Search

Enhancing drought tolerance in crops and understanding the underlying mechanisms have been subject of intense research. The precise function and molecular mechanisms of B-box zinc finger proteins (BBX) remain elusive. Here, we report a natural allele of BBX18 (BBX18 TT ) that encodes a C-terminal truncated protein. While most wild tomato germplasms contain the BBX18 CC allele and show more drought tolerant, modern cultivated tomatoes mostly carry BBX18 TT allele and are more drought sensitive. Knockout of BBX18 leads to improved drought tolerance in transgenic plants of cultivated tomato. Ascorbate peroxidase 1 (APX1) is identified as a BBX18-interacting protein that acts as a positive regulator of drought resistance in tomato. Chromatin immunoprecipitation sequencing analyses reveal that BBX18 binds to a unique cis-acting element of the APX1 promoter and represses its gene expression. This study provides insights into the molecular mechanism underlying drought resistance mediated by the BBX18-APX1 module in plants., (© 2024. The Author(s).)

Due to low success rates and long cycles of traditional drug development, the clinical tendency is to apply omics techniques to reveal patient-level disease characteristics and individualized responses to treatment. However, the heterogeneous form of data and uneven distribution of targets make drug discovery and precision medicine a non-trivial task. This study takes pyroptosis therapy for triple-negative breast cancer (TNBC) as a paradigm and uses data mining of a large TNBC cohort and drug databases to establish a biofactor-regulated neural network for rapidly screening and optimizing compound pyroptosis drug pairs. Subsequently, biomimetic nanococrystals are prepared using the preferred combination of mitoxantrone and gambogic acid for rational drug delivery. The unique mechanism of obtained nanococrystals regulating pyroptosis genes through ribosomal stress and triggering pyroptosis cascade immune effects are revealed in TNBC models. In this work, a target omics-based intelligent compound drug discovery framework explores an innovative drug development paradigm, which repurposes existing drugs and enables precise treatment of refractory diseases., (© 2024. The Author(s).)

Oxides with a face-centred cubic (fcc) anion sublattice are generally not considered as solid-state electrolytes as the structural framework is thought to be unfavourable for lithium (Li) superionic conduction. Here we demonstrate Li superionic conductivity in fcc-type oxides in which face-sharing Li configurations have been created through cation over-stoichiometry in rocksalt-type lattices via excess Li. We find that the face-sharing Li configurations create a novel spinel with unconventional stoichiometry and raise the energy of Li, thereby promoting fast Li-ion conduction. The over-stoichiometric Li-In-Sn-O compound exhibits a total Li superionic conductivity of 3.38 × 10 -4  S cm -1 at room temperature with a low migration barrier of 255 meV. Our work unlocks the potential of designing Li superionic conductors in a prototypical structural framework with vast chemical flexibility, providing fertile ground for discovering new solid-state electrolytes., (© 2024. The Author(s).)

Chemical short-range-order has been widely noticed to dictate the electrochemical properties of Li-excess cation-disordered rocksalt oxides, a class of cathode based on earth abundant elements for next-generation high-energy-density batteries. Existence of short-range-order is normally evidenced by a diffused intensity pattern in reciprocal space, however, derivation of local atomic arrangements of short-range-order in real space is hardly possible. Here, by a combination of aberration-corrected scanning transmission electron microscopy, electron diffraction, and cluster-expansion Monte Carlo simulations, we reveal the short-range-order is a convolution of three basic types: tetrahedron, octahedron, and cube. We discover that short-range-order directly correlates with Li percolation channels, which correspondingly affects Li transport behavior. We further demonstrate that short-range-order can be effectively manipulated by anion doping or post-synthesis thermal treatment, creating new avenues for tailoring the electrochemical properties. Our results provide fundamental insights for decoding the complex relationship between local chemical ordering and properties of crystalline compounds., (© 2023. The Author(s).)

Na Super Ionic Conductor (NASICON) materials are an important class of solid-state electrolytes owing to their high ionic conductivity and superior chemical and electrochemical stability. In this paper, we combine first-principles calculations, experimental synthesis and testing, and natural language-driven text-mined historical data on NASICON ionic conductivity to achieve clear insights into how chemical composition influences the Na-ion conductivity. These insights, together with a high-throughput first-principles analysis of the compositional space over which NASICONs are expected to be stable, lead to the successful synthesis and electrochemical investigation of several new NASICONs solid-state conductors. Among these, a high ionic conductivity of 1.2 mS cm -1 could be achieved at 25 °C. We find that the ionic conductivity increases with average metal size up to a certain value and that the substitution of PO 4 polyanions by SiO 4 also enhances the ionic conductivity. While optimal ionic conductivity is found near a Na content of 3 per formula unit, the exact optimum depends on other compositional variables. Surprisingly, the Na content enhances the ionic conductivity mostly through its effect on the activation barrier, rather than through the carrier concentration. These deconvoluted design criteria may provide guidelines for the design of optimized NASICON conductors., (© 2023. Springer Nature Limited.)

