We discuss two-dimensional (2D) topological insulators (TIs) based on planar Bi/Sb honeycombs on a SiC(0001) substrate using first-principles computations. The Bi/Sb planar honeycombs on SiC (0001) are shown to support a nontrivial band gap as large as 0.56 eV, which harbors a Dirac cone lying within the band gap. Effects of hydrogen atoms placed on either just one side or on both sides of the planar honeycombs are examined. The hydrogenated honeycombs are found to exhibit topologically protected edge states for zigzag as well as armchair edges, with a wide band gap of 1.03 and 0.41 eV in bismuth and antimony films, respectively. Our findings pave the way for using planar bismuth and antimony honeycombs as potential new 2D-TI platforms for room-temperature applications.Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence.Any further distribution of this work must maintain attribution to the author (s) and the title of the work, journal citation and DOI. 4 After this work was completed, we recently became aware of an independent study of BiX and SbX films by Song et al [23] who consider passivation with X atoms on both sides of the film. In contrast, we consider one-sided H-passivation, which is the key for breaking the inversion symmetry and inducing large spin-splittings. The effect of the one-sided H-passivation is similar to that of the SiC substrate.

Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.tumor suppression | tryptophan metabolism | inflammation control C yclooxygenase-2 (COX-2) is a rate-limiting enzyme in the production of diverse prostanoids with potent biological activities. It is involved in multiple physiological functions and triggers key pathological processes, such as tumorigenesis and inflammation (1, 2). COX-2 is constitutively overexpressed in a wide variety of human cancers and is enhanced by proinflammatory stimuli (3, 4). There is convincing evidence for a causal role of COX-2 in tumorigenesis. Inhibition of COX-2 activities was reported to control human colorectal cancer (5-8). COX-2 induces tumorigenesis by promoting important cellular functions including cell proliferation, migration, and resistance to apoptosis (9-11). The induced COX-2 expression by proinflammatory and mitogenic factors in normal cells is tightly controlled (12) whereas its overexpression in cancer cells is attributed to dysregulated transcription (13). The endogenous control mechanisms for COX-2 expression in normal cells and the mechanisms underlying the dysregulation in cancer cells are poorly understood. We previously identified in the conditioned medium of human fibroblasts small molecules (named cytoguardins) that suppress COX-2 expression induced by proinflammatory mediators (14). NMR analysis of a semipurified fraction revealed compounds with indole moieties (14). However, the exact chemical structures remain elusive. In this study, we elucidated the structure of cytoguardins by comparing the metabolomic profiles between normal and cancer cells. ResultsCytoguardins Inhibit Cancer Cell COX-2. To determine that fibroblast factors are capable of suppressing cancer cell COX-2 expression, we cocultured human Hs68 foreskin fibroblasts (HsFb) with A549 lung cancer cells in a Boyden chamber for 24 h. A549 cells were removed and treated with phorbol 12-myristate 13-acetate (PMA) for 4 h, and COX-2 proteins were analyzed. HsFb suppressed A549 ...

Rationale: Systemic inflammation has emerged as a key pathophysiological process that induces multiorgan injury and causes serious human diseases. Endothelium is critical in maintaining cellular and inflammatory homeostasis, controlling systemic inflammation, and progression of inflammatory diseases. We postulated that endothelium produces and releases endogenous soluble factors to modulate inflammatory responses and protect against systemic inflammation. Objective: To identify endothelial cell–released soluble factors that protect against endothelial barrier dysfunction and systemic inflammation. Methods and Results: We found that conditioned medium of endothelial cells inhibited cyclooxgenase-2 and interleukin-6 expression in macrophages stimulated with lipopolysaccharide. Analysis of conditioned medium extracts by liquid chromatography–mass spectrometry showed the presence of 5-methoxytryptophan (5-MTP), but not other related tryptophan metabolites. Furthermore, endothelial cell–derived 5-MTP suppressed lipopolysaccharide-induced inflammatory responses and signaling in macrophages and endotoxemic lung tissues. Lipopolysaccharide suppressed 5-MTP level in endothelial cell-conditioned medium and reduced serum 5-MTP level in the murine sepsis model. Intraperitoneal injection of 5-MTP restored serum 5-MTP accompanied by the inhibition of lipopolysaccharide-induced endothelial leakage and suppression of lipopolysaccharide- or cecal ligation and puncture–mediated proinflammatory mediators overexpression. 5-MTP administration rescued lungs from lipopolysaccharide-induced damages and prevented sepsis-related mortality. Importantly, compared with healthy subjects, serum 5-MTP level in septic patients was decreased by 65%, indicating an important clinical relevance. Conclusions: We conclude that 5-MTP belongs to a novel class of endothelium-derived protective molecules that defend against endothelial barrier dysfunction and excessive systemic inflammatory responses.

