Sequential oxygen evolution and decoupled water splitting via electrochemical redox reaction of nickel hydroxides.

Alkaline water electrolysis is a promising low-cost strategy for clean and sustainable hydrogen production but is largely limited by the sluggish anodic oxygen evolution reaction and the challenges in maintaining adequate separation between H2 and O2. Here, we reveal an anodic-cathodic sequential oxygen evolution process via electrochemical oxidation and subsequent reduction of Ni hydroxides, enabling much lower overpotentials than conventional anodic oxygen evolution. By using (isotope-labeled) differential electrochemical mass spectrometry and in situ Raman spectroscopy combined with density functional theory calculations, we evidence that the sequential oxygen evolution originates from the electrochemical oxidation of Ni hydroxides to NiOO- active species while undergoing a different, reductive step of NiOO- for the final release of O2 due to weakened Ni-O covalency. Based on this sequential process, we propose and demonstrate a hybrid water electrolysis and energy storage device, which enables time-decoupled hydrogen and oxygen evolution and electrochemical energy storage in the Ni hydroxides.

Aromaticity in Isoelectronic Analogues of Benzene, Carborazine and Borazine, from Electronic Structure and Magnetic Property.

Carborazine (B2C2N2H6) and borazine (B3N3H6) are isoelectronic analogues of benzene (C6H6). The aromatic character of borazine have basically reached a consensus after a long period of controversy, but the related properties of carborazine are even rarely reported. In this work, we systematically investigated the geometric structure, charge distribution, frontier molecular orbital characteristics, bonding, electronic delocalization, magnetic shielding effect, and induced ring current of carborazine and borazine, and compared the studied characteristics with those of benzene to determine the aromatic character of the two analogues. The combination of multiple properties shows that although they are isoelectronic, carborazine is evidently aromatic, while borazine only exhibits rather weak aromaticity. The C atom acting as a connecting bridge between B and N atoms in carborazine reduces the electronegativity difference on the molecular backbone and enhances the electronic delocalization over the conjugated path, which is the essence of the distinct disparity of aromaticity between carborazine and borazine.

Mimic Lipoproteins Responsive to Intratumoral pH and Allosteric Enzyme for Efficient Tumor Therapy.

Discoid-reconstituted high-density lipoprotein (d-rHDL) is advantageous for tumor-targeted drug delivery due to its small size, long circulation, and efficient internalization into cancer cells. Nevertheless, an allosteric reaction catalyzed by serum lecithin-cholesterol acyltransferase (LCAT) may cause drug leakage from d-rHDL and reduce its targeting efficiency. Conversely, similar "structural weakening" catalyzed by acyl-coenzyme A-cholesterol acyltransferase (ACAT) inside tumor cells can stimulate precise intracellular drug release. Therefore, we synthesized and characterized a pH-sensitive n-butyraldehyde bi-cholesterol (BCC) to substitute for cholesterol in the d-rHDL particle, and bovine serum albumin (BSA) was used as the targeting agent. This dual pH- and ACAT-sensitive d-rHDL (d-d-rHDL) was small with a disk-like appearance. Morphological transformation observation, in vitro release assays, and differences in internalization upon LCAT treatment confirmed that BCC effectively inhibited the remodeling behavior and enhanced the tumor-targeting efficiency. The accumulation of d-d-rHDL in HepG2 cells was significantly higher than that in LO2 cells, and accumulation was inhibited by free BSA. The pH sensitivity was verified, and d-d-rHDL achieved efficient drug release in vitro and inside tumor cells after exposure to acidic conditions and ACAT. Confocal laser scanning microscopy demonstrated that d-d-rHDL escaped from lysosomes and became distributed evenly throughout cells. Moreover, in vivo imaging assays in a tumor-bearing mouse model demonstrated tumor-targeting properties of d-d-rHDL, and paclitaxel-loaded d-d-rHDL showed strong anticancer activity in these mice. This dual-sensitive d-d-rHDL thus combines structural stability in plasma and an intracellular pH/ACAT-triggered drug release to facilitate inhibition of tumor growth.

6-Phosphogluconolactonase Promotes Hepatocellular Carcinogenesis by Activating Pentose Phosphate Pathway.

