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Open Access Publications from the University of California

Scholarly Works (92 results)

  • Article
  • Peer Reviewed
UC Irvine Previously Published Works (2009)
    Cover page: The Origins of Korean Adoption: Cold War Geopolitics and Intimate Diplomacy
    • Thesis
    • Peer Reviewed
    UC San Francisco Electronic Theses and Dissertations (1987)

      Cover page: Emotional predictors of self-care strategies in patients with asthma
      • Thesis
      • Peer Reviewed
      UC San Diego Electronic Theses and Dissertations (2020)

      Non-typhoidal Salmonella is one of the most burdensome foodborne diarrheal pathogens. Previous work has shown a decrease in expression of the chloride/bicarbonate exchanger SLC26A3 (Down-Regulated in Adenoma; DRA) following Salmonella infection and it is thought that diarrheal symptoms could stem from the downregulation of DRA. However, despite its prevalence, the mechanism by which Salmonella elicits diarrhea is not entirely known. To elucidate this, we have developed an enteroid model to recapitulate both the absorptive and secretory lineages of the intestinal epithelium. Enteroid-derived monolayers (EDMs) were infected with Salmonella where relevant protein expression was studied using qRT-PCR and western blot. Infection reduced expression of DRA and Hes1 while upregulating ATOH1 and Muc2. Hes1 is a Notch pathway downstream signaling molecule and thus a precursor to the absorptive epithelial lineage that expresses DRA. ATOH1, in contrast, is a Wnt pathway downstream signaling molecule and a precursor to secretory lineages, including goblet cells that express Muc2. The involvement of Notch was further investigated by inhibiting Notch signaling using a γ-secretase inhibitor, which reproduced the downregulation in Hes1 and DRA and upregulation in ATOH1 and Muc2 seen with infection. Secretory transporters NKCC1 and CLCA1 were also upregulated following infection, which might contribute to the imbalance between absorption and secretion. Our findings suggest that the pathogenesis of diarrheal disease in the setting of Salmonella infection may reflect Notch inhibition and an accompanying shift in differentiation from absorptive to secretory cell types and transporters, a decreased capacity for absorption, and thus the accumulation of diarrheal fluid.

