Developmental arsenic exposure impairs cognition, directly targets DNMT3A, and reduces DNA methylation.

Developmental arsenic exposure has been associated with cognitive deficits in epidemiological studies, but the underlying mechanisms remain poorly understood. Here, we establish a mouse model of developmental arsenic exposure exhibiting deficits of recognition and spatial memory in the offspring. These deficits are associated with genome-wide DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. Arsenic atoms directly bind to the cysteine-rich ADD domain of DNA methyltransferase 3A (DNMT3A), triggering ubiquitin- and proteasome-mediated degradation of DNMT3A in different cellular contexts. DNMT3A degradation leads to genome-wide DNA hypomethylation in mouse embryonic fibroblasts but not in non-embryonic cell lines. Treatment with metformin, a first-line antidiabetic agent reported to increase DNA methylation, ameliorates the behavioral deficits and normalizes the aberrant expression of cognition-related genes and DNA methylation in the hippocampus of arsenic-exposed offspring. Our study establishes a DNA hypomethylation effect of developmental arsenic exposure and proposes a potential treatment against cognitive deficits in the offspring of pregnant women in arsenic-contaminated areas.

Elucidating the links between N2O dynamics and changes in microbial communities following saltwater intrusions.

Saltwater intrusion in estuarine ecosystems alters microbial communities as well as biogeochemical cycling processes and has become a worldwide problem. However, the impact of salinity intrusion on the dynamics of nitrous oxide (N2O) and associated microbial community are understudied. Here, we conducted field microcosms in a tidal estuary during different months (December, April and August) using dialysis bags, and microbes inside the bags encountered a change in salinity in natural setting. We then compared N2O dynamics in the microcosms with that in natural water. Regardless of incubation environment, saltwater intrusion altered the dissolved N2O depending on the initial saturation rates of N2O. While the impact of saltwater intrusion on N2O dynamics was consistent across months, the dissolved N2O was higher in summer than in winter. The N-related microbial communities following saltwater intrusion were dominated by denitrifers, with fewer nitrifiers and bacterial taxa involved in dissimilatory nitrate reduction to ammonium. While denitrification was a significant driver of N2O dynamics in the studied estuary, nitrifier-involved denitrification contributed to the additional production of N2O, evidenced by the strong associations with amoA genes and the abundance of Nitrospira. Higher N2O concentrations in the field microcosms than in natural water limited N2O consumption in the former, given the lack of an association with nosZ gene abundance. The differences in the N2O dynamics observed between the microcosms and natural water could be that the latter comprised not only indigenous microbes but also those accompanied with saltwater intrusion, and that immigrants might be functionally rich individuals and able to perform N transformation in multiple pathways. Our work provides the first quantitative assessment of in situ N2O concentrations in an estuary subjected to a saltwater intrusion. The results highlight the importance of ecosystem size and microbial connectivity in the source-sink dynamics of N2O in changing environments.

Involvement of functional metabolism promotes the enrichment of antibiotic resistome in drinking water: Based on the PICRUSt2 functional prediction.

Biofilters are the important source and sink of antibiotic resistance genes (ARGs) and antibiotic resistance bacteria (ARB) in the drinking water. Current studies generally ascribed the prevalence of BAR in biofilter from the perspective of gene behavior, i.e. horizontal gene transfer (HGT), little attentions have been paid on the ARGs carrier- ARB. In this study, we proposed the hypothesis that ARB participating in pollutant metabolism processes and becoming dominant is an important way for the enrichment of ARGs. To verify this, the antibiotic resistome and bacterial functional metabolic pathways of a sand filter was profiled using heterotrophic bacterial plate counting method (HPC), high-throughput qPCR, Illumina Hiseq sequencing and PICRUSt2 functional prediction. The results illustrated a significant leakage of ARB in the effluent of the sand filter with an average absolute abundance of approximately 102-103 CFU/mL. Further contribution analysis revealed that the dominant genera, such as Acinetobacter spp., Aeromonas spp., Elizabethkingia spp., and Bacillus spp., were primary ARGs hosts, conferring resistance to multiple antibiotics including sulfamethoxazole, tetracycline and ß-lactams. Notably, these ARGs hosts were involved in nitrogen metabolism, including extracellular nitrate/nitrite transport and nitrite reduction, which are crucial in nitrification and denitrification in biofilters. For example, Acinetobacter spp., the dominant bacteria in the filter (relative abundance 69.97 %), contributed the majority of ARGs and 53.79 % of nitrite reduction function. That is, ARB can predominate by participating in the nitrogen metabolism pathways, facilitating the enrichment of ARGs. These findings provide insights into the stable presence of ARGs in biofilters from a functional metabolism perspective, offering a significant supplementary to the mechanisms of the emergence, maintenance, and transmission of BARin drinking water.

