Showing papers by "Thomas A. Wynn published in 2020"

Fibrosis: from mechanisms to medicines

Abstract: Fibrosis can affect any organ and is responsible for up to 45% of all deaths in the industrialized world. It has long been thought to be relentlessly progressive and irreversible, but both preclinical models and clinical trials in various organ systems have shown that fibrosis is a highly dynamic process. This has clear implications for therapeutic interventions that are designed to capitalize on this inherent plasticity. However, despite substantial progress in our understanding of the pathobiology of fibrosis, a translational gap remains between the identification of putative antifibrotic targets and conversion of this knowledge into effective treatments in humans. Here we discuss the transformative experimental strategies that are being leveraged to dissect the key cellular and molecular mechanisms that regulate fibrosis, and the translational approaches that are enabling the emergence of precision medicine-based therapies for patients with fibrosis.

Unveiling the Stable Nature of the Solid Electrolyte Interphase between Lithium Metal and LiPON via Cryogenic Electron Microscopy

Abstract: The solid electrolyte interphase (SEI) is regarded as the most complex but the least understood constituent in secondary batteries using liquid and solid electrolytes The nanostructures of SEIs were recently reported to be equally important to the chemistry of SEIs for stabilizing Li metal in liquid electrolyte However, the dearth of such knowledge in all-solid-state battery (ASSB) has hindered a complete understanding of how certain solid-state electrolytes, such as LiPON, manifest exemplary stability against Li metal Characterizing such solid-solid interfaces is difficult due to the buried, highly reactive, and beam-sensitive nature of the constituents within By employing cryogenic electron microscopy (cryo-EM), the interphase between Li metal and LiPON is successfully preserved and probed, revealing a multilayer mosaic SEI structure with concentration gradients of nitrogen and phosphorous, materializing as crystallites within an amorphous matrix This unique SEI nanostructure is less than 80 nm and is shown stable and free of any organic lithium containing species or lithium fluoride components, in contrast to SEIs often found in state-of-the-art organic liquid electrolytes Our findings reveal insights on the nanostructures and chemistry of such SEIs as a key component in lithium metal batteries to stabilize Li metal anode

Metastability and Reversibility of Anionic Redox-Based Cathode for High-Energy Rechargeable Batteries.

Abstract: Great focus has recently been placed on anionic redox, to which high capacities of Li-rich layered oxides are attributed. With almost doubled capacity compared with state-of-the-art cathode materials, Li-rich layered oxides still fall short in other performance metrics. Among these, voltage decay upon cycling remains the most hindering obstacle, in which defect electrochemistry plays a critical role. Here, we reveal that the metastable state of cycled Li-rich layered oxide, which stems from structural defects in different dimensions, is responsible for the voltage decay. More importantly, through mild thermal energy, the metastable state can be driven to a stable state, bringing about structural and voltage recovery. However, for the classic layered oxide without reversible anionic redox, thermal energy can only introduce cation disordering, leading to performance deterioration. These insights elucidate that understanding the structure metastability and reversibility is essential for implementing design strategies to improve cycling stability for high-capacity layered oxides.

Metformin and 2-Deoxyglucose Collaboratively Suppress Human CD4+ T Cell Effector Functions and Activation-Induced Metabolic Reprogramming.

Abstract: Metabolic reprogramming plays a central role in T cell activation and differentiation, and the inhibition of key metabolic pathways in activated T cells represents a logical approach for the development of new therapeutic agents for treating autoimmune diseases. The widely prescribed antidiabetic drug metformin and the glycolytic inhibitor 2-deoxyglucose (2-DG) have been used to study the inhibition of oxidative phosphorylation and glycolysis, respectively, in murine immune cells. Published studies have demonstrated that combination treatment with metformin and 2-DG was efficacious in dampening mouse T cell activation-induced effector processes, relative to treatments with either metformin or 2-DG alone. In this study, we report that metformin + 2-DG treatment more potently suppressed IFN-γ production and cell proliferation in activated primary human CD4+ T cells than either metformin or 2-DG treatment alone. The effects of metformin + 2-DG on human T cells were accompanied by significant remodeling of activation-induced metabolic transcriptional programs, in part because of suppression of key transcriptional regulators MYC and HIF-1A. Accordingly, metformin + 2-DG treatment significantly suppressed MYC-dependent metabolic genes and processes, but this effect was found to be independent of mTORC1 signaling. These findings reveal significant insights into the effects of metabolic inhibition by metformin + 2-DG treatment on primary human T cells and provide a basis for future work aimed at developing new combination therapy regimens that target multiple pathways within the metabolic networks of activated human T cells.

