Search

The carbon emissions trading (CET) policy internalises the cost of carbon emission reductions borne by companies, which will affect the companies' investment and management decisions. From a micro perspective, this paper analyzes the impact on company investment expenditure and its transmission mechanism by implementing the CET policy. Based on panel data of China's A-share listed companies from eight carbon-intensive industries spanning 2010 to 2020, the time-varying difference-in-difference model and its extended model are used to evaluate the impact of the policy in the pilot areas. The results show that: first, based on the cost effect and legality theories, CET policy can reduce the investment expenditure of the companies by 71.95%. Second, CET policy reduces corporate investment expenditures by increasing corporate debt financing costs. When debt financing costs increase by 120.25%, the investment expenditures will reduce by 2.56% indirectly while the intermediary effect of equity financing costs is not significant. Finally, with the implementation of CET policy, the inhibitory effect on corporate investment expenditures has gradually increased. CET policy has a more significant inhibitory effect on investment expenditures of nonstate-owned companies and small-scale companies. The results have passed the robustness test and provide evidence for the policy-maker to balance microeconomic entity development and carbon reduction, and for companies to make optimization investment and financing decisions in response to policy shocks effectively. • The impact of policies is explored from the enterprise level. • A time-varying difference-in-difference model is used to evaluate the impact of China's CET policy. • Results reveal the inhibitory effect of carbon emission trading on corporate investment expenditure. • The mediation effects of debt financing costs and equity financing costs are discussed. • The focus on the discussion of dynamic heterogeneity is provided. [ABSTRACT FROM AUTHOR]

Stroke and major depression disorder are common neurological diseases, and a large number of clinical studies have shown that there is a close relationship between the two diseases, but whether the two diseases are linked at the genetic level needs to be further explored. The purpose of this study was to explore the comorbidity mechanism of stroke and major depression by using bioinformatics technology and animal experiments. From the GEO database, we gathered transcriptome data of stroke and depression mice (GSE104036, GSE131712, GSE81672, and GSE146845) and identified comorbid gene set through edgR and WGCNA analyses. Further analysis revealed that these genes were enriched in pathways associated with cell death. Programmed cell death gene sets (PCDGs) are generated from genes related to apoptosis, necroptosis, pyroptosis and autophagy. The intersection of PCDGs and comorbid gene set resulted in two hub genes, Mlkl and Nlrp3. Single-cell sequencing analysis indicated that Mlkl and Nlrp3 are mainly influential on endothelial cells and microglia, suggesting that the impairment of these two cell types may be a factor in the relationship between stroke and major depression. This was experimentally confirmed by RT–PCR and immunofluorescence staining. Our research revealed that two specific genes, namely, Mlkl and Nlrp3 , play crucial roles in the complex mechanism that links stroke and major depression. Additionally, we have predicted six possible therapeutic agents and the outcomes of docking simulations of target proteins and drug molecules. • The changes of gene expression in brain tissues of stroke and major depression have some overlap. • Programmed cell death plays an important role in molecular interactions between stroke and major depression. • Mlkl and Nlrp3 are the hub genes involved in the comorbidity mechanism of stroke and major depression. • Necroptosis and pyroptosis of endothelial cells and microglia are common pathological changes of stroke and major depression. [ABSTRACT FROM AUTHOR]

Abstract Pesticides and medications have adverse effects in non-target organisms that can lead to different modes of action (MOAs). However, no study has been performed to compare the MOAs between different levels of aquatic species. In this study, theoretical equations of interspecies relationship and excess toxicity have been developed and used to investigate the MOAs among fish, Daphnia magna, Tetrahymena pyriformis and Vibrio fischeri for pesticides and medications. The analysis on the interspecies correlation and excess toxicity suggested that fungicides, herbicides and medications share the similar MOAs among the four species. On the other hand, insecticides share different MOAs among the four species. Exclusion of insecticides from the interspecies correlation can significantly improve regression coefficient. Interspecies relationship is dependent not only on the difference in interaction of chemicals with the target receptor(s), but also on the difference in bio-uptake between two species. The difference in physiological structures will result in the difference in bioconcentration potential between two different trophic levels of organisms. Increasing of molecular size or hydrophobicity will increase the toxicity to higher level of aquatic organisms; on the other hand, chemical ionization will decrease the toxicity to higher level organisms. Hydrophilic compounds can more easily pass through cell membrane than skin or gill, leading to greater excess toxicity to Vibrio fischeri , but not to fish and Daphnia magna. Graphical abstract Image 1 Highlights • Theoretical interspecies correlation equation has been developed based on the toxic mechanism. • Fungicides, herbicides and medications share same modes of action to four aquatic organisms. • Insecticides share different mode of actions between species. • Molecular size, hydrophobicity, acidity and ionization affect interspecies correlation. [ABSTRACT FROM AUTHOR]

Abstract Floxuridine (5'-fluorodeoxyuridine, FUdR) acts as an inhibitor of DNA replication by binding to thymidylate synthase and is widely used to treat colorectal cancer. FUdR is also frequently used in research on aging in C. elegans since by blocking reproduction it allows maintenance of synchronous nematode populations. Here we examine age-specific effects of exposure to 50 μM FUdR on pathology and mortality. We report that initiating exposure to FUdR at late development or early adulthood reduces lifespan but later initiation increases it. Moreover, earlier initiation leads to enhancement of senescent intestinal atrophy, but amelioration of several other senescent pathologies (pharyngeal degeneration and uterine tumors). These results provide further evidence of the complex effects of FUdR on aging in C. elegans , and therefore support the argue against its routine use in studies of nematode aging due to its possible confounding effects. However, they also illustrate how effects of FUdR on aging are interesting in their own right. Highlights • Opposite effects of FUdR on lifespan in wild-type C. elegans are age-dependent. • FUdR induced decreased tumor size is not the main cause for lifespan changes. • FUdR-accelerated pathologies (intestinal atrophy) contributes to decreased lifespan. • Our results provide a better understanding of FUdR drug action on late-life disease. [ABSTRACT FROM AUTHOR]

Abstract Although mode of action (MOA) plays a key role in the understanding of the toxic mechanism of chemicals, the MOAs of class-based compounds to tadpoles have not been investigated. To explore the MOAs, acute toxicity (expressed as log 1/LC 50) to Rana chensinensis tadpoles were determined and molecular descriptors were calculated. Quantitative structure-activity relationship (QSAR) showed that toxicity to tadpoles is closely related to the chemical octanol/water partition coefficient (log K OW), energy of the lowest unoccupied molecular orbital (E LUMO), and number of hydrogen bond donors and acceptors (NH DA), representing the bio-uptake potential in tadpoles, the electrophilicity and hydrogen bonding capacity with target site(s), respectively. Comparison of the toxicity values between tadpoles and fish revealed that there were no significant differences for the overlapping compounds (average residual = 0.29 between tadpole and fish toxicity) with P values of interspecies correlation substantially less than 0.001. Classification of MOAs for the class-based compounds based on the excess toxicity calculated from toxicity ratio suggested that baseline, less inert compounds and some reactive or specifically-acting compounds share same MOAs between tadpoles and fish. Fish and tadpoles can serve as surrogates for each other in the safety evaluation of organic pollutants. Graphical abstract fx1 Highlights • Tadpole toxicity is related to chemical bio-uptake, electrophilicity and H-bonding capacity. • The toxicity to fish is close to the toxicity to R. chensinensis tadpoles. • Majority of compounds share the same mode of action between tadpoles and fish. • Fish and tadpoles can serve as surrogates for each other in safety evaluation of pollutants. [ABSTRACT FROM AUTHOR]

