Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

Aldose reductase is involved in the polyol pathway, catalyzing the reduction of glucose to sorbitol. However, due to pronounced binding site adaptations, the enzyme can operate on a broad palette of structurally diverse substrates ranging from small aliphatic and aromatic aldehydes up to steroid-type ligands. A comparative analysis of the presently accessible crystal structures of aldose reductase complexes reveals four binding-competent protein conformations. Additional relevant conformers are detected through molecular dynamics simulations. They indicate an equilibrium of several conformers which is shifted towards the binding-competent geometries upon ligand binding. Such a manifold system with several alternative binding site conformers requires some tailored concepts in virtual screening. We followed two strategies, both successfully suggesting new micromolar inhibitors. In a first attempt, we concentrated on one preferred conformer and performed a virtual screening, assuming that the binding pocket of aldose reductase adopts only this conformation. In a second approach, we followed a ligand superpositioning method. Ligands were extracted in their bound conformations from three different crystal structures, all accommodating the ligands with different active site conformations. After merging these ligands into one supermolecule, mutual alignments were computed, taking candidate ligands from a screening database. The latter strategy also retrieved several structurally new inhibitors of micromolar potency.     

革命历史题材剧对相关红色旅游景点网络关注度的影响研究——以《觉醒年代》为例

革命历史题材剧在促进大众情感认知和文化认同、激发旅游需求、增强红色旅游景点吸引力等方面发挥着重要作用.该文以重大革命历史题材剧《觉醒年代》为例,以2020—2021年相关红色旅游景点百度指数为数据基础,采用赫芬达尔指数、空间自相关、回归分析等方法探讨革命历史题材剧对其相关红色景点网络关注度时空特征的影响.研究发现：1) 《觉醒时代》播出后,相关红色景点网络关注度与播出前同期水平相比显著增加,且非知名景点的增长幅度大于知名景点;年内均衡程度变动较小,年内分布趋势呈现倒“U”型分布;2) 《觉醒时代》播出后,相关红色景点网络关注度空间集聚程度提升,冷热点空间格局较为稳定,呈现胡焕庸线分割特征,热点区主要集聚在长江中游城市群及邻近区域;延乔路、龙华烈士陵园、毛泽东故居网络关注度的空间响应较为明显;长江中游城市群网络关注度的提升较为显著;3) 《觉醒年代》相关联旅游景点的平均每日互联网关注度与电视剧的受欢迎程度呈正相关.     

Detection and imaging of atmospheric radio flashes from cosmic ray air showers

The nature of ultrahigh-energy cosmic rays (UHECRs) at energies >10(20) eV remains a mystery. They are likely to be of extragalactic origin, but should be absorbed within approximately 50 Mpc through interactions with the cosmic microwave background. As there are no sufficiently powerful accelerators within this distance from the Galaxy, explanations for UHECRs range from unusual astrophysical sources to exotic string physics. Also unclear is whether UHECRs consist of protons, heavy nuclei, neutrinos or gamma-rays. To resolve these questions, larger detectors with higher duty cycles and which combine multiple detection techniques are needed. Radio emission from UHECRs, on the other hand, is unaffected by attenuation, has a high duty cycle, gives calorimetric measurements and provides high directional accuracy. Here we report the detection of radio flashes from cosmic-ray air showers using low-cost digital radio receivers. We show that the radiation can be understood in terms of the geosynchrotron effect. Our results show that it should be possible to determine the nature and composition of UHECRs with combined radio and particle detectors, and to detect the ultrahigh-energy neutrinos expected from flavour mixing.     

Boost PFC变换器快时标分岔分析及其双积分滑模控制

为了分析峰值电流型Boost PFC(power factor correction)在快时标下的非线性现象,建立Boost PFC变换器的离散迭代映射,并基于此映射推导其状态转移矩阵的表达式,得到系统分岔的条件,通过仿真观察系统电感电流在输入电压周期内出现的间歇性分岔和混沌现象.为了避免分岔,使系统稳定工作在单周期态,采用双积分滑模的控制方法.仿真结果表明:与常规的斜坡补偿法相比,双积分滑模法不需要施加外部扰动,且具有良好的鲁棒性,在有效地避免因输入电压变化所产生的分岔现象的同时,让Boost PFC具有较高的功率因数(PF),且算法简单,易于实现,对PFC变换器的分岔控制提供了借鉴.     

