HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine.

Small-molecule inhibitors for the 90-kDa heat shock protein (HSP90) have been extensively exploited in preclinical studies for the therapeutic interventions of human diseases accompanied with proteotoxic stress. By using an unbiased quantitative proteomic method, we uncover that treatment with three HSP90 inhibitors results in elevated expression of a large number of heat shock proteins. We also demonstrate that the HSP90 inhibitor-mediated increase in expression of DNAJB4 protein occurs partly through an epitranscriptomic mechanism, and is substantially modulated by the writer, eraser, and reader proteins of N6-methyladenosine (m6A). Furthermore, exposure to ganetespib leads to elevated modification levels at m6A motif sites in the 5'-UTR of DNAJB4 mRNA, and the methylation at adenosine 114 site in the 5'-UTR promotes the translation of the reporter gene mRNA. This m6A-mediated mechanism is also at play upon heat shock treatment. Cumulatively, we unveil that HSP90 inhibitors stimulate the translation of DNAJB4 through an epitranscriptomic mechanism

SUVH1, a Su(var)3-9 family member, promotes the expression of genes targeted by DNA methylation.

Transposable elements are found throughout the genomes of all organisms. Repressive marks such as DNA methylation and histone H3 lysine 9 (H3K9) methylation silence these elements and maintain genome integrity. However, how silencing mechanisms are themselves regulated to avoid the silencing of genes remains unclear. Here, an anti-silencing factor was identified using a forward genetic screen on a reporter line that harbors a LUCIFERASE (LUC) gene driven by a promoter that undergoes DNA methylation. SUVH1, a Su(var)3-9 homolog, was identified as a factor promoting the expression of the LUC gene. Treatment with a cytosine methylation inhibitor completely suppressed the LUC expression defects of suvh1, indicating that SUVH1 is dispensable for LUC expression in the absence of DNA methylation. SUVH1 also promotes the expression of several endogenous genes with promoter DNA methylation. However, the suvh1 mutation did not alter DNA methylation levels at the LUC transgene or on a genome-wide scale; thus, SUVH1 functions downstream of DNA methylation. Histone H3 lysine 4 (H3K4) trimethylation was reduced in suvh1; in contrast, H3K9 methylation levels remained unchanged. This work has uncovered a novel, anti-silencing function for a member of the Su(var)3-9 family that has previously been associated with silencing through H3K9 methylation

Institutional determinants of construction safety management strategies of contractors in Hong Kong

published_or_final_versio

Transcription-associated mutation promotes RNA complexity in highly expressed genes - a major new source of selectable variation

Alternatively spliced transcript isoforms are thought to play a critical role for functional diversity. However, the mechanism generating the enormous diversity of spliced transcript isoforms remains unknown, and its biological significance remains unclear. We analyzed transcriptomes in saker falcons, chickens, and mice to show that alternative splicing occurs more frequently, yielding more isoforms, in highly expressed genes. We focused on hemoglobin in the falcon, the most abundantly expressed genes in blood, finding that alternative splicing produces 10-fold more isoforms than expected from the number of splice junctions in the genome. These isoforms were produced mainly by alternative use of de novo splice sites generated by transcription-associated mutation (TAM), not by the RNA editing mechanism normally invoked. We found that high expression of globin genes increases mutation frequencies during transcription, especially on nontranscribed DNA strands. After DNA replication, transcribed strands inherit these somatic mutations, creating de novo splice sites, and generating multiple distinct isoforms in the cell clone. Bisulfate sequencing revealed that DNA methylation may counteract this process by suppressing TAM, suggesting DNA methylation can spatially regulate RNA complexity. RNA profiling showed that falcons living on the high Qinghai–Tibetan Plateau possess greater global gene expression levels and higher diversity of mean to high abundance isoforms (reads per kilobases per million mapped reads ≥18) than their low-altitude counterparts, and we speculate that this may enhance their oxygen transport capacity under low-oxygen environments. Thus, TAM-induced RNA diversity may be physiologically significant, providing an alternative strategy in lifestyle evolution

Future groundwater extraction scenarios based on COMSOL multiphysics for the confined aquifer at Linfen basin, Shanxi Province, China

As one of the six largest river basins in Shanxi Province, China, Linfen basin has been in severe groundwater level declining status caused by over-extraction of groundwater since 1976, along with dense distribution of land subsidence and ground fissures. Future Groundwater drawdown analysis due to over-extraction is a major concern for not only water resource management, but also preventive and controlling measures of land subsidence and ground fissures. Consequently, in this paper groundwater extraction dynamic process for the confined aquifer at Linfen basin was simulated based on COMSOL Multiphysics. Then future groundwater extraction scenarios, namely, groundwater drawdown values within a period of consecutive 20 years and their consequent impacts on confined aquifer discharge amount to the Yellow River were predicted. The results demonstrated that the groundwater drawdown value and lateral discharge to the Yellow River would reach 7.07 m/a and 0.56 × 108 m3/a respectively in 10 years, while these two numbers drop to 3.44 m/a and 0.25 × 108 m3/a in 20 years. In order to provide valuable information for local government and policy makers, the paper would finally quantify a sustainable groundwater extraction value—20% of current groundwater extraction amount

