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We consider a two-player game of war of attrition under complete information. It is well-known that this class of games admits equilibria in pure, as well as mixed strategies, and much of the literature has focused on the latter. We show that if the players' payoffs whilst in "war" vary stochastically and their exit payoffs are heterogeneous, then the game admits Markov Perfect equilibria in pure strategies only. This is true irrespective of the degree of randomness and heterogeneity, thus highlighting the fragility of mixed-strategy equilibria to a natural perturbation of the canonical model. In contrast, when the players' flow payoffs are deterministic or their exit payoffs are homogeneous, the game admits equilibria in pure and mixed strategies., Comment: 36 pages

Zinc and copper are considered as excellent metals for oxidation and reducibility, respectively. This study aims to obtain a redox-coupled composite semiconductor, wherein oxides of Zn and Cu were obtained and junctioned, for application as a photocatalyst in hydrogen production. To create a large number of activated sites on the catalyst's surface, the morphologies of the catalysts were controlled and several angular parts were formed. During the junction process, Cu2O and ZnO particles were controlled in cubic and starfish shapes, respectively, and the structure of the junctioned Cu2O/ZnO composite was similar to that of a chrysanthemum flower. Kubelka–Munk and Mott–Schottky plots demonstrated that ZnO and Cu2O have band gaps of 3.2 and 1.9 eV, respectively, and they are n- and p-type semiconductors, respectively. The TRPL and IMVS, as well as the photocurrent density and IMPS, confirmed that the recombination between electrons and holes in the junctioned Cu2O/ZnO particles was very slow, and effective charge separation was achieved. As a result, the amount of hydrogen generated from the junction catalyst was significantly higher than that generated from the single catalysts. In particular, the accumulated amount of evolved hydrogen after 10 h in the 2Cu2O/1ZnO junction catalyst was 2089.5 μmol. Results obtained from spin-trapping ESR experiments suggest that the charge-transfer mechanism in the redox-coupled 2Cu2O/1ZnO junction catalyst follows the S-scheme with a stronger reducing power.

Objective Post–bariatric surgery hypoglycemia (PBH) is defined as the presence of neuroglycopenic symptoms accompanied by postprandial hypoglycemia in bariatric surgery patients. Recent clinical studies using continuous glucose monitoring (CGM) technology revealed that PBH is more frequently observed in vertical sleeve gastrectomy (VSG) patients than previously recognized. PBH cannot be alleviated by current medication. Therefore, a model system to investigate the mechanism and treatment is required. Methods We used CGM in a rat model of VSG and monitored the occurrence of glycemic variability and hypoglycemia in various meal conditions for 4 weeks after surgery. Another cohort of VSG rats with CGM was used to investigate whether the blockade of glucagon-like peptide-1 receptor (GLP-1R) signaling alleviates these symptoms. A mouse VSG model was used to investigate whether the impaired glucose counterregulatory system causes postprandial hypoglycemia. Results Like in humans, rats have increased glycemic variability and hypoglycemia after VSG. Postprandial hypoglycemia was specifically detected after liquid versus solid meals. Further, the blockade of GLP-1R signaling raises the glucose nadir but does not affect glycemic variability. Conclusions Rat bariatric surgery duplicates many features of human post–bariatric surgery hypoglycemia including postprandial hypoglycemia and glycemic variability, while blockade of GLP-1R signaling prevents hypoglycemia but not the variability., Highlights • VSG causes glycemic variability during ad lib feeding condition. • Single liquid meal ingestion causes post-VSG hypoglycemia. • Blockade of GLP-1 receptor prevents post-VSG hypoglycemia.

The free rider problem is widely observed in investments in the common good. For example, if Best Buy offers corporate social responsibility (CSR) programs, such as recycling, tech training, and supplier audit, at its own expense, other firms in the industry can benefit from these programs at no cost (i.e., they become the free riders). Such a free rider effect often manifests itself as a mixed strategy equilibrium, in which potential investors unnecessarily delay their investments. The article “Investment in the common good: Free rider effect and the stability of mixed strategy equilibria” finds that recurring investment opportunities can be a major driver of delays in investment in the common good. It also shows that sufficient heterogeneity in investment cost among potential investors can alleviate the free rider effect. Therefore, the policy makers may try to facilitate investments in public goods (e.g., CSR activities) through some form of selective benefits to potential investors.

Natural killer (NK) cell-based therapy has been studied for the treatment of patients with cancers, but the inadequate infiltration of NK cells into solid tumors remains a big challenge to its clinical application. In this study, we examined the interaction between NK cells and endothelial cells, which might play a major role in NK cell homing to solid tumors. We found that endothelial cells were activated by TNF-α and IL-1β, which were produced by tumor-associated CD11b

