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Open Access Publications from the University of California

Scholarly Works (65 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (1998)

    Cover page: Regulation of atonal expression and the role of proneural genes in neuronal type specification in Drosophila
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2019)
    While unbiased central moment estimators of lower orders (such as a sample variance) are easily obtainable and often used in practice, derivation of unbiased estimators of higher orders might be more challenging due to long math and tricky combinatorics. Moreover, higher orders necessitate calculation of estimators of powers and products that also amount to these orders. We develop a software algorithm that allows the user to obtain unbiased estimators of an arbitrary order and provide results up to the 6th order, including powers and products of lower orders. The method also extends to finding pooled estimates of higher central moments of several different populations (e.g. for two-sample tests). We introduce an R package Umoments that calculates one- and two-sample estimates and generates intermediate results used to obtain these estimators.
      Cover page: Computer algebra and algorithms for unbiased moment estimation of arbitrary order
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2014)
      Fusarium and Aspergillus species of mold are major causes of corneal infections in the United States and worldwide, resulting in severe visual impairment and blindness. As there is evidence for T cell responses to these pathogenic fungi in infected individuals, we examined the role of IL-17A (IL-17) and IFN-γ in murine models of fungal keratitis. We found that C57BL/6 mice given intratracheal or s.c. immunization of conidia prior to corneal infection exhibited enhanced fungal killing and lower corneal opacity compared with unimmunized mice. Protective immunity was associated with temporal recruitment of IL-17-producing neutrophils and Th17 and Th1 cells and dependent on production of IL-17 but not IFN-γ. Protection was also impaired in neutrophil-depleted and Rag2(-/-) mice. Together, the results of these studies identify an essential role for IL-17-producing neutrophils and Th17 cells in regulating the growth of fungal hyphae and the severity of corneal disease.
        Cover page: Aspergillus and Fusarium Corneal Infections Are Regulated by Th17 Cells and IL-17–Producing Neutrophils
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2015)

        Purpose

        To investigate the role of the lipid mediator, resolvin E1 (RvE1), in corneal inflammation.

        Methods

        The effect of RvE1 on stimulated human corneal epithelial cells (HCECs) and neutrophils, and mouse macrophage was assessed. C57BL/6 mouse corneas were abraded and treated with RvE1 either before or after stimulation with lipopolysaccharide (LPS) and antibiotic-killed Pseudomonas aeruginosa and Staphylococcus aureus. The levels of CXC chemokines in the cornea were quantified, and the presence of neutrophils in corneal infiltrates was detected by immunohistochemistry and by in vivo confocal microscopy. The effect of RvE1 on apoptosis in the corneal epithelium was assessed using the TUNEL assay.

        Results

        RvE1 significantly inhibited cytokine production in HCECs and neutrophils, and mouse macrophages and cornea. The development of corneal infiltrates, specifically neutrophils, in response to stimulation with LPS, P. aeruginosa, and S. aureus was also significantly reduced. There was no apoptotic effect of RvE1 on mouse corneal epithelial cells.