Hepatocellular carcinoma (HCC) has a poor prognosis due to the rapid disease progression and early metastasis. The metabolism program determines the proliferation and metastasis of HCC; however, the metabolic approach to treat HCC remains uncovered. Here, by analyzing the liver cell single-cell sequencing data from HCC patients and healthy individuals, we found that 6-phosphogluconolactonase (PGLS), a cytosolic enzyme in the oxidative phase of the pentose phosphate pathway (PPP), expressing cells are associated with undifferentiated HCC subtypes. The Cancer Genome Atlas database showed that high PGLS expression was correlated with the poor prognosis in HCC patients. Knockdown or pharmaceutical inhibition of PGLS impaired the proliferation, migration, and invasion capacities of HCC cell lines, Hep3b and Huh7. Mechanistically, PGLS inhibition repressed the PPP, resulting in increased reactive oxygen species level that decreased proliferation and metastasis and increased apoptosis in HCC cells. Overall, our study showed that PGLS is a potential therapeutic target for HCC treatment through impacting the metabolic program in HCC cells.

An Immune Risk Score Predicts Survival of Patients with Acute Myeloid Leukemia Receiving Chemotherapy.

PURPOSE: Prediction models for acute myeloid leukemia (AML) are useful, but have considerable inaccuracy and imprecision. No current model includes covariates related to immune cells in the AML microenvironment. Here, an immune risk score was explored to predict the survival of patients with AML. EXPERIMENTAL DESIGN: We evaluated the predictive accuracy of several in silico algorithms for immune composition in AML based on a reference of multi-parameter flow cytometry. CIBERSORTx was chosen to enumerate immune cells from public datasets and develop an immune risk score for survival in a training cohort using least absolute shrinkage and selection operator Cox regression model. RESULTS: Six flow cytometry-validated immune cell features were informative. The model had high predictive accuracy in the training and four external validation cohorts. Subjects in the training cohort with low scores had prolonged survival compared with subjects with high scores, with 5-year survival rates of 46% versus 19% (P < 0.001). Parallel survival rates in validation cohorts-1, -2, -3, and -4 were 46% versus 6% (P < 0.001), 44% versus 18% (P = 0.041), 44% versus 24% (P = 0.004), and 62% versus 32% (P < 0.001). Gene set enrichment analysis indicated significant enrichment of immune relation pathways in the low-score cohort. In multivariable analyses, high-risk score independently predicted shorter survival with HRs of 1.45 (P = 0.005), 2.12 (P = 0.004), 2.02 (P = 0.034), 1.66 (P = 0.019), and 1.59 (P = 0.001) in the training and validation cohorts, respectively. CONCLUSIONS: Our immune risk score complements current AML prediction models.

Methylation of the Promoter Region of the Tight Junction Protein-1 by DNMT1 Induces EMT-like Features in Multiple Myeloma.

The molecular alterations that initiate the development of multiple myeloma (MM) are not fully understood. Our results revealed that TJP1 was downregulated in MM and positively related to the overall survival of MM patients in The Cancer Genome Atlas (TCGA) database and patient samples. In parallel, cell adhesion capacity representing MM metastasis was decreased in MM patients compared with healthy samples, together with the significantly activated epithelial-to-mesenchymal transition (EMT) transcriptional-like patterns of MM cells. Further analyses demonstrated that TJP1 negatively regulated EMT and consequently positively regulated cell adhesion in MM from TCGA database and MM1s cells. Furthermore, the methylation level of each CpG site on the TJP1 promoter was negatively correlated with TJP1 expression levels. Quantitative real-time PCR and western blot assays demonstrated that methylase DNMT1 regulated the methylation of TJP1. Finally, treatment with a combination of the MM clinical medicine bortezomib, methylation inhibitor, or TJP1 overexpression significantly suppressed the viability and progression of tumor cells of MM orthotopic models. In summary, our results indicate that DNMT1 promotes the methylation of TJP1 promoter, thereby decreasing its expression and regulating the development of EMT-inhibited MM cell adhesion. Therefore, methylation of TJP1 is a potential therapeutic agent to prevent the progression of MM disease.

Systematic Construction and Validation of a Metabolic Risk Model for Prognostic Prediction in Acute Myelogenous Leukemia.