益肾方对db/db糖尿病小鼠肾保护作用的疗效观察

目的:探讨益肾方对db/db糖尿病小鼠肾保护作用的效果.方法:60只db/db糖尿病小鼠随机分为模型组、益肾方低剂量组、益肾方高剂量组和洛汀新组,15只同背景db/m小鼠为正常对照组,分别灌胃12周,检测肾功能相关生化指标,并对肾组织进行HE、PAS染色.结果:与对照组相比,模型组、益肾方低剂量组、益肾方高剂量组和洛汀新组的血糖、尿肌酐/尿微量白蛋白比(ACR)、胱抑素C和肾病病理学评分均显著升高,提示模型构建成功;与模型组对比,益肾方低剂量组、益肾方高剂量组和洛汀新组的ACR、胱抑素C和肾病病理学评分均显著降低,且益肾方高剂量组上述指标的改善优于益肾方低剂量组和洛汀新组,而各组的血糖无显著性差异,益肾方可有效改善db/db糖尿病小鼠的生化指标,减轻肾脏病理变化.结论:益肾方对db/db糖尿病小鼠的肾保护作用疗效确切,且其疗效呈剂量依赖性,并独立于血糖水平.     

Influence of environmental conditions on the amount of N2O released from activated sludge in a domestic waste water treatment plant

Waste water purification is characterized by intensive mineralization and nitrification processes. Because of the high O₂ demand, temporarily anaerobic conditions may be produced, and denitrification by nitrifying organisms as well as heterotropic denitrification may contribute to N₂O release. In situ measurements (1993–1994) suggest that N₂O is released from activated sludge in a domestic waste water treatment plant at an average rate of 1040 g m^–2h^–1 with a range between zero and 6198 g m^–2h^–1. The production of N₂O seems to be related to the concentration of NO ₂ ^– and NO ₃ ^– as well as to the pH. In the waste water about 75–200 g N₂O l^–1 is dissolved. This N₂O is released after discharge into the receiving waters. The N₂O is produced essentially by nitrification rather than by heterotropic denitrification. On a long-term scale the increasing use of mechanical-biological waste water purification plants world-wide may add increasingly to the anthropogenic production of N₂O, although the present amount of N₂O produced is negligible compared to its global terrestrial production.     

Electronic Medical Records (EMR) and Nurses in Turkish Hospitals

Electronic medical records (EMR) are generally used by nurses in hospitals. However, studies investigating views on and evaluations of EMR by nurses are limited in Turkey and in other countries around the world. In this study, nurses’ views on EMR systems were investigated in terms of “Nursing care management”, “Order entry”, “Information Management”, “Information quality”, “Service quality”, “Impact of EMR system on clinical care”. The purpose of this study was to investigate the views/perceptions on EMR used by nurses working at hospital clinics in Turkey. The research questions were: (a) What are nurses’ perceptions on EMR? (b) Were there relationships among nurses’ perceptions on EMR? (c) Were there differences among nurses’ perceptions on EMR according to hospitals in Turkey. This study is composed of field research conducted using questionnaires. To prepare the data-measuring instrument, the literature on EMR was reviewed. A Likert scale type was used in this questionnaire. The study was planned and conducted on nurses working at inpatient care units at four Turkish hospitals. At the end of this study, the questionnaire had been conducted on 517 nurses. Total response rate is 66.70 %. We found that the Information quality of EMR, impact of EMR system on clinical care and service quality were high level. Information quality has the highest mean score. EMR system is an important system for nurses’ hospital has the highest mean score in this study. Nurses feel about impact of EMR system on clinical care that generally ‘EMR system’s usefulness’, ‘improving quality of information due to EMR system’, ‘improving quality of nurses’ work’, ‘improving quality of information due to EMR system’. All of the six subscales of EMR were positively correlated with each other. This study revealed that there are significant differences among the mean scores for six subscales according to the ownership of hospitals. EMR systems were not well integrated into their workflow. In addition, half of all respondents had not been trained in using EMR systems. This study will added to evaluation views and assessments of nurses about EMR literature. The results will assist in determining “Information quality”, “Service quality”, of EMR, and “Impact of EMR system on clinical for nurses in Turkish health system”. This survey suggests that nurses favor the use of an EMR and suggests opportunities for EMR enhancement.     

On assessing the relative performance of default predictions

We compare the accuracy of default predictions as, for instance, produced by professional rating agencies. We extend previous results on partial orderings to nonidentical sets of obligors and show that the calibration requirement virtually rules out the possibility of some partial orderings and that the partial ordering based on the ROC curve is most easily achieved in practice. As an example, we show for more than 5,000 firms rated by Moody's and S&P that these ratings cannot be ranked according to their grade distributions given default or nondefault, but that Moody's dominate S&P with respect to the ROC criterion and the Gini curve.