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Histone lysine demethylases facilitate the activity of oncogenic transcription factors, including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells, where MYC is often overexpressed. We also identified the approved small-molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases, including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC-targeting approach for cancer therapy. Cancer Res; 77(17); 4626–38. ©2017 AACR.

Figure S1 shows siRNA screening in neuroblastoma cells. Figure S2 shows the dentification of ciclopirox that targets KDM4B. Figure S3 shows the CPX effect on other histone methyl marks. Figure S4 shows that CPX targets the Myc pathway. Figure S5 shows that CPX inhibits oxidative phosphorylation. Figure S6 shows the CPX effect on BE2C xenografts with KDM4B knockdown. Table S1 shows the sequences of the focused KDM siRNA library. Table S2 shows the primers for real time PCR.

The MOF-808/AgI Z-scheme heterojunction expanded the light absorption range and promoted the separation of electron–hole pairs, thus enhancing the photocatalytic activity.

A multifunctional α-MnO2/ZnO–C Z-scheme photocatalyst is fabricated for the effective degradation of tetracycline under visible light irradiation.

The formation of a CuBi2O4/BiOCl p–n heterojunction enhances visible light absorption and promotes the separation of photogenerated electron–hole pairs.

In this paper, the element nitrogen (N) is used to partially replace the element nickel (Ni) in flux-cored wire. A 44%Ni-24%Cr-0.18N nitrogen-containing low-nickel flux-cored wire with excellent corrosion resistance is prepared. The corrosion behavior of nitrogen-containing low-nickel weld cladding and Inconel 625 weld cladding in 40 KCl + 60 MgCl2 (wt%) molten salt at 900 °C is studied. The results show that the selective dissolution of Cr occurs in both weld claddings. The corrosion resistance of the 44%Ni-24%Cr-0.18N nitrogen-containing low-nickel weld cladding is better than that of the Inconel 625 weld cladding. The reason is that added N can react with H+ in molten salt to generate NH4+, remove corrosive impurities of MgOH+ in molten salt and change the corrosion environment. N preferentially combines with Cr to form Cr2N, reduces the diffusion precipitation of Cr and improves the corrosion resistance.

In order to research the hot deformation of Inconel 625 deposited metal, the Inconel 625 flux-cored wire was surfaced on carbon steel by GMAW. The true stress–strain curves of the deposited metal were obtained by high-temperature tensile test at temperatures of 600–900 °C and strain rate of 8.33 × 10−5 s−1. The tensile fracture morphology and microstructure were observed by OM, SEM, XRD and TEM, and the thermal deformation behavior and strengthening mechanism of the Inconel 625 deposited metal were analyzed. The results show that the longitudinal section of the tensile fracture of specimen can be judged to be mainly composed of γ austenite, MC and Laves phase at different temperatures. And the flow stress decreases with the increase of temperature. The tensile stress–strain curves of the specimens show obvious work-hardening behavior after yielding at RT, 600 °C and 700 °C, while it decreases obviously, and the stress basically maintains a constant at 760 °C, 800 °C and 900 °C. When the temperature is 700 °C, the plasticity of the sample has a low valley, that is medium temperature brittleness. Inconel 625 deposited metal is divided into three stages by Arrhenius relation: the low-temperature zone (T ≤ 600 °C), the medium-temperature zone (600 °C 760 °C). In the low-temperature zone, it consists of a/2 dislocation pairs cutting the precipitates or continuous cutting matrix channel and stacking faults of precipitates (continuous stacking fault). The strengthening mechanism is dominated by dislocations cutting γ-phase. With the increase of temperature, some dislocation bands and loops appear in the microstructure, and the dislocation bypass mechanism (Orowan mechanism) has been initiated; in the medium-temperature zone, the complex dislocation reactions occur and form dislocation locks and tangles at 700 °C; it is a mixed mechanism of dislocation cutting and bypassing; in the high-temperature zone, a large number of dislocation loops appear in the microstructure, and some irregular dislocation networks can be observed. With the increase of temperature, the dislocation networks become more regular. It shows that the bypass mechanism of dislocation is the main deformation mechanism.