Background: Acute myelogenous leukemia (AML) is a heterogeneous disease with recurrent gene mutations and variations in disease-associated gene expression, which may be useful for prognostic prediction. Methods: RNA matrix and clinical data of AML were downloaded from GEO, TCGA, and TARGET databases. Prognostic metabolic genes were identified by LASSO analysis to establish a metabolic model. Prognostic accuracy of the model was quantified by time-dependent receiver operating characteristic curves and the area under the curve (AUC). Survival analysis was performed by log-rank tests. Enriched pathways in different metabolic risk statuses were evaluated by gene set enrichment analyses (GSEA). Results: We identified nine genes to construct a prognostic model of shorter survival in the high-risk vs. low-risk group. The prognostic model showed good predictive efficacy, with AUCs for 5-year overall survival of 0.78 (0.73-0.83), 0.76 (0.62-0.89), and 0.66 (0.57-0.75) in the training, adult external, and pediatric external cohorts, respectively. Multivariable analysis demonstrated that the metabolic signature had independent prognostic value with hazard ratios of 2.75 (2.06-3.66), 1.89 (1.09-3.29), and 1.96 (1.00-3.84) in the training, adult external, and pediatric external cohorts, respectively. Combining metabolic signatures and classic prognostic factors improved 5-year overall survival prediction compared to the prediction by classic prognostic factors (p < 0.05). GSEA revealed that most pathways were metabolism-related, indicating potential mechanisms. Conclusion: We identified dysregulated metabolic features in AML and constructed a prognostic model to predict the survival of patients with AML.

Lactobacillus plantarum C88 protects against aflatoxin B1-induced liver injury in mice via inhibition of NF-κB-mediated inflammatory responses and excessive apoptosis.

BACKGROUND: Probiotics play an important role in the human and animal defense against liver damage. However, the protective mechanism of Lactobacillus plantarum C88 on chronic liver injury induced by mycotoxin remains unclear. RESULTS: In this study, the addition of L. plantarum C88 obviously ameliorated the increased contents of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total cholesterol and triglyceride, the diminish contents of total protein and albumin in serum of mice challenged with AFB1. Simultaneously, L. plantarum C88 attenuated the inflammatory response via significantly reducing the levels of pro-inflammatory factors, including interleukin-1ß (IL-1ß), IL-6, IL-8, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in serum. Furthermore, L. plantarum C88 remarkably down-regulated the nuclear factor kappa B (NF-κB) signaling pathways by weakening the expression of toll-like receptor 2 (TLR2) and TLR4, and inhibited NF-κB nuclear translocation through enhancing the expression of NF-κB inhibitor (IκB). Neutralization experiments confirmed that L. plantarum C88 decreased the levels of some pro-inflammatory factors due to the suppression of the NF-κB signaling pathways. Besides, L. plantarum C88 decreased the levels of Bax and Caspase-3, elevated the level of Bcl-2, and reduced mRNA expressions of Fatty acid synthetase receptor (Fas), FAS-associated death domain (FADD), TNF receptor associated death domain (TRADD) and Caspase-8 in the liver. CONCLUSIONS: Probiotic L. plantarum C88 prevented AFB1-induced secretion of pro-inflammatory cytokines by modulating TLR2/NF-κB and TLR4/NF-κB pathways. The molecular mechanisms of L. plantarum C88 in ameliorating AFB1-induced excessive apoptosis included regulating the mitochondrial pathway and cell death receptor pathways.

AgsA response to cadmium and copper effects at different temperatures in Escherichia coli.

Small heat shock proteins (sHsps), present from prokaryotes to eukaryotes, are a highly conserved molecular chaperone family. They play a crucial role in protecting organisms against cellular insults from single or multiple environmental stressors including heavy metal exposure, heat or cold shock, oxidative stress, desiccation, etc. Here, the toxicity of cadmium and copper, and their ability to modify the cellular growth rate at different temperatures in Escherichia coli cells were tested. Also, the response mechanism of the sHSP aggregation-suppressing protein (AgsA) in such multiple stress conditions was investigated. The results showed that the half effect concentration (EC50 ) of cadmium in AgsA-transformed E. coli cells at 37°C, 42°C, and 50°C were 11.106, 29.50, and 4.35 mg/L, respectively, and that of the control cells lacking AgsA were 5.05, 0.93, and 0.18 mg/L, respectively, while the half effect concentration (EC50 ) of copper in AgsA-transformed E. coli cells at 37°C, 42°C, and 50°C were 27.3, 3.40, and 1.28 mg/L, respectively, and that of the control cells lacking AgsA were 27.7, 5.93, and 0.134 mg/L, respectively. The toxicities of cadmium and copper at different temperatures as observed by their modification of the cellular growth rate and inhibitory effects were in a dose-dependent manner. Additionally, biochemical characterization of AgsA protein in cells subjected to cadmium and copper stresses at different temperatures implicated suppressed aggregation of cellular proteins in AgsA-transformed E. coli cells. Altogether, our data implicate the AgsA protein as a sensitive protein-based biomarker for metal-induced toxicity monitoring.

