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SIRT6 belongs to the conserved NAD+-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD+. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC50 of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

Zinc is generally considered to be one of the most promising materials to be used in biodegradable implants, and many zinc alloys have been optimized to improve implant biocompatibility, degradation, and mechanical properties. However, long-term degradation leads to the prolonged presence of degradation products, which risks foreign body reactions. Herein, we investigated the in vivo biocompatibility and degradation of a biodegradable Zn–Mg–Fe alloy osteosynthesis system in the frontal bone, mandible, and femur in beagles for 1 year. Results of the routine blood, biochemical, trace element, and histological analyses of multiple organs, peripheral blood CD4/CD8a levels, and serum interleukin 2 and 4 levels showed good biocompatibility of the Zn–Mg–Fe alloy. Zinc content analysis revealed zinc accumulation in adjacent bone tissue, but not in the liver, kidney, and spleen, which was related to the degradation of the Zn–Mg–Fe alloy. The alloy demonstrated a uniform slowing degradation rate in vivo. No degradation differences in the frontal bone, mandible, and femur were observed. The degradation products included zinc oxide [ZnO], zinc hydroxide [Zn(OH)2], hydrozincite [Zn5(OH)6(CO3)2], and hopeite [Zn3(PO4)2·4H2O]. The good biocompatibility and degradation properties of the Zn–Mg–Fe alloy render it a very attractive osteosynthesis system for clinical applications., Graphical abstract Image 1, Highlights • Zn–Mg–Fe alloy possesses good biocompatibility. • Zn–Mg–Fe alloy demonstrates a uniform slowing-down degradation rate in vivo. • No degradation differences are observed in different sites, which supports the design of degradable osteosynthesis systems. • The degradation products are zinc oxide, zinc hydroxide, hydrozincite, and hopeite. • Zn–Mg–Fe alloy is a promising candidate for an osteosynthesis system.

YycFG, one of the two-component systems involved in the regulation of biofilm formation, has attracted increasing interest as a potential target of antibacterial and antibiofilm agents. YycG inhibitors for Staphylococcus aureus and Staphylococcus epidermidis have been developed, but Enterococcus faecalis remains underexplored. Herein, we selected and identified novel candidate molecules against E. faecalis targeting histidine kinase YycG using high-throughput virtual screening; six molecules (compound-16, -30, -42, -46, -59, and -62) with low cytotoxicity toward mammalian cells were verified as potential YycG inhibitors through an autophosphorylation test and binding kinetics. Compound-16 inhibited planktonic cells of E. faecalis, including the vancomycin- or linezolid-resistant strains. In contrast, compound-62 did not affect planktonic growth but significantly inhibited biofilm formation in static and dynamic conditions. Compound-62 combined with ampicillin could synergistically eradicate the biofilm-embedded viable bacteria. The study demonstrates that YycG inhibitors may be valuable approaches for the development of novel antimicrobial agents for difficult-to-treat bacterial infections.

Cytosolic DNA from pathogens activates the DNA sensor cyclic GMP–AMP (cGAMP) synthase (cGAS) that produces the second messenger, cGAMP. cGAMP triggers a signal cascade leading to type I IFN expression. Host DNA is normally restricted in the cellular compartments of the nucleus and mitochondria. Recent studies have shown that DNA virus infection triggers mitochondrial stress, leading to the release of mitochondrial DNA to the cytosol and activation of cGAS; however, the regulatory mechanism of mitochondrial DNA-mediated cGAS activation is not well elucidated. In this study, we analyzed cGAS protein interactome in mouse RAW264.7 macrophages and found that cGAS interacted with C1QBP. C1QBP predominantly localized in the mitochondria and leaked into the cytosol during DNA virus infection. The leaked C1QBP bound the NTase domain of cGAS and inhibited cGAS enzymatic activity in cells and in vitro. Overexpression of the cytosolic form of C1QBP inhibited cytosolic DNA-elicited innate immune responses and promoted HSV-1 infection. By contrast, deficiency of C1QBP led to the elevated innate immune responses and impaired HSV-1 infection. Taken together, our study suggests that C1QBP is a novel cGAS inhibitor hidden in the mitochondria.

Retinoblastoma (RB) is the most common intraocular tumor among children. Leucine-rich pentatricopeptide repeat (PPR)-motif-containing protein (LRPPRC), a suppressor gene of autophagy, has been proven to play a regulatory role in tumor progression. However, little is known about functional roles and mechanisms of LRPPRC in RB progression. First, we performed a detailed analysis for RB and normal control. The expression of LRPPRC in the RB tissues was significantly higher than that in normal tissues. Moreover, LRPPRC suppression could repress tumor cell migration, invasion, glycolysis, and reactive oxygen species (ROS)/hypoxia-inducible factor-1α (HIF1-α) pathway activation by mediating autophagy. Furthermore, overexpression of HIF1-α partially reversed the above changes induced by LRPPRC knockdown. The regulation of LRPPRC on tumor metastasis and glycolysis was also validated by a xenograft tumor assay. In summary, LRPPRC could regulate metastasis and glycolysis of RB by mediating autophagy suppression and further activating the ROS/HIF1-α pathway, and LRPPRC could be a promising prognostic biomarker for RB., Graphical abstract, In this study, LRPPRC may regulate metastasis and glycolysis of retinoblastoma by mediating autophagy inhibition and further promoting ROS/HIF1-α pathway activation, which is beneficial for better understanding of retinoblastoma pathogenesis, and might provide a novel idea about the therapeutic strategies of retinoblastoma.

Thiazolidinediones (TZDs), such as rosiglitazone (RSG), which activates peroxisome proliferator activated receptor-γ (PPARγ), are a potent class of oral antidiabetic agents with good durability. However, the clinical use of TZDs is challenging because of their side effects, including weight gain and hepatotoxicity. Here, we found that bavachinin (BVC), a lead natural product, additively activates PPARγ with low-dose RSG to preserve the maximum antidiabetic effects while reducing weight gain and hepatotoxicity in db/db mice caused by RSG monotherapy. Structural and biochemical assays demonstrated that an unexplored hotspot around Met329 and Ser332 in helix 5 is triggered by BVC cobinding to RSG-bound PPARγ, thereby allosterically stabilizing the active state of the activation-function 2 motif responsible for additive activation with RSG. Based on this hotspot, we discovered a series of new classes of allosteric agonists inducing the activity of TZDs in the same manner as BVC. Together, our data illustrate that the hotspot of PPARγ is druggable for the discovery of new allosteric synergists, and the combination therapy of allosteric synergists and TZD drugs may provide a potential alternative approach to the treatment of type 2 diabetes mellitus.

