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Open Access Publications from the University of California

Scholarly Works (69 results)

  • Thesis
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UC Berkeley Electronic Theses and Dissertations (2020)

Metazoan development is dependent on the robust spatiotemporal execution of stem cell cell-fate determination programs. Although changes in transcriptional and translational landscapes have been well characterized throughout many differentiation paradigms, their regulatory mechanisms remain poorly understood. Ubiquitin has recently been found to be a key modulator of developmental programs. Ubiquitylation of target proteins occurs through a cascade of enzymatic reactions beginning with a ubiquitin activating enzyme (E1) which transfer the ubiquitin moiety to a ubiquitin conjugating enzyme (E2). The reaction is finalized by the transfer of ubiquitin to its target protein by a ubiquitin ligase (E3). Post-translational modification of proteins can lead to several different outcomes, depending on the context of the modification, known as the ubiquitin code. The precise spatiotemporal execution of ubiquitylation is critical for organismal development and homeostasis. Due to the modular and reversible nature of ubiquitylation, it is an ideal moiety in the control of a plethora of cellular processes.

Cell-cell fusion is a frequent and essential event during development, whose dysregulation causes diseases ranging from infertility to muscle weakness. Critical to this process, cells repeatedly need to remodel their plasma membrane through orchestrated formation and disassembly of cortical actin filaments. In Chapter 2, I describe the identification of a ubiquitin-dependent toggle switch that establishes reversible actin bundling during mammalian cell fusion. My work identified KCTD10 as a modulator of the EPS8-IRSp53 complex, which stabilizes cortical actin bundles at sites of cell contact to push fusing cells towards each other. This work highlights how cytoskeletal rearrangements during development are precisely controlled, raising the possibility of modulating the efficiency of cell fusion for therapeutic benefit.

Organismal development must rely on the timely and robust execution of quality control responses. However, how these responses modulate metazoan development is poorly understood. Showcasing the versatility of ubiquitin signaling, Chapters 3 and 4 provide insight into the role of ubiquitin in controlling stress and quality control responses. Chapter 3 describes the reductive stress response, in which FEM1B senses and reacts to persistent depletion of reactive oxygen species. Loss of ROS is detrimental for development, as it inhibits myogenesis. Concomitant to this stress response is the identification of multimerization quality control, regulated by BTBD9. MQC surveys multimeric BTB complex composition, ensuring that multimeric complexes contain the correct stoichiometries and compositions. MQC is critical for development, as loss of MQC als prevents myogenesis. These two chapters showcase the integration of ubiquitin signaling, stress/quality control pathways, and development. These writings provide a more holistic understanding into the robust regulatory underpinnings of organismal formation

