Electrolyte additive is an effective strategy to inhibit the uncontrolled growth of Li dendrites for lithium metal batteries (LMBs). However, most of the additives are complex synthesis and prone to ...decompose in cycling. Herein, in order to guide the homogeneous deposition of Li+, carbonized polymer dots (CPDs) as electrolyte additives are successfully designed and synthesized by microwave (M‐CPDs) and hydrothermal (H‐CPDs) approaches. The controllable functional groups containing N or O (especially pyridinic‐N, pyrrolic‐N, and carboxyl group) enable CPDs to keep stable in electrolytes for at least 3 months. Meanwhile, the clusters formed between CPDs and Li+ through electrostatic interaction effectively guide the uniform Li dispersion and limit the “tip effect” and dendrite formation. Moreover, as lithiophilic groups increase, the strong electrostatic interference for the solvation effect of Li+ in the electrolyte is formed, which induces faster Li+ diffusion/transfer. As expected, H‐CPDs achieve the ultra‐even Li+ transfer. The corresponding Li//LiFePO4 full cell delivers a high capacity retention rate of 93.8% after 200 cycles, which is much higher than that of the cells without additives (61.2%) and with M‐CPDs (83.7%) as additives. The strategy in this work provides a theoretical direction for CPDs as electrolyte additives used in energy storage devices.
Two kinds of carbonized polymer dots (CPDs) (M‐CPDs and H‐CPDs) as electrolyte additives are successfully designed and synthesized. H‐CPDs with more pyridinic‐N, pyrrolic‐N, and COOH deliver more even Li+ flux through abundant H‐CPDs‐Li clusters bound by strong electrostatic interaction. The symmetrical cell exhibits enhanced cycling stability of 3700 h.
Gastric cancer (GC) is the second cause of cancer-related death. Cisplatin (CDDP) is widely used as the standard GC treatment, but relapse and metastasis are common because of intrinsic or acquired ...drug resistance. The mitogen-activated protein kinase phosphatases (MAPK)-extracellular signal regulated kinases (ERK) pathway contributes to GC progression and drug resistance, but targeting the MAPK-ERK pathway is challenging in GC therapy. Here, we demonstrated that dual-specificity phosphatases 6 (DUSP6) was overexpressed in GC and predicted poor overall survival and progression-free survival. Knockdown DUSP6 inhibited GC proliferation, migration, invasion and induced apoptosis. (E/Z)-BCI hydrochloride (BCI), a DUSP6 small molecule inhibitor, increased the activity of ERK but interestingly decreased the expression of ERK response genes in BGC823, SGC7901 and CDDP-resistant SGC7901/DDP cells. BCI also caused cell death through the DNA damage response (DDR) pathway. Moreover, BCI inhibited cell proliferation, migration and invasion in a receptor-independent manner and enhanced CDDP cytotoxicity at pharmacological concentrations in the GC cells. In vivo experiments further showed that BCI enhances the antitumor effects of CDDP in cell-based xenografts and PDX models. In summary, our findings indicated that disruption of DUSP6 by BCI enhanced CDDP-induced cell death and apoptosis in GC may partly through ERK and DDR pathways. Thus, this study suggests that DUSP6 is a potential prognostic biomarker and a promising target for GC therapy.
•DUSP6 was overexpressed and promote proliferation, metastasis and predict poor prognosis in GC.•BCI inhibited cell proliferation, migration and invasion and enhanced CDDP cytotoxicity in GC through DUSP6.•In vivo experiments showed that BCI enhances the antitumor effects of CDDP in cell-based xenografts and PDX models.•BCI enhanced CDDP-induced cell death and apoptosis may partly through ERK and DDR pathways in GC.
The role of IL-17 producing cells in tumors is controversial. In the present study, we investigated the prognostic value of measuring tumor-infiltrating IL-17 producing cell levels in human ...esophageal squamous cell carcinoma (ESCC).