Abstract Objective As the most prevalent internal modification in mammalian messenger RNA, N6‑methyladenosine (m6A) plays an important role in posttranscriptional gene regulation. METTL3 is a key component of the m6A methyltransferase complex and has recently been shown to play important roles in cancer development and progression. The current study was aimed to explore the function and underlying mechanism of METTL3 in ovarian cancer. Methods METTL3 expression was assessed by immunohistochemistry in 162 ovarian carcinoma patients. Stable cell lines with METTL3 gene overexpression or knockdown were established to investigate the function of METTL3 in ovarian cancer in vitro and in vivo. Results METTL3 was frequently upregulated in ovarian carcinoma and that a high level of METTL3 was significantly associated with tumor grade (P = 0.001), pT status (P = 0.002), pN/pM status (P < 0.001), FIGO stage (P < 0.001), and overall survival rate (P < 0.001). Stable overexpression of METTL3 in the OVCAR3 and COV504 cell lines significantly increased cellular proliferation, focus formation, motility, invasion, and tumor formation in nude mice. Silencing METTL3 expression in the SKOV3 and HO-8910 cell lines with short hairpin RNA effectively inhibited its oncogenic function. Further study found that METTL3 promoted epithelial-mesenchymal transition (EMT) by upregulating the receptor tyrosine kinase AXL. Conclusion Our findings suggest that METTL3 plays very important oncogenic roles in ovarian carcinoma development and/or aggressiveness by stimulating AXL translation and EMT and that METTL3 may serve as a novel prognostic and/or therapeutic target of interest in ovarian cancer. Highlights • METTL3 upregulation is associated with poor overall survival in ovarian carcinoma patients. • METTL3 promotes the proliferation, invasion and tumor formation of ovarian cancer cells. • METTL3 promotes epithelial to mesenchymal transition in ovarian cancer cells. • METTL3 promotes AXL translation independent of its catalytic activity. [ABSTRACT FROM AUTHOR]

Plant polyphenol (PP), a natural polymer from the Larix gmelinii , was selected as the surfactant to synthesize Fe 3 O 4 . The Fe 3 O 4 -PP composite was prepared by in-situ self-assembly in solvothermal synthesis, and characterized using FE-SEM, TEM, XRD, FTIR, XPS, TGA, and VSM. The harvesting efficiency of Chlorella vulgaris was investigated under different parameters, including algal organic matter, dosage, and pH. The results showed that the core-shell sphere of Fe 3 O 4 -PP (∼150 nm) was coated by ∼50 nm PP with a saturated magnetization of 40.0 emu/g. The Fe 3 O 4 -PP could be directly applied to the culture broth (1.5 g dry cell weight/L, pH = 9.03), achieving 93.0% of harvesting efficiency at 20 g/L. Cells were detached from the harvested aggregates by adjusting pH value to 9.80 and with ultrasonication, which achieved 95.6% of recovery efficiency. The recycled Fe 3 O 4 -PP showed high stabilities in surface properties, maintaining more than 87.5% of harvesting efficiency after five recycles. [ABSTRACT FROM AUTHOR]

Sulfur mustard (SM) can be hydrolyzed by haloalkane dehalogenases such as DhaA, LinB and DmbA. However, the low resistance to the elevated temperatures limited the practical application of haloalkane dehalogenases. Here we reported a new thermotolerant dehalogenase FM2382 from Fulvimarina manganoxydans sp. nov. 8047. The specific activity of FM2382 to SM is 0.6 U/mg. FM2382 possessed high heat stability (45 °C) in slight alkali environment (pH 7.5) and retained approximately 50% activity after incubation at 70 °C for 40 min. The catalytic activity of FM2382 was activated by Co 2+ and Mg 2+ , and inhibited by Zn 2+ , Cu 2+ and Fe 3+ . Furthermore, site-specific mutagenesis proved that D34, K207 D232, D237 were amino acid residues related to the catalytic activity of SM. In conclusion, we found a thermostable haloacid dehalogenases (HAD) family dehalogenase showing SM-degradation activity, which may be useful for practical application in the future. [ABSTRACT FROM AUTHOR]

Natural and potent tyrosinase inhibitors are in high demand in the food, cosmetic, and pharmaceutical industries. In this study, the hydrolysate was prepared from the peony (Paeonia ostii) seed meal proteins (PSMP) by Neutrase with high tyrosinase inhibitory activity. The peptide profile analysis exhibited that there were 594 peptides from 28 proteins, among which 39 peptides were predicted to have high bioactivity, good solubility, and non-toxicity, and were suitable for oral or topical administration by in silico analysis. Molecular docking demonstrated that 38 of the 39 peptides can be promising tyrosinase inhibitors as they had lower or the same binding energies as the tyrosinase inhibitor kojic acid. The interaction mechanism analysis for the top 3 potent peptides demonstrated that 5 out of 8 catalytic residues were involved in each interaction, in which hydrogen bonding was crucial for the peptide SFAPRFD, and both hydrogen bonding and hydrophobic interaction were important for peptides HYGR and SPGRLP. As demonstrated by in vitro test, these three peptides were potent tyrosinase inhibitors with IC 50 ranging from 0.95 to 1.58 mmol/L. Our findings highlight that PSMP can be a valuable source of natural tyrosinase inhibitory peptides for various industrial applications. • The Neutrase hydrolysate from PSMP has the highest tyrosinase inhibitory activity. • The peptide profile analysis identified 594 peptides from 28 proteins. • Peptides were screened with bioactivity and favorable physiochemical properties. • Peptides in the hydrolysate had lower binding energy than kojic acid. • The inhibition mechanisms of SFAPRFD, HYGR, and SPGRLP were clarified. [ABSTRACT FROM AUTHOR]

Tris(2-chloroethyl) phosphate (TCEP) has been detected all over the world as a typical refractory organic phosphate, especially in groundwater. This work applied a calcium-rich biochar derived from shrimp shell as a low-cost adsorbent for TCEP removal. Based on the kinetics and isotherm studies, the adsorption of TCEP on biochar was monolayer adsorbed on a uniform surface, with SS1000 (the biochar was prepared at the carbonization temperature of 1000 °C) achieving the maximum adsorption capacity of 264.11 mg·g−1. The prepared biochar demonstrated stable TCEP removal ability throughout a wide pH range, in the presence of co-existing anions, and in diverse water bodies. A rapid removal rate of TCEP was observed during the adsorption process. When the dosage of SS1000 was 0.2 g·L−1, 95% of TCEP could be removed within the first 30 min. The mechanism analysis indicated that the calcium species and basic functional groups on the SS1000 surface were highly involved in the TCEP adsorption process. [Display omitted] • Shrimp shell (SS) was valorized by low-cost pyrolysis. • High temperature biochar exhibited excellent removal performance for TCEP. • TCEP removal mechanisms revealed that basic functional groups and calcium species played key roles. • The hydrolysis of TCEP was promoted through the formation of inner layer complexes (Ca-OP). [ABSTRACT FROM AUTHOR]

Estrogen receptors (Er) play a critical role in vitellogenesis. Three ers ( erα , erβ1 and erβ2 ) and vitellogenins (v tg-A , v tg-B and v tg-C ) subtypes were isolated in various fish species, while the contribution of each Er to the regulation of vtgs expression was not analyzed in detail. Here, erα , erβ1 and erβ2 were cloned and all were found to be expressed in female liver in Scatophagus argus . During proteic vitellogenesis stage, er α was simultaneously up-regulated, while er β 1 and er β 2 were not, with three vtgs in female liver. The effects of 17β-estradiol (E 2 ) alone or combined with Er antagonists on ers , vtgs mRNA expressions and Vtg protein content in incubated male liver were examined by real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. The expressions of erα , erβ1, vtgs mRNA and Vtg protein increased significantly after 24 h incubation with E 2 (0.1, 1 and 10 μM), while Er nonselective antagonist ICI 182 780 (0.01, 0.1 and 1 μM) significantly attenuated the up-regulation effects of E 2 on ers, vtgs mRNA and Vtg protein in a dose-dependent manner. Erα selective antagonist Methyl-piperidinopyrazole (MPP) (0.01, 0.1 and 1 μM) significantly attenuated the up-regulation effects of E 2 on erα , vtg-B , vtg-C mRNA and Vtg protein, while promoted the expression of erβ1 and vtg-A . Erβ selective antagonist Cyclofenil (0.01, 0.1 and 1 μM) attenuated the up-regulation effects of E 2 on erβ1 , erβ2 , vtg-A , vtg-C mRNA and Vtg protein while promoted the expression of erα and vtg-B . Our results suggest that the regulation of Ers on different vtgs was divergent in S. argus . [ABSTRACT FROM AUTHOR]

