world to guide adaptive behavior. Individual features of the environment may not initially carry meaning, but through reinforcement, animals learn which cues predict salient outcomes and whether those cues should be approached, avoided, or ignored. A central challenge, however, is that many stimuli share overlapping features despite carrying different meanings. For example, a person in a new apartment building may initially struggle to distinguish among several similar-looking doors, only one of which is their own. To behave appropriately, the brain must balance two competing demands: it must generalize across related experiences that share useful structure, while also discriminating between similar cues when small differences predict different outcomes. Too much generalization can blur important distinctions, whereas too much discrimination can prevent related experiences from being linked. One way neural... https://escholarship.org/uc/item/6w51r8dw Thu, 4 Jun 2026 00:00:00 +0000 Choi, Hye Sun https://orcid.org/0009-0001-4207-1486 https://escholarship.org/uc/item/6s5236f8 Adolescent patients undergoing gender-affirming medical care are being treated with gonadotropin-releasing hormone agonists (GnRHas) and gender-affirming hormone therapy (GAHT), but the effects of these medications on craniofacial growth potential or temporomandibular joint (TMJ) health have not been studied. This gap in knowledge is significant for the orthodontic clinician especially as this underrepresented population continues to grow. This retrospective pilot study examined orthodontic records and cone-beam computed tomography (CBCT) data from six transgender patients, three transgender male patients taking testosterone therapy and three transgender female patients taking estrogen and spironolactone, to generate preliminary hypotheses on the effects of GAHT on craniofacial growth and TMJ health in the orthodontic context.A transgender male adolescent demonstrated condylar length growth of 2.7 mm between ages 15 and 16, exceeding the expected female norm of 1 mm, suggesting... https://escholarship.org/uc/item/6s5236f8 Thu, 4 Jun 2026 00:00:00 +0000 O'Neal, Yvonne https://orcid.org/0009-0009-6476-9816 https://escholarship.org/uc/item/6gx6r8x2 Purpose: The translation of modern clinical radiotherapy techniques to preclinical small-animal models is often hindered by hardware limitations, soft-tissue imaging deficits, and inefficient treatment planning. This dissertation aims to address these translational challenges by developing an integrated automated framework for precision preclinical radiotherapy, incorporating high throughput hardware, deep learning-based segmentation, and advanced plan optimization. Methods: The framework was developed across three interconnected domains. First, a custom high-throughput automated platform and a sparse orthogonal collimator were integrated into a commercial small animal irradiator to enable streamlined treatment delivery. Second, deep learning architectures were developed for micro-cone-beam computed tomography segmentation. A transformer-based network was trained for robust multi-organ contouring, and a generative adversarial network was utilized for anatomy-constrained... https://escholarship.org/uc/item/6gx6r8x2 Thu, 4 Jun 2026 00:00:00 +0000 Jiang, Lu https://orcid.org/0000-0002-7616-1746 https://escholarship.org/uc/item/6g4299xz Accurate and efficient radiation dose calculation and treatment plan optimization are central to modern radiotherapy. This dissertation addresses computational challenges in two complementary areas: GPU-accelerated photon dose calculation and 4-pi non-coplanar treatment planning, and the statistical modeling of primary proton transport as a foundation for analytical proton dose calculation. The first contribution is UHPP (Ultra-High Performance Parallel), a GPU-accelerated framework for 4-pi non-coplanar radiotherapy planning. 4-pi plans exploit the full solid angle of beam directions accessible to a standard linac, offering superior dose conformality compared to coplanar VMAT, but require computing dose-loading matrices for thousands of candidate beams—a task that exceeds the throughput of existing methods. UHPP addresses this through three technical innovations: a two-step TERMA computation with area rescaling that eliminates aliasing artifacts, a synchronized collapsed-cone... https://escholarship.org/uc/item/6g4299xz Thu, 4 Jun 2026 00:00:00 +0000 Xu, Qifan https://orcid.org/0000-0002-7155-9552 https://escholarship.org/uc/item/632503qb KCNT1-related epilepsy is a severe neurodevelopmental disorder caused by pathogenic variants in KCNT1, which encodes a sodium-activated potassium channel. In addition to frequent, often treatment-resistant seizures, affected individuals may experience respiratory complications, cardiac abnormalities, hypotonia, skeletal fragility, and gastrointestinal dysfunction. Standard anti-seizure medications are typically ineffective, leaving patients and their caregivers to manage a broad and complex set of symptoms. Although there has been a concerted effort to find better treatment and care for KCNT1 individuals, the underlying mechanism in which mutations in KCNT1 result in multi-organ disorder remains unclear. This dissertation focuses on the role of KCNT1 beyond the synapse, specifically on cilia. In chapter 2, we provide evidence that KCNT1 localizes to both motile and primary cilia across cell types and species and explored overexpression of KCNT1. In chapter 3, we characterized... https://escholarship.org/uc/item/632503qb Thu, 4 Jun 2026 00:00:00 +0000 Chemel, Angeline Katia https://orcid.org/0000-0002-7040-2270 https://escholarship.org/uc/item/5mw247w0 The genome is broadly organized into compartments of active chromatin (euchromatin) and inactive chromatin (heterochromatin). These compartments were first described by cytological staining due to differences in chromatin density (1), then later characterized via Hi-C contact maps (2). In general, heterochromatin is less accessible than euchromatin. It has been proposed that the difference in accessibility is due to nucleosomes in heterochromatin having more restricted motion compared to euchromatic nucleosomes, and heterochromatin having higher viscoelastic resistance than euchromatin (3-5).The molecular mechanisms that underlie these differences between eu- and heterochromatin are not well understood. We know that some euchromatic regions have epigenetic modifications that inherently cause chromatin de-condensation (6, 7), but this only accounts for a small set of genomic regions. Thus, it is likely that proteins enriched in euchromatin could further decondense euchromatin and... https://escholarship.org/uc/item/5mw247w0 Thu, 4 Jun 2026 00:00:00 +0000 Moore, Camille Marie https://orcid.org/0000-0002-3324-789X https://escholarship.org/uc/item/4wt407xs Platelet-rich fibrin (PRF) is an autologous biomaterial used in periodontal and oral regenerative procedures because it contains growth factors that support wound healing. Diabetes mellitus is associated with impaired healing and may affect PRF composition, but the relationships among diabetic status, age, and PRF growth factor levels are not well defined. This exploratory case-control study examined platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor (VEGF) concentrations in PRF from 15 subjects: 10 healthy, non-diabetic controls and 5 subjects with diabetes. PRF was made using a standardized centrifugation protocol, and ELISA measured PDGF-BB and VEGF. Two readings were taken for each sample, and the mean value was used for analysis. Descriptive summaries and exploratory regression models were used to examine possible correlations among diabetic status, age, sex, and HbA1c. A mean PDGF-BB concentration of 4,292.6 ± 922.8 pg/mL was found in healthy... https://escholarship.org/uc/item/4wt407xs Thu, 4 Jun 2026 00:00:00 +0000 Viets, Helena Louise https://orcid.org/0009-0003-8584-9600 https://escholarship.org/uc/item/3xk5x1mz The superior colliculus (SC) is a highly conserved sensorimotor midbrain structure implicated in the control of orienting movements. Yet, despite decades of research, it remains unclear how neural activity in this structure unfolds during internally-driven behaviors like spatial navigation, when orienting movements need to be coordinated with other ongoing behavioral and cognitive processes. This dissertation aims to address this gap. By recording from neurons in the intermediate and deep motor layers of the SC (dSC) of mice navigating a Y-maze, it is demonstrated that: 1) About 30% of neurons fire selectively for left or right turns at the maze bifurcation (left- or right-preferring ‘turn cells’). 2) Turn cell activity is rhythmically modulated during locomotion, firing in-phase with the ongoing stepping cycle of the animal, such that left and right turn cells fire at opposite phases of the stepping cycle. 3) Simultaneous recordings from turn cells and populations of hippocampal... https://escholarship.org/uc/item/3xk5x1mz Thu, 4 Jun 2026 00:00:00 +0000 Wilhite, Cameron https://orcid.org/0000-0002-5655-2010 https://escholarship.org/uc/item/3pp5p18g Bone is a unique tissue that carries both mineralized and connective components, contributing to its malleability and strength in resisting fractures and protecting internal organs. Despite the stagnant look of the tissue, bone undergoes constant remodeling to resorb and replenish its mineral and organic constituents. Of the bone cells, osteocytes contribute to bone health maintenance by orchestrating bone remodeling in response to mechanical load. Osteocytes are housed inside an intricate network of lacunae and canaliculi called the lacunocanalicular network (LCN) and serve to directly remodel the matrix surrounding LCN as well as regulate osteoclastic bone resorption and osteoblastic bone formation at the whole bone level. Mechanical load on the bone at the tissue level stimulates fluid shear stress in the lacunocanalicular network, allowing osteocytes to sense and transmit the mechanical force to downstream intracellular signaling pathways. However, specific molecular mechanisms... https://escholarship.org/uc/item/3pp5p18g Thu, 4 Jun 2026 00:00:00 +0000 Yoon, Jihee https://orcid.org/0000-0001-9677-3419 https://escholarship.org/uc/item/3p65m7gq Background Fear during pregnancy and birth can worsen health care experiences and outcomes, especially among populations experiencing racism, disrespect and reproductive inequities. Far less is known about an important counterpart, confidence. Methods This dissertation aimed to elucidate the pathways through which midwifery-led care impacts prenatal confidence for physiologic birth and to inform future care, centering the perspectives of Black populations. The work includes a participatory instrument adaptation resulting in the Preparation for Community-based Labor and Birth (P-CLAB) to measure confidence for community-based birth; a mixed methods study of prenatal confidence from the perspective of birth center patients and providers; and the qualitative and psychometric evaluation of the P-CLAB. Findings The iterative development of the P-CLAB resulted in a Likert-response survey prioritizing measures of safety, dignity, and racial concordance. Through engagement with patients... https://escholarship.org/uc/item/3p65m7gq Thu, 4 Jun 2026 00:00:00 +0000 Mitchell, Ashley https://orcid.org/0000-0002-6351-3204 https://escholarship.org/uc/item/3nn3811r Zebrafish fully regenerate and recover locomotor function after spinal cord injury (SCI), but whether and/or how developmental signals are redeployed to rebuild functional circuits remains unclear. During development, Bone Morphogenetic Protein (BMP) signaling patterns dorsal neural tube fates, but whether this pathway fulfills a similar function during SCI-based regeneration is unknown. Here we show that SCI triggers a broad elevation in BMP pathway activity in the larval zebrafish spinal cord, accompanied by upregulation of the BMP receptor bmpr2b in neural progenitors. Disruption of BMP signaling impairs locomotor recovery, producing a phenotype in which larvae initiate movement but fail to sustain or propagate swimming. At the cellular level, BMP inhibition selectively reduces regeneration of dI1 and dI2 dorsal sensory-relay interneurons and v1 and v2a ventral premotor interneurons, with reduced consequences for other neuronal subclasses. Together, these findings reveal that... https://escholarship.org/uc/item/3nn3811r Thu, 4 Jun 2026 00:00:00 +0000 Roy, Irena https://orcid.org/0000-0002-6924-4471 https://escholarship.org/uc/item/3fv1c4tj Communication, the transfer of social information from one individual to another via sensory signals, is essential for life across animal species. The neural circuitry that supports sending and interpreting these signals is incompletely understood. Responding to communication signals involves sensory processing, representation of internal states such as reproductive status, and representation of the other party in an interaction. This work addresses sensory processing systems, communication behaviors, neuromodulator