FV520B stainless steel is an important material for compression turbine impellers. Its corrosion resistance at high temperatures is critical for the manufacturing and service reliability management...

Fish contain many important nutrients and are primarily known for high n-3 polyunsaturated fatty acids (n-3 PUFA) content. Studies have shown that supplementation of fish oil-derived n-3 PUFA improves muscle mass and strength. Here, we hypothesized that fish consumption might improve muscle strength. To test this hypothesis, we performed this cross-sectional study (n = 29,084) in Tianjin, China. The frequency of fish consumption was assessed using a valid self-administered food frequency questionnaire. Handgrip strength (HGS) was used as the indicator of muscle strength, and was measured using a handheld digital dynamometer. Analysis of covariance was used to examine the relationship between fish consumption and HGS. In men, after adjusted potential confounding factors, the least square means (95% confidence intervals) of HGS across saltwater fish consumption categories were 41.5 (41.1, 43.7) kg for1 time/week, 44.6 (43.2, 45.8) kg for 1 time/week, and 44.7 (43.3, 46.1) kg for ≥2 to 3 times/week (P for trend0.001). In men, the least square means (95% confidence intervals) of HGS across the ascending quartiles of dietary n-3 PUFA intake were 43.6 (43.2, 44.4) kg, 43.7 (43.2, 44.6) kg, 44.4 (43.0, 45.8) kg, and 44.6 (43.1, 46.0) kg (P for trend0.01). The results showed that saltwater fish consumption was positively related to HGS in men, but not in women, suggesting that saltwater fish contain nutrients that may be used to improve HGS.

Serotonin (5-HT) is a phylogenetically conserved monoamine neurotransmitter modulating important processes in the brain. To directly visualize the release of 5-HT, we developed a genetically encoded G-protein-coupled receptor (GPCR)-activation-based 5-HT (GRAB5-HT) sensor with high sensitivity, high selectivity, subsecond kinetics and subcellular resolution. GRAB5-HT detects 5-HT release in multiple physiological and pathological conditions in both flies and mice and provides new insights into the dynamics and mechanisms of 5-HT signaling.

Seaweeds have numerous biologically active ingredients, such as polysaccharides, polyphenols and carotenoids, that are beneficial to human health. Although these benefits might be related to the synthesis, secretion or reabsorption of uric acid, no studies have explored the relationship between seaweeds consumption and hyperuricaemia (HUA) in the general population. The aim of this study was to investigate whether seaweeds consumption is related to HUA in a large-scale adult population. A cross-sectional study was conducted with 32 365 adults (17 328 men and 15 037 women) in Tianjin, People’s Republic of China. Frequency of seaweeds consumption was assessed by a validated self-administered FFQ. HUA was defined as serum uric acid levels >420 μmol/L in men and >350 μmol/L in women. The association between seaweeds consumption and HUA was assessed by multiple logistic regression analysis. Restricted cubic spline functions were used for non-linearity tests. The prevalence of HUA in men and women was 21·17 % and 5·93 %, respectively. After adjustments for potential confounding factors, the OR (95 % CI) for HUA across seaweed consumption (g/1000 kcal per d) were 1·00 (reference) for level 1, 0·91 (95 % CI 0·81, 1·02) for level 2; 0·90 (95 % CI 0·81, 1·01) for level 3; 0·86 (95 % CI 0·78, 0·97) for level 4 in men and 0·90 (95 % CI 0·73, 1·10) for level 2; 0·82 (95 % CI 0·67, 1·00) for level 3; 0·84 (95 % CI 0·68, 1·03) for level 4 in women, respectively. A negative correlation between seaweeds consumption and HUA in males but not in females was observed. Further studies are needed to explore the causal relationship.

Background: Sarcopenia is an aging-related loss of muscle mass and function, which induces numerous adverse outcomes. Capsaicin and capsiate, separately extracted from chilies and sweet peppers, have the potential to induce muscle hypertrophy via activation of transient receptor potential vanilloid 1. The present study aimed to investigate whether chili and sweet pepper consumption are related to sarcopenia in the elderly general population. Methods: A cross-sectional study with 2,451 participants was performed. Dietary chili and sweet pepper consumption were assessed using a validated self-administered food frequency questionnaire. Sarcopenia was defined according to the consensus of the Asian Working Group for Sarcopenia. Logistic regressions were performed to measure the effect of chili and sweet pepper consumption on sarcopenia. Results: The prevalence of sarcopenia was 16.1%. After adjustment for potential confounding variables, the odds ratios (95% confidence intervals) for sarcopenia across chili and sweet pepper consumption categories were 1.00 (reference) for almost never, 0.73 (0.55, 0.97) and 0.73 (0.56, 0.96) for ≤1 time/week, 0.60 (0.39, 0.90) and 0.66 (0.45, 0.95) for ≥2-3 times/week (both P for trend

Fe3O4 nanoparticles/iodized oil magnetic fluids (FIOMFs) have showed potential in targeted hyperthermia for liver tumors; in this paper, FIOMFs were simply and conveniently prepared by dispersing the synthesized hydrophobic Fe3O4 nanoparticles (FNPs) in iodized oil; the stability, magnetothermal effects, and the biotoxicity of FIOMFs were evaluated. The results showed that the stability of FIOMFs was mainly influenced by the morphology and the size of FNPs. FNPs prepared with FeCl3·6H2O, oleylamine (OAm), ethylene glycol (EG), and stearic acid exhibited the best suspension stability, which could suspend in iodized oil stably for a long time. Depending on the FNP content and the parameters of the alternating magnetic field (AMF), the temperature of FIOMF in AMF can reach up to more than 70 °C within 60 s, exhibited excellent magnetothermal effects. The in vitro cytotoxicity tests indicated the cytotoxicity of FNPs is mainly influenced by its concentration in cells.

