Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma.

Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter's tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.

Metabolic factors are not the direct mediators of the association between type 2 diabetes and osteoporosis.

Objective: The causal relationship between type 2 diabetes mellitus (T2DM) and osteoporosis (OS) remains unclear. This study aims to investigate the causal relationship and explore the potential metabolic mechanism and its mediating role. Methods: We conducted a comprehensive study, gathering data on 490,089 T2DM patients from the genome-wide association study (GWAS) database and selecting OS data from FinnGen and MRC-IEU sources, including 212,778 and 463,010 patients, respectively, for causal analysis. Simultaneously, we explored the potential roles of three obesity traits and 30 metabolic and inflammation-related mediating variables in the causal relationship. Results: There is a strong causal relationship between T2DM and OS. The data from our two different database sources appeared in the same direction, but after correcting for body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR), the direction became the same. T2DM may increase the risk of OS [odds ratio (OR) > 1.5, p < 0.001]. Steiger's test results show that there is no reverse causality. No risk factors related to glycolipid metabolism, amino acid metabolism, and inflammation were found to mediate the causal relationship. Conclusion: This study's findings indicate a robust causal relationship between T2DM and OS, influenced by relevant factors such as BMI. Our results shed light on the pathogenesis of OS and underscore the importance for clinicians to treat metabolic disorders to prevent osteoporosis.

Towards a better understanding of ethylmercury in the environment: Addressing propylation derivatization artifact and verifying its occurrence in Chinese wetlands.

Ethylmercury (EtHg), similar to methylmercury (MeHg), is highly neurotoxic and bioaccumulative. Although recent studies suggested its occurrence in natural soils and sediments, the common propylation derivatization for EtHg analysis might generate EtHg artifacts, potentially leading to its overestimation in environmental samples. Furthermore, the extensive environmental prevalence of EtHg remains unverified, keeping its importance largely uncertain. This study investigated the formation of EtHg artifacts during propylation derivatization, evaluating artifacts formation and recoveries under different extraction methods with real samples, and confirmed the widespread occurrence of EtHg in Chinese wetlands. EtHg artifacts were obviously present during the propylation derivatization and strongly dependent on the levels of Hg2+ (0.1-10 ng) in the derivatization solution (R² = 0.99), accounting for 1.38-2.14% of Hg2+. CuSO4-HNO3CH2Cl2 extraction (effectively removing Hg2+) combined with propylation derivatization offers excellent recovery (81-86%) and low artifacts (< LOD: 1.98 × 10-4 ng/g) for EtHg measurement in soils/sediments, with results aligning with those from online solid phase extraction-high performance liquid chromatography-inductively coupled plasma mass spectrometry (R2 = 0.99). Additionally, we observed the occurrence of EtHg in soil and sediment samples across 14 Chinese wetlands, with concentrations varying from 6.08 to 171 pg/g, similar to MeHg concentrations at some sites. EtHg positively correlates with MeHg, total Hg, and total organic carbon across all samples, indicating a possible biological formation. These findings help better understand and predict the prevalence of EtHg in wetlands and its key role in environmental Hg cycle.

MGMT promoter methylation is a strong prognostic factor for survival after progression in high-grade gliomas.

BACKGROUND: High-grade gliomas (HGGs) have a rapid relapse and short survival. Studies have identified many clinical characteristics and biomarkers associated with progression-free survival (PFS) and over-survival (OS). However, there has not yet a comprehensive study on survival after the first progression (SAP). METHODS: From CGGA and TCGA, 319 and 308 HGGs were confirmed as the first progression. The data on clinical characteristics and biomarkers were analyzed in accordance with OS, PFS, and SAP. RESULTS: Analysis of 319 patients from CGGA, significant predictors of improved OS/PFS/SAP were WHO grade, MGMT promoter methylation, and Ki-67 expression in univariate analysis. Further multivariate analysis showed MGMT promoter methylation and Ki-67 expression were independent predictors. However, an analysis of 308 patients from TCGA found MGMT promoter methylation is the only prognostic marker. A longer SAP was observed in patients with methylated MGMT promoter after standard chemoradiotherapy. In our data, HGGs could be divided into low, intermediate, and high-risk groups for SAP by MGMT methylation and Ki-67 expression. CONCLUSIONS: Patients with MGMT promoter methylation have a prolonger SAP after standard chemoradiotherapy. HGGs could be divided into low, intermediate, and high-risk groups for SAP according to MGMT status and Ki-67 expression.