Spartina alterniflora invasion altered phosphorus retention and microbial phosphate solubilization of the Minjiang estuary wetland in southeastern China.

Spartina alterniflora invasion is considered a critical event affecting sediment phosphorus (P) availability and stock. However, P retention and microbial phosphate solubilization in the sediments invaded with or without S. alterniflora have not been fully investigated. In this study, a sequential fractionation method and high-throughput sequencing were used to analyze P transformation and the underlying microbial mechanisms in the sediments of no plant (NP) zone, transition (T) zone, and plant (P) zone. Results showed that except for organic phosphate (OP), total phosphate (TP), inorganic phosphate (IP), and available phosphate (AP) all followed a significant decrease trend from the NP site to the T site, and to the P site. The vertical decrease of TP, IP, and AP was also observed with an increase in soil depth. Among the six IP fractions, Fe-P, Oc-P, and Ca10-P were the predominant forms, while the presence of S. alterniflora resulted in an obvious P depletion except for Ca8-P and Al-P. Although S. alterniflora invasion did not significantly alter the alpha diversity of phosphate-solubilizing bacteria (PSB) harboring phoD gene, several PSB belonging to p_Proteobacteria, p_Planctomycetes, and p_Cyanobacteriota showed close correlations with P speciation and IP fractions. Further correlation analysis revealed that the reduced soil pH, soil TN and soil EC, and the increased soil TOC mediated by the invasion of S. alterniflora also significantly correlated to these PSB. Overall, this study elucidates the linkage between PSB and P speciation and provides new insights into understanding P retention and microbial P transformation in the coastal sediment invaded by S. alterniflora.

Burkholderia cepacia immobilized onto rGO as a biomaterial for the removal of naphthalene from wastewater.

As one of the polycyclic aromatic hydrocarbons (PAHs), naphthalene is of serious environmental concern due to its carcinogenicity, persistence and refractory degradation. In this study, a new functional biomaterial based on Burkholderia cepacia (BK) immobilized on reduced graphene oxide (rGO) was prepared, resulting in the removal of 99.0% naphthalene within 48 h. This was better than the 67.3% for free BK and 55.6% for rGO alone. Various characterizations indicated that reduced graphene oxide-Burkholderia cepacia (rGO-BK) was successfully synthesized and secreted non-toxic and degradable surfactants which participated in the degradation of naphthalene. The adsorption kinetics and degradation kinetics conformed best to non-linear pseudo-second-order and pseudo-first-order kinetic models, respectively. Demonstrated in this work is that removing naphthalene by rGO-BK involved both chemically dominated adsorption and biodegradation. As well, GC-MS analysis revealed two things: firstly, that the degraded products of naphthalene were dibutyl phthalate, diethyl phthalate, phthalic acid, and benzoic acid; and secondly, two potentially viable biodegradation pathways of naphthalene by rGO-BK could be proposed. Finally, for practical application experiment, the rGO-BK was exposed to river water samples and generated 99% removal efficiency of naphthalene, so this study offers new insights into biomaterials that can remove naphthalene.

TIMING 2.0: high-throughput single-cell profiling of dynamic cell-cell interactions by time-lapse imaging microscopy in nanowell grids.

