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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2020)

As the world’s largest annually harvested crop, optimization of maize (Zea mays) protective biochemical defenses that impede pest and pathogen attack will be essential to mitigate significant yield losses that could compromise our global food security. To better understand the diversity of pathogen elicited maize antibiotics, we leveraged a rapid sample preparation technique termed Vapour Phase Extraction (VPE) coupled with mass spectrometry (MS), high-performance liquid chromatography (HPLC) and Nuclear Magnetic Resonance (NMR) spectroscopy. We focused experiments on roots of field-grown maize lines discovered to produce high levels of terpenoid defenses. Leveraging the power of VPE, HPLC, and NMR, we found a series of novel modified dolabradiene derivatives, predictably part of the dolabralexin diterpenoid family of maize defenses. To generate endogenous evidence that the novel dolabralexins are products of diterpene synthases Anther ear 2 (ZmAn2) and Kaurene Synthase-Like 4 (ZmKSL4), we analyzed Zman2 and Zmksl4 mutants and demonstrated an absence of all dolabralexin-related metabolites. Chemical analyses of maize Biparental Recombinant Inbred Line (RIL) mapping population and an association panel coupled with global gene co-expression analyses using Mutual Ranks and Agrobacterium-mediated transient overexpression enzyme assays in Nicotiana benthamiana using different combinations of ZmAn2 and ZmKSL4 with cytochrome (CYP) P450 monooxygenases have revealed that ZmCYP71Z16 may contribute to the production of complex dolabralexin products.

    Cover page: Discovery of novel root specific maize dolabralexin defenses: an expanding family of antibiotics
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2021)
    Roots remain an understudied site of complex and important biological interactions mediating plant productivity. In grain and bioenergy crops, grass root specialized metabolites (GRSM) are central to key interactions, yet our basic knowledge of the chemical language remains fragmentary. Continued improvements in plant genome assembly and metabolomics are enabling large-scale advances in the discovery of specialized metabolic pathways as a means of regulating root-biotic interactions. Metabolomics, transcript coexpression analyses, forward genetic studies, gene synthesis and heterologous expression assays drive efficient pathway discoveries. Functional genetic variants identified through genome wide analyses, targeted CRISPR/Cas9 approaches, and both native and non-native overexpression studies critically inform novel strategies for bioengineering metabolic pathways to improve plant traits.
      Cover page: Getting back to the grass roots: harnessing specialized metabolites for improved crop stress resilienceCreative Commons 'BY-NC-ND' version 4.0 license
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2020)
      Recent clinical trials of new revascularization therapies in acute ischemic stroke have highlighted the importance of physiological imaging to identify optimal treatments for patients. Oxygen extraction fraction (OEF) is a hallmark of at-risk tissue in stroke, and can be quantified from the susceptibility effect of deoxyhemoglobin molecules in venous blood on MRI phase scans. We measured OEF within cerebral veins using advanced quantitative susceptibility mapping (QSM) MRI reconstructions in 20 acute stroke patients. Absolute OEF was elevated in the affected (29.3 ± 3.4%) versus the contralateral hemisphere (25.5 ± 3.1%) of patients with large diffusion-perfusion lesion mismatch (P = 0.032). In these patients, OEF negatively correlated with relative CBF measured by dynamic susceptibility contrast MRI (P = 0.004), suggesting compensation for reduced flow. Patients with perfusion-diffusion match or no hypo-perfusion showed less OEF difference between hemispheres. Nine patients received longitudinal assessment and showed OEF ratio (affected to contralateral) of 1.2 ± 0.1 at baseline that normalized (decreased) to 1.0 ± 0.1 at follow-up three days later (P = 0.03). Our feasibility study demonstrates that QSM MRI can non-invasively quantify OEF in stroke patients, relates to perfusion status, and is sensitive to OEF changes over time. Clinical trial registration: Longitudinal MRI examinations of patients with brain ischemia and blood brain barrier permeability; clinicaltrials.org : NCT02077582.
        Cover page: Elevated brain oxygen extraction fraction measured by MRI susceptibility relates to perfusion status in acute ischemic stroke
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2023)
        Vaccines and drugs have helped reduce disease severity and blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease [Mpro; 3C-like protease (3CLpro)] of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different resistance mutation profile. Importantly, phylogenetic analyses indicate that several of these resistant variants have pre-existed the introduction of these drugs into the human population and are capable of spreading. These results encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy.
          Cover page: Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2023)
          Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family of receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, ErbB2, and ErbB4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, proinflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production, and disruption of blood-brain barrier integrity in microfluidics-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof of principle for a repurposed, ErbB-targeted approach to combat emerging viruses.
            Cover page: Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effectsCreative Commons 'BY' version 4.0 license
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