Based on a growing need for additional dietary sources of choline, this research developed a choline rich cereal based functional food. Egg yolk lipids were extracted using ethanol to produce an egg yolk extract (EYE) of high choline content. Corn meal, wheat flour, sugar, salt and EYE were mixed and extrudates made using a twin-screw extruder with an exit temperature of 120 °C. Products were packaged and stored at −20 °C and room temperature for 12 weeks. Initial processing decreased the total fat and total choline content by up to 30% and 19% respectively. Similarly, tocopherols, tocotrienols and cholesterol decreased after processing. However, the total fat and choline content and tocopherols and tocotrienols did not significantly change during the storage stability study. A shelf-stable choline rich (115 mg/30 g serving) functional food product was developed that could provide a way for consumers to meet their choline requirement. [ABSTRACT FROM AUTHOR]

Abstract: A novel approach to develop colloidosomes with enhanced barrier properties that can reduce the oxidation of encapsulated bioactive compound is described. These novel colloidosomes were stabilized using silica aggregates. Silica aggregates were prepared based on electrostatic complexation between anionic and cationic silica nanoparticles and were subsequently used to stabilize sub-micron scale oil-in-water colloidosomes. Control colloidosomes stabilized using negative charged silica nanoparticles were also prepared. Particle size and ζ-potential results confirmed the formation of silica aggregates. Curcumin was used as a model encapsulant. Fluorescence microscopy results showed that curcumin was encapsulated within the lipid core of the colloidosomes. Curcumin showed significantly higher stability in colloidosomes stabilized by silica aggregates as compared to those stabilized by negative charged silica nanoparticles (p < 0.05). Enhanced stability of curcumin in silica aggregate stabilized colloidosomes could be attributed to higher interfacial thickness of silica aggregates compared to silica nanoparticles. The proposed approach can be a simple and efficient alternative to layer-by-layer assembly of interfacial materials. [Copyright &y& Elsevier]

Acetochlor is one of the most widely used herbicides in the world, however, there are few data on the sub-lethal effects of acetochlor on early developmental stages of fish. To address this, we measured survival, deformity, swim bladder formation, embryo oxygen consumption rates, reactive oxygen species (ROS) levels, transcripts (related to swim bladder formation, oxidative damage response, and apoptosis) and behavior responses following exposure to acetochlor (0.001 µM up to 125 µM). Exposure to acetochlor at concentrations 50 µM and above exerted 100% mortality after 3 dpf, and significantly reduced the size of the swim bladder (25 µM). In embryos, basal respiration, oligomycin-induced ATP production, and maximal respiration were decreased 30–60% following a 24 h exposure to 125 μM acetochlor. Acetochlor did not affect ROS levels up to 25 µM in larvae with acute exposure. Acetochlor at 25 µM increased mRNA levels of bax1 , hsp70 , and hsp90a by ~4-fold in larval zebrafish. In both the visual motor response and light-dark preference test, 25 µM acetochlor increased locomotor activity of larval fish. At lower exposure concentrations, 100 and 1000 nM acetochlor increased the mean time spent in the dark zone, suggesting promotion of anxiolytic behavior. This study presents a comprehensive evaluation of sublethal effects of acetochlor, spanning molecular responses to behavior, which can be used to refine risk assessment decisions for aquatic environments. [Display omitted] • Swim bladder malformation was observed with 25 µM acetochlor exposure. • Oxygen consumption rates were decreased following 24 h exposure to 125 µM acetochlor. • Pro-apoptotic bax 1 and heat shock protein expression were induced by 25 µM acetochlor. • Hyperactivity in larvae was observed following exposure to 25 µM acetochlor. • Concentrations of 100 and 1000 nM acetochlor increased the mean time spent in the dark zone, indicating anxiolytic behavior. [ABSTRACT FROM AUTHOR]

Strobilurin fungicides are among the most widely used in the world and have characteristics that include high water solubility and toxicity to aquatic organisms. While several studies report on mechanisms of toxicity of strobilurins in fish, there are no data on the sub-lethal toxicity of fish to the fungicide fenamidone. To address this gap, survival and hatch rate, deformities, mitochondrial bioenergetics, expression of oxidative stress and apoptotic genes, and behavior (locomotor activity and anxiolytic-related behaviors) were assessed in zebrafish embryos and larvae following exposure to fenamidone. Fenamidone negatively affected development of zebrafish embryos, causing a delay of hatching time at concentrations of 2.5 and 5 μM. Fenamidone caused morphological deformities in zebrafish, including pericardial edema, yolk sac edema, tail deformities, and spinal curvature. Exposure to 1.5 μM fenamidone reduced surface area of swim bladder in larvae at 6 dpf. Fenamidone significantly reduced oxygen consumption rates of embryos; 5 μM fenamidone decreased basal respiration (~85%), oligomycin induced ATP-linked respiration (~70%), FCCP-induced maximal respiration (~75%) and non-mitochondrial respiration (~90%) compared to controls. Sod2 mRNA levels were decreased by fenamidone in larval fish. Locomotor activity was significantly decreased in zebrafish larvae following exposure to 2 μM fenamidone but there was no evidence for anxiolytic nor anxiety-related behaviors (exposures of 100 nM up to 1.5 µM). This study addresses a data gap for potential risks associated with fenamidone exposure in developing fish. [Display omitted] • Deformities and reduced hatch rates were observed in fish exposed to 2.5 µM fenamidone. • Swim bladder formation was reduced in larvae by 1.5 µM fenamidone. • Fenamidone lowered basal, maximum, and non-mitochondrial respiration in embryos. • Sod2 expression was downregulated in larvae exposed to fenamidone. • Hypoactivity in larvae was observed with exposure between 1 and 2 µM fenamidone. [ABSTRACT FROM AUTHOR]

Abstract: In the development of nonlinear reproductive dispersion mixed models, it is commonly assumed that distribution of random effects is normal. The normality assumption is likely violated in many practical applications. In this paper, we assume that distribution of random effects is specified by a Dirichlet process prior for relaxing this limitation. A semiparametric Bayesian approach combining the stick-breaking prior and the blocked Gibbs sampler as well as the Metropolis–Hastings algorithm is developed for simulating observations from the posterior distributions and producing the joint Bayesian estimates of unknown parameters and random effects. Two goodness-of-fit statistics are presented to assess the plausibility of the posited model, and the procedures for computing the Bayes factor, pseudo-Bayes factor and deviance information criterion for model comparison are given. Also, we propose two Bayesian case deletion influence measures including the -divergence and Cook’s posterior mean distance. Four simulation studies and a real example are presented to illustrate the newly developed Bayesian methodologies. [Copyright &y& Elsevier]

