Integrative transcriptomic and genomic analyses unveil the IFI16 variants and expression as MASLD progression markers.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a broad and continuous spectrum of liver diseases ranging from fatty liver to steatohepatitis. The intricate interactions of genetic, epigenetic, and environmental factors in the development and progression of MASLD remain elusive. Here, we aimed to achieve an integrative understanding of the genomic and transcriptomic alterations throughout the progression of MASLD. APPROACH AND RESULTS: RNA-Seq profiling (n = 146) and whole-exome sequencing (n = 132) of MASLD liver tissue samples identified 3 transcriptomic subtypes (G1-G3) of MASLD, which were characterized by stepwise pathological and molecular progression of the disease. Macrophage-driven inflammatory activities were identified as a key feature for differentiating these subtypes. This subtype-discriminating macrophage interplay was significantly associated with both the expression and genetic variation of the dsDNA sensor IFI16 (rs6940, A>T, T779S), establishing it as a fundamental molecular factor in MASLD progression. The in vitro dsDNA-IFI16 binding experiments and structural modeling revealed that the IFI16 variant exhibited increased stability and stronger dsDNA binding affinity compared to the wild-type. Further downstream investigation suggested that the IFI16 variant exacerbated DNA sensing-mediated inflammatory signals through mitochondrial dysfunction-related signaling of the IFI16-PYCARD-CASP1 pathway. CONCLUSIONS: This study unveils a comprehensive understanding of MASLD progression through transcriptomic classification, highlighting the crucial roles of IFI16 variants. Targeting the IFI16-PYCARD-CASP1 pathway may pave the way for the development of novel diagnostics and therapeutics for MASLD.

Intravital Multiphoton Imaging of the Bone and Bone Marrow Environment.

Over the last two decades, numerous advances in our understanding of bone cell biology and bone mineral homeostasis have been achieved. As a dynamic connective and supportive tissue, bone is constantly sensing and responding to both external mechanical forces and internal systemic and local signals. A variety of intravital imaging approaches have been investigated to identify molecular and cellular processes and to decipher signaling pathways involved in the cellular communication between different types of bone cells that form bone multicellular units. Furthermore, bone multicellular units interact with cells of the immune and hematopoietic system to maintain bone homeostasis. Bone-forming osteoblasts and bone-degrading osteoclasts are situated on the endosteal surface of bone influencing the dynamic remodeling and the regeneration of bone tissue. Osteocytes are found at very unique locations in the bone, closely surrounded by bone matrix, forming a cellular network through their interconnected dendritic processes. Bone marrow cells fill the numerous large cavities inside the bones with various blood cell lineages arising from hematopoietic stem and progenitor cells. A highly complex and interconnected network of arterial vessels and sinusoidal capillaries span through the bone marrow spaces forming an interface between the blood circulation and the bone marrow which allows cell trafficking between both compartments. Live imaging of animals using multiphoton microscopy represents a powerful approach to address the cellular behaviors of bone and bone marrow cells over time and space in their natural tissue microenvironment. The in vivo environment is crucial, because the dynamic behavior of cells is critically influenced by many tissue factors including extracellular components, cytokine and growth factor gradients, and fluid forces, such as blood flow. The review article focuses upon recent advances in multiphoton imaging technologies as well as novel experimental approaches in the understanding of the dynamic molecular and cellular mechanisms underlying bone tissue homeostasis, remodeling, and regeneration under physiological and pathological conditions. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

Two-Dimensional WO3 Nanosheets Chemically Converted from Layered WS2 for High-Performance Electrochromic Devices.

