Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia.

Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1S34F and U2AF1Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA sequencing. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway. SIGNIFICANCE: U2AF1 mutations induce the integrated stress response by disrupting splicing of mRNA translation genes that improves AML cell fitness to enable resistance to chemotherapy, which can be targeted to improve AML treatment.

Intercropped Amygdalus persica and Pteris vittata applied with additives presents a safe utilization and remediation mode for arsenic-contaminated orchard soil.

Intercropping the arsenic (As) hyperaccumulator Pteris vittata with fruit trees can safely yield peaches in As-polluted orchards in South China. However, the soil As remediation effects and the related mechanisms of P. vittata intercropped with peach trees with additives in the north temperate zone have rarely been reported. A field experiment was conducted to systematically study the intercropping of peach (Amygdalus persica) with P. vittata with three additives [calcium magnesium phosphate (CMP), ammonium dihydrogen phosphate (ADP), and Stevia rebaudiana Bertoni residue (SR)] in a typical As-contaminated peach orchard surrounding a historical gold mine in Pinggu County, Beijing City. The results showed that compared with monoculture (PM) and intercropping without addition (LP), the remediation efficiency of P. vittata intercropping was significantly increased by 100.9 % (CMP) to 293.5 % (ADP). CMP and ADP mainly compete with available As (A-As) adsorbed to the surface of Fe-Al oxide through PO43-, while SR might activate A-As by enhancing dissolved organic carbon (DOC) in P. vittata rhizospheres. The photosynthetic rates (Gs) of intercropped P. vittata were significantly positively correlated with pinna As. The intercropping mode applied with the three additives did not obviously affect fruit quality, and the net profit of the intercropping mode (ADP) reached 415,800 yuan·ha-1·a-1. The As content in peaches was lower than the national standard in the intercropping systems. Comprehensive analysis showed that A. persica intercropped with P. vittata applied with ADP is better than other treatments in improving risk reduction and agricultural sustainability. In this study, a theoretical and practical basis is provided for the safe utilization and remediation of As-contaminated orchard soil in the north temperate zone.

Colonization of Fusobacterium nucleatum is an independent predictor of poor prognosis in gastric cancer patients with venous thromboembolism: a retrospective cohort study.

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) often colonizes cancerous gastric tissues and is characterized by the promotion of platelet aggregation and the development of visceral thrombosis. Venous thromboembolism (VTE) leads to a significant increase in the mortality of gastric cancer (GC) patients. However, the relationship between the colonization of F. nucleatum and the prognosis of GC patients is still unknown. AIM: The aim of this study was to explore whether the colonization of F. nucleatum is related to the prognosis of GC patients complicated with VTE and to explore other potential risk factors. METHODS: From 2017-2021, the data of 304 patients with new VTEs during the treatment of GC at the Affiliated Cancer Hospital of Zhengzhou University were collected. Fluorescence in situ hybridization of F. nucleatum was performed on pathological sections of cancer tissues from the patients. Survival analysis methods, including the Kaplan‒Meier method and Cox proportional hazard model, were performed. RESULTS: F. nucleatum colonization was significantly associated with splanchnic vein thrombosis, higher platelet-lymphocyte ratio (PLR), and lower absolute lymphocyte count. In the multivariable Cox model, F. nucleatum colonization was found to be an independent risk factor for the prognosis of GC, with an adjusted HR of 1.77 (95% CI, 1.17 to 2.69 [P = 0.007]). In addition, patients with high PLR (HR: 2.65, P = 0.004) or VTE occurring during four cycles of chemotherapy (HR: 2.32, P = 0.012) exhibited shorter survival. Conversely, those experiencing VTE later (HR per month from diagnosis of GC: 0.95, P = 0.006) or using IVC filters (HR: 0.27, P = 0.011) had longer survival. CONCLUSION: Colonization of F. nucleatum in GC tissues was associated with lower absolute lymphocyte count and higher PLR in GC patients with VTE. F. nucleatum colonization also appeared to be associated with the development of VTE in specific sites, in particular the splanchnic vein. Colonization of F. nucleatum may potentially represent an independent predictor of poor prognosis in GC patients. Additional research is necessary to validate these findings.

Iron-based nanomaterials reduce cadmium toxicity in rice (Oryza sativa L.) by modulating phytohormones, phytochelatin, cadmium transport genes and iron plaque formation.

Rice is known to accumulate cadmium (Cd) in its grains, causing a severe threat to billions of people worldwide. The possible phytotoxicity and mechanism of 50-200 mg/L hydroxyapatite NPs (nHA), iron oxide NPs (nFe2O3) or nano zero valent iron (nZVI) co-exposed with Cd (100 µM) in rice seedlings were investigated. Three types of nanoparticles significantly reduced the bioaccumulation of Cd in rice shoots by 16-63%, with nZVI showing the greatest effect, followed by nHA and nFe2O3. A decrease in Cd content in the roots was observed only in the nZVI treatment, with values ranging from 8 to 19%. Correspondingly, nZVI showed the best results in promoting plant growth, increasing rice plant height, shoot and root biomass by 13%, 29% and 42%. In vitro studies showed that nZVI reduced the content of Cd in the solution by 20-52% through adsorption, which might have contributed to the immobilization of Cd in root. Importantly, the nZVI treatment resulted in 267% more iron plaques on the root surface, which acted as a barrier to hinder the entry of Cd. Moreover, all three nanoparticles significantly reduced the oxidative stress induced by Cd by regulating phytohormones, phytochelatin, inorganic homeostasis and the expression of genes associated with Cd uptake and transport. Overall, this study elucidates for the first time the multiple complementing mechanisms for some nanoparticles to reduce Cd uptake and transport in rice and provides theoretical basis for applying nanoparticles for reducing Cd accumulation in edible plants.