        Cover page: Salmonella biases epithelial differentiation through Wnt and Notch signaling, which may contribute to diarrheal pathogenesis
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2018)
        Every year, enteric infections and associated diarrhea kill millions of people. The situation is compounded by increases in the number of enteric pathogens that are acquiring resistance to antibiotics, as well as (hitherto) a relative paucity of information on host molecular targets that may contribute to diarrhea. Many forms of diarrheal disease depend on the dysregulation of intestinal ion transporters, and an associated imbalance between secretory and absorptive functions of the intestinal epithelium. A number of major transporters have been implicated in the pathogenesis of diarrheal diseases and thus an understanding of their expression, localization, and regulation after infection with various bacteria, viruses, and protozoa likely will prove critical in designing new therapies. This article surveys our understanding of transporters that are modulated by specific pathogens and the mechanism(s) involved, thereby illuminating targets that might be exploited for new therapeutic approaches.
          Cover page: The Role of Ion Transporters in the Pathophysiology of Infectious Diarrhea
          • Article
          Western Journal of Emergency Medicine: Integrating Emergency Care with Population Health, Volume 16, Issue 4.1 (2015)
            Cover page: Low-Cost, Ultrasound-Compatible Paracentesis Model for Medical TraineesCreative Commons 'BY' version 4.0 license
            • Article
            • Peer Reviewed
            UC Riverside Previously Published Works (2016)
            Reactive oxygen species (ROS) such as hydrogen peroxide (H2 O2 ) contribute to epithelial damage and ion transport dysfunction (key events in inflammatory diarrhoea) in inflammatory bowel disease (IBD). The aim of this study was to identify if H2 O2 mediates suppression of colonic ion transport function in the murine dextran sulfate sodium (DSS) colitis model by using the H2 O2 degrading enzyme, catalase. Colitis was induced by administering DSS (4%) in drinking water for 5 days followed by 3 days on normal H2 O. Mice were administered either pegylated catalase or saline at day -1, 0 and +1 of DSS treatment. Ion transport responses to the Ca2+ -dependent agonist, carbachol (CCh), or the cAMP-dependent agonist, forskolin, were measured across distal colonic mucosa mounted in Ussing chambers. Parameters of DSS-induced inflammation (loss in body weight, decreased colon length, altered stool consistency), were only partially alleviated by catalase while histology was only minimally improved. However, catalase significantly reversed the DSS-induced reduction in baseline ion transport as well as colonic Isc responses to CCh. However, ion transport responses to forskolin were not significantly restored. Catalase also reduced activation of ERK MAP kinase in the setting of colitis, and increased expression of the Na+ -K+ -2Cl- cotransporter, NKCC1, consistent with restoration of ion transport function. Ex vivo treatment of inflamed colonic mucosae with catalase also partially restored ion transport function. Therefore, catalase partially prevents, and rescues, the loss of ion transport properties in DSS colitis even in the setting of unresolved tissue inflammation. These findings indicate a prominent role for ROS in ion transport dysfunction in colitis and may suggest novel strategies for the treatment of inflammatory diarrhoea.
              Cover page: Hydrogen peroxide scavenger, catalase, alleviates ion transport dysfunction in murine colitis
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2020)
              Epidermal growth factor receptor tyrosine kinase inhibitors (EGFr TKIs) are first-line therapies for various cancers, and cause dose-limiting severe diarrhea in many patients. We hypothesized that diarrhea caused by EGFr TKIs might reflect actions on epithelial transport, barrier function, or both, which we tested using cell cultures including murine and human enteroid-derived monolayers (EDMs), analyzed using electrophysiological and other relevant methods. EGFr TKIs (such as afatinib, erlotinib, and osimertinib) reversed the acute inhibitory effect of EGF on chloride secretion induced by carbachol (CCh) across T84 human colonic epithelial cells, which correlated with the diarrhea-inducing effect of each agent clinically. EGFr TKIs also reduced transepithelial electrical resistance (TEER), whereas co-treatment with CCh delayed the decrease in TEER compared with that of cells co-treated with EGF. Furthermore, afatinib and erlotinib prevented EGF- or CCh-induced EGFr phosphorylation. EGFr TKIs also suppressed phosphorylation of extracellular signal-regulated kinase (Erk)1/2 in response to EGF, whereas they had weaker effects on CCh-induced Erk1/2 phosphorylation. In human EDMs, EGF potentiated ion transport induced by CCh, whereas afatinib reversed this effect. The ability of EGFr TKIs to reverse the effects of EGF on calcium-dependent chloride secretion could contribute to the diarrheal side effects of these agents, and their disruption of epithelial barrier dysfunction is likely also pathophysiologically significant. CCh-activated Erk1/2 phosphorylation was relatively insensitive to EGFr TKIs and delayed the deleterious effects of EGFr TKIs on barrier function. These findings confirm and extend those of other authors, and may be relevant to designing strategies to overcome the diarrheal side effects of EGFr TKIs.
                Cover page: Potentiation of calcium‐activated chloride secretion and barrier dysfunction may underlie EGF receptor tyrosine kinase inhibitor‐induced diarrhea
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2021)
                Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by the inability to properly terminate an immune response. Familial HLH (FHLH) and related immune dysregulation syndromes are associated with mutations in the genes PRF1, UNC13D, STX11, STXBP2, LYST, AP3B1, and RAB27A, all of which are required for the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. Loss-of-function mutations in these genes render the cytotoxicity pathway ineffective, thereby failing to eradicate immune stimuli, such as infectious pathogens or malignant cells. The resulting persistent immune system stimulation drives hypercytokinemia, ultimately leading to severe tissue inflammation and end-organ damage. Traditionally, a diagnosis of FHLH requires the identification of biallelic loss-of-function mutations in one of these degranulation pathway genes. However, this narrow definition fails to encompass patients with other genetic mechanisms underlying degranulation pathway dysfunction. In particular, mounting clinical evidence supports a potential digenic mode of inheritance of FHLH in which single loss-of-function mutations in two different degranulation pathway genes cooperate to impair pathway activity. Here, we review the functions of the FHLH-associated genes within the degranulation pathway and summarize clinical evidence supporting a model in which cumulative defects along this mechanistic pathway may underlie HLH.
                  Cover page: Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis
                  • Article
                  • Peer Reviewed
                  UC Berkeley Previously Published Works (2022)
                  The capability of a reinforcement learning (RL) agent heavily depends on the diversity of the learning scenarios generated by the environment. Generation of diverse realistic scenarios is challenging for real-time strategy (RTS) environments. The RTS environments are characterized by intelligent entities/non-RL agents cooperating and competing with the RL agents with large state and action spaces over a long period of time, resulting in an infinite space of feasible, but not necessarily realistic, scenarios involving complex interaction among different RL and non-RL agents. Yet, most of the existing simulators rely on randomly generating the environments based on predefined settings/layouts and offer limited flexibility and control over the environment dynamics for researchers to generate diverse, realistic scenarios as per their demand. To address this issue, for the first time, we formally introduce the benefits of adopting an existing formal scenario specification language, SCENIC, to assist researchers to model and generate diverse scenarios in an RTS environment in a flexible, systematic, and programmatic manner. To showcase the benefits, we interfaced SCENIC to an existing RTS environment Google Research Football(GRF) simulator and introduced a benchmark consisting of 32 realistic scenarios, encoded in SCENIC, to train RL agents and testing their generalization capabilities. We also show how researchers/RL practitioners can incorporate their domain knowledge to expedite the training process by intuitively modeling stochastic programmatic policies with SCENIC.
                    Cover page: Programmatic Modeling and Generation of Real-Time Strategic Soccer Environments for Reinforcement Learning
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2006)

