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Open Access Publications from the University of California

Scholarly Works (11 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2024)

Oxide solid electrolytes (OSEs) have the potential to achieve improved safety and energy density for lithium-ion batteries, but their high grain-boundary (GB) resistivity generally is a bottleneck. In the well-studied perovskite oxide solid electrolyte, Li3xLa2/3-xTiO3 (LLTO), the ionic conductivity of grain boundaries is about three orders of magnitude lower than that of the bulk. In contrast, the related Li0.375Sr0.4375Ta0.75Zr0.25O3 (LSTZ) perovskite exhibits low grain boundary resistivity for reasons yet unknown. Here, we use aberration-corrected scanning transmission electron microscopy and spectroscopy, along with an active learning moment tensor potential, to reveal the atomic scale structure and composition of LSTZ grain boundaries. Vibrational electron energy loss spectroscopy is applied for the first time to reveal atomically resolved vibrations at grain boundaries of LSTZ and to characterize the otherwise unmeasurable Li distribution therein. We find that Li depletion, which is a major reason for the low grain boundary ionic conductivity of LLTO, is absent for the grain boundaries of LSTZ. Instead, the low grain boundary resistivity of LSTZ is attributed to the formation of a nanoscale defective cubic perovskite interfacial structure that contained abundant vacancies. Our study provides new insights into the atomic scale mechanisms of low grain boundary resistivity.

To further improve the total ionic conductivity of LSTZ, we explore the wide compositional space of compositionally complex ceramics (CCCs). Herein, we propose and demonstrate strategies for tailoring CCCs via a combination of non-equimolar compositional designs and control of grain boundaries and microstructures. A class of compositionally complex perovskite oxides (CCPOs) with improved lithium ionic conductivities beyond the limit of conventional doping was discovered. For example, we demonstrate that the ionic conductivity can be improved by >60% in (Li0.375Sr0.4375)(Ta0.375Nb0.375Zr0.125Hf0.125)O3-d compared with the (Li0.375Sr0.4375)(Ta0.75Zr0.25)O3-d baseline that is synthesized using the same conditions. Furthermore, the ionic conductivity can be improved by another >70% via air quenching, achieving >270% of the LSTZ. Notably, we demonstrate GB enabled conductivity improvements via both promoting grain growth and altering GB structures through compositional designs and processing. In a broader perspective, this work suggests new routes for discovering and tailoring CCCs for energy storage and many other applications. In comparison with the ionic conductivities of the other compositions we have studied, i.e., (Li0.375Sr0.4375)(Ta0.75Zr0.125Hf0.125)O3, (Li0.375Sr0.4375)(Ta0.375Nb0.375Hf0.25)O3, (Li0.375Sr0.4375)(Ta0.375Nb0.375Zr0.25)O3, (Li0.375Sr0.4375)(Ta0.375Nb0.375Zr0.125Hf0.125)O3, and (Li0.375Sr0.4375)(Ta0.75Zr0.25)O3, the ionic conductivity of (Li0.375Sr0.4375)(Nb0.75Zr0.125Hf0.125)O3 (LSNZH) is at least one order of magnitude lower. This abnormally low total ionic conductivity intrigued us to investigate its microstructure. In depth investigation of periodic lattice and none-periodic features is crucial for understanding Li-ion transport in crystalline solid electrolytes. Identifying the crystal lattices of new Li-ion conductors has been a standard practice in physical science and is valuable for both pure and applied science. In comparison, the atomistic mechanisms that control the Li-ion migration of many non-periodic features are not as well studied. Herein, we discover a new atypical, ordered structure and a new self-interstitial point defect in solid electrolyte (Li0.375Sr0.4375)(Nb0.75Zr0.125Hf0.125)O3, and the names “Lee-Ko phase” and “defected Lee-Ko phase” are coined to describe them. The Lee-Ko phase degrades bulk ionic conductivity by its ordered structure. It also reduces the grain boundary ionic conductivity by creating a gradual change in composition at around the phase boundaries. In conclusion, both the Lee-Ko phase and defected Lee-Ko phase hinder Li-ion transport and are key factors contributing to the low total ionic conductivity of LSNZH perovskite solid electrolyte. Our discoveries highlight the importance of thoroughly investigating crystal lattices and none-periodic features and motivates similar studies for other solid electrolytes.