Phytoavailability, translocation, and accompanying isotopic fractionation of cadmium in soil and rice plants in paddy fields.

Rice consumption is a major pathway for human cadmium (Cd) exposure. Understanding Cd behavior in the soil-rice system, especially under field conditions, is pivotal for controlling Cd accumulation. This study analyzed Cd concentrations and isotope compositions (δ114/110Cd) in rice plants and surface soil sampled at different times, along with urinary Cd of residents from typical Cd-contaminated paddy fields in Youxian, Hunan, China. Soil water-soluble Cd concentrations varied across sampling times, with δ114/110Cdwater lighter under drained than flooded conditions, suggesting supplementation of water-soluble Cd by isotopically lighter Cd pools, increasing Cd phytoavailability. Both water-soluble Cd and atmospheric deposition contributed to rice Cd accumulation. Water-soluble Cd's contribution increased from 28-52% under flooded to 58-87% under drained conditions due to increased soil Cd phytoavailability. Atmospheric deposition's contribution (12-72%) increased with potential atmospheric deposition flux among sampling areas. The enrichment of heavy Cd isotopes occurred from root-stem-grain to prevent rice Cd accumulation. The different extent of enrichment of heavy isotopes in urine indicated different Cd exposure sources. These findings provide valuable insights into the speciation and phytoavailability changes of Cd in the soil-rice system and highlight the potential application of Cd isotopic fingerprinting in understanding the environmental fate of Cd.

Competitive Binding Kinetics of Methylmercury-Cysteine with Dissolved Organic Matter: Critical Impacts of Thiols on Adsorption and Uptake of Methylmercury by Algae.

Complexes with low-molecular-weight thiols are crucial species of methylmercury (MeHg) excreted by anaerobic Hg-methylating microbes, notably, MeHg-cysteine (MeHg-Cys). As MeHg-Cys diffuses into surface water, it would undergo a ligand exchange process with dissolved organic matter (DOM) under nonsulfidic conditions, inevitably altering MeHg speciation and bioavailability to phytoplankton. In this study, we investigated the competitive binding kinetics between MeHg-Cys and Suwannee River natural organic matter, and their influence on the adsorption and uptake of MeHg by the cyanobacterium, Synechocystis sp. PCC6803. Liquid chromatography-inductively coupled plasma mass spectrometry was employed to monitor the kinetics processes involving competition of DOM with Cys for MeHg binding, which revealed that competitive binding kinetics were dictated by the abundance of thiol moieties in DOM. Thiol concentrations of 0.97 and 49.34 µmol of thiol (g C)-1 resulted in competitive binding rate constant (k values) of 0.30 and 3.47 h-1, respectively. Furthermore, the time-dependent competitive binding of DOM toward MeHg-Cys significantly inhibited MeHg adsorption and uptake by cyanobacteria, an effect that was amplified by an increased thiol abundance in DOM. These findings offer valuable insights into the kinetic characteristics of MeHg's fate and transport, as well as their impact on bioconcentration in aquatic organisms within natural aquatic ecosystems.

Revealing the Sources of Cadmium in Rice Plants under Pot and Field Conditions from Its Isotopic Fractionation.

The highly excessive uptake of cadmium (Cd) by rice plants is well known, but the transfer pathway and mechanism of Cd in the paddy system remain poorly understood. Herein, pot experiments and field investigation were systematically carried out for the first time to assess the phytoavailability of Cd and fingerprint its transfer pathway in the paddy system under different treatments (slaked lime and biochar amendments), with the aid of a pioneering Cd isotopic technique. Results unveiled that no obvious differences were displayed in the δ114/110Cd of Ca(NO3)2-extractable and acid-soluble fractions among different treatments in pot experiments, while the δ114/110Cd of the water-soluble fraction varied considerably from -0.88 to -0.27%, similar to those observed in whole rice plant [Δ114/110Cdplant-water ≈ 0 (-0.06 to -0.03%)]. It indicates that the water-soluble fraction is likely the main source of phytoavailable Cd, which further contributes to its bioaccumulation in paddy systems. However, Δ114/110Cdplant-water found in field conditions (-0.39 ± 0.05%) was quite different from those observed in pot experiments, mostly owing to additional contribution derived from atmospheric deposition. All these findings demonstrate that the precise Cd isotopic compositions can provide robust and reliable evidence to reveal different transfer pathways of Cd and its phytoavailability in paddy systems.