The combustion of combustible gaseous mixture with/without oil droplet is studied based on a rapid compression machine under conditions comparable with the state at the end of compression in SI-eng...

This paper uses the differential game approach to construct a model of cooperative emission reduction involving the government, manufacturing firms, and retail firms under different power structures. It is found that the dominant player receives more subsidies; the development of a mechanism for horizontal technology R&D among enterprises can reduce the financial pressure on the government to implement compensation strategies and improve the effectiveness and performance of supply chain emission reduction; and the government can develop differentiated subsidy schemes to achieve Pareto optimality in the supply chain and environmental performance based on different game strategies and revenue-sharing agreements by enterprises.

The voltage-gated ion channel activity depends on both activation (transition from the resting state to the open state) and inactivation. Inactivation is a self-restraint mechanism to limit ion conduction and is as crucial to membrane excitability as activation. Inactivation can occur when the channel is open or closed. Although open-state inactivation is well understood, the molecular basis of closed-state inactivation has remained elusive. We report cryo-EM structures of human KV4.2 channel complexes in inactivated, open, and closed states. Closed-state inactivation of KV4 involves an unprecedented symmetry breakdown for pore closure by only two of the four S4-S5 linkers, distinct from known mechanisms of open-state inactivation. We further capture KV4 in a putative resting state, revealing how voltage sensor movements control the pore. Moreover, our structures provide insights regarding channel modulation by KChIP2 and DPP6 auxiliary subunits. Our findings elucidate mechanisms of closed-state inactivation and voltage-dependent activation of the KV4 channel.

Sphingolipids are essential lipids in eukaryotic membranes. In humans, the first and rate-limiting step of sphingolipid synthesis is catalyzed by the serine palmitoyltransferase holocomplex, which consists of catalytic components (SPTLC1 and SPTLC2) and regulatory components (ssSPTa and ORMDL3). However, the assembly, substrate processing and regulation of the complex are unclear. Here, we present 8 cryo-electron microscopy structures of the human serine palmitoyltransferase holocomplex in various functional states at resolutions of 2.6–3.4 A. The structures reveal not only how catalytic components recognize the substrate, but also how regulatory components modulate the substrate-binding tunnel to control enzyme activity: ssSPTa engages SPTLC2 and shapes the tunnel to determine substrate specificity. ORMDL3 blocks the tunnel and competes with substrate binding through its amino terminus. These findings provide mechanistic insights into sphingolipid biogenesis governed by the serine palmitoyltransferase complex. Cryo-EM structures of the enzyme complexes catalyzing the rate-limiting step in sphingolipid synthesis reveal mechanisms of substrate recognition and modulation by regulatory subunits.

Ketones have been considered as potential biofuels and main components of blend stock for internal engines. To better understand the chemical kinetics of ketones, ignition delay times of 2-pentanone (propyl methyl ketone, PMK) and 3-pentanone (diethyl ketone, DEK) were measured at temperatures of 895–1128 K under 10 and 20 bar, at equivalence ratios (ϕ) of 0.5 and 1.0 in a rapid compression machine (RCM). To explore the impact of carbonyl functionality and resonance stabilized structures of fuel radicals on their combustion kinetics, high-temperature pyrolysis at 1130 K and relatively low-temperature oxidation at 950 K studies were performed in an RCM, and the time-resolved species concentration profiles under these two conditions were quantified using a fast sampling system and gas chromatography (GC). A new kinetic model containing low-temperature reactions was built aiming at predicting the pyrolysis and oxidation behaviors of both ketones. The consumption pathways of the resonance stabilization fuel radicals through oxygen addition and following reactions are promoted since the decomposition rates of these radicals are about 4 orders magnitudes lower than regular fuel radicals. The occurrences of the so-called “addition-dissociation reactions”, i.e., ketones reacting with a hydrogen yielding aldehyde or reacting with a methyl radical yielding shorter-chain-length ketones, are verified in pyrolysis experiments. Based on experiments and model analysis, the carbonyl functionality in both ketones is preserved during the process of β-scissions of fuel radicals and α-scissions of fuel-related acyl radicals, resulting in the direct formation of CO and ketene. However, the position of carbonyl functionality has a significant impact on the species pools.

