A TNFα/Miz1-positive feedback loop inhibits mitophagy in hepatocytes and propagates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is a chronic inflammatory disease that can further progress to cirrhosis and hepatocellular carcinoma. However, the key molecular mechanisms behind this process have not been clarified. METHODS: We analyzed human NASH and normal liver tissue samples by RNA-sequencing and liquid chromatography-mass spectrometry, identifying hepatocyte cytosolic protein Myc-interacting zinc-finger protein 1 (Miz1) as a potential target in NASH progression. We established a Western diet+fructose-induced NASH model in hepatocyte-specific Miz1 knockout and adeno-associated virus type 8-overexpressing mice. Human NASH liver organoids were used to confirm the mechanism, and immunoprecipitation and mass spectrometry were used to detect proteins that could interact with Miz1. RESULTS: We demonstrate that Miz1 is reduced in hepatocytes in human NASH. Miz1 is shown to bind to peroxiredoxin 6 (PRDX6), retaining it in the cytosol, blocking its interaction with mitochondrial Parkin at Cys431, and inhibiting Parkin-mediated mitophagy. In NASH livers, loss of hepatocyte Miz1 results in PRDX6-mediated inhibition of mitophagy, increased dysfunctional mitochondria in hepatocytes, and production of proinflammatory cytokines, including TNFα, by hepatic macrophages. Crucially, the increased production of TNFα results in a further reduction in hepatocyte Miz1 by E3-ubiquitination. This produces a positive feedback loop of TNFα-mediated hepatocyte Miz1 degradation, resulting in PRDX6-mediated inhibition of hepatocyte mitophagy, with the accumulation of dysfunctional mitochondria in hepatocytes and increased macrophage TNFα production. CONCLUSIONS: Our study identified hepatocyte Miz1 as a suppressor of NASH progression via its role in mitophagy; we also identified a positive feedback loop by which TNFα production induces degradation of cytosolic Miz1, which inhibits mitophagy and thus leads to increased macrophage TNFα production. Interruption of this positive feedback loop could be a strategy to inhibit the progression of NASH. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) is a chronic inflammatory disease that can further develop into cirrhosis and hepatocellular carcinoma. However, the key molecular mechanism of this process has not been fully clarified. Herein, we identified a positive feedback loop of macrophage TNFα-mediated hepatocyte Miz1 degradation, resulting in PRDX6-mediated inhibition of hepatocyte mitophagy, aggravation of mitochondrial damage and increased macrophage TNFα production. Our findings not only provide mechanistic insight into NASH progression but also provide potential therapeutic targets for patients with NASH. Our human NASH liver organoid culture is therefore a useful platform for exploring treatment strategies for NASH development.

Perspective and Prospects for Ordered Functional Materials.

Many functional materials are approaching their performance limits due to inherent trade-offs between essential physical properties. Such trade-offs can be overcome by engineering a material that has an ordered arrangement of structural units, including constituent components/phases, grains, and domains. By rationally manipulating the ordering with abundant structural units at multiple length scales, the structural ordering opens up unprecedented opportunities to create transformative functional materials, as amplified properties or disruptive functionalities can be realized. In this perspective article, a brief overview of recent advances in the emerging ordered functional materials across catalytic, thermoelectric, and magnetic materials regarding the fabrication, structure, and property is presented. Then the possibility of applying this structural ordering strategy to highly efficient neuromorphic computing devices and durable battery materials is discussed. Finally, remaining scientific challenges are highlighted, and the prospects for ordered functional materials are made. This perspective aims to draw the attention of the scientific community to the emerging ordered functional materials and trigger intense studies on this topic.

Efficient Probabilistic Computing with Stochastic Perovskite Nickelates.

Probabilistic computing has emerged as a viable approach to solve hard optimization problems. Devices with inherent stochasticity can greatly simplify their implementation in electronic hardware. Here, we demonstrate intrinsic stochastic resistance switching controlled via electric fields in perovskite nickelates doped with hydrogen. The ability of hydrogen ions to reside in various metastable configurations in the lattice leads to a distribution of transport gaps. With experimentally characterized p-bits, a shared-synapse p-bit architecture demonstrates highly parallelized and energy-efficient solutions to optimization problems such as integer factorization and Boolean satisfiability. The results introduce perovskite nickelates as scalable potential candidates for probabilistic computing and showcase the potential of light-element dopants in next-generation correlated semiconductors.

