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Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [14C]-uric acid in URAT1-expressing HEK293 cells with an IC50value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC50value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC50value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg−1· d−1) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg−1· d−1) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.

Herpes simplex virus (HSV) infection induces a rapid and transient increase in intracellular calcium concentration ([Ca2+]i), which plays a critical role in facilitating viral entry. T-type calcium channel blockers and EGTA, a chelate of extracellular Ca2+, suppress HSV-2 infection. But the cellular mechanisms mediating HSV infection-activated Ca2+signaling have not been completely defined. In this study we investigated whether the TRPV4 channel was involved in HSV-2 infection in human vaginal epithelial cells. We showed that the TRPV4 channel was expressed in human vaginal epithelial cells (VK2/E6E7). Using distinct pharmacological tools, we demonstrated that activation of the TRPV4 channel induced Ca2+influx, and the TRPV4 channel worked as a Ca2+-permeable channel in VK2/E6E7 cells. We detected a direct interaction between the TRPV4 channel protein and HSV-2 glycoprotein D in the plasma membrane of VK2/E6E7 cells and the vaginal tissues of HSV-2–infected mice as well as in phallic biopsies from genital herpes patients. Pretreatment with specific TRPV4 channel inhibitors, GSK2193874 (1−4 μM) and HC067047 (100 nM), or gene silence of the TRPV4 channel not only suppressed HSV-2 infectivity but also reduced HSV-2-induced cytokine and chemokine generation in VK2/E6E7 cells by blocking Ca2+influx through TRPV4 channel. These results reveal that the TRPV4 channel works as a Ca2+-permeable channel to facilitate HSV-2 infection in host epithelial cells and suggest that the design and development of novel TRPV4 channel inhibitors may help to treat HSV-2 infections.

Dysregulation of NLRP3 inflammasome results in uncontrolled inflammation, which participates in various chronic diseases. TWIK2 potassium channel mediates potassium efflux that has been reported to be an essential upstream mechanism for ATP-induced NLRP3 inflammasome activation. Thus, TWIK2 potassium channel could be a potential drug target for NLRP3-related inflammatory diseases. In the present study we investigated the effects of known K2P channel modulators on TWIK2 channel expressed in a heterologous system. In order to increase plasma membrane expression and thus TWIK2 currents, a mutant channel with three mutations (TWIK2I289A/L290A/Y308A) in the C-terminus was expressed in COS-7 cells. TWIK2 currents were assessed using whole-cell voltage-clamp recording. Among 6 known K2P channel modulators tested (DCPIB, quinine, fluoxetine, ML365, ML335, and TKDC), ML365 was the most potent TWIK2 channel blocker with an IC50value of 4.07 ± 1.5 μM. Furthermore, ML365 selectively inhibited TWIK2 without affecting TWIK1 or THIK1 channels. We showed that ML365 (1, 5 μM) concentration-dependently inhibited ATP-induced NLRP3 inflammasome activation in LPS-primed murine BMDMs, whereas it did not affect nigericin-induced NLRP3, or non-canonical, AIM2 and NLRC4 inflammasomes activation. Knockdown of TWIK2 significantly impaired the inhibitory effect of ML365 on ATP-induced NLRP3 inflammasome activation. Moreover, we demonstrated that pre-administration of ML365 (1, 10, 25 mg/kg, ip) dose-dependently ameliorated LPS-induced endotoxic shock in mice. In a preliminary pharmacokinetic study conducted in rats, ML365 showed good absolute oral bioavailability with Fvalue of 22.49%. In conclusion, ML365 provides a structural reference for future design of selective TWIK2 channel inhibitors in treating related inflammatory diseases.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in controlling pacemaker activity in both heart and nervous system. Developing HCN channel inhibitors has been proposed to be an important strategy for the treatment of pain, heart failure, arrhythmias, and epilepsy. One HCN channel inhibitor, ivabradine, has been clinically approved for the treatment of angina pectoris and heart failure. In this study, we designed and synthesized eight alkanol amine derivatives, and assessed their effects on HCN channels expressed in COS7 cells using a whole-cell patch clamp method. Among them, compound 4edisplayed the most potent inhibitory activity with an IC50of 2.9 ± 1.2 µM at − 120 mV on HCN2 channel expressed in COS7 cells. Further analysis revealed that application of compound 4e(10 μM) caused a slowing of activation and a hyperpolarizing shift (ΔV1/2= − 30.2 ± 2.9 mV, n= 5) in the voltage dependence of HCN2 channel activation. The inhibitory effect of compound 4eon HCN1 and HCN4 channel expressed in COS7 cells was less potent with IC50of 17.2 ± 1.3 and 7.3 ± 1.2 μM, respectively. Besides, we showed that application of compound 4e(10 μM) inhibited Ihand action potential firing in acutely dissociated mouse small dorsal root ganglion neurons. Our study provides a new strategy for the design and development of potent HCN channel inhibitors.