MOTIVATION: Automated profiling of cell-cell interactions from high-throughput time-lapse imaging microscopy data of cells in nanowell grids (TIMING) has led to fundamental insights into cell-cell interactions in immunotherapy. This application note aims to enable widespread adoption of TIMING by (i) enabling the computations to occur on a desktop computer with a graphical processing unit instead of a server; (ii) enabling image acquisition and analysis to occur in the laboratory avoiding network data transfers to/from a server and (iii) providing a comprehensive graphical user interface. RESULTS: On a desktop computer, TIMING 2.0 takes 5 s/block/image frame, four times faster than our previous method on the same computer, and twice as fast as our previous method (TIMING) running on a Dell PowerEdge server. The cell segmentation accuracy (f-number = 0.993) is superior to our previous method (f-number = 0.821). A graphical user interface provides the ability to inspect the video analysis results, make corrective edits efficiently (one-click editing of an entire nanowell video sequence in 5-10 s) and display a summary of the cell killing efficacy measurements. AVAILABILITY AND IMPLEMENTATION: Open source Python software (GPL v3 license), instruction manual, sample data and sample results are included with the Supplement (https://github.com/RoysamLab/TIMING2). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PKC and Ras are Involved in M1 Muscarinic Receptor-Mediated Modulation of AMPA Receptor GluA1 Subunit.

M1 muscarinic acetylcholine receptors (M1 mAChRs) have long been an attractive target for the treatment of Alzheimer's disease (AD), the most common cause of dementia in the elderly. M1 mAChR agonists show desirably preclinical activities; however, most have not gone further into late clinical trials due to ineffectiveness or side effects. Thus, to understand the signaling pathways involved in M1 mAChR-mediated memory improvement may be important for design of biased agonists with on-target therapeutic effects. M1 mAChRs are classically coupled to Gαq or ectopically to Gαs to activate multiple kinases such as protein kinase C (PKC), Ras and protein kinase A (PKA). Our previous studies have found that M1 mAChRs could improve learning and memory through modulating AMPA receptor GluA1 subunit via PKA-PI3K-Akt signaling. Here, we further investigated whether PKC and Ras were involved in M1 mAChR-mediated modulation of GluA1. We demonstrated the role of PKC and Ras in the signaling pathway, as both PKC inhibitors Ro-31-8425 or Gö6983 and Ras inhibitor salirasib abolished the membrane insertion of GluA1 and enhancement of its phosphorylation at Ser845 induced by M1 mAChRs in the primary cultured neurons and hippocampus in vivo. We further showed that PKC and Ras modulated PKA-PI3K-Akt signaling since the increases of PKA, Akt and mTOR activities by M1 mAChR activation were blocked by PKC and Ras inhibitors. These data demonstrated the detailed mechanism underlying M1 mAChR-mediated modulation of GluA1 through Gαq/11 coupling, broadening the knowledge of the downstream signaling after M1 mAChR-Gαq/11 coupling.

M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt.

M1 muscarinic acetylcholine receptors are highly expressed in key areas that control cognition, such as the cortex and hippocampus, representing one potential therapeutic target for cognitive dysfunctions of Alzheimer's disease and schizophrenia. We have reported that M1 receptors facilitate cognition by promoting membrane insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor AMPA receptor subunit 1 (GluA1) through phosphorylation at Ser845. However, the signaling pathway is still unclear. Here we showed that adenylyl cyclase inhibitor 2',5'-dideoxyadenosine and PKA inhibitor KT5720 inhibited enhancement of phosphorylation of Ser845 and membrane insertion of GluA1 induced by M1 receptor activation. Furthermore, PI3K inhibitor LY294002 and protein kinase B (Akt) inhibitor IV blocked the effects of M1 receptors as well. Remarkably, the increase of the activity of PI3K-Akt signaling induced by M1 receptor activation could be abolished by cAMP-PKA inhibitors. Moreover, inhibiting the mammalian target of rapamycin (mTOR) complex 1, an important downstream effector of PI3K-Akt, by short-term application of rapamycin attenuated the effects of M1 receptors on GluA1. Furthermore, such effect was unrelated to possible protein synthesis promoted by mTOR. Taken together, these data demonstrate that M1 receptor activation induces membrane insertion of GluA1 via a signaling linking cAMP-PKA and PI3K-Akt-mTOR pathways but is irrelevant to protein synthesis.-Zhao, L.-X., Ge, Y.-H., Li, J.-B., Xiong, C.-H., Law, P.-Y., Xu, J.-R., Qiu, Y., Chen, H.-Z. M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt.

Neuroglobin Regulates Wnt/ß-Catenin and NFκB Signaling Pathway through Dvl1.