Electrochemical tests were developed to investigate the electrochemical dissolution behavior of gold and its main coexistent sulfide minerals in acid thiocyanate solutions. The optimal leaching conditions for gold in acidic thiocyanate system were pH 2, 0.15 mol·L−1 thiocyanate and 0.2 g·L−1 Fe3+. Fe3+ addition to the acidic thiocyanate system promoted gold dissolution significantly, arsenopyrite dissolution was inhibited, chalcopyrite dissolution was increased, and the dissolution behavior of other associated minerals remained mostly unchanged. Thiocyanate made gold and associated mineral leaching easier. The galvanic corrosion effect of gold and its main coexistent sulfide minerals in an acidic thiocyanate-free system was that the chalcocite, arsenopyrite and pyrite acted as a cathode to reduce anodic gold dissolution; galena as an anode undergoes oxidation to inhibit anodic gold dissolution. There was almost no galvanic corrosion behavior between stibnite, yellow sphalerite and black sphalerite and gold. Thiocyanate addition changed the galvanic corrosion behavior of stibnite and yellow sphalerite in the thiocyanate system, which inhibited anodic gold dissolution. In the acidic thiocyanate system in the presence of ferric iron, the arsenopyrite promoted anodic gold dissolution, the chalcocite and gold were mostly free of galvanic corrosion, and the remaining minerals inhibited anodic gold dissolution.

Hydrogen generation via water electroreduction is pivotal for exploiting clean-energy skills. Nevertheless, developing a low price and high-performance catalytic activity substance to take the place of expensive precious metal currently in use is still a precedent condition for technology commercialization. In this study, large-scale hierarchical few-layer MoSe2 nanosheets were successfully grown on the surface of sodium sulfide crystals. The water solubility of sodium sulfide makes it advantageous to generate MoSe2 nanolayers via a simple and inexpensive means. The micron-level sodium sulfide crystal surface has a very critical function in the nucleus formation and development of few-layer MoSe2. The ultrathin hierarchical MoSe2 nanolayers obtained using the proposed approach have preferable hydrogen evolution reaction. Furthermore, it is a fascinating technique that the template can be reused without environmental pollution. This research can be used to manufacture other ultrathin hierarchical transition-metal dichalcogenide nanolayers for high-performance many-sided applications.

A Mn–Ce co-doped TNU-9 (Mn–Ce/TNU-9) catalyst was synthesized via a simple ion exchange method and then its catalytic activity, water resistance and sulfur resistance were studied in the selective catalytic reduction of NOx with NH3 as the reducing agent (NH3-SCR). The results show that the NOx conversion of Mn–Ce/TNU-9 is higher than those of Mn/TNU-9 and Ce/TNU-9 at a wide temperature window (150–450 °C), corresponding to >94.0% conversion of NOx and >99% selectivity of N2. The redox cycle of Mn4+ + Ce3+ ↔ Mn3+ + Ce4+ improves the redox performance for the Mn–Ce/TNU-9 catalyst and facilitates electron transfer, which further accelerates the oxidation of NO to NO2 that could lead to the “Fast SCR” reaction, therefore increasing the SCR performance. Furthermore, the synergistic effect between TNU-9 and bimetals can also enhance the activity. In addition, the Mn–Ce/TNU-9 catalyst demonstrates excellent sulfur and water resistance due to the hydrophobicity of TNU-9 and the easy sulfation of Ce protected from the active site Mn. Moreover, Mn–Ce/TNU-9 has a very good catalytic stability. These results prove that the bimetallic catalyst prepared by TNU-9 as the carrier will have a broad application prospect in the field of environmental catalysis.

The design and preparation of a reduced graphene oxide (rGO) paper electrode with a reinforced concrete structure is an effective strategy to improve the mechanical properties of flexible electrodes. Therefore, PEDOT:PSS is added as a binder, toughening and conductive agent. CNTs, with good mechanical properties, are added to enhance the strength. Fe2O3 nanoparticles are added to increase the energy storage. According to these assumptions, we successfully prepared a flexible hydrophilic paper electrode with rGO nanosheets, PEDOT:PSS, CNTs and Fe2O3 nanoparticles by a constant temperature vacuum drying method. In addition, the assembled symmetrical supercapacitor exhibits a high capacitance of 1924 mF cm−3 at 1 mA cm−3, an excellent energy density of 35.6 W h kg−1 (at 166 W kg−1) and a remarkable cycle stability of 98.2% retention over 10 000 cycles at 1 mA cm−2.

We report here a fragment screen directed toward the c-MET kinase from which we discovered a series of inhibitors able to bind to a rare conformation of the protein in which the P-loop adopts a collapsed, or folded, arrangement. Preliminary SAR exploration led to an inhibitor (7) with nanomolar biochemical activity against c-MET and promising cell activity and kinase selectivity. These findings increase our structural understanding of the folded P-loop conformation of c-MET and provide a sound structural and chemical basis for further investigation of this underexplored yet potentially therapeutically exploitable conformational state.

In this work, the optimal sintering temperature and time of commercial copper paste were tested experimentally. The electrical properties of conductive paste including square resistance and resistivity were characterized and analyzed. The influence of diatomite with different purification processes on the electrical properties of commercial copper paste was analyzed. The performance of copper slurry modified by copper-based modified diatomite prepared by two-step reduction method was analyzed. The optimum square resistance and resistivity was obtained with copper paste doped by 0.25wt.% and 1 h-ball milled diatomite and was 0.02Ω/ϒ and 0.011Ω·mm, respectively.

In this paper, we propose a novel mechanism for the $\text{V}_{{\text {th}}}$ shift of amorphous-indium gallium zinc oxide (a-IGZO) thin film transistors under negative bias illumination stress (NBIS). Three kinds of IGZO TFTs with different gate dielectrics and valence band offsets (VBO) were used in this experiment. Gate dielectric materials used were Al2O3, HfO2 and SiO2. Initial parameters, VBO, and state density (DOS) for each TFT were extracted. After NBIS, the $\text{V}_{\text {th}}$ shift was greatest at −3.82 V using a TFT with an HfO2 gate dielectric. VBO was the lowest at 0.38 eV using a TFT with an HfO2 gate dielectric. The smaller the VBO, the larger the generated $\text{V}_{\text {th}}$ shift. DOS measurements confirmed the interfacial properties between the gate dielectric and IGZO, and the highest DOS resulted from the interface between Al2O3 and IGZO. Through the experimental results, the correlation between VBO and $\Delta \text{V}_{{\text {th}}}$ after NBIS was investigated. We found that the main cause of $\text{V}_{{\text {th}}}$ shift in NBIS is injection of photoinduced hole carriers that cross the VBO by tunneling from IGZO channel to gate oxide.

