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Open Access Publications from the University of California

Scholarly Works (25 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2019)

Silica micro and nanomaterials have been widely used in the biomedical field due to its chemical stability and flexibility, biocompatibility and ease of functionalization. Herein, silica micro and nanoshells were synthesized as a multifunctional theranostic tool in cancer imaging and therapy. Templated sol-gel method was employed to synthesize monodispersed silica hollow shells with thickness tunable by modulating the composition of silica precursors and organically modified alkoxysilanes. When ultrathin silica shells were filled with perfluorocarbon, a decreased acoustic threshold was observed when compared to silica shells synthesized with pure tetramethyl orthosilicate as a precursor. Furthermore, an increased ultrasound signal lifetime was achieved when compared to commercial microbubble based ultrasound contrast agents. Ultrathin silica shells with liquid perfluoropentane filled core were shown to exhibit a bimodal acoustic excitation profile where low acoustic power resulted in bubble oscillation and high acoustic power promoted bubble cavitation. Liquid filled ultrathin silica shells were chemically and physically stable, acting as a long-term ultrasound tumor marking agent when intravenously injected into mice that were subcutaneously grafted with tumor. When intratumorally injected into tumor, liquid filled silica shells act as effect acoustic enhancer for high intensity focused ultrasound ablation. The presence of silica stabilized liquid perfluorocarbon resulted in generation of ultrasound signal in the form of cavitation clouds and decreased ultrasound intensity to generate mechanical ablation of tumor tissue and promote release of tumor neo-antigens. With concomitant administration of checkpoint blockade immunotherapy, three quarters of mice grafted with glioblastoma were induced into remission along with acquired immunity. These mice were characterized by increased tumor-infiltrating lymphocytes and T-cell activation. Silica hollow particles have been demonstrated as a flexible theranostic platform that can be used with ultrasound imaging and tumor ablation. When combined with current immunotherapies, silica hollow particles provide a myriad of opportunities to enhance efficacy without increasing potential drug burden.

    Cover page: Silica Hollow Particles as Theranostic Agents for Tumor Imaging and Therapy
    • Article
    Recent Work (2005)

    We develop a model of a two-division firm in which the “strong” division has,on average, higher quality investment projects than the “weak” division. We show that the firm optimally biases its project selection policy in favor of the weak division and this bias is stronger when there is a greater spread in average project quality. The cost of such a policy is that the firm sometimes funds an inferior project but the benefit is that it motivates the manager of the strong division to set (and meet) more aggressive cash flow targets.

