All‐solid‐state batteries (ASSBs) comprising solidified cathodes, electrolytes, and Li–metal anodes have attracted notable attention as promising future batteries for electric vehicles owing to their ...exceptional stability and expectation of achieving high energy density. However, its permanent operation has been hindered by Li dendrite growth, chemo–mechanical degradation, and interfacial instability, leading to Li exhaustion, increased resistance, and internal short‐circuiting. Herein, for the first time, the authors report the effects of a lithium nitride (Li3N) sacrificial cathode on the cycling performance of ASSBs combined with a Li‐free In layer. Through in situ evolved gas and internal pressure change analyses of the cells, it is found that, as with the liquid electrolyte cell, the decomposed Li3N compensates for active Li consumed by side reactions in the cell. Moreover, it is demonstrated that the improved interparticle contact by volume expansion of In through additionally supplied Li as well as the interfacial stability at the anode side by the dendrite‐free In layer, are strongly responsible for the improved cyclability of the ASSBs. The findings reveal the effectiveness of the Li compensation approach for the stable cycling of ASSBs based on the secured interfacial stability at the anode side.
A sulfide‐based all‐solid‐state battery consisting of a lithium nitride (Li3N) sacrificial cathode and a Li‐free indium layer shows stable cycling performance owing to the combined effects of the Li3N compensating for Li loss caused by interfacial side reactions along with contributing to improved interparticle contact by additional volume expansion of In and the dendrite‐free In layer exhibiting exceptional interfacial stability.
Genomic and precision medicine research has afforded notable advances in human cancer treatment, yet applicability to other species remains uncertain. Through whole-exome and transcriptome analyses ...of 191 spontaneous canine mammary tumors (CMTs) that exhibit the archetypal features of human breast cancers, we found a striking resemblance of genomic characteristics including frequent PIK3CA mutations (43.1%), aberrations of the PI3K-Akt pathway (61.7%), and key genes involved in cancer initiation and progression. We also identified three gene expression-based CMT subtypes, one of which segregated with basal-like human breast cancer subtypes with activated epithelial-to-mesenchymal transition, low claudin expression, and unfavorable disease prognosis. A relative lack of ERBB2 amplification and Her2-enrichment subtype in CMT denoted species-specific molecular mechanisms. Taken together, our results elucidate cross-species oncogenic signatures for a better understanding of universal and context-dependent mechanisms in breast cancer development and provide a basis for precision diagnostics and therapeutics for domestic dogs.
The influence of hydrogen on the mechanical behavior of the CoCrFeMnNi high-entropy alloy (HEA) was examined through tensile and nanoindentation experiments on specimens hydrogenated via gaseous and ...electrochemical methods. Results show that the HEA's resistance to gaseous hydrogen embrittlement is better than that of two representative austenitic stainless steels, in spite of the fact that it absorbs a larger amount of hydrogen than the two steels. Reasons for this were discussed in terms of hydrogen-enhanced localized plasticity mechanism and the critical amount of hydrogen required for it. These were further substantiated by additional experiments on electrochemically charged specimens.
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Defects of autophagy and endoplasmic reticulum (ER) stress are related to many diseases and tumors. However, only a few studies have examined hepatocellular carcinoma (HCC) as related to these ...processes. Therefore, in this study, we investigated the expression and extent of autophagy and ER stress-related markers in HCC and their influence on clinical characteristics and prognosis for each protein.
The expression of autophagy-related markers (LC3 and Beclin-1) and ER stress-related markers (GRP78 and CHOP) was analyzed by immunohistochemistry on tissues from completely resected specimens of 190 HCC patients. Their influence on clinicopathologic features and prognosis were evaluated using the chi-square test and Kaplan-Meier analysis. Correlations of each protein were determined by Spearman's correlation analysis.
LC3 expression was not correlated with TNM, BCLC stage, or Edmonson-Steiner grading, whereas it was correlated with longer overall survival (OS) (p = 0.039) and tended to be related with longer time to recurrence (TTR) (p=0.068) although it did not show statistical significance. Multivariate analysis indicated that LC3 expression was a significantly independent prognostic factor of OS (HR, 0.42; 95% CI, 0.22-0.80; p-value=0.009) and TTR (HR, 0.54; 95% CI, 0.33-0.90; p=0.017). Expression of LC3 in advanced stages of TNM (III) (p=0.045) and Edmonson-Steiner Grades (III and IV) (p=0.043) was correlated with longer survival, but not in the early stages. A positive correlation was not observed between the expression of autophagy-related markers and ER stress-related markers.