This research work is focusing on the toxicities of heavy metals of industrial origin to anaerobic digestion of the industrial wastewater. Photobacterium phosphoreumT3S was used as an indicator organism. The acute toxicities of heavy metals on P. phosphoreumT3S were assessed during 15-min half inhibitory concentration (IC50) as indicator at pH 5.5–6. Toxicity assays involved the assessment of multicomponent mixtures using TU and MTI approaches. The results of individual toxicity indicated that the toxicity of Cd, Cu and Pb on P. phosphoreumincreased with increasing concentrations and there was a linear correlation. The 15-min IC50values of Cd, Cu and Pb were 0.537, 1.905 and 1.231 mg/L, respectively, and their toxic order was Cd > Pb > Cu. The combined effects of Cd, Cu and Pb were assayed by equivalent concentration mixing method. The results showed that the combined effects of Cd + Cu, Cd + Pb, Cu + Pb, Cd + Cu + Pb were antagonistic, antagonistic and partly additive. The combined effect of three heavy metals was partly additive.

We have constrained the charge-mass (ε-m) phase space of millicharged particles through the simulation of the rotational evolution of neutron stars, where an extra slow-down effect due to the accretions of millicharged dark matter particles is considered. For a canonical neutron star of M = 1.4M⊙ and R = 10 km with typical magnetic field strength B0 = 1012 G, we have shown an upper limit of millicharged particles, which is compatible with recently experimental and observational bounds. Meanwhile, we have also explored the influences on the ε-m phase space of millicharged particles for different magnetic fields B0 and dark matter density ρDM in the vicinity of the neutron star. [ABSTRACT FROM AUTHOR]

In the view of many Japanese, Mao Zedong remains the key to interpreting contemporary China. Japanese studies on Mao from 2009 to 2012 show the following characteristics. In terms of research institutions and researchers, the traditional research institutes and academic organizations are still the major forces, while the newly established research bases are expected to achieve results in making the study on Mao Zedong more systematic, penetrating and international. Chinese scholars studying in Japan are beginning to enter the academic mainstream and have some ability to make their views heard. In terms of research methods, the Japanese scholars still cherish the tradition of attaching great importance to historical evidence, but they are also beginning to value research results obtained outside of Japan. In terms of content, they focus on relevant topics and trends outside Japan, and seek to benefit from Western and Chinese studies on Mao.

Based on the Monte Carlo simulation conjoined with the embedded atom method (EAM) potentials, a double species model is employed to study the Ni_75−3x/4Al_25−x/4Cr_x (x<3) structure, i.e. impure Ni₃Al together with a grain boundary structure at the equilibrium. At the grain boundary, the model shows that Ll₂-Ni₃Al transforms into fcc-Ni when x increases from 0 to 0.40; then fcc-Ni transforms into Ll₂-Ni₃Cr when x increases from 0.40 to 2.40.

The first-principles, all-electron, ab initio calculations have been performed for an the amazing stable planar structure of Ga5N5 cluster based on the density functional theory. Electronic structure, electron affinity, ionization potential and binding energy are obtained. No spin magnetic moment is found. The results show that the planar structure of the Ga5N5 cluster is stable. It is found that for the planar structure of Ga5N5 cluster, three nitrogen atoms in the N3 subunit bind together with large electron transfer although no free N3 can exist. This may be important to the stability of the planar structure of the Ga5N5 cluster which has the lowest ground-state energy.

Novel interpenetrating polymer network membranes were made from poly(vinyl alcohol)/poly(vinyl pyrrolidone) blends of different compositions. The two polymer components were independently crosslinked chemically with glutaraldehyde and photochemically with 4,4'-diazostilbene-2,2'-disulfonic acid disodium salt. The membrane performances were studied in pervaporation of tetrahydrofuran (THF)/water and THF/methanol mixtures. It was found that the membranes were excellent in THF dehydration, but much less efficient for the separation of THF/methanol mixtures. The pervaporation results were consistent with the membrane swelling data. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 2808–2814, 2003

In the relativistic model, the influences of the parameters in the potential to the incompressibility, effective mass and binding energy of the nuclear matter are studied in detail. The calculation of equation of state of nuclear matter shows that the values of depend on the renormalization condition, we also find that a soft equation of state of nuclear matter can be obtained in a suitable renormalization condition, and the experimental incompressibility coefficient can be reproduced. These results are also used to study the thermal properties of hot -resonant nuclear matter.