Neuroglobin is an endogenous neuroprotective protein, but the underlying neuroprotective mechanisms remain to be elucidated. Our previous yeast two-hybrid screening study identified that Dishevelled-1, a key hub protein of Wnt/ß-Catenin signaling, is an interaction partner of Neuroglobin. In this study, we further examined the role of Neuroglobin in regulating Dishevelled-1 and the downstream Wnt/ß-Catenin and NFκB signaling pathway. We found that Neuroglobin directly interacts with Dishevelled-1 by co-immunoprecipitation, and the two proteins are co-localized in both cytoplasma and nucleus of SK-N-SH cells. Moreover, the ectopic expression of Neuroglobin promotes the degradation of exogenous and endogenous Dishevelled-1 through the proteasomal degradation pathway. Furthermore, our results showed that Neuroglobin significantly inhibits the luciferase activity of Topflash reporter and the expression of ß-Catenin mediated by Dishevelled-1 in SK-N-SH cells. In addition, we also documented that Neuroglobin enhances TNF-α-induced NFκB activation via down-regulating Dishevelled-1. Finally, 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assays showed that Neuroglobin is an important neuroprotectant that protects SK-N-SH cells from TNF-α-induced decrease in cell viability. Taken together, these findings demonstrated that Neuroglobin functions as an important modulator of the Wnt/ß-Catenin and NFκB signaling pathway through regulating Dishevelled-1.

Response of gaseous carbon emissions to low-level salinity increase in tidal marsh ecosystem of the Min River estuary, southeastern China.

Although estuarine tidal marshes are important contributors to the emission of greenhouse gases into the atmosphere, the relationship between carbon dioxide (CO2), methane (CH4) emission, and environmental factors, with respect to estuarine marshes, has not been clarified thoroughly. This study investigated the crucial factors controlling the emission of CO2 and CH4 from a freshwater marsh and a brackish marsh located in a subtropical estuary in southeastern China, as well as their magnitude. The duration of the study period was November 2013 to October 2014. Relevant to both the field and incubation experiments, the CO2 and CH4 emissions from the two marshes showed pronounced seasonal variations. The CO2 and CH4 emissions from both marshes demonstrated significant positive correlations with the air/soil temperature (p<0.01), but negative correlations with the soil electrical conductivity and the pore water/tide water Cl- and SO42- (p<0.01). The results indicate no significant difference in the CO2 emissions between the freshwater and brackish marshes in the subtropical estuary, whereas there was a difference in the CH4 emissions between the two sites (p<0.01). Although future sea-level rise and saltwater intrusion could reduce the CH4 emissions from the estuarine freshwater marshes, these factors had little effect on the CO2 emissions with respect to an increase in salinity of less than 5‰. The findings of this study could have important implications for estimating the global warming contributions of estuarine marshes along differing salinity gradients.

Identification of a cancer driver gene-associated lncRNA signature for prognostic prediction and immune response evaluation in clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) predominates among kidney cancer cases and is influenced by mutations in cancer driver genes (CDGs). However, significant obstacles persist in the early diagnosis and treatment of ccRCC. While various genetic models offer new hopes for improving ccRCC management, the relationship between CDG-related long non-coding RNAs (CDG-RlncRNAs) and ccRCC remains poorly understood. Therefore, this study aims to construct prognostic molecular features based on CDG-RlncRNAs to predict the prognosis of ccRCC patients, and aims to provide a new strategy to enhance clinical management of ccRCC patients. Methods: This study employed Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses to comprehensively investigate the association between lncRNAs and CDGs in ccRCC. Leveraging The Cancer Genome Atlas (TCGA) dataset, we identified 97 prognostically significant CDG-RlncRNAs and developed a robust prognostic model based on these CDG-RlncRNAs. The performance of the model was rigorously validated using the TCGA dataset for training and the International Cancer Genome Consortium (ICGC) dataset for validation. Functional enrichment analysis elucidated the biological relevance of CDG-RlncRNA features in the model, particularly in tumor immunity. Experimental validation further confirmed the functional role of representative CDG-RlncRNA SNHG3 in ccRCC progression. Results: Our analysis revealed that 97 CDG-RlncRNAs are significantly associated with ccRCC prognosis, enabling patient stratification into different risk groups. Development of a prognostic model incorporating key lncRNAs such as HOXA11-AS, AP002807.1, APCDD1L-DT, AC124067.2, and SNHG3 demonstrated robust predictive accuracy in both training and validation datasets. Importantly, risk stratification based on the model revealed distinct immune-related gene expression patterns. Notably, SNHG3 emerged as a key regulator of the ccRCC cell cycle, highlighting its potential as a therapeutic target. Conclusions: Our study established a concise CDG-RlncRNA signature and underscored the pivotal role of SNHG3 in ccRCC progression. It emphasizes the clinical relevance of CDG-RlncRNAs in prognostic prediction and targeted therapy, offering potential avenues for personalized intervention in ccRCC.