Lithium-rich cathodes are promising energy storage materials due to their high energy densities. However, voltage hysteresis, which is generally associated with transition metal migration, limits their energy efficiency and implementation in practical devices. Here we reveal that voltage hysteresis is related to the collective migration of metal ions, and that isolating the migration events from each other by creating partial disorder can create high-capacity reversible cathode materials, even when migrating transition metal ions are present. We demonstrate this on a layered Li-rich chromium manganese oxide that in its fully ordered state displays a substantial voltage hysteresis (>2.5 V) associated with collective transition metal migration into Li layers, but can be made to achieve high capacity (>360 mAh g -1 ) and energy density (>1,100 Wh kg -1 ) when the collective migration is perturbed by partial disorder. This study demonstrates that partially cation-disordered cathode materials can accommodate a high level of transition metal migration, which broadens our options for redox couples to those of mobile cations., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

A pro-inflammatory intestinal microbiome is characteristic of Parkinson's disease (PD). Prebiotic fibers change the microbiome and this study sought to understand the utility of prebiotic fibers for use in PD patients. The first experiments demonstrate that fermentation of PD patient stool with prebiotic fibers increased the production of beneficial metabolites (short chain fatty acids, SCFA) and changed the microbiota demonstrating the capacity of PD microbiota to respond favorably to prebiotics. Subsequently, an open-label, non-randomized study was conducted in newly diagnosed, non-medicated (n = 10) and treated PD participants (n = 10) wherein the impact of 10 days of prebiotic intervention was evaluated. Outcomes demonstrate that the prebiotic intervention was well tolerated (primary outcome) and safe (secondary outcome) in PD participants and was associated with beneficial biological changes in the microbiota, SCFA, inflammation, and neurofilament light chain. Exploratory analyses indicate effects on clinically relevant outcomes. This proof-of-concept study offers the scientific rationale for placebo-controlled trials using prebiotic fibers in PD patients. ClinicalTrials.gov Identifier: NCT04512599., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In this paper we develop the stability rules for NASICON-structured materials, as an example of compounds with complex bond topology and composition. By first-principles high-throughput computation of 3881 potential NASICON phases, we have developed guiding stability rules of NASICON and validated the ab initio predictive capability through the synthesis of six attempted materials, five of which were successful. A simple two-dimensional descriptor for predicting NASICON stability was extracted with sure independence screening and machine learned ranking, which classifies NASICON phases in terms of their synthetic accessibility. This machine-learned tolerance factor is based on the Na content, elemental radii and electronegativities, and the Madelung energy and can offer reasonable accuracy for separating stable and unstable NASICONs. This work will not only provide tools to understand the synthetic accessibility of NASICON-type materials, but also demonstrates an efficient paradigm for discovering new materials with complicated composition and atomic structure., (© 2021. The Author(s).)

The cytoplasmic domain of PD-L1 (PD-L1-CD) regulates PD-L1 degradation and stability through various mechanism, making it an attractive target for blocking PD-L1-related cancer signaling. Here, by using NMR and biochemical techniques we find that the membrane association of PD-L1-CD is mediated by electrostatic interactions between acidic phospholipids and basic residues in the N-terminal region. The absence of the acidic phospholipids and replacement of the basic residues with acidic residues abolish the membrane association. Moreover, the basic-to-acidic mutations also decrease the cellular abundance of PD-L1, implicating that the electrostatic interaction with the plasma membrane mediates the cellular levels of PD-L1. Interestingly, distinct from its reported function as an activator of AMPK in tumor cells, the type 2 diabetes drug metformin enhances the membrane dissociation of PD-L1-CD by disrupting the electrostatic interaction, thereby decreasing the cellular abundance of PD-L1. Collectively, our study reveals an unusual regulatory mechanism that controls the PD-L1 level in tumor cells, suggesting an alternative strategy to improve the efficacy of PD-L1-related immunotherapies., (© 2021. The Author(s).)

The Wnt signaling pathway is intricately connected with bone mass regulation in humans and rodent models. We designed an antibody-based platform that generates potent and selective Wnt mimetics. Using this platform, we engineer bi-specific Wnt mimetics that target Frizzled and low-density lipoprotein receptor-related proteins and evaluate their effects on bone accrual in murine models. These synthetic Wnt agonists induce rapid and robust bone building effects, and correct bone mass deficiency and bone defects in various disease models, including osteoporosis, aging, and long bone fracture. Furthermore, when these Wnt agonists are combined with antiresorptive bisphosphonates or anti-sclerostin antibody therapies, additional bone accrual/maintenance effects are observed compared to monotherapy, which could benefit individuals with severe and/or acute bone-building deficiencies. Our data support the continued development of Wnt mimetics for the treatment of diseases of low bone mineral density, including osteoporosis.