Our results suggest that the expression and extent of LC3 might be a strong prognostic factor of HCC, especially in patients with surgical resection.
Reactive oxygen species (ROS) regulate the migration and invasion of fibroblast-like synoviocytes (FLS), which are key effector cells in rheumatoid arthritis (RA) pathogenesis. Nicotinamide adenine ...dinucleotide phosphate oxidase 4 (NOX4) induces ROS generation and, consequently, enhances cell migration. Despite the important interrelationship between RA, FLS, and ROS, the effect of NOX4 on RA pathogenesis remains unclear.
FLS isolated from RA (n = 5) and osteoarthritis (OA, n = 5) patients were stimulated with recombinant interleukin 17 (IL-17; 10 ng/ml) and tumor necrosis factor alpha (TNF-α; 10 ng/ml) for 1 h. Cell migration, invasion, adhesion molecule expression, vascular endothelial growth factor (VEGF) secretion, and ROS expression were examined. The mRNA and protein levels of NOX4 were analyzed by RT-qPCR and western blotting, respectively. The NOX4 inhibitor GLX351322 and NOX4 siRNA were used to inhibit NOX4 to probe the effect of NOX4 on these cellular processes.
Migration of RA FLS was increased 2.48-fold after stimulation with IL-17 and TNF-α, while no difference was observed for OA FLS. ROS expression increased in parallel with invasiveness of FLS following cytokine stimulation. When the expression of NOX was examined, NOX4 was significantly increased by 9.73-fold in RA FLS compared to unstimulated FLS. Following NOX4 inhibition, cytokine-induced vascular cell adhesion molecule 1 (VCAM1), VEGF, and migration and invasion capacity of RA FLS were markedly decreased to unstimulated levels.
NOX4 is a key contributor to cytokine-enhanced migration and invasion via modulation of ROS, VCAM1, and VEGF in RA FLS.
Background and Aims
Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to ...identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV‐infected iCCA (HBV‐iCCA) tumors.
Approach and Results
We profiled a cohort of 108 HBV‐iCCAs using whole‐genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV‐infected HCC (HBV‐HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV‐cHCC/CCA; n = 59), and conventional (n = 154) and fluke‐related iCCAs (n = 16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at nine different sites. The most common insertional hotspot (7 tumors) was in the TERT (telomerase reverse transcriptase) promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2 (FAT atypical cadherin 2), and were associated with enrichment of epithelial–mesenchymal transition–related genes. A distinctive intergenic insertion (chr9p21.3), between DMRTA1 (DMRT like family A1) and LINC01239 (long intergenic non‐protein coding RNA 1239), had oncogenic effects through activation of the mammalian target of rapamycin (mTOR)/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV‐iCCA was closer to that of nonviral conventional iCCA, than to HBV‐HCC and HBV‐cHCC/CCA.
Conclusions
Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.
The production and oxidation mechanism of reactive oxygen species (ROS) are out of balance in rheumatoid arthritis (RA). However, the correlation between ROS and T cell subsets in RA remains unclear. ...Peripheral blood mononuclear cells (PBMCs) from patients with RA (n = 40) and healthy controls (n = 10) were isolated from whole blood samples. Synovial tissues (n = 3) and synovial fluid (n = 10) were obtained from patients with RA. The repartition of T cell subsets and expression of ROS and cytokines were examined according to RA severity. Fibroblast-like synoviocytes (FLSs) from patients with RA were stimulated with PBMCs and the expression of inflammation-related molecules were measured by RT-PCR and cytokine array. Regulatory T cells from patients with moderate (5.1 > DAS28 ≥ 3.2) RA showed the highest expression of mitochondrial ROS among the groups based on disease severity. Although ROS levels steadily increased with RA severity, there was a slight decline in severe RA (DAS28 ≥ 5.1) compared with moderate RA. The expression of inflammatory cytokines in RA FLSs were significantly inhibited when FLSs were co-cultured with PBMCs treated with ROS inhibitor. These findings provide a novel approach to suppress inflammatory response of FLSs through ROS regulation in PBMCs.
