Isolated Diatomic Ni-Fe Metal-Nitrogen Sites for Synergistic Electroreduction of CO2

Polynary single‐atom structures can combine the advantages of homogeneous and heterogeneous catalysts while providing synergistic functions based on different molecules and their interfaces. However, the fabrication and identification of such an active‐site prototype remain elusive. Here we report isolated diatomic Ni‐Fe sites anchored on nitrogenated carbon as an efficient electrocatalyst for CO2 reduction. The catalyst exhibits high selectivity with CO Faradaic efficiency above 90 % over a wide potential range from −0.5 to −0.9 V (98 % at −0.7 V), and robust durability, retaining 99 % of its initial selectivity after 30 hours of electrolysis. Density functional theory studies reveal that the neighboring Ni‐Fe centers not only function in synergy to decrease the reaction barrier for the formation of COOH* and desorption of CO, but also undergo distinct structural evolution into a CO‐adsorbed moiety upon CO2 uptake.This research was undertaken with the assistance of resources provided by the National Computing Infrastructure (NCI) facility at the Australian National University allocated through both the National Computational Merit Allocation Scheme supported by the Australian Government and the Australian Research Council grant LE160100051 (Maintaining and enhancing merit-based access to the NCI National Facility, 2016–2018). This work was supported by the Australian Research Council (DP160103107, FT170100224)

Phosphine vapor-assisted construction of heterostructured Ni2P/NiTe2 catalysts for efficient hydrogen evolution

Heterostructured catalysts with unique interfaces and properties endow distinct advantages for many electrochemical reactions. Herein, a phosphine (PH3) vapor-assisted phase and structure engineering strategy is developed for the controllable conversion of non-active NiTe into a heterostructured active Ni2P/NiTe2 catalyst for alkaline hydrogen evolution reaction (HER). The crystalline NiTe2 phase in situ generated in a PH3 vapor environment and the nanosheet morphology both contribute to the outstanding alkaline HER performance with an overpotential of only 62 mV to achieve a current density of −10 mA cm−2. Experimental and DFT mechanistic studies suggest the Ni2P/NiTe2 interfaces provide abundant exposed active sites. The Ni2P/NiTe2 catalyst shows the lowest kinetic barrier for water dissociation and the adsorbed H* can simultaneously bind to two Ni atoms at the interface of Ni2P/NiTe2(011), which greatly enhances the H* binding and HER activities. DFT simulation also shows that more electrons transfer from Ni atoms to H* on Ni2P/NiTe2(011) (0.22 e−) than that on NiTe2(011) (0.13 e−), which explains the enhanced H* binding at the Ni2P/NiTe2(011) interface. The PH3 vapor synthetic approach is also applied to treat other chalcogenide-based materials with low HER activities, such as Ni3S2, to create Ni2P/NiS2 interfaces for significantly enhanced HER activity.This research was undertaken with the assistance of resources provided by the National Computational Infrastructure (NCI) facility at the Australian National University; allocated through both the National Computational Merit Allocation Scheme supported by the Australian Government and the Australian Research Council (LE190100021). C. Zhao acknowledges the award of Future Fellowship from Australian Research Council (FT170100224)

Total ginsenosides extract induce autophagic cell death in NSCLC cells through activation of endoplasmic reticulum stress.

