Lifshitz phase transitions in a one-dimensional Gamma model.

In this paper, we study quantum phase transitions and magnetic properties of a one-dimensional spin-1/2 Gamma model, which describes the off-diagonal exchange interactions between edge-shared octahedra with strong spin-orbit couplings along the sawtooth chain. The competing exchange interactions between the nearest neighbors and the second neighbors stabilize the semimetallic ground state in terms of spinless fermions, and give rise to a rich phase diagram, which consists of three gapless phases. We find distinct phases are characterized by the number of Weyl nodes in the momentum space, and such changes in the topology of the Fermi surface without symmetry breaking produce a variety of Lifshitz transitions, in which the Weyl nodes situating at k=π change from type I to type II. A coexistence of type-I and type-II Weyl nodes is found in phase II. The information measures including concurrence, entanglement entropy, and relative entropy can effectively signal the second-order transitions. The results indicate that the Gamma model can act as an exactly solvable model to describe Lifshitz phase transitions in correlated electron systems.

Pyrolytic Kinetics of Polystyrene Particle in Nitrogen Atmosphere: Particle Size Effects and Application of Distributed Activation Energy Method.

This work was motivated by a study of particle size effects on pyrolysis kinetics and models of polystyrene particle. Micro-size polystyrene particles with four different diameters, 5, 10, 15, and 50 µm, were selected as experimental materials. Activation energies were obtained by isoconversional methods, and pyrolysis model of each particle size and heating rate was examined through different reaction models by the Coats-Redfern method. To identify the controlling model, the Avrami-Eroféev model was identified as the controlling pyrolysis model for polystyrene pyrolysis. Accommodation function effect was employed to modify the Avrami-Eroféev model. The model was then modified to f() = n0.39n - 1.15(1 - )[-ln(1 - )]1 - 1/n, by which the polystyrene pyrolysis with different particle sizes can be well explained. It was found that the reaction model cannot be influenced by particle geometric dimension. The reaction rate can be changed because the specific surface area will decrease with particle diameter. To separate each step reaction and identify their distributions to kinetics, distributed activation energy method was introduced to calculate the weight factor and kinetic triplets. Results showed that particle size has big impacts on both first and second step reactions. Smaller size particle can accelerate the process of pyrolysis reaction. Finally, sensitivity analysis was brought to check the sensitivity and weight of each parameter in the model.

Experimental study of the effect of typical halides on pyrolysis of ammonium nitrate using model reconstruction.

The energetic material ammonium nitrate (AN) is used as an industrial raw material; however, it presents a pyrolysis and explosion hazard during transportation and storage, especially when mixed with impurities. To study the effects of typical halides on the thermal decomposition kinetics of AN, a series of precision thermogravimetric analysis experiments at four heating rates were carried out in a nitrogen atmosphere. Based on derivative thermogravimetric analysis, the addition of sodium halides was found to change the kinetic reaction mechanism of AN pyrolysis. The activation energies were obtained using the isoconversional method, and the pre-exponential factor was derived from the kinetic compensation effect. Models of the kinetic reaction mechanism were reliably reconstructed by combining composite kinetic data processing methods, namely, model-free method, model-fitting method, and parameter simulation. A comprehensive analysis showed that the addition of sodium halides shifts the kinetic mechanism of the pyrolysis of AN toward different dominant reaction models (such as reaction order models, power law models, or phase boundary control models) than those of the original reaction model. The results are helpful as a reference and provide guidance for the determination of AN pyrolysis behavior and the simulation of parameters.

An experimental and theoretical study of optimized selection and model reconstruction for ammonium nitrate pyrolysis.

Ammonium nitrate (AN) is a commonly-used industrial raw material in industrial explosives and fertilizers areas. However, as an energetic material, its danger exists during the production, transportation, and storage, resulting in a large number of accidents involving personal injury and property loss. To obtain the accurate kinetic triplet parameters of AN thermal decomposition, a series of thermogravimetry analysis (TGA) experiments was conducted with four different heating rates. Activation energies were calculated by different isoconversional methods Then the kinetic triplet of AN pyrolysis was optimized using a combination of experimental and simulant methods. Combined with the traditional model-free and model-fitting approaches, the experimental kinetic model for AN pyrolysis was optimized and then reconstructed. Through the pyrolysis reaction of AN, a reliable methodology for processing TGA data of hazardous material is proposed in the paper, and the kinetic parameters can be accurately obtained by using such a kinetics method.