Abstract: Paraoxonase 1 (PON1) is reported to have antioxidant and cardioprotective properties. The relationship between PON1 activity and coronary heart disease (CHD) risk in humans has been reported among various ethnic populations in the past decade. However, these studies have yielded contradictory results. To investigate this inconsistency, we conducted a meta-analysis of 43 studies involving a total of 20,629 subjects to evaluate the effect of PON1 activity on susceptibility for CHD. We also systematically explored potential sources of heterogeneity using subgroup analysis and meta-regression. Significant decreases paraoxonase activity of PON1 were observed in CHD patients compared with non-CHD controls with SMD of −0.78 (95% CI: −0.98, −0.57; P <0.001). Similar results were also found for arylesterase activity of PON1 with SMD of −0.50 (95% CI: −0.64, −0.36; P <0.001). In the subgroup analysis by ethnicity, CHD phenotype, sample size, source of controls, mean age and BMI of cases, significantly increased risks were also found. In addition, our analyses detected a possibility of publication bias with an overestimate of the true association by smaller studies. This meta-analysis demonstrated that decreasing in PON1 activity is a risk factor associated with increased CHD susceptibility. However, additional very large-scale studies are warranted to provide conclusive evidence on the effects of PON1 activity on risk of CHD. [Copyright &y& Elsevier]

Abstract: The fluorescence-encoded microspheres were prepared by the simple and controllable microfluidic device for the first time. The polycaprolactone (PCL) microspheres were encoded with different quantum dots (QDs) at various ratios, and the fluorescence was decoded successfully. The designed fluorescence encoding method was easily manipulated, and generated the uniform microspheres with different size. This research demonstrated a very facile and promising technique for fluorescence encoding over traditional methods. [ABSTRACT FROM AUTHOR]

Abstract: Gene therapy vectors based on lentiviruses persist in the host and are ideally suited for long-term therapies of genetic disorders. However, recent incidences of T cell leukemia in X-SCID children receiving gene therapy reveal discrepancy among the preclinical and clinical studies. Divergent results on the potential oncogenic property of integrating vectors obtained from different animal models further raise concern about the relevance and sensitivity of available preclinical systems used to assess their toxicity. Evaluation of transcriptional responses to vector transduction in different in vivo models may provide us with early indications of the potential adverse effects of these vectors and comparative information on the sensitivity and suitability of these models. For this purpose, we used cDNA microarray to examine transcriptional changes in BALB/c and CD-1 (IRC) mice, the two common murine strains used in pharmacological and toxicological studies. Our results revealed a significant difference in the transcriptional responses to vector transduction between the two mouse strains. Modest gene changes, in terms of gene numbers and gene expression were observed in BALB/c mice, whereby expression of 15 oncogenes was up-regulated in CD-1 (ICR) mice. We confirmed the up-regulation of oncogenes, e.g., N-myc, A-Raf, Fli-1, Wnt-2b, and c-jun in CD-1 (IRC) mice using RT-PCR. This study provided an insight into the function of lentiviral transduction in different mouse strains. Distinctive toxicogenomic profiles of two mouse strains should be considered in the context of future development of sensitive models for toxicity evaluation of lentiviral vector products. [Copyright &y& Elsevier]

• miR-135b and versican regulate proliferation and migration of multiple myeloma cells. • miR-135b regulates the Wnt/β-catenin signaling pathway in multiple myeloma cells. • miR-135b regulates versican by mediating the Wnt/β-catenin in multiple myeloma cells. MicroRNA (MiR)-135b and its mediated Wnt/β-catenin signaling pathway are involved in human malignancies. However, their roles in multiple myeloma (MM) remained poorly understood. Our study aimed to uncover their roles in MM. MiR-135b and Versican expressions were measured using quantitative real-time polymerase chain reaction (qRT-PCR). MM cell proliferation, apoptosis, migration and invasion were detected by cell counting kit-8 (CCK-8) assay, flow cytometry, wound healing assay and transwell assay, respectively. Relative expression of Wnt/β-catenin signaling pathway-related protein was quantified by Western blot. MiR-135b was upregulated in the serum of MM patients, and miR-135b upregulation promoted MM cell proliferation, migration and invasion but suppressed apoptosis. Also, miR-135b upregulation promoted activation of Wnt/β-catenin signaling pathway. However, downregulation of miR-135b caused an opposite effect. After incubating cells with miR-135b inhibitor and Wnt/β-catenin signaling pathway agonist Lithium chloride (LiCl), which reversed the effects of downregulating miR-135b. Versican is the downstream effector of the Wnt/β-catenin signaling pathway, and its silencing reversed the effects of LiCl on MM cells. In conclusion, miR-135b and its mediated Wnt/β-catenin signaling pathway promoted proliferation, migration and invasion but suppressed apoptosis of MM cells through regulating Versican, providing a possible treatment for MM. [ABSTRACT FROM AUTHOR]

Endocrine disrupting chemicals can mimic, block, or interfere with hormones in organisms and subsequently affect their development and reproduction, which has raised significant public concern over the past several decades. To investigate (quantitative) structure–activity relationship, 8280 compounds were compiled from the Tox21 10K compound library. The results show that 50% activity concentrations of agonists are poorly related to that of antagonists because many compounds have considerably different activity concentrations between the agonists and antagonists. Analysis on the chemical classes based on mode of action (MOA) reveals that estrogen receptor (ER) is not the main target site in the acute toxicity to aquatic organisms. Binomial analysis of active and inactive ER agonists/antagonists reveals that ER activity of compounds is dominated by octanol/water partition coefficient and excess molar refraction. The binomial equation developed from the two descriptors can classify well active and inactive ER chemicals with an overall prediction accuracy of 73%. The classification equation developed from the molecular descriptors indicates that estrogens react with the receptor through hydrophobic and π-n electron interactions. At the same time, molecular ionization, polarity, and hydrogen bonding ability can also affect the chemical ER activity. A decision tree developed from chemical structures and their applications reveals that many hormones, proton pump inhibitors, PAHs, progestin, insecticides, fungicides, steroid and chemotherapy medications are active ER agonists/antagonists. On the other hand, many monocyclic/nonaromatic chain compounds and herbicides are inactive ER compounds. The decision tree and binomial equation developed here are valuable tools to predict active and inactive ER compounds. [Display omitted] • Many active agonists are also active antagonists but there is poorly correlation between their activity concentrations. • Estrogen receptor is not the target receptors in the acute toxicity to aquatic organisms. • Hydrophobic and π-n electron interactions are the main interactions between ER and compounds. • A decision tree has been developed to identify active and inactive ER compounds. [ABSTRACT FROM AUTHOR]

Autophagy dysregulation plays a pivotal role in cadmium (Cd)-induced nephrotoxicity. Quercetin (Qu), a flavonoid antioxidant with autophagy-enhancing effect, has protective effect on Cd-induced toxicity, but whether it can prevent Cd-induced nephrotoxicity via restoration of autophagy remains unknown. Here, primary rat proximal tubular (rPT) cells were exposed to Cd and/or Qu in vitro to clarify this issue. Data first showed that Cd-impaired autophagic flux was markedly alleviated by Qu, including decreased levels of autophagy marker proteins and recovery of autophagosome-lysosome fusion targeted for lysosomes. Meanwhile, Cd-induced lysosomal alkalization due to v-ATPases inhibition was prominently recovered by Qu. Accordingly, Qu enhanced Cd-diminished lysosomal degradation capacity and lysosome-related gene transcription levels. Notably, Qu improved Cd-inhibited TFEB nuclear translocation and its gene transcription level. Furthermore, data showed that the restoration of Cd-impaired autophagy-lysosome pathway and resultant alleviation of cytotoxicity by Qu are TFEB-dependent using TFEB gene silencing and overexpression technologies. In summary, these data provide novel evidences that the protective action of Qu against Cd-induced autophagy inhibition is attributed to its restoration of lysosomal dysfunction, which is dependent on TFEB. ga1 • Quercetin (Qu) alleviates cadmium (Cd)-induced autophagy inhibition. • Qu enhances lysosome biogenesis and degradation via activation of TFEB. • Qu relieves Cd-induced autophagy inhibition via TFEB-dependent lysosomal restoration. [ABSTRACT FROM AUTHOR]