The liver is exposed to gut-derived bacterial endotoxin via portal circulation, and recognizes it through toll-like receptor 4 (TLR4). Endotoxin lipopolysaccharide (LPS) stimulates the self-ubiquitination of ubiquitin ligase TRAF6, which is linked to scaffold with protein kinase TAK1 for auto-phosphorylation and subsequent activation. TAK1 activity is a signal transducer in the activating pathways of transcription factors NF-κB and AP-1 for production of various cytokines. Here, we hypothesized that TRAF6-TAK1 axis would be implicated in endotoxin-induced liver disease. Following exposure to endotoxin LPS, TLR4-mediated phosphorylation of TAK1 and transcription of cell-death cytokine TNF-α were triggered in Kupffer cells but not in hepatocytes as well as TNF receptor-mediated and caspase-3-executed apoptosis was occurred in D-galactosamine (GalN)-sensitized hepatocytes under co-culture with Kupffer cells. Treatment with pyridinylmethylene benzothiophene (PMBT) improved endotoxin LPS-induced hepatocyte apoptosis in GalN-sensitized C57BL/6 mice via suppressing NF-κB- and AP-1-regulated expression of TNF-α in Kupffer cells, and rescued the mice from hepatic damage-associated bleeding and death. As a mechanism, PMBT directly inhibited Lys 63-linked ubiquitination of TRAF6, and mitigated scaffold assembly between TRAF6 and the TAK1-activator adaptors TAB1 and TAB2 complex in Kupffer cells. Thereby, PMBT interrupted TRAF6 ubiquitination-induced activation of TAK1 activity in the TLR4-mediated signal cascade leading to TNF-α production. However, PMBT did not directly affect the apoptotic activity of TNF-α on GalN-sensitized hepatocytes. Finally, we propose chemical inhibition of TRAF6-TAK1 axis in Kupffer cells as a strategy for treating liver disease due to gut-derived endotoxin or Gram-negative bacterial infection.

Antisense oligonucleotides (ASOs) are a novel therapeutic approach to target difficult-to-drug protein classes by targeting their corresponding mRNAs. Significantly enhanced ASO activity has been achieved by the targeted delivery of ASOs to selected tissues. One example is the targeted delivery of ASOs to hepatocytes, achieved with N-acetylgalactosamine (GalNAc) conjugation to ASO, which results in selective uptake by asialoglycoprotein receptor (ASGR). Here we have evaluated the potential of GalNAc-conjugated ASOs as a therapeutic approach to targeting difficult-to-drug pathways in hepatocellular carcinoma (HCC). The activity of GalNAc-conjugated ASOs was superior to that of the unconjugated parental ASO in ASGR (+) human HCC cells in vitro, but not in ASGR (−) cells. Both human- and mouse-derived HCC displayed reduced levels of ASGR, however, despite this, GalNAc-conjugated ASOs showed a 5- to 10-fold increase in potency in tumors. Systemically administered GalNAc-conjugated ASOs demonstrated both enhanced antisense activity and antitumor activity in the diethylnitrosamine-induced HCC tumor model. Finally, GalNAc conjugation enhanced ASO activity in human circulating tumor cells from HCC patients, demonstrating the potential of this approach in primary human HCC tumor cells. Taken together, these results provide a strong rationale for a potential therapeutic use of GalNAc-conjugated ASOs for the treatment of HCC., Kim et al. report that the activity of antisense oligonucleotides (ASOs) can be significantly enhanced in hepatocellular carcinoma (HCC) through conjugation with N-acetylgalactosamine (GalNAc), a ligand for asialoglycoprotein receptor (ASGR) expressed highly in hepatocytes, demonstrating the potential application of targeted delivery of ASOs to treat HCC.

We have designed and synthesized twenty-six N-arylindazole-3-carboxamide (3a-p) and N-benzoylindazole (6a-j) derivatives to discover with excellent inhibition activities of α-MSH-stimulated melanogenesis. In the bio evaluation studies of these compounds, we discovered eighteen compounds, out of twenty-six exhibited more potent inhibition than the positive control arbutin. From the SAR studies, we identified 3k and 6g as lead compounds which displayed almost 5 and 9 times more potent inhibition of α-MSH-stimulated melanogenesis respectively than the reference arbutin. It is also evident the presence of electron withdrawing group at para position (R3) for the compounds (3a-p) and presence of +M group at ortho position (R5) for the compounds (6a-j) were crucial for their excellent inhibition activities of α-MSH-stimulated melanogenesis.

The quality of the jet injected from a nozzle is one of the key factors that affects the performance of Pelton turbines. In this study, for the first time, experiments and numerical simulation were conducted to investigate the effect of the spear needle eccentricity on the jet flow in micro Pelton turbines. Results show that the eccentricity of the spear needle causes jet diffusion under low flow conditions and significantly increases the loss of the spear nozzle (injector). Furthermore, the increase in the eccentricity ratio causes extreme jet separation and jet diffusion, and the loss of the spear nozzle increases by 52% (from 453 W to 688 W) when the eccentricity ratio increases by 6%. Analysis of the results confirmed that the pressure deviation and jet velocity imbalance caused by eccentricity are the primary causes of jet diffusion. Furthermore, the results confirm that the eccentricity of the spear needle in the case of a low-capacity Pelton turbine has a significant effect on the jet quality. Thus, further studies on the eccentricity are required to improve the performance of the Pelton turbine.