control of neural responses to social behavior, and the genetics of the circuits that control these processes. I demonstrated that amplitude modulated sounds are processed differently in laboratory mice and squirrel monkey primary auditory cortex. I documented the evolution of prairie vole ultrasonic vocalizations across pair bonding. I examined the neural activity associated with chemosensory investigation during pair bonding and showed that loss of oxytocin... https://escholarship.org/uc/item/3fv1c4tj Thu, 4 Jun 2026 00:00:00 +0000 Hoglen, Nerissa https://orcid.org/0000-0002-4841-4275 https://escholarship.org/uc/item/3cc0n9v7 Introduction: Postpartum depression (PPD) is a common mental health condition that occurs within the first 12 months after childbirth. Complications of severe and untreated PPD are associated with increased risk of maternal mortality. Risk factors are well-established in the general population; however, far less is known about PPD in specific occupational groups, including registered nurses (RNs). The RN profession is one of the few professions dominated by women in the United States, and nurses have much higher rates of depression unrelated to pregnancy compared to the general population, which is a strong predictor for the development of PPD. The prevalence and unique risk factors of PPD among RNs are unknown. To better understand how personal and occupational factors may contribute to PPD, two theories were leveraged to create a conceptual model: 1) Teetering on the Edge: A substantive theory of postpartum depression, and 2) the Person-Environment Fit Theory. These theories,... https://escholarship.org/uc/item/3cc0n9v7 Thu, 4 Jun 2026 00:00:00 +0000 Mariano, Karley https://orcid.org/0000-0002-0933-5769 https://escholarship.org/uc/item/344666gv Prognosis refers to the prediction of a disease’s course and outcome. While several systems exist for natural dentition, implant-specific prognosis systems remain limited. Kwok et al. 2023 proposed a dental implant prognosis system based on peri-implant supporting tissue stability and patient-related risk factors. This study aims to evaluate the predictability of this system by assessing implant survival across initial prognosis categories over a five-year period. A total of 651 implants from 291 patients were included. Baseline examinations were conducted at the time of implant-supported prosthesis delivery, with follow-up examinations at least 12 months later. Implants were categorized as favorable, questionable, unfavorable, or hopeless according to the Kwok et al. classification. Recorded variables included age, sex, follow-up duration, supportive care, history of Grade C periodontitis, smoking, diabetes, and use of intravenous bone-sparing agents. Implants initially classified... https://escholarship.org/uc/item/344666gv Thu, 4 Jun 2026 00:00:00 +0000 Young, Kristen Hsi https://orcid.org/009-0000-8679-8102 https://escholarship.org/uc/item/2zz2f159 Brain function depends on a tightly regulated interplay between vascular delivery, neuronal activity, glial support, and energy metabolism. Disturbances in this coupling are central to two of the most common causes of age-related cognitive decline — Alzheimer's disease (AD) and cerebral small vessel disease (cSVD) — yet the tools most commonly used to study them in vivo remain fragmented. Positron emission tomography (PET) with [¹⁸F]FDG reports glucose uptake but requires ionizing radiation and cyclotron infrastructure; magnetic resonance imaging (MRI) offers structural, vascular, and spectroscopic contrast but has historically lacked a practical, non-ionizing readout of glucose metabolism, and the multimodal datasets it produces have outpaced the analyses applied to them. This dissertation advances metabolic MRI as an integrated framework along three steps: combining established MRI contrasts to phenotype a monogenic cerebrovascular disease; developing a new MRI contrast to fill... https://escholarship.org/uc/item/2zz2f159 Thu, 4 Jun 2026 00:00:00 +0000 Gao, Xiao https://orcid.org/0000-0002-6175-5840 https://escholarship.org/uc/item/2cf296dp The Western diet, characterized by high consumption of refined, processed grains, has been epidemiologically associated with elevated periodontal disease risk, yet the mechanisms underlying this relationship remain incompletely understood. Grain refinement simultaneously removes dietary fiber and reduces food texture, producing a soft, rapidly fermentable substrate that may promote oral biofilm dysbiosis through two distinct but potentially synergistic pathways: augmented saccharide substrate availability to saccharolytic pioneer species, and loss of the masticatory mechanical challenge that limits biofilm maturation and sustains homeostatic gingival immune signaling. Whether the protective effects of whole grain consumption are attributable to its fiber content, its structural and textural properties, or both has not been experimentally resolved.The present thesis employed a multi-diet murine experimental framework to dissociate the contributions of dietary texture and fiber... https://escholarship.org/uc/item/2cf296dp Thu, 4 Jun 2026 00:00:00 +0000 Sedghi, Lea Maryam https://orcid.org/0000-0002-0263-3683 https://escholarship.org/uc/item/28t6r55j Tuberculosis (TB) is the deadliest infectious disease worldwide, taking the lives of 1.23 million individuals in 2024. While TB is curable, the current pharmacological standard-of-care is arduous—requiring months of strict adherence to a four-drug regimen that carries risks for significant toxicities. Thus, ongoing developmental efforts concentrate on advancing safe and effective regimens with shorter treatment durations for cure. Yet, in the past several decades, only a few novel, shortened regimens have been found successful in Phase 3 clinical trials. This paucity of new therapies is due to several facets associated with TB drug development, including the need for multi-drug regimens to prevent resistance, the presence of highly variable patient phenotypes, the prolonged final clinical endpoint of relapse-free cure, and the lack of a standardized paradigm in translational decision-making. The work presented here applies integrated preclinical and clinical modeling and simulation... https://escholarship.org/uc/item/28t6r55j Thu, 4 Jun 2026 00:00:00 +0000 Patel, Anu https://orcid.org/0000-0003-0628-668X https://escholarship.org/uc/item/26p1j8sw Periodontitis is a chronic, multifactorial inflammatory disease affecting 42% of US adults over the age of 30, characterized by progressive destruction of tooth-supporting structures associated with dysbiotic subgingival biofilms. Treponema denticola, a member of the Red complex, is one of the identified pathogenic bacteria that is strongly associated with the progression of periodontal disease. Advances in full-length 16S rRNA sequencing now allows for high-resolution taxonomic identification of Treponema species, including uncultivable phylotypes previously undetectable by traditional methods. The aim of this study was to investigate the relationship between subgingival Treponema community composition and clinical treatment outcomes following non-surgical periodontal therapy, with the hypothesis that greater reductions in Treponema relative abundance would be associated with improved clinical outcomes.Twenty-eight patients were initially enrolled in this study. Subjects over... https://escholarship.org/uc/item/26p1j8sw Thu, 4 Jun 2026 00:00:00 +0000 Arroyo, Nicholas https://orcid.org/0009-0004-7051-4821 https://escholarship.org/uc/item/1kp0z6hr Background: Cleft lip with or without cleft palate (CL/P) results from failed fusion of the facial prominences during embryogenesis. The cranial base, shaped largely by intrinsic developmental controls, serves as a practical proxy for the embryonic brain morphology that governs facial prominence positioning and fusion timing. Its relationship to CL/P severity in humans remains incompletely characterized.Objectives: To compare basicranial and facial shape between CL/P and non-cleft individuals, quantify their morphological covariation, and determine whether these parameters correlate with cleft severity.Materials and Methods: CBCT images from 30 children with non-syndromic CL/P (ages 7–11), acquired prior to alveolar bone grafting or orthodontic treatment, were compared to 29 age- and sex-matched controls. Thirty-nine basicranial and 29 facial three-dimensional landmarks were placed and analyzed using geometric morphometrics in MorphoJ, including Procrustes superimposition, PCA,... https://escholarship.org/uc/item/1kp0z6hr Thu, 4 Jun 2026 00:00:00 +0000 Ran-Sukkawala, Marrina Ruomei https://orcid.org/0009-0003-2736-7152 https://escholarship.org/uc/item/1b71m4h3 Tumors drive T cell exhaustion in both tumor-infiltrating lymphocytes and CAR T cells, marked by increased inhibitory receptor expression, impaired cytotoxicity, and reduced cytokine production, ultimately limiting durable clinical responses. In this work, I have performed a high-density base editor screen of A20/TNFAIP3, a multifunctional ubiquitin-modifying protein, to map variants to T cell functions. In addition, we performed genome-wide loss-of-function screening in repetitively stimulated human T cells and identified the multifunctional ubiquitin-modifying protein A20/TNFAIP3 as a major negative regulator of exhausted T cell persistence. Protein large language modeling, deep base-editing mutagenesis, and studies in immunocompetent mice with domain-specific inactivating mutations revealed A20’s non-enzymatic M1 ubiquitin-binding zinc finger 7 (A20ZF7) motif as critical to suppression of anti-tumor immunity. A20ZF7-deficient CD8+ tumor-infiltrating lymphocytes (TILs) resisted... https://escholarship.org/uc/item/1b71m4h3 Thu, 4 Jun 2026 00:00:00 +0000 Sandoval, Luis Roberto https://orcid.org/0000-0001-8654-7530 https://escholarship.org/uc/item/0wr1x24z BACKGROUND: In the United States, over 500,000 perioperative team members are exposed to surgical smoke annually. Surgical smoke, a by-product of electrocautery use during operative procedures, contains particulate matter and volatile organic compounds, which are known irritants and carcinogens with mutagenic potential. Surgical smoke adversely impacts the respiratory, cardiovascular, and neurological systems. Despite the exposure to surgical smoke in the operating room, little is known about the experience of surgical smoke by perioperative team members.PURPOSE: Past research has an almost exclusively quantitative approach, with scarce conceptual development beyond descriptions of the smoke’s content, mechanism, hazards, and mitigation strategies. The purpose of this dissertation is to use a mixed methods approach to advance the understanding of the experience of surgical smoke.METHODS: A scoping review with the aims to synthesize the evidence on how perioperative teams experience... https://escholarship.org/uc/item/0wr1x24z Thu, 4 Jun 2026 00:00:00 +0000 Lewis, Merideth https://orcid.org/0000-0002-5010-8664 https://escholarship.org/uc/item/82q1j0zg Although the evolutionary expansion of the human brain has been widely studied, the cellular processes that distinguish human cortical development are still not fully known. One major class of neurons, inhibitory interneurons, continue to migrate and mature well into the postnatal period in humans, suggesting that prolonged developmental timing may be a key evolutionary innovation. While studies in rodents have elucidated genetic programs guiding interneuron specification and migration, far less is known about how late-arriving interneurons contribute to circuit assembly and critical period plasticity. This gap is especially important in the context of newborn brain injury, where disruptions to ongoing interneuron development may underlie long-term cognitive and neurological deficits. Using comparative approaches exploring anatomy, cytoarchitecture, and transcriptomic profiles, we identified a new stream of migratory inhibitory interneurons that supports the distribution of VIP+... https://escholarship.org/uc/item/82q1j0zg Wed, 20 May 2026 00:00:00 +0000 Poddar, Aunoy https://orcid.org/0000-0002-5065-7321 https://escholarship.org/uc/item/9995469j Alzheimer's disease (AD) affects millions of individuals worldwide while imposing an escalating burden on healthcare systems and caregivers. The disease's complex pathophysiology is characterized by multiple concurrent pathological processes — including amyloid plaque deposition, neurofibrillary tangle accumulation, and progressive neurodegeneration — that unfold across multiple spatial and temporal scales with heterogeneous progression patterns and an often extensive pre-symptomatic phase. While advances in neuroimaging and fluid biomarkers have provided increasingly detailed in vivo windows into these disease mechanisms, the integration of high-dimensional, multimodal datasets presents significant computational and interpretive challenges that exceed traditional statistical approaches. This dissertation addresses these challenges by developing domain-guided machine learning methods that