Agricultural pesticides serve as effective controls of unwanted weeds and pests. However, these same chemicals can exert toxic effects in non-target organisms. To determine chemical modes of action, the toxicity ratio (TR) and critical body residues (CBRs) of 57 pesticides were calculated for Daphnia magna. Results showed that the CBR values of inert compounds were close to a constant while the CBR values of pesticides varied over a wider range. Although herbicides are categorized as specifically-acting compounds to plants, herbicides did not exhibit excess toxicity to Daphnia magna and were categorized as inert compounds with an average logTR = 0.41, which was less than a threshold of one. Conversely, fungicides and insecticides exhibited strong potential for toxic effects to Daphnia magna with an average logTR >2. Many of these chemicals act via disruption of the nervous, respiratory, or reproductive system, with high ligand-receptor binding activity which leads to higher toxicity for Daphnia magna. Molecular docking using acetylcholinesterase revealed that fungicides and insecticides bind more easily with the biological macromolecule when compared with inert compounds. Quantitative structure-activity relationship (QSAR) analysis revealed that the toxicity of fungicides was mainly dependent upon the heat of formation and polar surface area, while the toxicity of insecticides was more related to hydrogen-bond properties. This comprehensive analysis reveals that there are specific differences in toxic mechanisms between fungicides and insecticides. These results are useful for determining relative risk associated with pesticide exposure to aquatic crustaceans, such as Daphnia magna. Image 1 • Excess toxicity has been observed for insecticides and fungicides in D. magna toxicity. • Insecticides and fungicides can be identified as specific compounds in D. magna toxicity. • Critical body residues of insecticides and fungicides are much lower than those of baselines. • Different QSAR models have been developed for insecticides, fungicides and herbicides. [ABSTRACT FROM AUTHOR]

Hyperspectral images (HSIs) are widely used in various tasks such as mineral detection and food safety. However, during the imaging process, they are often contaminated by various noises. In this paper for HSIs restoration tasks, we firstly investigate the advantages of traditional physical restoration models and the denoising convolutional neural networks (CNN). For the physical prior of HSIs, a Tucker decomposition based low-rank tensor approximation can fully explore the global correlations in both the spatial and spectral domains. And for the implicit prior, a CNN based method can represent the prior which cannot be designed by mathematical theory tools. Then, we combine the advantages of the two methods to introduce the HSI restoration CNN with the low-rank tensor approximation based regularization in the flexible and extensible plug-and-play framework. The proposed model can be quickly solved using the alternating direction method of multipliers method. Experiments with simulated data and real data show that, compared with competitive methods, the proposed method achieves better HSI restoration results in various quantitative evaluation indicators. • The Tucker decomposition can be used to represent the global spatial–spectral correlation of hyperspectral image. • The implicit convolutional neural network with tensor low-rank decomposition regularization can be introduced into the plug-and-play framework. • Convolutional neural network can help to recover the details of hyperspectral image. [ABSTRACT FROM AUTHOR]

[Display omitted] Reprogramming immunosuppressive M2 macrophages into M1 macrophages in tumor site provides a new strategy for the immunotherapy of colorectal cancer. In this study, M1 macrophage-derived exosome nanoprobe (M1UC) with Ce6-loaded upconversion material is designed to enhance the photodynamic performance of Ce6 while reprogramming M2 macrophages at tumor site and producing NO gas for three-mode synergistic therapy. Under the excitation of near-infrared light at 808 nm, the probe can generate 660 nm up-conversion fluorescence, which enables the photosensitizer Ce6 to produce ROS efficiently. In addition, the probe leads the production of NO by nitric oxide synthase on exosomes. Confocal laser and flow cytometry results show that M1UC probe reprograms M2 macrophages into M1 macrophages with an efficiency of 95.12%. The cell experiments show that the apoptosis rate of the three-mode synergistic therapy group is 78.8%, and the therapeutic effect is significantly higher than those of the other single treatment groups. In vivo experiments results show that M1UC probes maximally gather at the tumor site after 12 h of intravenous injection in orthotopic colorectal cancer mice. After 808 nm laser irradiation, the survival rate of mice is 100% and the recurrence rate was 0 within 60 d, and the therapeutic effect is significantly higher than those of other single treatment groups, which is also confirmed by immunohistochemistry. This M1 macrophage-derived exosome nanoplatform which is based on the three modes of immunotherapy, gas therapy and photodynamic therapy, provides a new design idea for the diagnosis and treatment of deep tumors. [ABSTRACT FROM AUTHOR]

Abstract Dexmedetomidine (DEX) protects against liver damage caused by sepsis. The purpose of this study was to confirm the regulatory effects of DEX on glycogen synthase kinase 3 beta (GSK-3β) via the α2 adrenergic receptor (α2AR) and evaluate the role of GSK-3β in lipopolysaccharide (LPS)-induced liver injury. Sprague-Dawley (SD) rats were administered an intraperitoneal injection of DEX (30 μg/kg) 30 min before an intraperitoneal injection of LPS (10 mg/kg). HE staining and serum biochemical test results indicated that DEX significantly improved liver histopathological damage and liver function indices. Furthermore, DEX increased super oxide dismutase (SOD) activity and L-glutathione (GSH) levels, and inhibited malondialdehyde (MDA) production. Western blot (WB) analysis demonstrated that treatment with the GSK-3β inhibitor SB216763 increased antioxidant-related protein mitogen-activated protein kinase phosphatase 1 (MKP-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. In addition, anti-apoptosis-related proteins were up-regulated and pro-apoptosis-related proteins were down-regulated by SB21676 administration. WB analysis also showed that DEX increased anti-apoptosis-related protein levels and decreased pro-apoptotic protein levels in LPS-induced liver injury. Nrf2, p53, and activated caspase-3 levels were further evaluated using immunohistochemistry (IHC), producing results consistent with WB results. The α2AR antagonist atipamezole (AT) significantly reversed the protective effects of DEX, as shown by WB analysis. Our data suggested that α2AR plays an important role in reversing the effects of liver oxidative stress and apoptosis via DEX, and that DEX exerts antioxidant and anti-apoptosis effects through regulation of the GSK-3β/MKP-1/Nrf2 pathway. Highlights • DEX can regulate GSK-3β via α2 adrenergic receptor. • GSK-3β can regulate the MKP-1 /Nrf2 pathway in LPS model. • DEX can inhibit LPS-induced oxidative stress and apoptosis by regulating GSK-3β. [ABSTRACT FROM AUTHOR]

Adeno-associated viruses (AAV) contain minimal viral proteins necessary for their replication. During virus assembly, AAV acquire, inherently and submissively, various cellular proteins. Our previous studies identified the association of AAV vectors with the DNA binding protein nucleophosmin (NPM1). Nucleophosmin has been reported to enhance AAV infection by mobilizing AAV capsids into and out of the nucleolus, indicating the importance of NPM1 in the AAV life cycle; however the role of NPM1 in AAV production remains unknown. In this study, we systematically investigated NPM1 function on AAV production using NPM1 knockdown cells and revealing for the first time the presence of G-quadruplex DNA sequences (GQRS) in the AAV genome, the synergistic NPM1-GQRS function in AAV production and the significant enhancement of NPM1 gene knockdown on AAV vector production. Understanding the role of cellular proteins in the AAV life cycle will greatly facilitate high titre production of AAV vectors for clinical use. [ABSTRACT FROM AUTHOR]

