Allosteric p97 Inhibitors Can Overcome Resistance to ATP-Competitive p97 Inhibitors for Potential Anticancer Therapy

Abstract : A major challenge of targeted cancer therapy is the selection for drug-resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is central regulator of protein homeostasis and a promising anticancer target because of its vital role in cell growth and survival. One ATP-competitive p97 inhibitor, CB-5083, has entered clinical trials. Selective pressure on HCT116 cells dosed with CB-5083 identified five different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB-5083 resistant p97 mutants, N660 K and T688 A, were also resistant to several other ATP-competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS-873 and UPCDC-30245 were unaffected by these mutations. We also established a CB-5083 resistant cell line that harbors a new p97 double mutation (D649 A/T688 A). While CB-5083, NMS-873, and UPCDC-30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS-873 and UPCDC-30245 were 30-fold more potent in inhibiting the CB-5083 resistant D649 A/T688 A double mutant than CB-5083. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP-competitive p97 inhibitors arises during anticancer treatment.     

二层沟槽织构对机床导轨表面润滑特性的影响

通过构建二层沟槽织构模型，仿真研究沟槽织构表面的流体动力效应。结果表明：沟槽容积相同时，与单层沟槽相比，二层沟槽的平均油膜压力可以达到单层沟槽的2.31倍；保持二层沟槽的量纲一总深度[β]1、第一层沟槽量纲一宽度[α]1不变时，随着第二层量纲一深度[β]2的增大，平均油膜压力先增大后减小，[β]2为4.4时，平均油膜压力达到最大值；第二层沟槽的量纲一宽度[α]2从0.25增大到0.45时，沟槽内的旋涡区也随之增大，平均油膜压力逐渐减小。     

下荆江熊家洲至城陵矶弯曲型河段河床调整规律

三峡水库运用后, 坝下游水沙过程发生了较大调整, 对下荆江熊家洲至城陵矶弯曲型河段河床冲淤演变造成较大影响, 从而对本河段河势稳定、防洪、航运等可能造成不利的影响, 基于此, 根据最新实测资料分析水沙条件变 化及其对本河段河床调整规律的影响。研究成果显示: 三峡水库运用后, 水流含沙量大幅减小, 且水库调蓄导致熊 家洲至城陵矶河段在枯水期径流量明显增加, 使弯道主流长期偏向于凸岸, 引起凸岸边滩大幅冲刷, 这是近期该河段发生“撇弯切滩”的主要原因之一; 随着三峡上游干支流水库群陆续建成运用, 坝下游河道将会长期遭受清水冲 刷, 河床仍将呈单向冲刷下切的趋势, 弯顶段主流平面摆动仍将较大, 弯道顶冲点也将相应下移, 导致主流贴岸距离 进一步下延, 引起河道岸线的崩退, 未来一段时期内典型弯曲型河道的局部河势变化仍将明显。     

Headspace fingerprinting approach to identify the major pathway influencing volatile patterns of vinasse-cured duck processed by high pressure,as well as its impact on physicochemical and sensory attributes

As a decisive attribute, flavour could be influenced by HP treatments through multiple physical and chemical pathways within the high pressure (HP)-assisted meat curing process. This investigation aimed to identify the major pathway influencing volatile flavour patterns of two representative vinasse-cured duck (VCD) products with HP treatments (150–300 MPa/15 min), including wet and dry types, by employing headspace fingerprinting as an untargeted approach. Results suggested that HP treatments greatly lowered moisture contents and increased Warner-Bratzler shear force and thiobarbituric acid reactive substances of the cured samples. According to multivariate models, the volatile flavour patterns of the HP-processed VCD could be clearly separated from the unprocessed samples, but the VCD pressurised at different intensities represented similar volatile fingerprinting, which was validated by e-nose analysis. The discriminant analysis (OPLS-DA) model outlined vinasse-derived ethanol, acetic acid, 3-methyl-1-butanol, 2-methyl-1-butanol, phenethyl alcohol and 2-methyl-3-octanone as the major discriminant aromas across the unpressurised and pressurised samples.     

Facile preparation of highly dispersed Pt nanoparticles supported on heteroatom-containing porous carbon nanospheres and their catalytic properties for the reduction of 4-nitrophenol

Heteroatom-containing porous carbon nanospheres with a high surface area were firstly fabricated by pyrolysis of poly(cyclotriphosphazene-co-4,4′-sulfonyldiphenol) (PZS) nanospheres which were fabricated by a facile polycondensation between hexachlorocyclotriphosphazene and 4,4′-sulfonydiphenol. Then the porous carbon nanosphere-supported Pt nanoparticles (Pt NPs@C-PZS) were synthesized by a simple microwave reduction method, during which Pt NPs were highly dispersed on the surface of carbon supports. The surface morphologies and chemical composition of the as-obtained C-PZS and Pt NPs@C-PZS nanocomposites were characterized by SEM, TEM, XRD, XPS, and Raman spectroscopy. Characterization results showed that the Pt NPs with an average diameter of 2 nm was well anchored onto the surface of C-PZS nanospheres. In addition, the as-prepared Pt NPs@C-PZS nanocomposites exhibited an excellent catalytic capability towards the reduction of 4-nitrophenol to 4-aminophenol by excessive sodium borohydride (NaBH₄) at room temperature.     

