Prediction of acute toxicity for Chlorella vulgaris caused by tire wear particle-derived compounds using quantitative structure-activity relationship models.

Tire wear particles (TWPs) enter aquatic ecosystems through various pathways, such as rainwater and urban runoff. Additives in TWPs can harm aquatic organisms in these ecosystems. Therefore, it is essential to investigate their toxicity to aquatic organisms. In our study, we initially recorded the median effective concentrations of 21 TWP-derived compounds on Chlorella vulgaris growth, ranging from 0.04 to 8.60 mg/L. Subsequently, through an extensive review of the literature, we incorporated 112 compounds with specific toxicity endpoints to construct the QSAR model using genetic algorithm and multiple linear regression techniques, followed by the construction of the consensus model and the quantitative read-across structure-activity relationship (q-RASAR) model. Meanwhile, we employed rigorous internal and external validation measures to assess the performance of the model. The results indicated that the developed q-RASAR model exhibited strong adaptation, robustness, and reliable prediction, with q-RASAR indicators of Q2LOO = 0.7673, R2tr = 0.8079, R2test = 0.8610, Q2Fn = 0.8285-0.8614, and CCCtest = 0.9222. Based on an external dataset containing 128 emerging TWP-derived compounds, the model's applicability domain coverage was 90.6 %. The q-RASAR model predicted that the structure of diphenylamine was associated with higher toxicity, possibly liked to the SpMax2_Bhm and LogBCF descriptors. The established model reliably provides prediction and fills a critical data gap. These findings highlight the potential risks posed by emerging TWP-derived compounds to aquatic organisms.

Neurological impairment is crucial for tire rubber-derived contaminant 6PPDQ-induced acute toxicity to rainbow trout.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPDQ) has attracted significant attention due to its highly acute lethality to sensitive salmonids. However, studies investigating the mechanisms underlying its acute toxicity have been lacking. In this work, we demonstrated the sensitivity of rainbow trout to 6PPDQ-induced mortality. Moribund trout exhibited significantly higher brain concentrations of 6PPDQ compared to surviving trout. In an in vitro model using human brain microvascular endothelial cells, 6PPDQ can penetrate the blood-brain barrier and enhance blood-brain barrier permeability without compromising cell viability. The time spent in the top of the tank increased with rising 6PPDQ concentrations, as indicated by locomotion behavior tests. Furthermore, 6PPDQ influenced neurotransmitter levels and mRNA expression of neurotransmission-related genes in the brain and exhibited strong binding affinity to target neurotransmission-related proteins using computational simulations. The integrated biomarker response value associated with neurotoxicity showed a positive linear correlation with trout mortality. These findings significantly contribute to filling the knowledge gap between neurological impairments and apical outcomes, including behavioral effects and mortality, induced by 6PPDQ.

Metabolic engineering of Escherichia coli for 2,4-dinitrotoluene degradation.

2,4-Dinitrotoluene (2,4-DNT) as a common industrial waste has been massively discharged into the environment with industrial wastewater. Due to its refractory degradation, high toxicity, and bioaccumulation, 2,4-DNT pollution has become increasingly serious. Compared with the currently available physical and chemical methods, in situ bioremediation is considered as an economical and environmentally friendly approach to remove toxic compounds from contaminated environment. In this study, we relocated a complete degradation pathway of 2,4-DNT into Escherichia coli to degrade 2,4-DNT completely. Eight genes from Burkholderia sp. strain were re-synthesized by PCR-based two-step DNA synthesis method and introduced into E. coli. Degradation experiments revealed that the transformant was able to degrade 2,4-DNT completely in 12 h when the 2,4-DNT concentration reached 3 mM. The organic acids in the tricarboxylic acid cycle were detected to prove the degradation of 2,4-DNT through the artificial degradation pathway. The results proved that 2,4-DNT could be completely degraded by the engineered bacteria. In this study, the complete degradation pathway of 2,4-DNT was constructed in E. coli for the first time using synthetic biology techniques. This research provides theoretical and experimental bases for the actual treatment of 2,4-DNT, and lays a technical foundation for the bioremediation of organic pollutants.