        Conclusions

        RvE1 inhibits corneal inflammation induced by LPS, Gram negative (P. aeruginosa) and Gram positive (S. aureus) bacteria. These findings indicate that RvE1 as a potential anti-inflammatory therapy for patients with corneal inflammation and also, when given together with antibiotics, for bacterial keratitis.
          Cover page: Inhibition of Corneal Inflammation by the Resolvin E1RvE1 Inhibits Corneal Inflammation
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2023)
          Fusarium, Aspergillus and Candida are important fungal pathogens that cause visual impairment and blindness in the USA and worldwide. This review will summarize the epidemiology and clinical features of corneal infections and discuss the immune and inflammatory responses that play an important role in clinical disease. In addition, we describe fungal virulence factors that are required for survival in infected corneas, and the activities of neutrophils in fungal killing, tissue damage and cytokine production.
            Cover page: Immunity to pathogenic fungi in the eye.
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2024)
            BACKGROUND: Heart failure (HF) is a serious condition with increasing prevalence, high morbidity, and increased mortality. Obesity is an established risk factor for HF. Fluctuation in body mass index (BMI) has shown a higher risk of cardiovascular outcomes. We investigated the association between BMI variability and incident HF. METHODS AND RESULTS: In the UK Biobank, we established a prospective cohort after excluding participants with prevalent HF or cancer at enrollment. A total of 99 368 White participants with ≥3 BMI measures during >2 years preceding enrollment were included, with a median follow-up of 12.5 years. The within-participant variability of BMI was evaluated using standardized SD and coefficient of variation. The association of BMI variability with incident HF was assessed using Fine and Grays competing risk model, adjusting for confounding factors and participant-specific rate of BMI change. Higher BMI variability measured in both SD and coefficient of variation was significantly associated with higher risk in HF incidence (SD: hazard ratio [HR], 1.05 [95% CI, 1.03-1.08], P<0.0001; coefficient of variation: HR, 1.07 [95% CI, 1.04-1.10], P<0.0001). CONCLUSIONS: Longitudinal health records capture BMI fluctuation, which independently predicts HF incidence.
              Cover page: High Variability of Body Mass Index Is Independently Associated With Incident Heart Failure.
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2018)
              Neutrophil extracellular trap (NET) formation requires chromatin decondensation before nuclear swelling and eventual extracellular release of DNA, which occurs together with nuclear and cytoplasmic antimicrobial proteins. A key mediator of chromatin decondensation is protein deiminase 4 (PAD4), which catalyzes histone citrullination. In the current study, we examined the role of PAD4 and NETosis following activation of neutrophils by A. fumigatus hyphal extract or cell wall β-glucan (curdlan) and found that both induced NET release by human and murine neutrophils. Also, using blocking antibodies to CR3 and Dectin-1 together with CR3-deficient CD18-/- and Dectin-1-/- murine neutrophils, we found that the β-glucan receptor CR3, but not Dectin-1, was required for NET formation. NETosis was also dependent on NADPH oxidase production of reactive oxygen species (ROS). Using an antibody to citrullinated histone 3 (H3Cit) as an indicator of PAD4 activity, we show that β-glucan stimulated NETosis occurs in neutrophils from C57BL/6, but not PAD4-/- mice. Similarly, a small molecule PAD4 inhibitor (GSK484) blocked NET formation by human neutrophils. Despite these observations, the ability of PAD4-/- neutrophils to release calprotectin and kill A. fumigatus hyphae was not significantly different from C57BL/6 neutrophils, whereas CD18-/- neutrophils exhibited an impaired ability to perform both functions. We also detected H3Cit in A. fumigatus infected C57BL/6, but not PAD4-/- corneas; however, we found no difference between C57BL/6 and PAD4-/- mice in either corneal disease or hyphal killing. Taken together, these findings lead us to conclude that although PAD4 together with CR3-mediated ROS production is required for NET formation in response to A. fumigatus, PAD4-dependent NETosis is not required for A. fumigatus killing either in vitro or during infection.
                Cover page: Protein Deiminase 4 and CR3 Regulate Aspergillus fumigatus and β-Glucan-Induced Neutrophil Extracellular Trap Formation, but Hyphal Killing Is Dependent Only on CR3Creative Commons 'BY' version 4.0 license
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2018)

                Purpose

                Aspergillus and Fusarium molds cause blinding corneal infections as a consequence of ocular trauma and in association with contact lens wear. As these fungi require zinc for fungal growth, we examined the effect of atovaquone, a ubiquinone analog that disrupts zinc homeostasis, on fungal growth in vitro and in vivo.

                Methods

                In vitro: Aspergillus and Fusarium germinating conidia were incubated overnight with atovaquone, and hyphal growth was measured by fluorimetry. In vivo: C57BL/6 mouse corneas were infected with Aspergillus or Fusarium conidia. Atovaquone was added topically and corneal opacification and fungal growth were quantified.