Indoor formaldehyde from substandard furniture and decorative materials seriously endangers human health. How to remove effectively indoor formaldehyde with low concentration at room temperature is...

Colorectal cancer (CRC) is the leading cause of cancer death; however, targets with broad anti-CRC effects are limited. Sirtuin6 (SIRT6) is a conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that is widely pathologically downregulated in CRC, but its pharmacological effect in CRC remains undefined due to the lack of small-molecule SIRT6 activators. We searched for a compound activating SIRT6 and investigated its anti-CRC effect in various models. Methods: We identified an allosteric SIRT6 activator, MDL-811. Its ability to enhance SIRT6 deacetylation at protein and cellular levels was evaluated by Fluor de Lys (FDL) and western blots. We assessed the proliferation of 26 CRC cell lines and patient-derived organoids (PDOs) treated with MDL-811. In vivo efficacy of MDL-811 was evaluated in HCT116 cell line- and patient-derived xenografts as well as a spontaneous CRC model. RNA sequencing and real-time quantitative PCR assays were performed to analyze gene expression changes in MDL-811-treated HCT116 cells. Along with controls in SIRT6-overexpressing HCT116 cells, the SIRT6-mediated histone H3 deacetylation at the Cytochrome P450 family 24 subfamily A member 1 (CYP24A1) gene locus was assessed by chromatin immunoprecipitation (ChIP) in MDL-811-treated HCT116 cells. A combination therapy against CRC based on the downstream gene of SIRT6 activation was evaluated in cells and mouse models. Results: MDL-811 significantly activated SIRT6 histone H3 deacetylation (H3K9Ac, H3K18Ac, and H3K56Ac) in vitro and had broad antiproliferative effects on diverse CRC cell lines and PDOs. More importantly, the in vivo anti-tumor efficacy of MDL-811 was demonstrated across cell line- and patient-derived xenografts and in the APCmin/+ spontaneous CRC model. Mechanically, we identified a new downstream target gene of SIRT6 in CRC, CYP24A1. Based on these findings, a combination drug strategy with MDL-811 to synergistically enhance the anti-CRC effect of vitamin D3 was validated in vitro and in vivo. Conclusions: Our data provide proof of concept that targeting SIRT6 using a small-molecule activator is an attractive therapeutic strategy for CRC and that MDL-811 could be a promising lead compound for further preclinical and clinical studies of treatments for CRC.

A novel bio-based benzoxazine (Ca-g) surfactant was synthesized via a Mannich reaction using renewable glycine and cardanol as raw materials. The structure of Ca-g was characterized by NMR, FT-IR, and elemental analysis. Styrene containing emulsions and polystyrene (PS) latex were prepared based on the Ca-g surfactant. These results showed that the Ca-g surfactant exhibited high efficiency for stabilizing styrene emulsions. An addition of only 1.7 (w/v)% stabilized the high internal phase emulsion (HIPE) with a styrene volume fraction up to 90%. More interestingly, HIPE exhibited pH-sensitivity and could be formed at pH values from 9.0 to 12.0. Furthermore, PS particles were obtained via HIPE polymerization. In addition, the in vitro cytotoxicity of Ca-g and its triglyceride emulsion was also investigated. Ca-g showed lower cytotoxicity against the HeLa cell line. A stable triglyceride-in-water emulsion stabilized by Ca-g was prepared. The bio-based Ca-g surfactant may have potential use in cosmetics and daily cleaning products.

Background PARP inhibitors have been the most promising target drugs with widely proven benefits among ovarian cancer patients. Although platinum-response, HR-related genes, or HRD genomic scar detection are acceptably used in assessment of Olaparib response, there are still evident limitations in the present approaches. Therefore, we aim to investigate more accurate approaches to predict Olaparib sensitivity and effective synergistic treatment strategies. Methods We probed two databases (TCGA and Qilu Hospital) in order to quest novel miRNAs associated with platinum-sensitivity or HR-related genes. Cellular experiments in vitro or in vivo and PDX models were utilized to validate their role in tumor suppression and Olaparib sensitizing. Furthermore, HR gene mutation was analyzed through WES to explore the relation between HR gene mutation and Olaparib response. Results High miR-509-3 expression indicated better response to platinum and longer progression-free and overall survival in two independent ovarian cancer patient cohorts (high vs. low miR-509-3 expression; PFS: TCGA P P P P P P P Conclusions MiR-509-3 can sensitize ovarian cancer cells to Olaparib by impeding HR, which makes it a potential target in PARPi synergistic treatment. HR core gene analysis and RAD51 functional detection are prospectively feasible in prediction of PARPi response.

Broadband topological metamaterials hold the key for designing the next generation of integrated photonic platforms and microwave devices given their protected back-scattering-free and unidirectional edge states, among other exotic properties. However, synthesizing such metamaterial has proven challenging. Here, a broadband bandgap (relative bandwidth of more than 43%) Valley-Hall topological metamaterial with deep subwavelength thickness is proposed. The present topological metamaterial is composed of three layers printed circuit boards whose total thickness is 1.524 mm ≈ λ/100. The topological phase transition is achieved by introducing an asymmetry parameter δr. Three mechanically reconfigurable edge states can be obtained by varying interlayer displacement. Their robust transmission is demonstrated through two kinds of waveguide domain walls with cavities and disorders. Exploiting the proposed topological metamaterial, a six-way power divider is constructed and measured as a proof-of-concept of the potential of the proposed technology for future electromagnetic devices.&nbsp