Local Structure of Glassy Lithium Phosphorus Oxynitride Thin Films: A Combined Experimental and Ab Initio Approach

Abstract: Lithium phosphorus oxynitride (LiPON) is an amorphous solid-state lithium ion conductor displaying exemplary cyclability against lithium metal anodes There is no definitive explanation for this stability due to the limited understanding of the structure of LiPON Herein, we provide a structural model of RF-sputtered LiPON Information about the short-range structure results from 1D and 2D solid-state NMR experiments These results are compared with first principles chemical shielding calculations of Li-P-O/N crystals and ab initio molecular dynamics-generated amorphous LiPON models to unequivocally identify the glassy structure as primarily isolated phosphate monomers with N incorporated in both apical and as bridging sites in phosphate dimers Structural results suggest LiPON's stability is a result of its glassy character Free-standing LiPON films are produced that exhibit a high degree of flexibility, highlighting the unique mechanical properties of glassy materials

Local structure of glassy lithium phosphorus oxynitride thin films: a combined experimental and ab initio approach

Abstract: Lithium phosphorus oxynitride (LiPON) is an amorphous solid-state lithium ion conductor displaying exemplary cyclability against lithium metal anodes There is no definitive explanation for this stability due to the limited understanding of the structure of LiPON We provide a structural model of RF-sputtered LiPON via experimental and computational spectroscopic methods Information about the short-range structure results from 1D and 2D solid-state nuclear magnetic resonance experiments investigating chemical shift anisotropy and dipolar interactions These results are compared with first principles chemical shielding calculations of Li-P-O/N crystals and ab initio molecular dynamics-generated amorphous LiPON models to unequivocally identify the glassy structure as primarily isolated phosphate monomers with N incorporated in both apical and as bridging sites in phosphate dimers Structural results suggest LiPON's stability is a result of its glassy character Free-standing LiPON films are produced that exhibit a high degree of flexibility highlighting the unique mechanical properties of glassy materials

Opinion on Immune Tolerance Therapeutic Development.

Abstract: Immune tolerance is defined by an active state of immune system unresponsiveness to foreign and self-antigens. Loss of immune tolerance to self-antigens and the resulting overexpression of autoantibodies can lead to tissue injury and development of various autoimmune diseases. In drug development, the goal of newly emerging immune tolerance therapies is to treat autoimmune disorders by restoring the immunoregulatory capacity of the immune system. Development of immune tolerance targets is initiated with the establishment of pharmacological efficacy in relevant disease animal models, followed by their stepwise translation to humans. This review discusses the major challenges to developing tolerance inducing pharmaceutical drugs, including the selection of appropriate disease models to establish efficacy, adequate, and acceptable in vitro and in vivo safety assessments, relevant biomarkers of human safety and efficacy, and finally, some regulatory guidelines to successfully develop immune tolerance therapeutics. [Box: see text].

Unveiling the Stable Nature of the Solid Electrolyte Interphase between Lithium Metal and Lipon Via Cryogenic Electron Microscopy

Abstract: The solid electrolyte interphase (SEI) is regarded as the most complex but the least understood constituent in secondary batteries using liquid and solid electrolytes. The nanostructures of SEIs were recently reported to be equally important to the chemistry of SEIs for stabilizing Li metal in liquid electrolyte. However, the dearth of such knowledge in all-solid-state battery (ASSB) has hindered a complete understanding of how certain solid-state electrolytes, such as LiPON, manifest exemplary stability against Li metal. Characterizing such solid-solid interfaces is difficult due to the buried, highly reactive, and beam-sensitive nature of the constituents within. By employing cryogenic electron microscopy (cryo-EM), the interphase between Li metal and LiPON is successfully preserved and probed, revealing a multilayer mosaic SEI structure with concentration gradients of nitrogen and phosphorous, materializing as crystallites within an amorphous matrix. This unique SEI nanostructure is less than 80 nm and is shown stable and free of any organic lithium containing species or lithium fluoride components, in contrast to SEIs often found in state-of-the-art organic liquid electrolytes. Our findings reveal insights on the nanostructures and chemistry of such SEIs as a key component in lithium metal batteries to stabilize Li metal anode.