Gelsolin knockdown confers radiosensitivity to glioblastoma cells.

OBJECTIVE: Radiotherapy (RT) is a cornerstone of the glioblastoma (GBM) treatment. However, the resistance of tumour cells to radiation results in early recurrence. The mechanisms underlying GBM radioresistance remain unclear. Screening for differentially expressed genes (DEGs) related to radiation might be a potential solution to this problem. METHOD: RT-associated DEGs were screened based on the RNA sequencing of 15 paired primary and recurrent GBMs. The mRNA and protein expression of candidate genes were validated in RNA sequencing of The Chinese Genome Atlas (CGGA) dataset and 18 cases of GBM samples. The relationship between the candidate gene and radiation was confirmed in irradiated GBM cells. The association of candidate gene with clinical characteristics and survival was investigated in the CGGA and TCGA dataset. Biological function and pathway analysis were explored by gene ontology analysis. The association of the candidate gene with radiosensitivity was verified using cell counting Kit-8, comet, and colony formation assays in vitro and subcutaneous tumour xenograft experiments in vivo. RESULTS: Gelsolin (GSN) was selected for further study. GSN expression was significant elevated in recurrent GBM and up-regulated in irradiated GBM cell lines. High expression of GSN was enriched in malignant phenotype of glioma. Moreover, high expression of GSN was associated with poor prognosis. Further investigation demonstrated that GSN-knockdown (GSN-KD) combined with RT significantly inhibited cell proliferation and enhanced radiosensitivity in vivo and in vitro. Mechanistically, GSN-KD could lead to more serious DNA damage and promotes apoptosis after RT. CONCLUSION: Radiation induced up-regulated of GSN. GSN-KD could enhance the radiosensitivity of GBM.

Stereotactic puncture surgery combined with early hyperbaric oxygen therapy may be better for long-term functional recovery in patients with moderate amounts of thalamic-inner capsule region haemorrhage.

BACKGROUND: The prognosis of patients with thalamic hemorrhage is poor, and their long-term neurological impairment is heavy, which seriously affects their work and life.To comparatively analyse the efficacy and prognosis of patients with moderate hemorrhage in the thalamic region who underwent conservative treatment, stereotactic puncture surgery and neuroendoscopic surgery. METHOD: This study retrospectively analyzed hospitalization data from 139 adult patients with moderate-volume cerebral hemorrhage in the thalamo-endocapsular region. They were categorized into a stereotactic group (39cases), a neuroendoscopic group (36cases), and a conventional conservative group (64cases). Logistic regression analysis was used to assess risk factors for severe neurological deficits in patients. Multivariate regression modeling was used to compare the correlation of severe neurological deficits among the three groups of patients. RESULTS: Patients with thalamic moderate-volume cerebral hemorrhage had statistically significantly higher Assessment of Daily Living (ADL) scores in the stereotactic surgery group than in the conservative treatment group and the neuroendoscopic surgery group after 6 months of treatment (p< 0.001).The amount of residual hematoma was significantly lower in the surgery groups than in the conservative treatment group at 3 days, 7 days, and 2 weeks after the onset of the disease (P< 0.001).In multivariate logistic regression analyses, after adjusting for all covariates, the odds ratios for severe neurologic dysfunction in the stereotactic group and the neuroendoscopy group were, respectively, OR: 0.37 (0.12-0.87), P< 0.001 and 0.42 (0.23-1.13), P=0.361). CONCLUSION: In patients with moderate volume cerebral hemorrhage in the thalamus-inner capsule region cerebral hemorrhage, patients treated with stereotactic surgery combined with early hyperbaric oxygen therapy may have better long-term neurological recovery compared with conservative and neuroendoscopic surgical treatments.

The PTPRZ1-MET/STAT3/ISG20 axis in glioma stem-like cells modulates tumor-associated macrophage polarization.