HYL derived from the venom of the solitary bee Hylaeus signatus (Hymenoptera: Colletidae) is an α-helical antimicrobial peptide with 16 residues. To explore whether HYL can be applied in anti-tumor therapy, we synthesized HYL and further modified its structure by using a solid-phase synthesis method, and then evaluated their antitumor activities. Firstly, we identified the key residues of HYL by alanine scanning strategy, and then a series of stapled peptides were synthesized by hydrocarbon stapling strategy without destroying the key residues. All the stapled peptides of HYL showed significant improvement not only in α-helicity, but also in antitumor activity and protease resistance when compared to the parent peptide HYL. The results showed that hydrophobicity and amphiphilicity are important factors affecting the antitumor activity of HYL, and the stapling strategy can significantly affect the proteolytic stability and helicity of HYL. What's more, we find that the stapled peptides HYL-14, HYL-16 and HYL-18 show a promising prospect for novel anti-tumor drug development.

Individuals who follow a reinforcement learning heuristic put too much weight on recent failures or successes in placing their next bets. Using a large sample of equity-linked notes (ELNs) investments in South Korea, we find evidence showing a negative effect of reinforcement learning on future investments that lasts longer than one investment period. After losses, investors are less likely to repurchase equity-linked notes and spend less on their repurchases. This behavior also results in reinforcement learners underperforming rational agents. The difference in returns received by reinforcement and non-reinforcement groups is economically large at approximately 10.7%. However, these negative effects of reinforcement learning are mitigated by investors’ higher risk attitudes. We find that more risk-seeking investors are less likely to shun ELNs after undesirable prior returns and that this effect persists for more than one period. The underperformance of reinforcement learners is also reduced with high risk-taking. Overall, our findings highlight how combining different psychological traits can diagnose and improve biases in investor decision-making.

Depression is a common and serious mental disorder. Data on its pathogenesis remain unclear and the options of drug treatments are limited. Here, we explored the role of pyroptosis, a novel pro-inflammatory programmed cell death process, in depression as well as the anti-depression effects and mechanisms of salidroside (Sal), a bioactive extract from

The voltage-gated ion channel activity depends on both activation (transition from the resting state to the open state) and inactivation. Inactivation is a self-restraint mechanism to limit ion conduction and is as crucial to membrane excitability as activation. Inactivation can occur when the channel is open or closed. While open-state inactivation is well understood, the molecular basis of closed-state inactivation has remained elusive. We report cryo-EM structures of human K(V)4.2 channel complexes in inactivated, open, and closed states. Closed-state inactivation of K(V)4 involves an unprecedented symmetry breakdown for pore closure by only two of the four S4-S5 linkers, distinct from known mechanisms of open-state inactivation. We further capture K(V)4 in a putative resting state, revealing how voltage sensor movements activate the pore. Moreover, our structures provide insights regarding channel modulation by KChIP2 and DPP6 auxiliary subunits. Our findings elucidate mechanisms of closed-state inactivation and voltage-dependent activation of the K(V)4 channel.