We study the thermodynamic properties of a two-site coupled complex q-body Sachdev-Ye-Kitaev (SYK) model in the large-N limit by solving the saddle-point Schwinger-Dyson (SD) equations. We find that its phase diagram is richer than in the Majorana case. In the grand canonical ensemble, we identify a region of small chemical potential and weak coupling between the two SYKs, for which two first order thermodynamic phase transitions occur as a function of temperature. First, we observe a transition from a cold wormhole phase to an intermediate phase that may correspond to a charged wormhole. For a higher temperature, there is another first order transition to the black hole phase. As in the Majorana case, the low temperature wormhole phase is gapped, and for sufficiently large coupling between the two complex SYK, or chemical potential, the first order transitions become crossovers. The total charge is a good indicator to study the phase diagram of the model; it is zero in the cold wormhole phase and jumps discontinuously at the temperatures at which the transitions take place. Based on the approximate conformal symmetry of the ground state, expected to be close to a thermofield double state, we identify the effective low energy action of the model. It is a generalized Schwarzian action with SL(2,R)×U(1) symmetry with an additional potential and an extra degree of freedom related to the charge. In the large N and low temperature limit, results from this low energy action are consistent with those from the solution of the SD equations. Likewise, a large-q analytical calculation of thermodynamic properties confirms the existence of the wormhole phase. Our findings are a preliminary step toward the characterization of traversable wormholes by its field theory dual, a charged strongly interacting fermionic system, that is easier to model experimentally. [ABSTRACT FROM AUTHOR]

Through Introducing using status of a thermal automation control in a typical thermal power station, this thesis analyze the problems in process for improving automatic level in design, installation, adjusting and testing, using, put forward possibility countermeasures of solving these problems.

We have carried out smoothing by averaging at one second intervals for the solar ultrafast fine structure (UFFS) data of Beijing Observatory at 2.84 GHz on May 16, 1981. The result is compared to the burst record with a time constant t = 1 s. We find there is a difference of more than one order of magnitude in the flux calibration, and the burst curves are very different. So we are led to think that the UFFS data of the event are not likely to be reliable.

Abstract: In this paper by using the concept of mixed boundary functions, an analytical method is proposed for a mixed boundary value problem of circular plates. The trial functions are constructed by using the series of particular solutions of the biharmonic equations in the polar coordinate system. Three examples are presented to show the stability and high convergence rate of the method.

A query on the behaviour of a 2.84 GHz ms-resolution receiver developed by Jinet al. at the Beijing Astronomical Observatory (BAO) in the early 1980s is raised in this paper. As an inappropriate use of an electrically controlled attenuator (ECA) and a A/D converter in the receiver, taking an attenuation by 12 db (i.e., a factor of 16) in the intermediate frequency (IF) flux for the equivalent of a data shift to the right by 4 bits, along with other design defects, could have made artificial errors creep into the observations, we throw doubt upon the 205 published solar ultrafast fine structure (UFFS) data taken with such a receiver.

Based on the theory of Euler-Bernoulli beam and Winkler assumption for elastic foundation, a mathematical model is presented. By using Fourier transformation for space variable, Laplace transformation for time variable and convolution theorem for their inverse transformations, a general solution for dynamical problem of infinite beam on an elastic foundation is obtained. Finally, the cases of free vibration,impulsive response and moving load are also discussed.

Zusammenfassung: Mastzellen in Nitrosomorpholin-induzierten adenoiden Lebertumoren der Ratte wurden elektronenmikroskopisch, zytochemisch und morphometrisch untersucht. Alle Befunde sprachen dafür, daß die Mastzellen, die in die epitheliale Komponente der adenoiden Lebertumoren eingestreut sind, Schleimhaut-Mastzellen sind, die, beeinflußt durch einen bisher noch unbekannten Reiz oder Anlockungsfaktor, in die Gangstruktur der Tumoren eingebrochen sind. Die ursprünglich dicht aneinanderliegenden Epithelzellen der Tumoren werden dadurch voneinander getrennt. Unseren Beobachtungen nach dürften die Mastzellen dadurch eine gewisse Rolle bei der Metastasierung der Tumoren spielen.