Macroscopic Gradient Ordered α-Fe/Pr2Fe14B Nanocomposites with Ultrahigh Energy Density.

Nanoparticle self-assembly enables the generation of complex ordered nanostructures with enhanced properties or new functionalities. However, the ordering is often limited to the micrometer scale with chemical strategies due to the relative weak supramolecular interactions that govern the self-assembly process. Here a physical strategy via temperature-gradient-assisted self-assembly is reported to create three-dimensional (3D) macroscopic ordered nanocomposites with different gradient variations in grain size, constituent content, and crystal orientation. The resulting α-Fe/Pr2Fe14B ordered nanostructure with reverse gradients in both the grain size and α-Fe content exhibits a record-high energy density of about 25 MGOe for isotropic α-Fe/Pr2Fe14B systems, approximately 130% higher than that of its disordered counterpart. Both experiments and micromagnetic simulations demonstrate that creating ordered nanostructures is an alternative approach to develop high-performance permanent-magnet materials. Our findings make a significant step toward creating 3D macroscopic ordered nanostructures and will stimulate the development of ordered nanomaterials.

TOX deficiency facilitates the differentiation of IL-17A-producing γδ T cells to drive autoimmune hepatitis.

The specification of the αß/γδ lineage and the maturation of medullary thymic epithelial cells (mTECs) coordinate central tolerance to self-antigens. However, the mechanisms underlying this biological process remain poorly clarified. Here, we report that dual-stage loss of TOX in thymocytes hierarchically impaired mTEC maturation, promoted thymic IL-17A-producing γδ T-cell (Tγδ17) lineage commitment, and led to the development of fatal autoimmune hepatitis (AIH) via different mechanisms. Transfer of γδ T cells from TOX-deficient mice reproduced AIH. TOX interacted with and stabilized the TCF1 protein to maintain the balance of γδ T-cell development in thymic progenitors, and overexpression of TCF1 normalized αß/γδ lineage specification and activation. In addition, TOX expression was downregulated in γδ T cells from AIH patients and was inversely correlated with the AIH diagnostic score. Our findings suggest multifaceted roles of TOX in autoimmune control involving mTEC and Tγδ17 development and provide a potential diagnostic marker for AIH.

Manipulating Offense and Defense Signaling to Fight Cold Tumors with Carrier-Free Nanoassembly of Fluorinated Prodrug and siRNA.

Chemoimmunotherapy has shown great potential to activate an immune response, but the immunosuppressive microenvironment associated with T cell exhaustion remains a challenge in cancer therapy. The proper immune-modulatory strategy to provoke a robust immune response is to simultaneously regulate T-cell exhaustion and infiltration. Here, a new kind of carrier-free nanoparticle is developed to simultaneously deliver chemotherapeutic drug (doxorubicin, DOX), cytolytic peptide (melittin, MPI), and anti-TOX small interfering RNA (thymocyte selection-associated high mobility group box protein, TOX) using a fluorinated prodrug strategy. In this way, the enhanced immunogenic cell death (ICD) induced by the combination of DOX and MPI can act as "offense" signaling to increase CD8+ T-cell infiltration, while the decreased TOX expression interfered with siTOX can serve as "defense" signaling to mitigate CD8+ T-cell exhaustion. As a result, the integration of DOX, MPI, and siTOX in such a bifunctional system produced a potent antitumor immune response in liver cancer and metastasis, making it a promising delivery platform and effective strategy for converting "cold" tumors into "hot" ones.

Erratum: PTPROt aggravates inflammation by enhancing NF-κB activation in liver macrophages during nonalcoholic steatohepatitis: Erratum.

[This corrects the article DOI: 10.7150/thno.42658.].

Preparation of sodium alginate/konjac glucomannan active films containing lycopene microcapsules and the effects of these films on sweet cherry preservation.

In this study, lycopene microcapsules (LMs) were prepared using chitosan (CS) and carboxymethyl CS (CMCS) as the wall materials. Sodium alginate (SA) and konjac glucomannan (KGM) were used as substrates to fabricate LM/SA/KGM composite films. Results showed that when 2.0 % CMCS was employed, the resulting LMs had the maximum embedding rate of 83.17 %, smallest particle sizes, and stable zeta potentials. The LMs still had a high retention rate after 10 days of storage at 4 and 25 °C. When 2.0 % LMs were used, the corresponding composite film exhibited the best antibacterial properties, oxidation resistance, a high transparency (82.3 %), and a strong water vapor barrier (2.39 × 10-10 g/m·s·Pa). Finally, the effects of the as-prepared composite films on the preservation of sweet cherries stored at 0 °C for 15 days were investigated. The results indicated that the LM/SA/KGM composite film effectively prolonged the shelf lives of sweet cherries and efficiently delayed the decline in the decay rate, pH, contents of soluble solids, and other indicators. The application of LM/SA/KGM composite films in fruit and vegetable preservation has development prospects and provides a reference for expanding the application range of lycopene and enhancing fruit and vegetable preservation.