Amyloid β-protein (Aβ) is reported to activate NLRP3 inflammasomes and drive pyroptosis, which is subsequently involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). To date, the pathogenesis of AD is unfortunately insufficiently elucidated. Therefore, this study was conducted to explore whether Salidroside (Sal) treatment could benefit AD by improving pyroptosis. Firstly, two animal models of AD, induced, respectively, by Aβ1-42 and D-galactose (D-gal)/AlCl3, have been created to assist our appreciation of AD pathophysiology. We then confirmed that pyroptosis is related to the pathogenesis of AD, and Sal can slow the progression of AD by inhibiting pyroptosis. Subsequently, we established the D-gal and Nigericin-induced PC12 cells injury model in vitro to verify Sal blocks pyroptosis mainly by targeting the NLRP3 inflammasome. For in vivo studies, we observed that Aβ accumulation, Tau hyperphosphorylation, neurons of hippocampal damage, and cognitive dysfunction in AD mice, caused by bilateral injection of Aβ1-42 into the hippocampus and treatments with D-gal combine AlCl3. Besides, accumulated Aβ promotes NLRP3 inflammasome activation, which leads to the activation and release of a pro-inflammatory cytokine, interleukin-1 beta (IL-1β). Notably, both Aβ accumulation and hyperphosphorylation of Tau decreased and inhibited pyroptosis by downregulating the expression of IL-1β and IL-18, which can be attributed to the treatment of Sal. We further found that Sal can reverse the increased protein expression of TLR4, MyD88, NF-κB, P-NF-κB, NLRP3, ASC, cleaved Caspase-1, cleaved GSDMD, IL-1β, and IL-18 in vitro. The underlying mechanism may be through inhibiting TLR4/NF-κB/NLRP3/Caspase-1 signaling pathway. Our study highlights the importance of NLRP3 inflammasome-mediated pyroptosis in AD, and how the administration of pharmacological doses of Sal can inhibit NLRP3 inflammasome-mediated pyroptosis and ameliorate AD. Thus, we conclude that NLRP3 inflammasome-mediated pyroptosis plays a significant role in AD and Sal could be a therapeutic drug for AD.

Spark assistance for homogeneous charge compression ignition (HCCI) can control combustion phasing, improve thermal efficiency, and reduce emissions in gasoline engines. As the characteristics of flame propagation determine the control authority of ignition timing, it is important and necessary to investigate pressure dependence of flame speed in the lean-premixed mixture relative to engine operating conditions. Experimental study in an optical rapid compression machine (RCM) and simulation work were carried out using two fuels comprising n-heptane/iso-octane/ethanol with varied octane sensitivity (S). The effective pressure ranged from 10 to 35 bar, temperature from 715 to 860 K, and equivalence ratios between 0.3 and 0.7 to cover the region of lean flammability limits of low and high S fuels with ethanol blended. Based on pressure profiles, flame speed extracted from images, and sensitivity analysis of flame speed, the dependence of flame speed on the effective pressure in low and high S fuels was discovered and the fundamental mechanism behind this phenomena became to be understood in the negative temperature coefficient (NTC) and non-NTC regions, respectively. In the studied temperature conditions, the flame speed of high S fuel has stronger dependence on the pressure than that of low S fuel does. In the NTC region, this phenomenon is attributed to the dependence of H radical concentration on pressure in the unburned mixture and flame structure. In the non-NTC region, promoting effect of dominant reactions varied with pressure can significantly influence pressure dependence of flame speed. Although quite limited data of laminar burning velocity for studied fuels were obtained in high pressures (>15 bar), the trend of flame speed's dependence on pressure was well predicted by two models with different but well-accepted core mechanisms, showing consistent results with the experimental ones in the RCM.

Super-knock has been the main obstacle to improve power density and engine efficiency of modern highly turbocharged gasoline engines. Previous researches show that pre-ignition is the inducement of super-knock, while detonation is the root reason of how super-knock could damage engines dramatically. Lots of studies have been conducted to eliminate pre-ignition for suppressing super-knock indirectly. This work applies the fuel of methane to suppress detonation and then to suppress super-knock directly using a rapid compression machine (RCM). Furthermore, 1-D simulation model was set up to investigate the mechanism why methane could suppress detonation and super-knock. Finally, through single cylinder engine tests, this suppression strategy in engine practical usage was validated. The experiment and simulation results show that replacing the fuel from iso-octane or gasoline to methane while keeping other conditions identically could transfer detonation combustion mode to flame propagation. The peak pressure could be reduced dramatically and there is no pressure oscillation. Therefore, methane mixture could suppress detonation and then to suppress super-knock effectively, even if pre-ignition already exists. It could be an effective and practical control strategy to protect modern highly turbocharged engines.

