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Open Access Publications from the University of California

Scholarly Works (27 results)

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

    Cover page: Effects of continuous background noise on the representations of tonal and speech stimuli in cat primary auditory cortex
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2016)

    Background

    Autism spectrum disorders (ASD) are a growing concern with more than 1 in every 68 children affected in the United States by age 8. Limited scientific advances have been made regarding the etiology of autism, with general agreement that both genetic and environmental factors contribute to this disorder.

    Objective

    To explore the link between exposure to PBDE, mitochondrial dysfunction and autism risk.

    Results

    Perinatal exposures to PBDEs may contribute to the etiology or morbidity of ASD including mitochondrial dysfunction based on (i) their increased environmental abundance and human exposures, (ii) their activity towards implicated in neuronal development and synaptic plasticity including mitochondria, and (iii) their bioaccumulation in mitochondria.

    Conclusion

    In this review, we propose that PBDE, and possibly other environmental exposures, during child development can induce or compound mitochondrial dysfunction, which in conjunction with a dysregulated antioxidant response, increase a child's susceptibility of autism.
      Cover page: Autism, Mitochondria and Polybrominated Diphenyl Ether Exposure.
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2016)

      Background

      Autism spectrum disorders (ASD) are a growing concern with more than 1 in every 68 children affected in the United States by age 8. Limited scientific advances have been made regarding the etiology of autism, with general agreement that both genetic and environmental factors contribute to this disorder.

      Objective

      To explore the link between exposure to PBDE, mitochondrial dysfunction and autism risk.

      Results

      Perinatal exposures to PBDEs may contribute to the etiology or morbidity of ASD including mitochondrial dysfunction based on (i) their increased environmental abundance and human exposures, (ii) their activity towards implicated in neuronal development and synaptic plasticity including mitochondria, and (iii) their bioaccumulation in mitochondria.

      Conclusion

      In this review, we propose that PBDE, and possibly other environmental exposures, during child development can induce or compound mitochondrial dysfunction, which in conjunction with a dysregulated antioxidant response, increase a child's susceptibility of autism.
        Cover page: Autism, Mitochondria and Polybrominated Diphenyl Ether Exposure.
        • Thesis
        • Peer Reviewed
        UC San Francisco Electronic Theses and Dissertations (2018)

        The majority of fracture research has been conducted in long bones with significantly less work done in the craniofacial skeleton. Craniofacial bones differ from long bones in both their developmental mechanism and embryonic origin. Thus, it is possible that their healing mechanisms may differ as well. We sought to determine the regulatory mechanisms that govern fracture repair in both the craniofacial and appendicular skeletons using mandibular and tibial fracture models. Stabilized and unstabilized mandible fracture models were created which heal via intramembranous and endochondral ossification, respectively. Whereas bone forms directly via intramembranous ossification, endochondral ossification occurs through a cartilage intermediate that is gradually replaced with bone. Using our mandible fracture models, we confirmed that mechanical motion promotes robust cartilage formation whereas mechanical stabilization favors intramembranous ossification, a phenomenon previously demonstrated in long bone fractures. Due to the mobility experienced at the fracture site, the majority of clinical fractures heal through the process of endochondral ossification. Recent genetic studies conducted in the appendicular skeleton have demonstrated that during endochondral ossification a significant portion of callus chondrocytes transform into osteoblasts that derive the new bone. Using genetic lineage tracing and immunohistochemistry, we demonstrated that mandibular callus chondrocytes also undergo chondrocyte-to-osteoblast transformation, that they significantly contribute to new bone formation, and that they express pluripotent stem cell (Sox2) and osteogenic (OC) markers while undergoing their transition. Due to the important role of cartilage during fracture repair, we tested the efficacy of using cartilage grafts to heal critical-sized mandibular defects. Cartilage grafts not only produced complete bony-bridging of the defects, but the newly formed bone was also highly vascularized and primarily derived from donor / graft tissue. Using unstabilized tibial fracture models which heal via endochondral ossification, we sought to determine the molecular signals that regulate chondrocyte-to-osteoblast transformation. We hypothesized that canonical Wnt signaling plays a key role in this process and used loss-of-function and gain-of-function experiments to test our hypothesis. By inhibiting or over-activating the pathway through conditional expression in chondrocytes of a truncated or stabilized form of β-catenin, a key downstream co-factor required for canonical Wnt signaling, we demonstrated that pathway inhibition leads to impaired bone formation whereas pathway overstimulation results in osteopetrotic bone. Interestingly, inhibition of canonical Wnt signaling did not significantly increase chondrocyte cell death. Rather chondrocytes remained as detached cells in the marrow space. Additionally, global inhibition of Wnt ligand palmitoylation, a key step in ligand packaging and release, through conditional Porcupine deletion did not significantly inhibit chondrocyte-to-osteoblast transformation. Thus, although canonical Wnt signaling plays a key role in chondrocyte-to-osteoblast transformation during endochondral repair, this process appears to be independent of Wnt ligands modified via Porcupine-mediated palmitoylation. These data confirm that chondrocyte-to-osteoblast transformation occurs in both the craniofacial and appendicular skeletons, that canonical Wnt signaling plays a critical role in regulating chondrocyte transformation, and that this process is independent of Wnt ligands palmitoylated via Porcupine. Moreover, these data lend key insight into the development of novel and improved fracture therapies including the use of cartilage as a graft alternative for craniofacial fractures.