The DNA sensor cGAS detects cytosolic foreign DNA from pathogens or self-DNA from cellular damage and instigates type I interferon (IFN) expression. Recent studies find that cGAS also localizes in the nucleus and tethers to the chromatin. Despite how cGAS is inhibited in the nucleus is well elucidated, whether nuclear cGAS participates in DNA sensing is not clear. Here, we report that herpes simplex virus 1 (HSV-1) infection causes the release of cGAS from the chromatin into the nuclear soluble fraction, and the free nuclear cGAS senses viral DNA to induce innate immune response. We first found that the infection of several HSV-1 strains led to cGAS release from the chromatin in several types of cells, including in RAW264.7 macrophages, THP-1 monocytes, and bone marrow-derived macrophages. DNA damage agent cisplatin failed to induce nuclear soluble cGAS, suggesting that cGAS release from the chromatin is not due to DNA damage or apoptosis. Interestingly, inhibition of HSV-1 replication blocked the release of nuclear soluble cGAS. To determine the role of nuclear cGAS in DNA virus infection, we reconstituted a Dox-induced nuclear-only cGAS mutant into cGAS knockout RAW264.7 cells. After induction, only chromatin-bound cGAS was found in the reconstituted cells. Similarly, HSV-1 infected also induced nuclear soluble cGAS in this cell line. More importantly, the nuclear-only cGAS stable cells limited HSV-1 infection by producing cGAMP and inducing mRNA expression of type I IFN and interferon-stimulated genes. Taken all together, our study demonstrates that nuclear soluble cGAS is a DNA sensor inside the nucleus. This research was funded by the National Institutes of Health (R21AI137750 and R01AI141399 to S.L.).

Purpose: To develop and evaluate paclitaxel (PTX) loaded pegylated gelatin targeted nanoparticles for improved efficacy in non-small cell lung cancer (NSCLC) treatment. Method: PTX loaded gelatin nanoparticles (PTX-GNP) were prepared by crosslinking with glutaraldehyde aqueous solution. These nanoparticles (NPs) were further incubated with PEG 400 to form PEGylated NPs (PEG-PTX-GNP). The NPs were evaluated for surface morphology, size, zeta potential, encapsulation efficiency, drug loading, in vitro drug release, cytotoxicity in an assay on cancer cell lines L132, in vitro cellular uptake in an assay in L132 and 293T cell lines, in vivo antitumor activity on female Balb/c mice, pulmonary deposition, histopathology, and immunohistochemical properties. Results: The nanoparticles were of spherical shape with smooth surface characteristics. The observed DL was of 20.18 to 32.11%, as particle size was of 90 to 115 nm. Zeta potential and polydispersity index (PDI) were within acceptable ranges. Encapsulation was effective when the NPs had a size of 80.50 nm to 98.12 nm. The PEGylated PTX loaded nanoparticles (PEG-PTX-GNP, GNP4) showed similar PTX release profile to that of the NP4 formulation. PEGylated NPs showed the desired PTX release pattern that is required for cancer treatment. In an in vitro cytotoxicity study, PEG-PTX-GNP showed the maximum antiproliferative activity over the period of 24 hours, followed by PTX-GNP, pure PTX and BPEG-GNP. PEG-PTX-GNP showed the highest internalization within both cell lines, followed by PTX-GNP and pure PTX. The survival rate of animals in PEG-PTX-GNP group was 100%, proving the safety and efficacy of the treatment. PEG-PTX-GNP showed the highest antitumor activity as compared to other formulations. The pulmonary deposition rate was the highest (6.5 to 12.55 μg/g) in PEG-PTX-GNP formulations. Histopathology and immunohistochemical study proved that PEG-PTX-GNP had greater anticancer potential than other tested formulations. Conclusion: This study confirms the potential use of paclitaxel loaded PEGylated gelatin targeted nanoparticles for improved efficacy in non-small cell lung cancer (NSCLC) treatment.

Retinoic acid-inducible gene I (RIG-I) senses viral RNA and instigates an innate immune signaling cascade to induce type I interferon expression. Currently, the regulatory mechanisms controlling RIG-I activation remain to be fully elucidated. Here we show that the FAK family kinase-interacting protein of 200 kDa (FIP200) facilitates RIG-I activation. FIP200 deficiency impaired RIG-I signaling and increased host susceptibility to RNA virus infection. In vivo studies further demonstrated FIP200 knockout mice were more susceptible to RNA virus infection due to the reduced innate immune response. Mechanistic studies revealed that FIP200 competed with the helicase domain of RIG-I for interaction with the two tandem caspase activation and recruitment domains (2CARD), thereby facilitating the release of 2CARD from the suppression status. Furthermore, FIP200 formed a dimer and facilitated 2CARD oligomerization, thereby promoting RIG-I activation. Taken together, our study defines FIP200 as an innate immune signaling molecule that positively regulates RIG-I activation., Lingyan Wang et al. report that the autophagy-associated protein FIP200 interacts with the RNA sensor RIG-I to trigger activation of the type I interferon pathway.

Objective: To study subclinical thyroid dysfunction (SCTD)—subclinical hyperthyroidism and subclinical hypothyroidism—in Chinese patients in relation to body mass index (BMI) and to determine whether a difference between sexes exists. Methods: This cross-sectional study recruited 13,503 healthy participants (8,345 male, 5,158 female) who participated in a health examination. Clinical data, including anthropometric measurements and serum parameters, were collected. The association between SCTD and the BMI of each sex was analyzed separately by stratifying the data by SCTD type and regarding BMI as a categorical or as a continuous variable in different models. The odds ratio of SCTD was calculated from binary logistic regression models. Results: The prevalence of both subclinical hyperthyroidism and subclinical hypothyroidism was significantly lower in males compared to females. For subclinical hypothyroidism, we found no significant association with BMI in females. In males, there was a significant negative relationship between BMI and subclinical hypothyroidism. For subclinical hyperthyroidism, we did not find any significant relationship with BMI in either sex after stratifying the data and treating BMI as a categorical or as a continuous variable. Conclusion: For subclinical hyperthyroidism, no significant effect was found in either sex. For subclinical hypothyroidism, high BMI was associated with lower rates of subclinical hypothyroidism in males, and no significant correlation was found in females. The mechanism of this sex-specific association between BMI and SCTD needs more verification. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; BUN = blood urea nitrogen; CI = confidence interval; Cr = creatinine; DBP = diastolic blood pressure; FG = fasting glucose; FT3 = free triiodothyronine; FT4 = free thyroxine; HDL = high-density lipoprotein; LDL = low-density lipoprotein; OR = odds ratio; SBP = systolic blood pressure; SCTD = subclinical thyroid dysfunction; TBIL = total bilirubin; TC = total cholesterol; TG = triglyceride; TSH = thyroid-stimulating hormone; UA = uric acid; WBC = white blood cell; WC = waist circumference

