Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC₅₀) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC₅₀ shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.     

Invader amphipods Gmelinoides fasciatus (Stebbing, 1899) inhabiting distant waterbodies demonstrate differences in tolerance and energy metabolism under elevated temperatures

Gmelinoides fasciatus is a successful invasive amphipod (Amphipoda, Crustacea) that dispersed from Lake Baikal to various waterbodies. Here we studied whether Baikal conditions are optimal for G. fasciatus in terms of thermotolerance and investigated lethal temperatures, 70 kDa heat shock protein level, energy metabolism, and antioxidant defense of animals from three geographically distant waterbodies under changing temperatures. We used acute heat exposure to 28 °C to assess the median lethal times and gradual temperature increase from 6 °C to determine the lethal temperatures. Mortality under heat shock was explainable by the baseline content of Hsp70 that correlated with thermal history. But it was not the case under gradual temperature increase where Hsp70 levels became similar and the mortality pattern changed. The most thermotolerant amphipods from the Gulf of Finland demonstrated a higher amount of free glucose during the temperature increase that may be related to the higher salinity of this waterbody and less energy required for ion regulation. Even though concentrations of major physiological ions in Lake Baikal are lower than in Lake Ladoga, G. fasciatus from Ladoga was slightly more sensitive to the gradual temperature increase. This difference could be explained by the influence of high levels of humic and other potentially toxic substances in Lake Ladoga indicated by increased activities of catalase and glutathione S-transferase. Importantly, all G. fasciatus populations accumulated relatively low levels of lactate during the temperature increase, which may reflect the ability of this invasive species to effectively maintain aerobic metabolism under various conditions.     

郭庄煤业选煤厂振动筛筛选形式的优化研究

针对郭庄煤业选煤厂振动筛振动筛分方式可靠性差、筛分效率低下、物料筛分率低的难题,本文提出了三种新的振动筛分方案,对不同筛分方案的实际应用效果进行了分析。结果表明三移动一摆动的振动筛分方式对物料的综合分散度最高,稳定性好,该筛分方案已在郭庄煤业选煤厂煤炭筛分过程中得到了全面的应用。     

Sleep Disorders Reduce Health-Related Quality of Life in Multiple Sclerosis (Nottingham Health Profile Data in Patients with Multiple Sclerosis)

Quality of Life (QoL) is decreased in multiple sclerosis (MS), but studies about the impact of sleep disorders (SD) on health-related quality of Life (HRQoL) are lacking. From our original cohort, a cross-sectional polysomnographic (PSG) study in consecutive MS patients, we retrospectively analysed the previously unpublished data of the Nottingham Health Profile (NHP). Those MS patients suffering from sleep disorders (n = 49) showed significantly lower HRQoL compared to MS patients without sleep disorders (n = 17). Subsequently, we classified the patients into four subgroups: insomnia (n = 17), restless-legs syndrome, periodic limb movement disorder and SD due to leg pain (n = 24), obstructive sleep apnea (n = 8) and patients without sleep disorder (n = 17). OSA and insomnia patients showed significantly higher NHP values and decreased HRQoL not only for the sleep subscale but also for the “energy” and “emotional” area of the NHP. In addition, OSA patients also showed increased NHP values in the “physical abilities” area. Interestingly, we did not find a correlation between the objective PSG parameters and the subjective sleep items of the NHP. However, this study demonstrates that sleep disorders can reduce HRQoL in MS patients and should be considered as an important confounder in all studies investigating HRQoL in MS.     

Strength and dilatancy behaviors of deep sands in Shanghai with a focus on grain size and shape effect

With rapid development of infrastructures like tunnels and open excavations in Shanghai, investigations on deeper soils have become critically important. Most of the existing laboratory works were focused on the clayey strata up to Layer 6 in Shanghai, i.e. at depth of up to 40 m. In this paper, Layers 7, 9, and 11, which were mostly formed of sandy soils at depth of up to 150 m, were experimentally investigated with respect to physico-mechanical behaviors. The stress–strain behaviors were analyzed by the consolidated drained/undrained (CD/CU) triaxial tests under monotonic loading. One-dimensional (1D) oedometer tests were performed to investigate the consolidation properties of the sandy soils. Specimens were prepared at three different relative densities for each layer. Also, the micro-images and particle size analyzers were used to analyze the shape and size of the sand grains. The influences of grain size, density, and angularity on the stress–strain behaviors and compressibility were also studied. Compared to the other layers, Layer 11 had the smallest mean grain size (D₅₀), highest compressibility, and lowest shear strength. In contrast, Layer 9 had the largest mean grain size, lowest compressibility, and highest shear strength. Layer 7 was of intermediate mean grain size, exhibiting more compressibility and less shear strength than that of Layer 9. Also, the critical state parameters and maximum dilatancy rate of different layers were discussed.     

叠合盆地凸起区多期复杂断裂特征及形成机制——以准噶尔盆地车排子凸起为例

以高精度三维地震资料为基础,结合构造演化恢复和区域构造背景,系统研究了准噶尔盆地车排子凸起断裂分布和形成机制。结果表明,车排子凸起发育深部和浅部2套断裂体系,深部断裂体系和浅部断裂体系分别发育3种断裂样式。车排子凸起共经历5个构造演化阶段,其中,晚二叠世挤压-逆冲控制了深部断裂体系的初始形成,晚侏罗世逆冲-走滑控制了深部断裂体系的最终定型,新近纪叠加掀斜、局部伸展控制了浅部断裂体系的形成。不同断裂体系在油气成藏过程中均起到了重要作用。其中:深部断裂体系的红车断裂是重要的油源断裂,低序级断层控制形成了石炭系火山岩优质储集体;浅部断裂体系使得油气向浅部层系运移调整,同时形成了断块圈闭、断鼻圈闭和断层-岩性圈闭等丰富的圈闭类型。     

Identification of digital technologies and digitalisation trends in the mining industry

Digitalisation in mining refers to the use of computerised or digital devices or systems and digitised data that are to reduce costs, improve business productivity, and transform mining practices. However, it remains increasingly difficult for mining companies to decide which digital technologies are most relevant to their needs and individual mines. This paper provides an overview of digital technologies currently relevant to mining companies as presented and discussed by mining journals, the media and insight reports of leading consultancy agencies. Relevant technologies were systematically identified using text-mining techniques, and network analyses established the relations between significant technologies. Results demonstrated that currently 107 different digital technologies are pursued in the mining sector. Also, an analysis of the actual implementation of digital technologies in 158 active surface and underground mines reveals a limited uptake of digital technologies in general and that the uptake increases with the run-of-mine production. Large-scale mining operations appear to select and apply digital technologies suitable to their needs, whereas operations with lower production rates do not implement the currently available digital technologies to the same extent. These minor producers may require other digital transformation solutions tailored to their capabilities and needs and applicable to their scale of operations.