Two-dimensional (2D) transitional metal oxides (TMOs) are an attractive class of materials due to the combined advantages of high active surface area, enhanced electrochemical properties, and stability. Among the 2D TMOs, 2D tungsten oxide (WO3) nanosheets possess great potential in electrochemical applications, particularly in electrochromic (EC) devices. However, feasible production of 2D WO3 nanosheets is challenging due to the innate 3D crystallographic structure of WO3. Here we report a novel solution-phase synthesis of 2D WO3 nanosheets through simple oxidation from 2D tungsten disulfide (WS2) nanosheets exfoliated from bulk WS2 powder. The complete conversion from WS2 into WO3 was confirmed through crystallographic and elemental analyses, followed by validation of the 2D WO3 nanosheets applied in the EC device. The EC device showed color modulation of 62.57% at 700 nm wavelength, which is 3.43 times higher than the value of the conventional device using bulk WO3 powder, while also showing enhancement of ∼46.62% and ∼62.71% in switching response-time (coloration and bleaching). The mechanism of enhancement was rationalized through comparative analysis based on the thickness of the WO3 components. In the future, 2D WO3 nanosheets could also be used for other promising applications such as sensors, catalysis, thermoelectric, and energy conversion.

Fast P3HT Exciton Dissociation and Absorption Enhancement of Organic Solar Cells by PEG-Functionalized Graphene Quantum Dots.

PEG-functionalized graphene quantum dots (GQDs) are shown to promote fast exciton dissociation in organic solar cells. Short-chain PEG promotes the most favorable interaction with other organic layers, and the overall efficiency is improved by 36% when compared to the reference devices. The mechanism of enhancement is shown to be increased absorption due to fewer charges remain-ing in the bound state.

Moisture Barrier Composites Made of Non-Oxidized Graphene Flakes.

Graphene flakes (GFs) with minimized defects and oxidation ratios are incorporated into polyethylene (PE) to enhance the moisture barrier. GFs produced involving solvothermal intercalation show extremely low oxidation rates (3.17%), and are noncovalently functionalized in situ, inducing strong hydrophobicity. The fabricated composite possesses the best moisture barrier performance reported for a polymer-graphene composite.

Stem cell factor is a potent endothelial permeability factor.

OBJECTIVE: Although stem cell factor (SCF) has been shown to play a critical role in hematopoiesis, gametogenesis, and melanogenesis, the function of SCF in the regulation of vascular integrity has not been studied. APPROACH AND RESULTS: We demonstrated that SCF binds to and activates the cKit receptor in endothelial cells, thereby increasing the internalization of vascular endothelial-cadherin and enhancing extravasation of dyes to a similar extent as vascular endothelial growth factor. SCF-mediated cKit activation in endothelial cells enhanced the phosphorylation of endothelial nitric oxide (NO) synthase via the phosphoinositide 3-kinase/Akt signaling pathway and subsequently increased the production of NO. Inhibition of endothelial NO synthase expression and NO synthesis using small interfering RNA knockdown and chemical inhibitors substantially diminished the ability of SCF to increase the internalization of vascular endothelial-cadherin and in vitro endothelial permeability. SCF-induced increase in extravasation of the dyes was abrogated in endothelial NO synthase knockout mice, which indicates that endothelial NO synthase-mediated NO production was responsible for the SCF-induced vascular leakage. Furthermore, we demonstrated that the expression of SCF and cKit was significantly higher in the retina of streptozotocin-injected diabetic mice than in the nondiabetic control animals. Depletion of SCF by intravitreous injection of anti-SCF-neutralizing immunoglobulin G significantly prevented vascular hyperpermeability in the retinas of streptozotocin-injected diabetic mice. CONCLUSIONS: Our data reveal that SCF disrupts the endothelial adherens junction and enhances vascular leakage, as well as suggest that anti-SCF/cKit therapy may hold promise as a potential therapy for the treatment of hyperpermeable vascular diseases.

Defect-free, size-tunable graphene for high-performance lithium ion battery.

The scalable preparation of graphene in control of its structure would significantly improve its commercial viability. Despite intense research in this area, the size control of defect-free graphene (df-G) without any trace of oxidation or structural damage remains a key challenge. Here, we propose a new scalable route for generating df-G with a controllable size of submicron to micron through sequential insertion of potassium and pyridine at low temperature. Structural and chemical analyses confirm that the df-G perfectly preserves the intrinsic properties of graphene. The Co3O4 (<50 nm) wrapped by ∼ 10.5 µm(2) df-G has unprecedented capacity, rate capability, and cycling stability with capacities as high as 1050 mAh g(-1) at 500 mA g(-1) and 900 mAh g(-1) at 1000 mA g(-1) even after 200 cycles, which suggests enticing potential for the use in high performance lithium ion batteries.