                    Study Objective: We investigated the short-term effectiveness of continuous positive airway pressure (CPAP) and oxygen in improving sleep quality in patients with obstructive sleep apnea (OSA). Design: Randomized, double-blind, placebo-controlled, parallel study. Setting: General Clinical Research Center at a university hospital. Patients: Seventy-six patients with untreated OSA. Interventions: Patients were randomly assigned to 1 of 3 treatments (CPAP, placebo-CPAP, or nocturnal oxygen at 3 L per minute) for 2 weeks. Sleep quality was assessed at baseline and after 1 and 14 days of therapy. Repeated-measures analysis of variance was used to evaluate treatment and time effects, and their interaction. Measurements and Results: Sixty-three patients completed the protocol. When compared with placebo-CPAP and nocturnal oxygen, CPAP increased rapid eye movement (REM) sleep and significantly reduced stage I sleep and the number of stage shifts (p <= .003). CPAP improved, to within normal limits, the apnea-hypopnea index, total arousal index, and mean oxyhemoglobin saturation (p <= .001). The effects of CPAP were apparent during the first night of therapy. Oxygen improved only mean nocturnal saturation (p = .009). CPAP had no significant effect on stage 2 sleep or slow-wave sleep. Conclusions: CPAP was associated with an improvement in sleep quality in patients with OSA by consolidating sleep, reducing stage I sleep, and improving REM sleep. CPAP was effective in correcting the respiratory and arousal abnormalities of OSA. The effectiveness of supplemental oxygen was limited to oxyhemoglobin desaturation.

                      Cover page: Effect of continuous positive airway pressure versus supplemental oxygen on sleep quality in obstructive sleep apnea: A placebo-CPAP-controlled study
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