The leaves of Laurus nobilis, commonly called as bay leaves, have been traditionally used for the treatment of inflammatory symptoms. As a part of the research on the characterization of bioactive constituents from natural products, twenty one sesquiterpene lactones were isolated from the leaves of L. nobilis. Among them, laurenoperoxylides A (1) and B (2) were first reported in nature and sivosinolide (11), altissin (12), maroniolid (13) and 4α-hydroxy-guaia-10(14), 11(13)-diene-12,6α-olide (20) were first isolated from this plant. The anti-inflammatory activity of isolated compounds was evaluated by measuring their effects on the NF-κB transcriptional activity induced by lipopolysaccharide (LPS) in RAW 264.7 macrophages cells. Among twenty one sesquiterpenes, 11-exo-methylenesantonin (9) exerted the most potent inhibition with an IC50 value of 4.0 μM. Santamarine (4), magnolialide (5) and zaluzanin D (18) also significantly inhibited NF-κB activity with IC50 values of

Natural killer (NK) cell killing of melanoma cells involves perforin-mediated delivery of granzymes from NK cells to cancer cells; however, how melanoma cells die remains poorly characterized. Here, we examined the dying process of melanoma cells by using time-lapse imaging. Upon contact with NK cells, B16-F10 cells rounded and most of them showed membrane rupture (98 min); however, B16 parent cells showed writhing and delayed membrane rupture (235 min). This morphological difference depended on the expression levels of myosin regulatory light chain 9 (MYL9) but not activating ligands (CD112, CD155, Rae-1, and MULT-1), SPI, FasL, or PD-L1. Taken together, our data show that melanoma cells show two distinct types of morphological changes upon contact with NK cells and suggest that a strategy to decrease MYL9 expression by melanoma cells may improve the efficacy of NK cell–based immunotherapy.

An undescribed unusual sesquiterpene trimer and three sesquiterpene dimers were isolated from the flowers of Inula japonica. Their structures were elucidated by extensive analysis of 1D and 2D NMR spectroscopic data as well as HRESIMS data. Inulajaponicolide A has an undescribed carbon skeleton comprising of one xanthanolide and two guaianolide units with the linkage mode of C-11/C-3ʹ and C-11ʹ/C-1ʹʹ via a Diels-Alder cycloaddition reaction. Inulajaponicolides C and D exhibited moderate cytotoxic activity against A 549 and NCI-H460 human cancer cell lines with IC50 values ranging from 8.5 to 17.8 μM. Inulajaponicolides A-D and lineariifolianoid A possessed significant inhibitory potency against nitric oxide production in LPS-induced RAW264.7 cells with IC50 values ranging from 1.0 to 4.1 μM.

Two new sesquiterpenoids (1 and 2) and a new ent-pimarane type diterpenoid (3), together with eighteen known compounds (4–21), were isolated from the whole plants of Siegesbeckia pubescens. The structures of the new compounds were determined on the basis of 1D-, 2D NMR and HRESIMS data. All compounds were evaluated for their inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 macrophages. Of these, highly oxygenated germacrane type sesquiterpenoids (1–2 and 13–14) showed significant inhibitory effects with IC50 values ranging from 3.9 to 16.8 μM.

Natural killer (NK) cells eliminate cancer cells in a contact-dependent manner. However, how NK cells find cancer cells remain unclear. Here, using time-lapse imaging, we investigated how individual NK cells migrate toward cancer cells. Although naïve B16F10 cancer cells produce low levels of chemokines, IFN-γ-treated B16F10 cells secreted high levels of CXCL10, low levels of CCL5, but did not secrete CCL2, CCL7, or CXCL12. Wild-type NK cells migrated well toward cancer cells and killed them, whereas NK cells deficient in CXCR3 did not. CXCR3-deficient NK cells also showed slower migration speed than did wild-type NK cells. Taken together, our data show that NK cells find cancer cells, at least in part, by sensing CXCL10 produced by cancer cells and suggest that a strategy to increase CXCL10 secretion by cancer cells may improve the efficacy of NK cell-based immunotherapy.

Cytological examination of urine is the most widely used noninvasive pathologic screen for bladder urothelial carcinoma (BLCA); however, inadequate diagnostic accuracy remains a major challenge. We performed mass spectrometry-based proteomic analysis of urine samples of ten patients with BLCA and ten paired patients with benign urothelial lesion (BUL) to identify ancillary proteomic markers for use in liquid-based cytology (LBC). A total of 4,839 proteins were identified and 112 proteins were confirmed as expressed at significantly different levels between the two groups. We also performed an independent proteomic profiling of tumor tissue samples where we identified 7,916 proteins of which 758 were differentially expressed. Cross-platform comparisons of these data with comparative mRNA expression profiles from The Cancer Genome Atlas identified four putative candidate proteins, AHNAK, EPPK1, MYH14 and OLFM4. To determine their immunocytochemical expression levels in LBC, we examined protein expression data from The Human Protein Atlas and in-house FFPE samples. We further investigated the expression of the four candidate proteins in urine cytology samples from two independent validation cohorts. These analyses revealed AHNAK as a unique intracellular protein differing in immunohistochemical expression and subcellular localization between tumor and non-tumor cells. In conclusion, this study identified a new biomarker, AHNAK, applicable to discrimination between BLCA and BUL by LBC. To our knowledge, the present study provides the first identification of a clinical biomarker for LBC based on in-depth proteomics.