      Cover page: A Theory of Socialistic Internal Capital Markets
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2017)
      Huntington's disease (HD) is a progressive and autosomal dominant neurodegeneration caused by CAG expansion in the huntingtin gene (HTT), but the pathophysiological mechanism of mutant HTT (mHTT) remains unclear. To study HD using systems biological methodologies on all published data, we undertook the first comprehensive curation of two key PubMed HD datasets: perturbation genes that impact mHTT-driven endpoints and therefore are putatively linked causally to pathogenic mechanisms, and the protein interactome of HTT that reflects its biology. We perused PubMed articles containing co-citation of gene IDs and MeSH terms of interest to generate mechanistic gene sets for iterative enrichment analyses and rank ordering. The HD Perturbation database of 1,218 genes highly overlaps the HTT Interactome of 1,619 genes, suggesting links between normal HTT biology and mHTT pathology. These two HD datasets are enriched for protein networks of key genes underlying two mechanisms not previously implicated in HD nor in each other: exosome synaptic functions and homeostatic synaptic plasticity. Moreover, proteins, possibly including HTT, and miRNA detected in exosomes from a wide variety of sources also highly overlap the HD datasets, suggesting both mechanistic and biomarker links. Finally, the HTT Interactome highly intersects protein networks of pathogenic genes underlying Parkinson's, Alzheimer's and eight non-HD polyglutamine diseases, ALS, and spinal muscular atrophy. These protein networks in turn highly overlap the exosome and homeostatic synaptic plasticity gene sets. Thus, we hypothesize that HTT and other neurodegeneration pathogenic genes form a large interlocking protein network involved in exosome and homeostatic synaptic functions, particularly where the two mechanisms intersect. Mutant pathogenic proteins cause dysfunctions at distinct points in this network, each altering the two mechanisms in specific fashion that contributes to distinct disease pathologies, depending on the gene mutation and the cellular and biological context. This protein network is rich with drug targets, and exosomes may provide disease biomarkers, thus enabling drug discovery. All the curated datasets are made available for other investigators. Elucidating the roles of pathogenic neurodegeneration genes in exosome and homeostatic synaptic functions may provide a unifying framework for the age-dependent, progressive and tissue selective nature of multiple neurodegenerative diseases.
        Cover page: Exosomes and Homeostatic Synaptic Plasticity Are Linked to Each other and to Huntington's, Parkinson's, and Other Neurodegenerative Diseases by Database-Enabled Analyses of Comprehensively Curated DatasetsCreative Commons 'BY' version 4.0 license
        • Article
        Replication/Extension Papers 2019 - 2020 (2020)
        The purpose of this study is to expand upon the findings published by Junhong Yu, Qian Tao,Ruibin Zhang, Chetwyn C.H. Chan, and Tatia M.C. Lee in their paper, “Can fMRI discriminatebetween deception and false memory? A meta-analytic comparison between deception and falsememory studies” by conducting a meta-analysis to compare brain activation between deceptionand general memory1 recollection (Yu et al., 2019). Meta-analyses compile fMRI results frommany individual studies with regard to a specific cognitive task into one, cumulative dataset. Themeta-analyses for this extension were compiled by Neurosynth using FMRIB Software Library(FSL) to measure the amount of brain activation corresponding to areas involved in bothdeception and memory in general (“Nipype: Neuroimaging in Python,” 2020). The purpose ofthis extension is to understand how general memory recollection might compare to deception.The prediction of this study is that by broadening the memory dataset to include data from falseand true memory, activation will be reported in more areas than those reported in Yu and hiscolleagues separate analysis of each kind of memory. This, in turn, should make it more difficultto differentiate deception from memory recollection when it is not known to be true or false.While Yu et al. 2019 concluded that areas associated with truthful memory and false memorywere both separately distinguishable from deception, the results found in this study indicate thatactivation involved with general memory was distinguishable from deception only in theprecuneus and cingulate gyrus.
        • 1 supplemental PDF
        Cover page: An Extension Study: fMRI use to Distinguish Between Deception andGeneral Memory
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2018)
        A versatile platform for the development of new ultrasound contrast agents is demonstrated through a one-pot synthesis and fluorination of submicron polydopamine (PDA-F) nanoparticles. The fluorophilicity of these particles allows loading with perfluoropentane (PFP) droplets that display strong and persistent ultrasound contrast in aqueous suspension and ex vivo tissue samples. Contrast under continuous imaging by color Doppler persists for 1 h in 135 nm PDA-F samples, even at maximum clinical imaging power (MI = 1.9). Additionally, use of a Cadence Contrast Pulse Sequence (CPS) results in a non-linear response suitable for imaging at 0.5 mg mL-1. Despite the PFP volatility and the lack of a hollow core, PDA-F particles display minimal signal loss after storage for over a week. The ability to tune size, metal-chelation, and add covalently-bound organic functionality offers myriad possibilities for extending this work to multimodal imaging, targeted delivery, and therapeutic functionality.
          Cover page: Perfluorocarbon-loaded polydopamine nanoparticles as ultrasound contrast agents
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2023)
          Nature harnesses exquisite enzymatic cascades to construct N-heterocycles and further uses these building blocks to assemble the molecules of life. Here we report an enzymatic platform to construct important chiral N-heterocyclic products, pyrrolidines and indolines, via abiological intramolecular C(sp3)-H amination of organic azides. Directed evolution of cytochrome P411 (a P450 enzyme with serine as the heme-ligating residue) yielded variant P411-PYS-5149, capable of catalyzing the insertion of alkyl nitrene into C(sp3)-H bonds to build pyrrolidine derivatives with good enantioselectivity and catalytic efficiency. Further evolution of activity on aryl azide substrates yielded variant P411-INS-5151 that catalyzes intramolecular C(sp3)-H amination to afford chiral indolines. In addition, we show that these enzymatic aminations can be coupled with a P411-based carbene transferase or a tryptophan synthase to generate an α-amino lactone or a noncanonical amino acid, respectively, underscoring the power of new-to-nature biocatalysis in complexity-building chemical synthesis.
            Cover page: Biocatalytic Construction of Chiral Pyrrolidines and Indolines via Intramolecular C(sp3)-H Amination.Creative Commons 'BY' version 4.0 license
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2013)

            Purpose

            Calyceal selection for percutaneous renal access is critical for safe, effective performance of percutaneous nephrolithotomy. Available anatomical evidence is contradictory and incomplete. We present detailed renal calyceal anatomy obtained from in vivo 3-dimentional computerized tomography renderings.

            Materials and methods

            A total of 60 computerized tomography urograms were randomly selected. The renal collecting system was isolated and 3-dimensional renderings were constructed. The primary plane of each calyceal group of 100 kidneys was determined. A coronal maximum intensity projection was used for simulated percutaneous access. The most inferior calyx was designated calyx 1. Moving superiorly, the subsequent calyces were designated calyx 2 and, when present, calyx 3. The surface rendering was rotated to assess the primary plane of the calyceal group and the orientation of the select calyx.