Recent studies have revealed that PTPRZ1-MET (ZM) fusion plays a pivotal role in the progression of glioma to glioblastoma multiforme (GBM), thus serving as a biomarker to distinguish between primary GBM and secondary GBM (sGBM). However, the mechanisms through which ZM fusion influences this progression remain to be elucidated. GBMs with ZM showed poorer prognoses and greater infiltration of tumor-associated macrophages (TAMs) than those without ZM. Glioma stem-like cells (GSCs) and TAMs play complex roles in glioma recurrence, glioma progression and therapy resistance. In this study, we analyzed RNA-seq data from sGBM patients' glioma tissues with or without ZM fusion, and found that stemness and macrophage markers were more highly expressed in sGBM patients harboring ZM than in those without ZM fusion. ZM enhanced the self-renewal and proliferation of GSCs, thereby accelerating glioma progression. In addition, ZM-positive GSCs facilitated the infiltration of TAMs and drove their polarization toward an immunosuppressive phenotype, which was primarily accomplished through the extracellular secretion of ISG20. Our research identified the MET-STAT3-ISG20 axis within GSCs, thus demonstrating the critical role of ZM in GBM initiation and progression. Our study demonstrated that, in contrast to ZM-positive differentiated glioma cells, ZM-positive GSCs upregulated ISG20 expression through the MET-STAT3-ISG20 axis. The extracellular secretion of ISG20 recruited and induced M2-like polarization in macrophages, thereby promoting tumor progression. Our results reveal a novel mechanism involved in ZM-positive GBM pathogenesis and identify potential therapeutic targets.

Transformation of Mercurous [Hg(I)] Species during Laboratory Standard Preparation and Analysis: Implication for Environmental Analysis.

Hg(I) may control Hg redox kinetics; however, its metastable nature hinders analysis. Herein, the stability of Hg(I) during standard preparation and analysis was studied. Gravimetric analysis showed that Hg(I) was stable in its stock solution (1000 mg L-1), yet completely disproportionated when its dilute solution (10 µg L-1) was analyzed using liquid chromatography (LC)-ICPMS. The Hg(I) dimer can form through an energetically favorable comproportionation between Hg(0) and Hg(II), as supported by density functional theory calculation and traced by the rapid isotope exchange between 199Hg(0)aq and 202Hg(II). However, the separation of Hg(0) and Hg(II) (e.g., LC process) triggered its further disproportionation. Polypropylene container, increasing headspace, decreasing pH, and increasing dissolved oxygen significantly enhanced the disproportionation or redox transformations of Hg(I). Thus, using a glass container without headspace and maintaining a slightly alkaline solution are recommended for the dilute Hg(I) stabilization. Notably, we detected elevated concentrations of Hg(I) (4.4-6.1 µg L-1) in creek waters from a heavily Hg-polluted area, accounting for 54-70% of total dissolved Hg. We also verified the reductive formation of Hg(I) in Hg(II)-spiked environmental water samples, where Hg(I) can stably exist in aquatic environments for at least 24 h, especially in seawater. These findings provide mechanistic insights into the transformation of Hg(I), which are indicative of its further environmental identification.

The Combination of Biochar and Bacillus subtilis Biological Agent Reduced the Relative Abundance of Pathogenic Bacteria in the Rhizosphere Soil of Panax notoginseng.