PI3K involvement has been implicated in the TLR signal pathway. However, the precise roles of the different classes of PI3K in the pathway remain elusive. In this study, we have explored the functions of class I and class III PI3K in the TLR signal pathway using specific kinase mutants and PI3K lipid products. Our results reveal that class III PI3K specifically regulates CpG oligodeoxynucleotide (ODN)-induced cytokine and NO production as well as NF-κB activation, whereas class I PI3K regulates both CpG ODN- and LPS-induced IL-12 production and NF-κB activation. Additional studies of CpG ODN uptake with flow cytometric analysis show that class III PI3K, but not class I, regulates cellular CpG ODN uptake. Furthermore, experiments with MyD88-overexpressing fibroblast cells transfected with dominant-negative mutants of PI3K demonstrate that class III PI3K regulates CpG ODN-mediated signaling upstream of MyD88, while class I PI3K regulation is downstream of MyD88. These results suggest that class I and class III PI3K play distinct roles in not only the uptake of CpG ODN, but also responses elicited by CpG ODN and LPS.

BackgroundThe epidermis forms a critical barrier that is maintained by orchestrated programs of proliferation, differentiation, and cell death. Gene mutations that disturb this turnover process may cause skin diseases. Human GASDERMIN A (GSDMA) is frequently silenced in gastric cancer cell lines and its overexpression has been reported to induce apoptosis. GSDMA has also been linked with airway hyperresponsiveness in genetic association studies. The function of GSDMA in the skin was deduced by dominant mutations in mouse gasdermin A3 (Gsdma3), which caused skin inflammation and hair loss. However, the mechanism for the autosomal dominance of Gsdma3 mutations and the mode of Gsdma3’s action remain unanswered.ResultsWe demonstrated a novel function of Gsdma3 in modulating mitochondrial oxidative stress. We showed that Gsdma3 is regulated by intramolecular fold-back inhibition, which is disrupted by dominant mutations in the C-terminal domain. The unmasked N-terminal domain of Gsdma3 associates with Hsp90 and is delivered to mitochondrial via mitochondrial importer receptor Tom70, where it interacts with the mitochondrial chaperone Trap1 and causes increased production of mitochondrial reactive oxygen species (ROS), dissipation of mitochondrial membrane potential, and mitochondrial permeability transition (MPT). Overexpression of the C-terminal domain of Gsdma3 as well as pharmacological interventions of mitochondrial translocation, ROS production, and MPT pore opening alleviate the cell death induced by Gsdma3 mutants.ConclusionsOur results indicate that the genetic mutations in the C-terminal domain of Gsdma3 are gain-of-function mutations which unmask the N-terminal functional domain of Gsdma3. Gsdma3 regulates mitochondrial oxidative stress through mitochondrial targeting. Since mitochondrial ROS has been shown to promote epidermal differentiation, we hypothesize that Gsdma3 regulates context-dependent response of keratinocytes to differentiation and cell death signals by impinging on mitochondria.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0152-0) contains supplementary material, which is available to authorized users.