Objectives Malignant ascites is a sign of peritoneal seeding, which is one of the most frequent forms of incurable distant metastasis . Because the development of malignant ascites is associated with an extremely poor prognosis, determining whether it resulted from peritoneal seeding has critical clinical implications in diagnosis, choice of treatment, and active surveillance. At present, the molecular characterizations of malignant ascites are especially limited in case of gastric cancer. We aimed to identify malignant ascites-specific proteins that may contribute to the development of alternative methods for diagnosis and therapeutic monitoring and also increase our understanding of the pathophysiology of peritoneal seeding. Design & methods First, comprehensive proteomic strategies were employed to construct an in-depth proteome of ascitic fluids. Label-free quantitative proteomic analysis was subsequently performed to identify candidates that can differentiate between malignant ascitic fluilds of gastric cancer patients from benign ascitic fluids. Finally, two candidate proteins were verified by ELISA in 84 samples with gastric cancer or liver cirrhosis . Results Comprehensive proteome profiling resulted in the identification of 5347 ascites proteins. Using label-free quantification , we identified 299 proteins that were differentially expressed in ascitic fluids between liver cirrhosis and stage IV gastric cancer patients. In addition, we identified 645 proteins that were significantly expressed in ascitic fluids between liver cirrhosis and gastric cancer patients with peritoneal seeding. Finally, Gastriscin and Periostin that can distinguish malignant ascites from benign ascites were verified by ELISA. Conclusions This study identified and verified protein markers that can distinguish malignant ascites with or without peritoneal seeding from benign ascites. Consequently, our results could be a significant resource for gastric cancer research and biomarker discovery in the diagnosis of malignant ascites.

A novel series of 2-benzyl-1-indanone analogs were investigated as IL-5 inhibitory activity. Among the synthesized compounds, 7-(cyclohexylmethoxy)-2-(4-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7s, 100.0% inhibition at 30 μM, IC50 = 4.0 μM), and 7-(cyclohexylmethoxy)-2-(3-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7t, 95.0% inhibition at 30 μM, IC50 = 6.0 μM) showed the best inhibitory activity against IL-5. The 2-benzyl-1-indanone analogs showed moderate to strong IL-5 inhibitory activity. Especially, hydroxyl (HBD/HBA) substituent at position 3 or 4 on phenyl ring B showed potent IL-5 inhibition. Additionally, the bulky hydrophobic cyclohexylmethoxy group at position 7 of the 1-indanone ring is favorable for the inhibitory activity.

Bioassay-guided fractionation of the methanolic extract from the roots of Cynanchum atratum has resulted in the isolation of three new pregnane glycosides (1-3) along with four known compounds (4-7). Their structures were identified by analysis of the spectroscopic data including extensive 2D NMR. All of the isolates were evaluated for their potential to inhibit the melanin production in α-melanocyte stimulating hormone (α-MSH)-activated B16 melanoma cells. Of these, compounds 4-7 dose-dependently inhibited the melanin production with the IC50 values ranging from 4 μM to 33 μM.

To synthesize durable catalysts, cobalt sulfide (CoS) microsheet particles are woven into a polyhedral cage shape to prevent dissolution and light corrosion during photochemical reactions. Titanium dioxide (TiO2) nanoparticles with excellent stability against water and light are used to enclose the cage. The surface of the dodecahedral CoS particle is positively charged, and the surface of the spherical TiO2 particles is negatively charged, resulting in a core–shell shaped xCoS@yTiO2 heterojunction particle. The xCoS@yTiO2 heterojunction catalyst has a stronger ability to absorb visible light and greater photocatalytic hydrogen evolution activity than pure TiO2 or CoS catalysts: When lactic acid is used as an electronic sacrificial agent, the hydrogen production of 1CoS@2TiO2 reaches 1945 μmol g−1 for 10 h, and the catalytic activities are 114.4 and 13.2 times those of CoS and TiO2, respectively. Spin-trapping ESR results reveal that charge transfer in the core–shell shaped xCoS@yTiO2 heterojunction follows the S-scheme mechanism. The excellent catalytic activity of the core–shell shaped xCoS@yTiO2 heterojunction catalyst is because of its favorable bandgap location for water splitting, higher photocurrent density, lower photoluminescence, and having strong redox sites. These factors ultimately delay the recombination of photo-induced electron/hole pairs and, as a result, high catalytic efficiency is stably maintained up to the fifth recycling test.

Many enveloped viruses bud from cholesterol-rich lipid rafts on the cell membrane. Depleting cellular cholesterol impedes this process and results in viral particles with reduced viability. Viperin (Virus Inhibitory Protein, Endoplasmic Reticulum-associated, Interferon iNducible) is an endoplasmic reticulum membrane-associated enzyme that exerts broad-ranging antiviral effects, including inhibiting the budding of some enveloped viruses. However, the relationship between viperin expression and the retarded budding of virus particles from lipid rafts on the cell membrane is unclear. Here, we investigated the effect of viperin expression on cholesterol biosynthesis using transiently expressed genes in the human cell line human embryonic kidney 293T (HEK293T). We found that viperin expression reduces cholesterol levels by 20% to 30% in these cells. Following this observation, a proteomic screen of the viperin interactome identified several cholesterol biosynthetic enzymes among the top hits, including lanosterol synthase (LS) and squalene monooxygenase (SM), which are enzymes that catalyze key steps in establishing the sterol carbon skeleton. Coimmunoprecipitation experiments confirmed that viperin, LS, and SM form a complex at the endoplasmic reticulum membrane. While coexpression of viperin was found to significantly inhibit the specific activity of LS in HEK293T cell lysates, coexpression of viperin had no effect on the specific activity of SM, although did reduce SM protein levels by approximately 30%. Despite these inhibitory effects, the coexpression of neither LS nor SM was able to reverse the viperin-induced depletion of cellular cholesterol levels, possibly because viperin is highly expressed in transfected HEK293T cells. Our results establish a link between viperin expression and downregulation of cholesterol biosynthesis that helps explain viperin's antiviral effects against enveloped viruses.

