Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor.

Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in ∼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.

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.

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.

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.

Compact single-shot soft X-ray photon spectrometer for free-electron laser diagnostics.

The photon spectrum from free-electron laser (FEL) light sources offers valuable information in time-resolved experiments and machine optimization in the spectral and temporal domains. We have developed a compact single-shot photon spectrometer to diagnose soft X-ray spectra. The spectrometer consists of an array of off-axis Fresnel zone plates (FZP) that act as transmission-imaging gratings, a Ce:YAG scintillator, and a microscope objective to image the scintillation target onto a two-dimensional imaging detector. This spectrometer operates in segmented energy ranges which covers tens of electronvolts for each absorption edge associated with several atomic constituents: carbon, nitrogen, oxygen, and neon. The spectrometer's performance is demonstrated at a repetition rate of 120 Hz, but our detection scheme can be easily extended to 200 kHz spectral collection by employing a fast complementary metal oxide semiconductor (CMOS) line-scan camera to detect the light from the scintillator. This compact photon spectrometer provides an opportunity for monitoring the spectrum downstream of an endstation in a limited space environment with sub-electronvolt energy resolution.

Molecular and clinical characterization of PTRF in glioma via 1,022 samples.

Polymerase I and transcript release factor (PTRF) plays a role in the regulation of gene expression and the release of RNA transcripts during transcription, which have been associated with various human diseases. However, the role of PTRF in glioma remains unclear. In this study, RNA sequencing (RNA-seq) data (n = 1022 cases) and whole-exome sequencing (WES) data (n = 286 cases) were used to characterize the PTRF expression features. Gene ontology (GO) functional enrichment analysis was used to assess the biological implication of changes in PTRF expression. As a result, the expression of PTRF was associated with malignant progression in gliomas. Meanwhile, somatic mutational profiles and copy number variations (CNV) revealed the glioma subtypes classified by PTRF expression showed distinct genomic alteration. Furthermore, GO functional enrichment analysis suggested that PTRF expression was associated with cell migration and angiogenesis, particularly during an immune response. Survival analysis confirmed that a high expression of PTRF is associated with a poor prognosis. In summary, PTRF may be a valuable factor for the diagnosis and treatment target of glioma.

Superoxide-Mediated Extracellular Mercury Reduction by Aerobic Marine Bacterium Alteromonas sp. KD01.

Microbial reduction plays a crucial role in Hg redox and the global cycle. Although intracellular Hg(II) reduction mediated by MerA protein is well documented, it is still unclear whether or how bacteria reduce Hg(II) extracellularly without its internalization. Herein, for the first time, we discovered the extracellular reduction of Hg(II) by a widely distributed aerobic marine bacterium Alteromonas sp. KD01 through a superoxide-dependent mechanism. The generation of superoxide by Alteromonas sp. KD01 was determined using 3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide and methyl cypridina luciferin analogue as probes via UV-vis and chemiluminescence detection, respectively. The results demonstrated that Hg(II) reduction was inhibited by superoxide scavengers (superoxide dismutase (SOD) and Cu(NO3)2) or inhibitors of reduced nicotinamide adenine dinucleotide (NADH) oxidoreductases. In contrast, the addition of NADH significantly improved superoxide generation and, in turn, Hg(II) reduction. Direct evidence of superoxide-mediated Hg(II) reduction was provided by the addition of superoxide using KO2 in deionized water and seawater. Moreover, we observed that even superoxide at an environmental concentration of 9.6 ± 0.5 nM from Alteromonas sp. KD01 (5.4 × 106 cells mL-1) was capable of significantly reducing Hg(II). Our findings provide a greater understanding of Hg(II) reduction by superoxide from heterotrophic bacteria and eukaryotic phytoplankton in diverse aerobic environments, including surface water, sediment, and soil.

Unraveling Multiple Pathways of Electron Donation from Phenolic Moieties in Natural Organic Matter.