Immunohistochemical staining was performed to investigate the levels of IL-17+ tumor infiltrating lymphocytes (TILs), as well as CD8+ cytotoxic T lymphocytes (CTLs) and CD57+ natural killer (NK) cells from 181 ESCC patients. The prognostic value of measuring the densities of IL-17+TILs and the correlation with CTLs and NK was evaluated. IL-17 producing cells were detected in esophageal squamous cell carcinoma tissues. The IL-17 producing cells were major CD4 positive, but Foxp3 negative. The median level of IL-17+TILs was 3.90 cells/high power microscopic field (HPF). The density of IL-17 producing cells correlated negatively with T stage (P=0.042). The higher densities of tumor infiltrating IL-17+ lymphocytes were associated with better overall survival (P=0.031). Furthermore, we found that there were positive correlations between levels of IL-17 producing cells and the densities of CD8+cells, as well as CD57+cells (r=0.198, P=0.008 for CD8+ cells and r=0.261, P<0.001 for CD57+ cells, respectively). The prognosis analysis also showed that the higher levels of CD8+ CTLs and CD57+ NK cells correlated with better overall survival of ESCC patients.
Our study suggests that tumor infiltrating IL-17 producing cells in ESCC patients may have protective roles in the tumor microenvironment and may be treated as a prognostic marker for ESCC patients.
The prognostic value and clinical relevance of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA) remain unclear. Thus, we aimed to investigate the prognostic value and ...functional involvement of TLSs in iCCA.
We retrospectively included 962 patients from 3 cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples.
A quaternary TLS scoring system was established for the intra-tumor region (T score) and peri-tumor region (P score) respectively. T scores positively correlated with favorable prognosis (p <0.001), whereas a high P score signified worse survival (p <0.001). mIHC demonstrated that both T follicular helper and regulatory T cells were significantly increased in intra-tumoral TLSs compared to peri-tumoral counterparts (p <0.05), and regulatory T cell frequencies within intra-tumoral TLSs were positively associated with P score (p <0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into 4 immune classes with distinct prognoses (p <0.001) that differed in the abundance and distribution pattern of TLSs. Patients displaying an immune-active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with an immune-excluded pattern survived at 5 years (p <0.001). The C-index of the immune class was statistically higher than the TNM staging system (0.73 vs. 0.63, p <0.001). These results were validated in an internal and 2 external cohorts.
The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. T follicular helper and regulatory T cells may play a critical role in determining the functional orientation of spatially different TLSs.
Tertiary lymphoid structures (TLSs) are associated with favorable prognosis in a number of cancers. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed the opposite prognostic impacts of TLSs located within or outside the tumor. This difference could be mediated by the different immune cell subsets present within the spatially distinct TLSs. Based on our analysis, we were able to stratify iCCAs into 4 immune subclasses associated with varying prognoses.
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•Tertiary lymphoid structures (TLSs) within and outside the tumor have opposite prognostic impacts on patients with iCCA.•The heterogeneous distribution of Tfh and Treg cells within distinct TLSs might be a determinant of their functional state.•The geographic integration of TLSs stratified iCCAs into 4 immune subclasses with distinct clinical outcomes.
ATP-binding cassette transporter A1 (ABCA1), which promotes cholesterol efflux from cells and inhibits inflammatory responses, is highly expressed in the kidney. Research has shown that exendin-4, a ...glucagon-like peptide-1 receptor (GLP-1R) agonist, promotes ABCA1 expression in multiple tissues and organs; however, the mechanisms underlying exendin-4 induction of ABCA1 expression in glomerular endothelial cells are not fully understood. In this study we investigated the effect of exendin-4 on ABCA1 in glomerular endothelial cells of diabetic kidney disease (DKD) and the possible mechanism. We observed a marked increase in glomerular lipid deposits in tissues of patients with DKD and diabetic apolipoprotein E knock-out (apoE−/−) mice by Oil Red O staining and biochemical analysis of cholesterol. We found significantly decreased ABCA1 expression in glomerular endothelial cells of diabetic apoE−/− mice and increased renal lipid, cholesterol, and inflammatory cytokine levels. Exendin-4 decreased renal cholesterol accumulation and inflammation and increased cholesterol efflux by up-regulating ABCA1. In human glomerular endothelial cells, GLP-1R-mediated signaling pathways (e.g. Ca2+/calmodulin-dependent protein kinase, cAMP/PKA, PI3K/AKT, and ERK1/2) were involved in cholesterol efflux and inflammatory responses by regulating ABCA1 expression. We propose that exendin-4 increases ABCA1 expression in glomerular endothelial cells, which plays an important role in alleviating renal lipid accumulation, inflammation, and proteinuria in mice with type 2 diabetes.