Sample width and thickness effects on upward flame spread over PMMA surface.

Upward flame spread has the same propagating direction with air flow and buoyancy, and features as the most hazardous fire case in all flame spread configurations. It has been a long time for fire researchers to find a simple and effective method to evaluate upward flame spread behaviors, especially for different materials and sample sizes. The aim of this work was motivated by the research of sample width and thickness effects on upward flame spread behavior, including flame spread rate during acceleration propagation for different sample thickness and width, theoretical global mass loss prediction based on Emmons's hypothesis, and dimensionless flame height scaling with dimensionless heat release rate for steady stage burning. Four kinds of sample thicknesses were selected, including 1.7, 3.5, 5, and 7mm. For each kind of thickness, six sample widths ranging from 40 to 90mm were prepared. To eliminate the side flame spreading effects, one set of contrast experiments with sample sides sealed was also performed, by which way flame could only spread along sample front surface and flame propagation was inhibited along both sides. Based on Emmons's hypothesis, a method for calculation of global mass loss rate was developed. Theoretical global mass loss rate over pyrolysis surface of upward flame spread configurations was calculated and could fit the experimental data well. Finally, a dimensionless heat-release rate for wall flames of different sample sizes was used to scale the dimensionless flame height with a power-law exponent 0.58. The results of this study have implications concerning designs for high-rise building fire safety problems and can help to get better understandings of upward flame spread mechanism from aspects of heat and mass transfer.

Experimental study on thermal hazard of tributyl phosphate-nitric acid mixtures using micro calorimeter technique.

During PUREX spent nuclear fuel reprocessing, mixture of tributyl phosphate (TBP) and hydrocarbon solvent are employed as organic solvent to extract uranium in consideration of radiation contaminated safety and resource recycling, meanwhile nitric acid is utilized to dissolve the spent fuel into small pieces. However, once TBP contacts with nitric acid or nitrates above 130°C, a heavy "red oil" layer would occur accompanied by thermal runaway reactions, even caused several nuclear safety accident. Considering nitric acid volatility and weak exothermic detection, C80micro calorimeter technique was used in this study to investigate thermal decomposition of TBP mixed with nitric acid. Results show that the concentration of nitric acid greatly influences thermal hazard of the system by direct reactions. Even with a low heating rate, if the concentration of nitric acid increases due to evaporation of water or improper operations, thermal runaway in the closed system could start at a low temperature.

Synergistic Activity of Combined NS5A Inhibitors.

Daclatasvir (DCV) is a first-in-class hepatitis C virus (HCV) nonstructural 5A replication complex inhibitor (NS5A RCI) that is clinically effective in interferon-free combinations with direct-acting antivirals (DAAs) targeting alternate HCV proteins. Recently, we reported NS5A RCI combinations that enhance HCV inhibitory potential in vitro, defining a new class of HCV inhibitors termed NS5A synergists (J. Sun, D. R. O'Boyle II, R. A. Fridell, D. R. Langley, C. Wang, S. Roberts, P. Nower, B. M. Johnson F. Moulin, M. J. Nophsker, Y. Wang, M. Liu, K. Rigat, Y. Tu, P. Hewawasam, J. Kadow, N. A. Meanwell, M. Cockett, J. A. Lemm, M. Kramer, M. Belema, and M. Gao, Nature 527:245-248, 2015, doi:10.1038/nature15711). To extend the characterization of NS5A synergists, we tested new combinations of DCV and NS5A synergists against genotype (gt) 1 to 6 replicons and gt 1a, 2a, and 3a viruses. The kinetics of inhibition in HCV-infected cells treated with DCV, an NS5A synergist (NS5A-Syn), or a combination of DCV and NS5A-Syn were distinctive. Similar to activity observed clinically, DCV caused a multilog drop in HCV, followed by rebound due to the emergence of resistance. DCV-NS5A-Syn combinations were highly efficient at clearing cells of viruses, in line with the trend seen in replicon studies. The retreatment of resistant viruses that emerged using DCV monotherapy with DCV-NS5A-Syn resulted in a multilog drop and rebound in HCV similar to the initial decline and rebound observed with DCV alone on wild-type (WT) virus. A triple combination of DCV, NS5A-Syn, and a DAA targeting the NS3 or NS5B protein cleared the cells of viruses that are highly resistant to DCV. Our data support the observation that the cooperative interaction of DCV and NS5A-Syn potentiates both the genotype coverage and resistance barrier of DCV, offering an additional DAA option for combination therapy and tools for explorations of NS5A function.

