Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA‐mediated synthetic ...lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib‐induced ferroptosis. Mechanistically, in a TEAD‐dependent manner, YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib‐induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization, and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovers a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ‐based rewiring strategies as potential approaches to overcome HCC therapy resistance.
SYNOPSIS
Resistance to therapy occurs in most liver cancer patients treated with Sorafenib, and patients succumb to the disease. A synthetic lethal screen identified a regulatory circuit, which prevents ferroptosis and promotes cancer cell survival, thus promoting resistance to Sorafenib.
The transcription factors YAP and TAZ stabilize ATF4 by promoting its nuclear import to cooperatively induce expression of SLC7A11, a cystine importer critical for glutathione synthesis.
Glutathione synthesis and homeostasis are required to repress ferroptosis and to maintain Sorafenib resistance in liver cancer cells.
Inhibition of Glutathione synthesis re‐sensitizes Sorafenib‐resistant cancer cells to Sorafenib therapy, which then induces ferroptosis and represses tumor growth in murine liver cancer models.
Pharmacological repression of the anti‐oxidant pathways regulated by YAP/TAZ and ATF4 could re‐sensitize therapy‐resistant liver cancers to Sorafenib treatment.
Resistance to therapy occurs in most liver cancer patients treated with Sorafenib, and patients succumb to the disease. A synthetic lethal screen identified a regulatory circuit, which prevents ferroptosis and promotes cancer cell survival, thus promoting resistance to Sorafenib.
•The effects of water immersion on spontaneous combustion of coal were studied.•N2 adsorption and SEM showed the changes of pore characteristics of soaked coal.•Free radical characteristics of ...untreated and soaked coal were investigated.•Immersion process increases the chance of coal contact with oxygen during combustion.
To investigate the effect of water immersion on the structure and low-temperature oxidation of coal, the untreated coal and soaked coal for 90 days and 180 days were prepared and compared. The surface morphology, pore structure, physical oxygen absorption and free radical parameters were characterized by scanning electron microscope (SEM), N2 adsorption, chromatography oxygen absorption and electron spin resonance spectrometer (ESR). The crossing point temperature (CPT) and oxidation products of coal samples were investigated using oxidation kinetics experiment. Compared with the untreated coal, larger average pore diameter, more free radical species and concentration were found in the soaked coal. Moreover, more pores with diameter >10 nm were formed due to soaking process, which would improve the transport capacity of O2 in pores to react with active sites on pore surfaces in the soaked coal. At the same time, the soaking process increased the physical oxygen absorption of coal by opening up more obturator channels. Moreover, the longer the soaking time, the more obvious the effect of the soaking process on the long flame coal. In addition, immersion process increased the indicator gas production rate of the soaked coal, and decreased its crossing point temperature, increased the risk of spontaneous combustion of Shendong long flame coal in general.
New cinchona‐based primary amine catalysts were prepared and screened as organocatalysts for the γ‐alkylation of α,β‐unsaturated aldehydes with bis(4‐dimethylaminophenyl)methanol. Catalyst C3 ...containing acetic acid group yielded γ‐alkylated products in good yields (up to 94 %) with up to 90 % ee. This new primary aminocatalyst provide new opportunities to explore novel asymmetric transformations.
New cinchona‐based primary amine catalysts were prepared and screened as organocatalysts for the γ‐alkylation of α,β‐unsaturated aldehydes with bis(4‐dimethylaminophenyl)methanol. Catalyst C3 containing acetic acid group yielded γ‐alkylated products with good enatioselectivities.
This study comparatively evaluated the effects of different extraction methods on yield, structural features and antioxidant activities of Laminaria japonica (L. japonica) polysaccharides. Results ...showed that acid, water and alkaline extracted L. japonica polysaccharides (LJP-CA, LJP-W and LJP-A, respectively) differed significantly. Among three polysaccharides, LJP-W showed the highest viscosity with high uronic acid content and average molecular weight, whereas LJP-CA showed the lowest viscosity with low uronic acid and high sulfate content with moderate average molecular weight. LJP-CA was mainly composed of fucose, mannose and galactose, but the proportion of glucose was greatly increased in LJP-W and LJP-A. LJP-W had an even and smooth sheet-like appearance, while LJP-CA and LJP-A exhibited irregular and rough fragments or particles with stronger antioxidant activities. These results suggest that acid and alkali would propose an improved process for polysaccharide preparation from L. japonica and to exploit its potential application as a functional ingredient in food application.