Ignition delay times of methane-n-hexane-oxygen-dulent mixtures were studied experimentally and numerically in a wide temperature range (640–2335 K) using both a rapid compression machine (RCM) and a shock tube (ST). The RCM results demonstrated a two-stage ignition and negative temperature coefficient (NTC) behavior. Increasing n-hexane concentration, pressure and equivalence ratio shortened the ignition delay time. For the ST experiments, the addition of 10% n-hexane (relative to methane) can reduce the ignition delay time dramatically. However, no further reduction effect can be achieved with increasing addition of n-hexane from 10% to 20%. In addition, increasing equivalence ratio reduces the effect of n-hexane addition on ignition delay time. Three detailed chemical mechanisms, CaltechMech, GalwayMech and LLNLMech, were evaluated based on a quantitative error analysis. LLNLMech and CaltechMech demonstrated the best performance in the RCM and ST temperature ranges, respectively. Chemical kinetic analyses showed that the addition of n-hexane to methane provides some chemical pathways not available for methane oxidation which result in the production of active radicals and eventually accelerate the ignition of the methane-oxygen mixtures. The crucial intermediate species for the ignition process are H_2O_2 and H under RCM and ST conditions, respectively.

Using a large sample of institutional investors’ investments in private equity funds raised between 1991 and 2011, we estimate the extent to which investors’ skill affects their returns. Bootstrap analyses show that the variance of actual performance is higher than would be expected by chance, suggesting that some investors consistently outperform. Extending the Bayesian approach of Korteweg and Sorensen, we estimate that a one‐standard‐deviation increase in skill leads to an increase in annual returns of between one and two percentage points. These results are stronger in the earlier part of the sample period and for venture funds.

Super-knock has been the main obstacle to improve power density and engine efficiency of modern gasoline engines. Previous researches show that the key points of super-knock are composed of pre-ignition and detonation. The former is the inducement and the latter is the root reason why super-knock could damage engines dramatically. Lots of studies have been conducted to suppress super-knock by eliminating pre-ignition. Using a rapid compression machine, this work explores the lean mixture control strategy to eliminate detonation and thus suppressing super-knock. Furthermore, a one-dimensional simulation model was set up to investigate the mechanism of how lean mixture could suppress detonation and super-knock. The experimental and simulation results show that based on detonation and super-knock operating condition, adding 80% additional air while keeping the same fuel energy density could transfer combustion from detonation mode to super-sonic auto-ignitive deflagration mode. The peak pressure and pressure oscillation could be reduced significantly. This indicates that boosted lean burn could suppress detonation and thus suppress super-knock effectively, even if pre-ignition occurs. It could be an effective and practical control strategy to protect modern highly turbocharged gasoline engines.

Overall ignition delay time (OID) is used as indicator to characterize reactivity and anti-knock quality of fuel. In this work, both experimental measurement and modeling work have been conducted to evaluate OID properties for six ternary blends comprising n-heptane/iso-octane/ethanol. Experimental measurement was performed in a rapid compression machine, while modeling work was based on the gasoline surrogate mechanism. The decoupling study on research octane number (RON)/motor octane number (MON) and octane sensitivity (S) has been carried out by adjusting fuel composition. The thermal conditions of experiments cover low-to-medium temperatures from 640 K to 740 K and pressures from 9.5 bar to 21 bar. Oxygen is utilized as the oxidizer while nitrogen and argon are regarded as the buffer gas to adjust thermal conditions. Combined with chemical kinetics analysis, negative temperature coefficient (NTC) behavior in the experiment is entirely attributed to iso-octane and the timing of the first peak HO2 radical concentration has more significant influence on NTC behavior than peak value itself. Octane number and/or S cannot fully revealed fuel anti-knock quality, which is substantially influence by the property of fuels and thermal conditions. At low temperature (640 K), fuels with higher S exhibit better anti-knock performance. However, this advantage will disappear when temperature falls into NTC region. For engine operating in this area, high RON but low S fuels are recommended. Ethanol extends the beneficial area of high S contents due to its low temperature chemical inertness. The low temperature boundary of NTC for iso-octane can be regarded as the demarcation line to determine whether high S contents should be utilized, which is an important reference for fuel-engine co-optima research.