In the continuous cropping of Panax notoginseng, the pathogenic fungi in the rhizosphere soil increased and infected the roots of Panax notoginseng, resulting in a decrease in yield. This is an urgent problem that needs to be solved in order to effectively overcome the obstacles associated with the continuous cropping of Panax notoginseng. Previous studies have shown that Bacillus subtilis inhibits pathogenic fungi in the rhizosphere of Panax notoginseng, but the inhibitory effect was not stable. Therefore, we hope to introduce biochar to help Bacillus subtilis colonize in soil. In the experiment, fields planted with Panax notoginseng for 5 years were renovated, and biochar was mixed in at the same time. The applied amount of biochar was set to four levels (B0, 10 kg·hm-2; B1, 80 kg·hm-2; B2, 110 kg·hm-2; B3, 140 kg·hm-2), and Bacillus subtilis biological agent was set to three levels (C1, 10 kg·hm-2; C2, 15 kg·hm-2; C3, 25 kg·hm-2). The full combination experiment and a blank control group (CK) were used. The experimental results show that the overall Ascomycota decreased by 0.86%~65.68% at the phylum level. Basidiomycota increased by -73.81%~138.47%, and Mortierellomycota increased by -51.27%~403.20%. At the genus level, Mortierella increased by -10.29%~855.44%, Fusarium decreased by 35.02%~86.79%, and Ilyonectria increased by -93.60%~680.62%. Fusarium mainly causes acute bacterial wilt root rot, while Ilyonectria mainly causes yellow rot. Under different treatments, the Shannon index increased by -6.77%~62.18%, the Chao1 index increased by -12.07%~95.77%, the Simpson index increased by -7.31%~14.98%, and the ACE index increased by -11.75%~96.12%. The good_coverage indices were all above 0.99. The results of a random forest analysis indicated that Ilyonectria, Pyrenochaeta, and Xenopolyscytalum were the top three most important species in the soil, with MeanDecreaseGini values of 2.70, 2.50, and 2.45, respectively. Fusarium, the primary pathogen of Panax notoginseng, ranked fifth, and its MeanDecreaseGini value was 2.28. The experimental results showed that the B2C2 treatment had the best inhibitory effect on Fusarium, and the relative abundance of Fusarium in Panax notoginseng rhizosphere soil decreased by 86.79% under B2C2 treatment; the B1C2 treatment had the best inhibitory effect on Ilyonectria, and the relative abundance of Ilyonectria in the Panax notoginseng rhizosphere soil decreased by 93.60% under B1C2 treatment. Therefore, if we want to improve the soil with acute Ralstonia solanacearum root rot, we should use the B2C2 treatment to improve the soil environment; if we want to improve the soil with yellow rot disease, we should use the B1C2 treatment to improve the soil environment.

Bioconcentration of Inorganic and Methyl Mercury by Algae Revealed Using Dual-Mass Single-Cell ICP-MS with Double Isotope Tracers.

Algae are an entry point for mercury (Hg) into the food web. Bioconcentration of Hg by algae is crucial for its biogeochemical cycling and environmental risk. Herein, considering the cell heterogeneity, we investigated the bioconcentration of coexisting isotope-labeled inorganic (199IHg) and methyl Hg (201MeHg) by six typical freshwater and marine algae using dual-mass single-cell inductively coupled plasma mass spectrometry (scICP-MS). First, a universal pretreatment procedure for the scICP-MS analysis of algae was developed. Using the proposed method, the intra- and interspecies heterogeneities and the kinetics of Hg bioconcentration by algae were revealed at the single-cell level. The heterogeneity in the cellular Hg contents is largely related to cell size. The bioconcentration process reached a dynamic equilibrium involving influx/adsorption and efflux/desorption within hours. Algal density is a key factor affecting the distribution of Hg between algae and ambient water. Cellular Hg contents were negatively correlated with algal density, whereas the volume concentration factors almost remained constant. Accordingly, we developed a model based on single-cell analysis that well describes the density-driven effects of Hg bioconcentration by algae. From a novel single-cell perspective, the findings improve our understanding of algal bioconcentration governed by various biological and environmental factors.

Simultaneous determination of 19 bromophenols by gas chromatography-mass spectrometry (GC-MS) after derivatization.

Bromophenols (BPs) are a class of ubiquitous emerging halogenated pollutants. Their 19 congeners are problematically separated and detected. This work described the separation and detection of 19 BP congeners by gas chromatography-mass spectrometry (GC-MS). Investigations into the derivatization of bromophenols were carried out using two silylation reagents (N,O-bis(trimethylsilyl)trifluoroacetamide and N-methyl-N-(trimethylsily)trifluoroacetamide), two alkylation reagents (methyl iodide and trimethylsilyldiazomethane) and acetic anhydride prior to GC-MS analysis. Optimal chromatographic separation, sensitivity, and linearity were achieved after BP derivatization using acetic anhydride, featuring the equipment detection limits of 0.39-1.26 pg and correlation coefficients of 0.9948-0.9999 (linear range: 0.5-250 ng mL-1) for all 19 BP congeners. Furthermore, the simultaneous determination of 19 bromophenols and 19 bromoanisoles, common environmental transformation products of BPs, is also demonstrated. The improved analytical performance on GC-MS after derivatization would benefit investigations on the environmental origins, behaviors and fates of BPs and their environmental metabolites.

Stereotactic Puncture Surgery for the Treatment of Moderate Volume of Thalamus-Internal Capsule Area Hemorrhage: An Analysis of Real-World Data.

