Therapeutic Approaches of Dual-targeted Nanomedicines for Tumor Multidrug Resistance.

Currently, the main cause of cancer chemotherapy failure is multi-drug resistance (MDR), which involves a variety of complex mechanisms. Compared with traditional small-molecule chemotherapy, targeted nanomedicines offer promising alternative strategies as an emerging form of therapy, especially active targeted nanomedicines. However, although single-targeted nanomedicines have made some progress in tumor therapy, the complexity of tumor microenvironment and tumor heterogeneity limits their efficacy. Dual-targeted nanomedicines can simultaneously target two tumor-specific factors that cause tumor MDR, which have the potential in overcoming tumor MDR superior to single-targeted nanomedicines by further enhancing cell uptake and cytotoxicity in new forms, as well as the effectiveness of tumor-targeted delivery. This review discusses tumor MDR mechanisms and the latest achievements applied to dual-targeted nanomedicines in tumor MDR.

Highly efficient and chemoselective blocking of free amino group by ortho-phthalaldehyde (OPA) for comprehensive analysis of protein terminome.

Herein, we introduced ortho-phthalaldehyde (OPA) for blocking free amino groups and established a simple and robust method for comprehensive profiling of protein terminome based on strong cation exchange chromatography (SCX) fractionation. With the highly efficient and chemoseletive amine-group blocking, we identified 2271 canonical human protein N-termini, 1650 canonical human protein C-termini, as well as 645 protein neo-N-termini from HeLa cells.

Xinmaikang (XMK) tablets alleviate atherosclerosis by regulating the SREBP2-mediated NLRP3/ASC/Caspase-1 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xinmaikang (XMK) tablets, a Chinese patent medicine, have been used for the prevention and treatment of atherosclerosis (AS) clinically. However, the underlying mechanism of XMK is far from completely illustrated. AIM OF THE STUDY: This study aimed to determine whether XMK alleviates AS in Apolipoprotein E-knockout (ApoE-/-) mice and to explore the potential mechanism of action in bone marrow-derived macrophages (BMDMs). MATERIALS AND METHODS: XMK decoction was analyzed by an LC‒MS/MS assay. Molecular docking was conducted to determine the interaction of XMK molecular ligands and AS targets. In vivo, 10 ApoE-/- mice were selected as the control group. Fifty ApoE-/- mice were randomly divided into 5 groups: the model group, low-, medium-, and high-dose XMK groups and the simvastatin group. Mice in the control group were fed a chow diet, and the other 5 groups were fed a high-fat diet (HFD) for 12 weeks. After 12 weeks, the treatment groups were administered low-dose XMK (2.28·kg-1·d), medium-dose XMK (4.55·kg-1·d), high-dose XMK (9.1 kg-1 d) and simvastatin (91 mg-1 d) for another 12 weeks. Serum enzymology assays tested AST/ALT, Cr, LDH and CK-MB levels. The atherosclerotic plaques and lipid deposition were measured by Oil red O (ORO) staining and Hematoxylin and Eosin (H&E) staining. Then, we examined the body weight and serum lipids (TC, TG, LDL-C and HDL-C) of the mice. ELISA was performed to determine the levels of inflammatory factors (IL-6, TNF-ɑ, VCAM-1, CXCL8 and CCL2). SREBP2/NLRP3 signaling pathway-related genes (SREBP2, NLRP3, ASC, IL-1ß and Caspase-1) were analyzed by RT‒qPCR and western blotting. In vitro, LPS-stimulated BMDMs were treated with different concentrations of XMK (1, 2.5, 5, 10, 20, and 40 µg/ml). Immunofluorescence staining (SREBP2, NLRP3), adenovirus infection and siRNA knockdown (SREBP2, NLRP3, Caspase-1 and ASC) were conducted as complements to the in vivo experiment. RESULTS: Molecular docking showed a stable interaction between the effective components of XMK and SREBP2 and NLRP3. Serum enzymology assays revealed the medication safety of XMK in cardiac, hepatic and renal function. Studies in vivo indicated that XMK improved serum lipids (TC, TG, LDL-C and HDL-C) and reduced plaque area. Body weight decreased, and the expression of inflammatory cytokines (IL-6, TNF-ɑ and VCAM-1) was inhibited. Then, XMK downregulated the mRNA and protein expression of SREBP2, NLRP3, ASC, IL-1ß and Caspase-1. In vitro, the above findings were reinforced in BMDMs, and knocking down SREBP2 restrained the effect of XMK on the NLRP3/ASC/Caspase-1 signaling pathway. CONCLUSIONS: XMK restrains AS by improving inflammation through the SREBP2-mediated NLRP3/ASC/Caspase-1 signaling pathway.