Structural characterization of lignin and lignin-carbohydrate complex (LCC) of sesame hull.

In the present study, lignin and lignin-carbohydrate complex (LCC) constituting the cell wall structure of sesame hulls were investigated to explore novel techniques of dehulling. Milled wood lignin (MWL), Björkman LCC, and acid-soluble LCC (LCC-AcOH) were extracted from sesame hulls and characterized by carbohydrate composition analysis, molecular weight analysis, UV-vis spectroscopy, FT-IR, thermal analysis, Py-GC/MS, 2D HSQC NMR, and 31P NMR. The results showed that rhamnose accounted for the largest proportion of the lignin and LCC fractions, followed by glucose. Björkman LCC had the largest molecular weight, MWL had the smallest molecular weight, and LCC-AcOH had the largest polydispersity index. The lignin of sesame hulls consisted of syringyl (S), guaiacyl (G), p-hydroxyphenyl (H), and caffeyl alcohol (C) units. The most abundant monomer was guaiacyl (G), followed by caffeyl alcohol (C). C-type lignin is a new type of lignin that is different from the three traditional lignin monomers. The major lignin-linked bonds in the MWL and LCC-AcOH were ß-O-4' and ß-ß', and ß-5' bonds were present in the Björkman LCC. The major LCC chemical bonds in the three fractions were PhGly. These findings will provide the factual basis for exploring different dehulling methods to enhance the quality of sesame products.

Pectic polysaccharides extracted from sesame seed hull: Physicochemical and functional properties.

The objective of the present investigation was to extract pectic polysaccharides from sesame seed hull and to determine their physicochemical and functional characteristics. The pectic polysaccharides in the seed hull were extracted with HCl and then collected at three ethanol concentrations of 30% (SSP30), 50% (SSP50), and 90% (SSP90). We found that SSP30 represented 75.6% of the total polysaccharides, and that it contained 76.39% galacturonic acid, with many HG domains and few short side chains in the RG-I domains. SSP30 exhibited the strongest hydroxyl radical scavenging activity among the three fractions, and was better able to stabilize the emulsions. Higher Mw pectic polysaccharides were firstly precipitated at lower ethanol concentrations, and the Mw of the precipitated pectic polysaccharides decreased with increasing ethanol concentration. These results provide important information on the structure and functional characteristics of sesame hull polysaccharides. This information can contribute to the future development of sesame hull polysaccharides for industrial purposes.

Effects of Soil Amendments on Soil Pb Bioavailability and Pb Absorption by a low-Pb Accumulator Kumquat Grown in Two Types of Pb-Contaminated Soils.

A pot experiment was conducted to investigate the effects of 0.5% and 1% alkaline, clay mineral and phosphorus amendments, as well as 2% and 5% organic amendments, on lead (Pb) soil bioavailability and Pb absorption by the low-Pb accumulator kumquat (Citrus japonica Thunb.) 'Cuipi' in two typical Pb-contaminated soils, Jiyuan and Yangshuo, from northern and southern China, respectively. The diethylenetriaminepentaacetic acid-extractable Pb soil concentration and Pb accumulation in kumquat significantly decreased with amendment additions. High amendment doses had greater inhibitory effects than low doses but no significant effects on the kumquat's biomass in the two typical soils. Alkaline, but not clay mineral, amendments greatly increased the soil pH level. Organic amendments effectively reduced Pb accumulation owing to their strong adsorptive capacities. Thus, using organic amendments combined with a low-Pb accumulator kumquat forms a suitable farming practice for producing safe fruit in the two common types of Pb-contaminated soils in China.

[Cd Accumulation Characteristics in Different Populations of Hylotelephium spectabile Under Salt Stress].

A pot experiment was conducted to investigate the growth response and Cd accumulation characteristics among different populations of Hylotelephium spectabile in Cd-contaminated cinnamon soil (2.22 mg·kg-1) with the addition of different concentrations of NaCl. Results showed that the biomasses and Cd concentrations of H. spectabile showed significant differences among different populations under Cd alone or Cd-salt combined stress. Moreover, salt stress aggravated the growth inhibition of H. spectabile and the Cd concentrations in different H. spectabile populations showed a declining trend, which may be related to the salt-derived pH increase leading to a decrease in Cd bioavailability. In addition, the growth and Cd absorption responses of H. spectabile under salt stress were significantly different in the different populations. The shoot biomasses of the LN population were significantly higher than in other populations under different treatment, and showed no significant decrease with the addition of 1% NaCl when compared with the control treatment and the tolerance index remained 0.91. At the same time, the shoot Cd concentration of the LN population was significantly higher than in other populations under different treatments. The result may be attributed to the Cd accumulation and detoxification mechanisms in LN are prior than other populations that may also have important physiological mechanisms for tolerance of salt stress. In summary, although Cd uptake in H. spectabile decreased with salt stress, there were significant differences among different populations. LN populations accumulated 84.4 µg·plant-1 Cd in shoots with 2% NaCl addition, which was 48.4%-89.3% higher than in other populations. Therefore, H. spectabile, especially LN populations, is a good candidate for phytoremediation of Cd-contaminated saline soil.