Hepatic stellate cell (HSC) line LX-2 is activated by liver cancer stem-like cells (LCSLCs) and produces various cytokines that make up most of the hepatocellular carcinoma (HCC) microenvironment. The new genistein derivative, 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), shows anticancer effects in multiple malignancies by controlling forkhead box M1 (FOXM1). In this study, we aimed to assess whether DFOG disrupts the crosstalk between human HSC LX-2 cells and LCSLCs. Distinct generations of MHCC97H-derived spheres were obtained with the second generation considered as LCSLCs which displayed enhanced self-renewal ability and elevated expression levels of CD133, CD44, and EpCAM proteins, as well as tumorigenicity, as revealed by colony formation assay in vitro and tumorigenicity assay in vivo. LX-2 and MHCC97H cells were co-cultured with/without DFOG (1, 5, and 10 μM, respectively) using the transwell system. FOXM1 overexpression and/or knockdown were employed for mechanistic investigations. Our results suggested that Co-CM promoted LX-2 cell transformation into liver cancer-associated HSCs. Meanwhile, FOXM1 was up-regulated and the level of hepatocyte growth factor (HGF) was increased in LX-2 cells and in the supernatant after Co-CM stimulation. Sphere and colony formation abilities in MHCC97H cells, and protein levels of CD133, CD44, and EpCAM, were also markedly elevated. DFOG dose-dependently inhibited the above effects, similar to FOXM1 knockdown in LX-2 cells. FOXM1 overexpression reversed the inhibitory effects of DFOG or FOXM1 knockdown or both on LX-2 cell activation and LCSLC feature induction in MHCC97H cells by LCSLC/LX-2 co-culture. This study demonstrated that DFOG disrupts the crosstalk between HSCs and LCSLCs to suppress LCSLC features via down-regulating FOXM1 expression and reducing HGF secretion in HSCs.

NF-κB signaling regulates diverse processes such as cell death, inflammation, immunity, and cancer. The activity of NF-κB is controlled by methionine 1-linked linear polyubiquitin, which is assembled by the linear ubiquitin chain assembly complex (LUBAC) and the ubiquitin-conjugating enzyme UBE2L3. Recent studies found that the deubiquitinase OTULIN breaks the linear ubiquitin chain, thus inhibiting NF-κB signaling. Despite the essential role of OTULIN in NF-κB signaling has been established, the regulatory mechanism for OTULIN is not well elucidated. To discover the potential regulators of OTULIN, we analyzed the OTULIN protein complex by proteomics and revealed several OTULIN-binding proteins, including LUBAC and tripartite motif-containing protein 32 (TRIM32). TRIM32 is known to activate NF-κB signaling, but the mechanism is not clear. Genetic complement experiments found that TRIM32 is upstream of OTULIN and TRIM32-mediated NF-κB activation is dependent on OTULIN. Mutagenesis of the E3 ligase domain showed that the E3 ligase activity is essential for TRIM32-mediated NF-κB activation. Further experiments found that TRIM32 conjugates polyubiquitin onto OTULIN and the polyubiquitin blocks the interaction between HOIP and OTULIN, thereby activating NF-κB signaling. Taken together, we report a novel regulatory mechanism by which TRIM32-mediated non-proteolytic ubiquitination of OTULIN impedes the access of OTULIN to the LUBAC and promotes NF-κB activation.

Hybrid supercapacitors using metal–organic frameworks (MOFs) exhibit high power and remarkable rate capability with consistent cyclability. The key limitations in developing MOF supercapacitors are the limited number of ligands and extensive laboratory protocols for synthesis. To solve these problems, we introduce the liquid–liquid interfacial reaction method for synthesising layered MOF using p-phenylenediamine (pPDA) building block as an organic ligand. The method is straightforward, consumes less energy and can be deployed in a small space at room temperature. We synthesise two types of layered MOFs, Ni-pPDA and Mn-pPDA, and fabricate hybrid supercapacitors by combining the positive MOF electrodes with a negative graphite carbon (GC) electrode. The supercapacitors using Ni-pPDA//GC and Mn-pPDA//GC exhibit high performances of approximately 184.7 F/g and 109.3 F/g, respectively. In particular, the Ni-pPDA supercapacitor exhibits high energy and power densities. The supercapacitors using Ni-pPDA and Mn-pPDA MOFs exhibit the capacitive retention of about 80% and 97%, respectively, after 5000 cycles.

Classical swine fever virus (CSFV), the etiological agent of classical swine fever in pigs, is a member of the Pestivirus genus within the Flaviviridae family. It has been proposed that CSFV infection is significantly inhibited by methyl-β-cyclodextrin (MβCD) treatment. However, the exact engagement of cellular cholesterol in the life cycle of CSFV remains unclear. Here, we demonstrated that pretreatment of PK-15 cells with MβCD significantly decreased the cellular cholesterol level and resulted in the inhibition of CSFV infection, while replenishment of exogenous cholesterol in MβCD-treated cells recovered the cellular cholesterol level and restored the viral infection. Moreover, we found that depletion of cholesterol acted on the early stage of CSFV infection and blocked its internalization into the host cells. Furthermore, we showed that 25-hydroxycholesterol, a regulator of cellular cholesterol biosynthesis, exhibited a potent anti-CSFV activity by reducing cellular cholesterol level. Taken together, our findings highlight the engagement of cholesterol in the life cycle of CSFV and its potential use as an antiviral target.