embed established neuroscientific knowledge — temporal biomarker dynamics, neuropathological... https://escholarship.org/uc/item/9995469j Thu, 19 Mar 2026 00:00:00 +0000 Sorensen, Clara https://orcid.org/0000-0003-3012-0057 https://escholarship.org/uc/item/9122m4vv Hsp70s are essential molecular chaperones that are increasingly recognized to be regulated by post-translational modifications. Here, we show that phosphorylation of a conserved threonine (T495), previously shown to be exploited by a Legionella pneumophila kinase to inhibit Hsp70, occurs endogenously in human cells in response to DNA damage, particularly when base excision repair is overburdened. This modification is cell cycle dependent, and in yeast, phosphomimetic or phosphonull Hsp70 variants disrupt G1/S progression under normal and DNA-damaging conditions. Biochemically, the phosphomimetic T495E mutation locks Hsp70 in an open-like conformation without blocking substrate engagement. Together, our results reveal a conserved mechanism by which dynamic Hsp70 phosphorylation regulates the G1/S transition, and delays cell cycle progression during DNA damage, highlighting how pathogen-derived insights can uncover fundamental cell biology principles. https://escholarship.org/uc/item/9122m4vv Thu, 19 Mar 2026 00:00:00 +0000 Moss, Thomas Hofheimer https://orcid.org/0000-0003-3647-9319 https://escholarship.org/uc/item/90w2m4nv Computational drug discovery is in a period of unprecedented abundance. Advances in high-throughput combinatorial chemistry have expanded the space of inexpensive, readily accessible compounds into the trillions. As these chemical libraries grow, so too does the success of their computational screening. Yet their sheer scale requires new methods capable of searching them efficiently and effectively. At the same time, this expansion marks a departure from the metabolites, natural products, and drugs that proteins have evolved to recognize. This raises an important question: do molecules from these libraries have not only improved on-target binding, but also greater selectivity and reduced off-target interactions? This dissertation approaches these questions through the unifying mathematical framework of a graph. After a brief introduction to graphs, computational drug discovery, and molecular docking, we present Retrieval Augmented Docking (RAD), a graph-based virtual screening... https://escholarship.org/uc/item/90w2m4nv Thu, 19 Mar 2026 00:00:00 +0000 Hall, Brendan William https://orcid.org/0000-0003-1616-1303 https://escholarship.org/uc/item/8wc2532t CD4⁺ T cell differentiation is essential for protective immunity against infection and cancer, yet the programs that enable productive effector differentiation across contexts remain incompletely understood. Emerging evidence implicates dynamic metabolic remodeling as a key regulator of T cell fate, but how these programs support effector differentiation and are disrupted in disease remain unclear. Here, we identify a transient CD4⁺ T cell state characterized by simultaneously high glycolysis and oxidative phosphorylation that serves as a critical metabolic intermediate during effector differentiation. During acute bacterial infection, CD4⁺ cells that enter this early-activated state exhibit elevated mitochondrial reactive oxygen species and sustained AP-1 activity, supporting Th1 effector programs even as proximal TCR signaling wanes. This program is conserved across CD4⁺ lineages, including Th2 cells, which similarly transit through an early-activated state with elevated AP-1... https://escholarship.org/uc/item/8wc2532t Thu, 19 Mar 2026 00:00:00 +0000 Lopez-Ichikawa, Maya https://orcid.org/0000-0001-8609-1561 https://escholarship.org/uc/item/8cs0d403 A fundamental aspect of life as a microbe is to live inside microbial communities, where constant interactions occur between members of different species and even different kingdoms of life. Massive changes in gene expression result from these interspecies interactions, with significant effects on both the microbial organisms involved, and the ways the microbial community as a whole interacts with its environment, such as that of an infection with the host. Despite the relevance to human health, genes mediating interspecies interactions are broadly uncharacterized. The study of microbes in multi-species communities, where the expression of such genes is induced, therefore, is an important and necessary way to investigate the molecular mechanisms behind interspecies interactions. The yeast, Candida albicans, is a normal resident of the human microbiome, but is also an opportunistic pathogen that can cause life-threatening bloodstream infections. The gram-negative bacterium, Pseudomonas... https://escholarship.org/uc/item/8cs0d403 Thu, 19 Mar 2026 00:00:00 +0000 Zhang, Jenny Y https://orcid.org/0000-0003-1352-8018 https://escholarship.org/uc/item/809743jk Cell states provide valuable information about the regulatory networks that dictate cellular function and behavior, thereby offering deeper insights into disease mechanisms. Identifying transcriptional programs that are functionally relevant and persist throughout disease progression remains a significant challenge, and addressing it is critical for developing therapies tailored to disease biology. Here, we present two case studies investigating the interplay between pre-existing transcriptional programs and drug response. In chapter 1, we leverage single-cell RNA sequencing to map cancer cell transcriptional states present in treatment naïve triple negative breast cancer models. Through integrated computational and experimental approaches, we characterize the functional consequence of a recurrent inflamed subpopulation and its contribution to chemotherapy resistance. In chapter 2, we explore MYC-driven transcriptional rewiring of mitotic processes to uncover a previously unrecognized... https://escholarship.org/uc/item/809743jk Thu, 19 Mar 2026 00:00:00 +0000 Jacobo Jacobo, Mauricio https://orcid.org/0000-0003-4907-3369 https://escholarship.org/uc/item/7ks984fp In response to inflammatory insults, lymph nodes (LNs), major organs responsible for initiation of adaptive immunity, remodel themselves to produce an optimal response. Sustained lymphocyte migration from blood into LNs is one key aspect of this. The CC-chemokine receptor-7 (CCR7) ligand CCL21 is required for LN entry but is downregulated during inflammation, and it has been unclear how recruitment is maintained. Here, we show that LNs switch from total CCL21 dependency for lymphocyte recruitment to utilizing oxidized cholesterol, whose production is upregulated in LN high endothelial venules during viral infection. Lymphocytes also switch from CCR7 to the oxysterol receptor EBI2 for inflamed LN entry. Additionally, LN CCL19, a second ligand for CCR7 that is dispensable for LN homing in homeostasis, becomes critical in lymphocyte recruitment during inflammation. After entry into LNs, B cells then organize themselves into germinal centers (GCs), sites of antibody somatic mutation... https://escholarship.org/uc/item/7ks984fp Thu, 19 Mar 2026 00:00:00 +0000 Chen, Kevin Y. https://orcid.org/0000-0001-5299-8368 https://escholarship.org/uc/item/6x36552q Global inequities in early cancer detection and diagnosis continue to drive preventable mortality from breast and childhood cancers across low- and middle-income countries (LMICs). While high-income countries have achieved substantial reductions in cancer mortality through advances in diagnostics, therapeutics, and precision medicine, these gains have not been equitably extended to LMICs. Instead, limited diagnostic capacity, financial barriers, and fragmented care pathways contribute to delays in timely diagnosis and treatment. Using implementation science frameworks and methodologies, this dissertation examines multilevel barriers and facilitators to screening and diagnosis across two African health systems, and identifies opportunities to strengthen diagnostic delivery and support the implementation of diagnostic innovations.The first study in this dissertation (Chapter 2) quantitatively evaluates the performance of Morocco’s National Breast Cancer Screening Program (NBCSP)... https://escholarship.org/uc/item/6x36552q Thu, 19 Mar 2026 00:00:00 +0000 Carvalho, Melissa Marie Emilie https://orcid.org/0000-0002-9607-0999 https://escholarship.org/uc/item/6sg7s4v1 Complex neurodegenerative diseases such as Alzheimer’s disease are characterized by the progressive, age-related death of neurons in the brain. This leads to cognitive decline, dementia, and ultimately death. Despite significant advances in our understanding of these diseases, our only treatments have a mild effect at slowing disease progression and there are no known treatments that stop, prevent, or reverse decline. However, recent advances in functional genomics technologies, such as CRISPR screening, have completely changed what is possible in the study of molecular mechanisms driving these diseases. Understating these fundamental mechanisms is an essential leap towards developing therapies that precisely target and ameliorate neurodegenerative disease processes. Using large-scale CRISPRi screening in human iPSC-derived astrocytes, two distinct reactive signatures were uncovered in a model of astrocyte reactivity: IL-1/IL-6-responsive and TNF/IFN-responsive states, differentially... https://escholarship.org/uc/item/6sg7s4v1 Thu, 19 Mar 2026 00:00:00 +0000 Rose, Indigo V. L. https://orcid.org/0000-0003-0491-1269 https://escholarship.org/uc/item/4nj7m2v2 Targeted protein degradation (TPD) has emerged in the past decade as a major new drug modality to remove intracellular proteins with bispecific small molecules that recruit the protein of interest (POI) to an E3 ligase for degradation in the proteasome. Unlike classic occupancy-based drugs, intracellular TPD (iTPD) eliminates the target and works catalytically, and so can be more effective and sustained, with lower dose requirements. Recently, this approach has been expanded to the extracellular proteome, including both secreted and membrane proteins. Extracellular targeted protein degradation (eTPD) uses bispecific antibodies, conjugates or small molecules to degrade extracellular POIs by trafficking them to the lysosome for degradation. Most eTPD receptors are expressed broadly or are restricted to the liver, limiting specific degradation in other tissues. Cytokine receptor targeting chimeras (kineTACs) are genetically encoded bispecifics for eTPD that fuse a natural ligand... https://escholarship.org/uc/item/4nj7m2v2 Thu, 19 Mar 2026 00:00:00 +0000 Kumru, Kaan https://orcid.org/0000-0002-8015-0775 https://escholarship.org/uc/item/4bn56665 Targeted epigenetic engineering of gene expression in cell therapies would allow programming of desirable phenotypes without many of the challenges and safety risks associated with double strand break-based genetic editing approaches. Here, we develop an all-RNA platform for efficient, durable, and multiplexed epigenetic programming in primary human T cells, stably turning endogenous genes off or on using CRISPRoff and CRISPRon epigenetic editors. We achieve epigenetic programming of diverse targeted genomic elements without the need for sustained expression of CRISPR systems. CRISPRoff-mediated gene silencing is maintained through numerous cell divisions, T cell stimulations, and in vivo adoptive transfer, avoiding cytotoxicity or chromosomal abnormalities inherent to multiplexed Cas9-mediated genome editing. Finally, we successfully combined genetic and epigenetic-engineering using orthogonal CRISPR Cas12a/dCas9 systems for targeted CAR knockin and CRISPRoff silencing of therapeutically... https://escholarship.org/uc/item/4bn56665 Thu, 19 Mar 2026 00:00:00 +0000 Goudy, Laine https://orcid.org/0009-0004-0290-2734 https://escholarship.org/uc/item/3st0g0dq Studying dynamic biological processes requires tools that can control gene expression with both precision and reversibility, a challenge that static gene editing methods cannot fully address. This thesis explores the development and application of inducible CRISPR interference (CRISPRi) systems that integrate degron-mediated control to achieve high-resolution temporal regulation of target genes. By fusing catalytically inactive Cas9 (dCas9) to transcriptional effectors tagged with degrons, effector CRISPRi protein stability can rapidly and reversibly be modulated, enabling the study of the phenotypic consequences of hypomorphic gene expression levels in mammalian cells. I review inducible strategies for their ability to fine-tune genetic perturbations in diverse cellular contexts. I provide experimental data demonstrating the utility of these temporally-gated systems for tackling key questions in functional genomics and cancer biology, such as defining windows of gene essentiality,... https://escholarship.org/uc/item/3st0g0dq Thu, 19 Mar 2026 00:00:00 +0000 Wang, Yuhao https://orcid.org/0000-0002-1543-6187 https://escholarship.org/uc/item/3n70t1sp Medulloblastoma (MB) is the most common malignant brain tumor in children, and Group 3 (G3) MB—frequently