Authentication of recycled and virgin polyethylene terephthalate based on UPLC-Q-TOF-MS using non-volatile organic compounds and chemometrics.

Plastic packaging waste, such as polyethylene terephthalate (PET) has increased significantly in recent decades, arousing a considerable and serious public concern regarding the environment, economy, and policy. Plastic recycling is a useful tool to mitigate this issue. Here, a feasible study was performed to investigate the potential of a novel method for identifying virgin and recycled PET. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was combined with various chemometrics, as a simple and reliable method that achieved a high discrimination rate for 105 batches of virgin PET (v-PET) and recycled PET (r-PET) based on 202 non-volatile organic compounds (NVOCs). Making use of orthogonal partial least-squares discrimination analysis (OPLS-DA) together with non-parametric tests, 26 marker compounds (i.e. 12 intentionally added substances (IAS) and 14 non-intentionally added substances (NIAS) as well as 31 marker compounds (i.e. 11 IAS and 20 NIAS) obtained from positive and combination of positive and negative ionization modes of UPLC-Q-TOF-MS, respectively, were successfully identified. Moreover, 100% accuracy was obtained using a decision tree (DT). Cross-discrimination based on misclassified samples using various chemometrics allowed the prediction accuracy to be improved and to identify a large sample set, thus greatly enhancing the application scope of this method. The possible origins of these detected compounds can be the plastic itself, as well as contamination from food, medicine, pesticides, industry-related substances, and degradation and polymerization products. As many of these compounds are toxic, especially those pesticide related, this indicates an urgent requirement for closed loop recycling. Overall, this analytical method provides a quick, accurate, and robust way to distinguish virgin from recycled PET and thus addresses the issue of potential virgin PET adulteration thereby detecting fraud in the area of PET recycling.

Identifying potential toxic organic substances in leachates from tire wear particles and their mechanisms of toxicity to Scenedesmus obliquus.

Tire wear particles (TWPs) are increasingly being found in the aquatic environment. However, there is limited information available on the environmental consequences of TWP constituents that may be release into water. In this study, TWP leachate samples were obtained by immersing TWPs in ultrapure water. Using high-resolution mass spectrometry and toxicity identification, we identified potentially toxic organic substances in the TWP leachates. Additionally, we investigated their toxicity and underlying mechanisms. Through our established workflow, we structurally identified 13 substances using reference standards. The median effective concentration (EC50) of TWP leachates on Scenedesmus obliquus growth was comparable to that of simulated TWP leachates prepared with consistent concentrations of the 13 identified substances, indicating their dominance in the toxicity of TWP leachates. Among these substances, cyclic amines (EC50: 1.04-3.65 mg/L) were found to be toxic to S. obliquus. We observed significant differential metabolites in TWP leachate-exposed S. obliquus, primarily associated with linoleic acid metabolism and purine metabolism. Oxidative stress was identified as a crucial factor in algal growth inhibition. Our findings shed light on the risk posed by TWP leachable substances to aquatic organisms.

Adsorption of 2-hydroxynaphthalene, naphthalene, phenanthrene, and pyrene by polyvinyl chloride microplastics in water and their bioaccessibility under in vitro human gastrointestinal system.