Abstract
Oxidative degradation of chitin, initiated by lytic polysaccharide monooxygenases (LPMOs), contributes to microbial bioconversion of crystalline chitin, the second most abundant biopolymer ...in nature. However, our knowledge of oxidative chitin utilization pathways, beyond LPMOs, is very limited. Here, we describe a complete pathway for oxidative chitin degradation and its regulation in a marine bacterium,
Pseudoalteromonas prydzensis
. The pathway starts with LPMO-mediated extracellular breakdown of chitin into C1-oxidized chitooligosaccharides, which carry a terminal 2-(acetylamino)−2-deoxy-D-gluconic acid (GlcNAc1A). Transmembrane transport of oxidized chitooligosaccharides is followed by their hydrolysis in the periplasm, releasing GlcNAc1A, which is catabolized in the cytoplasm. This pathway differs from the known hydrolytic chitin utilization pathway in enzymes, transporters and regulators. In particular, GlcNAc1A is converted to 2-keto-3-deoxygluconate 6-phosphate, acetate and NH
3
via a series of reactions resembling the degradation of D-amino acids rather than other monosaccharides. Furthermore, genomic and metagenomic analyses suggest that the chitin oxidative utilization pathway may be prevalent in marine Gammaproteobacteria.
MnO is a promising high‐capacity anode material for lithium‐ion batteries (LIBs), but pristine material suffers short cycle life and poor rate capability, thus hindering the practical application. In ...this work, a new type of porous MnO microballs stringed with N‐doped porous carbon (3DHB‐MnO@NC) with a well‐connected hierarchical three‐dimensional network structure was prepared by the facile self‐template method. The 3DHB‐MnO@NC electrode can effectively promote the ion/electron transfer and buffer the large volume change of electrode during the electrochemical reaction. As the anode for LIBs, the 3DHB‐MnO@NC possesses outstanding cycling performance (1247.7 mA h g−1 after 90 cycles at 200 mA g−1) and good rate capabilities (949.6 mA h g−1 after 450 cycles at 1000 mA g−1). The facile self‐template method of the prepared 3DHB‐MnO@NC composite paves a new way for practical applications of MnO in high performance LIBs.
Small balls: New MnO 3D hierarchical microballs prepared by the facile self‐template method achieves ultrafast, ultralong‐lifespan lithium storage (see figure).
CONTEXT Weight gain, a common adverse effect of antipsychotic medications,
is associated with medical comorbidities in psychiatric patients. OBJECTIVE To test the efficacy of lifestyle intervention ...and metformin alone and in combination for antipsychotic-induced weight gain and abnormalities in insulin sensitivity. DESIGN, SETTING, AND PATIENTS A randomized controlled trial (October 2004-December 2006) involving 128 adult patients with schizophrenia in the Mental Health Institute of the Second Xiangya Hospital, Central South University, China. Participants who gained more than 10% of their predrug weight were assigned to 1 of 4 treatment groups. INTERVENTIONS Patients continued their antipsychotic medication and were randomly assigned to 12 weeks of placebo, 750 mg/d of metformin alone, 750
mg/d of metformin and lifestyle intervention, or lifestyle intervention only. MAIN OUTCOME MEASURES Body mass index, waist circumference, insulin levels, and insulin resistance index. RESULTS All 128 first-episode schizophrenia patients maintained relatively stable psychiatric improvement. The lifestyle-plus-metformin group had mean decreases in body mass index (BMI) of 1.8 (95% confidence interval CI, 1.3-2.3), insulin resistance index of 3.6 (95% CI,
2.7-4.5), and waist circumference of 2.0 cm (95% CI, 1.5-2.4 cm).
The metformin-alone group had mean decreases in BMI of 1.2 (95% CI,
0.9-1.5), insulin resistance index of 3.5 (95% CI, 2.7-4.4), and waist circumference of 1.3 cm (95% CI, 1.1-1.5 cm). The lifestyle-plus-placebo group had mean decreases in BMI of 0.5 (95% CI, 0.3-0.8) and insulin resistance index of 1.0 (95% CI, 0.5-1.5). However, the placebo group had mean increases in BMI of 1.2 (95% CI, 0.9-1.5), insulin resistance index of 0.4 (95% CI, 0.1-0.7), and waist circumference of 2.2 cm (95% CI, 1.7-2.8 cm). The lifestyle-plus-metformin treatment was significantly superior to metformin alone and to lifestyle plus placebo for weight,
BMI, and waist circumference reduction. CONCLUSIONS Lifestyle intervention and metformin alone and in combination demonstrated efficacy for antipsychotic-induced weight gain. Lifestyle intervention plus metformin showed the best effect on weight loss.
