The development of a stable, functional electrolyte is urgently required for fast-charging and high-voltage lithium-ion batteries as well as next-generation advanced batteries (e.g., Li−O 2 systems). Acetonitrile (AN) solutions are one of the most promising electrolytes with remarkably high chemical and oxidative stability as well as high ionic conductivity, but its low stability against reduction is a critical problem that hinders its extensive applications. Herein, we report enhanced reductive stability of a superconcentrated AN solution (>4 mol dm −3 ). Applying it to a battery electrolyte, we demonstrate, for the first time, reversible lithium intercalation into a graphite electrode in a reduction-vulnerable AN solvent. Moreover, the reaction kinetics is much faster than in a currently used commercial electrolyte. First-principle calculations combined with spectroscopic analyses reveal that the peculiar reductive stability arises from modified frontier orbital characters unique to such superconcentrated solutions, in which all solvents and anions coordinate to Li + cations to form a fluid polymeric network of anions and Li + cations. ■ INTRODUCTIONWith growing public concern about environmental and energy issues, considerable effort has been devoted to the development of cutting-edge electrochemical energy-storage technologies such as high-voltage and fast-charging lithium-ion batteries as well as next-generation lithium−oxygen batteries. 1−4 A key material in such advanced batteries is a stable, functional electrolyte that allows for reversible and rapid positive/negative electrode reactions without suffering from severe oxidative/ reductive decompositions. In particular, an oxidation-tolerant electrolyte is primarily required to meet the recent remarkable progress and diversification of positive-electrode materials for high-voltage advanced batteries.Acetonitrile (AN) is one of the most oxidation-tolerant organic solvents. In addition, due to its high dielectric constant, 5 AN can easily dissolve electrolyte salts to exhibit considerably high ionic conductivity. Because of these attractive features, AN solutions are a promising electrolyte for various electrochemical devices. 6−9 Particularly, applying them to lithium-ion batteries will eliminate the conventional voltage limitation (∼4.2 V) based on the electrochemical window of currently used carbonate-based electrolytes to open the possibility of high-voltage operation with a 5 V-class positive electrode. 4,10 Furthermore, the excellent ionic transport property will possibly realize fast-charging lithium-ion batteries, which are urgently required for automobile applications.Despite these remarkable advantages, AN has not found extensive application in batteries. This is primarily due to its crucially poor reductive stability. AN spontaneously reacts with lithium metal (i.e., a strong reducing agent), and thus, a lithium metal electrode does not work reversibly in AN electrolytes. 11 For the same reason, there is no report on reversible lithium intercalati...

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Lithium-ion batteries have exclusively employed an ethylene carbonate (EC)-based electrolyte to ensure the reversibility of the graphite negative electrode reaction. Because of the limitation of electrolyte compositions, there has been no remarkable progress in commercial lithium-ion batteries despite active research on positive electrode materials. Herein, we present a salt-superconcentrating strategy as a simple and effective method of universalizing a graphite negative electrode reaction in various organic solvents. A dilute electrolyte (e.g., 1 mol dm(-3)) of sulfoxide, ether, and sulfone results in solvent cointercalation and/or severe electrolyte decomposition at a graphite electrode, whereas their superconcentrated electrolyte (e.g., >3 mol dm(-3)) allows for highly reversible lithium intercalation into graphite. We have found a unique coordination structure in the superconcentrated solution and an anion-based inorganic SEI film on the cycled graphite electrode, which would be the origin of the reversible graphite negative electrode reaction without EC. Our salt-superconcentrating strategy, expanding the graphite negative electrode reaction in various organic solvents other than EC, will contribute to the development of advanced lithium-ion batteries with high-voltage and fast-charging characters based on new EC-free functional electrolytes.

Our results, showing downregulation of the cornified envelope genes and upregulation of the alternative keratinization pathway, are the first to suggest abnormal epidermal differentiation and defective defences as key abnormalities in AD.

BACKGROUND: Thromboembolic events are a major complication in ovarian cancer patients. Tissue factor (TF) is frequently overexpressed in ovarian cancer tissue and correlates with intravascular thrombosis. TF binds to coagulation factor VII (fVII), changing it to its active form, fVIIa. This leads to activation of the extrinsic coagulation cascade. fVII is produced by the liver and believed to be supplied from blood plasma at the site of coagulation. However, we recently showed that ovarian cancer cells express fVII transcripts under normoxia and that this transcription is inducible under hypoxia. These findings led us to hypothesise that ovarian cancer cells are intrinsically associated with TF-fVIIa coagulation activity, which could result in thrombosis. METHODS: In this study, we examined whether ectopically expressed fVII could cause thrombosis by means of immunohistochemistry, RT -PCR, western blotting and flow cytometry. RESULTS: Ectopic fVII expression occurs frequently in ovarian cancers, particularly in clear cell carcinoma. We further showed that ovarian cancer cells express TF-fVIIa on the cell surface under normoxia and that this procoagulant activity is enhanced by hypoxic stimuli. Moreover, we showed that ovarian cancer cells secrete microparticles (MPs) with TF-fVIIa activity. Production of this procoagulant secretion is enhanced under hypoxia. CONCLUSION: These results raise the possibility that cancer cell-derived TF-fVIIa could cause thrombotic events in ovarian cancer patients.