The study of Social Dilemmas originated in common resources management field. Recently it has been developed to study the puzzling social problems in which a short-term or individual need is pitted against its long-term or group need. Some research and discussions are focused on the choice and decision making in socioeconomic system. In this paper, based on the principle of game theory, a mathematical model is proposed to describe and analyze a typical social dilemma---N-Person Prisoner’s Dilemma in which the individual interest conflicts with the group interest. From the model, a structural cooperation index is defined to indicate the extent of the dilemma and the cooperation trend of the players. An important proposition has been proved that the cooperation choice probability of the players is a monotone increasing function of the structural cooperation index. The way of increasing cooperativeness in N-person Prisoner’s Dilemma is discussed. Using the model, we proved the proposition that the territorial division can break out of the dilemma. In other words, decreasing the size of the group can raise the cooperativeness. Some more discussions and significant results are given.

A ``double perturbation'' theory is presented in the framework of the kinetic theory of quark-gluon plasma. A solvable set of equations from the double perturbation are derived and proven to be gauge invariant. The Landau damping rate for the plasmon at zero momentum is shown to be a convergent series in correlators.

In this paper a new probabilistic model of serial production line with finite buffer was proposed by means of new “Probabilistic Flow Method”. Based on this new model and methodology, steady performance measures (e.g. steady state distribution and mean sojourn time, etc.) are evaluated, and simulation results validate the analytical results.

In this paper, near-comp 1ete decomposabllity of closed networks with finite buffer and serial production line with finite buffer is studide. The sufficient conditions for systems to be nearly completely decomposable are derived, which can be expressed as a function of aggregates. The steady-state probabi1ities of systems are sought.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

The thermal evolution of strange stars in both normal and color-flavor-locked (CFL) phases are investigated together with the evolutions of the stellar rotation and the r-mode instability. The heating effects due to the deconfinement transition of the stellar crust and the dissipation of the r-modes are considered. As a result, the cooling of the stars in the normal phase is found to be not very different from the standard one. In contrast, for the stars in the CFL phase, a big bump during the first hundred years and a steep decay (~ 7% in ten years) at the ages of ~ 104"6 yrs are predicted in their thermal evolution curves. These unique features provide an effective observational test for determining whether or not the CFL phase is reached in strange stars. This thermal test method is independent of and complementary to the rotational test method, which is a direct consequence of the r-mode instability [ABSTRACT FROM AUTHOR]

Different measures have been presented to depict the deviation of quantum time evolution in open systems from Markovian processes. We demonstrate that the measure proposed by Breuer, Laine, and Piilo [Phys. Rev. Lett. 103, 210401 (2009)] and the two measures proposed by Rivas, Huelga, and Plenio [Phys. Rev. Lett. 105, 050403 (2010)] have exactly the same non-Markovian time-evolution intervals and thus are really equivalent to each other when they are applied to open two-level systems coupled to environments via the Jaynes-Cummings or dephasing models. This equivalence implies that the three measures, in different ways, capture the intrinsic character of the non-Markovianity of quantum evolutional processes. We also show that the maximization in the definition of the first measure can be actually removed for the considered models without influencing the sensibility of the measure to detect non-Markovianity. [ABSTRACT FROM AUTHOR]

We investigate the structure and the tidal deformability of strange stars with a mirror-dark-matter core for the standard MIT bag model. We find that to explain the observations of GW170817, PSR J0740 + 6620 and PSR J0030 + 0451 simultaneously, strange stars in GW170817 should have a mirror-dark-matter core although it is unnecessary for PSR J0740 + 6620 and PSR J0030 + 0451 to contain one. More generally, our study leads to the result that for the standard MIT bag model, the observations of compact stars mentioned above could serve as evidence for the existence of a dark-matter core inside strange stars. [ABSTRACT FROM AUTHOR]

Using a density dependent quark mass (QMDD) model for strange quark matter, we investigate the effects of non-Newtonian gravity on the properties of strange stars and constrain the parameters of the QMDD model by employing the mass of PSR J0740+6620 and the tidal deformability of GW170817. We find that for the QMDD model these mass and tidal deformability observations would rule out the existence of strange stars if non-Newtonian gravity effects are ignored. For the current quark masses of mu0=2.16 MeV, md0=4.67 MeV, and ms0=93 MeV, we find that a strange star can exist for values of the non-Newtonian gravity parameter g²/μ² in the range of 4.58 GeV-2≤g²/μ²≤9.32 GeV-2, and that the parameters D and C of the QMDD model are restricted to 158.3 MeV≤D1/2≤181.2 MeV and -0.65≤C≤-0.12. It is found that the largest possible maximum mass of a strange star obtained with the QMDD model is 2.42 M⊙ and that the secondary component of GW190814 with a mass of 2.59+0.08-0.09 M⊙ could not be a static strange star. We also find that for the mass and radius of PSR J0030+0451 given by Riley et al. through the analysis of observational data of NICER, there exists a very tiny allowed parameter space for which strange stars computed for the QMDD model agree with the observations of PSR J0740+6620, GW170817 and PSR J0030+0451 simultaneously. However, for the mass and radius given by Miller et al., no such parameter space exist. [ABSTRACT FROM AUTHOR]