Natural organic matter (NOM) exhibits a distinctive electron-donating capacity (EDC) that serves a pivotal role in the redox reactions of contaminants and minerals through the transformation of electron-donating phenolic moieties. However, the ambiguity of the molecular transformation pathways (MTPs) that engender the EDC during NOM oxidation remains a significant issue. Here, MTPs that contribute to EDC were investigated by identifying the oxidized products of phenolic model compounds and NOM samples in direct or mediated electrochemical oxidation (DEO or MEO, respectively) using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). It was found that the oxidation of newly formed phenolic-OH (ArOH) and the oxidative coupling reaction of the phenoxy radical are the main MTPs that directly contribute to EDC, in addition to the transformation of hydroquinones to quinones. Notably, the oxidative coupling reaction of ArOH contributed at least 22-42% to the EDC. Ferulic acid-like structures can also directly contribute to EDC by incorporating H2O into their acrylic substituents. Furthermore, the opening of C rings can indirectly attenuate the EDC through structural alterations in the electron-donating process of NOM. Decarboxylation can either weaken or enhance the EDC depending on the structure of the phenolic moieties in NOM. These findings suggest that the EDC of NOM is a comprehensive result of multiple NOM MTPs, involving not only ArOH oxidation but also the addition of H2O to olefinic bonds and bond-breaking reactions. Our work provides molecular evidence that aids in the comprehension of the multiple EDC-associated transformation pathways of NOM.

Direct Uptake and Intracellular Dissolution of HgS Nanoparticles: Evidence from a Bacterial Biosensor Approach.

Mercury sulfide nanoparticles (HgSNPs), which occur widely in oxic and anoxic environments, can be microbially converted to highly toxic methylmercury or volatile elemental mercury, but it remains challenging to assess their bioavailability. In this study, an Escherichia coli-based whole-cell fluorescent biosensor was developed to explore the bioavailability and microbial activation process of HgSNPs. Results show that HgSNPs (3.17 ± 0.96 nm) trigger a sharp increase in fluorescence intensity of the biosensor, with signal responses almost equal to that of ionic Hg (Hg(II)) within 10 h, indicating high bioavailability of HgSNP. The intracellular total Hg (THg) of cells exposed to HgSNPs (200 µg L-1) was 3.52-8.59-folds higher than that of cells exposed to Hg(II) (200 µg L-1), suggesting that intracellular HgSNPs were only partially dissolved. Speciation analysis using size-exclusion chromatography (SEC)-inductively coupled plasma mass spectrometry (ICP-MS) revealed that the bacterial filtrate was not responsible for HgSNP dissolution, suggesting that HgSNPs entered cells in nanoparticle form. Combined with fluorescence intensity and intracellular THg analysis, the intracellular HgSNP dissolution ratio was estimated at 22-29%. Overall, our findings highlight the rapid internalization and high intracellular dissolution ratio of HgSNPs by E. coli, and intracellular THg combined with biosensors could provide innovative tools to explore the microbial uptake and dissolution of HgSNPs.

Circulating mir-199-3p screens the onset of type 2 diabetes mellitus and the complication of coronary heart disease and predicts the occurrence of major adverse cardiovascular events.

BACKGROUND: Coronary heart disease (CHD) is a major complication of type 2 diabetes mellitus (T2DM), which causes an adverse prognosis. There is an urgent need to explore effective biomarkers to evaluate the patients' adverse outcomes. OBJECTIVE: This study aimed to identify a novel indicator for screening T2DM and T2DM-CHD and predicting adverse prognosis. MATERIALS AND METHODS: The study enrolled 52 healthy individuals, 85 T2DM patients, and 97 T2DM patients combined with CHD. Serum miR-199-3p levels in all study subjects were detected with PCR, and its diagnostic significance was evaluated by receiver operating curve (ROC) analysis. The involvement of miR-199-3p in disease development was assessed by the Chi-square test, and the logistic regression analysis was performed to estimate the risk factor for major adverse cardiovascular events (MACE) in T2DM-CHD patients. RESULTS: Significant downregulation of miR-199-3p was observed in the serum of both T2DM and T2DM-CHD patients, which discriminated patients from healthy individuals and distinguished T2DM and T2DM-CHD patients. Reduced serum miR-199-3p was associated with the increasing blood glucose, glycated hemoglobin (HbA1c), and homeostasis model assessment-insulin resistance index (HOMA-IR) of T2DM patients and the increasing triglycerides (TG), low-density lipoprotein (LDL), fibrinogen, and total cholesterol (TC) and decreasing high-density lipoprotein (HDL) of T2DM-CHD patients. miR-199-3p was also identified as a biomarker predicting the occurrence of MACE. CONCLUSION: Downregulated miR-199-3p could screen the onset of T2DM and its complication with CHD. Reduced serum miR-199-3p was associated with the severe development of T2DM and T2DM-CHD and predicted the adverse outcomes of T2DM-CHD patients.