Ultra-Mild Fabrication of Highly Concentrated SWCNT Dispersion Using Spontaneous Charging in Solvated Electron System.

The efficient dispersion of single-walled carbon nanotubes (SWCNTs) has been the subject of extensive research over the past decade. Despite these efforts, achieving individually dispersed SWCNTs at high concentrations remains challenging. In this study, we address the limitations associated with conventional methods, such as defect formation, excessive surfactant use, and the use of corrosive solvents. Our novel dispersion method utilizes the spontaneous charging of SWCNTs in a solvated electron system created by dissolving potassium in hexamethyl phosphoramide (HMPA). The resulting charged SWCNTs (c-SWCNTs) can be directly dispersed in the charging medium using only magnetic stirring, leading to defect-free c-SWCNT dispersions with high concentrations of up to 20 mg/mL. The successful dispersion of individual c-SWCNT strands is confirmed by their liquid-crystalline behavior. Importantly, the dispersion medium for c-SWCNTs exhibits no reactivity with metals, polymers, or other organic solvents. This versatility enables a wide range of applications, including electrically conductive free-standing films produced via conventional blade coating, wet-spun fibers, membrane electrodes, thermal composites, and core-shell hybrid microparticles.

Hierarchically Porous Carbon Networks Derived from Chitosan for High-Performance Electrochemical Double-Layer Capacitors.

Activated carbon (AC) compounds derived from biomass precursors have garnered significant attention as electrode materials in electric double-layer capacitors (EDLCs) due to their ready availability, cost-effectiveness, and potential for mass production. However, the accessibility of their active sites in electrochemistry has not been investigated in detail. In this study, we synthesized two novel macro/micro-porous carbon structures prepared from a chitosan precursor using an acid/potassium hydroxide activation process and then examined the relationship between their textural characteristics and capacitance as EDLCs. The material characterizations showed that the ACs, prepared through different activation processes, differed in porosity, with distinctive variations in particle shape. The sample activated at 800 °C (Act-chitosan) was characterized by plate-shaped particles, a specific surface area of 4128 m2/g, and a pore volume of 1.87 cm3/g. Assessment of the electrochemical characteristics of Act-chitosan showed its remarkable capacitance of 183.5 F/g at a scan rate of 5 mV/s, and it maintained exceptional cyclic stability even after 10,000 cycles. The improved electrochemical performance of both chitosan-derived carbon structures could thus be attributed to their large, well-developed active sites within pores < 2 nm, despite the fact that interconnected macro-porous particles can enhance ion accessibility on electrodes. Our findings provide a basis for the fabrication of biomass-based materials with promising applications in electrochemical energy storage systems.

Eco-Friendly Dispersant-Free Purification Method of Boron Nitride Nanotubes through Controlling Surface Tension and Steric Repulsion with Solvents.

Boron nitride nanotubes (BNNTs) were purified without the use of a dispersant by controlling the surface tension and steric repulsion of solvent molecules. This method effectively enhanced the difference in solubilities of impurities and BNNTs. The purification process involved optimizing the alkyl-chains of alcohol solvents and adjusting the concentration of alcohol solvent in water to regulate surface tension and steric repulsion. Among the solvents tested, a 70 wt% t-butylalcohol in water mixture exhibited the highest selective isolation of BNNTs from impurities based on differences in solubilities. This favorable outcome was attributed to the surface tension matching with BNNTs, steric repulsion from bulky alkyl chain structures, and differences in interfacial energy between BNNT-liquid and impurity-liquid interfaces. Through this optimized purification process, impurities were removed to an extent of up to 93.3%. Additionally, the purified BNNTs exhibited a distinct liquid crystal phase, which was not observed in the unpurified BNNTs.