The interaction of microplastics (MPs) and organic pollutants has recently become a focus of investigation. To understand how microplastic residues affect the migration of organic pollutants, it is necessary to examine the adsorption and desorption behavior of organic pollutants on MPs. In this study, integrated adsorption/desorption experiments and theoretical calculations were used to clarify the adsorption mechanism of 2-hydroxynaphthalene (2-OHN), naphthalene (NAP), phenanthrene (PHE), and pyrene (PYR) by polyvinyl chloride microplastics (PVC-MPs). Based on the phenomenological mathematical models, the rate-limiting step for analyte adsorption onto PVC-MPs was adsorption onto active sites (R2 = 0.865-0.995). Except for PHE, analyte adsorption isotherms were well described by the Freundlich model (R2 = 0.992-0.998), and adsorption thermodynamics showed that analyte adsorption on PVC-MPs was a spontaneous exothermic process (ΔH0 < 0; ΔG0 < 0). Based on the order of adsorption efficiency of 2-OHN < NAP < PHE < PYR, which is identical to the competitive adsorption experiment, polycyclic aromatic hydrocarbon (PAH) adsorption on PVC-MPs increased as the aromatic ring number increased and the hydroxyl content decreased. The release of 2-OHN (49 %-52 %) from PVC-MPs into the simulated gastrointestinal environment was greater than that of NAP (5.5 %-5.7 %). Theoretical calculations and adsorption tests indicated that hydrophobic interaction was the primary influence on the adsorption of PAHs and their hydroxylated derivatives by PVC-MPs. These findings improve our understanding of MPs' behavior and dangers as pollutant carriers in the aquatic environment and help us develop recommendations for the pollution control of MPs.

Multigene manipulation of photosynthetic carbon metabolism enhances the photosynthetic capacity and biomass yield of cucumber under low-CO2 environment.

Solar greenhouses are important in the vegetable production and widely used for the counter-season production in the world. However, the CO2 consumed by crops for photosynthesis after sunrise is not supplemented and becomes chronically deficient due to the airtight structure of solar greenhouses. Vegetable crops cannot effectively utilize light resources under low-CO2 environment, and this incapability results in reduced photosynthetic efficiency and crop yield. We used cucumber as a model plant and generated several sets of transgenic cucumber plants overexpressing individual genes, including ß-carbonic anhydrase 1 (CsßCA1), ß-carbonic anhydrase 4 (CsßCA4), and sedoheptulose-1,7-bisphosphatase (CsSBP); fructose-1,6-bisphosphate aldolase (CsFBA), and CsßCA1 co-expressing plants; CsßCA4, CsSBP, and CsFBA co-expressing plants (14SF). The results showed that the overexpression of CsßCA1, CsßCA4, and 14SF exhibited higher photosynthetic and biomass yield in transgenic cucumber plants under low-CO2 environment. Further enhancements in photosynthesis and biomass yield were observed in 14SF transgenic plants under low-CO2 environment. The net photosynthesis biomass yield and photosynthetic rate increased by 49% and 79% compared with those of the WT. However, the transgenic cucumbers of overexpressing CsFBA and CsSBP showed insignificant differences in photosynthesis and biomass yield compared with the WT under low-CO2.environment. Photosynthesis, fluorescence parameters, and enzymatic measurements indicated that CsßCA1, CsßCA4, CsSBP, and CsFBA had cumulative effects in photosynthetic carbon assimilation under low-CO2 environment. Co-expression of this four genes (CsßCA1, CsßCA4, CsSBP, and CsFBA) can increase the carboxylation activity of RuBisCO and promote the regeneration of RuBP. As a result, the 14SF transgenic plants showed a higher net photosynthetic rate and biomass yield even under low-CO2environment.These findings demonstrate the possibility of cultivating crops with high photosynthetic efficiency by manipulating genes involved in the photosynthetic carbon assimilation metabolic pathway.

Azole-Induced Color Vision Deficiency Associated with Thyroid Hormone Signaling: An Integrated In Vivo, In Vitro, and In Silico Study.