High-entropy (HE) ceramics, by analogy with HE metallic alloys, are an emerging class of solid solutions composed of a large number of species. These materials offer the benefit of large compositional flexibility and can be used in a wide variety of applications, including thermoelectrics, catalysts, superionic conductors and battery electrodes. We show here that the HE concept can lead to very substantial improvements in performance in battery cathodes. Among lithium-ion cathodes, cation-disordered rocksalt (DRX)-type materials are an ideal platform within which to design HE materials because of their demonstrated chemical flexibility. By comparing a group of DRX cathodes containing two, four or six transition metal (TM) species, we show that short-range order systematically decreases, whereas energy density and rate capability systematically increase, as more TM cation species are mixed together, despite the total metal content remaining fixed. A DRX cathode with six TM species achieves 307 mAh g -1 (955 Wh kg -1 ) at a low rate (20 mA g -1 ), and retains more than 170 mAh g -1 when cycling at a high rate of 2,000 mA g -1 . To facilitate further design in this HE DRX space, we also present a compatibility analysis of 23 different TM ions, and successfully synthesize a phase-pure HE DRX compound containing 12 TM species as a proof of concept.

Nanoparticle delivery to solid tumours over the past ten years has stagnated at a median of 0.7% of the injected dose. Varying nanoparticle designs and strategies have yielded only minor improvements. Here we discovered a dose threshold for improving nanoparticle tumour delivery: 1 trillion nanoparticles in mice. Doses above this threshold overwhelmed Kupffer cell uptake rates, nonlinearly decreased liver clearance, prolonged circulation and increased nanoparticle tumour delivery. This enabled up to 12% tumour delivery efficiency and delivery to 93% of cells in tumours, and also improved the therapeutic efficacy of Caelyx/Doxil. This threshold was robust across different nanoparticle types, tumour models and studies across ten years of the literature. Our results have implications for human translation and highlight a simple, but powerful, principle for designing nanoparticle cancer treatments.

In the synthesis of inorganic materials, reactions often yield non-equilibrium kinetic byproducts instead of the thermodynamic equilibrium phase. Understanding the competition between thermodynamics and kinetics is a fundamental step towards the rational synthesis of target materials. Here, we use in situ synchrotron X-ray diffraction to investigate the multistage crystallization pathways of the important two-layer (P2) sodium oxides Na 0.67 MO 2 (M = Co, Mn). We observe a series of fast non-equilibrium phase transformations through metastable three-layer O3, O3' and P3 phases before formation of the equilibrium two-layer P2 polymorph. We present a theoretical framework to rationalize the observed phase progression, demonstrating that even though P2 is the equilibrium phase, compositionally unconstrained reactions between powder precursors favour the formation of non-equilibrium three-layered intermediates. These insights can guide the choice of precursors and parameters employed in the solid-state synthesis of ceramic materials, and constitutes a step forward in unravelling the complex interplay between thermodynamics and kinetics during materials synthesis.

The delivery of medical agents to a specific diseased tissue or cell is critical for diagnosing and treating patients. Nanomaterials are promising vehicles to transport agents that include drugs, contrast agents, immunotherapies and gene editors. They can be engineered to have different physical and chemical properties that influence their interactions with their biological environments and delivery destinations. In this Review Article, we discuss nanoparticle delivery systems and how the biology of disease should inform their design. We propose developing a framework for building optimal delivery systems that uses nanoparticle-biological interaction data and computational analyses to guide future nanomaterial designs and delivery strategies.

The concept of nanoparticle transport through gaps between endothelial cells (inter-endothelial gaps) in the tumour blood vessel is a central paradigm in cancer nanomedicine. The size of these gaps was found to be up to 2,000 nm. This justified the development of nanoparticles to treat solid tumours as their size is small enough to extravasate and access the tumour microenvironment. Here we show that these inter-endothelial gaps are not responsible for the transport of nanoparticles into solid tumours. Instead, we found that up to 97% of nanoparticles enter tumours using an active process through endothelial cells. This result is derived from analysis of four different mouse models, three different types of human tumours, mathematical simulation and modelling, and two different types of imaging techniques. These results challenge our current rationale for developing cancer nanomedicine and suggest that understanding these active pathways will unlock strategies to enhance tumour accumulation.

The liver and spleen are major biological barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examined the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1,000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 ± 6.4%), hepatic B cells (81.5 ± 9.3%) and liver sinusoidal endothelial cells (64.6 ± 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 ± 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.