Gatekeeping role of Nf2/Merlin in vascular tip EC induction through suppression of VEGFR2 internalization.

In sprouting angiogenesis, the precise mechanisms underlying how intracellular vascular endothelial growth factor receptor 2 (VEGFR2) signaling is higher in one endothelial cell (EC) compared with its neighbor and acquires the tip EC phenotype under a similar external cue are elusive. Here, we show that Merlin, encoded by the neurofibromatosis type 2 (NF2) gene, suppresses VEGFR2 internalization depending on VE-cadherin density and inhibits tip EC induction. Accordingly, endothelial Nf2 depletion promotes tip EC induction with excessive filopodia by enhancing VEGFR2 internalization in both the growing and matured vessels. Mechanistically, Merlin binds to the VEGFR2-VE-cadherin complex at cell-cell junctions and reduces VEGFR2 internalization-induced downstream signaling during tip EC induction. As a consequence, nonfunctional excessive sprouting occurs during tumor angiogenesis in EC-specific Nf2-deleted mice, leading to delayed tumor growth. Together, Nf2/Merlin is a crucial molecular gatekeeper for tip EC induction, capillary integrity, and proper tumor angiogenesis by suppressing VEGFR2 internalization.

Refractoriness of STING therapy is relieved by AKT inhibitor through effective vascular disruption in tumour.

Stimulator of interferon genes (STING) promotes anti-tumour immunity by linking innate and adaptive immunity, but it remains unclear how intratumoural treatment with STING agonists yields anti-tumour effects. Here we demonstrate that intratumoural injection of the STING agonist cGAMP induces strong, rapid, and selective apoptosis of tumour endothelial cells (ECs) in implanted LLC tumour, melanoma and breast tumour, but not in spontaneous breast cancer and melanoma. In both implanted and spontaneous tumours, cGAMP greatly increases TNFα from tumour-associated myeloid cells. However, compared to spontaneous tumour ECs, implanted tumour ECs are more vulnerable to TNFα-TNFR1 signalling-mediated apoptosis, which promotes effective anti-tumour activity. The spontaneous tumour's refractoriness to cGAMP is abolished by co-treatment with AKT 1/2 inhibitor (AKTi). Combined treatment with cGAMP and AKTi induces extensive tumour EC apoptosis, leading to extensive tumour apoptosis and marked growth suppression of the spontaneous tumour. These findings propose an advanced avenue for treating primary tumours that are refractory to single STING agonist therapy.

Boosting Photovoltaic Performance in Organic Solar Cells by Manipulating the Size of MoS2 Quantum Dots as a Hole-Transport Material.

The design of photoactive materials and interface engineering between organic/inorganic layers play a critical role in achieving enhanced performance in energy-harvesting devices. Two-dimensional transitional dichalcogenides (TMDs) with excellent optical and electronic properties are promising candidates in this regard. In this study, we demonstrate the fabrication of size-controlled MoS2 quantum dots (QDs) and present fundamental studies of their optical properties and their application as a hole-transport layer (HTL) in organic solar cells (OSCs). Optical and structural analyses reveal that the as-prepared MoS2 QDs show a fluorescence mechanism with respect to the quantum confinement effect and intrinsic/extrinsic states. Moreover, when incorporated into a photovoltaic device, the MoS2 QDs exhibit a significantly enhanced performance (5/10-nanometer QDs: 8.30%/7.80% for PTB7 and 10.40%/10.17% for PTB7-Th, respectively) compared to those of the reference device (7.24% for PTB7 and 9.49% for PTB7-Th). We confirm that the MoS2 QDs clearly offer enhanced transport characteristics ascribed to higher hole-mobility and smoother root mean square (Rq) as a hole-extraction material. This approach can enable significant advances and facilitate a new avenue for realizing high-performance optoelectronic devices.

Nasal ciliated cells are primary targets for SARS-CoV-2 replication in the early stage of COVID-19.