FOXA2 suppresses PKM2 transcription and affects the Wnt/ß-catenin activity to block aerobic glycolysis in thyroid carcinoma.

Aerobic glycolysis is critical for the energy metabolism of cancer cells. This study focuses on the regulation of forkhead box A2 (FOXA2) on pyruvate kinase M2 (PKM2) and their effects on the glycolytic activity and malignant phenotype of thyroid carcinoma (THCA) cells. By analysing four Gene Expression Omnibus datasets and querying bioinformatics systems, we obtained FOXA2 as a poorly expressed transcription factor in THCA. Later, we validated decreased mRNA and protein levels of FOXA2 in THCA cells by quantitative polymerase chain reaction and western blot assays. FOXA2 upregulation in THCA cells suppressed the glucose uptake and lactate production, and it reduced the extracellular acidification rate, but increased the oxygen consumption rate of cells. Meanwhile, the FOXA2 overexpression blocked the proliferation and mobility, and the tumourigenic activity of cancer cells. The chromatin immunoprecipitation and luciferase assays showed that FOXA2 bound to PKM2 promoter and suppressed the transcription of PKM2, which was highly expressed in THCA cells. Further upregulation of PKM2 elevated the ß-catenin, c-Myc and cyclin D1 levels and restored the glycolytic activity as well as the malignant properties of cancer cells. Collectively, this work reveals that FOXA2 suppresses aerobic glycolysis and progression of THCA by blocking PKM2 transcription and inactivating the Wnt/ß-catenin pathway.

Novel prognostic indicator combining inflammatory indicators and tumor markers for gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors worldwide, and we hope to identify an economical but practical prognostic indicator. It has been reported that inflammatory indicators and tumor markers are associated with GC progression and are widely used to predict prognosis. However, existing prognostic models do not comprehensively analyze these predictors. METHODS: This study retrospectively reviewed 893 consecutive patients who underwent curative gastrectomy from January 1, 2012, to December 31, 2015, in the Second Hospital of Anhui Medical University. Prognostic factors predicting overall survival (OS) were analyzed using univariate and multivariate Cox regression analyses. Nomograms including independent prognostic factors were plotted for predicting survival. RESULTS: Ultimately, 425 patients were enrolled in this study. Multivariate analyses demonstrated that the neutrophil-to-lymphocyte ratio (NLR, total neutrophil count/lymphocyte count × 100%) and CA19-9 were independent prognostic factors for OS (p=0.001, p=0.016). The NLR-CA19-9 score (NCS) is constructed as the combination of the NLR and CA19-9. We defined NLR<2.46 and CA19-9≤37 U/ml as an NCS of 0, NLR≥2.46 or CA19-9>37 U/ml as an NCS 1, and NLR≥2.46 and CA19-9>37 U/ml as an NCS of 2. The results showed that higher NCS was significantly associated with worse clinicopathological characteristics and OS (p<0.05). Multivariate analyses revealed that the NCS was an independent prognostic factor for OS (NCS1: p<0.001, HR=3.172, 95% CI=2.120-4.745; NCS2: p<0.001, HR=3.052, 95% CI=1.928-4.832). Compared with traditional predictive indices, the NCS had the highest AUC for a 12-month survival, a 36-month survival, a 60-month survival, and OS (AUC= 0.654, 0.730, 0.811, 0.803, respectively). The nomogram had a higher Harrell's C-index than the TNM stage alone (0.788 vs. 0.743). CONCLUSIONS: The NCS provides more accurate predictions of the prognosis of GC patients, and its predictive value is significantly better than that of traditional inflammatory indicators or tumor markers. It is an effective complement to existing GC assessment systems.

The inhibition of ecdysone signal pathway was the key of pyriproxyfen poisoning for silkworm, Bombyx mori.