Azoles that are used in pesticides, pharmaceuticals, and personal care products can have toxic effects on fish. However, there is no information regarding azole-induced visual disorder associated with thyroid disruption. We evaluated changes in retinal morphology, optokinetic response, transcript abundance of the genes involved in color perception and hypothalamic-pituitary-thyroid (HPT) axis, and thyroid hormone (TH) levels in zebrafish larvae exposed to common azoles, such as climbazole (CBZ, 0.1 and 10 µg/L) and triadimefon (TDF, 50 and 500 µg/L), at environmentally relevant and predicted worst-case environmental concentrations. Subsequently, the effect of azoles on TH-dependent GH3 cell proliferation and thyroid receptor (TR)-regulated transcriptional activity, as well as the in silico binding affinity between azoles and TR isoforms, was investigated. Azole exposure decreased cell densities of the ganglion cell layer, inner nuclear layer, and photoreceptor layer. Zebrafish larvae exposed to environmentally relevant concentrations of CBZ and TDF showed a decrease in optokinetic response to green-white and red-white stripes but not blue-white stripes, consistent with disturbance in the corresponding opsin gene expression. Azole exposure also reduced triiodothyronine levels and concomitantly increased HPT-related gene expression. Molecular docking analysis combined with in vitro TR-mediated transactivation and dual-luciferase reporter assays demonstrated that CBZ and TDF exhibited TR antagonism. These results are comparable to those obtained from a known TR antagonist, namely, TR antagonist 1, as a positive control. Therefore, damage to specific color perception by azoles appears to result from lowered TH signaling, indicating the potential threat of environmental TH disruptors to the visual function of fish.

The protective effects of taurine and fish oil supplementation on PM2.5-induced heart dysfunction among aged mice: A random double-blind study.

As it is nearly impossible to reduce PM2.5 concentrations in most cities to safe limits in a short period of time, dietary supplementation presents a promising approach for mitigating the adverse effects of PM2.5 exposure. A cross-sectional study showed that the elderly population of Linfen (PM2.5: 102 µg/m3) exhibited significantly lower serum taurine levels, as well as higher oxidative stress levels and cardiovascular health risks, than the corresponding population in Guangzhou (PM2.5: 39 µg/m3). We conducted a random double-blind study on aged mice that employed a "real-world" PM2.5 exposure system to simulate the conditions of Linfen with the aim of investigating the protective effects of taurine and fish oil supplementation on PM2.5-induced heart dysfunction. When compared with the placebo group, supplementation with taurine and fish oil not only maintained normal taurine levels, but also suppressed oxidative stress and inflammation in aged mice subjected to high concentrations of PM2.5. Variations in heart rate, contractile function, cardiac oxidative stress, inflammation and fibrosis among different groups of aged mice were used to clarify the beneficial effects of taurine and fish oil supplementation. Our results not only revealed the protective effects of taurine and fish oil supplementation on heart dysfunction induced by PM2.5 exposure from the aged mice experiments and also provided new means for the elderly to resist PM2.5 pollution at the individual level.

Short term outcomes of extremely low birth weight infants from a multicenter cohort study in Guangdong of China.

With the increase in extremely low birth weight (ELBW) infants, their outcome attracted worldwide attention. However, in China, the related studies are rare. The hospitalized records of ELBW infants discharged from twenty-six neonatal intensive care units in Guangdong Province of China during 2008-2017 were analyzed. A total of 2575 ELBW infants were enrolled and the overall survival rate was 55.11%. From 2008 to 2017, the number of ELBW infants increased rapidly from 91 to 466, and the survival rate improved steadily from 41.76% to 62.02%. Increased survival is closely related to birth weight (BW), regional economic development, and specialized hospital. The incidence of complications was neonatal respiratory distress syndrome (85.2%), oxygen dependency at 28 days (63.7%), retinopathy of prematurity (39.3%), intraventricular hemorrhage (29.4%), necrotizing enterocolitis (12.0%), and periventricular leukomalacia (8.0%). Among the 1156 nonsurvivors, 90.0% of infants died during the neonatal period (≤ 28 days). A total of 768 ELBW infants died after treatment withdrawal, for reasons of economic and/or poor outcome. The number of ELBW infants is increasing in Guangdong Province of China, and the overall survival rate is improving steadily.

The effects of continuous renal replacement therapy with different anticoagulation methods on the expression of cytokines in severe acute pancreatitis.