The upper respiratory tract is compromised in the early period of COVID-19, but SARS-CoV-2 tropism at the cellular level is not fully defined. Unlike recent single-cell RNA-Seq analyses indicating uniformly low mRNA expression of SARS-CoV-2 entry-related host molecules in all nasal epithelial cells, we show that the protein levels are relatively high and that their localizations are restricted to the apical side of multiciliated epithelial cells. In addition, we provide evidence in patients with COVID-19 that SARS-CoV-2 is massively detected and replicated within the multiciliated cells. We observed these findings during the early stage of COVID-19, when infected ciliated cells were rapidly replaced by differentiating precursor cells. Moreover, our analyses revealed that SARS-CoV-2 cellular tropism was restricted to the nasal ciliated versus oral squamous epithelium. These results imply that targeting ciliated cells of the nasal epithelium during the early stage of COVID-19 could be an ideal strategy to prevent SARS-CoV-2 propagation.

Highly Conductive and Fracture-Resistant Epoxy Composite Based on Non-oxidized Graphene Flake Aerogel.

Graphene aerogel (GA) has shown great promise as reinforcement of polymeric composites with exceptional electrical and mechanical characteristics. Although there has been significant progress in controlling the structure of GAs, no studies have appeared on the enhanced properties of GAs by employing high-quality precursor graphene flakes (GFs). However, the assembly of high-quality GFs is particularly challenging due to their highly hydrophobic and agglomerative nature in aqueous media, and of the few methods available to synthesize high-quality GFs, most produce flakes with very small lateral sizes. Herein, we report the fabrication of highly crystalline GAs using large nonoxidized graphene flakes (NOGFs) prepared by a novel graphite intercalation compound-based method. Bidirectional freeze casting is utilized for aligning NOGFs in two orthogonal directions, vertically and laterally, where the NOGF walls individually function as effective conductive pathways. The as-prepared nonoxidized graphene aerogel (NOGA) exhibits a defect concentration as low as 1.4% of impurity oxygen with an excellent electrical conductivity of 202.9 S/m at a low density of 5.7 mg/cm3. The corresponding NOGA-epoxy composite shows a remarkable electrical conductivity of 122.6 S/m and a fracture toughness of 1.74 MPa·m1/2 at a low filler content of 0.45 vol %.

Efficient Solid-State Photoluminescence of Graphene Quantum Dots Embedded in Boron Oxynitride for AC-Electroluminescent Device.

Emerging graphene quantum dots (GQDs) have received much attention for use as next-generation light-emitting diodes. However, in the solid-state, π-interaction-induced aggregation-caused photoluminescence (PL) quenching (ACQ) in GQDs makes it challenging to realize high-performance devices. Herein, GQDs incorporated with boron oxynitride (GQD@BNO) are prepared from a mixture of GQDs, boric acid, and urea in water via one-step microwave heating. Due to the effective dispersion in the BNO matrix, ACQ is significantly suppressed, resulting in high PL quantum yields (PL-QYs) of up to 36.4%, eightfold higher than that of pristine GQD in water. The PL-QY enhancement results from an increase in the spontaneous emission rate of GQDs due to the surrounding BNO matrix, which provides a high-refractive-index material and fluorescence energy transfer from the larger-gap BNO donor to the smaller-gap GQD acceptor. A high solid-state PL-QY makes the GQD@BNO an ideal active material for use in AC powder electroluminescent (ACPEL) devices, with the luminance of the first working GQD-based ACPEL device exceeding 283 cd m-2 . This successful demonstration shows promise for the use of GQDs in the field of low-cost, ecofriendly electroluminescent devices.

Low-Cost Black Phosphorus Nanofillers for Improved Thermoelectric Performance in PEDOT:PSS Composite Films.