    Creative Commons 'BY' version 4.0 license
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2018)
    In Escherichia coli thymidylate synthase (EcTS), rate-determining hydride transfer from the cofactor 5,10-methylene-5,6,7,8-tetrahydrofolate to the intermediate 5-methylene-2'-deoxyuridine 5'-monophosphate occurs by hydrogen tunneling, requiring precise alignment of reactants and a closed binding cavity, sealed by the C-terminal carboxyl group. Mutations that destabilize the closed conformation of the binding cavity allow small molecules such as β-mercaptoethanol (β-ME) to enter the active site and compete with hydride for addition to the 5-methylene group of the intermediate. The C-terminal deletion mutant of EcTS produced the β-ME adduct in proportions that varied dramatically with cofactor concentration, from 50% at low cofactor concentrations to 0% at saturating cofactor conditions, suggesting communication between active sites. We report the 2.4 Å X-ray structure of the C-terminal deletion mutant of E. coli TS in complex with a substrate and a cofactor analogue, CB3717. The structure is asymmetric, with reactants aligned in a manner consistent with hydride transfer in only one active site. In the second site, CB3717 has shifted to a site where the normal cofactor would be unlikely to form 5-methylene-2'-deoxyuridine 5'-monophosphate, consistent with no formation of the β-ME adduct. The structure shows how the binding of the cofactor at one site triggers hydride transfer and borrows needed stabilization from substrate binding at the second site. It indicates pathways through the dimer interface that contribute to allostery relevant to half-sites reactivity.
      Cover page: A Single Mutation Traps a Half-Sites Reactive Enzyme in Midstream, Explaining Asymmetry in Hydride Transfer
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2022)
      Augmented reality (AR) devices, as smart glasses, enable users to see both the real world and virtual images simultaneously, contributing to an immersive experience in interactions and visualization. Recently, to reduce the size and weight of smart glasses, waveguides incorporating holographic optical elements in the form of advanced grating structures have been utilized to provide light-weight solutions instead of bulky helmet-type headsets. However current waveguide displays often have limited display resolution, efficiency and field-of-view, with complex multi-step fabrication processes of lower yield. In addition, current AR displays often have vergence-accommodation conflict in the augmented and virtual images, resulting in focusing-visual fatigue and eye strain. Here we report metasurface optical elements designed and experimentally implemented as a platform solution to overcome these limitations. Through careful dispersion control in the excited propagation and diffraction modes, we design and implement our high-resolution full-color prototype, via the combination of analytical-numerical simulations, nanofabrication and device measurements. With the metasurface control of the light propagation, our prototype device achieves a 1080-pixel resolution, a field-of-view more than 40°, an overall input-output efficiency more than 1%, and addresses the vergence-accommodation conflict through our focal-free implementation. Furthermore, our AR waveguide is achieved in a single metasurface-waveguide layer, aiding the scalability and process yield control.
        Cover page: Metasurface wavefront control for high-performance user-natural augmented reality waveguide glasses
        • Book
        Reports (2007)
          Cover page: <strong>The Gathering Storm:</strong>Infectious Diseases and Human Rights in Burma
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2023)
          Oxide solid electrolytes (OSEs) have the potential to achieve improved safety and energy density for lithium-ion batteries, but their high grain-boundary (GB) resistance generally is a bottleneck. In the well-studied perovskite oxide solid electrolyte, Li3xLa2/3-xTiO3 (LLTO), the ionic conductivity of grain boundaries is about three orders of magnitude lower than that of the bulk. In contrast, the related Li0.375Sr0.4375Ta0.75Zr0.25O3 (LSTZ0.75) perovskite exhibits low grain boundary resistance for reasons yet unknown. Here, we use aberration-corrected scanning transmission electron microscopy and spectroscopy, along with an active learning moment tensor potential, to reveal the atomic scale structure and composition of LSTZ0.75 grain boundaries. Vibrational electron energy loss spectroscopy is applied for the first time to reveal atomically resolved vibrations at grain boundaries of LSTZ0.75 and to characterize the otherwise unmeasurable Li distribution therein. We find that Li depletion, which is a major reason for the low grain boundary ionic conductivity of LLTO, is absent for the grain boundaries of LSTZ0.75. Instead, the low grain boundary resistivity of LSTZ0.75 is attributed to the formation of a nanoscale defective cubic perovskite interfacial structure that contained abundant vacancies. Our study provides new insights into the atomic scale mechanisms of low grain boundary resistivity.