[Display omitted] A method for simultaneous labeling and multicolor fluorescence imaging of different hepatic immune cells below freezing point is established based on quantum dots. In the experiment, carbon quantum dots with emission wavelength of 435 nm, CdTe@CdS quantum dots at 542 nm and CdSe@ZnS quantum dots at 604 nm are synthesized respectively, it is found that when the mass fractions of KCl (as antifreeze) are 12 %, 14 %, and 12 %, respectively, the three quantum dot dispersion systems remain liquid state at −20 °C. After they are conjugated with the corresponding secondary antibodies, agarose gel electrophoresis, circular dichroism and capillary electrophoresis confirm the effectiveness of conjugation. By indirect immunofluorescence method, the above three quantum dot fluorescent probes are used to simultaneously and specifically target a variety of liver immune cells, and the multi-color simultaneous imaging of different liver immune cells is realized under the same excitation wavelength, it is found that hepatic macrophages are arranged radially in the liver, hepatic stellate cells present punctate distribution, and hepatic sinusoidal endothelial cells present circular distribution, which is consistent with the results of H&E staining and ultrathin section TEM. This study provides an important technical means for elucidating the structure and function of the liver. [ABSTRACT FROM AUTHOR]

[Display omitted] Single treatment often faces the problem that it cannot completely eradicate tumor and inhibit the tumor metastasis. In order to overcome this shortcoming, multi-modal tumor treatment has attracted widespread attention. In the present article, based on ascorbyl palmitate (PA) and l -arginine (l -Arg), a multifunctional nanocarrier is designed for synergetic treatment of tumor with photothermal and nitric oxide (NO) gas therapy. Firstly, PA and l -Arg were self-assembled to form novel functional micelles, PL, with high biosafety using electrostatic interaction and hydrogen bonding. The functional micelles could self-catalyze to produce NO at the tumor site. Then, Ag 2 S quantum dots having fluorescence imaging and photothermal properties were encapsulated to obtain the nanocarrier, A@PL. The results show that A@PL had a hydrated size of around 78 nm and presented good stability within 30 d. Moreover, in vitro studies indicate that it was efficient with regards to NO self-generating capacity, whereas the photothermal conversion efficiency was as high as 34% under near-infrared light irradiation. The cytotoxicity results show that, when the concentration of A@PL was as high as 2 mM, the survival rate of 3 T3 cells was still 78.23%, proving that the probe has good safety characteristics. Fluorescence imaging results show that its maximum enrichment can be achieved at the tumor site after tail vein injection for 3 h, and out of the body after 24 h, indicating good internal circulation. The in vivo studies show that the rate of inhibition of tumor using the nanocarrier was as high as 98%, and almost overcame the problem of tumor recurrence caused by single treatment, thus presenting a significant tumor treatment effect. This new multifunctional nanocarrier with self-catalytic production of NO provides a new idea for the efficient treatment of tumors. [ABSTRACT FROM AUTHOR]

Background Angiogenesis plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Placental growth factor (PlGF) is a specific regulator of pathological angiogenesis and is upregulated in the sera of IBD patients. Therefore, the role of PlGF in IBD angiogenesis was investigated here using HIMECs. Methods The expression of PlGF and its receptors in human intestinal microvascular endothelial cells (HIMECs) and inflamed mucosa of IBD patients were examined using quantitative PCR and western blot analysis and the role of PlGF in IBD HIMECs was further explored using small interfering RNA (siRNA). The induction of pro-inflammatory cytokine by PlGF in HIMECs was confirmed by ELISA. The capacity of PlGF to induce angiogenesis in HIMECs was tested through proliferation, cell-migration, matrigel tubule-formation assays and its underlying signaling pathway were explored by western blot analysis of ERK1/2 and PI3K/Akt phosphorylation. Results mRNA and protein expression of PlGF and its receptor NRP-1 were significantly increased in IBD HIMECs. Inflamed mucosa of IBD patients also displayed higher expression of PIGF. The production of IL-6 and TNF-α in culture supernatant of HIMECs treated with exogenous recombinant human PlGF-1 (rhPlGF-1) were increased. Furthermore, rhPlGF-1 significantly induced HIMECs migration and tube formation in a dose-dependent manner and knockdown of endogenous PlGF in IBD HIMECs using siRNA substantially reduced these angiogenesis activities. PlGF induced PI3K/Akt phosphorylation in HIMECs and pretreatment of PlGF-stimulated HIMECs with PI3K inhibitor (LY294002) significantly inhibited the PlGF-induced cell migration and tube formation. Conclusion Our results demonstrated the pro-inflammatory and angiogenic effects of PlGF on HIMECs in IBD through activation of PI3K/Akt signaling pathway. PlGF/PI3K/Akt signaling may serve as a potential therapeutic target for IBD. [ABSTRACT FROM AUTHOR]

In this work, the total choline and choline-containing moieties (free choline, glycerophosphocholine, phosphocholine, phosphatidylcholine, lysophosphatidylcholine and sphingomyelin) of 48 dairy products or dairy alternatives available in Canada were determined by hydrophilic interaction liquid chromatography-tandem mass spectrometry (LC–MS/MS). The average total choline content for one serving of fluid milk and alternative (i.e. 250 mL as defined by Canada's Food Guide) was 32.9 ± 2.4 mg for cow's milk, 24.9 ± 0.1 mg for goat's milk and 31.2 ± 4.2 mg for soy beverage. The average total choline content for one serving of yogurt (175 g) was 25.6 ± 3.2 mg. One serving of cheese (50 g) provided 7.1 ± 1.1 mg of total choline on average. Our data show that for dairy products there is a negative correlation between the total choline content on a dry weight basis and the fat content ( r = −0.734, P < 0.001). Overall, we determined the choline content of a variety of dairy products which can supplement the data in the existing United States Department of Agriculture (USDA) choline database and be used in accurately estimating dietary choline intake in epidemiological studies. Hence, dairy products are a good source of choline with low fat products generally being a better source of choline than high fat dairy products. [ABSTRACT FROM AUTHOR]

With Sitophilus zeamais as the target organism, the present study for the first time attempted to elucidate the comparative effects between allyl isothiocyanate (AITC) and calcium phosphide (Ca 3 P 2 ), exposure on mitochondrial electron transport chain (ETC.) complex I & IV and their downstream effects on enzymes relevant to reactive oxygen species (ROS). In vivo, both AITC and Ca 3 P 2 inhibited complex I and IV with similar downstream effects. In contrast with Ca 3 P 2 , the inhibition of complex I caused by AITC was dependent on time and dose. In vitro, AITC inhibited complex IV more significantly than complex I. These results indicate that mitochondrial complex IV is the primary target of AITC, and that complex I is another potential target. [ABSTRACT FROM AUTHOR]

Peroxyl radical sensitive fluorescent dye (BODIPY 665/676) encapsulated nanostructured lipid carriers (NLCs) were prepared by blending solid (eicosane) and liquid (glyceryl trioctanoate) lipid in various proportions (10:90, 30:70, 50:50, 100:0 liquid: solid). Peroxyl radical transport rate was measured by adding 20 mmol/l 2,2′-azobis-2-methyl-propanimidamide, dihydrochloride in the aqueous phase. Fluorescence imaging of NLCs revealed that fluorescent dye was distributed in the liquid lipid regions of 10 and 30% NLCs. However, 50% NLC resembled NLCs with 100% liquid lipid in that, little or no solid domains were observed and the dye was more or less uniformly distributed. Peroxyl radical transport was in the order, 100% < 50% <30% < 10% NLCs. More uniform distribution of the encapsulant possibly reduced the effective peroxyl radical transport rate, particularly when solid domains were present in the core of NLCs. Thus, 100% liquid lipid emulsions may be better than NLCs in improving the oxidative stability of the encapsulant. [ABSTRACT FROM AUTHOR]

