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Open Access Publications from the University of California

Scholarly Works (12 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2013)

Diabetes mellitus is growing at an alarming rate globally. My dissertation aims at understanding the epigenetic mechanisms of Diabetes pathogenesis and how we can utilize this knowledge to develop treatments for patients with this debilitating disease.

Diabetes is associated with loss of pancreatic beta cells and islet replacement therapy is limited by the source of donor islets. Two promising alternative approaches for beta cell replenishment are regeneration of endogenous beta cells and directed stem cell differentiation. In chapter 1, I used a transgenic mouse model that ectopically expresses Ezh2, to offset the loss of endogenous protein and uncovered new insights into plasticity of beta cell regeneration in adulthood. I show that reprogramming of the Ink4a chromatin by modulating the conserved Polycomb-Trithorax mechanism can rejuvenate the replication capacity of aged beta cells to provide a new strategy for beta cell expansion. In chapter 2, I studied mouse embryonic stem (ES) cells to understand endodermal lineage specification, as current attempts to bring endoderm-derived stem cell therapy to a state of effectiveness have been hampered by the paucity of knowledge of the underlying mechanisms. I show that the pluripotency transcription factors and epigenetic modifications of the chromatin interact in order to implement control pathways that drive differentiation of stem cells towards the definitive endoderm lineage.

Type 1 Diabetes is caused by autoimmune assault of pathogenic T cells escaping the tolerance selection. In Chapter 3, I identified a novel interaction partner of the autoimmune regulator (Aire), JmjD6. My data suggest that JmjD6-mediated histone demethylation at Arginine 2 residues of target chromatin is essential to prime the chromatin of otherwise repressed peripheral tissue antigen (PTA), for subsequent Aire activation of the antigen peptides for tolerance selection.

Maternal obesity is concerning because of the deleterious effects in offspring of increased risks of metabolic syndromes including Type 2 diabetes and obesity. My current work is focused on whole genome methylation mapping of trans-generational epigenetic inheritance in a maternal high-fat diet mouse model. The single nucleotide resolution of this screening will reveal information on how inherited methylation markers contribute to the predisposition of metabolic diseases in progeny in the context of maternal obesity, which can be further utilized for intervention and disease prevention.