Engineered EGCG-Containing Biomimetic Nanoassemblies as Effective Delivery Platform for Enhanced Cancer Therapy.

Nano-based immunotherapy of therapeutic biomolecules is attractive but tremendously hampered by the poor delivery efficiency. This study reports a novel delivery system of fluorinated-coordinative-epigallocatechin gallate (EGCG), referring as FEGCG/Zn, through the integration of fluorination and zinc ions (Zn2+ ) into EGCG. The robust therapeutics of FEGCG/Zn are measured in terms of the regulating effect on programmed cell death ligand 1 (PD-L1), the effective delivery of diverse biomolecules, and the hitchhiking ability using living cells. Taking small interfering RNA of PD-L1 (siPD-L1) and erythrocytes as an example, the fabricated biomimetic system achieves excellent siPD-L1 delivery and further improves siPD-L1 accumulation in tumors. Finally, the combination of FEGCG/Zn and siPD-L1 promotes antitumor immunotherapy through alleviation of T cells exhaustion by regulating PD-L1 expression in tumor cells. The results demonstrate that FEGCG/Zn substantially regulates PD-L1 expression and improves immune-biomolecule delivery by forming biomimetic nanoassemblies, offering a versatile platform for cancer immunotherapy.

Reconfigurable perovskite nickelate electronics for artificial intelligence.

Reconfigurable devices offer the ability to program electronic circuits on demand. In this work, we demonstrated on-demand creation of artificial neurons, synapses, and memory capacitors in post-fabricated perovskite NdNiO3 devices that can be simply reconfigured for a specific purpose by single-shot electric pulses. The sensitivity of electronic properties of perovskite nickelates to the local distribution of hydrogen ions enabled these results. With experimental data from our memory capacitors, simulation results of a reservoir computing framework showed excellent performance for tasks such as digit recognition and classification of electrocardiogram heartbeat activity. Using our reconfigurable artificial neurons and synapses, simulated dynamic networks outperformed static networks for incremental learning scenarios. The ability to fashion the building blocks of brain-inspired computers on demand opens up new directions in adaptive networks.

Discotic Liquid Crystal Epoxy Resins Integrating Intrinsic High Thermal Conductivity and Intrinsic Flame Retardancy.

The integration of intrinsic thermal conductivity and intrinsic flame retardancy of epoxy resins shows wider application prospects in electricals and electronics. Discotic liquid crystal epoxy (D-LCE) is synthesized from pyrocatechol, 2-allyloxyethanol, and 3-chloroperoxybenzoic acid. P/Si synergistic flame-retardant co-curing agent (DOPO-POSS, DP) is synthesized from p-hydroxybenzaldehyde, 9, 10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide (DOPO), and amino terminated polysilsesquioxane (POSS). Finally, D-LCE is cured within liquid crystal range with 4, 4'-diaminodiphenyl methane (DDM) and DP, to obtain intrinsic highly thermal conductive/flame-retardant epoxy resins (D-LCERDP ). D-LCERDP-10.0 (10.0 wt% DP) synchronously possesses excellent intrinsic thermal conductivity and intrinsic flame retardancy, with thermal conductivity coefficient in vertical and parallel direction (λ⊥ and λ∥ ) of 0.34 and 1.30 W m-1 K-1 , much higher than that of general bisphenol A epoxy resin (E-51, λ⊥ of 0.19 W m-1 K-1 , λ∥ of 0.65 W m-1 K-1 ). The limiting oxygen index (LOI) value of D-LCERDP-10.0 reaches 31.1, also better than those of E-51 (19.8) and D-LCER (21.3).

In vitro digestion of sodium alginate/pectin co-encapsulated Lactobacillus bulgaricus and its application in yogurt bilayer beads.