Enhanced removal of Pb(II) from acid mine drainage using green reduced graphene oxide/silver nanoparticles.

Mining activities can potentially release high levels of Pb(II) in acid mine drainage (AMD), which thereafter poses a significant threat to ecological security. In this study, green reduced graphene oxide/silver nanoparticles (rGO/Ag NPs) were successfully synthesized via a one-step approach using a green tea extract and subsequently used as a cost-effective absorbent to remove Pb(II) from AMD. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy indicated that organic functional groups in the green tea extracts, such as C=O-C, CO, and CC, acted both as reductants and stabilizers in the synthesis of rGO/Ag NPs. In addition, the removal efficiency of Pb(II) by rGO/Ag NPs (84.2 %) was much better than either rGO (75.4 %) or Ag NPs (12.3 %) alone. Also, in real AMD, the distribution coefficient (Kd) of Pb(II) (4528 mL/g), was much higher than other heavy metal indicating the adsorbent had a high selective affinity for Pb(II). Interestingly, after five cycles of use, the removal efficiency of Pb(II) by rGO/Ag NPs from AMD actually increased from 46.4 to 65.2 % due to iron oxides (i.e., Fe2O3 and Fe3O4) being generated when rGO/Ag NPs was exposed to AMD. The removal of Pb(II) via adsorption on the rGO/Ag NPs surface involved formation of hexagonal rod-like precipitates. This work demonstrated the potential of rGO/Ag NPs to be continuously used for the removal of Pb(II) from AMD.

Isotopic compositions (δD, δ18O) and end-member mixing for the control interface in a complex tidal region.

Identifying the mixing processes of waters and currents in tidal reach is an important aspect of environmental management to protect freshwater resources and prevent water pollution. In this study, three field investigations conducted in a typical tidal reach in August, November and the following April focused on two isotopes (δD and δ18O) and salinity. A salinity-isotope conservative mixing model was established to differentiate water flows of the important control interface (CI) from freshwater, transition zone and saltwater end-members. Results suggested that the average δD and δ18O values during the ebb and flood tides depleted from August to November, then enriched significantly in the following April and were even higher than those in August. The δD and δ18O values in the saltwater zone enriched markedly compared with those in freshwater zone and transition zone due to the stronger evaporation occurring in the saltwater zone. Based on the revised model, the average contributions of freshwater end-member, transition zone end-member and saltwater end-member in three months were, respectively, 51.50 %, 36.93 % and 11.57 %. However, the contributions of freshwater and transition zones in April end-member were equivalent (47.45 % vs 44.31 %). Meanwhile the largest contribution of saltwater end-member was 20.56 % and occurred in August. The proportions of three end-members that contributed to CI changed with different evaporation scenarios and moisture sources of precipitation. Our research provides important information that furthers our understanding of the isotopes and their applications to environmental management in estuarine regions.

Toward green nano adsorbents and catalysts: Highly active Fe/Mn nanoparticles for enhanced oxidation of oxytetracycline and levofloxacin.