Pyriproxyfen is a juvenile hormone-like pesticide. Once intake occurs, it leads to a series of poisoning characters consequences in silkworm, Bombyx mori (ID: 7091, Lepidoptera), such as non- cocooning, non-pupation, production of low-active eggs, and extended stages. However, the poisoning mechanism is still unclear. Here, silkworms were fed mulberry leaves soaked with different pyriproxyfen concentrations, and the heads were dissected for transcriptome analysis, while the hemolymph was used for determinations of ecdysone and juvenile hormone titers. As a result, after conjoint analysis of 3 feeding groups and a control group, 555 differentially expressed genes (DEGs) were obtained, which were mainly involved in hormone metabolism, glycometabolism and protein metabolism. Meanwhile, 119 genes were significantly correlated with the pyriproxyfen concentrations, and they were mainly involved in drug metabolism and glycometabolism. The ecdysone titers in several feeding groups were significantly lower than those of the control group, while juvenile hormone was not detected in all groups, including the control and feeding groups. Correspondingly, due to activation of the juvenile hormone signaling pathway by pyriproxyfen, key genes in the ecdysone synthesis pathway were downregulated, and a large number of downstream genes were up- or downregulated. In addition, nearly all genes in the detoxification pathway were upregulated. These results suggested that, affected by the juvenile hormone signaling pathway, ecdysone titers decreased and further affected a series of downstream processes, and this was the key reason for pyriproxyfen poisoning in silkworm, B. mori, which could lay a foundation for the study of pyriproxyfen resistance in silkworm.

Association of high-dose radiotherapy with improved survival in patients with newly diagnosed low-grade gliomas.

BACKGROUND: The radiation dose for patients with low-grade gliomas (LGGs) is controversial. The objective of this study was to investigate the impact of the radiation dose on survival for patients with LGGs and especially for molecularly defined subgroups. METHODS: Three hundred fifty-one patients with newly diagnosed LGGs from the multicenter Chinese Glioma Cooperative Group received postoperative radiotherapy (RT) in 2005-2018. The RT dose, as a continuous variable, was entered into a Cox regression model using penalized spline regression to allow for a nonlinear relationship between the RT dose and overall survival (OS) or progression-free survival (PFS). Inverse probability of treatment weighting (IPTW)-adjusted propensity scores were used to correct for potential confounders. Dose effects on survival within IDH mutation and 1p/19q codeletion defined subgroups were analyzed. RESULTS: The risk of mortality and disease progression decreased sharply until 54 Gy. High-dose RT (≥54 Gy) was associated with significantly better 5-year OS (81.7% vs 64.0%; hazard ratio [HR], 0.33; P < .001) and PFS (77.4% vs 54.5%; HR, 0.46; P < .001) than low-dose RT (<54 Gy). IPTW correction confirmed the associations (HR for OS, 0.44; P = .001; HR for PFS, 0.48; P = .003). High-dose RT was associated with longer PFS (HR, 0.25; P = .002; HR, 0.21; P = .039) and OS (HR, 0.27; P = .006; HR, 0.07; P = .017) in IDH-mutant/1p/19q noncodeleted and IDH wild-type subgroups, respectively. No significant difference in survival was observed with high-dose RT in the IDH-mutant/1p/19q codeleted subgroup. CONCLUSIONS: High-dose RT (≥54 Gy) was effective in LGGs. Patients with an IDH mutation/1p/19q noncodeletion or IDH wild-type may need to be considered for high-dose RT. LAY SUMMARY: The radiotherapy dose-response was observed in patients with low-grade gliomas, and high-dose radiotherapy (≥54 Gy) was associated with improved survival. Patients with an IDH mutation/1p/19q noncodeletion or wild-type IDH may have improved survival with the administration of high-dose radiotherapy.

Multi-frame, ultrafast, x-ray microscope for imaging shockwave dynamics.