In this study, we synthesized a high removal efficiency catalyst using biochar-supported nanoscale zero-valent iron and g-C 3 N 4 , denoted as g-C 3 N 4 /nZVI@SBC, to activate persulfate (PS) for the degradation of total petroleum hydrocarbon (TPH) in groundwater. We characterized the morphology and physiochemical properties of g-C 3 N 4 /nZVI@SBC with scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR), BET surface area analysis, and X-ray photoelectron spectroscopy (XPS). To assess the performance of the g-C 3 N 4 /nZVI@SBC catalyst, we investigated various reaction parameters, such as the mass ratio of g-C 3 N 4 to nZVI@SBC, PS concentration, initial pH, initial TPH concentration, and the presence of coexisting ions in the system. The results from batch experiments and repeated use trials indicate that g-C 3 N 4 /nZVI@SBC exhibited both excellent catalytic activation capability and impressive durability, making it a promising choice for TPH degradation. Specifically, when the PS concentration reached 1 mM, the catalyst dosage was 0.3 g/L, and the g-C 3 N 4 to nZVI@SBC mass ratio was 2, we achieved a remarkable TPH removal efficiency of 93.8%. Through electron paramagnetic resonance (EPR) testing and quenching experiments, we identified sulfate radicals, hydroxyl radicals, and superoxide radicals as the primary active substance involved in the TPH degradation process. Moreover, the g-C 3 N 4 /nZVI@SBC composite proved highly effective for in-situ TPH removal from groundwater and displayed an 86% removal rate, making it a valuable candidate for applications in permeable reactive barriers (PRB) aimed at enhancing environmental remediation. In summary, by skillfully utilizing g-C 3 N 4 /nZVI@SBC, this study has made notable advancements in synthesis and characterization, presenting a feasible and innovative approach to addressing TPH pollution in groundwater. • Synthesized and characterized a novel nanocomposite. • Studied total petroleum hydrocarbon removal with the nanocomposite under different conditions. • Elucidated the persulfate activation mechanism in the novel nanocomposite system. • Assessed the performance of nanocomposite as permeable reactive barriers medium for contaminated groundwater. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) are of significant public concern because of their toxicity and long-range transport potential. Extensive studies have been conducted to explore the source-receptor relationships of PAHs via atmospheric transport. However, the transfer of trade-driven regional and global PAHs is poorly understood. This study estimated the virtual PAHs emission transfer embodied in global trade from 2004 to 2014 and simulated the impact of international trade on global contamination and associated human inhalation exposure risk of PAHs. Results show that trade-driven PAHs flowed primarily from developed to less-developed regions, particularly in those regions with intensive heavy industries and transportation. As the result, international trade resulted in an increasing risk of lung cancer induced by exposure to PAHs (27.8% in China, 14.7% in India, and 11.3% in Southeast Asia). In contrast, we found decreasing risks of PAHs-induced lung cancer in Western Europe (63.2%) and the United States (45.9%) in 2004. Our findings indicate that final demand and emission intensity are the key driving factors contributing to rising and falling consumption-based PAHs emissions and related health risk respectively. The results could provide a useful reference for global collaboration in the reduction of PAHs pollution and related health risks. [Display omitted] • Virtual transfer of PAHs emission embodied in global trade was estimated. • The impact of global trade on human inhalation exposure risk of PAHs was assessed. • Contribution of driving factors to PAHs emissions and health risks were quantified. • Global trade enhanced health risks in less-developed countries and reduced in developed countries. • Developed countries should also undertake responsibility for emissions in less-developed countries. [ABSTRACT FROM AUTHOR]

Microbes mediate the arsenic detoxification in paddy soils, determining the fate of arsenic in soils and its availability to rice plants, yet little is known about the structures and abundances of functional genes as well as the driving forces in low-arsenic paddy fields. To depict the arsenic detoxification functional gene patterns, 429 soil samples were collected from 39 paddy fields across four climatic zones in China, with the arsenic contents ranged from 9.76 to 19.74 mg kg−1. GeoChip, a microarray-based metagenomic technique, was used to analyze the functional genes involved in arsenic detoxification. A total of three arsenic detoxification gene families were detected, aoxB , arxA (arsenite oxidase), and arsM (methyltransferase). Both the diversity and abundance of functional genes varied significantly among sampling sites (p < 0.05) and decreased along the arsenic gradient. Arsenic detoxification genes were carried by bacteria, archaea, and eukaryotes. Redundancy analysis showed that soil samples were grouped according to both climatic zones they located in and arsenic gradients at the continental scale. Soil pH, average annual temperature (AAT), arsenic, annual average precipitation (AAP), and CEC were the most important factors in shaping the functional structure. Structural equation modeling showed that AAT (r = 0.21), pH (r = −0.20), and arsenic contents (r = −0.11) directly affected the arsenic detoxification gene abundances. These findings provide an overall picture of microbial communities involved in arsenic detoxification in paddy soils and reveal the importance of climatic factors in shaping functional genes across a large spatial scale. • Arsenic detoxification gene diversity decreased along the soil arsenic gradient. • Arsenic detoxification genes were carried by bacteria, archaea, and eukaryotes. • Climatic factors, soil pH, and arsenic contents shaped detoxification functional structures. [ABSTRACT FROM AUTHOR]

Background. This study was designed to identify the potassium-channel opener pinacidil as a cardioplegic agent vs hyperkalemic cardioplegia in terms of its efficacy in immature cardioprotection.Methods. By a Langendorff model, 21 hearts of 21- to 28-day-old New Zealand rabbits underwent 90 min of global hypothermic (15°C) ischemia protected with a different single dose of hypothermic (4°C) cardioplegia (pinacidil [50 μmol/l], St. Thomas’ solution combined with pinacidil [50 μmol/l], and St. Thomas’ solution). The percent recovery of the cardiac function, creatine kinase release, and cellular ultrastructure were compared.Results. Pinacidil (50 μmol/l) provided significantly the best postreperfused percentage recovery of the function than the other groups; pinacidil cardioplegia showed a significant reduction of creatine kinase release in the coronary flow compared with the other groups; St. Thomas’ solution combined with pinacidil showed the highest release. Percentage recovery of the coronary flow, water contents, and ultrastructural changes were similar between the groups.Conclusions. Pinacidil provided better protection during ischemia-reperfusion in the immature rabbit heart than St. Thomas’ solution, whereas pinacidil combined with St. Thomas’ solution showed the worst protective effects in immature hearts. [Copyright &y& Elsevier]

The number of ribs is an important economic trait in the sheep industry when the sheep are raised for mutton. However, in sheep, the genetic mechanisms regulating rib number are poorly understood. In the present study, we aimed to identify important candidate genes that affect the increase in rib number in sheep. Whole-genome resequencing of 36 Hu sheep with an increased number of ribs (R14) and 36 sheep with normal (R13) rib numbers was carried out. Analysis using three methods (fixation index (F ST), Fisher's exact test, and Chi-squared test) showed that 219 single nucleotide polymorphism sites overlapped among the results of the three methods, which represented 206 genes. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that the genes were mainly associated with regulation of developmental process, inorganic anion transport, cellular biosynthetic process, tight junction, the oxytocin signaling pathway, and arrhythmogenic right ventricular cardiomyopathy. Four mutations were selected according to the significantly selected genomic regions and important pathways for genotyping and association analysis. The result demonstrated that three synonymous mutations correlated significantly with the rib number. Importantly, we revealed that the CPOX (encoding coproporphyrinogen oxidase), KCNH1 (encoding potassium voltage-gated channel subfamily H member 1), and CPQ (encoding carboxypeptidase Q) genes have a combined effect on rib number in Hu sheep. Our results identified candidate molecular markers for rib number in sheep breeding. • The major candidate genes associated with the rib number were identified using whole-genome resequencing in Hu sheep. • A total of 219 single nucleotide polymorphism sites were found using three methods. • Four single nucleotide polymorphism sites were selected for subsequent genetic effect analysis in a large population. [ABSTRACT FROM AUTHOR]