driven by MYC amplification—is the most aggressive subgroup, with limited targeted therapies and a strong propensity for metastatic dissemination. In this thesis, I discuss the generation of a novel, MYC-driven G3 model of MB derived from human neuroepithelial stem cells (NESCs), enabling systematic interrogation of the regulatory programs that sustain tumor growth and metastasis. In Chapter 2, I establish that a MYC-expressing NESC model aligns transcriptionally with human G3 MB. Using this platform, I perform the first in vivo genome-wide CRISPR interference (CRISPRi) screen in MB, nominating epigenetic regulators as key oncogenic dependencies. In particular, the chromatin modifiers SIN3B and MTA3 emerge as functional drivers of G3 MB growth, and their knockdown impairs proliferation in vitro and tumor growth in vivo, implicating the histone deacetylation complexes Sin3... https://escholarship.org/uc/item/3n70t1sp Thu, 19 Mar 2026 00:00:00 +0000 Beytagh, Mary Clare https://orcid.org/0000-0002-1882-1515 https://escholarship.org/uc/item/3kz2n7rt Representation learning is a subfield of machine learning dedicated to extract useful representations of data for downstream, domain specific tasks. This class of workflows is particularly important in modern computational biology and bioinformatics, where the large scale of datasets makes manual human interpretation and analysis infeasible. Though the representation learning field is increasingly concerned with general techniques to extract representations with desirable characteristics, its optimal application in the biosciences has not yet been established. In particular, diversity and scale of data modalities observed in the field, not limited to images, sequences, and timeseries, may require more tailored workflows. This thesis aims to describe methods by which prior biological knowledge can be incorporated into the representation learning workflow resulting in significant performance improvements.Chapter 2 focuses on the development of new methods for analysis of large-scale... https://escholarship.org/uc/item/3kz2n7rt Thu, 19 Mar 2026 00:00:00 +0000 Lee, Alex Jihun https://orcid.org/0000-0003-0001-2848 https://escholarship.org/uc/item/3h25t8kb Humans have evolved multiple specialized traits compared to other non-human primates (NHP), including human cognition, complex social behaviors, and susceptibility to certain neuropsychiatric disorders. The neocortex of the human brain plays a primary role in cognition, behavior, and disease. Human neocortex has disproportionately expanded about three-fold compared to our closest living evolutionary relative chimpanzee, since our divergence 6-8 million years ago.Despite clearly observable phenotypic differences, identifying causative genetic changes underlying human-specific traits including cortical expansion remains challenging. The remarkable sequence similarity of protein coding sequences between humans and chimpanzees, highlights the importance of studying non-coding sequences to better understand the evolution of human-specific traits. Importantly, non-coding regulatory elements provide context-specific means of altering gene expression patterns such as in different cell... https://escholarship.org/uc/item/3h25t8kb Thu, 19 Mar 2026 00:00:00 +0000 Abeykoon, Yashodara https://orcid.org/0000-0002-0900-138X https://escholarship.org/uc/item/2p08h71j Cancer heterogeneity, between and within tumors, remains a central obstacle to durable therapeutic responses. Addressing this challenge requires scalable experimental systems that capture the genetic and phenotypic diversity of human tumors, and molecular tools to monitor disease progression and identify new therapeutic strategies. This dissertation develops and applies integrative approaches to interrogate tumor biology across diverse genetic backgrounds, identify cancer-emergent molecules with diagnostic and functional relevance, and uncover metabolic vulnerabilities amenable to therapeutic intervention.In Chapter 1, we introduce GENEVA (Genetically Diverse and Endogenously Controlled Phenotypic Variation Assay), a platform enabling scalable, single-cell resolution profiling of drug responses across multiplexed tumor models. By combining patient-derived and cancer cell lines into mosaic 3D cultures and xenografts, GENEVA captures inter- and intra-population heterogeneity in... https://escholarship.org/uc/item/2p08h71j Thu, 19 Mar 2026 00:00:00 +0000 Suh, Jung Min https://orcid.org/0000-0002-1210-8460 https://escholarship.org/uc/item/2kq4g3tr Future behavior is guided by current experience, memory of the past, and imagination of possible futures. A major hippocampal subfield, CA1, encodes spatial information about present location as well as previously visited and potential future locations. CA1 is often described as a single structure that alternates between these representational modes; however, the hippocampal formation is organized along a dorsoventral (longitudinal) axis into anatomically distinct subregions. The dorsal and ventral poles of CA1 serve different roles in spatial navigation and emotional processing, but whether the intermediate subregion is functionally distinct from dorsal CA1 remains unclear. Although sharp gene-expression boundaries divide CA1 into dorsal, intermediate, and ventral subregions, electrophysiological signatures vary gradually along the dorsoventral axis, suggesting that function may also change in a graded manner.We leverage these gradual electrophysiological changes to test whether... https://escholarship.org/uc/item/2kq4g3tr Thu, 19 Mar 2026 00:00:00 +0000 Nevers, Rhino https://orcid.org/0000-0003-2144-6952 https://escholarship.org/uc/item/1zp976nb Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion of naïve CD4+ T cells into regulatory T cells (Tregs). Here, we demonstrate heightened capacity for FOXP3 expression and tolerogenic function among cord blood versus adult blood naive CD4+ T cells and that this is linked to their unique metabolic profile and elevated expression of the NADase, CD38. Early life naïve CD4+ T cells demonstrate a metabolic preference for glycolysis, which directly facilitates their differentiation trajectory. We reveal an age-dependent gradient in CD38 levels on naïve CD4+ T cells and show that high CD38 expression contributes to both the glycolytic state and tolerogenic potential of neonatal CD4+ T cells, effects that are mediated at least in part via the NAD-dependent deacetylase SIRT1. Thus, the early life window for peripheral tolerance in humans is critically enabled by the immunometabolic state of the naïve CD4+ compartment. https://escholarship.org/uc/item/1zp976nb Thu, 19 Mar 2026 00:00:00 +0000 Dwyer, Laura https://orcid.org/0000-0002-5689-2541 https://escholarship.org/uc/item/1nc2m4cf The gastrointestinal tract is a complex organ system whose function depends on coordinated activity of epithelial, mesenchymal, and neural compartments. During embryonic development, these compartments undergo orchestrated morphogenetic events to establish the architectural and functional features of the mature intestine. This thesis integrates developmental biology, stem cell biology, and human genetics to elucidate mechanisms governing intestinal morphogenesis and enteric nervous system (ENS) development, and to identify genetic and cellular pathways underlying disorders of gut-brain interaction (DGBIs).Chapter 1 provides an introduction to intestinal villus morphogenesis, ENS development and patterning, motor neuron specification, and the genetic susceptibility to DGBIs, establishing the context for the experimental work presented in subsequent chapters.Chapter 2 investigates the role of extracellular matrix (ECM) adhesion and remodeling in intestinal villus morphogenesis.... https://escholarship.org/uc/item/1nc2m4cf Thu, 19 Mar 2026 00:00:00 +0000 Kalantari, Ali https://orcid.org/0009-0008-9524-6623 https://escholarship.org/uc/item/9np1d2fp Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). Within the CNS, APOE is produced by a variety of cell types under different conditions, each of which differentially influences disease progression. While astrocytes are the primary producers of APOE in the CNS, neurons exhibit a striking upregulation of APOE expression in conditions of stress and aging. Here, we asked whether neuronal APOE4 alone is sufficient to drive AD pathologies. We generated a PS19 tauopathy mouse model selectively expressing APOE4 in neurons, and found that neuronal APOE4 expression alone proved sufficient to promote pathological tau accumulation and propagation, neurodegeneration, and neuroinflammation at levels comparable to tauopathy models with human APOE4 knocked-in to all cells. Single-nucleus RNA sequencing further revealed similar neuronal and glial disease signatures between the two models. Together, these findings demonstrate that neuronal... https://escholarship.org/uc/item/9np1d2fp Thu, 18 Dec 2025 00:00:00 +0000 Blumenfeld, Jessica https://orcid.org/0000000254706901 https://escholarship.org/uc/item/9197b1bv Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). Within the central nervous system (CNS), APOE is produced by a variety of cell types under different conditions. It has become evident that the APOE4 produced in different CNS cells plays differential roles in AD pathogenesis. In particular, studies have shown that APOE4 produced by neurons plays a central role in promoting the development of major AD pathologies such as tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability, and myelin deficits, highlighting its ability to influence other CNS cells and its role as an upstream factor either directly or indirectly affecting numerous downstream AD-related cell types, genes, and pathways. Here we demonstrate that targeted reduction of a neuron-specific splicing variant of APOE mRNA (APOE-I3) using antisense oligonucleotides (ASOs) effectively reduces APOE expression in neurons in vitro and in vivo. Treating PS19... https://escholarship.org/uc/item/9197b1bv Thu, 18 Dec 2025 00:00:00 +0000 Yip, Oscar https://orcid.org/0000-0001-9096-7167 https://escholarship.org/uc/item/8jz3t43r Bacteria are subject to predation by bacteriophages, leading to an evolutionary arms race where bacteria-encoded immune systems and phage-encoded anti-immune factors evolve to counteract each other. A classic example of this evolutionary arms race dynamic is bacterial CRISPR-Cas immune systems, which are inhibited by phage-encoded anti-CRISPR proteins (Acrs). While CRISPR-Cas and Acr interactions have been characterized in vitro, their impact on fitness, and the evolutionary benefits and drawbacks of the mechanistic diversity in the Acr family, are best investigated in the native context of phage infection, which I explore in Chapter 1. On the other hand, for anti-immune factors that are less well-characterized than Acrs such as the jumbophage nucleus, in vitro biochemistry can aid in establishing molecular mechanisms of protein import, which I present preliminary work for in Chapter 2. Altogether, my thesis characterizes anti-immune factors at different scales, from molecular... https://escholarship.org/uc/item/8jz3t43r Thu, 18 Dec 2025 00:00:00 +0000 Chen, Daphne Flora https://orcid.org/0000-0002-5571-3548 https://escholarship.org/uc/item/80t5777k Gram-negative bacterial pathogens rely on a dynamic peptidoglycan (PG) cell wall to maintain viability, withstand antibiotic stress, and interface with their hosts. Although numerous PG-active enzymes and PG-sensing proteins have been identified, the principles that govern how their activities are structurally coordinated, acutely perturbed, and encoded in primary sequence remain incompletely defined. This dissertation addresses these questions by integrating high-resolution structural biology, nanobody-based perturbation, and machine learning to elucidate mechanisms of PG remodeling and recognition across multiple scales, from a single enzyme complex to proteome-wide families of PG-binding domains.Chapter 1 delineates the structural and biochemical basis of conformational gating in the LtgA–Ape1 PG-remodeling complex from Neisseria meningitidis. Single-particle cryo–electron microscopy, structure-guided mutagenesis, and kinetic analyses reveal how Ape1 binding reorganizes the... https://escholarship.org/uc/item/80t5777k Thu, 18 Dec 2025 00:00:00 +0000 Soriano, Berliza Marie https://orcid.org/0000-0002-0454-2611 https://escholarship.org/uc/item/7cs7291d Targeted intracellular delivery remains limited by poor the rate-limiting nature of endosomal escape for most lipid nanoparticles. We developed enzyme-triggered Fusogenic Nano Encapsulations (eFugene), a protease-gated, membrane-fusogenic nanoencapsulation that converts local proteolysis into a switch that drive cell selective rapid delivery. eFugene operates through a peptide-gated interfacial charge switch, maintaining an mildly anionic “off” state in off-target environments that limit uptake while rapidly unmasking a fusogenic core that drives plasma-membrane merger and direct cytosolic release near target microenvironments. Using high-throughput, on-particle peptide