Rhei Radix et Rhizoma in Xuanbai-Chengqi decoction strengthens the intestinal barrier function and promotes lung barrier repair in preventing severe viral pneumonia induced by influenza A virus.

ETHNOPHARMACOLOGICAL RELEVANCE: Xuanbai-Chengqi decoction (XCD) is a traditional prescription for treating multiple organ injuries, which has been used to manage pneumonia caused by various pathogens. However, the effects of XCD on repairing pulmonary/intestinal barrier damage remain unclear, and there is a need to understand the compatibility mechanism of rhubarb. AIM OF THE STUDY: This work aims to investigate the protective effect and mechanism of XCD on the pulmonary/intestinal barrier guided by the theory of "gut-lung concurrent treatment". Moreover, we elucidate the compatibility mechanism of rhubarb in XCD. MATERIALS AND METHODS: An H1N1 virus-infected mouse model was adopted to investigate the reparative effects of XCD on the lung-intestinal barrier by assessing lung-intestinal permeability. Additionally, the characterization of type I alveolar epithelial cells (AT1) and type II alveolar epithelial cells (AT2) was performed to evaluate the damage to the alveolar epithelial barrier. The specific barrier-protective mechanisms of XCD were elucidated by detecting tight junction proteins and the epithelial cell repair factor IL-22. The role of rhubarb in XCD to pneumonia treatment was investigated through lung tissue transcriptome sequencing and flow cytometry. RESULTS: XCD significantly improved lung tissue edema, inflammation, and alveolar epithelial barrier damage by regulating IL-6, IL-10, and IL-22, which, could further improve pulmonary barrier permeability when combined with the protection of alveolar epithelial cells (AT1 and AT2) as well as inhibition of H1N1 virus replication. Simultaneously, XCD significantly reduced intestinal inflammation and barrier damage by regulating IL-6, IL-1ß, and tight junction protein levels (Claudin-1 and ZO-1), improving intestinal barrier permeability. The role of rhubarb in the treatment of pneumonia is clarified for the first time. In the progression of severe pneumonia, rhubarb can significantly protect the intestinal barrier, promote the repair of AT2 cells, and inhibit the accumulation of CD11b+Ly6Gvariable aberrant neutrophils by regulating the S100A8 protein. CONCLUSION: In summary, our findings suggest that rhubarb in XCD plays a critical role in protecting intestinal barrier function and promoting lung barrier repair in preventing severe viral pneumonia caused by influenza A virus.

Nitro substituent caused negative impact on occurrence and development of atherosclerotic plaque by PM2.5-bound polycyclic aromatic compounds.

PM2.5 exposure is a significant risk factor for the occurrence and development of atherosclerosis. Polycyclic aromatic hydrocarbons (PAHs) play prominent roles in PM2.5-related toxicity. However, the nitrated derivatives of PAHs, nitrated polycyclic aromatic hydrocarbons (NPAHs), have strong oxidizing properties due to the nitro substituents. Thus, the in vivo and in vitro experiments exposure to benzo[a]pyrene (BaP) and 6-nitro benzo[a]pyrene (NBaP) were conducted to evaluate the effect of nitro substituent on the atherosclerosis due to (or attributable to) PAHs. The results showed that NBaP exposure induced the inhibition of human umbilical vein endothelial cells (HUVECs) viability and cell morphology damage via more severe oxidative stress than BaP exposure. Furthermore, exposure to PM2.5-bound NBaP caused dyslipidemia in the Apolipoprotein E-deficient (ApoE-/-) mice, including the increment of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and malondialdehyde levels, and the decrement of high-density lipoprotein cholesterol levels, superoxide dismutase and glutathione peroxidase levels in serum and aorta. Furthermore, histology showed atherosclerotic plaque in the aorta of ApoE-/- mice. However, there were no significant differences of the physiological and pathological changes between BaP and control groups. Thus, NPAHs induced endothelial dysfunction and dyslipidemia via severe oxidative stress, and further accelerated the occurrence and development of atherosclerosis compared with the parent PAHs. Our findings provide the first evidence that nitro substituent caused much severer negative health impact of polycyclic aromatic compounds, which highlight the significance of NPAHs in health risk estimation of polycyclic aromatic compounds.