Introduction This study was performed to determine whether the disturbed maturation of oligodendrocyte (OL) progenitors might be related to lipopolysaccharide (LPS)-induced hypomyelination. Material and methods We created organotypic cultures of forebrain slices from neonatal rats and explored the morphological changes of glial cells expressing tumour necrosis factor  (TNF-) following LPS exposure. Results We observed marked activation of glial fibrillary acidic protein-positive astrocytes and OX42-positive microglia co-labelled with TNF- four days following LPS exposure. Our results further demonstrated a reduced expression of O4-positive and O1-positive OL progenitors; moreover, we found that their morphologies were suggestive of degeneration (e.g., scanty, rounded bodies with short, fragmented processes and/or cytoplasmic condensation). At seven days following LPS exposure, astrocytes and microglia were still co-labelled for TNF-; however, the expression of O4-positive and O1-positive cells somewhat increased compared to the number observed at 4 days; despite remaining undifferentiated and exhibiting immature morphologies, the cells were likely indicative of regeneration. In contrast, O4-positive and O1-positive cells in controls were well-differentiated, displaying round, thick cell bodies and long, branching processes. Conclusions In conclusion, maturation arrest and/or under-differentiation of OL progenitors commonly occur during regeneration: they may underlie the degeneration and consequent hypomyelination occurring late after injury, or apoptosis during the acute stage post-injury. Microglia and astrocytes expressing TNF- may also contribute to later myelination failure.

Loquat fruit accumulates lignin in its flesh when undergoing chilling injury during postharvest storage, making it a suitable model for the study of flesh lignification. Transcriptional regulation of lignin biosynthesis is principally controlled by the NAC-MYB transcriptional cascade in model plants. Previous research has demonstrated that EjMYB8 activates lignin biosynthesis through direct interaction with the promoter of Ej4CL1. However, the classic NAC-MYB gene regulation network has not been established. Here, the MADS-box gene EjAGL65 was discovered by screening a cDNA library using the EjMYB8 promoter as bait in yeast. A phylogenetic analysis and structural comparisons revealed that EjAGL65 belongs to the Mδ subgroup of the MADS-box family, whose members have not been reported as being involved in the regulation of lignin deposition. EjAGL65 transcription was downregulated at 0°C compared to 5°C, indicating a negative correlation with the change of lignin content. A dual-luciferase assay indicated that EjAGL65 is capable of inhibiting the promoter activity of EjMYB8 in vivo. These results showed that the Mδ MADS-box gene EjAGL65 transcriptionally regulates EjMYB8 during postharvest chilling induced flesh lignification, which differs from the classical regulation model of lignin biosynthesis that has been illustrated for developmental lignin accumulation.

In this paper, a Janus metasurface is designed by breaking the structural symmetry based on the polarization selection property of subwavelength grating. The structure comprises three layers: a top layer having a metallic nanostructure, a dielectric spacer, and a bottom layer having subwavelength grating. For a forward incidence, the metal-insulator-metal (MIM) structure operates as a gap plasmonic cavity if the linearly polarized (LP) component is parallel to the grating wires. It also acts as a high-efficiency dual-layer grating polarizer for the orthogonal LP component. For the backward incidence, the high reflectance of the grating blocks the function of the gap plasmonic cavity, leading to its pure functioning as a polarizer. A bifunctional Janus metasurface for 45 degrees beam deflector and polarizer, with a transmission of 0.87 and extinction ratio of 3840, is designed at 1.55 μm and is investigated to prove the validity of the proposed strategy. Moreover, the proposed metasurface can be cascaded to achieve more flexible functions since these functions are independent in terms of operational mechanism and structural parameters. A trifunctional Janus metasurface that acts as a focusing lens, as a reflector, and as a polarizer is designed based on this strategy. The proposed metasurface and the design strategy provide convenience and flexibility in the design of multifunctional, miniaturized, and integrated optical components for polarization-related analysis and for detection systems.

Conventional RGB sub-pixel layout for displays has low geometric fill factor, which show limitations in application for high resolution and efficiency improvement. Color-tunable pixel, which can reproduce various colors with a single pixel, can be an innovative approach to improve the fill factor issue. The bilayered emission layer (EML) structure is a method to implement the color-tunable pixels. However, a simple bilayer structure exhibit limited color-tuning range. Thus, color-modulation layer (CML) insertion between EMLs is essential to control the carrier distribution. CML materials are usually dissolved in organic solvent for solution process. Here, a process issue occurs as organic solvents can damage the previous QD layer. In this research, we analyze the effects of various organic solvents on the QD layer and suggest the most suitable solvent that minimizes the damage. The bilayer QD-LED structure is ITO/PEDOT:PSS/PVK/green QD(CdSe@ZnS)/organic solvents/red QD(CdSe@ZnS)/ZnO/Al. Toluene, chlorobenzene, 1,4-dioxane, and n-octane are used for organic solvent process and deposited on the QD layer. The current density and the luminance of the device without solvent process and with toluene, 1,4-dioxane, and n-octane process are (99.5 mA/cm2 and 908 cd/m2), (63.7 mA/cm2 and 490 cd/m2), (63.1 mA/cm2 and 304 cd/m2), and (43 mA/cm2 and 200 cd/m2), respectively, at 9.5V. These results indicate that toluene, 1,4-dioxane, and n-octane process caused severe damage on the green QD layer. However, current density and luminance of chlorobenzene process are 208.8 mA/cm2, 934 cd/m2, respectively, at 8V. Moreover, chlorobenzene treated device showed even wider color-tuning range than the one without solvent process. Therefore, chlorobenzene is the most suitable solvent for the CML..

Use of thinner oxides to improve the operating speed of a complementary metal-oxidesemiconductor (CMOS) device causes serious gate leakage problems. Leakage current of the dielectric analysis method has I–V, C–V, and charge pumping, but the procedure is very complicated. In this premier work, we analyzed the leakage current of metal insulator semiconductor (MIS) capacitors with different initiators through low-frequency noise (LFN) measurement with simplicity and high sensitivity. The LFN measurement results show a correlation between power spectral density (SIG) and gate leakage current (IG). MIS capacitors of hafnium zirconium silicate (HZS, (HfZrO4)1-x (SiO2)x) were used for the experiments with varying SiO2 ratio (x = 0, 0.1, 0.2) of hafnium zirconium oxide (HZO, HfZrO4). As the SiO2 ratio increased, the leakage current decreased according to J–V measurement. Further, the C–V measurement confirmed that the oxide-trapped charge (Not) increased with increasing SiO2 ratio. Finally, the LFN measurement method revealed that the cause of leakage current reduction was trap density reduction of the insulator.