            Results

            The primary plane of the upper pole calyceal group was mediolateral in 95% of kidneys and the primary plane of the lower pole calyceal group was anteroposterior in 95%. Calyx 2 was chosen in 90 of 97 simulations and it was appropriate in 92%. Calyx 3 was chosen in 7 simulations but it was appropriate in only 57%. Calyx 1 was not selected in any simulation and it was anteriorly oriented in 75% of kidneys.

            Conclusions

            Appropriate lower pole calyceal access can be reliably accomplished with an understanding of the anatomical relationship between individual calyceal orientation and the primary plane of the calyceal group. Calyx 2 is most often appropriate for accessing the anteroposterior primary plane of the lower pole. Calyx 1 is most commonly oriented anterior.
              Cover page: Renal Calyceal Anatomy Characterization with 3-Dimensional In Vivo Computerized Tomography Imaging
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2024)
              Biomaterial-based agents have been demonstrated to regulate the function of immune cells in models of autoimmunity. However, the complexity of the kinetics of immune cell activation can present a challenge in optimizing the dose and frequency of administration. Here, we report a model of autoreactive T cell activation, which are key drivers in autoimmune inflammatory joint disease. The model is termed a multi-scale Agent-Based, Cell-Driven model of Inflammatory Arthritis (ABCD of IA). Using kinetic rate equations and statistical theory, ABCD of IA simulated the activation and presentation of autoantigens by dendritic cells, interactions with cognate T cells and subsequent T cell proliferation in the lymph node and IA-affected joints. The results, validated with in vivo data from the T cell driven SKG mouse model, showed that T cell proliferation strongly correlated with the T cell receptor (TCR) affinity distribution (TCR-ad), with a clear transition state from homeostasis to an inflammatory state. T cell proliferation was strongly dependent on the amount of antigen in antigenic stimulus event (ASE) at low concentrations. On the other hand, inflammation driven by Th17-inducing cytokine mediated T cell phenotype commitment was influenced by the initial level of Th17-inducing cytokines independent of the amount of arthritogenic antigen. The introduction of inhibitory artificial antigen presenting cells (iaAPCs), which locally suppress T cell activation, reduced T cell proliferation in a dose-dependent manner. The findings in this work set up a framework based on theory and modeling to simulate personalized therapeutic strategies in IA.
                Cover page: ABCD of IA: A multi-scale agent-based model of T cell activation in inflammatory arthritis
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2015)
                Perfluoropentane (PFP) gas filled biodegradable iron-doped silica nanoshells have been demonstrated as long-lived ultrasound contrast agents. Nanoshells are synthesized by a sol-gel process with tetramethyl orthosilicate (TMOS) and iron ethoxide. Substituting a fraction of the TMOS with R-substituted trialkoxysilanes produces ultrathin nanoshells with varying shell thicknesses and morphologies composed of fused nanoflakes. The ultrathin nanoshells had continuous ultrasound Doppler imaging lifetimes exceeding 3 hours, were twice as bright using contrast specific imaging, and had decreased pressure thresholds compared to control nanoshells synthesized with just TMOS. Transmission electron microscopy (TEM) showed that the R-group substituted trialkoxysilanes could reduce the mechanically critical nanoshell layer to 1.4 nm. These ultrathin nanoshells have the mechanical behavior of weakly linked nanoflakes but the chemical stability of silica. The synthesis can be adapted for general fabrication of three-dimensional nanostructures composed of nanoflakes, which have thicknesses from 1.4-3.8 nm and diameters from 2-23 nm.
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2019)
                  Silica particles are convenient ultrasound imaging contrast agents because of their long imaging time and ease of modification; however, they require a relatively high insonation power for imaging and have low biodegradability. In this study, 2 μm ultrathin asymmetric hollow silica particles doped with iron (III) (Fe(III)-SiO2) are synthesized to produce biodegradable hard shelled particles with a low acoustic power threshold comparable with commercial soft microbubble contrast agents (Definity) yet with much longer in vivo ultrasound imaging time. Furthermore, high intensity focused ultrasound ablation enhancement with these particles shows a 2.5-fold higher temperature elevation than with Definity at the same applied power. The low power visualization improves utilization of the silica shells as an adjuvant in localized immunotherapy. The data are consistent with asymmetric engineering of hard particle properties that improve functionality of hard versus soft particles.
                    Cover page: Thickness and Sphericity Control of Hollow Hard Silica Shells through Iron (III) Doping: Low Threshold Ultrasound Contrast Agents
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