In recent years, two-dimensional black phosphorus (BP) has seen a surge of research because of its unique optical, electronic, and chemical properties. BP has also received interest as a potential thermoelectric material because of its high Seebeck coefficient and excellent charge mobility, but further development is limited by the high cost and poor scalability of traditional BP synthesis techniques. In this work, high-quality BP is synthesized using a low-cost method and utilized in a PEDOT:PSS film to create the first ever BP composite thermoelectric material. The thermoelectric properties are found to be greatly enhanced after the BP addition, with the power factor of the film, with 2 wt % BP (36.2 µW m-1 K-2) representing a 109% improvement over the pure PEDOT:PSS film (17.3 µW m-1 K-2). A simultaneous increase of mobility and decrease of the carrier concentration is found to occur with the increasing BP wt %, which allows for both Seebeck coefficient and electrical conductivity to be increased. These results show the potential of this low-cost BP for use in energy devices.

The within-host population dynamics of normal flora in the presence of an invading pathogen and antibiotic treatments.

A mathematical competition model between normal flora and an invading pathogen was devised to allow analysis of bacterial infections in a host. The normal flora includes the various microorganisms that live on or within the host and act as a primary human immune system. Despite the important role of the normal flora, no mathematical study has been undertaken on models of the interaction between it and invading pathogens against a background of antibiotic treatment. To quantify key elements of bacterial behavior in a host, pairs of nonlinear differential equations were used to describe three categories of human health conditions, namely, healthy, latent infection, and active infection. In addition, a cutoff value was proposed to represent the minimum population level required for survival. The recovery of normal flora after antibiotic treatment was also included in the simulation because of its relation to human health recovery. The significance of each simulation parameter for the bacterial growth model was investigated. The devised simulation showed that bacterial proliferation rate, carrying capacity, initial population levels, and competition intensity have a significant effect on bacterial behavior. Consequently, a model was established to describe competition between normal flora and an infiltrating pathogen. Unlike other population models, the recovery process described by the devised model can describe the human health recovery mechanism.

Three-Dimensional Continuous Conductive Nanostructure for Highly Sensitive and Stretchable Strain Sensor.

The demand for wearable strain gauges that can detect dynamic human motions is growing in the area of healthcare technology. However, the realization of efficient sensing materials for effective detection of human motions in daily life is technically challenging due to the absence of the optimally designed electrode. Here, we propose a novel concept for overcoming the intrinsic limits of conventional strain sensors based on planar electrodes by developing highly periodic and three-dimensional (3D) bicontinuous nanoporous electrodes. We create a 3D bicontinuous nanoporous electrode by constructing conductive percolation networks along the surface of porous 3D nanostructured poly(dimethylsiloxane) with single-walled carbon nanotubes. The 3D structural platform allows fabrication of a strain sensor with robust properties such as a gauge factor of up to 134 at a tensile strain of 40%, a widened detection range of up to 160%, and a cyclic property of over 1000 cycles. Collectively, this study provides new design opportunities for a highly efficient sensing system that finely captures human motions, including phonations and joint movements.

Transcriptional regulation of endothelial cell behavior during sprouting angiogenesis.

Mediating the expansion of vascular beds in many physiological and pathological settings, angiogenesis requires dynamic changes in endothelial cell behavior. However, the molecular mechanisms governing endothelial cell activity during different phases of vascular growth, remodeling, maturation, and quiescence remain elusive. Here, we characterize dynamic gene expression changes during postnatal development and identify critical angiogenic factors in mouse retinal endothelial cells. Using actively translating transcriptome analysis and in silico computational analyses, we determine candidate regulators controlling endothelial cell behavior at different developmental stages. We further show that one of the identified candidates, the transcription factor MafB, controls endothelial sprouting in vitro and in vivo, and perform an integrative analysis of RNA-Seq and ChIP-Seq data to define putative direct MafB targets, which are activated or repressed by the transcriptional regulator. Together, our results identify novel cell-autonomous regulatory mechanisms controlling sprouting angiogenesis.Angiogenesis is a complex process that requires coordinated changes in endothelial cell behavior. Here the authors use Ribo-tag and RNA-Seq to determine temporal profiles of transcriptional activity during postnatal retinal angiogenesis, identifying transcriptional regulators of the process.