          Cover page: Determining Mechanisms of Endochondral Repair in the Craniofacial and Appendicular Skeletons: A Story of Chondrocyte-to-Osteoblast Transformation via Wnt Signaling
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2013)
          Abstract Background The mitochondrial genome (mtDNA) is particularly susceptible to damage mediated by reactive oxygen species (ROS). Although elevated ROS production and elevated biomarkers of oxidative stress have been found in tissues from children with autism spectrum disorders, evidence for damage to mtDNA is lacking. Findings mtDNA deletions were evaluated in peripheral blood monocytic cells (PBMC) isolated from 2–5 year old children with full autism (AU; n = 67), and typically developing children (TD; n = 46) and their parents enrolled in the CHildhood Autism Risk from Genes and Environment study (CHARGE) at University of California Davis. Sequence variants were evaluated in mtDNA segments from AU and TD children (n = 10; each) and their mothers representing 31.2% coverage of the entire human mitochondrial genome. Increased mtDNA damage in AU children was evidenced by (i) higher frequency of mtDNA deletions (2-fold), (ii) higher number of GC→AT transitions (2.4-fold), being GC preferred sites for oxidative damage, and (iii) higher frequency of G,C,T→A transitions (1.6-fold) suggesting a higher incidence of polymerase gamma incorporating mainly A at bypassed apurinic/apyrimidinic sites, probably originated from oxidative stress. The last two outcomes were identical to their mothers suggesting the inheritance of a template consistent with increased oxidative damage, whereas the frequency of mtDNA deletions in AU children was similar to that of their fathers. Conclusions These results suggest that a combination of genetic and epigenetic factors, taking place during perinatal periods, results in a mtDNA template in children with autism similar to that expected for older individuals.
            Cover page: Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism
            • Peer Reviewed
            UC Davis Previously Published Works (2016)
              • Article
              • Peer Reviewed
              UC Davis Previously Published Works (2014)
              Despite the emerging role of mitochondria in immunity, a link between bioenergetics and the immune response in autism has not been explored. Mitochondrial outcomes and phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst were evaluated in granulocytes from age-, race-, and gender-matched children with autism with severity scores of ≥7 (n = 10) and in typically developing (TD) children (n = 10). The oxidative phosphorylation capacity of granulocytes was 3-fold lower in children with autism than in TD children, with multiple deficits encompassing ≥1 Complexes. Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children's mean values) of the nuclear factor erythroid 2-related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network.
                Cover page: Deficits in bioenergetics and impaired immune response in granulocytes from children with autism.
                • Article
                • Peer Reviewed
                UC Davis Previously Published Works (2016)
                Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder, characterized by tremors, ataxia, impaired coordination, and cognitive decline. While all FXTAS individuals are carriers of a 55-200 CGG expansion at the 5'-UTR of the fragile X mental retardation gene (FMR1), also known as premutation, not all carriers develop FXTAS symptoms and some display other types of psychological/emotional disorders (e.g., autism, anxiety). The goal of this study was to investigate whether the mitochondrial dysfunction previously observed in fibroblasts from older premutation individuals (>60 years) was already present in younger (17-48 years), non-FXTAS-affected carriers and to identify the type and severity of the bioenergetic deficit. Since FXTAS affects mostly males, while