    Cover page: Ubiquitin-Dependent Control of Myogenic Development: Mechanistic Insights into Getting Huge, and Staying Huge
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    UC Berkeley Previously Published Works (2018)
    A transcription factor called SALL4 could be the missing link between thalidomide and the limb defects caused by the drug.
      Cover page: Unlocking a dark past
      • Article
      Frontiers of Biogeography, Volume 7, Issue 1 (2015)
        Cover page: Advances in the biogeography of littoral environments: a multidisciplinary perspectiveCreative Commons 'BY' version 4.0 license
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2013)
        Abstract Background Enhanced EGF receptor (EGFR) signaling is a hallmark of many human cancers, though the role of enhanced EGFR signaling within the surrounding tumor stroma has not been well studied. The myofibroblast is an important stromal cell that demonstrates enhanced EGFR expression in the setting of inflammation, though the functional relevance is not known. We recently reported that TNF-α and the G protein-coupled receptor (GPCR) agonist lysophosphatidic acid (LPA) lead to synergistic cyclo-oxygenase-2 (COX-2) expression, an enzyme strongly associated with the development of colitis-associated cancer. Here, we investigate whether EGFR signaling plays a role in the synergistic COX-2 expression induced by LPA and TNF-α. Methods 18Co cells, a model of human colonic myofibroblasts, were grown to confluence on 35 × 10mm cell culture dishes and were used from passages 10–14. 18Co cells were treated with TNF-α (8.3 ng/ml) and LPA (10 μM). EGFR and COX-2 protein expression, Y1068 phosphorylation, and p42/44 MAPK phosphorylation were assessed by Western Blot, in the presence and absence of various inhibitors. Results Exposure of 18Co cells to either TNF-α or LPA alone had no effect on EGFR autophosphorylation at Y1068. However, chronic exposure to TNF-α led to upregulation of EGFR in association with sustained LPA-mediated EGFR phosphorylation at Y1068. TNF-α and LPA also led to sustained p42/44 MAPK phosphorylation and synergistic COX-2 expression, effects that were partially inhibited by the EGFR tyrosine kinase inhibitor AG1478. p42/44 MAPK phosphorylation and COX-2 expression were inhibited to the same degree by the MMP inhibitors GM6001 and BB-94, suggesting that LPA-mediated EGFR transactivation involved MMP-mediated release of EGFR ligands from the cell surface. The Src inhibitor SU6556 inhibited TNF-α/LPA-mediated EGFR phosphorylation at Y1068, p42/44 MAPK phosphorylation, and COX-2 expression in a dose-dependent fashion, suggesting an upstream role of Src in the transactivation of EGFR. Conclusion Synergistic COX-2 expression induced by TNF-α and LPA involves Src/MMP-mediated transactivation of EGFR and downstream p42/44 MAPK activation in human colonic myofibroblasts. Enhanced EGFR expression induced by TNF-α promotes GPCR-mediated EGFR transactivation in colonic myofibroblasts, providing an important mechanism for stromal COX-2 over-expression that may predispose to the development of colitis-associated cancer.
          Cover page: TNF-¿ and LPA promote synergistic expression of COX-2 in human colonic myofibroblasts: role of LPA-mediated transactivation of upregulated EGFR
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          • Peer Reviewed
          UC Berkeley Previously Published Works (2021)
          Although oxidative phosphorylation is best known for producing ATP, it also yields reactive oxygen species (ROS) as invariant byproducts. Depletion of ROS below their physiological levels, a phenomenon known as reductive stress, impedes cellular signaling and has been linked to cancer, diabetes, and cardiomyopathy. Cells alleviate reductive stress by ubiquitylating and degrading the mitochondrial gatekeeper FNIP1, yet it is unknown how the responsible E3 ligase CUL2FEM1B can bind its target based on redox state and how this is adjusted to changing cellular environments. Here, we show that CUL2FEM1B relies on zinc as a molecular glue to selectively recruit reduced FNIP1 during reductive stress. FNIP1 ubiquitylation is gated by pseudosubstrate inhibitors of the BEX family, which prevent premature FNIP1 degradation to protect cells from unwarranted ROS accumulation. FEM1B gain-of-function mutation and BEX deletion elicit similar developmental syndromes, showing that the zinc-dependent reductive stress response must be tightly regulated to maintain cellular and organismal homeostasis.
            Cover page: Structural basis and regulation of the reductive stress responseCreative Commons 'BY' version 4.0 license
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            UC Davis Previously Published Works (2020)