BACKGROUND: The efficacy of surgical intervention in ameliorating long-term prognosis for moderate volume of cerebral hemorrhage in the thalamus-internal capsule region remains unsubstantiated by clinical investigations. Consequently, the acquisition of credible evidence is imperative to authenticate the effectiveness of these methodologies. METHODS: One hundred and three eligible patients with moderate-volume thalamus-internal capsule region cerebral hemorrhage. Twenty-seven pairs of successful matches after using the 1:1 propensity score matching method, totaling 54 patients, were analyzed. The short- and long-term treatment outcomes of patients in the stereotactic surgery and conservative treatment groups were compared. The prognosis of the 2 groups of patients was analyzed by logistic regression analysis and model comparison. RESULTS: The primary outcome of this study was to assess the assessment of daily living scores after 6 months of treatment. Based on the analysis of this study, the assessment of daily living of the surgical group were significantly higher than those of the conservative treatment group after 6 months of treatment (P < 0.001), and the difference was statistically significant. The amount of residual hematoma was significantly lower in the stereotactic surgery group than in the conservative treatment group at 3 days, 7 days, and 2 weeks after the onset of the disease (P < 0.001), and the complication rate was lower than the conservative treatment group (P < 0.05). Univariate logistic regression showed that the risk of severe neurological dysfunction for patients in the surgery group was (odds ratio -0.27, 95% confidence interval: 0.08-0.86, P < 0.05). In multivariate logistic regression analysis, the odds ratio was 0.29 (95% confidence interval: 0.09-0.96, P < 0.05) after adjusting for all covariates. CONCLUSIONS: For moderate-volume thalamus-internal capsule region cerebral hemorrhage, stereotactic paracentesis has the advantage of a shorter hospital stay and a lower complication rate than conservative treatment. Moreover, it yields superior outcomes in terms of daily living assessment scores after six months of treatment and enhanced neurological recovery.

Gecko-Inspired Controllable Adhesive: Structure, Fabrication, and Application.

The gecko can achieve flexible climbing on various vertical walls and even ceilings, which is closely related to its unique foot adhesion system. In the past two decades, the mechanism of the gecko adhesion system has been studied in-depth, and a verity of gecko-inspired adhesives have been proposed. In addition to its strong adhesion, its easy detachment is also the key to achieving efficient climbing locomotion for geckos. A similar controllable adhesion characteristic is also key to the research into artificial gecko-inspired adhesives. In this paper, the structures, fabrication methods, and applications of gecko-inspired controllable adhesives are summarized for future reference in adhesive development. Firstly, the controllable adhesion mechanism of geckos is introduced. Then, the control mechanism, adhesion performance, and preparation methods of gecko-inspired controllable adhesives are described. Subsequently, various successful applications of gecko-inspired controllable adhesives are presented. Finally, future challenges and opportunities to develop gecko-inspired controllable adhesive are presented.

TRIM21 Promotes Oxidative Stress and Ferroptosis through the SQSTM1-NRF2-KEAP1 Axis to Increase the Titers of H5N1 Highly Pathogenic Avian Influenza Virus.

Tripartite motif-containing protein 21 (TRIM21) is involved in signal transduction and antiviral responses through the ubiquitination of protein targets. TRIM21 was reported to be related to the imbalance of host cell homeostasis caused by viral infection. Our studies indicated that H5N1 highly pathogenic avian influenza virus (HPAIV) infection up-regulated TRIM21 expression in A549 cells. Western blot and qPCR results showed that knockdown of TRIM21 alleviated oxidative stress and ferroptosis induced by H5N1 HPAIV and promoted the activation of antioxidant pathways. Co-IP results showed that TRIM21 promoted oxidative stress and ferroptosis by regulating the SQSTM1-NRF2-KEAP1 axis by increasing SQSTM1 K63-linked polyubiquitination under the condition of HPAIV infection. In addition, TRIM21 attenuated the inhibitory effect of antioxidant NAC on HPAIV titers and enhanced the promoting effect of ferroptosis agonist Erastin on HPAIV titers. Our findings provide new insight into the role of TRIM21 in oxidative stress and ferroptosis induced by viral infection.

Order-disorder transition during shear thickening in bidisperse dense suspensions.