Self-organized patterning of supported nanoclusters by virtue of low cost and readiness for mass production is considered as one of the most promising methods; however, this approach is challenging, since the capability of controlling the patterns relies on a suitable combination of clusters and templates. In this paper we demonstrate that Co nanoclusters grown from vapour deposition over Al2O3 thin films on NiAl(100) substrate make a perfect combination for self-organized patterning. Uniform and sizeable Co nanoclusters are formed only on crystalline Al2O3 films and they are highly aligned by protrusion structures of the crystalline Al2O3. Through simple thermal treatments we can pattern the crystalline Al2O3 films and consequently the grown Co nanoclusters. The patterns are robust as they are sustained even when the Co nanoclusters are flashed to 750 K, exposed to atmosphere or the coverage is increased to coalescence. Moreover, the patterns can be further refined by using STM tips. The results imply potential applications in both fundamental and applied researches for electronic and magnetic nanodevices as well as catalysis.

The realization of molecular electronics requires comprehension of single-molecule I-V characteristics. Aside from the electron-transport properties of the molecular framework, the molecule-electrode binding contributes significantly to the contact resistance, R n)0 , and thus to the values of single-molecule resistance. Isothiocyanate (-NCS), a versatile ligand for organometallics, can bind to a metal substrate to complete a metal-moleculemetal configuration for external measurements. Isothiocyanate has the advantage of being a π-conjugated moiety that presumably exhibits a relatively smaller impedance than the commonly used methylene thiol headgroup (-CH 2 SH) in many molecular wires. For example, this study shows that the single-molecule conductance of n-butanediisothiocyanate is an order of magnitude better than that of n-octanedithiol even though they both contain 10 atoms counted from sulfur to sulfur. For a homologous series of molecules, R n)0 can be extrapolated from the intercept of the resistance obtained by the repeated formation of molecular junctions using scanning tunneling microscopy. To isolate the contact effect of the -NCS-Au electrode from other factors, alkanediisothiocyanates were studied because the large HOMO-LUMO gap of alkyl chains is not sensitive to the number of methylene units. The results show two sets of R n)0 values, with the smaller set being 128 kΩ, about 1/12 the other value. A detailed examination of the results suggests that the preferential adsorption site for isothiocyanate on gold is the atop site rather than the 3-fold-hollow sites of thiol on gold.

Objective— Vascular smooth muscle cell (VSMC) transformation to an osteochondrogenic phenotype is an initial step toward arterial calcification, which is highly correlated with cardiovascular disease–related morbidity and mortality. TLR2 (Toll-like receptor 2) plays a pathogenic role in the development of vascular diseases, but its regulation in calcification of arteries and VSMCs remains unclear. We postulate that TLR2-mediated inflammation participates in mediating atherosclerotic arterial calcification and VSMC calcification. Approach and Results— We found that ApoE −/− Tlr2 −/− genotype in mice suppressed high-fat diet–induced atherosclerotic plaques formation during initiation but progressively lost its preventative capacity, compared with ApoE −/− mice. However, TLR2 deficiency prohibited high-fat diet–induced advanced atherosclerotic calcification, chondrogenic metaplasia, and OPG (osteoprotegerin) downregulation in the calcified lesions. Incubation of VSMCs in a calcifying medium revealed that TLR2 agonists significantly increased VSMC calcification and chondrogenic differentiation. Furthermore, TLR2 deficiency suppressed TLR2 agonist–mediated VSMC chondrogenic differentiation and consequent calcification, which were triggered via the concerted actions of IL (interleukin)-6–mediated RANKL (receptor activator of nuclear factor κB ligand) induction and OPG suppression. Inhibition experiments with pharmacological inhibitors demonstrated that IL-6–mediated RANKL induction is signaled by p38 and ERK1/2 (extracellular signal-regulated kinase 1/2) pathways, whereas the OPG is suppressed via NF-κB (nuclear factor κB) dependent signaling mediated by ERK1/2. Conclusions— We concluded that on ligand binding, TLR2 activates p38 and ERK1/2 signaling to selectively modulate the upregulation of IL-6–mediated RANKL and downregulation of OPG. These signaling pathways act in concert to induce chondrogenic transdifferentiation of VSMCs, which in turn leads to vascular calcification during the pathogenesis of atherosclerosis.