A series of catechol and dioxolane analogs containing thiazole CGA derivatives have been synthesized and evaluated for their inhibitory activity against α-MSH. The inhibitory activity was improved by replacing an α,β-unsaturated carbonyl of previously reported caffeamides with thiazole motif. Surprisingly, compound 7d , one of the derivatives of dioxolane analogs, displayed the most potent inhibitory activity with an IC 50 of 0.90 μM. Further studies on metabolic stability and bioactivation potential were also accomplished.

This study presents the improvement of step-climbing capability of a new mobile robot called as RHyMo via kineto-static analysis. To this end, the kinematic analysis of the RHyMo is first performed to obtain the trajectory of its center of mass (CM) when it climbs up a step. Based on this CM trajectory, the linear/angular speeds and accelerations of its links are sequentially calculated. Different from the quasi-static analysis, the linear/angular accelerations are combined with the dynamic equations describing the force and moment equilibriums of RHyMo climbing the step, which are optimally solved by introducing the concept of the required friction coefficient in this study. This kineto-static analysis is repeatedly performed by changing the contact angle between the front track of RHyMo and the ground in order to minimize the torque required to climb the step. The simulations with different contact angles are carried out and then, the experiments using the RHyMo are performed, which can demonstrate that the trend of measured motor current is similar to that simulated by the kineto-static analysis and moreover, the step-climbing capability of the RHyMo is significantly improved by reducing the required motor currents by virtue of the kineto-static analysis.

A number of N -acyl substituted hydroxyethylaminomethyl-4 H -chromen-4-ones 6a – u were prepared and evaluated for their IL-5 inhibitory activity. Among them, the compound 6r (95.0% inhibition at 30 µM, IC 50 = 10.0 µM, C log P = 4.1549) showed most potent inhibitory activity. The structure activity relationship revealed that the bulkier or hydrophobic substituents at urea, carbamate or amide group resulted in good inhibitory activity against IL-5. Moreover, electron donating group at phenyl ring ( 6g and 6s ) is much more active than electron withdrawing group ( 6f ). Finally, replacement of cyclohexylmethoxy group at 5 th position of ring A with bulky aliphatic substituents resulted in the loss of activity.

Parkin is associated with various inflammatory diseases, including Parkinson's disease (PD) and rheumatoid arthritis (RA). However, the precise role of Parkin in RA is unclear. The present study addressed this issue by comparing the development of RA between non-transgenic (non-Tg) mice and PARK2 knockout (KO) mice. We found that cyclooxygenase-2 and inducible nitric oxide synthase expression and nuclear factor-κB activity were reduced but p53 activation was increased in PARK2 KO as compared to non-Tg mice. These effects were associated with reduced p53 degradation. Parkin was found to interact with p53; however, this was abolished in Parkin KO mice, which prevented p53 degradation. Treatment of PARK2 KO mice with p53 inhibitor increased Parkin expression as well as inflammation and RA development while decreasing nuclear p53 translocation, demonstrating that PARK2 deficiency inhibits inflammation in RA via suppression of p53 degradation. These results suggest that RA development may be reduced in PD patients. Keywords: Parkin, Arthritis, p53, Ubiquitination

Sorafenib is the only standard treatment for unresectable hepatocellular carcinoma (HCC), but it provides modest survival benefits over placebo, necessitating predictive biomarkers of the response to sorafenib. Serum samples were obtained from 115 consecutive patients with HCC before sorafenib treatment and analyzed by multiple reaction monitoring-mass spectrometry (MRM-MS) and ELISA to quantify candidate biomarkers. We verified a triple-marker panel to be predictive of the response to sorafenib by MRM-MS, comprising CD5 antigen-like (CD5L), immunoglobulin J (IGJ), and galectin-3-binding protein (LGALS3BP), in HCC patients. This panel was a significant predictor (AUROC > 0.950) of the response to sorafenib treatment, having the best cut-off value (0.4) by multivariate analysis. In the training set, patients who exceeded this cut-off value had significantly better overall survival (median, 21.4 months) than those with lower values (median, 8.6 months; p = 0.001). Further, a value that was lower than this cutoff was an independent predictor of poor overall survival [hazard ratio (HR), 2.728; 95% confidence interval (CI), 1.312–5.672; p = 0.007] and remained an independent predictive factor of rapid progression (HR, 2.631; 95% CI, 1.448–4.780; p = 0.002). When applied to the independent validation set, levels of the cut-off value for triple-marker panel maintained their prognostic value for poor clinical outcomes. On the contrast, the triple-marker panel was not a prognostic factor for patients who were treated with transarterial chemoembolization (TACE). The discriminatory signature of a triple-marker panel provides new insights into targeted proteomic biomarkers for individualized sorafenib therapy.

We consider a two-player game of war of attrition under complete information. It is well- known that this class of games admits equilibria in pure, as well as mixed strategies, and much of the literature has focused on the latter. We show that if the players’ payoffs whilst in “war” vary stochastically and their exit payoffs are heterogeneous, then the game admits Markov Perfect equilibria in pure strategies only. This is true irrespective of the degree of randomness and heterogeneity, thus highlighting the fragility of mixed-strategy equilibria to a natural perturbation of the canonical model. In contrast, when the players’ flow payoffs are deterministic or their exit payoffs are homogeneous, the game admits equilibria in pure and mixed strategies.