•Laminaria japonica polysaccharide was extracted by acidic, water and alkaline method.•The yield of alkaline extraction (LJP-A) was the highest.•LJP-W had the highest uronic acid content, Mw, and viscosity.•CD and SEM showed the difference in surface and conformational characteristics.•LJP-CA presented the highest superoxide and hydroxyl radical scavenging activities.
Recently, long noncoding RNAs have emerged as new gene regulators and prognostic markers in several cancers, including renal cell carcinoma (RCC). Here, we focused on the long noncoding RNA lung ...cancer associated transcript 1 (LUCAT1) based on clear cell RCC (ccRCC) the cancer genome atlas (TCGA) data. However, whether aberrant expression of LUCAT1 in ccRCC is correlated with malignancy, metastasis or prognosis has not been elucidated. In the current study, we found that the expression of LUCAT1 was upregulated in ccRCC tissues and cancer cell lines. Upregulated LUCAT1 was positively correlated with larger tumor size, advanced tumor‐node‐metastasis (TNM) stage, higher smoking frequency, nodal metastasis and shorter overall survival in patients with ccRCC. Inhibition of LUCAT1 by small interfering RNA reduced cell proliferation and invasion of ccRCC cells in vitro. In vivo assay showed that the tumor volume and weight were lower in the group of LUCAT1 inhibition than that in the control group. We then found that LUCAT1 directly bound and inhibited the expression of micoRNA‐495‐3p (miR‐495‐3p), which subsequently regulated the expression of special adenine‐thymine (AT)‐rich DNA‐binding protein 1 (SATB1). Collectively, LUCAT1 was critical for proliferation and invasion of ccRCC cells by regulating miR‐495‐3p and SATB1. Our findings indicated that LUCAT1 and miR‐495‐3p may offer potential novel therapeutic targets of treatment of ccRCC.
LUCAT1 was critical for proliferation and invasion of ccRCC cells by regulating miR‐495‐3p and SATB1. LUCAT1 and miR‐495‐3p may offer potential novel therapeutic targets of treatment of ccRCC.
Differences in how writing systems represent language raise important questions about the extent to which the role of linguistic skills such as phonological awareness (PA) and morphological awareness ...(MA) in reading is universal. In this meta-analysis, the authors examined the relationship between PA, MA, and reading (accuracy, fluency, and comprehension) in 2 languages (English and Chinese) representing different writing systems (alphabetic and logographic). A random-effects model analysis of data from 64 studies with native speakers of each language revealed significant correlations between PA, MA, and all reading outcomes in both languages. The correlations remained significant even after controlling for each other's effect on reading. However, PA was a stronger correlate of reading in English than in Chinese. MA was as good a correlate of reading in English as in Chinese (except for comprehension, where it was better). In addition, complex PA tasks in English and production/compounding MA tasks in Chinese produced significantly larger correlations with reading accuracy. Taken together, the findings of this meta-analysis suggest that PA and MA are significant correlates of reading, but their role is influenced by the writing system, the type of reading outcome, and the type of task used to operationalize PA and MA. The implications of these findings are discussed.
Educational Impact and Implications Statement
The authors examined the role of writing system in the relationship between phonological awareness, morphological awareness, and reading. The results of the meta-analysis revealed significant relationships between these linguistic skills and reading in each language, but the strength of the relationships was influenced by the writing system, the type of reading outcome, and the type of task used to operationalize phonological awareness and morphological awareness. These findings help us better understand the linguistic skills that are most important for reading acquisition in different writing systems.