Background: Aortic aneurysm (AA) is an aortic disorder prone to sudden, life-threatening aortic dissection or rupture, with poor clinical outcomes. In this study, we aimed to analyze the clinical characteristics of AA in MIMIC-III to explore implications for management. Methods: All patients with AA, including abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm (TAA), in the MIMIC-III database were included. Clinical and laboratory variables were analyzed and compared in AAA and TAA. Results: A total of 345 patients, including 183 patients with AAA and 162 patients with TAA, were enrolled in this study. The in-hospital mortality in AAA and TAA groups was 6.01% and 3.7%, respectively. In the nonsurvivor groups in both AAA and TAA, patients were older, and the incidence of surgery was lower. In the nonsurvivor group of AAA, the levels of alanine aminotransferase, aspartate aminotransferase, urea nitrogen, creatinine, lactate dehydrogenase (LDH), creatine kinase, anion gap, and lactate were significantly higher in the nonsurvivor group, whereas the level of albumin was lower. In the nonsurvivor group of TAA, the level of LDH significantly increased and the level of albumin decreased. In the nonsurgery group, in-hospital mortality was higher, and patients were older, with higher levels of glucose, total bilirubin, urea nitrogen, and creatinine and longer length of stay in ICU and hospital. Conclusion: Age, surgery, albumin, and LDH showed significant differences between survivor and nonsurvivor groups in both AAA and TAA. In the nonsurgery group, the mean age was older and disease severity was worse, with poorer clinical outcomes. Older AA patients without surgery and with lower levels of albumin and higher levels of LDH had higher risk of in-hospital mortality.

Research on wall rock alteration is of great importance to the understanding and exploration of ore deposits. The microscopic changes of the same mineral in different alteration zones can provide information about the migration and enrichment of ore-forming elements. In this paper, a typical profile of a high-grade iron ore body in Gongchangling iron deposit was investigated and sampled. The samples were checked by polarized microscopy, and alterations zonation were delineated according to the hydrothermal mineral assemblages and paragenesis. Moreover, hyperspectral images of wall rocks from each alteration zone were obtained by Norsk Elektro Optikk (NEO) HySpex-320m imaging system. A customer Interactive Data Language (IDL) software package was used to process the images, and spectral features were extracted from the selected samples. The results indicate that spectral characteristics manifest obviously regular variations, i.e., from proximal to distal for the high-grade iron ore body, the wavelengths at ca. 1200 nm of chlorite and garnet, which accounts for most of the hydrothermal alteration minerals, become longer, and the absorption depths gradually smaller. The spectral features at 1200 nm of chlorite and garnet are always caused by the crystal field effect of Fe2+, therefore, the wavelength variations indicate the increase of Fe2+ and a reduced environment, which can provide more detailed information about the metallogeny and water&ndash, rock interaction. Since the hyperspectral features of the altered rocks can disclose unique mineralogical and structural information, the conventional classification of alteration zonation should be combined with the spectral feature, i.e., spectral alteration zonation, which is of great help to the understanding of the forming conditions of wall rock alteration and also the high-grade iron ore bodies.

We systematically investigate the detailed structure in the flow-induced crystallization of a lightly cross-linked high-density polyethylene as a model semicrystalline polymer sample by combining the small-angle X-ray scattering (SAXS) and the spherical harmonic expansion (SHE) method. The SHE divides the two-dimensional SAXS pattern into several components according to the deformation geometry, and allows extraction of the most relevant information. Employing the first two anisotropic components in the expansion and a comprehensive model, we determine the crystalline morphological parameters, such as the long period, the lamellar diameter and thickness, and their polydispersities. In particular, we find that the lamellar diameter exhibits bimodal distributions at high strains. Lamellae with similar diameters tend to gather rather than to randomly distribute with others, suggesting the existence of heterogeneity in the semicrystalline structure. Moreover, we observe the strong polydispersities of the lamellar structure at low strains. The structural heterogeneity and polydispersities could be related to the inhomogeneities in crystal growth and nucleation processes.

Anshan-Benxi area in Liaoning province is an important banded iron formations (BIFs) ore-mining district in China. Chlorite is widely distributed in this area, which is related to BIFs and high-grade iron ore, respectively. A fast and convenient method to identify the type and spatial distribution of different chlorites is crucial to the evaluation of high-grade iron ore in this area. Qidashan iron mine is a typical BIFs deposit, and its BIFs-related high-grade iron ore reserves are the second largest in the area. In this paper, the laboratory-based HySpex-320m hyperspectral imaging was used to study the wall rock in Qidashan iron mine. A hyperspectral imaging processing model was established for mineral identification, mineralogy mapping, and chlorite spectral features extraction. The results show that the wavelength positions of OH, Fe-OH, and Mg-OH absorptions of chlorite in the altered wall rock of high-grade iron ore are between 1400 and 1410, 2260 and 2265, and 2360 and 2370 nm, respectively, which are longer than those around BIFs. The relationship between cations in the octahedral layer of chlorite and the wavelengths of OH, Fe-OH, and Mg-OH indicates that Mg and Mg/(Mg + Fe) are inversely related to these wavelengths, whereas Fe is positively related. The wavelengths appear to be weakly influenced by AlVI. Since the bandpass of hyperspectral imaging systems is usually less than 10 nm, these chlorite wavelength differences can be used as a favorable tool for the high-grade iron ore exploration and the iron resources evaluation in the Anshan-Benxi area.

Sleep and basal forebrain activity Different patterns of neural activity in the brain control the sleep-wake cycle. However, how this activity contributes to sleep homeostasis remains largely unknown. Adenosine in the basal forebrain is a prominent physiological mediator of sleep homeostasis. Using a newly developed indicator, Peng et al. monitored adenosine concentration in the mouse basal forebrain. There was a clear correlation with wake state and REM sleep. Activity-dependent release of adenosine could also be elicited after optogenetic stimulation of basal forebrain glutamatergic, but not cholinergic, neurons. These findings offer new insights into how neuronal activity during wakefulness contributes to sleep pressure through the release of sleep-inducing factors. Science , this issue p. eabb0556