A novel double-network hydrogel made from electrolytic manganese slag and polyacrylic acid-polyacrylamide for removal of heavy metals in wastewater.

Electrolytic manganese slag (EMS), a bulk waste generated in industrial electrolytic manganese production, can be a cost-effective adsorbent for heavy metals removal after appropriate modification. In this study, EMS was activated by NaOH and then used to make the EMS-based double-network hydrogel (an EMS/PAA hydrogel) via a one-pot method. The results showed that the EMS/PAA hydrogel exhibits a high selective adsorption capacity of 153.85, 113.63 and 54.35 mg·g-1 for Pb (II), Cd (II) and Cu (II), respectively. In addition, Density Functional Theory (DFT) suggests that the adsorption energies (Ead) of Pb, Cd and Cu on SiO2/PAA of the EMS/PAA gels are - 4.15, - 1.96, and - 2.83 eV, respectively, and SiO2/PAA, with a strong affinity to Pb2+, is one of the reasons for the selective adsorption capacity of EMS/PAA gel for Pb2+. The removal efficiency of the EMS/PAA gel for Pb2+, Cd2+, Cu2+ decreased after four adsorption-desorption cycles by 20.00 %, 24.56 % and 46.56 %, respectively. Mechanism studies suggested that the elimination of the heavy metals by EMS/PAA gels mainly involves electrostatic attraction, inner-sphere complexation, and coordination interactions. The EMS/PAA hydrogels not only have high adsorption capacity, but are also easy to prepare and circulate, making them ideal for practical applications.

MicroRNA-217-5p triggers dopaminergic neuronal degeneration via autophagy activation under Atrazine exposure.

Atrazine (ATR) is a widely used agricultural herbicide, and its accumulation in soil and water can cause various environmental health problems. ATR has neurotoxic effects on dopaminergic neurons, which can lead to a Parkinson's disease (PD)-like syndrome. Epigenetics regulates gene expression dynamically through DNA methylation, histone post-translational modification, microRNA (miRNA) interaction, and RNA methylation. MicroRNA (miRNA), representing one of the primary epigenetic mechanisms responsible for regulating gene expression, plays a crucial role in maintaining normal cellular function, while dysregulation of miRNA expression has been observed in PD. This study aims to investigate the regulatory mechanisms of miRNA in ATR exposure. The results show that ATR-exposure significantly upregulates the expression level of miR-217-5p. Both miR-217-5p overexpression and ATR exposure is able to trigger the autophagy process and apoptosis. Conversely, inhibiting the expression of miR-217-5p can reverse the levels of ATR-induced autophagy and apoptosis. Moreover, ATR causes damage to dopaminergic neurons, as indicated by the altered expression of tyrosine hydroxylase and α-synuclein. Taken together, these results suggest that ATR-induced autophagy can accelerate the progression of neurodegenerative diseases and that miR-217-5p is probably an important target involved in ATR-induced dopaminergic damage, shedding important light on the development of a novel strategy for treating neurodegenerative diseases.

In situ study of structural changes: Exploring the mechanism of protein corona transition from soft to hard.

HYPOTHESIS: The process of protein corona changes has been widely believed to follow the Vroman effect, while protein structural change during the process is rarely reported, due to the lack of analytical methods. In-situ interpretation for protein structural change is critical to processes such as the recognition and transport of nanomaterials. EXPERIMENTS: Molecular dynamics (MD) simulation was used to predict the deflection and twist of the protein tertiary structure. The structural changes of the surface protein corona during the interaction of nanoparticles (NPs) with lipid bilayer were probed in situ and real-time by sum frequency generation (SFG) spectroscopy. FINDINGS: The ring tertiary structure of the protein corona is altered from vertical to horizontal on particle surface, a process of the soft-to-hard structural transition, which is contributed by the hydrogen bonding force between the protein and water molecules. The negatively charged protein corona can induce the redistribution of interfacial charge, leading to a more stable hydrogen bond network of the interfacial water. Our findings suggest that the structural change from flexible to rigid is a crucial process in the soft-to-hard transition of the protein corona, which will be a beneficial supplement to the Vroman effect of protein adsorption.

A novel intergenic (between REG3A and CTNNA2-AS1)-ALK fusion responds to alectinib in lung adenocarcinoma.