    Cover page: Epigenetic Studies of Diabetes
    • Article
    • Peer Reviewed
    Proceedings of the Annual Meeting of the Cognitive Science Society, Volume 44 (2022)
    Human adults can figure out what happened by combining evidence from different sensory modalities, such as vision and sound. How does the ability to integrate multi-modal information develop in early childhood? Inspired by prior computational work and behavioral studies with adults, we examined 3- to 8-year-old children's ability to reason about the physical trajectory of a ball that was dropped into an occluded Plinko box. Children had to infer in which one of three holes the ball was dropped based on visual information (i.e., where the ball landed) and auditory information (i.e., the sounds of the ball colliding with parts of the box). We compare children's responses to the predictions of four computational models. The results suggest that although even the youngest children make systematic judgments rather than randomly guessing, children's ability to integrate visual and auditory evidence continues to develop into late childhood.
      Cover page: Stop, children what’s that sound? Multi-modal inference through mental simulationCreative Commons 'BY' version 4.0 license
      • Article
      • Peer Reviewed
      Proceedings of the Annual Meeting of the Cognitive Science Society (2023)
      Infants must balance interacting with a caregiver and navigating the environment, driven by their curiosity and attachment. This decision involves trading off proximity seeking with the caregiver and novelty seeking in the surroundings. Our hypothesis is that different attachment styles may arise as adaptive reward-seeking strategies based on different frequencies and scales of rewards from both caregiver and environment, including negative rewards due to distressing encounters. We implement a computational model using a reinforcement learning framework to model infantsÕ attachment and exploratory behaviors as a bandit problem. We study how infantsÕ exploratory behaviors emerge as they learn from their caregiver and how these learned behaviors transfer to a new caregiver. Our work expands upon existing computational models of attachment and models how social factors can influence curiosity-seeking as infants learn to explore versus exploit.
        Cover page: Reinforcement learning models of tradeoffs between infant attachment and curiosity
        • Article
        • Peer Reviewed
        Proceedings of the Annual Meeting of the Cognitive Science Society, Volume 46 (2024)
        Attachment is crucial for infants' cognitive development and social relationships. Traditional attachment research has been qualitative, lacking a model to explain how infants' attachment styles develop from experience and how these are influenced by personal traits and environmental factors. We propose such a model, predicting how infants balance interaction with caregivers against exploring their surroundings. Our study is based in a grid-world environment containing an infant and caregiver agent. We vary the infant's temperamental factors (e.g., ability to regulate emotions and preferences for social vs. environmental reward), and caregiver behavior (whether positive or negative interactions are more likely). We find that different equilibria result that qualitatively correspond to different attachment styles. Our findings suggest that the characteristic exploratory behavior of each attachment style in real infants may arise from interactions of infant temperament and caregiver behaviors.
          Cover page: Simulating Infants' Attachment: Behavioral Patterns of Caregiver Proximity Seeking and Environment Exploration Using Reinforcement Learning Models.Creative Commons 'BY' version 4.0 license
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2018)
          Alzheimer's disease (AD) is a lifelong progressive neurodegenerativa disease related with accumulation of amyloid β peptide (Aβ) produced by processing of amyloid precursor protein (APP) in the brain. In spite of several-decades effort on AD, there is still no medicine used to intervene with its pathological processes. Our previous studies made in transgenic animal models harboring familial AD genes of mutant presenilin 1 and amyloid precursor protein (APP) showed that β2AR gene knock-out (β2AR-KO) is beneficial in senile AD animals. Consistently, an epidemiological study lasted for two decades showed that the sole usage of β blockers as antihypertensive medicines is associated with fewer brain lesions and less brain shrinkage seen in senile AD patients. In order to understand why senile β2AR-KO AD mice had better learning and memory, genomic effects of β2AR-KO in the double transgenic AD mice were investigated. In the analysis, major genomic significance of β2AR-KO was directed to influence protein-processing and presentation involving membrane structure and MHC class I and II protein complex, and lysosome and hydrolase activity for protein degradation, which are critical for accumulation of amyloid β peptide, the hallmark of AD.
            Cover page: Profiling of Differential Expression of Genes in Mice Carrying Both Mutant Presenilin 1 and Amyloid Precursor Protein Transgenes with or without Knockout of Β2 Adrenergic Receptor Gene
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2024)