                Results

                Atovaquone has antifungal activity against Aspergillus and Fusarium clinical isolates, with Fusarium species being more sensitive to atovaquone than Aspergillus species. Atovaquone also reduced labile intracellular zinc levels and increased the sensitivity of Aspergillus to metal shock. Atovaquone reduced vacuolar acidification, which regulates storage of intracellular free zinc, and also acted synergistically with voriconazole and itraconazole to kill hyphae. Furthermore, mitochondrial potential and ATP production were reduced in both Aspergillus and Fusarium following atovaquone treatment. Finally, topical application of atovaquone to the ocular surface significantly inhibited fungal growth and corneal opacification in murine models of fungal keratitis.

                Conclusions

                These studies demonstrate that atovaquone has pronounced in vitro and in vivo antifungal activity against filamentous fungi by disrupting both metal homeostasis and mitochondrial function, and therefore has potential as a novel antifungal agent.
                  Cover page: Atovaquone Impairs Growth of Aspergillus and Fusarium Keratitis Isolates by Modulating Mitochondrial Function and Zinc HomeostasisCreative Commons 'BY' version 4.0 license
                  • Article
                  • Peer Reviewed
                  UC Irvine Previously Published Works (2018)

                  Neutrophil extracellular trap (NET) formation requires chromatin decondensation before nuclear swelling and eventual extracellular release of DNA, which occurs together with nuclear and cytoplasmic antimicrobial proteins. A key mediator of chromatin decondensation is protein deiminase 4 (PAD4), which catalyzes histone citrullination. In the current study, we examined the role of PAD4 and NETosis following activation of neutrophils by A. fumigatus hyphal extract or cell wall β-glucan (curdlan) and found that both induced NET release by human and murine neutrophils. Also, using blocking antibodies to CR3 and Dectin-1 together with CR3-deficient CD18-/- and Dectin-1-/- murine neutrophils, we found that the β-glucan receptor CR3, but not Dectin-1, was required for NET formation. NETosis was also dependent on NADPH oxidase production of reactive oxygen species (ROS). Using an antibody to citrullinated histone 3 (H3Cit) as an indicator of PAD4 activity, we show that β-glucan stimulated NETosis occurs in neutrophils from C57BL/6, but not PAD4-/- mice. Similarly, a small molecule PAD4 inhibitor (GSK484) blocked NET formation by human neutrophils. Despite these observations, the ability of PAD4-/- neutrophils to release calprotectin and kill A. fumigatus hyphae was not significantly different from C57BL/6 neutrophils, whereas CD18-/- neutrophils exhibited an impaired ability to perform both functions. We also detected H3Cit in A. fumigatus infected C57BL/6, but not PAD4-/- corneas; however, we found no difference between C57BL/6 and PAD4-/- mice in either corneal disease or hyphal killing. Taken together, these findings lead us to conclude that although PAD4 together with CR3-mediated ROS production is required for NET formation in response to A. fumigatus, PAD4-dependent NETosis is not required for A. fumigatus killing either in vitro or during infection.

                    Cover page: Protein Deiminase 4 and CR3 Regulate Aspergillus fumigatus and β-Glucan-Induced Neutrophil Extracellular Trap Formation, but Hyphal Killing Is Dependent Only on CR3.
                    • Article
                    • Peer Reviewed
                    UC Santa Barbara Previously Published Works (2016)
                    Jealousy is not only a way of experiencing love but also a stabilizer of romantic relationships, although morbid romantic jealousy is maladaptive. Being engaged in a formal romantic relationship can tune one's romantic jealousy towards a specific target. Little is known about how the human brain processes romantic jealousy by now. Here, by combining scenario-based imagination and functional MRI, we investigated the behavioral and neural correlates of romantic jealousy and their development across stages (before vs. after being in a formal relationship). Romantic jealousy scenarios elicited activations primarily in the basal ganglia (BG) across stages, and were significantly higher after the relationship was established in both the behavioral rating and BG activation. The intensity of romantic jealousy was related to the intensity of romantic happiness, which mainly correlated with ventral medial prefrontal cortex activation. The increase in jealousy across stages was associated with the tendency for interpersonal aggression. These results bridge the gap between the theoretical conceptualization of romantic jealousy and its neural correlates and shed light on the dynamic changes in jealousy.
                      Cover page: Neural substrates and behavioral profiles of romantic jealousy and its temporal dynamics
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