OBJECTIVES: The wide implementation of next generation sequencing (NGS) technology has led to the identification of a greater number of uncommon partners of anaplastic lymphoma kinase (ALK) fusion. The clinical significance of the intergenic-ALK fusion was deemed limited due to the ambiguous functional partner. Herein, we reported a case of lung adenocarcinoma harboring a novel intergenic (between REG3A and CTNNA2-AS1)-ALK fusion which is sensitive to alectinib. MATERIALS AND METHODS: Hematoxylin-eosin staining (HE), immunohistochemistry (IHC), and DNA-based next-generation sequencing (NGS) based on a 168-gene panel were performed on the biopsy sample. RESULTS: A 50-year-old Chinese male patient diagnosed with stage IVA adenocarcinoma of the upper lobe of the right lung. A novel ALK fusion, resulting from the intergenic region between REG3A and CTNNA2-AS1 fusing with intron 19 of ALK, was unveiled by NGS analysis. Furthermore, positive expression of ALK was confirmed through IHC analysis. The patient was administered alectinib at a dose of 600 mg twice daily as first-line therapy, and partial response was assessed. To date, the progression-free survival (PFS) has exceeded 14 months without any observed serious toxicities. CONCLUSION: To the best of our knowledge, this represents the inaugural report of a patient harboring a novel intergenic-ALK fusion with a breakpoint situated between REG3A and CTNNA2-AS1, who exhibited favorable response to alectinib. This case warrants further investigation and offers valuable insights into the response of this novel intergenic-ALK fusion to alectinib.

Temperature-Dependent Color-Tunable Afterglow in Zirconium-Doped CsCdCl3 Perovskite for Advanced Anti-Counterfeiting and Thermal Distribution Detection.

Persistent luminescence (PersL) materials exhibit thermal-favored optical behavior, enabling their unique applications in security night vision signage, in vivo bioimaging, and optical anti-counterfeiting. Therefore, developing efficient and color-tunable PersL materials is significantly crucial in promoting advanced practical use. In this study, hexagonal Zr4+ -doped CsCdCl3 perovskite is synthesized via a hydrothermal reaction with a tunable photoluminescent (PL) behavior through heterovalent substitution. Moreover, the incorporation of Zr4+ ions result in an extra blue emission band, originating from the enhanced excitonic recombination in D3d octahedrons. Furthermore, the afterglow performances of the samples are dramatically improved, along with the noticeable temperature-dependent PersL as well as the thermo-luminescence with tunable color output. Detailed analysis reveals that the unique temperature-dependent PersL and thermo-luminescence color change are attributed to the presence of multiple luminous centers and abundant traps. Overall, this work facilitates the development of optical intelligence platforms and novel thermal distribution probes with the as-developed halides perovskite for its superior explored PersL characteristic.

Leukemia Inhibitory Factor Protects against Degeneration of Cone Photoreceptors Caused by RPE65 Deficiency.

BACKGROUND: Retinal pigment epithelium (RPE) 65 is a key enzyme in the visual cycle involved in the regeneration of 11-cis-retinal. Mutations in the human RPE65 gene cause Leber's congenital amaurosis (LCA), a severe form of an inherited retinal disorder. Animal models carrying Rpe65 mutations develop early-onset retinal degeneration. In particular, the cones degenerate faster than the rods. To date, gene therapy has been used successfully to treat RPE65-associated retinal disorders. However, gene therapy does not completely prevent progressive retinal degeneration in patients, possibly due to the vulnerability of cones in these patients. In the present study, we tested whether leukemia inhibitory factor (LIF), a trophic factor, protects cones in rd12 mice harboring a nonsense mutation in Rpe65. METHODS: LIF was administrated to rd12 mice by intravitreal microinjection. Apoptosis of retinal cells was analyzed by TUNEL assay. The degeneration of cone cells was evaluated by immunostaining of retinal sections and retinal flat-mounts. Signaling proteins regulated by LIF in the retinal and cultured cells were determined by immunoblotting. RESULTS: Intravitreal administration of LIF activated the STAT3 signaling pathway, thereby inhibiting photoreceptor apoptosis and preserving cones in rd12 mice. Niclosamide (NCL), an inhibitor of STAT3 signaling, effectively blocked STAT3 signaling and autophagy in cultured 661W cells treated with LIF. Co-administration of LIF with NCL to rd12 mice abolished the protective effect of LIF, suggesting that STAT3 signaling and autophagy mediate the protection. CONCLUSION: LIF is a potent factor that protects cones in rd12 mice. This finding implies that LIF can be used in combination with gene therapy to achieve better therapeutic outcomes for patients with RPE65-associated LCA.