Inertial confinement fusion (ICF) holds increasing promise as a potential source of abundant, clean energy, but has been impeded by defects such as micro-voids in the ablator layer of the fuel capsules. It is critical to understand how these micro-voids interact with the laser-driven shock waves that compress the fuel pellet. At the Matter in Extreme Conditions (MEC) instrument at the Linac Coherent Light Source (LCLS), we utilized an x-ray pulse train with ns separation, an x-ray microscope, and an ultrafast x-ray imaging (UXI) detector to image shock wave interactions with micro-voids. To minimize the high- and low-frequency variations of the captured images, we incorporated principal component analysis (PCA) and image alignment for flat-field correction. After applying these techniques we generated phase and attenuation maps from a 2D hydrodynamic radiation code (xRAGE), which were used to simulate XPCI images that we qualitatively compare with experimental images, providing a one-to-one comparison for benchmarking material performance. Moreover, we implement a transport-of-intensity (TIE) based method to obtain the average projected mass density (areal density) of our experimental images, yielding insight into how defect-bearing ablator materials alter microstructural feature evolution, material compression, and shock wave propagation on ICF-relevant time scales.

Improved Outcomes of Combined Main Branch Stenting and Side Branch Drug-Coated Balloon versus Two-Stent Strategy in Patients with Left Main Bifurcation Lesions.

BACKGROUND: Drug-eluting stent (DES) plus drug-coated balloon (DCB) is a safe and effective treatment strategy for coronary artery bifurcation lesions, but there is no report about this strategy being used for left main (LM) bifurcation lesions. We aim to explore the efficacy and safety of DES plus DCB in the treatment of LM bifurcation lesions. METHODS: A total of 100 patients diagnosed with LM bifurcation lesions by coronary angiography were retrospectively enrolled at our center from January 2018 to December 2019. They received either a two-stent strategy or a main branch (MB) stenting plus side branch (SB) DCB strategy and were accordingly divided into the 2-DES group and the DES + DCB group. Patients treated with DES + DCB were compared with a cohort of matched patients treated with a 2-DES strategy. Clinical data was collected and quantitative coronary analysis was performed. RESULTS: For immediate postoperative angiography, though the two groups had no differences in the minimal luminal diameter (MLD) and luminal stenosis of MB, the DES + DCB group had significantly lower SB ostial MLD and a higher degree of residual lumen stenosis than the 2-DES group (P < 0.05). At the time of follow-up, the SB ostial MLD of the DES + DCB group was higher than that of the 2-DES group, but lumen stenosis, late lumen loss (LLL), and LLL at the distal end of the left MB were all smaller than those of the 2-DES group (Ps < 0.05). Furthermore, the incidence of lumen restenosis and MACE between the two groups had no significance. CONCLUSION: The combination of DES and DCB is relatively safe and effective for the treatment of LM bifurcation lesions, and this strategy seems to have advantages in reducing LLL at the SB ostium.

Loss and Increase of the Electron Exchange Capacity of Natural Organic Matter during Its Reduction and Reoxidation: The Role of Quinone and Nonquinone Moieties.

Redox-active quinone and nonquinone moieties represent the electron exchange capacity (EEC) of natural organic matter (NOM), playing an important role in the electron transfer link of microbes and transformation of contaminants/metal minerals. However, the corresponding transformation of quinone/phenol and their respective influence on the EECs during reduction and reoxidation remain poorly characterized. Besides, it is still controversial whether nonquinones donate or accept electrons. Herein, we demonstrated that reoxidation of NOM after reduction can form new phenolic/quinone moieties, thus increasing the EEC. The assessment for the EEC, including the electron-donating capacity (EDC) and electron-accepting capacity (EAC), of nonquinones reflects the contribution of sulfur-containing moieties with considerable EDCs and EACs. In contrast, nitrogen-containing moieties donate negligible electrons even at Eh = +0.73 V. The contributions of both thiol and amine moieties to the EEC are greatly affected by adjacent functional groups. Meanwhile, aldehydes/ketones did not display an EAC during the electron transfer process of NOM. Furthermore, substantially increased EDC at Eh from +0.61 to +0.73 V could not be fully explained using thiol and phenolic moieties, suggesting the contribution of unknown moieties with high oxidation potential. The overall findings suggest that the roles of new quinones/phenol (derived from the addition of oxygen to condensed aromatic/lignin-like components) during redox dynamic cycling and thiol species should be considered in assessing the electron transfer processes of NOM.