OBJECTIVE: Severe acute pancreatitis (SAP) is a highly morbid condition in general population as well as in solid organ transplant (SOT) recipients. The present study aimed to investigate the effect of continuous renal replacement therapy (CRRT) with different anticoagulation methods on the expression levels of cytokines in SAP. METHODS: A total of 120 patients with SAP, admitted into our hospital between September 2017 and July 2020, were enrolled as the research subjects and randomly divided into a control group (60 cases) and a study group (60 cases). CRRT with low molecular weight (LMW) heparin­calcium anticoagulation was conducted on patients in the control group, and CRRT with topical citrate + low-dose LMW heparin­calcium anticoagulation was conducted on patients in the study group. The expressions of cytokines in the two groups were compared after treatment. RESULTS: There was no significant difference in white blood cells (WBC), C-reactive proteins (CRP), and procalcitonin (PCT) before treatment between the two groups (P > 0.05). After treatment, the levels of WBC (P = 0.006), CRP (P < 0.001), and PCT (P < 0.001) were significantly lower in the study group when compared with those in the control group. There was no significant difference in the concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) between the two groups before treatment (P > 0.05). After treatment, the concentrations of IL-6, IL-8, and TNF-α were significantly lower in the study group when compared with those in the control group. The APACHEII, SOFA and Ranson scores of the two groups were analyzed, and there was no difference between the two groups before treatment (P > 0.05). After treatment, the score of the study group was lower than that of the control group (P < 0.05). CONCLUSION: CRRT with topical citrate + low-dose LMW heparin­calcium anticoagulation in the treatment of patients with SAP reduces the levels of WBC, CRP, and PCT and the concentrations of cytokines, including IL-6, IL-8, and TNF-α. This inhibits the release of inflammatory mediators in patients with SAP and reduces damage to the body caused by the inflammatory response, thus effectively improving the patients' condition.

A QuEChERS-based UPLC-MS/MS method for rapid determination of organophosphate flame retardants and their metabolites in human urine.

Organophosphate flame retardants (OPFRs) have been widely used in consumer products to prevent fire spread. However, once released into the atmospheric environment, they may accumulate in humans and undergo metabolic transformation and excretion by urine. In order to clarify the human exposure to OPFRs, a quick, easy, cheap, effective, rugged, and safe method for the simultaneous determination of urinary OPFRs and their metabolites by ultra-performance liquid chromatography-tandem triple quadrupole mass spectrometry was developed. After the optimization by a single-factor or orthogonal experiment, the satisfactory recovery (87.8-119%), matrix effect (-8.88-9.29%), method quantitation limit (3.66-159 ng/L), and inter-day repeatability (1.24 - 10.6%) of most analytes were achieved in artificial urine samples. Based on a monitoring test by the developed method, we propose that urinary bis(1-chloro-2-propyl) phosphate and di-p-cresyl phosphate could be used to trace human exposure to tris(1-chloro-2-propyl) phosphate and tricresyl phosphate, respectively. Most importantly, this is the first study to reveal that 4-hydroxyphenyl diphenyl phosphate (4-OH-TPHP) was dominantly presented in its conjugated form rather than its free form in urine (p = 0.037). Overall, the obtained results contribute a relatively rapid method to help conduct large-scale urine monitoring for revealing the human exposure and risk of OPFRs.