Metformin alone was more effective in weight loss and improving insulin sensitivity than lifestyle intervention alone. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00451399
Little is known about Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) because of its rarity. We aimed to comprehensively investigate the clinicopathology, tumor immune ...microenvironment (TIME) and genomic landscape of this entity in southern China.
We evaluated 303 intrahepatic cholangiocarcinomas (ICCs) using in situ hybridization for EBV. We compared clinicopathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lymphocytes (TILs) and genomic features of EBVaICC by immunohistochemistry, double staining, nested PCR, multiplex immunofluorescence staining, fluorescence in situ hybridization and whole-exome sequencing.
EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. Patients with EBVaICC were more often female and younger, with solitary tumors, higher HBV infection rates and less frequent cirrhosis; the lymphoepithelioma-like (LEL) subtype was more common in EBVaICC. EBVaICC was associated with a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC – associated with a significantly increased density and proportion of CD20+ B cells and CD8+ T cells – was associated with significantly higher 2-year survival rates than conventional EBVaICC and nonEBVaICC. Both PD-1 and PD-L1 in TILs, and PD-L1 in tumor cells, were overexpressed in EBVaICC. High PD-L1 expression in tumor cells and high CD8+ TIL densities were significantly more common in EBVaICC than in nonEBVaICC. Seven genes (MUC4, DNAH1, GLI2, LIPE, MYH7, RP11-766F14.2 and WDR36) were mutated in at least 3 patients. EBVaICC had a different mutational pattern to liver fluke-associated cholangiocarcinoma and HBV-associated ICC.
EBVaICC, as a subset of ICC, has unique etiological, clinicopathological and genetic characteristics, with a significantly larger TIME component. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy.
Epstein-Barr virus (EBV) is associated with a subtype of intrahepatic cholangiocarcinoma, with unique clinicopathological and genetic characteristics. The tumor immune microenvironment is also different in this tumor subtype and patients with EBV-associated intrahepatic cholangiocarcinoma may respond well to immune checkpoint inhibitors.
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•EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates.•EBVaICChas unique characteristics related to etiology, clinicopathology and molecular genetics.•Both PD-1 and PD-L1 in tumor-infiltrating lymphocytes and PD-L1 in tumor cells are overexpressed in EBVaICC.•Patients with EBVaICC may respond well to immune checkpoint inhibitors.•The lymphoepithelioma-like subtype of EBVaICC is related to favorable survival.
Inflammasome involvement in Parkinson's disease (PD) has been intensively investigated. Absent in melanoma 2 (AIM2) is an essential inflammasome protein known to contribute to the development of ...several neurological diseases. However, a specific role for AIM2 in PD has not been reported. In this study, we investigated the effect of AIM2 in the N‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP)‐induced PD model by use of various knockout and bone marrow chimeric mice. The mechanism of action for AIM2 in PD was assessed by RNA‐sequencing and in vitro primary microglial transfection. Results were validated in the A30P transgenic mouse model of PD. In the MPTP mouse model, AIM2 activation was found to negatively regulate neuro‐inflammation independent of the inflammasome. Microglial AIM2 deficiency exacerbated behavioral and pathological features of both MPTP‐induced and transgenic PD mouse models. Mechanistically, AIM2 reduced cyclic GMP–AMP synthase (cGAS)‐mediated antiviral‐related inflammation by inhibition of AKT‐interferon regulatory factor 3 (IRF3) phosphorylation. These results demonstrate microglial AIM2 to inhibit the antiviral‐related neuro‐inflammation associated with PD and provide for a foundation upon which to identify new therapeutic targets for treatment of the disease.
Main Points
AIM2 plays an important role in mouse models of Parkinson's disease, independent of the inflammasome.
Microglial AIM2 inhibits Parkinson's disease neuro‐inflammation and pathology.
AIM2 inhibits AKT‐IRF3 phosphorylation, thereby alleviating cGAS‐mediated antiviral inflammation.
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