This paper explores the role of pre-opening price signals in price discovery and liquidity by analyzing the effect of Rule 48 on stock opening delay and various measures of liquidity. NYSE Rule 48 suspends the responsibility of designated market makers for disseminating pre-opening price indications in the event of extreme market-wide volatility. We show that Rule 48 speeds up the opening of stocks at the expense of lower liquidity. Specifically, the absence of pre-opening price indications results in decreases in various measures of liquidity during the first 30-minutes of the trading day that are statistically and economically significant. We interpret this finding as evidence that liquidity suppliers are less willing to provide liquidity in the absence of a reference point or benchmark regarding the value of a stock.

Operational risk is one of the major risks in the financial industry; major banks around the world lost nearly $210 billion from operational risk events between 2011 and 2016 (Huber and Funaro 2018) and inspection on operational risk is required by the Basel Committee on Banking Supervision. Motivated by the importance of operational risk and its current industry regulation, we study how a financial firm can optimally design inspection policies to manage operational risk losses. Specifically, we propose a continuous-time principal-agent model framework to examine a financial firm's (principal) optimal inspection policy and their employees' (agent) effort towards lowering the risk event occurrences. We first consider two commonly used inspection policies, namely, random and periodic policies, and characterize the optimal inspection strategy under each policy. We identify conditions for two different modes of inspection (effort inducement and error correction) as well as nuanced interactions among inspection frequency, penalty charged on errors, and wage paid to employees. We then compare the performances of random and periodic policies. We find that, contrary to conventional wisdom, the random policy is not always optimal; it is dominated by the periodic policy if the inspection cost is sufficiently low. Furthermore, we construct a hybrid policy that strictly dominates random policy and weakly dominates periodic policy, which suggests that a proper reduction of the random element in the inspection policy can always improve its performance. Finally, calibrating model parameters using operational risk data from a major bank in China, we numerically show that our key insights about random, periodic, and hybrid policies are robust to various model extensions.

Curdlan, a β-1,3-glucan isolated from Alcaligenes faecalis, is an agonist of dectin-1 in various immune cells, including dendritic cells (DCs). However, whether curdlan also activates DCs through other receptors remains unknown. In this study, we found that curdlan activates DCs through dectin-1 and toll-like receptor 4 (TLR4). Curdlan increased the expression levels of surface molecules (CD40, CD80, CD86, and MHC-I/II), the production of cytokines (IL-12, IL-1β, TNF-α, and IFN-β), migration toward MIP-3β, and allogeneic T cell stimulation activity of DCs. Curdlan increased the phosphorylation of Syk, Raf-1, Akt, MAPKs, IKK, and NF-κB p65 in DCs. However, curdlan only slightly activated DCs transfected with small interfering RNAs against dectin-1 or TLR4 and C3H/HeJ DCs, which have non-functional TLR4, in comparison with control DCs. Curdlan increased antitumor activity of DCs in a syngeneic tumor model. In summary, our data show that curdlan activates DCs through dectin-1 and TLR4 signaling and the combination of curdlan and DCs efficiently inhibit tumor growth in mice.

The antitumor activity of cytokine-induced killer (CIK) cells can be increased by co-culturing them with tumor lysate-pulsed dendritic cells (tDCs); this phenomenon has been studied mainly at the population level. Using time-lapse imaging, we examined how CIK cells gather information from tDCs at the single-cell level. tDCs highly expressed CCL5, which bound CCR5 expressed on CIK cells. tDCs strongly induced migration of Ccr5(+/+) CIK cells, but not that of Ccr5(-/-) CIK cells or Ccr5(+/+) CIK cells treated with the CCR5 antagonist Maraviroc. Individual tDCs contacted Ccr5(+/+) CIK cells more frequently and lengthily than with Ccr5(-/-) CIK cells. Consequently, tDCs increased the antitumor activity of Ccr5(+/+) CIK cells in vitro and in vivo, but did not increase that of Ccr5(-/-) CIK cells. Taken together, our data provide insight into the mechanism of CIK cell activation by tDCs at the single-cell level.

T-cell-mediated immune responses play an important role in body protection. However, aberrantly activated immune responses are responsible for inflammatory and autoimmune diseases. The regulation of pathologic immune responses may be a potential therapeutic strategy for the treatment of these diseases. Despite that multiple pharmacologic properties of benzoxathiole derivatives have been defined, the molecular mechanisms underlying these properties remain to be clarified. Here, we demonstrated the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) regulated immune responses and ameliorated experimentally induced inflammatory skin diseases both in vitro and in vivo. BOT-4-one inhibited the differentiation of CD4(+) T-cell subsets by regulating the expression and production of T-cell lineage-specific master transcription factors and cytokines and activating the signal transducer and activator of transcription proteins. In addition, BOT-4-one inhibited TCR-mediated Akt and NF-κB signaling. Topical application of BOT-4-one ameliorated experimentally induced inflammatory skin diseases in mice models such as 2,4,6-trinitrochlorobenzene-induced contact and atopic dermatitis and IL-23-induced psoriasis-like skin inflammation. Our study demonstrated that BOT-4-one ameliorates inflammatory skin diseases by suppressing the pathogenic CD4(+) T cell differentiation and overall immune responses.