screening enabled by rapid TCO–tetrazine coupling, we optimized eFugene to tune activity to the urokinase plasminogen activating system (uPA) via uPA-responsive surface (denoted u-eFugene). In 2D cocultures, u-eFugene showed a selectivity between uPA-high and uPA-low contexts and defined an operational window.... https://escholarship.org/uc/item/7cs7291d Thu, 18 Dec 2025 00:00:00 +0000 Mathur, Vineet Keshav https://orcid.org/0000-0002-4742-4113 https://escholarship.org/uc/item/68p7q675 Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Here, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal profiling of the human gut microbiome during colorectal cancer (CRC) treatment coupled to cell culture and mouse experiments. We show that the gut microbiome impacts anticancer drug toxicity through two mechanisms: drug inactivation and the biosynthesis of chemoprotective metabolites. Leveraging a cohort of CRC patients treated at UCSF, we found that the gut microbiota was altered during oral fluoropyrimidine chemotherapy, increasing the abundance of a bacterial operon (preTA) capable of inactivating 5-fluorouracil (5-FU). Colonization of mice with preTA+ bacteria decreased intestinal 5-FU levels and rescued drug toxicity. Bacterial preTA abundance predicted fluoropyrimidine toxicity in patients. We then performed longitudinal metagenomic... https://escholarship.org/uc/item/68p7q675 Thu, 18 Dec 2025 00:00:00 +0000 Trepka, Kai Robert https://orcid.org/0000-0002-8672-6317 https://escholarship.org/uc/item/63q0134v Prostate Cancer remains a major cause of cancer-related death in men, and many patients with prostate cancer will eventually progress to a metastatic, resistant disease. Prostate-specific membrane antigen (PSMA) is highly overexpressed on prostate cancer cells and has been successfully used for both nuclear imaging and radiotherapy purposes using small-molecule radiopharmaceuticals. However, small PSMA ligands clear rapidly and often require multiple high-dose treatments in order to achieve a therapeutic effect. Nanomedicine platforms have been developed to deliver imaging or therapy payloads passively by the enhanced permeability and retention (EPR) effect or actively using targeting agents. This enables nanocarriers with a longer biological half-life to accumulate and be retained in the tumor for a longer period. Passive nanocarrier delivery alone has shown limited and heterogeneous tumor penetration in EPR-low prostate cancer models. Building on prior work with ⁸⁹Zr-labeled... https://escholarship.org/uc/item/63q0134v Thu, 18 Dec 2025 00:00:00 +0000 Phaler, Richele Miranda Makanalani https://orcid.org/0009-0002-7268-597X https://escholarship.org/uc/item/4xc5x3gx Apolipoprotein E4 (APOE4) confers the greatest genetic risk for developing Alzheimer's disease (AD). With APOE4 broadly expressed in the brain, its cell-type specific roles in AD pathogenesis are only beginning to be defined. Here, we show that neuronal APOE4 expression drives damaging lipid accumulation in hippocampal neurons, oligodendrocytes, and microglia, with preferential buildup of peroxidized lipids in microglia in a tauopathy mouse model. Neuron-specific removal of APOE4 abolished this lipid phenotype, whereas neuron-specific expression of APOE4 was sufficient to recapitulate it, demonstrating that neuronal APOE4 is both necessary and sufficient lipid accumulation. Strikingly, the association between lipid burden, microgliosis, and neurodegeneration was strongest in mice with neuron-specific APOE4 expression. Single-nucleus RNA sequencing revealed neuronal APOE4-vulnerable neuron populations, as well as enrichment of disease-associated microglia and oligodendrocytes.... https://escholarship.org/uc/item/4xc5x3gx Thu, 18 Dec 2025 00:00:00 +0000 Kim, Min Joo https://orcid.org/0000-0002-7906-0115 https://escholarship.org/uc/item/4680m8nk Sacrococcygeal teratomas (SCTs) are the most common neonatal tumors, yet their developmental origins, molecular mechanisms, and female-sex bias remain poorly understood. This thesis integrates spatial transcriptomics, single-cell RNA sequencing, and experimental models to investigate SCT biology and its hypothesized origins from primordial germ cells (PGCs). We first examined female primate ovarian reserve establishment, showing that rhesus macaque primordial follicles arise from two pre-granulosa cell subtypes, with PG2 cells predominating and supporting early hormone production before birth. We then generated a cellular atlas of SCTs, revealing epithelia-rich and epithelia-poor subtypes, marked inter-tumor heterogeneity, and evidence that X-chromosome inactivation failure in female tumors may contribute to observed sex biases. Finally, using iPSC-derived PGC-like cells, we modeled germ cell reprogramming to pluripotency, identifying transcriptional, metabolic, and epigenetic... https://escholarship.org/uc/item/4680m8nk Thu, 18 Dec 2025 00:00:00 +0000 Rojas, Ernesto J. https://orcid.org/0000-0002-6837-7678 https://escholarship.org/uc/item/4606q3xn Cysteine-reactive covalent molecules have emerged as powerful therapeutic agents in the clinic and as useful chemical tools in the lab, but their successful development requires both strategies to enhance their selectivity and resources to better understand cysteine reactivity across biological contexts. This dissertation presents complementary approaches that advance both fronts. First, I describe a steric tuning strategy for electrophilic warheads that improves covalent inhibitor selectivity independent of the intrinsic electrophile reactivity. We demonstrate the utility of this approach by exchanging the acrylamide warhead on the Bruton’s tyrosine kinase (BTK) inhibitor, Ibrutinib (Ib), for fumarate-based electrophiles. The incorporation of a tert-butyl fumarate electrophile onto Ib (IbtBu) preserved on-target BTK engagement while markedly reducing time-dependent and time-independent off-target reactivity, decreasing proteome-wide labeling from 247 proteins to 7, with BTK as... https://escholarship.org/uc/item/4606q3xn Thu, 18 Dec 2025 00:00:00 +0000 Montano, Jose Luis https://orcid.org/0000-0002-8555-4197 https://escholarship.org/uc/item/3cj200fb Multicellular organisms rely on complex immune systems that initiate innate and adaptive responses to invading pathogens to survive. A crucial challenge for adaptive immunity is distinguishing self from invading non-self. For T cells, this self-education is established through central tolerance in the thymus, mediated largely by Aire-expressing medullary thymic epithelial cells (mTECs), and is reinforced through peripheral tolerance in the host’s tissues. While some aspects of central tolerance are well characterized, peripheral tolerance remains less well-defined; however recent work implicates an MHCII expressing, RORgt⁺ antigen-presenting cell in tolerance to food antigens and the gut microbiome. Because of the complexity of these tolerance mechanisms and the cellular diversity of their mediators, integrative bioinformatic analyses of large multi-modal ‘omics datasets can provide key insights to help unravel these biological processes. Using single-cell transcriptomics to investigate... https://escholarship.org/uc/item/3cj200fb Thu, 18 Dec 2025 00:00:00 +0000 Germino, Joe https://orcid.org/0000-0003-3939-3342 https://escholarship.org/uc/item/2ss738xz Cell surface proteins represent critical targets for cancer immunotherapy, yet most discovery efforts rely solely on differential expression rather than structural features. This dissertation advances "structural surfaceomics"—a methodology integrating surface-selective biotinylation with crosslinking mass spectrometry (XL-MS)—to systematically map conformational landscapes of tumor cell surfaces and identify epitopes suitable for therapeutic targeting. Chapter 1 establishes quantitative surfaceomics workflows for multiple myeloma, developing confidence scoring approaches for cell surface protein identification and enrichment validation. This proteomic foundation enables robust surfaceome characterization in myeloma. Chapter 2 presents AlphaCross-XL, a computational platform bridging experimental crosslinking data with AlphaFold-predicted structures. This visualization tool enables systematic structural validation and identification of conformational deviations from predicted... https://escholarship.org/uc/item/2ss738xz Thu, 18 Dec 2025 00:00:00 +0000 Kishishita, Audrey https://orcid.org/0000-0002-1984-222X https://escholarship.org/uc/item/2sr0v7h0 Remak bundles are groups of small-diameter unmyelinated nociceptive axons ensheathed by Schwann cells (SCs). Whereas the development and maturation of myelinating SCs has been extensively studied, the formation of Remak bundles remain poorly understood. By preventing the secretion of type IV collagen from SCs, we observe normal myelin but abnormal Remak bundles. There is a decrease in the density of Remak bundles, an increase in bundle size, improperly ensheathed axons, and a decrease in mechanosensitivity. While Remak bundle formation appears to be independent of integrin signaling, loss of type IV collagen leads to a decrease in postnatal SC proliferation. Inducing the emergence of supernumerary SCs rescues Remak bundle architecture and mechanosensitivity. Taken together, our results demonstrate that SC-secreted basal lamina critically regulates Remak SC number, bundle size, and structure. Our findings provide insight into the functional role of Remak bundles and highlight their... https://escholarship.org/uc/item/2sr0v7h0 Thu, 18 Dec 2025 00:00:00 +0000 Lillis, Monique https://orcid.org/0000-0002-9771-0126 https://escholarship.org/uc/item/2d33s8nk Background: Climate change is an escalating public health emergency that increasingly drives forced displacement, particularly through flooding. Although climate-driven disasters disrupt entire communities, their consequences are profoundly gendered. Women often shoulder disproportionate caregiving burdens, face barriers to healthcare access, and experience economic and psychological strain during and after displacement. In California’s Central Coast, recurrent flooding in the Watsonville and Pájaro region has repeatedly displaced agricultural, largely Latino, and low-income populations. Yet, little research has examined women’s lived experiences within these recurring climate events and the structural conditions that shape their recovery. Objectives: This dissertation aimed to (1) examine the health, safety, and recovery experiences of women displaced by flooding in the United States; (2) identify social, economic, and policy factors that influence women’s health and well-being... https://escholarship.org/uc/item/2d33s8nk Thu, 18 Dec 2025 00:00:00 +0000 Moore, Ashley Michelle https://orcid.org/0009-0009-6638-9892 https://escholarship.org/uc/item/28x3h9dd Chimeric antigen receptor (CAR) T-cells are a powerful therapeutic technology that has shown exceptional efficacy in B-cell cancers and multiple myeloma, but only limited effects in other hematological malignancies or solid cancers. A major challenge has been developing and optimizing strategies for targeting cancer-specific cell surface targets without targeting healthy tissues, especially given the heterogeneity of cell-surface protein expression in most tumors.Here, I first develop a dual-antigen targeting CAR T-cell therapy against the antigens CD70 and the active conformation of integrin β2 (aITGB2), two antigens known to be expressed in acute myeloid leukemia (AML) but on very few healthy tissues. I show that an OR-gated approach for these antigens significantly increases the proportion of AML blasts that can be targeted. I identify dual-targeting CAR-T constructs with superior anti-tumor cytotoxicity in vitro against AML cell line and patient-derived xenograft models. I... https://escholarship.org/uc/item/28x3h9dd Thu, 18 Dec 2025 00:00:00 +0000 Kang, Amrik Singh https://orcid.org/0000-0003-0445-5654 https://escholarship.org/uc/item/1wc2523q p97/VCP is a member of the AAA+ protein family (ATPases associated with diverse cellular activities) that serves as a molecular motor to unfold proteins and make them available for recycling or degradation. VCP is composed of three globular domains: an N-terminal domain (NTD), D1, and D2. These domains oligomerize with nearby copies of VCP to form a 530 kDa homohexameric complex composed of two stacked rings and a pore in the middle. The lower ring is composed of D2 domains and hydrolyzes ATP to provide the mechanical energy needed to pull protein substrates through the central pore. The upper D1 ring lacks the pore loop residues necessary to engage substrates. Instead, the nucleotide state of the D1 domains allosterically controls the position of the NTD relative to the body of the hexamer. When the D1 is bound to ADP, the NTDs lie in the plane of the D1 ring, adopting the “down” state. When ADP is released and ATP binds, there is a concerted swing of the NTD to the “up” state.... https://escholarship.org/uc/item/1wc2523q Thu, 18 Dec 2025 00:00:00 +0000 Altobelli, Chad Richard https://orcid.org/0000-0003-3732-6779 https://escholarship.org/uc/item/1sk4h091 