ETHNOPHARMACOLOGICAL RELEVANCE(#br)Ginseng (Panax ginseng C. A. Mey) has been widely used in Asian countries for thousands of years. It has auxiliary anticancer efficacy and its derived preparations (e.g. Shenmai injection) are prescribed for cancer patients as Traditional Chinese Medicines clinically in China.(#br)AIM OF THE STUDY(#br)The involved adjuvant anticancer mechanisms of ginseng are still unknown. The present study evaluated the anti-cancer effect of total ginsenosides extract (TGS) and determined the anticancer mechanisms of TGS-induced cell death in human non-small cell lung cancer (NSCLC) cells.(#br)MATERIALS AND METHODS(#br)The anti-cancer effect of TGS was evaluated in NSCLC by cell proliferation assay. The autophagy flux induction of TGS were tested and validated by Western blot, immunofluorescence and transmission electron microscope. The mechanisms of TGS in inducing autophagic cell death were validated by Western blot, gene knockdown and quantitative real time PCR assay.(#br)RESULTS(#br)We found TGS could induce cell death in concentration and time dependent manners, and the cell morphology of NSCLC changed from cobblestone shape to elongated spindle shape after treated with TGS. In the study of cell autophagy, we confirm that TGS could upregulate autophagy flux and induce autophagic cell death through activation endoplasmic reticulum stress. Further investigations demonstrated this process was mediated by the ATF4-CHOP-AKT1-mTOR axis in NSCLC cells.(#br)CONCLUSION(#br)Our findings suggested that TGS could induce autophagic cell death in NSCLC cells through activation of endoplasmic reticulum stress, disclosing another characteristic of TGS-induced cell death and a novel mechanism of TGS and its derived preparations in clinical treatment of cancer patients

LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal.

CONTEXT: Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumably due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APAs) may be a consequence of protection from cell loss by constitutive aldosterone production. OBJECTIVE: The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover. DESIGN: This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7). INTERVENTIONS: Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3). MAIN OUTCOME MEASURES: A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells were measured. RESULTS: LGR5 was the top gene up-regulated in ZG (25-fold). The gene for its cognate ligand R-spondin-3, RSPO3, was 5-fold up-regulated. In total, 18 genes associated with the Wnt pathway were greater than 2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR and immunohistochemistry. Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production. There was reduced proliferation and increased apoptosis of transfected cells, and the noncanonical activator protein-1/Jun pathway was stimulated more than the canonical Wnt pathway (3-fold vs 1.3-fold). ZG of adrenal sections stained positive for apoptosis markers. CONCLUSION: LGR5 is the most selectively expressed gene in human ZG and reduces aldosterone production and cell number. Such conditions may favor cells whose somatic mutation reverses aldosterone inhibition and cell loss.This work was supported by MJB is an NIHR Senior Investigator NF-SI-0512–10 052; LHS holds a British Heart Foundation PhD studentship FS/11/35/28871; JZ holds a Cambridge Overseas Trust Scholarship; AEDT is funded by the Wellcome Trust Translational Medicine and Therapeutics program 085 686/Z/08/A, and by Singapore A* program; EABA was supported by the Austin Doyle Award (Servier Australia); LHS, JZ and EABA were additionally supported by the NIHR Cambridge Biomedical Research Centre; GM are funded by MRC Programme Grants RDAG/287 and SKAG/001 awarded to Ashok Venkitaraman.This is the author accepted manuscript. The final version is available from the Endocrine Society via http://dx.doi.org/10.1210/jc.2015-173

DACH1, a zona glomerulosa selective gene in the human adrenal, activates transforming growth factor-β signaling and suppresses aldosterone secretion.

Common somatic mutations in CACNAID and ATP1A1 may define a subgroup of smaller, zona glomerulosa (ZG)-like aldosterone-producing adenomas. We have therefore sought signature ZG genes, which may provide insight into the frequency and pathogenesis of ZG-like aldosterone-producing adenomas. Twenty-one pairs of zona fasciculata and ZG and 14 paired aldosterone-producing adenomas from 14 patients with Conn's syndrome and 7 patients with pheochromocytoma were assayed by the Affymetrix Human Genome U133 Plus 2.0 Array. Validation by quantitative real-time polymerase chain reaction was performed on genes >10-fold upregulated in ZG (compared with zona fasciculata) and >10-fold upregulated in aldosterone-producing adenomas (compared with ZG). DACH1, a gene associated with tumor progression, was further analyzed. The role of DACH1 on steroidogenesis, transforming growth factor-β, and Wnt signaling activity was assessed in the human adrenocortical cell line, H295R. Immunohistochemistry confirmed selective expression of DACH1 in human ZG. Silencing of DACH1 in H295R cells increased CYP11B2 mRNA levels and aldosterone production, whereas overexpression of DACH1 decreased aldosterone production. Overexpression of DACH1 in H295R cells activated the transforming growth factor-β and canonical Wnt signaling pathways but inhibited the noncanonical Wnt signaling pathway. Stimulation of primary human adrenal cells with angiotensin II decreased DACH1 mRNA expression. Interestingly, there was little overlap between our top ZG genes and those in rodent ZG. In conclusion, (1) the transcriptome profile of human ZG differs from rodent ZG, (2) DACH1 inhibits aldosterone secretion in human adrenals, and (3) transforming growth factor-β signaling pathway is activated in DACH1 overexpressed cells and may mediate inhibition of aldosterone secretion in human adrenals.The work was funded by a National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0512-10052) to M.J. Brown, the Wellcome Trust (085687/Z/08/A), and the NIHR Cambridge Biomedical Research Centre (Cardiovascular). J. Zhou and E.A.B. Azizan were supported by The Cambridge Commonwealth, European & International Trust. J. Zhou was also supported by the Sun Hung Kai Properties–Kwoks’ Foundation.This is the final version of the article. It first appeared from the American Heart Association via http://dx.doi.org/10.1161/HYP.000000000000002

Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production

Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors.

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies

Distributed Economic Control for AC/DC Hybrid Microgrid

In this paper, a new double-layer droop control mode for island AC/DC microgrids is proposed to realize autonomous and cost-effective operation. The optimal power reference iterative algorithm is used to realize the internal active power distribution in the subnet. On this basis, secondary frequency and voltage adjustments are introduced to realize the economic operation, autonomy and stability of the subnet. At the microgrid level, the local control strategy of cost micro increment deviation is designed to optimize the exchange power between subnets. The cooperation of the two can realize the global economic operation of the microgrid, as well as voltage following and frequency regulation in the subnet. Based on the hybrid AC/DC microgrid simulation model, the effectiveness of the proposed method is verified

Expression of Carbonic Anhydrase IX in NSCLC and its Relationship with VEGF and Ki67 Expression

Background and objective It has been shown that carbonic anhydrase IX (CAIX) was closely related to tumor hypoxia. Proliferating cell nuclear antigen (Ki67) is considered to be an objective indicator which could reliable and comprehensive response to cell population proliferation; vascular endothelial growth factor (VEGF) was positively correlated with tumor angiogenesis. The aim of this study is to investigate the significance of the expression of CAIX in non-small cell lung cancer (NSCLC) tissues by analyzing the correlation between CAIX and clinical characteristics of patients with lung cancer and VEGF, Ki67 expressions. Methods CAIX, VEGF and Ki67 protein were detected in 76 cases of NSCLC and 10 cases of lung inflammatory pseudotumor by immunohistochemistry. Results CAIX was expressed in 45 of 64 cases of NSCLC and not expressed in benign lesion pulmonary tissues. VEGF was expressed in 55 of 76 cases and Ki67 was expressed in 30 of 76 cases. The expression of CAIX in squamous cell carcinoma (SC) was higher than that in adenocarcinoma (AC)(69.7% vs 27.9%, P=0.001). In 34 cases who received radiotherapy, the objective response rates of CAIX positive and negative groups were 27.8% and 62.5% respectively; the expression of CAIX was positively correlated with VEGF (r=0.231, P=0.043) and was not correlated with Ki67 (r=0.064, P=0.583). Conclusion Compared with benign lesion pulmonary tissue, the expression of CAIX in NSCLC tissues is significantly increased and is positively correlated with VEGF. The expression of CAIX was also correlated with the objective response rate of radiotherapy, which provided new evidence about that hypoxia can increase NSCLC radiotherapy resistance

Distributed Economic Control for AC/DC Hybrid Microgrid

In this paper, a new double-layer droop control mode for island AC/DC microgrids is proposed to realize autonomous and cost-effective operation. The optimal power reference iterative algorithm is used to realize the internal active power distribution in the subnet. On this basis, secondary frequency and voltage adjustments are introduced to realize the economic operation, autonomy and stability of the subnet. At the microgrid level, the local control strategy of cost micro increment deviation is designed to optimize the exchange power between subnets. The cooperation of the two can realize the global economic operation of the microgrid, as well as voltage following and frequency regulation in the subnet. Based on the hybrid AC/DC microgrid simulation model, the effectiveness of the proposed method is verified