Commercial and residential buildings account for 40% of total energy usage in the United Sates. Efforts have been made to better manage energy through the implementation of building energy management systems. In particular, heating, ventilating, and air conditioning consume 50% of energy used in buildings. The system air-conditioner, an individually as well as centrally controlled HVAC system, is widely used across Asia. As energy cost increases, building managers often take building-wide energy saving measures, such as intermittent indoor unit shut-down and setting units to uncomfortable temperatures. In this paper, we argue that a smarter approach is possible. Analyzing a large amount of data collected from indoor units, we see that these units have varying levels of energy consumption and that we can identify those that consume more energy than others, resulting in individual measures for each. We propose a business intelligence framework that allows us to see why certain rooms consume more energy than others through three variables: hours of power-on, hours of thermo-on, and a timeframe of power-on. All variables are visualized, providing building managers with an intuitive understanding of their buildings’ energy consumption. We used real-world data to validate the framework and received positive feedbacks from domain experts.

The silkworm silk glands are powerful secretory organs that can produce and secrete proteins at high levels. As such, it has been suggested that the biosynthetic and secretory power of the silk gland can be harnessed to produce and secrete recombinant proteins in tight or loose association with silk fibers. However, the utility of the silkworm platform is constrained by the fact that it has a relatively primitive protein N-glycosylation pathway, which produces relatively simple insect-type, rather than mammalian-type N-glycans. In this study, we demonstrate for the first time that the silk gland protein N-glycosylation pathway can be glycoengineered. We accomplished this by using a dual piggyBac vector encoding two distinct mammalian glycosyltransferases under the transcriptional control of a posterior silk gland (PSG)-specific promoter. Both mammalian transgenes were expressed and each mammalian N-glycan processing activity was induced in transformed silkworm PSGs. In addition, the transgenic animals produced endogenous glycoproteins containing significant proportions of mammalian-type, terminally galactosylated N-glycans, while the parental animals produced none. This demonstration of the ability to glycoengineer the silkworm extends its potential utility as a recombinant protein production platform.

With the aim of developing novel scaffolds as anticancer agents and inhibitors of NF-κB activity, 60 novel benzofuran- and 2,3-dihydrobenzofuran-2-carboxylic acid N-(substituted)phenylamide derivatives (1a-s, 2a-k, 3a-s, and 4a-k) were designed and synthesized from the reference lead compound KL-1156, which is an inhibitor of NF-κB translocation to the nucleus in LPS-stimulated RAW 264.7 macrophage cells. The novel benzofuran- and 2,3-dihydrobenzofuran-2-carboxamide derivatives exhibited potent cytotoxic activities (measured by the sulforhodamine B assay) at low micromolar concentrations against six human cancer cell lines: ACHN (renal), HCT15 (colon), MM231 (breast), NUGC-3 (gastric), NCI-H23 (lung), and PC-3 (prostate). In addition, these compounds also inhibited LPS-induced NF-κB transcriptional activity. The +M effect and hydrophobic groups on the N-phenyl ring potentiated the anticancer activity and NF-κB inhibitory activity, respectively. However, according to the results of structure-activity relationship studies, only benzofuran-2-carboxylic acid N-(4'-hydroxy)phenylamide (3m) was the lead scaffold with both an outstanding anticancer activity and NF-κB inhibitory activity. This novel lead scaffold may be helpful for investigation of new anticancer agents that act through inactivation of NF-κB.

Ethnopharmacological relevance Saururus chinensis is a medicinal plant used to treat jaundice, pneumonia, edema, fever, and several inflammatory diseases. Saucerneol D (SD), a lignan constituent of this plant, has antioxidant, anti-asthmatic, and anti-inflammatory activities. SD has been previously reported to inhibit the pro-inflammatory responses of RAW264.7 cells and primary mast cells. In this study, we investigated the effect of SD on the functions of dendritic cells (DCs). Materials and methods SD was isolated from methanol extract of the roots of S. chinensis . Bone marrow-derived DCs were used as target cells. The effects of SD on the following DC functions were examined: surface molecule expression, cytokine expression, migration, allogenic T cell activation, heme oxygenase-1 expression, and Toll-like receptor 4 signaling. Results In lipopolysaccharide (LPS)-treated DCs, SD inhibited the expression of cell surface molecules (MHC I/II, CD40, CD80, and CD86), the production of inflammatory mediators (nitric oxide, IL-12, IL-1β, and TNF-α), and allogenic T cell activation capacity. SD also inhibited DC migration toward MIP-3β by down-regulating CCR7 expression. SD attenuated LPS-induced activation of NF-κB and MAPK signaling in DCs, but did not directly inhibit kinase activities of IRAK1, IRAK4, TAK1, or IKKβ in enzymatic assays. SD did not inhibit LPS binding to myeloid differentiation protein-2, co-receptor of TLR4. SD increased the production of reactive oxygen species, Nrf-2, and heme oxygenase (HO)-1, which degrades the heme to immunosuppressive carbon monoxide and biliverdin, which may underlie the anti-inflammatory effects in SD-treated DCs. Conclusions Taken together, these data suggest that SD suppresses LPS-induced activation of DCs through the induction of HO-1, but not by directly affecting Toll-like receptor 4 signaling.