Pathogen inhibition and indication by gelatin nonwoven mats with incorporation of polyphenol derivatives.

There is a need for non-pharmaceutical intervention methods that can prevent and indicate the risk of airborne disease spread. In this study, we developed a nonwoven mat based on the polyphenol gallic acid, which can inhibit pathogens growth and also indicate pathogen levels in the surrounding environment. Using nuclear magnetic resonance, Fourier-transform infrared spectroscopy, and high-performance liquid chromatography, we characterized this novel gelatin-based nonwoven mat and investigated the mechanism governing its ability to indicate pathogen levels. We demonstrated that the incorporation of gallic acid serves a vital role in indicating the presence of bacteria, causing the nonwoven mat to change in color from white to brown. We have proposed a plausible mechanism for this color change behavior based on a reaction of gallic acid with components excreted by bacteria, including glutamate, valine, and leucine. The concentrations of these components reflect the bacterial counts, enabling a real-time indication of pathogen levels in the surrounding air. In summary, the nonwoven mat presented herein can serve as an excellent antibacterial agent and as an indicator of nearby bacteria for fabricating personal protection equipment like filtration mask.

Sleep disturbance and medical requests among university and college students in Chongqing, China: A cross-sectional study.

OBJECTIVES: To investigate the prevalence of sleep disturbance, sleep patterns, sleep-related factors, and medical demands among university and college students in Chongqing, China. METHODS: Demographic data and responses to the sleep problem questionnaire (SPQ) were collected from 1973 students from 11 universities and 10 colleges between November 2022 and January 2023. RESULTS: The prevalence of sleep disturbance in university and college students was different in different periods (58.17% during campus lockdown and 40.30% after the lifting of lockdown). The combined prevalence was 49.72%. The prevalence of the 6 types of sleep disturbance showed the same trend. The average sleep latency was 32.79 minutes and the average sleep duration was 7.53 hours. Male, university students, upper-class students, history of depression, academic stress, major life events, bad bedroom environment, and campus lockdown were factors related to sleep disturbance among respondents. Most of the respondents (52.09%) had no medical care requests, and the major reasons were a lack of access to medical care (75.15%), economic pressure (68.49%), concerns regarding curative effects (58.51%), and academic pressure (56.56%). CONCLUSION: The prevalence of sleep disturbance for university and college students was obviously improved after the lifting of campus lockdown, and the major factors related to sleep disturbance were study, life, mental health, and sleep environment. The students examined herein reported relatively low medical care requests when they experience sleep disturbance.

Influence of social deprivation on morbidity and all-cause mortality of cardiometabolic multi-morbidity: a cohort analysis of the UK Biobank cohort.

BACKGROUND: The relation of social deprivation with single cardiometabolic disease (CMD) was widely investigated, whereas the association with cardiometabolic multi-morbidity (CMM), defined as experiencing more than two CMDs during the lifetime, is poorly understood. METHODS: We analyzed 345,417 UK Biobank participants without any CMDs at recruitment to study the relation between social deprivation and four CMDs including type II diabetes (T2D), coronary artery disease (CAD), stroke and hypertension. Social deprivation was measured by Townsend deprivation index (TDI), and CMM was defined as occurrence of two or more of the above four diseases. Multivariable Cox models were performed to estimate hazard ratios (HRs) per one standard deviation (SD) change and in quartile (Q1-Q4, with Q1 as reference), as well as 95% confidence intervals (95% CIs). RESULTS: During the follow up, 68,338 participants developed at least one CMD (median follow up of 13.2 years), 16,225 further developed CMM (median follow up of 13.4 years), and 18,876 ultimately died from all causes (median follow up of 13.4 years). Compared to Q1 of TDI (lowest deprivation), the multivariable adjusted HR (95%CIs) of Q4 (highest deprivation) among participants free of any CMDs was 1.23 (1.20 ~ 1.26) for developing one CMD, 1.42 (1.35 ~ 1.48) for developing CMM, and 1.34 (1.27 ~ 1.41) for all-cause mortality. Among participants with one CMD, the adjusted HR (95%CIs) of Q4 was 1.30 (1.27 ~ 1.33) for developing CMM and 1.34 (1.27 ~ 1.41) for all-cause mortality, with HR (95%CIs) = 1.11 (1.06 ~ 1.16) for T2D patients, 1.07 (1.03 ~ 1.11) for CAD patients, 1.07 (1.00 ~ 1.15) for stroke patients, and 1.24 (1.21 ~ 1.28) for hypertension patients. Among participants with CMM, TDI was also related to the risk of all-cause mortality (HR of Q4 = 1.35, 95%CIs 1.28 ~ 1.43). CONCLUSIONS: We revealed that people living with high deprived conditions would suffer from higher hazard of CMD, CMM and all-cause mortality.