            OBJECTIVE: Cardiac magnetic resonance (CMR) is a diagnostic tool that provides precise and reproducible information about cardiac structure, function, and tissue characterization, aiding in the monitoring of chemotherapy response in patients with light-chain cardiac amyloidosis (AL-CA). This study aimed to evaluate the feasibility of CMR in monitoring responses to chemotherapy in patients with AL-CA. MATERIALS AND METHODS: In this prospective study, we enrolled 111 patients with AL-CA (50.5% male; median age, 54 [interquartile range, 49-63] years). Patients underwent longitudinal monitoring using biomarkers and CMR imaging. At follow-up after chemotherapy, patients were categorized into superior and inferior response groups based on their hematological and cardiac laboratory responses to chemotherapy. Changes in CMR findings across therapies and differences between response groups were analyzed. RESULTS: Following chemotherapy (before vs. after), there were significant increases in myocardial T2 (43.6 ± 3.5 ms vs. 44.6 ± 4.1 ms; P = 0.008), recovery in right ventricular (RV) longitudinal strain (median of -9.6% vs. -11.7%; P = 0.031), and decrease in RV extracellular volume fraction (ECV) (median of 53.9% vs. 51.6%; P = 0.048). These changes were more pronounced in the superior-response group. Patients with superior cardiac laboratory response showed significantly greater reductions in RV ECV (-2.9% [interquartile range, -8.7%-1.1%] vs. 1.7% [-5.5%-7.1%]; P = 0.017) and left ventricular ECV (-2.0% [-6.0%-1.3%] vs. 2.0% [-3.0%-5.0%]; P = 0.01) compared with those with inferior response. CONCLUSION: Cardiac amyloid deposition can regress following chemotherapy in patients with AL-CA, particularly showing more prominent regression, possibly earlier, in the RV. CMR emerges as an effective tool for monitoring associated tissue characteristics and ventricular functional recovery in patients with AL-CA undergoing chemotherapy, thereby supporting its utility in treatment response assessment.
              Cover page: Light-Chain Cardiac Amyloidosis: Cardiac Magnetic Resonance for Assessing Response to Chemotherapy.
              • Article
              • Peer Reviewed
              UC Davis Previously Published Works (2017)
              Voltage-gated sodium channels (NaVs) are activated by transiting the voltage sensor from the deactivated to the activated state. The crystal structures of several bacterial NaVs have captured the voltage sensor module (VSM) in an activated state, but structure of the deactivated voltage sensor remains elusive. In this study, we sought to identify peptide toxins stabilizing the deactivated VSM of bacterial NaVs. We screened fractions from several venoms and characterized a cystine knot toxin called JZTx-27 from the venom of tarantula Chilobrachys jingzhao as a high-affinity antagonist of the prokaryotic NaVs NsVBa (nonselective voltage-gated Bacillus alcalophilus) and NaChBac (bacterial sodium channel from Bacillus halodurans) (IC50 = 112 nM and 30 nM, respectively). JZTx-27 was more efficacious at weaker depolarizing voltages and significantly slowed the activation but accelerated the deactivation of NsVBa, whereas the local anesthetic drug lidocaine was shown to antagonize NsVBa without affecting channel gating. Mutation analysis confirmed that JZTx-27 bound to S3-4 linker of NsVBa, with F98 being the critical residue in determining toxin affinity. All electrophysiological data and in silico analysis suggested that JZTx-27 trapped VSM of NsVBa in one of the deactivated states. In mammalian NaVs, JZTx-27 preferably inhibited the inactivation of NaV1.5 by targeting the fourth transmembrane domain. To our knowledge, this is the first report of peptide antagonist for prokaryotic NaVs. More important, we proposed that JZTx-27 stabilized the NsVBa VSM in the deactivated state and may be used as a probe to determine the structure of the deactivated VSM of NaVs.-Tang, C., Zhou, X., Nguyen, P. T., Zhang, Y., Hu, Z., Zhang, C., Yarov-Yarovoy, V., DeCaen, P. G., Liang, S., Liu, Z. A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel.
                Cover page: A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel
                • Article
                • Peer Reviewed
                UC Riverside Previously Published Works (2014)
                A majority of viruses are composed of long single-stranded genomic RNA molecules encapsulated by protein shells with diameters of just a few tens of nanometers. We examine the extent to which these viral RNAs have evolved to be physically compact molecules to facilitate encapsulation. Measurements of equal-length viral, non-viral, coding and non-coding RNAs show viral RNAs to have among the smallest sizes in solution, i.e., the highest gel-electrophoretic mobilities and the smallest hydrodynamic radii. Using graph-theoretical analyses we demonstrate that their sizes correlate with the compactness of branching patterns in predicted secondary structure ensembles. The density of branching is determined by the number and relative positions of 3-helix junctions, and is highly sensitive to the presence of rare higher-order junctions with 4 or more helices. Compact branching arises from a preponderance of base pairing between nucleotides close to each other in the primary sequence. The density of branching represents a degree of freedom optimized by viral RNA genomes in response to the evolutionary pressure to be packaged reliably. Several families of viruses are analyzed to delineate the effects of capsid geometry, size and charge stabilization on the selective pressure for RNA compactness. Compact branching has important implications for RNA folding and viral assembly.
                  Cover page: Viral RNAs Are Unusually Compact
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2018)
                  Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I-III breast cancer, DCIS/LCIS, Paget's disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1β, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203-14. ©2018 AACRSee related editorial by Fabian and Kimler, p. 187.
                    Cover page: A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease.
                    • Article
                    • Peer Reviewed
                    UC Merced Previously Published Works (2015)
                    Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies.
                      Cover page: Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis
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