Novel amidochromen-4-one analogs 8a-k and 9a-f were prepared and studied for their IL-5 inhibitory activity. Among the synthesized compounds, (6-benzamido-2-cyclohexyl-4-oxo-4H-chromen-3-yl)methyl acetate (8a, 95% inhibition at 30 μM, IC50=6.1 μM) exhibited potent IL-5 inhibitory activity. The conformational restrictor at position 2 like bulky cyclohexyl group is favorable for the formation of effective conformer of side chain small ester like acetoxymethyl at position 3 of these chromenone analogs 8. In addition the hydrophobic planarity of benzamido group at position 6 should be important for the potent IL-5 inhibitory activity. Since replacing acetoxymethyl moiety with hydroxymethyl group at position 3 of chromenone decreases the activity, which indicates that the location of hydrogen bonding group should be near 4 atom distances away from chromenone ring is more optimum for the activity. Therefore, these benzamidochromen-4-one analogs 8 are novel scaffold for finding potent interleukin-5 inhibitors.

Although non-convulsive status epilepticus (NCSE) is an important type of epilepsy, it is not often recognized. In order to analyze the clinical characteristics and outcome in patients with NCSE, we examined the medical records of patients with NCSE admitted to the Seoul National University Hospital between June 2005 and October 2008. The clinical details and electroencephalography records of 34 adult NCSE patients (aged over 16 years) were collected. Their mean age was 47 years (standard deviation 20 years, range, 16–87 years), and 20 were female. Twenty-seven patients (79.4%) showed decreased awareness with acute onset, and seven (20.6%) were obtunded or comatose. Ten patients (29.4%) had a history of epilepsy, and four (11.8%) had a history of stroke. NCSE was etiologically attributed to acute medical or neurological problems in 25 patients (73.5%), was cryptogenic in three (8.8%), and was secondary to underlying epilepsy in six (17.7%). Acute symptomatic etiology was associated with poor recovery (p = 0.048), with all unresponsive patients in this acute symptomatic group. Eight (23.5%) of the 34 NCSE patients did not recover or died, whereas nine (26.5%) recovered. Our study shows that the presence of acute symptoms or central nervous system infection is associated with poor outcome, suggesting that a high level of vigilance is required to identify and prevent complications.

Sesquiterpenoid tussilagone (TUS) has a variety of pharmacological activities, such as anti-oxidant, anti-cancer, and anti-inflammatory activities. In this study, we investigated the effects of TUS on dendritic cell (DC) functions and the underlying mechanisms. TUS inhibited lipopolysaccharide (LPS)-induced activation of DCs, as shown by decrease in surface molecule expression, cytokine production, cell migration, and allo-T cell activation. In addition, TUS inhibited LPS-induced activation of NF-κB, MAPKs, and IRF-3 signalings in DCs, although it did not directly affect kinase activities of IRAK1/4, TAK1, and IKK, which suggests that TUS might indirectly inhibit TLR signaling in DCs. As a critical mechanism, we showed that TUS activated heme oxygenase-1 (HO-1), which degrades heme to immunosuppressive products, such as carbon monoxide and bilirubin. HO-1 inhibitor reversed the inhibitory activity of TUS in DCs. In conclusion, this study suggests that TUS inhibits DC function through the induction of HO-1.

To investigate the anti-proliferative effect of NF-κB inhibitor, a series of analogs of ( E )-1-(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one ( 5a ) were prepared and evaluated for their NF-κB inhibition and anti-proliferative activity against various human cancer cell lines. Compounds ( E )-1-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one ( 5e ) and ( E )-4-(3-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3-oxoprop-1-enyl)benzenesulfonamide ( 5p ) showed good NF-κB inhibition as well as potent anti-proliferative activity. SAR studies showed that all the compounds with potent or moderate NF-κB inhibition displayed good anti-proliferative activity. All the analogs ( 5b – r ) maintained a good correlation between their NF-κB inhibition and anti-proliferative activity though the extent is not directly proportional to each other.

Encephalitis associated with anti-γ-aminobutyric acid-B (GABAB) receptor antibodies has been identified recently. However, only a few cases have been reported to date and its clinical manifestations and prognosis have not been investigated systematically. We identified five cases of GABAB encephalitis in Korea. Here we present the clinical features, treatment responses, and brain positron emission tomography findings of the cases. The patients had a clinical triad of memory changes, seizure, and association with small-cell lung cancer. Early diagnosis and comprehensive immune modulation may provide a good outcome.

PurposeHyponatremia is one of the most common adverse effects in patients treated with oxcarbazepine (OXC). Most patients with OXC-induced hyponatremia are asymptomatic, so the presence of severe or symptomatic hyponatremia, which requires electrolyte correction or discontinuation of OXC therapy, has more important clinically implications. However, data for OXC-induced severe and symptomatic hyponatremia are limited.MethodsWe reviewed medical records of all patients with epilepsy who were treated with OXC at the Seoul National University Hospital. We analyzed serum sodium level results and attempted to identify correlations between various factors and the frequency of severe and symptomatic OXC-induced hyponatremia.ResultsData from a total 1009 patient were examined. The frequency of severe and symptomatic hyponatremia was 11.1% and 6.8%, respectively. Multivariate analysis revealed that age (P=0.014, OR 1.014), antiepileptic drug (AED) polytherapy (P=0.040, OR 1.540), and the concomitant use of diuretics (P