[Therapeutic Efficacy of Multigly-Cosidorum Tripterygium Combined with rhIL-11 for Immune Thrombocytopenia].

OBJECTIVE: To study the therapeutic efficacy of multigly-cosidorum Tripterygium combined with rhIL-11 for treating patients with immune thrombocytopenia (ITP). METHODS: A total of 75 patients with ITP were divided into 2 group: experimental group and control group. The experimental group included 40 patients who had been treated with multigly-cosidorum Tripterygium combined with rhIL-11. Multigly-cosidorum Tripterygium was given at a dose of 1mg/kg·d for 2 months and rhIL-11 was injected at a dose of 16,000,000 units per day. Control group included 35 patients who had been treated with prednisone at a dose of 1 mg/kg·d. Platelet counts were performed every day before platelet counts >30 × 109/L. Peripheral blood T cells were collected before and after treated for 2 months. The ratios of CD4⁺, CD8⁺ T cells in peripheral blood T cells were analyzed by flow cytometry. RESULTS: Totally effective rate in experimental group was 77.5%. Totally effective rate in control group was 82.9%. Totally effective rate showed no statistical difference between these two groups (P > 0.05). The average time of platelet count 30 × 109/L in experimental and control groups were 13.06 ± 6.10 days and 9.76 ± 5.71 days respectively; in experimental group, the ratio of CD4⁺ T cells in peripheral blood was 21.03% before treatment, then rised to 34.49% after treatment for 2 months (P < 0.01); The ratio of CD8⁺ T cells in peripheral blood was 26.35% before treatment, then decreased to 20.18% (P < 0.01). In control group, the ratio of CD4⁺ T cells was 22.30% before treatment, then rised to 25.11% after treatment for 2 months (P < 0.05); The ratio of CD8⁺ T cells in peripheral blood was 27.24% before treatment, then decreased to 21.35% (P < 0.01). CONCLUSION: Multigly-cosidorum tripterygium can correct disorder of T lymphocytes, the combination of multigly-cosidorum triptergium and rhIL-11 can accelerate therapeutic efficacy for treating ITP and with less adverse reaction, so this combination may be effective and safe for treating patients with ITP.

Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A.

It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by ~3-4 log10 in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.

Trait impulsivity and impaired prefrontal impulse inhibition function in adolescents with internet gaming addiction revealed by a Go/No-Go fMRI study.

BACKGROUND: Recent studies suggest that Internet gaming addiction (IGA) is an impulse disorder, or is at least related to impulse control disorders. In the present study, we hypothesized that different facets of trait impulsivity may be specifically linked to the brain regions with impaired impulse inhibition function in IGA adolescents. METHODS: Seventeen adolescents with IGA and seventeen healthy controls were scanned during performance of a response-inhibition Go/No-Go task using a 3.0 T MRI scanner. The Barratt Impulsiveness Scale (BIS)-11 was used to assess impulsivity. RESULTS: There were no differences in the behavioral performance on the Go/No-Go task between the groups. However, the IGA group was significantly hyperactive during No-Go trials in the left superior medial frontal gyrus, right anterior cingulate cortex, right superior/middle frontal gyrus, left inferior parietal lobule, left precentral gyrus, and left precuneus and cuneus. Further, the bilateral middle temporal gyrus, bilateral inferior temporal gyrus, and right superior parietal lobule were significantly hypoactive during No-Go trials. Activation of the left superior medial frontal gyrus was positively associated with BIS-11 and Chen Internet Addiction Scale (CIAS) total score across IGA participants. CONCLUSIONS: Our data suggest that the prefrontal cortex may be involved in the circuit modulating impulsivity, while its impaired function may relate to high impulsivity in adolescents with IGA, which may contribute directly to the Internet addiction process.

Comparison of daclatasvir resistance barriers on NS5A from hepatitis C virus genotypes 1 to 6: implications for cross-genotype activity.