Clinical treatment outcomes and their changes in extremely preterm twins: a multicenter retrospective study in Guangdong Province, China. / è¶ æœªæˆç†ŸåŒèƒŽå„¿ä¸´åºŠæ•‘æ²»ç»“å±€åŠå˜åŒ–åˆ†æžï¼šä¸€é¡¹å¹¿ä¸œçœå¤šä¸­å¿ƒå›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of <28 weeks who were admitted to the department of neonatology in 26 grade A tertiary hospitals in Guangdong Province from January 2008 to December 2017. According to the admission time, they were divided into two groups: 2008-2012 and 2013-2017. Besides, each pair of twins was divided into the heavier infant and the lighter infant subgroups according to birth weight. The perinatal data of mothers and hospitalization data of neonates were collected. The survival rate of twins and the incidence rate of complications were compared between the 2008-2012 and 2013-2017 groups. RESULTS: Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of severe asphyxia and smaller head circumference at birth (P<0.05). The mortality rates of both of the twins, the heavier infant of the twins, and the lighter infant of the twins were lower in the 2013-2017 group compared with the 2008-2012 group (P<0.05). Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of pulmonary hemorrhage, patent ductus arteriosus (PDA), periventricular-intraventricular hemorrhage (P-IVH), and neonatal respiratory distress syndrome (NRDS) and a higher incidence rate of bronchopulmonary dysplasia (P<0.05). CONCLUSIONS: There is a significant increase in the survival rate over time in extremely preterm twins with a gestational age of <28 weeks in the 26 grade A tertiary hospitals in Guangdong Province. The incidences of severe asphyxia, pulmonary hemorrhage, PDA, P-IVH, and NRDS decrease in both the heavier and lighter infants of the twins, but the incidence of bronchopulmonary dysplasia increases. With the improvement of diagnosis and treatment, the multidisciplinary collaboration between different fields of fetal medicine including prenatal diagnosis, obstetrics, and neonatology is needed in the future to jointly develop management strategies for twin pregnancy.

Manipulation of Skyrmion Motion Dynamics for Logical Device Application Mediated by Inhomogeneous Magnetic Anisotropy.

Magnetic skyrmions are promising potential information carriers for future spintronic devices owing to their nanoscale size, non-volatility and high mobility. In this work, we demonstrate the controlled manipulation of skyrmion motion and its implementation in a new concept of racetrack logical device by introducing an inhomogeneous perpendicular magnetic anisotropy (PMA) via micromagnetic simulation. Here, the inhomogeneous PMA can be introduced by a capping nano-island that serves as a tunable potential barriers/well which can effectively modulate the size and shape of isolated skyrmion. Using the inhomogeneous PMA in skyrmion-based racetrack enables the manipulation of skyrmion motion behaviors, for instance, blocking, trapping or allowing passing the injected skyrmion. In addition, the skyrmion trapping operation can be further exploited in developing special designed racetrack devices with logic AND and NOT, wherein a set of logic AND operations can be realized via skyrmion-skyrmion repulsion between two skyrmions. These results indicate an effective method for tailoring the skyrmion structures and motion behaviors by using inhomogeneous PMA, which further provide a new pathway to all-electric skyrmion-based memory and logic devices.

Pollution characteristics, exposure assessment and potential cardiotoxicities of PM2.5-bound benzotriazole and its derivatives in typical Chinese cities.

Benzotriazole and its derivatives (BTRs), classified as high-volume production chemicals, have been widely detected in various environmental media, including the atmosphere, water, soil and dust, as well as organisms. However, studies on the pollution characteristics and health impact of PM2.5 related BTRs are so far limited. This study is the first to demonstrate the regional scale distribution of PM2.5-bound BTRs and their potential cardiotoxicities. Optimized methods of extraction, purification and GC-EI-MS/MS were applied to characterize and analyze PM2.5-bound BTRs from three cities in China during the winter of 2018. The concentration of ∑BTRs in Taiyuan (6.28 ng·m-3) was more than three times that in Shanghai (1.53 ng·m-3) and Guangzhou (1.99 ng·m-3). Benzotriazole (BTR) and 5-methyl-1H-benzotriazole (5TTR) contributed more than 80% of ∑BTRs concentration as the major pollutants among three cities. The correlation analysis indicated that there was a positive correlation between temperature and concentration of BTR and a negative correlation between temperature and concentration of 5TTR. In addition, the risk of BTRs exposure to toddlers should be paid more attention in Taiyuan by the human exposure assessment. Furthermore, toxicity screening by experimental methods indicated that 4-methyl-1H-benzotriazole (4TTR) was the most harmful to cardiomyocytes. The western blot assay showed a ROS-mediated mitochondrial apoptosis signaling pathway was activated after exposure to 4TTR in neonatal rat cardiomyocytes (NRCMs). On the other hand, metabolomics revealed that exposure of 4TTR to NRCMs disturbed mitochondrial energy metabolism by disturbing pantothenate and coenzyme A synthesis pathway. Our study not only clarifies the contamination profiles of PM2.5-bound BTRs in typical Chinese cities but also reveals their cardiotoxicities associated with mitochondrial dysfunction.