Genetic risk prediction is an important problem in human genetics, and accurate prediction can facilitate disease prevention and treatment. Calculating polygenic risk score (PRS) has become widely ...used due to its simplicity and effectiveness, where only summary statistics from genome-wide association studies are needed in the standard method. Recently, several methods have been proposed to improve standard PRS by utilizing external information, such as linkage disequilibrium and functional annotations. In this paper, we introduce EB-PRS, a novel method that leverages information for effect sizes across all the markers to improve prediction accuracy. Compared to most existing genetic risk prediction methods, our method does not need to tune parameters nor external information. Real data applications on six diseases, including asthma, breast cancer, celiac disease, Crohn's disease, Parkinson's disease and type 2 diabetes show that EB-PRS achieved 307.1%, 42.8%, 25.5%, 3.1%, 74.3% and 49.6% relative improvements in terms of predictive r2 over standard PRS method with optimally tuned parameters. Besides, compared to LDpred that makes use of LD information, EB-PRS also achieved 37.9%, 33.6%, 8.6%, 36.2%, 40.6% and 10.8% relative improvements. We note that our method is not the first method leveraging effect size distributions. Here we first justify our method by presenting theoretical optimal property over existing methods in this class of methods, and substantiate our theoretical result with extensive simulation results. The R-package EBPRS that implements our method is available on CRAN.
Soybean is an important crop grown worldwide, and drought stress seriously affects the yield and quality of soybean. Therefore, it is necessary to elucidate the molecular mechanisms underlying ...soybean resistance to drought stress. In this study, RNA-seq technology and ultra-performance liquid chromatography-tandem mass spectrometry were used to analyze the transcriptome and metabolome changes in soybean leaves at the seedling stage under drought stress. The results showed that there were 4790 and 3483 DEGs (differentially expressed genes) and 156 and 124 DAMs (differentially expressed metabolites), respectively, in the HN65CK vs. HN65S0 and HN44CK vs. HN44S0 comparison groups. Comprehensive analysis of transcriptomic and metabolomic data reveals metabolic regulation of seedling soybean in response to drought stress. Some candidate genes such as
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showed different expression trends between the two cultivars, which may cause differences in drought resistance. Secondly, a large number of flavonoids were identified, and the expression of Monohydroxy-trimethoxyflavone-O-(6″-malonyl)glucoside was upregulated between the two varieties. Finally, several key candidate genes and metabolites involved in isoflavone biosynthesis and the TCA cycle were identified, suggesting that these metabolic pathways play important roles in soybean response to drought. Our study deepens the understanding of soybean drought resistance mechanisms and provides references for soybean drought resistance breeding.
Summary
Salicylic acid (SA) signalling plays an essential role in plant innate immunity. In this study, we identified a component in the SA signaling pathway in potato (Solanum tuberosum), the ...transcription factor StbZIP61, and characterized its function in defence against Phytophthora infestans. Expression of StbZIP61 was induced upon P. infestans infection and following exposure to the defense signaling hormones SA, ethylene and jasmonic acid. Overexpression of StbZIP61 increased the tolerance of potato plants to P. infestans while RNA interference (RNAi) increased susceptibility. Yeast two‐hybrid and pull down experiments revealed that StbZIP61 could interact with an NPR3‐like protein (StNPR3L) that inhibited its DNA‐binding and transcriptional activation activities. Moreover, StNPR3L interacted with StbZIP61 in an SA‐dependent manner. Among candidate genes involved in SA‐regulated defense responses, StbZIP61 had a significant impact on expression of StICS1, which encodes a key enzyme for SA biosynthesis. StICS1 transcription was induced upon P. infestans infection and this responsive expression to the pathogen was reduced in StbZIP61 RNAi plants. Accordingly, StICS1 expression was remarkably enhanced in StbZIP61‐overexpressing plants. Together, our data demonstrate that StbZIP61 functions in concert with StNPR3L to regulate the temporal activation of SA biosynthesis, which contributes to SA‐mediated immunity against P. infestans infection in potato.
Significance statement
The regulatory mechanism for dynamic biosynthesis of SA in plant immunity remains largely unknown. Here, we show that potato transcription factor StbZIP61 participates in defense against P. infestans by regulating SA biosynthesis. In response to pathogen infection, StbZIP61 promotes SA synthesis by inducing StICS1 expression and this activity is repressed by the NPR3‐like protein StNPR3L. Our results demonstrate that StbZIP61 functions in concert with StNPR3L to establish a temporal SA accumulation in immune responses.
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