Elevation of Lentilactobacillus rapi subsp. dabitei Li et al. 2022 to the species level as Lentilactobacillus dabitei sp. nov.

Lentilactobacillus rapi subsp. dabitei was proposed by Li et al. in 2022. The type strains of L. rapi subsp. dabitei and L. rapi subsp. rapi shared 93.1 % average nucleotide identity and 52.8 % digital DNA-DNA hybridization values. Strain IMAU80584T was proposed as a novel subspecies of L. rapi rather than a novel species of the genus Lentilactobacillus on the basis of similar phenotypic characteristics (including growth temperature and pH, tolerance to NaCl and features based on API 50CH and API ZYM). However, the phenotypic investigation performed by Li et al. was insufficient because some physiological and biochemical characteristics recommended by Mattarelli et al. were not included. In the present study, the taxonomic relationship between L. rapi subsp. dabitei and L. rapi subsp. rapi was re-evaluated. Based upon the data obtained in the present study, we propose to elevate L. rapi subsp. dabitei to the species level as Lentilactobacillus dabitei sp. nov. The type strain is IMAU80584T (=GDMCC 1.2566T=JCM 34647T).

A Distributed Proximal Consensus Algorithm for Energy Saving in Ethylene Production.

This article presents a distributed optimization framework in order to solve the plant-wide energy-saving problem of an ethylene plant. First, the ethylene production process is abstracted into a distributed network, and then, a new distributed consensus algorithm is proposed, which is called adaptive step-size-based distributed proximal consensus algorithm (ASS-DPCA). This algorithm can dynamically adjust the step size and automatically abandon the irrational evolutionary route while eliminating the dependence of optimization algorithms on model gradient information. Moreover, the designed algorithm is able to converge to an optimal solution for any convex cost functions and approach to a convex constraint set of agents over an undirected connected graph. Finally, the results of numerical simulation and industrial experiments show that the algorithm can reduce the total energy consumption of an ethylene plant with less computing time and assured consensus.

Monthly variations of groundwater arsenic risk under future climate scenarios in 2081-2100.

The seasonal variations of shallow groundwater arsenic have been widely documented. To gain insight into the monthly variations and mechanisms behind high groundwater arsenic and arsenic exposure risk in different climate scenarios, the monthly probability of high groundwater arsenic in Hetao Basin was simulated through random forest model. The model was based on arsenic concentrations obtained from 566 groundwater sample sites, and the variables considered included soil properties, climate, topography, and landform parameters. The results revealed that spatial patterns of high groundwater arsenic showed some fluctuations among months under different future climate scenarios. The probability of high total arsenic and trivalent arsenic was found to be elevated at the start of the rainy season, only to rapidly decrease with increasing precipitation and temperature. The probability then increased again after the rainy season. The areas with an increased probability of high total arsenic and trivalent arsenic and arsenic exposure risk under SSP126 were typically found in the high-arsenic areas of 2019, while those with decreased probabilities were observed in low-arsenic areas. Under SSP585, which involves a significant increase in precipitation and temperature, the probability of high total arsenic and trivalent arsenic and arsenic exposure risk was widely reduced. However, the probability of high total arsenic and trivalent arsenic and arsenic exposure risk was mainly observed in low-arsenic areas from SSP126 to SSP585. In conclusion, the consumption of groundwater for human and livestock drinking remains a threat to human health due to high arsenic exposure under future climate scenarios.

CD4+CCR8+ Tregs in ovarian cancer: a potential effector Tregs for immune regulation.