females account for a small part of the FXTAS-affected population displaying less severe symptoms, only fibroblasts from males were evaluated in this study. Based on polarographic and enzymatic measurements, a generalized OXPHOS deficit was noted accompanied by increases in the matrix biomarker citrate synthase, oxidative stress (as increased mtDNA copy number and deletions), and mitochondrial network disruption/disorganization. Some of the outcomes (ATP-linked oxygen uptake, coupling, citrate synthase activity, and mitochondrial network organization) strongly correlated with the extent of the CGG expansion, with more severe deficits observed in cell lines carrying higher CGG number. Furthermore, mitochondrial outcomes can identify endophenotypes among carriers and are robust predictors of the premutation diagnosis before the onset of FXTAS, with the potential to be used as markers of prognosis and/or as readouts of pharmacological interventions.
                  Cover page: Altered Bioenergetics in Primary Dermal Fibroblasts from Adult Carriers of the FMR1 Premutation Before the Onset of the Neurodegenerative Disease Fragile X-Associated Tremor/Ataxia Syndrome
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2016)
                  Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder, characterized by tremors, ataxia, impaired coordination, and cognitive decline. While all FXTAS individuals are carriers of a 55-200 CGG expansion at the 5'-UTR of the fragile X mental retardation gene (FMR1), also known as premutation, not all carriers develop FXTAS symptoms and some display other types of psychological/emotional disorders (e.g., autism, anxiety). The goal of this study was to investigate whether the mitochondrial dysfunction previously observed in fibroblasts from older premutation individuals (>60 years) was already present in younger (17-48 years), non-FXTAS-affected carriers and to identify the type and severity of the bioenergetic deficit. Since FXTAS affects mostly males, while females account for a small part of the FXTAS-affected population displaying less severe symptoms, only fibroblasts from males were evaluated in this study. Based on polarographic and enzymatic measurements, a generalized OXPHOS deficit was noted accompanied by increases in the matrix biomarker citrate synthase, oxidative stress (as increased mtDNA copy number and deletions), and mitochondrial network disruption/disorganization. Some of the outcomes (ATP-linked oxygen uptake, coupling, citrate synthase activity, and mitochondrial network organization) strongly correlated with the extent of the CGG expansion, with more severe deficits observed in cell lines carrying higher CGG number. Furthermore, mitochondrial outcomes can identify endophenotypes among carriers and are robust predictors of the premutation diagnosis before the onset of FXTAS, with the potential to be used as markers of prognosis and/or as readouts of pharmacological interventions.
                    • Article
                    • Peer Reviewed
                    UC Davis Previously Published Works (2014)
                    Despite the emerging role of mitochondria in immunity, a link between bioenergetics and the immune response in autism has not been explored. Mitochondrial outcomes and phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst were evaluated in granulocytes from age-, race-, and gender-matched children with autism with severity scores of ≥7 (n = 10) and in typically developing (TD) children (n = 10). The oxidative phosphorylation capacity of granulocytes was 3-fold lower in children with autism than in TD children, with multiple deficits encompassing ≥1 Complexes. Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children's mean values) of the nuclear factor erythroid 2-related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network.
                      Cover page: Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism
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