The purpose of this study was to prepare sodium alginate (SA)/pectin (PE) hydrogel microspheres using the extrusion method to encapsulate Lactobacillus bulgaricus. Microscopic observation showed that the beads were spherical with a smooth and uniform surface. For microspheres with a diameter range of 140-156 µm, the encapsulation efficiency reached 85.67%. After simulating saliva, gastric juice, and intestinal juice, the activity of the microcapsules was estimated to be 5.78 × 104 log colony forming unit (CFU)/mL. These data show that the use of SA and PE encapsulated probiotics exhibit enhanced viability. In addition, double-layer beads containing probiotic microspheres and yogurt were prepared, and physical and chemical analysis was performed using scanning electron microscopy, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. Texture and sensory property analysis revealed that the beads had good elasticity, chewiness, and high commercial value. Collectively, these findings indicate that SA and PE can be used for the encapsulation, protection, and gastrointestinal delivery of probiotics. Moreover, these microcapsules exhibit good stability in vitro and improve yogurt characteristics by increasing the survival rate of encapsulated probiotics, thus demonstrating their commercial application potential.

Directional Magnetization Reversal Enables Ultrahigh Energy Density in Gradient Nanostructures.

High-performance ferromagnetic materials are essential for energy conversion and electronic devices. However, the random and nonuniform magnetization reversal in ferromagnetics limits their performance that can be achieved. Here, through both micromagnetism simulations and experiments, a directional magnetization reversal that initiates first from large grains toward smaller ones is discovered by engineering Nd2 Fe14 B/α-Fe gradient nanostructures. Such directional magnetization reversal enables a rare combination of high magnetization and large coercivity, thus leading to a record-high energy density (26 MG Oe) for isotropic permanent magnetic materials, which is ≈50% higher than that of its gradient-free counterpart. The unusual magnetization reversal originates from an ordered arrangement of grain sizes in the gradient material, where the large grains have a lower reversal field than that of the smaller ones. These findings open up new opportunities for developing high-performance magnetic materials.

The zinc finger protein Miz1 suppresses liver tumorigenesis by restricting hepatocyte-driven macrophage activation and inflammation.

Chronic inflammation plays a central role in hepatocellular carcinoma (HCC), but the contribution of hepatocytes to tumor-associated inflammation is not clear. Here, we report that the zinc finger transcription factor Miz1 restricted hepatocyte-driven inflammation to suppress HCC, independently of its transcriptional activity. Miz1 was downregulated in HCC mouse models and a substantial fraction of HCC patients. Hepatocyte-specific Miz1 deletion in mice generated a distinct sub-group of hepatocytes that produced pro-inflammatory cytokines and chemokines, which skewed the polarization of the tumor-infiltrating macrophages toward pro-inflammatory phenotypes to promote HCC. Mechanistically, Miz1 sequestrated the oncoprotein metadherin (MTDH), preventing MTDH from promoting transcription factor nuclear factor κB (NF-κB) activation. A distinct sub-group of pro-inflammatory cytokine-producing hepatocytes was also seen in a subset of HCC patients. In addition, Miz1 expression inversely correated with disease recurrence and poor prognosis in HCC patients. Our findings identify Miz1 as a tumor suppressor that prevents hepatocytes from driving inflammation in HCC.

Three-Dimensional Covalent Organic Framework with ceq Topology.

Three-dimensional covalent organic frameworks (3D-COFs) are emerging as designable porous materials because of their unique structural characteristics and porous features. However, because of the lack of 3D organic building units and the less reversible covalent bonds, the topologies of 3D-COFs to date have been limited to dia, ctn, ffc, bor, rra, srs, pts, lon, stp, acs, tbo, bcu, and fjh. Here we report a 3D-COF with the ceq topology utilizing a D3h-symmetric triangular prism vertex with a planar triangular linker. The as-synthesized COF displays a twofold-interpenetrated structure with a Brunauer-Emmett-Teller surface area of 1148.6 m2 g-1. Gas sorption measurements revealed that 3D-ceq-COF could efficiently absorb CO2, CH4, and H2 under a moderate surface area. This work provides new building units and approaches for structural and application exploration of 3D-COFs.

Rewritable Nanoplasmonics through Room-Temperature Phase Manipulations of Vanadium Dioxide.