This dissertation addresses a long-standing issue in molecular docking: why do docking scores, particularly for hydrophobic ligands in buried pockets, reach unphysically large magnitudes? After testing alternative force field parameters and scoring models, I traced the problem to a missing physical term. The Lennard-Jones potential in docking captures favorable protein ligand van der Waals interactions but neglects the dispersion stabilization that ligands experience in water. Unlike rigorous free energy methods, which account for this via a thermodynamic cycle, docking double-counts dispersion inadvertently in favor of binding.To resolve this, I introduce a physically grounded correction: the solvent compensated van der Waals model. It estimates each ligand’s dispersion stabilization in water via explicit solvent molecular dynamics and subtracts this term from the protein ligand van der Waals score. This adjustment preserves pose ranking while restoring score magnitudes to experimentally... https://escholarship.org/uc/item/1sk4h091 Thu, 18 Dec 2025 00:00:00 +0000 Arzamasskaia, Alina https://orcid.org/0000-0001-5280-7621 https://escholarship.org/uc/item/1p422806 Iron is an essential yet potentially toxic metal that drives fundamental biochemical processes, including oxygen transport, mitochondrial energy production, and DNA synthesis. Its ability to alternate between ferrous (Fe²⁺) and ferric (Fe³⁺) states also enables the formation of reactive oxygen species through Fenton-type reactions, necessitating tight regulation by iron-handling proteins such as transferrin, ferritin, and ferroportin. Iron homeostasis is altered in many cancers, most often via upregulating iron uptake while suppressing iron export, leading to elevated labile iron pools (LIP) to sustain rapid proliferation and metastatic progression. This “iron addiction” has positioned iron metabolism as both a biomarker and therapeutic target in oncology.Herein, we developed and applied iron-activable chemical probes designed to exploit this dysregulated iron biology. Building upon the 1,2,4 trioxolane (TRX) pharmacophore—an endoperoxide motif activated by ferrous ions, the first... https://escholarship.org/uc/item/1p422806 Thu, 18 Dec 2025 00:00:00 +0000 Tram, Linh Que https://orcid.org/0009-0001-4041-9776 https://escholarship.org/uc/item/1db5m1fn Understanding speech is a rapid and seemingly effortless feat that humans perform every day. Yet this ability relies on complex neural computations that integrate language-specific knowledge in order to transform external acoustic signals into internal linguistic representations. This dissertation investigates how neural computations in the human temporal cortex, particularly in the superior temporal gyrus (STG), support speech processing across languages. In the first chapter, we introduce the theoretical and empirical foundations for studying speech processing in the STG and describe how high-resolution intracranial brain recordings, such as electrocorticography (ECoG), have enabled its functional description. Based on prior work, we argue that the STG performs fundamentally nonlinear and dynamic speech computations, including categorization, normalization, and the extraction of temporal structure. Open questions remain as to the extent to which speech computations in... https://escholarship.org/uc/item/1db5m1fn Thu, 18 Dec 2025 00:00:00 +0000 Bhaya-Grossman, Ilina https://orcid.org/0000-0003-2613-4528 https://escholarship.org/uc/item/180832rx Coronary artery disease (CAD) is the leading cause of death worldwide. Over the past twenty years, CAD genome-wide association studies (GWAS) have revealed a complex polygenic architecture in which plaque biology is a major axis of risk, with many loci acting through a dysregulated arterial microenvironment to drive atherosclerotic lesions. With larger and more diverse CAD cohorts spanning ancestry and sex, shared and distinct components of the genetic architecture are coming into focus. The presence or absence of specific loci across groups naturally prompts investigation. For any risk locus, we ask whether observed differences are explained by sample size and power, allele frequency differences, linkage disequilibrium structure, or unmodeled environmental interactions. One prominent example is the 9p21.3 locus—the most consistently replicated common-variant signal for CAD across several ancestries—yet it fails to replicate in African-ancestry groups. This dissertation... https://escholarship.org/uc/item/180832rx Thu, 18 Dec 2025 00:00:00 +0000 Alkhairo, Hasan Rayan https://orcid.org/0009-0007-9905-8358 https://escholarship.org/uc/item/15z5k675 Human APOBEC3G (A3G) is a potent cellular restriction factor against HIV-1. The viral protein Vif hijacks a Cullin5 RING (CRL5) E3 ubiquitin ligase to polyubiquitinate A3G for proteasomal degradation, neutralizing its antiviral potency. An ancient Molecular Arms race between lentiviruses and primate hosts modulates the Vif-A3G protein interface. Recently, we demonstrated in a cryo-EM structure that HIV-1 Vif also uses an RNA oligonucleotide as a molecular glue to bind A3G for polyubiquitination. Vif binds RNA and A3G in a manner that is compatible with polyubiquitination by coenzymes in the CRL5 complex. Vif utilizes RNA-binding to bind conserved residues in A3G, limiting its ability to escape antagonism. We demonstrate that RNA acts as a molecular glue, promoting the complex assembly of Vif and A3G. The role of RNA in promoting A3G ubiquitination is investigated using quantitative pulse-chase assays that monitor A3G mono-ubiquitination. The study of Vif-A3G binding, mediated... https://escholarship.org/uc/item/15z5k675 Thu, 18 Dec 2025 00:00:00 +0000 Dailey, Leandrew Allen https://orcid.org/0009-0006-5081-2260 https://escholarship.org/uc/item/0wc3c1dm How can a single cell learn without a brain? Although learning is often viewed as a unique feature of animals with complex nervous systems, single-celled organisms also demonstrate basic forms of learning and memory. The single cell Stentor coeruleus contracts in response to mechanical taps, but habituates and learns to ignore the taps after repeated stimulation. Here, we explored the molecular changes that occur during the formation of this cellular memory in order to improve our understanding of non-synaptic learning. We impaired cellular protein synthesis with cycloheximide and puromycin and found that, contrary to the effects of such treatments on metazoa, these drugs accelerate habituation and prolong memory retention in Stentor. Exploratory proteomic and transcriptomic analyses identified candidate proteins and genes that change over the course of learning and forgetting. These candidates, including EF-hand domain-containing proteins, metal-dependent protein phosphatases,... https://escholarship.org/uc/item/0wc3c1dm Thu, 18 Dec 2025 00:00:00 +0000 Rajan, Deepa https://orcid.org/0000-0003-2181-9413 https://escholarship.org/uc/item/0ts917qx The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) regulate exchange between the peripheral circulation and the central nervous system (CNS). During development, these barriers have a selective permeability that differs from adult states, creating both vulnerabilities and therapeutic opportunities. This dissertation addresses fundamental questions about blood-CNS barrier during development. (1) What endothelial and mural cell subtypes are present during early CNS vascular development? (2) How do these subtypes map to regions of differing barrier permeability? (3) What molecular signatures distinguish these regions? Chapter 2 presents a single-cell atlas of mouse brain and spinal cord vasculature at embryonic day (E)13.5 and E18.5, identifying endothelial and mural subtypes that establish arteriovenous zonation. Trajectory analysis revealed maturation programs progressing from proliferation through angiogenesis to transporter-rich barrier states, with region-specific... https://escholarship.org/uc/item/0ts917qx Thu, 18 Dec 2025 00:00:00 +0000 Wedderburn-Pugh, Kaylee https://orcid.org/0000-0002-5501-0519 https://escholarship.org/uc/item/09d8p5kq Transcription factors (TFs) have millions of potential binding sites across the human genome, but only a fraction are bound in a given context. Genomic footprinting aims to identify context-specific binding sites by detecting patterns in open chromatin data. This dissertation presents computational strategies to advance TF footprinting and evaluate its reproducibility in single-cell chromatin accessibility data. Chapter 2 introduces scBAMpler, a read-level downsampling framework that adjusts key dataset properties while preserving original cell attributes. Chapter 3 uses this framework to benchmark leading footprinting methods, providing systematic guidance to avoid statistical pitfalls and maximize detection of cell type-specific TF binding. Together, these tools and analyses provide a roadmap for dissecting TF binding and gene regulatory networks across diverse cell types, delivering practical guidance while laying a foundation for future computational advances. https://escholarship.org/uc/item/09d8p5kq Thu, 18 Dec 2025 00:00:00 +0000 Everitt, Amanda https://orcid.org/0000-0001-9720-1922 https://escholarship.org/uc/item/01n284q4 Anti-bacteriophage systems like restriction-modification and CRISPR-Cas have DNA substrate specificity mechanisms that enable identification of invaders. How Gabija, a highly prevalent nuclease-helicase anti-phage system, executes self- vs. non-self-discrimination remains unknown. In this dissertation, we first highlight the current understanding of how different DNA-targeting systems determine cleavage and counter-measures phages use to overcome them. We then characterize the activation requirements for Gabija, proposing that phage-encoded DNA end-binding proteins that antagonize host RecBCD sensitize phages to Gabija. When targeting a temperate Lambda-like phage in Pseudomonas aeruginosa, Gabija protects the cell by preventing phage genome circularization and subsequent replication. Phage and plasmid sensitivity to Gabija is licensed by DNA end-binding complexes such as a phage exonuclease together with a ssDNA-annealing protein or GamMu dimers, which prevent loading of host... https://escholarship.org/uc/item/01n284q4 Thu, 18 Dec 2025 00:00:00 +0000 Hong, Alex https://orcid.org/0000-0001-6438-9949 https://escholarship.org/uc/item/00h000kp Glioma is a highly heterogenous brain tumor, with the most aggressive subtype serving, essentially, as a death sentence. Many have investigated glioma from various angles, from biomarker discover to better target and develop therapies, to implementing machine/deep learning to improve diagnose and disease monitoring. Glioma’s location within the brain and heterogeneous nature create a unique challenge in the quest towards improved outcomes and a full cure. Currently, diagnosis and treatment methods fail to encapsulate full tumor heterogeneity, which can lead to over and under diagnosis and subsequent over or under treatment. This provides a ripe landscape for individualistic precision medicine implementation. Magnetic resonance imaging (MRI) is routine in the diagnosis and monitoring of glioma. Many recent studies have established links between this non-invasive imaging and histopathological metrics used to diagnose and grade glioma; helping to illuminate a path for artificial... https://escholarship.org/uc/item/00h000kp Thu, 18 Dec 2025 00:00:00 +0000 Adegbite, Oluwaseun S https://orcid.org/0009-0007-6043-6278 https://escholarship.org/uc/item/79x1q1tf 14-3-3 regulates the activity of thousands of client proteins in various biological pathways through physical occlusion, structural conformations, and scaffolding protein-protein interactions (PPIs). Utilizing the role of 14-3-3 to regulate client proteins, the Arkin lab has developed molecule glues (MGs) that stabilize native 14-3-3/client interactions, harnessing the negative regulatory interactions to “turn off” client proteins’ functions in disease. By targeting PPIs as opposed to singular proteins, selectivity can be enhanced through selective MGs that bind the unique composite interfaces for a PPI of interest. This also allows for unstructured proteins/regions that were previously difficult to target to gain new induced binding pockets for modulators for the development of novel therapeutics. The work presented in this dissertation showcases the work on exploring MGs for various 14-3-3/client interactions, with focus on the 14-3-3/ERα and 14-3-3/CRAF complexes. These... https://escholarship.org/uc/item/79x1q1tf Sat, 20 Sep 2025 00:00:00 +0000 Virta, Johanna Mae https://orcid.org/0000-0001-9893-5565 https://escholarship.org/uc/item/77n887n1 The ability of proteins to specifically interact with other molecular species—including small molecules, lipids, and metal ions—is known as molecular recognition. In this dissertation, I develop computational models of such interactions across diverse contexts, using design applications to assess and extend our understanding of molecular recognition principles. Chapter 1 introduces the concepts of