P300/CBP inhibition sensitizes mantle cell lymphoma to PI3Kδ inhibitor idelalisib.

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder lacking reliable therapies. PI3K pathway contributes to the pathogenesis of MCL, serving as a potential target. However, idelalisib, an FDA-approved drug targeting PI3Kδ, has shown intrinsic resistance in MCL treatment. Here we report that a p300/CBP inhibitor, A-485, could overcome resistance to idelalisib in MCL cells in vitro and in vivo. A-485 was discovered in a combinational drug screening from an epigenetic compound library containing 45 small molecule modulators. We found that A-485, the highly selective catalytic inhibitor of p300 and CBP, was the most potent compound that enhanced the sensitivity of MCL cell line Z-138 to idelalisib. Combination of A-485 and idelalisib remarkably decreased the viability of three MCL cell lines tested. Co-treatment with A-485 and idelalisib in Maver-1 and Z-138 MCL cell xenograft mice for 3 weeks dramatically suppressed the tumor growth by reversing the unsustained inhibition in PI3K downstream signaling. We further demonstrated that p300/CBP inhibition decreased histone acetylation at RTKs gene promoters and reduced transcriptional upregulation of RTKs, thereby inhibiting the downstream persistent activation of MAPK/ERK signaling, which also contributed to the pathogenesis of MCL. Therefore, additional inhibition of p300/CBP blocked MAPK/ERK signaling, which rendered maintaining activation to PI3K-mTOR downstream signals p-S6 and p-4E-BP1, thus leading to suppression of cell growth and tumor progression and eliminating the intrinsic resistance to idelalisib ultimately. Our results provide a promising combination therapy for MCL and highlight the potential use of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumor.

Comparison of the ability of UV-Vis and UPLC-Q-TOF-MS combined with chemometrics to discriminate recycled and virgin polyethylene.

A growing attention is attracted to the use of recycled plastics as food contact materials, and its chemical safety research and discrimination approach are indispensable. In current study, ultraviolet-visible spectrometry (UV-Vis) and ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) were used to provide spectral and mass fingerprinting for polyethylene (PE). Coupling with chemometrics, two methods were developed to discriminate recycled and virgin PE. UV-Vis combined with chemometrics could be a more accessible, simpler and faster approach. 237-331 nm in UV spectrum was regarded as marker region selected by orthogonal partial least-squares discrimination analysis (OPLS-DA) and the accuracy of both calibration and validation set could reach 100% in linear discrimination analysis (LDA) based on this region. Besides, 2314 ions were detected by UPLC-Q-TOF-MS and processed by MS-DIAL. 48 candidate chemicals were identified, including ketone, esters, carboxylic acid, alcohols and phenols, amine, nitriles, aldehydes and others. Possible origins of these compounds could be classified as plastic, food, drug, cosmetics and pesticide related. Many of these compounds are highly toxic, especially pesticide related, indicating that recycling in closed loop or sorting by the recycled plastic articles is very necessary if the recycled PE is going to be used as food contact material.

Investigation of PM2.5 pollution during COVID-19 pandemic in Guangzhou, China.