The widespread use of antibiotics, such as oxytetracycline (OTC) and levofloxacin (LEV), has led to dangerous levels of environmental contamination. In this study, functionalized iron/manganese nanoparticles (Fe/Mn NPs), which act as both adsorbent and Fenton catalyst, were green-synthesized using a reducing agent derived from a tea extract. The resulting pre-sorption/Fenton-like oxidation system effectively removed both OTC and LEV from the aqueous solution with adsorption capacities of Fe/Mn NPs for OTC and LEV of 58.8 and 192.3 mg·g-1, respectively. In addition, Fe/Mn NPs also showed high catalytic activity, oxidizing more than 99.9 % of both OTC and LEV, while sodium persulfate (PDS) removed only 26.6 and 29.0 % of OTC and LEV, respectively. Mechanisms of PDS activation typically involve either catalyst-initiated or mediated electron transfer reactions. Fe/Mn NPs through heterogeneous catalytic and metal leaching-induced homogeneous Fenton reactions, which generated various reactive oxygen species (ROS) including 1O2, ·OH, SO4-· and ·O2-. Characterization of Fe/Mn NPs before and after reaction, and the identification of specific OTC and LEV degradation products by LC-MS, helped to elucidate a potential degradation pathway, as well as the removal mechanism. Finally, the practicality of using this system for wastewater treatment was demonstrated using real wastewater samples indicating that the system has great potential for simultaneously degrading both OTC and LEV in contaminated wastewater.

Exposure to phthalate increases the risk of eczema in children: Findings from a systematic review and meta-analysis.

Emerging evidence indicated phthalate exposure might raise the risk of eczema in children. However, these findings were inconsistent. The relation between phthalate exposure and childhood eczema remained debated. Therefore, we performed this meta-analysis to assess their association. PubMed, Web of Science, and Embase were searched for eligible studies. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated for risk estimate. Thirty studies involving 12,615 participants were included in this meta-analysis. For prenatal phthalate exposure assessed with maternal samples, the pooled results showed gestational exposure to monobenzyl phthalate (MBzP) (OR: 1.17, 95% CI: 1.00-1.36), but not the other phthalates, was correlated with increased risk of eczema in children. For childhood exposure assessed using children's urine sample, our pooled results indicated that postnatal exposure to MBzP (OR: 1.10, 95% CI: 1.02-1.19), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) (OR: 1.32, 95% CI: 1.08-1.61), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) (OR: 1.24, 95% CI: 1.06-1.44), and molar summation of di-2-ethylhexyl phthalate (DEHP) (OR: 1.23, 95% CI: 1.06-1.42) were associated with higher risk of eczema. While for studies using household dust to estimate environmental phthalate exposure and eczema risk, the pooled results showed no significant association. Subgroup analyses indicated study country, diagnostic mode, and children's age contributed to the heterogeneity. The results of our meta-analysis demonstrated that phthalate exposure during both prenatal and postnatal periods was associated with elevated risk of eczema in children. However, such association was not strong as the pooled ORs were relatively small. Further studies are warranted to verify these findings and explore the underlying mechanism.

Changes of dissolved organic matter following salinity invasion in different seasons in a nitrogen rich tidal reach.

Dissolved organic matter (DOM) is a heterogeneous mixture of dissolved material found ubiquitously in aquatic systems and dissolved organic nitrogen is one of its most important components. We hypothesised nitrogen species and salinity intrusions affect the DOM changes. Here, using the nitrogen rich Minjiang River as an easily accessible natural laboratory 3 field surveys with 9 sampling sites (S1-S9) were conducted in November 2018, April and August 2019. The excitation emission matrices (EEMs) of DOM were explored with parallel factor (PARAFAC) and cosine-histogram similarity analysis. Four indices including fluorescence index (FI), biological index (BIX), humification index (HIX) and the fluorescent DOM (FDOM) were calculated and the impact of physicochemical properties was assessed. The results suggested that the highest salinities of 6.15, 2.98 and 10.10, during each campaign corresponded to DTN concentrations of 119.29-240.71, 149.12-262.42 and 88.27-155.29 µmol·L-1, respectively. PARAFAC analysis revealed the presence of tyrosine-like proteins (C1), tryptophan-like proteins or a combination of the peak N and tryptophan-like fluorophore (C2) and the humic-like material (C3). The EEMs in the upstream reach (i.e. S1-S3) were complex with larger spectra ranges, higher intensities and similar similarity. Subsequently, the fluorescence intensity of three components decreased significantly with low similarity of EEMs (i.e. S4-S7). At the downstream, the fluorescence levels dispersed significantly and no obvious peaks were seen except in August. In addition, FI and HIX increased, while BIX and FDOM decreased from upstream to downstream. The salinity positively correlated with FI and HIX, and negatively related to BIX and FDOM. Besides, the elevated DTN had a significant effect on the DOM fluorescence indices. Altogether, salinity intrusion and elevated nitrogen are relevant for the distribution of the DOM, which is helpful for the water management tracing the DOM source according to the on-line monitoring of salinity and nitrogen in estuaries.