A comparison of the daclatasvir (DCV [BMS-790052]) resistance barrier on authentic or hybrid replicons containing NS5A from hepatitis C virus (HCV) genotypes 1 to 6 (GT-1 to -6) was completed using a replicon elimination assay. The data indicated that genotype 1b (GT-1b) has the highest relative resistance barrier and genotype 2a (GT-2a M31) has the lowest. The rank order of resistance barriers to DCV was 1b>4a≥5a>6a≅1a>2a JFH>3a>2a M31. Importantly, DCV in combination with a protease inhibitor (PI) eliminated GT-2a M31 replicon RNA at a clinically relevant concentration. Previously, we reported the antiviral activity and resistance profiles of DCV on HCV genotypes 1 to 4 evaluated in the replicon system. Here, we report the antiviral activity and resistance profiles of DCV against hybrid replicons with NS5A sequences derived from HCV GT-5a and GT-6a clinical isolates. DCV was effective against both GT-5a and -6a hybrid replicon cell lines (50% effective concentrations [EC50s] ranging from 3 to 7 pM for GT-5a, and 74 pM for GT-6a). Resistance selection identified amino acid substitutions in the N-terminal domain of NS5A. For GT-5a, L31F and L31V, alone or in combination with K56R, were the major resistance variants (EC50s ranging from 2 to 40 nM). In GT-6a, Q24H, L31M, P32L/S, and T58A/S were identified as resistance variants (EC50s ranging from 2 to 250 nM). The in vitro data suggest that DCV has the potential to be an effective agent for HCV genotypes 1 to 6 when used in combination therapy.

Discovery and development of hepatitis C virus NS5A replication complex inhibitors.

Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogues that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clinical trials with HCV NS5A RCIs.

HCV NS5A replication complex inhibitors. Part 4. Optimization for genotype 1a replicon inhibitory activity.

A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and genotype 1b (G-1b) replicon inhibition and selectivity against BVDV and cytotoxicity. SAR emerging from an examination of the prolinamide cap region revealed 11 to be a selective HCV NS5A inhibitor exhibiting submicromolar potency against both G-1a and G-1b replicons. Additional structural refinements resulted in the identification of 30 as a potent, dual G-1a/1b HCV NS5A inhibitor.

Characterizations of HCV NS5A replication complex inhibitors.

The hepatitis C virus NS5A protein is an established and clinically validated target for antiviral intervention by small molecules. Characterizations are presented of compounds identified as potent inhibitors of HCV replication to provide insight into structural elements that interact with the NS5A protein. UV-activated cross linking and affinity isolation was performed with one series to probe the physical interaction between the inhibitors and the NS5A protein expressed in HCV replicon cells. Resistance mapping with the second series was used to determine the functional impact of specific inhibitor subdomains on the interaction with NS5A. The data provide evidence for a direct high-affinity interaction between these inhibitors and the NS5A protein, with the interaction dependent on inhibitor stereochemistry. The functional data supports a model of inhibition that implicates inhibitor binding by covalently combining distinct pharmacophores across an NS5A dimer interface to achieve maximal inhibition of HCV replication.

HCV NS5A replication complex inhibitors. Part 5: discovery of potent and pan-genotypic glycinamide cap derivatives.

The isoquinolinamide series of HCV NS5A inhibitors exemplified by compounds 2b and 2c provided the first dual genotype-1a/1b (GT-1a/1b) inhibitor class that demonstrated a significant improvement in potency toward GT-1a replicons compared to that of the initial program lead, stilbene 2a. Structure-activity relationship (SAR) studies that uncovered an alternate phenylglycine-based cap series that exhibit further improvements in virology profile, along with some insights into the pharmacophoric elements associated with the GT-1a potency, are described.

A 96-well based analysis of replicon elimination with the HCV NS5A replication complex inhibitor daclatasvir.

A 96-well based replicon elimination and colony formation assay is presented for comparing the resistance barrier of the hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (DCV, BMS-790052) on three HCV genotypes (gts) in a proof of concept experimental protocol. The 96-well assay format provides both individual colony as well as population characterization and is readily applicable to other HCV direct-acting antiviral agents (DAAs). The assay provides an assessment of HCV replication levels over a 5log10 range by measuring a luciferase reporter resident in the HCV replicons. Individual colony status can be measured with a separate and compatible resazurin assay to assess relative host cell fitness following inhibitor treatments. The methods employed are non-toxic and leave intact isolatable colonies that can be used for phenotyping and genotyping. The utility of the assay is demonstrated by the identification and isolation of resistant variants as well as in the ranking of the relative resistance barrier for the replication complex inhibitor DCV for gts 1a, 1b and 2a. The format provides a quantitative ranking based upon luciferase activity and has the ability to monitor DAA resistance development over time for large numbers of compounds.