Novel hydrophilic N-halamine polymer with enhanced antibacterial activity synthesized by inverse emulsion polymerization

N-halamine-based antibacterial agents have high efficiency and rechargeable antibacterial properties. However, their applications are limited due to their complex synthetic process and fuzzy antibacterial mechanism. In this study, a novel N-halamine antibacterial polymer was synthesized by inverse emulsion polymerization and characterized by Fourier transform infrared, nuclear magnetic resonance, scanning electron microscopy, thermogravimetric analysis, and X-ray photoelectron spectroscopy. Due to the difficulty of purification, most of the subjects studied previously were hydrophobic polymers, while little research on hydrophilic polymers. In this experiment, this difficulty was overcome by controlling the dosage of sodium hypochlorite and methods of dialysis. Because of the complex cell structure of Gram-negative bacteria, it is difficult for N-halamines to release the oxidizing chlorine into the cell. However, the hydrophilic N-halamines can solve this problem, which showed a stronger antibacterial effect on Gram-negative Escherichia coli synthesized in this study. In addition, the particle size and hydrophilic property of the polymer were changed by changing the amount of initiator, and the differences in their antibacterial properties were studied. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47419.     

Stochastic processes in renewable power systems: From frequency domain to time domain

With the increasing penetration of renewable energy resources(RESs), the uncertainties of volatile renewable generations significantly affect the power system operation. Such uncertainties are usually modeled as stochastic variables obeying specific distributions by neglecting the temporal correlations. Conventional approaches to hedge the negative effects caused by such uncertainties are thus hard to pursue a trade-off between computation efficiency and optimality. As an alternative, the theory of stochastic process can naturally model temporal correlation in closed forms. Attracted by this feature, our research group has been conducting thorough researches in the past decade to introduce stochastic processes within renewable power systems. This paper summarizes our works from the perspective of both the frequency domain and the time domain, provides the tools for the analysis and control of power systems under a unified framework of stochastic processes, and discusses the underlying reasons that stochastic process-based approaches can perform better than conventional approaches on both computational efficiency and optimality. These work may shed a new light on the research of analysis, control and operation of renewable power systems.Finally, this paper outlooks the theoretic developments of stochastic processes in future's renewable power systems.     

In‐plane shear damage behaviours of 2D needled C/SiC composites

Understanding the in‐plane shear behaviour of composites is essential to establish the design basis for practical applications. This study aims to investigate the shear damage behaviours of 2D needled C/SiC composites by various characterization techniques. The effect of layer arrangement on shear modulus and strength was discussed via shear stress‐strain responses. The shear strain field evolution and uniformity variation were studied by digital image correlation. It shows that the uniformity of shear strain field changes with the shear load, and the shear strain field evolution consist of 5 stages. The electrical resistivity measurement results indicate that structural deformation and damage evolution caused the electrical resistivity change. Furthermore, the damage evolution has a double effect on the electrical resistivity variation. The acoustic emission monitoring shows that the shear damage evolution is a 3‐stage nonlinear process before failure. The shear damages were categorized via acoustic characteristics. Besides, the postfailure behaviours were also discussed in this study.     

The isothermal reduction kinetics of chromium-bearing vanadium–titanium magnetite sinter

The reduction of chromium-bearing vanadium–titanium magnetite sinter (CVTMS) by CO was investigated at 1123–1223?K. The reduction degree increased with increasing temperature. The isothermal reduction kinetics of CVTMS was analysed, according to Sharp analysis and ln–ln analysis, the kinetic mechanism of reduction process for all samples in different basicity can be represented as f(α)?=?1.61(1?α)[?ln(1?α)]^1–1/1.61. The reaction activation energy of all samples (R?=?1.9, 2.1, 2.3, obtained according to the components of the materials burdening used in sintering process) at different reaction degrees were calculated by the model-free method. And the pre-exponential factors of reaction also were calculated by the mathematical method. The rate controlling step for the reduction process under the present reduction condition was chemical reaction.     

碱度对熔剂性球团生球性能的影响

 熔剂性铁矿球团具有优良的高温冶金性能，是高炉炼铁的优质炉料。为探明生产熔剂性铁矿球团时碱度对生球性能的影响规律，以某钢厂赤铁精矿为原料，通过添加石灰石粉调节碱度，进行了造球及生球干燥特性试验研究。结果发现，提高碱度，生球落下强度呈提高趋势，抗压强度变化不明显，适宜膨润土配比略有下降，生球爆裂温度明显提高，生球干燥速率则没有明显变化。与基准自然碱度（R＝0.14）相比，当碱度提高到0.6以上时，适宜膨润土配比由1.2%下降到1.1%，生球爆裂温度提高近50 ℃以上。