Effect of ocean warming on pigment and photosynthetic carbon fixation of plankton assemblage in Pingtan Island of Southeast China.

Temperature plays an important role in affecting the physiological traits of marine plankton. In this study, we conducted an outdoor incubation experiment to investigate the effects of elevated temperature on Chl a, photosynthetic carbon fixation and the composition of plankton communities in the surface seawater around Pingtan Island, the northwest Taiwan Strait in Autumn 2022. After 3-4 days of incubation, elevated temperature (1-4 °C higher than ambient temperature) led to a decrease in Chl a concentration across all three stations, did not result in significant increases in the particulate organic carbon (POC) and nitrogen (PON) concentrations in seawater with high nitrate concentrations, whereas increased POC and PON concentrations in nitrate-limited seawater. These findings suggest that the effect of temperature on the POC and PON contents of plankton is affected by the availability of nitrate. Diatoms were the dominant phytoplankton group in all three stations. Our results indicate that ocean warming has a potential to increase the POC contents of marine plankton per volume of seawater, which may increase the ability of phytoplankton to absorb atmospheric CO2 and to alleviate global warming.

Arsenic trioxide extends survival of Li-Fraumeni syndrome mimicking mouse.

Li-Fraumeni syndrome (LFS) is characterized by germline mutations occurring on one allele of genome guardian TP53. It is a severe cancer predisposition syndrome with a poor prognosis, partly due to the frequent development of subsequent primary tumors following DNA-damaging therapies. Here we explored, for the first time, the effectiveness of mutant p53 rescue compound in treating LFS-mimicking mice harboring a deleterious p53 mutation. Among the ten p53 hotspot mutations in IARC LFS cohorts, R282W is one of the mutations predicting the poorest survival prognosis and the earliest tumor onset. Among the six clinical-stage mutant p53 rescue compounds, arsenic trioxide (ATO) effectively restored transactivation activity to p53-R282W. We thus constructed a heterozygous Trp53 R279W (corresponding to human R282W) mouse model for the ATO treatment study. The p53R279W/+ (W/+) mice exhibited tumor onset and overall survival well mimicking the ones of human LFS. Further, 35 mg/L ATO addition in drink water significantly extended the median survival of W/+ mice (from 460 to 596 days, hazard ratio = 0.4003, P = 0.0008). In the isolated tumors from ATO-treated W/+ mice, the representative p53 targets including Cdkn1a, Mdm2, and Tigar were significantly upregulated, accompanying with a decreased level of the proliferation marker Ki67 and increased level of apoptosis marker TUNEL. Together, the non-genotoxic treatment of p53 rescue compound ATO holds promise as an alternative for LFS therapeutic.

p85S6K sustains synaptic GluA1 to ameliorate cognitive deficits in Alzheimer's disease.

BACKGROUND: Ribosomal protein S6 kinase 1 (S6K1) is a serine-threonine kinase that has two main isoforms: p70S6K (70-kDa isoform) and p85S6K (85-kDa isoform). p70S6K, with its upstream mammalian target of rapamycin (mTOR), has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer's disease (AD). However, the function of p85S6K has long been neglected due to its high similarity to p70S6k. The role of p85S6K in learning and memory is still largely unknown. METHODS: We fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K. Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor. The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence, Western blot, in situ proximity ligation assay, morphological staining and behavioral examination. Further, the expression level of p85S6K was measured in brains from AD patients and AD model mice. RESULTS: p85S6K, but not p70S6K, was enriched in the postsynaptic densities. Moreover, knockdown of p85S6K resulted in defective spatial and recognition memory. In addition, p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150. Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in synapses, thus sustaining synaptic function and spine densities. Moreover, p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice. Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice. CONCLUSIONS: These results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1. The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.

Diverse rescue potencies of p53 mutations to ATO are predetermined by intrinsic mutational properties.

Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor-suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations (www.rescuep53.net) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.