            Mosquito-borne viruses are emerging or re-emerging globally, afflicting millions of people around the world. Aedes aegypti, the yellow fever mosquito, is the principal vector of dengue, Zika, and chikungunya viruses, and has well-established populations across tropical and subtropical urban areas of the Americas, including the southern United States. While intense arboviral epidemics have occurred in Mexico and further south in the Americas, local transmission in the United States has been minimal. Here, we study Ae. aegypti and Culex quinquefasciatus host feeding patterns and vertebrate host communities in residential environments of South Texas to identify host-utilization relative to availability. Only 31% of Ae. aegypti blood meals were derived from humans, while 50% were from dogs and 19% from other wild and domestic animals. In Cx. quinquefasciatus, 67% of blood meals were derived from chicken, 22% came from dogs, 9% from various wild avian species, and 2% from other mammals including one human, one cat, and one pig. We developed a model for the reproductive number, R0, for Zika virus (ZIKV) in South Texas relative to northern Mexico using human disease data from Tamaulipas, Mexico. We show that ZIKV R0 in South Texas communities could be greater than one if the risk of human exposure to Ae. aegypti bites in these communities is at least 60% that of Northern Mexico communities. The high utilization of non-human vertebrates and low risk of human exposure in South Texas diminishes the outbreak potential for human-amplified urban arboviruses transmitted by Ae. aegypti.
              Cover page: High Rate of Non-Human Feeding by Aedes aegypti Reduces Zika Virus Transmission in South Texas
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              • Peer Reviewed
              LBL Publications (2013)
              An angular analysis of the decay J/ψ→μ+μ- is performed to measure the polarization of prompt J/ψ mesons produced in pp collisions at [Formula: see text]. The dataset corresponds to an integrated luminosity of 0.37 fb-1 collected with the LHCb detector. The measurement is presented as a function of transverse momentum, pT, and rapidity, y, of the J/ψ meson, in the kinematic region 2<pT<15 GeV/c and 2.0<y<4.5.
                Cover page: Measurement of J/ψ polarization in pp collisions at
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                LBL Publications (2013)
                The B0s and B0 mixing frequencies, Δms and Δmd, are measured using a data sample corresponding to an integrated luminosity of 1.0 fb−1 collected by the LHCb experiment in pp collisions at a centre of mass energy of 7 TeV during 2011. Around 1.8 × 106 candidate events are selected of the type B0(s) → D−(s)μ+ (+ anything), where about half are from peaking and combinatorial backgrounds. To determine the B decay times, a correction is required for the momentum carried by missing particles, which is performed using a simulation-based statistical method. Associated production of muons or mesons allows us to tag the initialstate flavour and so to resolve oscillations due to mixing. We obtain Δms = (17.93 ± 0.22 (stat) ± 0.15 (syst)) ps−1, Δmd = (0.503 ± 0.011 (stat) ± 0.013(syst)) ps−1. The hypothesis of no oscillations is rejected by the equivalent of 5.8 standard deviations for B0s and 13.0 standard deviations for B0. This is the first observation of B0s mixing to be made using only semileptonic decays.
                  Cover page: Observation of – mixing and measurement of mixing frequencies using semileptonic B decays
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                  LBL Publications (2012)
                  The relative rates of B-meson decays into J/ψ and ψ(2S) mesons are measured for the three decay modes in pp collisions recorded with the LHCb detector. The ratios of branching fractions ([Formula: see text]) are measured to be [Formula: see text] where the third uncertainty is from the ratio of the ψ(2S) and J/ψ branching fractions to μ+μ-.
                    Cover page: Measurement of relative branching fractions of B decays to ψ(2S) and J/ψ mesons
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                    UC Santa Cruz Previously Published Works (2019)
                    The Belle II detector will provide a major step forward in precision heavy flavor physics, quarkonium and exotic states, searches for dark sectors, and many other areas. The sensitivity to a large number of key observables can be improved by about an order of magnitude compared to the current measurements, and up to two orders in very clean search measurements. This increase in statistical precision arises not only due to the increased luminosity, but also from improved detector efficiency and precision for many channels. Many of the most interesting observables tend to have very small theoretical uncertainties that will therefore not limit the physics reach. This book has presented many new ideas for measurements, both to elucidate the nature of current anomalies seen in flavor, and to search for new phenomena in a plethora of observables that will become accessible with the Belle II dataset. The simulation used for the studiesinthis book was state ofthe artat the time, though weare learning a lot more about the experiment during the commissioning period. The detector is in operation, and working spectacularly well.
                      Cover page: The Belle II Physics Book
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