Summary
Organic‐inorganic composite membranes were prepared by introducing silicon dioxide (SiO2) or functionalized SiO2 (ƒ‐SiO2) with various particle sizes into sulfonated poly (arylene ether ...ketone) (SPAEK) containing pendant groups, and the membrane was manufactured via directly casting which is a cost‐competitive method. The structure and morphology of the composite membranes were confirmed by 1H NMR, FT‐IR, XRD, and FE‐SEM analysis which demonstrated that inorganic nanofillers were successfully introduced. The FE‐SEM surface images showed that SiO2 and ƒ‐SiO2 particles were very well dispersed within the membrane sheets. The water uptake and swelling ratio of the composite membranes including SiO2 or ƒ‐SiO2 almost did not change when compared with the pristine SPAEK membrane. All fabricated membranes demonstrated good thermal/dimensional stabilities, robust mechanical behavior, and excellent proton conductivity. In particular, the SPAEK/ƒ‐SiO2 composite membranes exhibited improved ionic conductivity compared with the pristine membrane at 70% relative humidity (RH) due to hydrogen bonding between ─SO3H groups of functionalized inorganic filler and polymer backbone. Furthermore, the maximum power density of SPAEK/ƒ‐SiO2 reached as high as 273.11 mW cm−2 at 60°C under 70% RH. Therefore, the composite membranes with ƒ‐SiO2 testify to great potential as polymer electrolyte membrane.
The ƒ‐SiO2 nanofiller are homogeneously dispersed in sulfonated poly(arylene ether ketone) (SPAEK) matrix. The SPAEK/ƒ‐SiO2 composite membranes exhibited superior proton conductivity. The SPAEK/ƒ‐iO2 composite membranes showed improved H+ conductivity above 70% relative humidity.
This study investigated the hydrogen embrittlement (HE) characteristics of advanced high-strength steels (AHSSs). Two different types of AHSSs with a tensile strength of 1.2 GPa were investigated. ...Slow strain rate tests (SSRTs) were performed under various applied potentials (E
) to identify the mechanism with the greatest effect on the embrittlement of the specimens. The SSRT results revealed that, as the E
increased, the elongation tended to increase, even when a potential exceeding the corrosion potential was applied. Both types of AHSSs exhibited embrittled fracture behavior that was dominated by HE. The fractured SSRT specimens were subjected to a thermal desorption spectroscopy analysis, revealing that diffusible hydrogen was trapped mainly at the grain boundaries and dislocations (i.e., reversible hydrogen-trapping sites). The micro-analysis results revealed that the poor HE resistance of the specimens was attributed to the more reversible hydrogen-trapping sites.
This study aimed to examine the role of CD70, which is highly expressed on fibroblast-like synoviocytes (FLS), in rheumatoid arthritis (RA) patients. FLS isolated from RA (
= 14) and osteoarthritis ...(OA,
= 4) patients were stimulated with recombinant interleukin-17 (IL-17; 5 ng/mL) and tumor necrosis factor alpha (TNF-α; 5 ng/mL) for 24 h. Expression of CD70, CD27/soluble CD27 (sCD27), and hypoxia-inducible factor-2 alpha (HIF-2α) was analyzed by RT-qPCR, flow cytometry, and ELISA assays, respectively. Reactive oxygen species (ROS) expression and cell migration were also examined. The HIF-2α inhibitor PT-2385 and CD70 inhibitor BU69 were used to specifically suppress these pathways. Stimulation with IL-17 and TNF-α significantly induced CD70 expression in RA FLS. Although the synovial fluids from patients with RA contained high levels of sCD27, surface expression of CD27, a ligand of CD70, was rarely detected in RA FLS. Cytokine-induced CD70 expression was significantly decreased following antioxidant treatment. Following HIF-2α inhibition, RA FLS had decreased expression of CD70 and ROS levels. Migration of RA FLS was also inhibited by inhibition of CD70 or HIF-2α. The surface expression of CD70 is regulated by HIF-2α and ROS levels and is a key contributor to cytokine-enhanced migration in RA FLS.
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