The interactions between light and plasmonic charge oscillations in conducting materials are important venues for realizing nanoscale light manipulations. Conventional metal-based plasmonic devices lack tunability due to the fixed material permittivities. Here, we show that reconfigurable plasmonic functionalities can be achieved using the spatially controlled phase transitions in strongly correlated oxide films. The experimental results discussed here are enabled by a recently developed scanning probe-based technique that allows a nonvolatile, monoclinic-metal VO2 phase to be reversibly patterned at the nanoscale in ambient conditions. Using this technique, rewritable waveguides, spatially modulated plasmonic resonators, and reconfigurable wire-grid polarizers are successfully demonstrated. These structures, effectively controlling infrared lights through spatially confined mobile carriers, showcase a great potential for building programmable nanoplasmonic devices on correlated oxide platforms.

Perovskite neural trees.

Trees are used by animals, humans and machines to classify information and make decisions. Natural tree structures displayed by synapses of the brain involves potentiation and depression capable of branching and is essential for survival and learning. Demonstration of such features in synthetic matter is challenging due to the need to host a complex energy landscape capable of learning, memory and electrical interrogation. We report experimental realization of tree-like conductance states at room temperature in strongly correlated perovskite nickelates by modulating proton distribution under high speed electric pulses. This demonstration represents physical realization of ultrametric trees, a concept from number theory applied to the study of spin glasses in physics that inspired early neural network theory dating almost forty years ago. We apply the tree-like memory features in spiking neural networks to demonstrate high fidelity object recognition, and in future can open new directions for neuromorphic computing and artificial intelligence.

PTPROt aggravates inflammation by enhancing NF-κB activation in liver macrophages during nonalcoholic steatohepatitis.

Rationale: Inflammation plays a crucial role in the progression of nonalcoholic steatohepatitis (NASH). Protein tyrosine phosphatase receptor type O truncated isoform (PTPROt) is an integral membrane protein that has been identified in osteoclasts, macrophages, and B lymphocytes. However, its relationship between inflammation and NASH is largely unknown. Herein, we aimed to study the function of PTPROt in NASH progression. Methods: We established a NASH mouse model in wild-type (WT), PTPRO knockout mice by western diet (WD) and methionine-choline-deficient diet (MCD). In addition, MCD-induced NASH model was established in BMT mice. Moreover, we determined the expression of PTPROt in liver macrophages in human subjects without steatosis, with simple steatosis, and with NASH to confirm the relationship between PTPROt and NASH. In vitro assays were also performed to study the molecular role of PTPROt in NASH progression. Results: Human samples and animal model results illustrated that PTPROt is increased in liver macrophages during NASH progression and is positively correlated with the degree of NASH. Our animal model also showed that PTPROt in liver macrophages can enhance the activation of the NF-κB signaling pathway, which induces the transcription of genes involved in the inflammatory response. Moreover, PTPROt promotes the transcription of pro-oxidant genes and inhibits antioxidant and protective genes via increased activation of the NF-κB signaling pathway, thereby causing an increased level of reactive oxygen species (ROS) and damaged mitochondria. This triggers the NLRP3-IL1ß axis and causes a heightened inflammatory response. Notably, PTPROt partially limits inflammation and ROS production by promoting mitophagy, which participates in a negative feedback loop in this model. Conclusions: Our data strongly indicate that PTPROt plays a dual role in inflammation via the NF-κB signaling pathway in liver macrophages during NASH. Further studies are required to explore therapeutic strategies and prevention of this common liver disease through PTPROt.

Long intergenic non-protein coding RNA 324 prevents breast cancer progression by modulating miR-10b-5p.

Mounting evidence suggests that long noncoding RNAs serve as specific biomarkers and potent modulators of multiple cancers. Long intergenic non-protein coding RNA 324 (LINC00324) is ubiquitously expressed in various tissues, including breast cancer. The biological function of LINC00324 in the development and progression of breast cancer remains unknown. Here, we fully elucidate the relation between LINC00324 expression and breast cancer, and suggest a potential mechanism of action. We found that decreased expression of LINC00324 was dramatically correlated with malignancy of breast cancer, both in breast cancer tissues and in cell lines. Overexpression of LINC00324 in MDA-MB-231 cells resulted in a decrease in cell proliferation, invasion, and migration, while increasing cells apoptosis. On the other hand, loss-of-function experiments indicated that deficiency of LINC00324 promoted malignant phenotypes in breast cancer cells. Mechanically, we found that LINC00324 is mainly distributed in the cytoplasm, fostering the expression of E-cadherin by sponging miR-10b-5p. Taken together, these findings suggest that LINC00324 plays a critical role in breast cancer progression by directly interacting with miR-10b-5p. LINC00324 can thus potentially act as an early diagnostic marker and a novel therapeutic agent for breast cancer.