Shear thickening of multimodal suspensions has proven difficult to understand because the rheology depends largely on the microscopic details of stress-induced frictional contacts at different particle size distributions (PSDs). Our discrete particle simulations below a critical volume fraction ϕc over a broad range of shear rates and PSDs elucidate the basic mechanism of order-disorder transition. Around the theoretical optimal PSD (relative content of small particles ζ1= 0.26), particles order into a layered structure in the Newtonian regime. At the onset of shear thickening, this layered structure transforms to a disordered one, accompanied by an abrupt viscosity jump. Minor increase in large-large particle contacts after the order-disorder transition causes apparent increase in radial force along the compressional axis. Bidisperse suspensions with less regular but stable layered structure at ζ1= 0.50 show good fluidity in the shear thickening regime. This work shows that in inertial flows where particle collisions dominate, order-disorder transition could play an essential role in shear thickening for bidisperse suspensions.

Effects of naturally aged microplastics on the distribution and bioavailability of arsenic in soil aggregates and its accumulation in lettuce.

Naturally aged microplastics (NAMPs) and arsenic (As) have been reported to coexist in and threaten potentially to soil-plant ecosystem. The research explored the combined toxic effects of NAMPs and As to lettuce (Lactuca sativa L.) growth, and the distribution, accumulation and bioavailability of As in soil aggregates. The As contaminated soil with low, medium and high concentrations (L-As, M-As, H-As) were treated with or without NAMPs, and a total of six treatments. The results displayed that, in comparison to separate treatments of L-As and M-As, the presence of NAMPs increased the total biomass of lettuce grown at these two As concentrations by 68.9 % and 55.4 %, respectively. Simultaneous exposure of NAMPs and L-As or M-As led to a decrease in As content in shoot (0.45-2.17 mg kg-1) and root (5.68-14.66 mg kg-1) of lettuce, indicating an antagonistic effect between them. In contrast, co-exposure to H-As and NAMPs showed synergistic toxicity, and the leaf chlorophyll and nutritional quality of lettuce were also reduced. NAMPs altered the ratio of different soil aggregate fractions and the distribution of bioavailable As within them, which influenced the absorption of As by lettuce. In conclusion, these direct observations assist us in enhancing the comprehend of the As migration and enrichment characteristics in soil-plant system under the influence of NAMPs.

IDH-mutant grade 4 astrocytoma: a comparison integrating the clinical, pathological, and survival features between primary and secondary patients.

OBJECTIVE: IDH-mutant grade 4 astrocytomas (AIDHmut/G4) are divided into primary de novo (pAIDHmut/G4) and secondary with a history of prior lower-grade gliomas (LGGs; sAIDHmut/G4). The mutational spectrum and DNA methylation patterns are homogeneous within de novo pAIDHmut/G4 and evolved sAIDHmut/G4, but the two groups have different diagnoses, management, and outcomes. This study sought to systematically compare the clinical, pathological, and survival characteristics between them. METHODS: Of the 871 grade 4 astrocytomas with data for IDH mutation, 698 (80.1%) were primary and 173 (19.9%) were secondary. Of the 698 primary tumors, 103 (14.8%) were pAIDHmut/G4, and of the 173 secondary tumors, 108 (62.4%) were sAIDHmut/G4. Clinical, pathological, and survival features were compared between pAIDHmut/G4 and sAIDHmut/G4. Multivariate analyses were performed to identify prognostic factors. RESULTS: Patients with sAIDHmut/G4 had significantly shorter median overall survival (OS; 11.8 vs 34.2 months, hazard ratio [HR] 2.69, 95% confidence interval [CI] 1.367-5.306, p = 0.004) and progression-free survival (PFS; 8.5 vs 24.3 months, HR 2.83, 95% CI 1.532-5.235, p = 0.001) than patients with pAIDHmut/G4. In patients with sAIDHmut/G4, resection status and chemotherapy were independent prognostic factors for OS and PFS; in patients with pAIDHmut/G4, LGG component, resection status, and O6-methylguanine DNA methyltransferase promoter methylation were independent prognostic factors. The therapeutic strategies of LGGs did not influence survival of patients with sAIDHmut/G4, but patients who had not received radiotherapy or chemotherapy when they were diagnosed with LGGs were found to benefit from radiotherapy or chemotherapy when they progressed to sAIDHmut/G4. CONCLUSIONS: The different clinical characteristics, survival, and risk factors between sAIDHmut/G4 and pAIDHmut/G4 provide a reference to guide treatment decisions in AIDHmut/G4.