BACKGROUND: Tregs are key drivers of immunosuppression in solid tumors. As an important chemokine receptor on Tregs, the regulatory effect of CCR8 on tumor immunity has received more and more attention. However, the current research on CCR8 in the immune microenvironment of ovarian cancer has not been clear. METHODS: Bioinformatics analysis was used to compare the transcriptome differences between CD4+ T cells in the peripheral circulation and infiltrated in ovarian tumor tissues. RT-PCR was used to detect the expression levels of chemokine receptor-related differential genes on CD4+ T cells in peripheral blood and ovarian tumor tissues. Multiparameter flow cytometry was used to detect the proportion and phenotypic characteristics of CD4+CCR8+ Tregs and CD4+CCR8- Tregs in different sample types. The expression level of CCR8 ligands was detected at multiple levels. To explore the important role of CCR8-CCL1 and CCR8-CCL18 axis in the migration and invasion of CD4+CCR8+ Tregs into ovarian tumor tissues by establishing a chemotaxis system in vitro. RESULTS: In this study, significantly different gene expression profiles were found between peripheral circulating CD4+ T cells and infiltrating CD4+ T cells in ovarian tumor tissues, in which chemokine-chemokine receptor signaling pathway was significantly enriched in all three groups of differential genes. The expression level of CCR8 in infiltrating CD4+ T cells of ovarian cancer tissue was significantly higher than that in peripheral blood of healthy controls and ovarian cancer patients, and high expression of CCR8 was significantly correlated with advanced tumor stage and poor differentiation. CD4+CCR8+ Tregs are the main type of infiltrating CD4+ Tregs in ovarian tumor tissues, which have stronger immunosuppressive phenotypes, secrete more inhibitory cytokines and have stronger proliferation ability. The ligands CCL1 and CCL18 corresponding to CCR8 were significantly overexpressed in ovarian tumor tissues, and the CCR8-CCL1 and CCR8-CCL18 axis played a key role in the migration and infiltration of CD4+CCR8+ Tregs into ovarian tumor tissues. CONCLUSIONS: The results of this study may help to understand the phenotypic characteristics and recruitment process of Tregs in the tumor, and provide new ideas for improving the immunosuppressive status of the ovarian cancer microenvironment.

Carbon and hydrogen isotopic evidence for atrazine degradation by electro-activated persulfate: Radical contributions and comparisons with heat-activated persulfate.

The activation ways of persulfate (PS) were dominate for pollutant degradation and energy consumption. For the first time, this research compared electro-activated PS and heat-activated PS from the perspective of isotope fractionation, in order to "fingerprinted" and precisely interpretate reaction contributions and degradation pathways. As results, PS can be electrochemically activated with atrazine (ATZ) removal rates of 84.8% and 88.8% at pH 4 and 7. The two-dimensional isotope plots (ɅC/H) values were 6.20 at pH 4 and 7.46 at pH 7, rather different from that of SO4·- -dominated process with ɅC/H value of -4.80 at pH 4 and -23.0 at pH 7, suggesting the weak contribution of SO4·-. ATZ degradation by electro-activated PS was controlled by direct electron transfer (DET) and ·OH radical, and ·OHPS (derived from PS activation) played the crucial role with contributing rate of 63.2%-69.1%, while DET and ·OHBDD (derived from electrolysis of H2O) contributed to 4.5-7.9% and 23.0%-30.8%, respectively. This was different from heat activation of PS, of which the latter was dominated by SO4·- with contributions of 83.9%-100%. The discrepant dominating reactive oxygen species should be responsible for their different degradation capabilities and pathways. This research provided isotopic interpretations for differences of PS activation mode, and further efforts can be made to realize the selective degradation by enhancing the specific reaction process.

Pan-genome analysis of 13 Malus accessions reveals structural and sequence variations associated with fruit traits.

Structural variations (SVs) and copy number variations (CNVs) contribute to trait variations in fleshy-fruited species. Here, we assemble 10 genomes of genetically diverse Malus accessions, including the ever-green cultivar 'Granny Smith' and the widely cultivated cultivar 'Red Fuji'. Combining with three previously reported genomes, we assemble the pan-genome of Malus species and identify 20,220 CNVs and 317,393 SVs. We also observe CNVs that are positively correlated with expression levels of the genes they are associated with. Furthermore, we show that the noncoding RNA generated from a 209 bp insertion in the intron of mitogen-activated protein kinase homology encoding gene, MMK2, regulates the gene expression and affects fruit coloration. Moreover, we identify overlapping SVs associated with fruit quality and biotic resistance. This pan-genome uncovers possible contributions of CNVs to gene expression and highlights the role of SVs in apple domestication and economically important traits.