In this study, we investigated the clinicopathologic significance of the low-affinity p75 neurotrophin receptor (p75NTR; which is expressed in the stem/progenitor cell fraction of normal esophageal epithelial cells) in 187 resected esophageal squamous cell carcinoma (ESCC) specimens and found that f50% of ESCC expressed p75NTR. Our investigation using ESCC cell lines showed that p75NTR was intensely expressed in the cells with high colony-forming capacity but they were sensitive to cell death on inhibition of p75NTR expression with transient transfection of small interfering RNA (siRNA). These findings suggest that p75NTR is necessary for survival and maintenance of ESCC tumors, providing us with a potential target for novel therapies. Purpose: p75NTR is expressed in a stem/progenitor cell fraction of human normal esophageal epithelial cells. In this study, we investigated the expression and biological role of p75NTR in ESCC.Experimental Design:The expression of p75NTR in 187 resected ESCC specimens was immunohistochemically investigated. The expression of p75NTR in 30 ESCC cell lines (KYSEs) was assessed by reverse transcription-PCR, immunocytochemistry, and flow cytometry. The p75NTR-bright and p75NTR-dim/negative cells were isolated from KYSE150 by magnetic beads and colony formation was investigated. The role of p75NTR in KYSEs was assessed by transient transfection of siRNA. Results: p75NTR was expressed in 92 of 187 (49.2%) tumors. In well-differentiated tumors, positive staining was apparent in the first one to two layers from infiltrative margin of the tumors where most of the cells were actively proliferating. In moderately differentiated tumors, p75NTR was expressed in wider range from the margin of the tumors whereas p75NTR was diffusely distributed in poorly differentiated tumors. p75NTR was expressed in all examined KYSEs and the mean proportion of the p75NTR-bright fraction was 30.1%.The size of p75NTR-positive colonies was larger than that of p75NTR-negative colonies derived from KYSE150 (P < 0.0001). The purified p75NTR-bright cells formed p75NTR-positive large colonies more frequently than the p75NTR-dim/negative cells (P < 0.0001). Down-regulation of p75NTR expression by siRNA resulted in marked growth inhibition with induction of apoptosis. Conclusions: Our findings suggest that p75NTR is necessary for survival and maintenance of ESCC tumors, providing us with a potential target for novel therapies.

I nvasive cancer cells possess abilities to break down the surrounding extracellular matrix (ECM) and to migrate through it, which are elemental processes in cancer metastasis.(1) Since these processes take place in non-cancerous cells engaged in inflammatory responses or wound healing, identification of invasive behaviors specific to cancer cells is crucial to elucidate the mechanism of cancer invasion and to prevent cancer metastasis. One of the invasive responses of cancer cells upon contact with the ECM is the formation of specialized actin-cytoskeletal protrusions towards the ECM, termed invadopodia ( (2-6) for reviews). Invadopodia were initially described with v-src-transformed fibroblasts, (7) and formed in several invasive cancer cells cultured on the ECM. Whereas the cell shapes of cancer cells invading the three-dimensional ECM are quite diverse, (8,9) the morphology of invadopodia is similar among the cells. They extend from the ventral cell membranes to the ECM and are 0.1-0.8 μm in diameter and over 2 μm in length.(10,11) Although a specific molecular marker that is exclusively present in invadopodia has not been identified so far, invadopodia are characterized by focalized degradation of the surrounding ECM and colocalization of multiple proteins that are involved in cell adhesion, signal transduction especially downstream of src kinase, regulation of the actin cytoskeleton and cellular motility. (2,5,6) One of the key components for rearrangement of the actin cytoskeleton in invadopodia is neural Wiskott-Aldrich Syndrome protein (N-WASP). (12,13) The N-WASP and related WASP family Verprolinhomologous protein (WAVE) family proteins that activate the Arp2/3 complex are important regulators of the initiation of actin polymerization ( (14) for a review). In two-dimensional cell cultures, N-WASP and WAVE family proteins have been shown to work in the formation of certain types of actin-based protrusions in the cell periphery, such as filopodia and lamellipodia. (15,16) Invadopodia are formed through the N-WASPArp2/3 signaling pathway. (12,17) Corresponding to these results, activation of N-WASP, as assessed by fluorescence resonance energy transfer analysis to detect the conformational change of N-WASP, was demonstrated to occur at the site of invadopodia formation.(18) Despite accumulating knowledge about the mechanism and dynamics of invadopodia formation, (11,13) it is as yet unknown whether the formation of invadopodia represents cell invasiveness through the ECM. (3,4) This may be partly because the formation of invadopodia has been studied in most cases with thin layers of ECM, the thickness of which is not sufficient to observe cell invasion into the ECM.To identify the protrusive structures that closely link to invasion through the ECM, we made a three-dimensional (3-D) culture system consisting of a thick layer of native collagen type-I gel overlaid with a thin layer of basement membrane equivalent (Matrigel) that mimics the configuration of epithelial tissues. When cultured on Matrigel, an i...

Telomerase activity is correlated with the immortality of various cultured cells and cancer cells. The activity, however, is also demonstrated in various normal regenerating cells which normally have a ®nite life span in vivo and in vitro, though its biological implication remains unclear. Using cultured normal human epithelial cells, we show that telomerase activity is associated with epithelial cell subsets which actively proliferate in vitro. Unlike in most cancer cell lines, telomerase activity was evidently up-regulated when the cells entered into S phase in primary human epithelial cells. To characterize the cells which have telomerase activity, the primary human epithelial cell population of uterine cervix was dissociated into several distinctive cellular subsets by means of immunocytochemical cell fractionation. Telomerase activity was found to be closely associated with the subset which expressed predominantly integrin b1 and epidermal growth factor receptor. We further identi®ed the telomerase-negative subpopulation which contained a small subset that strongly coexpresses p75 NGFR low a nity nerve growth factor receptor, integrin b4 and bcl-2 protein. The location of the p75 NGFR -expressing cells contrasts to that of the Ki-67 positive cells in vivo and is distinctive of telomerase positive cycling cells, indicating that these cells remain at the G0 phase. The present study supports the notion that telomerase activity is linked to cell cycle regulation, implying that telomerase is activated upon cell proliferation in regenerating normal human epithelial cells.