molecular recognition and de novo design that recur throughout the thesis. In Chapter 2, I validate a newly developed symmetric docking algorithm using the many-body neural force field ANI-2x, enabling the design of ligands that bind symmetrically to screw-symmetric protein targets such as amyloids. Chapter 3 presents a model of helical peptide behavior during translocation through the endoplasmic reticulum (ER) membrane, using data from an in vitro assay to construct a predictive scale for transmembrane, interfacial, or aqueous outcomes. Chapter 4 investigates an engineered histidine... https://escholarship.org/uc/item/77n887n1 Sat, 20 Sep 2025 00:00:00 +0000 Kormos, Rian Cort https://orcid.org/0000-0002-5831-1464 https://escholarship.org/uc/item/745304hd Background: Patellofemoral Joint Osteoarthritis (PFJ OA) is a chronic articular disease in the knee joint characterized by the degradation of cartilage and pain. Previous studies have found degraded cartilage in asymptomatic individuals while others suggest a correlation between inflammation and pain. 18F-fluorodeoxyglucose ([18F]-FDG), a glucose analog radiotracer, reflects glucose hypermetabolism and may suggest an influx of proinflammatory cells due to the need of oxygen consumption during the inflammatory process. This study aims to highlight the anatomical structures in the PFJ that experience hypermetabolism which may indicate the presence of inflammation before and after exercise using positron emission tomography (PET) with [ 18F]-FDG and magnetic resonance imaging (MRI). Methods: Five subjects were enrolled: one control subject and four subjects diagnosed with PFJ OA. Images were acquired before and after subjects performed 25 single-legged squats. Eight knee regions... https://escholarship.org/uc/item/745304hd Sat, 20 Sep 2025 00:00:00 +0000 Kulkarni, Bhakti https://orcid.org/0009-0004-0116-6739 https://escholarship.org/uc/item/72s7h3zn Cells manipulate the shapes of their plasma membrane to execute different cellular functions, ranging from endocytosis, developmental morphogenesis to the protrusions that drive cell migration. All those processes are dependent on the rearrangement of the actin cytoskeleton, whose patterns of organization are controlled by proteins known as nucleation-promoting factors (NPFs). Cells use different NPFs to orchestrate dramatically different actin networks. For example, N-WASP controls the finger-like actin networks that comprise invadopodia, filopodia, and sites of endocytosis. In contrast, the WAVE regulatory complex organizes sheet-like protrusions known as lamellipodia that are ancient highly conserved engines of cell motility. The multivalent interactions that generate N-WASP organization are relatively well-understood and have been reconstituted with purified proteins in vitro. But how the WAVE complex oligomerizes into lines is not understood and has not proven amenable to... https://escholarship.org/uc/item/72s7h3zn Sat, 20 Sep 2025 00:00:00 +0000 Wu, Muziyue https://orcid.org/0000-0003-3096-8269 https://escholarship.org/uc/item/72b5420d Resorcinolic macrolides (RMs) are a structurally diverse class of natural products characterized by a conserved resorcinolic ester core linked to a highly variable macrocyclic bridge. Their ability to interact with ATP-binding sites, particularly in heat-shock protein 90 (Hsp90) paralogs, has garnered significant interest for developing selective inhibitors with therapeutic potential. Despite their structural diversity, limitations in efficient synthetic routes have hindered the comprehensive exploration of their structure-activity relationships (SAR) and the development of analogs with enhanced binding and selectivity. This dissertation presents a modular, enantioselective synthetic framework to access novel RMs, enabling a thorough investigation of their biological activity and selectivity profiles.The first chapter describes the development of a protecting group-free synthesis of (±)-de-O-methyllasiodiplodin, a structurally minimal RM derived from the fungus Lasiodiplodia theobromae.... https://escholarship.org/uc/item/72b5420d Sat, 20 Sep 2025 00:00:00 +0000 Madrigal-Lombera, Jesus Marcial https://orcid.org/0000-0003-4424-0375 https://escholarship.org/uc/item/6r869912 Nature uses structural variations on protein folds to fine-tune the geometries of proteins for diverse functions, yet deep learning-based de novo protein design methods generate highly regular, idealized protein fold geometries that fail to capture natural diversity, limiting the complexity of protein functions that can be designed using these methods. In this dissertation, I describe my work in improving protein structure prediction for geometrically diverse de novo proteins (Chapter 2), analyzing what this improved model learned (Chapter 3), and predicting thermodynamic stability from protein sequence (Chapter 4). In Chapter 2, using physics-based design methods, we generated and experimentally validated a dataset of 5,996 stable, de novo designed proteins with diverse non-ideal geometries. We show that deep learning-based structure prediction methods applied to this set have a systematic bias towards idealized geometries. To address this problem, we present a fine-tuned version... https://escholarship.org/uc/item/6r869912 Sat, 20 Sep 2025 00:00:00 +0000 Orr, Benjamin David https://orcid.org/0009-0002-4135-4676 https://escholarship.org/uc/item/6123x4bh Extracorporeal membrane oxygenation (ECMO) is a life support therapy used in patients with severe respiratory or cardiovascular failure, where gas exchange occurs outside the body via a membrane oxygenator. However, current clinical oxygenators are limited by poor hemodynamics, large blood priming volumes, and the need for continuous anticoagulation, which can lead to bleeding and clot formation. These complications, in turn, increase the risk of embolism and device failure. Microfluidic oxygenators have emerged as a promising alternative, offering improved gas exchange efficiency and hemocompatibility by incorporating biomimetic features, physiological pressures, and reduced shear stresses. Here, we describe the development of a microfluidic oxygenator composed of semipermeable silicon membranes, consisting of a semiconductor silicon backbone and a thin, gas-permeable silicone layer. First, two silicon membrane designs were evaluated, both demonstrating strong mechanical robustness,... https://escholarship.org/uc/item/6123x4bh Sat, 20 Sep 2025 00:00:00 +0000 Higgins, Nicholas https://orcid.org/0000-0003-1092-930X https://escholarship.org/uc/item/5z62m37r Rationale: Responsive neurostimulation (RNS) is a promising therapy for medically refractory epilepsy (MRE), yet clinical outcomes remain highly variable and difficult to predict. Identifying preoperative biomarkers that forecast treatment response could improve patient selection and inform neuromodulation strategies. We investigated whether structural and diffusion MRI features from limbic white matter pathways and mesial temporal structures could predict seizure reduction with hippocampal-targeted RNS.Methods: We retrospectively analyzed 41 patients who underwent hippocampal-targeted RNS implantation at UCSF. Diffusion tensor imaging (DTI) metrics and volumetric measures from mesial temporal and limbic regions were analyzed. Clinical response was quantified as time weighted percent seizure reduction across follow up visits. ElasticNet regression was employed to identify imaging features associated with response, with performance assessed using leave-one-out cross-validation... https://escholarship.org/uc/item/5z62m37r Sat, 20 Sep 2025 00:00:00 +0000 Evangelista, Rocelle Cruz https://orcid.org/0009-0002-8798-9917 https://escholarship.org/uc/item/4s78s0fq Purpose: Early detection of symptomatic prion disease (PrD) is critical because it allows for earlier intervention, management, and treatment of symptoms. The goal of this project is to evaluate the utility of imaging biomarkers in identifying microstructural abnormalities within genetic prion disease (gPrD) patients prior to symptom onset. This was accomplished by comparing cross-sectional and longitudinal MRI (standard T1-weighted (T1w) and diffusion tensor imaging (DTI)) of healthy controls (HC) and presymptomatic (presymptomatic) gPrD carriers to assess for group-wise and individual-level abnormalities; and further analysis evaluated correlations between imaging abnormalities and clinical abnormalities of disease progression to investigate imaging’s potential as an early biomarker. Materials and Methods: This project utilizes standard structural T1w MRI and DTI images of HCs (recruited by the UCSF Memory and Aging Center) and presymptomatic gPrD participants (recruited by... https://escholarship.org/uc/item/4s78s0fq Sat, 20 Sep 2025 00:00:00 +0000 Wu, Alexandra https://orcid.org/0009-0009-9936-865X https://escholarship.org/uc/item/48v7x2m3 Regeneration and wound healing are essential biological processes that restore cellular and tissue integrity following injury from external perturbations. Central to these processes is the interpretation of positional cues which include chemical or mechanical signals that instruct cells on what to rebuild and where to place structures. While the mechanisms underlying tissue and organ regeneration have been extensively studied, the molecular and spatial logic of regeneration at the subcellular level remains less understood. The giant single-celled ciliate Stentor coeruleus offers a powerful model for uncovering how cells interpret positional information to reconstruct complex intracellular architecture. With a highly polarized body plan, anterior-posterior axis, and an oral apparatus critical for feeding, Stentor can regenerate entire structures from fragments, provided a part of the macronucleus is intact.Here, we explore how cytoskeletal patterning and cell cycle regulators support... https://escholarship.org/uc/item/48v7x2m3 Sat, 20 Sep 2025 00:00:00 +0000 Yan, Connie https://orcid.org/0000-0002-9961-0671 https://escholarship.org/uc/item/46x4404m Precision medicine seeks to tailor healthcare based on individual genetic and molecular profiles. However, most existing tools and datasets were developed using Eurocentric cohorts, limiting their accuracy and equity across diverse populations. This dissertation addresses disparities in precision medicine through the development and application of computational approaches rooted in evolutionary theory, population genetics, and multi-omic technologies. I first introduce py_ped_sim, a simulation tool to evaluate the performance of kinship inference methods across varied ancestry backgrounds. I then apply untargeted metabolomics to examine postnatal metabolic changes linked to respiratory disease in extremely premature infants. In a large-scale genome study using data from the TOPMed consortium, I assess ultra-rare variant patterns and show how genetic ancestry shapes trait architecture and variant discovery. Finally, I reflect on my efforts to foster equity in science through mentorship,... https://escholarship.org/uc/item/46x4404m Sat, 20 Sep 2025 00:00:00 +0000 Guardado, Miguel A https://orcid.org/0000-0002-1748-3956 https://escholarship.org/uc/item/45g1q48t Nutrients are essential for sustaining life as we know it. Therefore, organisms, including humans, have evolved complex brain networks to control the decision to seek food, consume it, and when to stop eating. Importantly, the desire to overeat and store excess energy for scarce times must be weighed against the harmful effects of overloading our digestive systems.The satiation of hunger has traditionally been viewed as a gradual process triggered during a meal by gastrointestinal feedback, which is relayed by sensory nerves to the caudal brainstem to suppress appetite. Therefore, brainstem circuits – namely, the caudal nucleus of the solitary tract - are thought to be activated over tens of minutes to promote satiety. However, this assumption has not been directly tested due to the challenge of studying such a deep brain structure. To address this longstanding question, we developed new methods for recording the activity of distinct cell types in this brain region and determined... https://escholarship.org/uc/item/45g1q48t Sat, 20 Sep 2025 00:00:00 +0000 Ly, Truong https://orcid.org/0000-0001-9366-1366 https://escholarship.org/uc/item/2mz5n3pq Lysosomes are critical organelles for maintaining proteostasis in cells. One of the defining characteristics of lysosomes is their relative acidity compared to other subcellular compartments. This acidic pH is critical for the efficient breakdown of macromolecules and cellular homeostasis, and disruptions in lysosomal pH homeostasis have been linked to aging and disease. The mechanisms through which lysosomal pH is maintained are incompletely understood, a question important in neurons which are susceptible to age associated decline in proteostasis. Supporting this, we found neuronal lysosomes have a unique pH optimum for tau degradation. To better understand neuronal lysosomal pH regulation, we conducted a genome-wide CRISPRi-based screen in