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

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

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

Predicting feature imputability in the absence of ground truth

Data imputation is the most popular method of dealing with missing values, but in most real life applications, large missing data can occur and it is difficult or impossible to evaluate whether data has been imputed accurately (lack of ground truth). This paper addresses these issues by proposing an effective and simple principal component based method for determining whether individual data features can be accurately imputed - feature imputability. In particular, we establish a strong linear relationship between principal component loadings and feature imputability, even in the presence of extreme missingness and lack of ground truth. This work will have important implications in practical data imputation strategies.Comment: 5 pages, 3 figures, 1 table. In: Proceedings of the 37th International Conference on Machine Learning (ICML), 202

SYK-targeted dendritic cell-mediated cytotoxic T lymphocytes enhance the effect of immunotherapy on retinoblastoma

Purpose: Retinoblastoma (RB) is the most common primary intraocular tumor in children. Chemotherapy is currently the main method of RB treatment. Unfortunately, RB often becomes chemoresistant and turns lethal. Here, we used in vitro cell immunotherapy to explore whether adoptive immunotherapy could be used as a potential treatment for RB. We focused on spleen tyrosine kinase (SYK), which is significantly upregulated in RB cells and serves as a marker for RB cells. Methods: Using lentiviruses, we genetically modified dendritic cells (DCs) to express and present the SYK peptide antigen to cytotoxic T lymphocytes (CTLs) in vitro. We used SYK-negative cell lines (MDA-MB-231, MCF-10A, and hTERT-RPE1) and SYK-positive cell lines (MCF-7 and RB-Y79) to evaluate the specificity and cytotoxicity of DC presented CTLs using FACS, live-cell imaging, and RNA interference. Results: The cytotoxicity of CTLs induced by SYK-overexpressing DCs (SYK-DC–CTLs) was enhanced more than three times in SYK-positive cell lines compared with SYK-negative cell lines. DCs primed with SYK could drive CTL cytotoxicity against SYK-positive cell lines but not against SYK-negative cell lines. Moreover, SYK-silenced RB-Y79 cells successfully evaded the cytotoxic attack from SYK-DC–CTLs. However, SYK-DC–CTLs could target SYK overexpressed hTERT-RPE1 cells, suggesting that SYK is a specific antigen for RB. Furthermore, SYK-DC–CTL exhibited specific cytotoxicity against carboplatin-resistant RB-Y79 cells in vitro. Conclusions: Our data showed that SYK could be a potential immunotherapy target mediated by DCs. We propose SYK as a candidate target for treatment of chemoresistant RB.Fil: Chen, Xuemei. Xi'an Jiaotong University; ChinaFil: Kunda, Patricia Elena. Instituto Universitario de Ciencias Biomédicas de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Lin, Jianwei. Shenzhen University; ChinaFil: Zhou, Meiling. Shenzhen Luohu Peoples Hospital; China. Shenzhen University; ChinaFil: Huang, Jinghan. Shenzhen Luohu Peoples Hospital; ChinaFil: Zhang, Huqin. Xi'an Jiaotong University; ChinaFil: Liu, Tao. Shenzhen University; China. Shenzhen Luohu Peoples Hospital; Chin

Structure and mechanism of a methyl transferase ribozyme

Known ribozymes in contemporary biology perform a limited range of chemical catalysis, but in vitro selection has generated species that catalyze a broader range of chemistry; yet, there have been few structural and mechanistic studies of selected ribozymes. A ribozyme has recently been selected that can catalyze a site-specific methyl transfer reaction. We have solved the crystal structure of this ribozyme at a resolution of 2.3 Å, showing how the RNA folds to generate a very specific binding site for the methyl donor substrate. The structure immediately suggests a catalytic mechanism involving a combination of proximity and orientation and nucleobase-mediated general acid catalysis. The mechanism is supported by the pH dependence of the rate of catalysis. A selected methyltransferase ribozyme can thus use a relatively sophisticated catalytic mechanism, broadening the range of known RNA-catalyzed chemistry. [Image: see text