Particle-Bound Hg(II) is Available for Microbial Uptake as Revealed by a Whole-Cell Biosensor.

Particle-bound mercury (HgP), ubiquitously present in aquatic environments, can be methylated into highly toxic methylmercury, but it remains challenging to assess its bioavailability. In this study, we developed anEscherichia coli-based whole-cell biosensor to probe the microbial uptake of inorganic Hg(II) and assess the bioavailability of HgP sorbed on natural and model particles. This biosensor can quantitatively distinguish the contribution of dissolved Hg(II) and HgP to intracellular Hg. Results showed that the microbial uptake of HgP was ubiquitous in the environment, as evidenced by the bioavailability of sorbed-Hg(II) onto particulate matter and model particles (Fe2O3, Fe3O4, Al2O3, and SiO2). In both oxic and anoxic environments, HgP was an important Hg(II) source for microbial uptake, with enhanced bioavailability under anoxic conditions. The composition of particles significantly affected the microbial uptake of HgP, with higher bioavailability being observed for Fe2O3 and lower for Al2O3 particles. The bioavailability of HgP varied also with the size of particles. In addition, coating with humic substances and model organic compound (cysteine) on Fe2O3 particles decreased the bioavailability of HgP. Overall, our findings highlight the role of HgP in Hg biogeochemical cycling and shed light on the enhanced Hg-methylation in settling particles and sediments in aquatic environments.

Metabolic expression profiling stratifies diffuse lower-grade glioma into three distinct tumour subtypes.

BACKGROUND: Lower-grade gliomas (LGGs) show highly metabolic heterogeneity and adaptability. To develop effective therapeutic strategies targeting metabolic processes, it is necessary to identify metabolic differences and define metabolic subtypes. Here, we aimed to develop a classification system based on metabolic gene expression profile in LGGs. METHODS: The metabolic gene profile of 402 diffuse LGGs from the Cancer Genome Atlas (TCGA) was used for consensus clustering to determine robust clusters of patients, and the reproducibility of the classification system was evaluated in three Chinese Glioma Genome Atlas (CGGA) cohorts. Then, the metadata set for clinical characteristics, immune infiltration, metabolic signatures and somatic alterations was integrated to characterise the features of each subtype. RESULTS: We successfully identified and validated three highly distinct metabolic subtypes in LGGs. M2 subtype with upregulated carbohydrate, nucleotide and vitamin metabolism correlated with worse prognosis, whereas M1 subtype with upregulated lipid metabolism and immune infiltration showed better outcome. M3 subtype was associated with low metabolic activities and displayed good prognosis. Three metabolic subtypes correlated with diverse somatic alterations. Finally, we developed and validated a metabolic signature with better performance of prognosis prediction. CONCLUSIONS: Our study provides a new classification based on metabolic gene profile and highlights the metabolic heterogeneity within LGGs.

Dual-Mode Learning of Ambipolar Synaptic Phototransistor Based on 2D Perovskite/Organic Heterojunction for Flexible Color Recognizable Visual System.

Artificial intelligence vision systems (AIVSs) with information sensing, processing, and storage functions are increasingly gaining attention in the science and technology community. Although synapse phototransistor (SPT) is one of the essential components in AIVSs, solution-processed large-area photonic synapses that can detect and recognize multi-wavelength light are highly desirable. One of the major challenges in this area is the inability of the available materials to distinguish colors from the visible light to the near-infrared (NIR) light for single carrier (hole-only or electron-only) SPTs owing to lack of cognitive elements. Herein, 2D perovskite/organic heterojunction (PEA2 SnI4 /Y6) ambipolar SPTs (POASPTs) are developed via solution process. The POASPTs can display dual-mode learning process, which can convert light signals into postsynaptic currents with excitement/inhibition modes (hole-transporting region) or inhibition/excitement (electron-transporting region). The POASPTs exhibit high responsivity to visible light (104 A W-1 ) and NIR light (200 A W-1 ), and effectively perform learning and memory simultaneously. The flexible POASPT arrays can successfully recognize the images of different colors of light. This study reveals that the fabricated POASPTs have great potentials in the development of large-area, high-efficiency, and low-cost AIVSs.