Analisis Portofolio Optimal Dengan Single Index Model Untuk Meminimumkan Risiko Bagi Investor Di Bursa Efek Indonesia (Studi Pada Saham Indeks Kompas 100 Periode Februari 2010-juli 2014)

Investments can be made in the capital market, capital market instruments which are mostly attractive for investors is stock. Stock provides a return in the form of capital gains and dividends yield, not only noticing the return, investors need to pay attention to the investments risk. Unsystematis risk can be minimized by forming the optimal portfolio using one of the methods that is single index model. Study purpose is to knowing the stocks forming the optimal portfolio, the proportion of funds allocated to each stocks, the level of expectation return and risk.The method used in this research is descriptive research method with a quantitative approach. The samples used were 46 stocks in Kompas 100 Index, which meets the criteria for sampling. The results showed that 12 stocks of forming optimal portfolio, the stocks of which are UNVR, TRAM, MNCN, BHIT, JSMR, BMTR, GJTL, KLBF, AALI, CPIN, AKRA, and ASRI. Stock with highest proportion of funds is TRAM (23,52%), stock with lowest proportion of funds is AALI (0,62%). Portfolio which are formed will give return expectations by 3,05477% and carry the risk for about 0,1228%

Enhancing the energy efficiency of domestic dryer by drying process optimization

The domestic tumble dryers are becoming indispensable household appliances and responsible for up to 10% of the total residential energy use in developed countries. However, their energy efficiency is low. In this paper, the development of a multi-sensor computer-controlled prototype platform for fabric drying is described for improving the efficiency of dryers. The prototype platform enables the real-time control and recording of key drying parameters including heater power, air flow velocity, rotating speed of drying drum and drying cycle time. These parameters are automatically adjusted according to the exhaust air humidity instead of the temperature which is used traditionally. Additionally, a new drying model of dividing the drying process into 4 stages based on the humidity of the exhaust air has been investigated in order to further increase the energy saving. The performance of this staged drying model is experimentally evaluated in respect to energy consumption, drying time, and the smoothness of fabric after drying. The results clearly indicate that the staged controlling of heating power input not only decreases energy consumption by 21.5% but also improves the fabric smoothness by 0.9 grade compared to using a single heating power input for the whole drying process. The research outcome can enable the design and production of new dryers that are more energy efficient and lead to dried clothes that require less ironing, which in turn further reduces energy consumption

Coordinate Attention Based 3D-CNN Using Ghost Multi-Scale for Diagnosing Alzheimer’s Disease

Alzheimer's disease (AD) is a neurodegenerative disease and mild cognitive impairment (MCI) is the early stage of AD. Previous studies have predominantly focused on binary classification using 3 dimensional - convolutional neural network (3D-CNN) for AD diagnosis, with limited progress in multi-classification. Moreover, the current 3D-CNNs often adopt a single-scale architecture with massive parameters growth. Additionally, obtaining precise location information of brain imaging data is crucial for improving the classification accuracy with 3D-CNN. Hence, we propose a multi-scale 3D-CNN based on coordinate attention mechanism to marvelously capture and integrate 3D features with fewer parameters, improving the accuracy of AD diagnosis. A total of 447 cognitively normal (CN), 512 MCI, and 358 AD sMRI images from the Alzheimer's Disease Neuroimaging Initiative datasets are used for multi-class classification task, yielding a classification accuracy of 92.8%. The model merely involves 2.41 M parameters and achieves the best classification results with the least number of parameters when compared to other representative CNN architectures including ResNet 18, ResNet 34, ConvNeXt tiny, and VGG 11. Through the ablation experiment, the addition of attention mechanism and the multi-scale classification enhances the classification performance by 4.5% and 1.5%, respectively. Furthermore, our model outperforms the other six existing studies in terms of accuracy for classifying AD vs. MCI vs. CN. Overall, this study underscores the efficacy of our approach for AD diagnosis, showcasing its utility in diagnosing AD patients and providing novel insights for diagnosing other neurological disorder diseases

Behaviour and design of duplex stainless steel bolted connections failing in block shear

Duplex stainless steel (DSS) is an emerging construction material for structural engineering, which is featured with high mechanical strength and superior corrosion resistance. Compared with considerable research on DSS structural members, available research is relatively limited for structural joints/connections between these members. In line with this concern, this paper presents a comprehensive experimental and numerical study of duplex stainless steel bolted connections (DSSBCs), focusing on the behaviour and design related to block shear failure. Eleven specimens are tested to investigate the effect of different bolt arrangements on the block shear behaviour. Furthermore, a detailed numerical study was performed as a supplement to the experimental tests, where the anisotropic mechanical properties of DSS are considered in the finite element modelling. Based on the test and analysis results, it is found that the block shear failure mode of DSSBCs resembles that of carbon steel bolted connections, which can be characterised as necking of the tensile section and yielding of the shear sections. Using the experimental and numerical data obtained in this and previous studies, the applicability of various block shear design methods to stainless steel bolted connections is assessed. An updated design method is proposed for predicting the block shear capacity of duplex and austenitic stainless steel bolted connections. A proper partial safety factor/resistance factor is suggested for the proposed method based on the results of reliability analyses