Gravitational wave emissions (GWEs) of pulsars could not only make them promising targets for continuous gravitational wave searches but also leave imprints in their timing data. We interpret the measured braking index of PSR J1640-4631 with a model involving both the GWE and dipole magnetic field decay. Combining the timing data of PSR J1640-4631 and the theory of magnetic field decay, we propose a new approach of constraining the number of precession cycles, ξ, which is highly uncertain currently but can be tightly related to the interior physics of a neutron star and its GWE. We suggest that future observation of the tilt angle χ of PSR J1640-4631 would not merely help to constrain ξ but also possibly provide information about the internal magnetic field configuration of this pulsar. We find that ξ would be larger than previous estimates unless a tiny angle χ≲5° is observed. Furthermore, a measured angle χ≳12° would indicate ξ≳106, which is at least 10 times larger than that suggested previously. [ABSTRACT FROM AUTHOR]

Newly born massive magnetars are generally considered to be produced by binary neutron star (NS) mergers, which could give rise to short gamma-ray bursts (SGRBs). The strong magnetic fields and fast rotation of these magnetars make them promising sources for gravitational wave (GW) detection using ground based GW interferometers. Based on the observed masses of Galactic NS-NS binaries, by assuming different equations of state (EOSs) of dense matter, we investigate the stochastic gravitational wave background (SGWB) produced by an ensemble of newly born massive magnetars. The massive magnetar formation rate is estimated through: (i) the SGRB formation rate (hereafter entitled as MFR1); (ii) the NS-NS merger rate (hereafter entitled as MFR2). We find that for massive magnetars with masses Mmg=2.4743 M⊙, if EOS CDDM2 is assumed, the resultant SGWBs may be detected by the future Einstein Telescope (ET) even for MFR1 with minimal local formation rate, and for MFR2 with a local merger rate ρco(0)≲10 Mpc-3Myr-1. However, if EOS BSk21 is assumed, the SGWB may be detectable by the ET for MFR1 with the maximal local formation rate. Moreover, the background spectra show cutoffs at about 350 Hz in the case of EOS BSk21, and at 124 Hz for CDDM2, respectively. We suggest that if the cutoff at ~100 Hz in the background spectrum from massive magnetars could be detected, then the quark star EOS CDDM2 seems to be favorable. Moreover, the EOSs, which present relatively small TOV maximum masses, would be excluded. [ABSTRACT FROM AUTHOR]

The central engines of some superluminous supernovae (SLSNe) are generally suggested to be newly born fast rotating magnetars, which spin down mainly through magnetic dipole radiation and gravitational wave emission. We calculate the magnetar-powered SLSNe light curves (LCs) with the tilt angle evolution of newly born magnetars involved. We show that, depending on the internal toroidal magnetic fields B̄t, the initial spin periods Pi, and the radii RDU of direct Urca (DU) cores of newly born magnetars, as well as the critical temperature Tc for 3P2 neutron superfluidity, bumps could appear in the SLSNe LCs after the maximum lights when the tilt angles grow to p/2. The value of Tc determines the arising time and the relative amplitude of a bump. The quantity RDU can affect the arising time and the luminosity of a bump, as well as the peak luminosity of a LC. For newly born magnetars with dipole magnetic fields Bd=5×1014G, B̄t=4.6×1016 G, and Pi=1 ms, there are no bumps in the LCs if Tc=2×109K, or RDU=1.5×105cm. Moreover, it is interesting that a stronger B̄t will lead to both a brighter peak and a brighter bump in a LC. While keeping other quantities unchanged, the bump in the LC disappears for the magnetar with smaller Pi. We suggest that, once the SLSNe LCs with such kinds of bumps are observed, by fitting these LCs with our model, not only Bd and Pi of newly born magnetars but also the crucial physical quantities B̄t, RDU, and Tc could be determined. Nonobservation of SLSNe LCs with such kinds of bumps hitherto may already put some (though very rough) constraints on B̄t, Pi, RDU, and Tc. Therefore, observation of SLSNe LCs may provide a new approach to probe the physics of newly born magnetars. [ABSTRACT FROM AUTHOR]