Fully Convolutional DenseNet with Multiscale Context for Automated Breast Tumor Segmentation.

Breast tumor segmentation plays a crucial role in subsequent disease diagnosis, and most algorithms need interactive prior to firstly locate tumors and perform segmentation based on tumor-centric candidates. In this paper, we propose a fully convolutional network to achieve automatic segmentation of breast tumor in an end-to-end manner. Considering the diversity of shape and size for malignant tumors in the digital mammograms, we introduce multiscale image information into the fully convolutional dense network architecture to improve the segmentation precision. Multiple sampling rates of atrous convolution are concatenated to acquire different field-of-views of image features without adding additional number of parameters to avoid over fitting. Weighted loss function is also employed during training according to the proportion of the tumor pixels in the entire image, in order to weaken unbalanced classes problem. Qualitative and quantitative comparisons demonstrate that the proposed algorithm can achieve automatic tumor segmentation and has high segmentation precision for various size and shapes of tumor images without preprocessing and postprocessing.

Multi-level features combined end-to-end learning for automated pathological grading of breast cancer on digital mammograms.

We propose to discriminate the pathological grades directly on digital mammograms instead of pathological images. An end-to-end learning algorithm based on the combined multi-level features is proposed. Low-level features are extracted and selected by supervised LASSO logistic regression. Convolutional Neural Network (CNN) is designed to extract high-level semantic features. These extracted multi-level features are combined to optimize the new CNN end to end to make different parts of the network learn to pay attention to different level of features. Results demonstrate that our proposed algorithm is superior to other CNN models and obtain comparable performance compared with pathological images.

The response of larvae Brachymystax lenok during continuous and single pulses exposure to copper, zinc, lead and cadmium.

The continuous and single pulses exposure of Cu, Zn, Pb and Cd on larvae Brachymystax lenok were tested in this study. The first-order kinetics was employed to obtain better comprehension on the time-toxicity relationship of tested heavy metals in continuous exposure test. For difference in time-varying exposure or recovery, 50% lethal time-averaged concentration (TAC) was used to assess the pulsed toxicity, which took both time and concentration into consideration in exposure and post-exposure period. TAC assessment to the single pulses and the regression analysis of first-order kinetic to continuous exposures demonstrated that Cu and Zn showed greater toxicity than Pb and Cd, indicating a slower uptake and/or depuration effect for zinc or copper. Furthermore, the results showed that recovery effect of larvae to all four metals was found in 24 h exposure followed by 72 h in fresh water, while for 72 h exposure and 24 h non-exposure the delayed lethal phenomenon occurred.

Vitamin D and DDX4 regulate the proliferation and invasion of ovarian cancer cells.

Ovarian cancer is one of the most commonly occurring types of cancer and one of the most common causes of cancer-associated mortality in women. Diagnosis of ovarian cancer at an early stage is difficult due to the lack of specific symptoms. In the present study, it is demonstrated that active vitamin D treatment prohibited the proliferation and invasion of ovarian cancer cells, and the expression level of a germ cell specific marker DEAD (Asp-Glu-Ala-Asp)-box helicase 4 (DDX4), which is overexpressed in ovarian cancer, was downregulated by active vitamin D treatment. Knockdown of DDX4 by siRNA could also suppress the invasive ability of ovarian cancer cells. Therefore, DDX4 may be considered as a diagnostic marker of ovarian cancer, and vitamin D may be a candidate drug for ovarian cancer therapy.

Puerarin reduces ischemia/reperfusion-induced myocardial injury in diabetic rats via upregulation of vascular endothelial growth factor A/angiotensin-1 and suppression of apoptosis.

Puerarin is an active ingredient of pueraria, which has been developed for puerarin injections, used in the treatment of cardiovascular diseases including arrhythmia, myocardial ischemia and hypertension. However, the molecular mechanisms of puerarin on ischemia/reperfusion (I/R)­induced myocardial apoptosis in diabetic rats are not fully understood. The present study aimed to investigate whether puerarin can attenuate I/R­induced myocardial apoptosis in diabetic rats, and to investigate the underlying mechanism. A hemodynamic analyzing system was employed to analyze the left ventricular developed pressure (LVDP), the left ventricular end­systolic interior dimension (LVIDs) and the left ventricular end diastolic interior dimension (LVIDd). ELISA kits were used to analyze malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor­α (TNF­α) and interleukin (IL)­6 levels, NO production and caspase­3 activity. Nuclear factor (NF)­κB, ascular endothelial growth factor A (VEGFA), angiotensin (Ang)­I, phosphorylated (p)­endothelial nitric oxide synthase protein expression was analyzed using western blot analysis. Puerarin significantly reduced the myocardial infarct area, and increased left ventricular developed pressure in diabetic rats with myocardial I/R. Oxidative stress, inflammation and nuclear factor­κB protein expression were significantly reduced by puerarin. Furthermore, puerarin activated the protein expression levels of VEGFA and Ang­I, and increased nitric oxide production, phosphorylated­endothelial nitric oxide synthase protein expression and caspase­3 activity. These results demonstrated that the myocardial protective effect of puerarin serves to reduce myocardial I/R injury, via upregulation of VEGFA/Ang­1 and suppression of apoptosis, in diabetic rats with myocardial I/R.