            Cover page: Atomic-scale origin of the low grain-boundary resistance in perovskite solid electrolyte Li<sub>0.375</sub>Sr<sub>0.4375</sub>Ta<sub>0.75</sub>Zr<sub>0.25</sub>O<sub>3</sub>.
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2020)
            Antibody-dependent cellular cytotoxicity (ADCC) is a key effector mechanism of natural killer (NK) cells that is mediated by therapeutic monoclonal antibodies (mAbs). This process is facilitated by the Fc receptor CD16a on human NK cells. CD16a appears to be the only activating receptor on NK cells that is cleaved by the metalloprotease a disintegrin and metalloproteinase-17 upon stimulation. We previously demonstrated that a point mutation of CD16a prevents this activation-induced surface cleavage. This noncleavable CD16a variant is now further modified to include the high-affinity noncleavable variant of CD16a (hnCD16) and was engineered into human induced pluripotent stem cells (iPSCs) to create a renewable source for human induced pluripotent stem cell-derived NK (hnCD16-iNK) cells. Compared with unmodified iNK cells and peripheral blood-derived NK (PB-NK) cells, hnCD16-iNK cells proved to be highly resistant to activation-induced cleavage of CD16a. We found that hnCD16-iNK cells were functionally mature and exhibited enhanced ADCC against multiple tumor targets. In vivo xenograft studies using a human B-cell lymphoma demonstrated that treatment with hnCD16-iNK cells and anti-CD20 mAb led to significantly improved regression of B-cell lymphoma compared with treatment utilizing anti-CD20 mAb with PB-NK cells or unmodified iNK cells. hnCD16-iNK cells, combined with anti-HER2 mAb, also mediated improved survival in an ovarian cancer xenograft model. Together, these findings show that hnCD16-iNK cells combined with mAbs are highly effective against hematologic malignancies and solid tumors that are typically resistant to NK cell-mediated killing, demonstrating the feasibility of producing a standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat malignancies that are otherwise refractory.
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2017)
              Circulating fetal nucleated cells (CFNCs) in maternal blood offer an ideal source of fetal genomic DNA for noninvasive prenatal diagnostics (NIPD). We developed a class of nanoVelcro microchips to effectively enrich a subcategory of CFNCs, i.e., circulating trophoblasts (cTBs) from maternal blood, which can then be isolated with single-cell resolution by a laser capture microdissection (LCM) technique for downstream genetic testing. We first established a nanoimprinting fabrication process to prepare the LCM-compatible nanoVelcro substrates. Using an optimized cTB-capture condition and an immunocytochemistry protocol, we were able to identify and isolate single cTBs (Hoechst+/CK7+/HLA-G+/CD45-, 20 μm > sizes > 12 μm) on the imprinted nanoVelcro microchips. Three cTBs were polled to ensure reproducible whole genome amplification on the cTB-derived DNA, paving the way for cTB-based array comparative genomic hybridization (aCGH) and short tandem repeats analysis. Using maternal blood samples collected from expectant mothers carrying a single fetus, the cTB-derived aCGH data were able to detect fetal genders and chromosomal aberrations, which had been confirmed by standard clinical practice. Our results support the use of nanoVelcro microchips for cTB-based noninvasive prenatal genetic testing, which holds potential for further development toward future NIPD solution.