The COVID-19 pandemic has raised awareness about various environmental issues, including PM2.5 pollution. Here, PM2.5 pollution during the COVID-19 lockdown was traced and analyzed to clarify the sources and factors influencing PM2.5 in Guangzhou, with an emphasis on heavy pollution. The lockdown led to large reductions in industrial and traffic emissions, which significantly reduced PM2.5 concentrations in Guangzhou. Interestingly, the trend of PM2.5 concentrations was not consistent with traffic and industrial emissions, as minimum concentrations were observed in the fourth period (3/01-3/31, 22.45 µg/m3) of the lockdown. However, the concentrations of other gaseous pollutants, e.g., SO2, NO2 and CO, were correlated with industrial and traffic emissions, and the lowest values were noticed in the second period (1/24-2/03) of the lockdown. Meteorological correlation analysis revealed that the decreased PM2.5 concentrations during COVID-19 can be mainly attributed to decreased industrial and traffic emissions rather than meteorological conditions. When meteorological factors were included in the PM2.5 composition and backward trajectory analyses, we found that long-distance transportation and secondary pollution offset the reduction of primary emissions in the second and third stages of the pandemic. Notably, industrial PM2.5 emissions from western, southern and southeastern Guangzhou play an important role in the formation of heavy pollution events. Our results not only verify the importance of controlling traffic and industrial emissions, but also provide targets for further improvements in PM2.5 pollution.

Chronic Exposure to Climbazole Induces Oxidative Stress and Sex Hormone Imbalance in the Testes of Male Zebrafish.

As the main active ingredient for the treatment of fungal infections, climbazole (CBZ) is commonly used in a variety of personal care products. After its use, CBZ enters the receiving environment directly or indirectly through domestic sewage. Its concentration can be up to several nanograms per liter in surface water. So far, the effects of CBZ on the reproductive system of female zebrafish have been systematically studied, but the potential toxicity mechanism of CBZ on male zebrafish still needs to be further explored. In this study, adult male zebrafish were exposed to CBZ at concentrations of 0.1, 10, and 1000 µg·L-1 for 28 days, and their testes were collected for histological, mass-spectrometry-based metabolomics, and biochemical analyses. We found that CBZ caused a significantly abnormal metabolism of purine and glutathione and triggered oxidative stress in zebrafish testes, thereby inducing testicular cell apoptosis. In addition, CBZ could inhibit the synthesis of essential sex hormones in the testis and thus reduce the sperm production. The conclusions of this study fill the data gap on the reproductive toxicity of CBZ to male zebrafish and highlight the ecotoxicological application of untargeted metabolomics in the biomarker discovery.

Occurrence, removal and mass loads of antiviral drugs in seven wastewater treatment plants with various treatment processes.

Antiviral drugs are among the most common and important classes of pharmaceuticals to treat viral infections, however their continuous emission and persistence in the receiving environment has attracted increasing attention about their potential ecological risks. Here we investigated the occurrence, fate and mass load of 9 antiviral drugs for acquired immunodeficiency syndrome and hepatitis B, in 7 wastewater treatment plants (WWTPs) with different treatment processes in Guangdong, China. Totally, 8 target antiviral drugs were detected in the WWTPs influent wastewater, effluent wastewater and sludge, with maximal concentrations up to 7624 ng/L (telbivudine), 568 ng/L (telbivudine), and 2013 ng/g wet weight (telbivudine), respectively. The removal efficiency varied widely between different antiviral drugs, with the mean aqueous removal efficiency and total removal efficiency ranging from -6.2% (nevirapine) to 100% (lamivudine) and -1.2% (nevirapine) to 100% (lamivudine), respectively. Mass balance analysis showed that their elimination was mostly attributed to the biodegradation/biotransformation. The total back-estimated usage and emission of 9 target antiviral drugs were 77.8 t/y and 13.2 t/y in Guangdong province, China, respectively. Based on the sewage epidemiology approach, the consumption and emission of antiviral drugs in seven studied WWTPs were ranged at 2.31 mg/d/1000 people (nevirapine) to 4970 mg/d/1000 people (telbivudine), and 0 (lamivudine) to 900 mg/d/1000 people (telbivudine), respectively. Preliminary risk assessment showed that the antiviral drugs of zidovudine, ritonavir, lopinavir, and telbivudine in the receiving rivers could pose high ecological risks for aquatic environment. The findings from the present study illustrate the persistence of nevirapine in WWTPs, and provide essential evidence for further study into the development of wastewater treatment technologies.