Low kilovoltage peak (kVp) with an adaptive statistical iterative reconstruction algorithm in computed tomography urography: evaluation of image quality and radiation dose.

PURPOSE: The purpose of this study was to evaluate the image quality and radiation dose in computed tomography urography (CTU) images acquired with a low kilovoltage peak (kVp) in combination with an adaptive statistical iterative reconstruction (ASiR) algorithm. METHODS: A total of 45 subjects (18 women, 27 men) who underwent CTU with kV assist software for automatic selection of the optimal kVp were included and divided into two groups (A and B) based on the kVp and image reconstruction algorithm: group A consisted of patients who underwent CTU with a 80 or 100 kVp and whose images were reconstructed with the 50% ASiR algorithm (n=32); group B consisted of patients who underwent CTU with a 120 kVp and whose images were reconstructed with the filtered back projection (FBP) algorithm (n=13). The images were separately reconstructed with volume rendering (VR) and maximum intensity projection (MIP). Finally, the image quality was evaluated using an image score, CT attenuation, image noise, the contrast-to-noise ratio (CNR) of the renal pelvis-to-abdominal visceral fat and the signal-to-noise ratio (SNR) of the renal pelvis. The radiation dose was assessed using volume CT dose index (CTDIvol), dose-length product (DLP) and effective dose (ED). RESULTS: For groups A and B, the subjective image scores for the VR reconstruction images were 3.9±0.4 and 3.8±0.4, respectively, while those for the MIP reconstruction images were 3.8±0.4 and 3.6±0.6, respectively. No significant difference was found (p>0.05) between the two groups' image scores for either the VR or MIP reconstruction images. Additionally, the inter-reviewer image scores did not significantly differ (p>0.05). The mean attenuation of the bilateral renal pelvis in group A was significantly higher than that in group B (271.4±57.6 vs. 221.8±35.3 HU, p<0.05), whereas the image noise in group A was significantly lower than that in group B (7.9±2.1 vs. 10.5±2.3 HU, p<0.05). The CNR and SNR in group A were both significantly higher than those in group B (53.61±24.74 vs. 32.30±6.52 for CNR; 38.13±19.86 vs. 21.76±4.85 for SNR; all p<0.05). The CTDIvol, DLP and ED in group A were significantly lower than those in group B (9.26±2.77 vs. 16.19±5.60 mGy for CTDIvol; 368.86±119.38 vs. 674.38±239.37 mGy×cm-1 for DLP; 5.53±1.79 vs. 10.12±3.59 mSv for ED; all p<0.05). CONCLUSIONS: The low kVp CTU images with 50% ASiR reconstruction exhibit sufficient image quality and facilitate up to a 44% radiation dose reduction.

The induction of metallothioneins during pulsed cadmium exposure to Daphnia magna: Recovery and trans-generational effect.

Although the importance of pulse exposure has gained ground in recent years, there were few studies on recovery and trans-generational effect of it. Two successive generations Daphnia magna were exposed to cadmium (Cd) pulses for 6h at the concentrations from 40 to 100 µg/l. The changes of tolerance and induction of MTs in exposed D. magna and their offspring were measured. The reduced tolerance of exposed D. magna was returned to levels similar to control after about 9 days in a generation. The level of MT still increased up to 3 days after exposure. In the experimental range, exposure duration played a decisive role in MT induction. The tolerance of F1 was lower than F0 and decreased with increasing pulsed concentrations of F0. Exposed to the same pulse, the MT levels of F1 were higher than the MT levels of F0, but the more obvious detoxification of MT in F1 had not been found. Our results suggest that pulsed cadmium exposure had impact on offspring of exposed organism and the risk assessment should take trans-generational effect into account.