                Cover page: Imprinted NanoVelcro Microchips for Isolation and Characterization of Circulating Fetal Trophoblasts: Toward Noninvasive Prenatal Diagnostics
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2022)
                The production of autologous T cells expressing a chimaeric antigen receptor (CAR) is time-consuming, costly and occasionally unsuccessful. T-cell-derived induced pluripotent stem cells (TiPS) are a promising source for the generation of off-the-shelf CAR T cells, but the in vitro differentiation of TiPS often yields T cells with suboptimal features. Here we show that the premature expression of the T-cell receptor (TCR) or a constitutively expressed CAR in TiPS promotes the acquisition of an innate phenotype, which can be averted by disabling the TCR and relying on the CAR to drive differentiation. Delaying CAR expression and calibrating its signalling strength in TiPS enabled the generation of human TCR- CD8αβ+ CAR T cells that perform similarly to CD8αβ+ CAR T cells from peripheral blood, achieving effective tumour control on systemic administration in a mouse model of leukaemia and without causing graft-versus-host disease. Driving T-cell maturation in TiPS in the absence of a TCR by taking advantage of a CAR may facilitate the large-scale development of potent allogeneic CD8αβ+ T cells for a broad range of immunotherapies.
                  Cover page: Generation of T-cell-receptor-negative CD8αβ-positive CAR T cells from T-cell-derived induced pluripotent stem cells.
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2020)
                  The development of immunotherapeutic monoclonal antibodies targeting checkpoint inhibitory receptors, such as programmed cell death 1 (PD-1), or their ligands, such as PD-L1, has transformed the oncology landscape. However, durable tumor regression is limited to a minority of patients. Therefore, combining immunotherapies with those targeting checkpoint inhibitory receptors is a promising strategy to bolster antitumor responses and improve response rates. Natural killer (NK) cells have the potential to augment checkpoint inhibition therapies, such as PD-L1/PD-1 blockade, because NK cells mediate both direct tumor lysis and T cell activation and recruitment. However, sourcing donor-derived NK cells for adoptive cell therapy has been limited by both cell number and quality. Thus, we developed a robust and efficient manufacturing system for the differentiation and expansion of high-quality NK cells derived from induced pluripotent stem cells (iPSCs). iPSC-derived NK (iNK) cells produced inflammatory cytokines and exerted strong cytotoxicity against an array of hematologic and solid tumors. Furthermore, we showed that iNK cells recruit T cells and cooperate with T cells and anti-PD-1 antibody, further enhancing inflammatory cytokine production and tumor lysis. Because the iNK cell derivation process uses a renewable starting material and enables the manufacturing of large numbers of doses from a single manufacture, iNK cells represent an "off-the-shelf" source of cells for immunotherapy with the capacity to target tumors and engage the adaptive arm of the immune system to make a "cold" tumor "hot" by promoting the influx of activated T cells to augment checkpoint inhibitor therapies.
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2015)
                    Previous studies have demonstrated focal but limited molecular similarities between circulating tumor cells (CTCs) and biopsies using isolated genetic assays. We hypothesized that molecular similarity between CTCs and tissue exists at the single cell level when characterized by whole genome sequencing (WGS). By combining the NanoVelcro CTC Chip with laser capture microdissection (LCM), we developed a platform for single-CTC WGS. We performed this procedure on CTCs and tissue samples from a patient with advanced prostate cancer who had serial biopsies over the course of his clinical history. We achieved 30X depth and ≥ 95% coverage. Twenty-nine percent of the somatic single nucleotide variations (SSNVs) identified were founder mutations that were also identified in CTCs. In addition, 86% of the clonal mutations identified in CTCs could be traced back to either the primary or metastatic tumors. In this patient, we identified structural variations (SVs) including an intrachromosomal rearrangement in chr3 and an interchromosomal rearrangement between chr13 and chr15. These rearrangements were shared between tumor tissues and CTCs. At the same time, highly heterogeneous short structural variants were discovered in PTEN, RB1, and BRCA2 in all tumor and CTC samples. Using high-quality WGS on single-CTCs, we identified the shared genomic alterations between CTCs and tumor tissues. This approach yielded insight into the heterogeneity of the mutational landscape of SSNVs and SVs. It may be possible to use this approach to study heterogeneity and characterize the biological evolution of a cancer during the course of its natural history.
                      Cover page: A comparison of isolated circulating tumor cells and tissue biopsies using whole-genome sequencing in prostate cancer
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