Altered default network resting-state functional connectivity in adolescents with Internet gaming addiction.

PURPOSE: Excessive use of the Internet has been linked to a variety of negative psychosocial consequences. This study used resting-state functional magnetic resonance imaging (fMRI) to investigate whether functional connectivity is altered in adolescents with Internet gaming addiction (IGA). METHODS: Seventeen adolescents with IGA and 24 normal control adolescents underwent a 7.3 minute resting-state fMRI scan. Posterior cingulate cortex (PCC) connectivity was determined in all subjects by investigating synchronized low-frequency fMRI signal fluctuations using a temporal correlation method. To assess the relationship between IGA symptom severity and PCC connectivity, contrast images representing areas correlated with PCC connectivity were correlated with the scores of the 17 subjects with IGA on the Chen Internet Addiction Scale (CIAS) and Barratt Impulsiveness Scale-11 (BIS-11) and their hours of Internet use per week. RESULTS: There were no significant differences in the distributions of the age, gender, and years of education between the two groups. The subjects with IGA showed longer Internet use per week (hours) (p<0.0001) and higher CIAS (p<0.0001) and BIS-11 (p = 0.01) scores than the controls. Compared with the control group, subjects with IGA exhibited increased functional connectivity in the bilateral cerebellum posterior lobe and middle temporal gyrus. The bilateral inferior parietal lobule and right inferior temporal gyrus exhibited decreased connectivity. Connectivity with the PCC was positively correlated with CIAS scores in the right precuneus, posterior cingulate gyrus, thalamus, caudate, nucleus accumbens, supplementary motor area, and lingual gyrus. It was negatively correlated with the right cerebellum anterior lobe and left superior parietal lobule. CONCLUSION: Our results suggest that adolescents with IGA exhibit different resting-state patterns of brain activity. As these alterations are partially consistent with those in patients with substance addiction, they support the hypothesis that IGA as a behavioral addiction that may share similar neurobiological abnormalities with other addictive disorders.

Persistence of resistant variants in hepatitis C virus-infected patients treated with the NS5A replication complex inhibitor daclatasvir.

Daclatasvir (DCV; BMS-790052) is a hepatitis C virus (HCV) NS5A replication complex inhibitor (RCI) with picomolar to low nanomolar potency and broad genotypic coverage in vitro. Viral RNA declines have been observed in the clinic for both alpha interferon-ribavirin (IFN-α-RBV) and IFN-RBV-free regimens that include DCV. Follow-up specimens (up to 6 months) from selected subjects treated with DCV in 14-day monotherapy studies were analyzed for genotype and phenotype. Variants were detected by clonal sequencing in specimens from baseline and were readily detected by population sequencing following viral RNA breakthrough and posttreatment. The major amino acid substitutions generating resistance in vivo were at residues M28, Q30, L31, and Y93 for genotype 1a (GT-1a) and L31 and Y93 for GT-1b, similar to the resistance substitutions observed with the in vitro replicon system. The primary difference in the resistance patterns observed in vitro and in vivo was the increased complexity of linked variant combinations observed in clinical specimens. Changes in the percentage of individual variants were observed during follow-up; however, the overall percentage of variants in the total population persisted up to 6 months. Our results suggest that during the 14-day monotherapy, most wild-type virus was eradicated by DCV. After the end of DCV treatment, viral fitness, rather than DCV resistance, probably determines which viral variants emerge as dominant in populations.

HCV NS5A replication complex inhibitors. Part 3: discovery of potent analogs with distinct core topologies.

In a recent disclosure, we described the discovery of dimeric, prolinamide-based NS5A replication complex inhibitors exhibiting excellent potency towards an HCV genotype 1b replicon. That disclosure dealt with the SAR exploration of the peripheral region of our lead chemotype, and herein is described the SAR uncovered from a complementary effort that focused on the central core region. From this effort, the contribution of the core region to the overall topology of the pharmacophore, primarily vector orientation and planarity, was determined, with a set of analogs exhibiting <10 nM EC(50) in a genotype 1b replicon assay.