iPSC derived neurons for modifiers of lysosomal pH. We validated several previously known regulators of lysosomal pH and discovered novel pathways capable of modifying lysosomal pH including the protein UFMylation and mitochondrial integrity.... https://escholarship.org/uc/item/2mz5n3pq Sat, 20 Sep 2025 00:00:00 +0000 Welch, Mackenzie https://orcid.org/0009-0007-6896-6193 https://escholarship.org/uc/item/2gr2266r Quantitative Susceptibility Mapping (QSM) provides valuable sensitivity to paramagnetic rim lesions (PRLs) in multiple sclerosis, but the influence of algorithmic choices within the processing pipeline remains unclear. This study systematically compared two phase unwrapping methods (ROMEO and PRELUDE), two background field removal strategies (V-SHARP and RESHARP), and dipole inversion with iLSQR to assess their impact on lesion visibility and contrast stability.ROMEO achieved rapid phase unwrapping (20–40 seconds per dataset) compared to the several hours required by PRELUDE, yet PRELUDE produced clearer boundaries for small lesions, particularly in anatomically complex regions. For background field removal, V-SHARP provided greater global stability across brain regions, while RESHARP enhanced local lesion-to-background discrimination, especially within the corpus callosum and basal ganglia. Case-specific analyses further revealed that lesion distribution strongly influenced outcomes:... https://escholarship.org/uc/item/2gr2266r Sat, 20 Sep 2025 00:00:00 +0000 Zhang, Jiuyi https://orcid.org/0009-0001-1288-8815 https://escholarship.org/uc/item/1n81p0j9 Hsp90 is a well conserved and highly expressed molecular chaperone that interacts with 10% of the proteome to facilitate folding and activation. These interacting partners, dubbed clients, interact with Hsp90 throughout their entire lifetime and not just in the stages of initial folding. This continual interaction with this clientele makes Hsp90 a hub of proteostasis regulation which includes folding, activation, and degradation triage decisions. Hectd3 has been shown to degrade Raf1 in an Hsp90 dependent manner, here we show Hectd3 in complex with Hsp90:Cdc37:Raf1 in a closed Hsp90 state. Hectd3 reveals a C terminal platform on Cdc37 providing a potential scaffold for Hectd3 ubiquitination. We show Hectd3 can mono ubiquitinate the kinase domain of Raf at multiple lysines when Hsp90 is not in a molybdate trapped closed protective state. This mono ubiquitination of Raf1 upon Hsp90 opening could potentially bias the kinase toward a degradative end when subsequent E3 ligases could... https://escholarship.org/uc/item/1n81p0j9 Sat, 20 Sep 2025 00:00:00 +0000 Nowotny, Carlos Andres https://orcid.org/0000-0002-1260-0279 https://escholarship.org/uc/item/1j39744p Background: Large language models (LLMs) can be utilized to summarize radiologist-written reports for abdominal MRI and CT scans of liver lesions suspicious for hepatocellular carcinoma (HCC), and identify and track the growth of lesions over time. The standardized liver lesion reporting method, Liver Imaging Reporting and Data Systems (LI-RADS), allows for consistent representation of lesion characteristics which aids in the consistency of feature extraction.Objective: This study evaluates the ability of an LLM to compile qualitative radiologist reports into a structured database containing liver lesion identification and developmental features, and subsequently using those features to identify and track specific lesions across scans. Methods: This retrospective study included patients at risk for HCC who underwent abdominal CT or MRI scans that contained a LI-RADS 5 lesion. The radiologist reports of 108 scans from 15 patients were inputted to an LLM (GPT-4.1) alongside... https://escholarship.org/uc/item/1j39744p Sat, 20 Sep 2025 00:00:00 +0000 Finke, Nicholas https://orcid.org/0009-0001-4328-589X https://escholarship.org/uc/item/19c904xd Natural products and their derivatives have long served as powerful tools for treating bacterial infections, but the rise of antibiotic resistance threatens their continued effectiveness and has significantly depleted the current antibiotic pipeline. Structural modifications to natural product antibiotics have proven to be effective in overcoming certain resistance mechanisms and extending their clinical utility. The development of C4-modified group A streptogramins that overcome acetyltransferase resistance, a pervasive resistance mechanism to the class, is an example of successful implementation of this strategy. However, the synthetic chemistry to reach these new analogs was inherently limiting, enabled access to only two analogs with modifications at the desired position on the scaffold.In chapter 1, we report the development of a modified route to group A streptogramins that enables access to a broad diversity of functionality at C4. Using cryo-EM binding data to guide structural... https://escholarship.org/uc/item/19c904xd Sat, 20 Sep 2025 00:00:00 +0000 Lee, Isabel Jean https://orcid.org/0000-0001-8359-3072 https://escholarship.org/uc/item/190920mh Animals engage in approach-avoidance behaviors when confronted with potentially threatening cues. These behaviors are supported by neural computations and peripheral reactions in the body, such as autonomic signals that give rise to the classic “fight-or-flight” response. Significant changes in heart rate during these situations are a hallmark of this response. Importantly, the brain exerts top-down control over cardiac activity and heart rate can also influence brain function. Fluctuations in heart rate modulate neural activity in the medial prefrontal cortex (mPFC), a region involved in evaluating social environments, anxiogenic contexts, and guiding adaptive decisions. However, how cardiac signals are mapped in the mPFC during approach-avoidance behaviors remains unclear. To address this, we developed a multidisciplinary approach to simultaneously record heart rate and measure single-cell calcium signals from mPFC neurons in freely moving mice navigating social and anxiogenic... https://escholarship.org/uc/item/190920mh Sat, 20 Sep 2025 00:00:00 +0000 Mateo Semidey, Gabriel https://orcid.org/0000-0002-3682-7064 https://escholarship.org/uc/item/0wv1m4ww Prostate-specific membrane antigen (PSMA) PET is central to prostate cancer imaging, yet it shows reduced sensitivity in PSMA-low disease, including neuroendocrine variants. To develop CD46-targeted peptide tracers suited for faster imaging, we carried out four rounds of phage display with a Ph.D.-12 library against recombinant CD46. Rounds alternated between bead-based (1, 3) and plate-based (2, 4) formats, with antigen reduced from 25 to 10 µg and wash stringency increased (Tween-20 from 0.1% to 0.5%). Phage enrichment was evident by titer: amplified outputs rose from 1.8×10¹⁰ pfu/mL in round 1 to 9×10¹¹ pfu/mL in round 3, then measured 6×10⁹ pfu/mL in round 4. Next-generation sequencing showed contraction of library diversity from 6,623 unique peptides (50,804 total reads) in round 1 to 427 (3,873 reads) in round 4. Normalized-frequency trends highlighted strong enrichment of Peptide A (2.08%→17.84, rounds 1→4) and a late rise of Peptide B (0.44% in round 3 to 6.82% in round... https://escholarship.org/uc/item/0wv1m4ww Sat, 20 Sep 2025 00:00:00 +0000 XUE, CHENG https://orcid.org/0009-0004-2322-9980 https://escholarship.org/uc/item/0rh5p8hf Lung cancer is the leading cause of cancer related deaths worldwide. Although mutation driven cancers, such as those harboring activating EGFR mutations, show a high rate of initial response to targeted tyrosine kinase inhibitors (TKIs), all patients eventually develop acquired resistance. This dissertation aims to investigate the residual disease state (RD) to better understand the responding, yet persistent, tumor and identify potentially targetable features of the tumor landscape.The first chapter leverages static genomic barcoding paired with single-cell RNA sequencing (scRNA-seq) to identify pre-existing features of two distinct TKI-resistant preclinical EGFRm models. The static genomic barcoding enabled the identification of cell lineages that were either susceptible or resistant to TKI therapy. scRNA-seq analysis of these lineages enabled identification of pre-treatment features, as well as the mapping of transcriptional changes over treatment time. First, in our patient-derived... https://escholarship.org/uc/item/0rh5p8hf Sat, 20 Sep 2025 00:00:00 +0000 Tamaki, Whitney https://orcid.org/0000-0002-1124-628X https://escholarship.org/uc/item/0gt9v55z Cells coordinate nearly countless numbers of signaling reactions within them at any given time. To distinguish between different signaling inputs and outputs, cells utilize spatially compartmentalized signaling hubs to regulate their biochemical processes. We review how the primary cilium, an organelle specialized in intracellular signaling, utilizes lipids to create a specialized microenvironment. Hedgehog (HH) signaling in vertebrates is dependent on the primary cilium, an organelle that scaffolds signal transduction. HH signals induce Smoothened (SMO) enrichment in the cilium and indirectly triggers the conversion of GLI proteins into transcriptional activators of HH target genes. Recently, SMO has been shown to inhibit protein kinase A (PKA). To test the hypothesis that SMO specifically inhibits PKA at cilia to activate the HH signal transduction pathway, we developed a ciliary PKA biosensor. Activation of the HH signal transduction pathway by either Sonic hedgehog (SHH) or... https://escholarship.org/uc/item/0gt9v55z Sat, 20 Sep 2025 00:00:00 +0000 Nguyen, Thi Dan https://orcid.org/0000-0001-7525-920X https://escholarship.org/uc/item/0fr180dj Genetic prion diseases (gPrDs) are rare, fatal neurodegenerative disorders caused by pathogenic variants in the PRNP gene. Identifying early markers of network dysfunction is critical for advancing early detection and intervention strategies. This study investigates default mode network (DMN) functional connectivity alterations in presymptomatic gPrD carriers, with a focus on differences between faster- and slower-progressing subgroups. Resting-state fMRI data was acquired from presymptomatic carriers, symptomatic participants, and matched healthy controls. Seed-to-voxel analyses were performed to compare DMN connectivity across groups, with statistical significance determined after correction for multiple comparisons. Presymptomatic carriers exhibited distinct connectivity alterations based on progression rate. Faster-progressing individuals showed reduced posterior DMN connectivity, centered in the posterior cingulate and precuneus, while slower-progressing carriers displayed... https://escholarship.org/uc/item/0fr180dj Sat, 20 Sep 2025 00:00:00 +0000 Gundamaraju, Bhavna https://orcid.org/0009-0000-1930-239X https://escholarship.org/uc/item/0893d1pq Lysine demethylase 5A (KDM5A) plays a key role in the regulation of chromatin accessibility by catalyzing the removal of trimethyl marks on histone H3K4 (H3K4me3). KDM5A is also an oncogenic driver, with overexpression of KDM5A observed in various cancers, including breast, lung, and ovarian cancer. Past studies have characterized the functions of KDM5A domains, including KDM5A interactions with the histone H3 tail, but have yet to identify the broader mechanisms that drive KDM5A binding to the nucleosome. Through investigation of binding and catalysis on nucleosome substrates, we uncovered multivalent interactions of KDM5A with the H2A/H2B acidic patch and DNA that play crucial roles in the regulation of catalytic activity. We also identified an intrinsically disordered region (IDR) containing bifunctional arginine-rich motifs capable of binding to both the histone H2A/H2B acidic patch and nucleosomal DNA that is necessary for catalysis on nucleosome substrates. Our findings... https://escholarship.org/uc/item/0893d1pq Sat, 20 Sep 2025 00:00:00 +0000 Palla, Ali Mohammad https://orcid.org/0000-0001-7380-3881 https://escholarship.org/uc/item/037709js Hemodynamic shear stress regulates endothelial phenotype through activation of Notch1 signaling, yet the mechanistic basis for this activation is unclear. Here, I establish a fluid shear stress-dependent mechanism of Notch1 activation in blood endothelia that is distinct from canonical ligand trans-endocytosis. Application of laminar flow triggers the rapid spatial polarization of full-length Notch1 heterodimers into downstream membrane microdomains. Unlike canonical transactivation, I find that this response occurs independently of ligand redistribution, and Notch1 receptors are cis-endocytosed into the receptor-bearing cell within polarized microdomains prior to proteolytic activation. Furthermore, I discover that the Notch1 intracellular domain (ICD) critically orchestrates receptor polarization and proteolytic activation in response to flow but is dispensable for canonical ligand trans-activation. Shear stress increases ICD interaction with annexin A2 and caveolar proteins... https://escholarship.org/uc/item/037709js Sat, 20 Sep 2025 00:00:00 +0000 Singh, Tania https://orcid.org/0000-0003-0692-4821