Both structure- and dynamics-driven allosteric effects are determined by the correlation of distance fluctuations in proteins.

Here we describe library design coupled with computational and intracellular screening as an effective methodology to derive an antagonist that is selective for Fra1 relative to Jun counterparts.

Intrinsically disordered proteins (IDPs) exist in highly dynamic conformational ensembles, which pose a major obstacle for drug development targeting IDPs because traditional rational drug design relies on unique three-dimensional structures. Here, we analyzed the conservation (especially structural conservation) of potentially druggable cavities in 22 ensembles of IDPs. It was found that there is considerable conservation for potentially druggable cavities within each ensemble. The average common atom percentage of potentially druggable cavities is as high as 54%. The average root-mean-squared deviation of common atoms ranges between 1 and 8 Å for multichain IDPs, and a common pocket is kept after direct alignment of cavities. In addition, the conservation of potentially druggable cavities varies among different proteins. In the comparison of multi- and single-chain IDPs, some multichain IDPs have an extremely high conservation, whereas another multichain IDPs’ conservation appears worse, and the single-chain IDPs have relatively moderate conservations. This study is a new attempt to generally assess the potentially druggable cavities in IDPs for taking IDPs as druggable targets, and this work also lends support to the opinion of IDPs tending to bind to “multiconformational affinity” compounds.

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Background This research aimed at exploring the mechanisms of alterations of metabolites and pathways in T2D from the perspective of metabolomics and transcriptomics, as well as uncovering novel drug candidate for T2D treatment. Methods Metabolites in human plasma from 42 T2D patients and 45 non‐diabetic volunteers were detected by liquid chromatography‐mass spectrometer (LC‐MS). Microarray dataset of the transcriptome was obtained from Gene Expression Omnibus (GEO) database. Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to conduct pathway enrichment analysis. Connectivity Map (CMap) was employed to select potential drugs for T2D therapy. In vivo assay was performed to verify above findings. The protein expression levels of ME1 , ME2 and MDH1 were detected by Western blot to determine the status of NAD/NADH cofactor system. Results In our study, differentially expressed metabolites were selected out between healthy samples and T2D samples with selection criteria P value < .05, |Fold Change| > 2, including N‐acetylglutamate and Malate. Genes set enrichment analysis (GSEA) revealed that 34 pathways were significantly enriched in T2D. Based on CMap analysis and animal experiments, Atractyloside was identified as a potential novel drug for T2D treatment via targeting ME1 , ME2 and MDH1 and regulating the NAD/NADH cofactor system. Conclusion The present research revealed differentially expressed metabolites and genes, as well as significantly altered pathways in T2D via an integration of metabolomics, transcriptomics and CMap analysis. It was also demonstrated that comprehensive analysis based on metabolomics and transcriptomics was an effective approach for identification and verification of metabolic biomarkers and alternated pathways.

A battery thermal management system (BTMS) ensures that batteries operate efficiently within a suitable temperature range and maintains the temperature uniformity across the battery. A strict requirement of the BTMS is that increases in the battery discharge rate necessitate an increased battery heat dissipation. The advantages of heat pipes (HPs) include a high thermal conductivity, flexibility, and small size, which can be utilized in BTMSs. This paper experimentally examines a BTMS using HPs in combination with an aluminum plate to increase the uniformity in the surface temperature of the battery. The examined system with high discharge rates of 50, 75, and 100 A is used to determine its effects on the system temperature. The results are compared with those for HPs without fins and in ambient conditions. At a 100 A discharge current, the increase in battery temperature using the heat pipe with fins (HPWF) method is 4.8 °C lower than for natural convection, and the maximum temperature difference between the battery surfaces is 1.7 °C and 6.0 °C. The pulse circulation experiment was designed considering that the battery operates with a pulse discharge and temperature hysteresis. The depth of discharge is also considered, and the states-of-charge (SOC) values were 0.2, 0.5, and 0.8. The results of the two heat dissipation methods are compared, and the optimal heat dissipation structure is obtained by analyzing the experimental results. The results show that when the ambient temperature is 37 °C, differences in the SOC do not affect the battery temperature. In addition, the HPWF, HP, and natural convection methods reached stable temperatures of 40.8, 44.3, and the 48.1 °C, respectively the high temperature exceeded the battery operating temperature range.

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