The environment is teeming with a wide variety of pollutants, but the complexity and diversity of their combinations make it difficult to fully assess their toxicity interaction. A novel toxicity interaction prediction method (TIPM) based on the three-dimensional (3D) surface form of the concentration addition (CA) deviation model (dCA) was proposed to predict the emergence of toxicity interaction in ternary mixtures. Doxycycline hyclate (DH), bromoacetic acid (BAA) and iodoacetic acid (IAA) were used as target pollutants. The toxicity of binary and ternary mixtures designed by the direct equipartition ray design method (EquRay) and the uniform design ray method (UD-Ray) against Escherichia coli (E. coli) was determined by using a time-dependent microplate toxicity analysis (t-MTA) method. The toxicity interaction within mixtures was characterized qualitatively and quantitatively using dCA 3D surface modeling and the emergence of DH-MAA-IAA toxicity interaction was predicted by TIPM. The results showed that the dCA 3D surface model could well characterize the toxicity interactions of the mixtures, and toxicity interaction was closely related to the components' concentration ratio (p i). TIPM could predict the emergence of DH-MAA-IAA toxicity interactions well based on the relationship. Due the model is only related to the toxicity interactions and p i value of a mixture, so it can be suggested to predict toxicity interaction within the more complex multicomponent mixtures, which provides a novel approach for the environmental risk assessment and prediction of hazardous substances. • Toxicity interaction within mixtures is well characterized by dCA 3D surface model. • Toxicity interaction is closely related to the components' concentration ratio (p i). • Based on the relation, a novel toxicity interaction prediction method (TIPM) is developed. • TIPM can predict the toxicity interaction within ternary mixture well. [ABSTRACT FROM AUTHOR]

[Display omitted] • None of the currently proposed sections from Camellia was monophyletic. • Gene tree discordance is prevalent in the backbone of Camellia. • Rapid diversification might be one of the possible causes of gene tree discordance of Camellia. • Selective pressure analysis indicated that integrating all orthologous genes provided improved phylogenetic resolution of the species tree of Camellia. Gene tree discordance is a significant legacy of biological evolution. Multiple factors can result in incongruence among genes, such as introgression, incomplete lineage sorting (ILS), gene duplication or loss. Resolving the background of gene tree discordance is a critical way to uncover the process of species diversification. Camellia , the largest genus in Theaceae, has controversial taxonomy and systematics due in part to a complex evolutionary history. We used 60 transcriptomes of 55 species, which represented 15 sections of Camellia to investigate its phylogeny and the possible causes of gene tree discordance. We conducted gene tree discordance analysis based on 1,617 orthologous low-copy nuclear genes, primarily using coalescent species trees and polytomy tests to distinguish hard and soft conflict. A selective pressure analysis was also performed to assess the impact of selection on phylogenetic topology reconstruction. Our results detected different levels of gene tree discordance in the backbone of Camellia , and recovered rapid diversification as one of the possible causes of gene tree discordance. Furthermore, we confirmed that none of the currently proposed sections of Camellia was monophyletic. Comparisons among datasets partitioned under different selective pressure regimes showed that integrating all orthologous genes provided the best phylogenetic resolution of the species tree of Camellia. The findings of this study reveal rapid diversification as a major source of gene tree discordance in Camellia and will facilitate future investigation of reticulate relationships at the species level in this important plant genus. [ABSTRACT FROM AUTHOR]

Aging presents profound structural and physiological changes in the cardiovascular system. Oxidative stress, a major contributing factor during the aging process, has been involved in various age-related cardiovascular pathologies. Nevertheless, the underlying mechanism of oxidative stress in the aging heart is still unclear. This study was designed to determine whether changes in cardiac structure and function in aged rats were associated with decreases in the antioxidative defense mechanism. Young (3-month-old) and aged (24-month-old) rats were used in this study, and the differences in function, structure, antioxidative capacity and the expression of antioxidative-related proteins between the two groups were compared. By using echocardiography, we observed that compared to young rats, the left ventricular internal end-diastolic diameter (LVID; d) and left ventricular volume at diastole (LV Vol; d) were significantly increased in aged rats, while the MV E/A (E wave and A wave ratio, the ratio of peak velocity of early to late filling of mitral inflow), which represents heart diastolic function, was significantly decreased in aged rats. In addition, we observed degenerative histological modifications and an increased number of apoptotic cells in aged rats. We further detected the protein expression of catalase (CAT), glutathione synthetase (GSS), superoxide dismutase-1 (SOD-1), heme oxygenase-1 (HO-1) and NADPH: quinone oxidoreductase 1 (NQO1) in cardiac tissue. Western blot results showed that the expression of GSS was significantly decreased and that the expressions of CAT, SOD-1, and HO-1 were slightly decreased in aged rats. Immunohistochemistry results further confirmed the decreased expression of GSS, SOD-1 and NQO1 in cardiomyocytes in aged rats. Taken together, our data suggest that aging may affect the morphology and function of the heart by oxidative stress and the antioxidative defense mechanism. • The heart morphology and the diastolic function was changed in natural aged rats. • The level of oxidative stress was increased and the activities of antioxidant enzymes was declined in aged rats. • The variation of heart morphology and function was associated with the decreased antioxidant ability in aged rats. [ABSTRACT FROM AUTHOR]

Abstract Increasing evidence has demonstrated that dexmedetomidine (DEX) possesses multiple pharmacological actions. Herein, we explored the protective effect and potential molecular mechanism of DEX on lipopolysaccharide (LPS)-induced early acute kidney injury (AKI) from the perspective of antioxidant stress. We found that DEX (30 μg/kg, i.p.) ameliorated the renal dysfunction and histopathological damage (tubular necrosis, vacuolar degeneration, infiltration of inflammatory cells and cast formation) induced by LPS (10 mg/kg). DEX also attenuated renal oxidative stress remarkably in LPS-induced early AKI, as evidenced by reduction in production of reactive nitrogen species, decreasing malondialdehyde levels, as well as increasing superoxide dismutase activity and glutathione content. DEX prevented activator protein-1 translocation, inhibited phosphorylation of I-kappa B (IκB) and activation of nuclear factor kappa B (NF-κB) in LPS-induced early AKI, as assessed by real-time quantitative polymerase chain reaction and protein levels of c-Jun, c-Fos, IκB and NF-κB. Notably, DEX pretreatment had the same effect as intraperitoneal injection of an inhibitor of inducible nitric oxide synthase inhibitor (1400W; 15 mg/kg), and inhibited the activity of renal inducible nitric oxide synthase (iNOS) and decreased the expression of iNOS mRNA and NO production. However, the protective effect of DEX on LPS-induced early AKI was reversed by the alpha 2 adrenal receptor (α 2 -AR) inhibitor atipamezole, whereas the imidazoline receptor inhibitor idazoxan did not. Taken together, DEX protects against LPS-induced early AKI in rats by inhibiting the iNOS/NO signaling pathway, mainly by acting on α 2 -ARs instead of IRs. Graphical abstract Image 1 Highlights • DEX alleviates the renal oxidative stress induced by LPS. • DEX prevents AP-1 translocation and inhibits NF-κB activation. • DEX inhibits LPS-induced renal transcription of iNOS mRNA and NO production. • DEX attenuates LPS-induced early AKI by acting on α 2 -AR, not imidazoline receptor. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cost-effective synthesis of deuterated Phe/Tyr/Trp precursors for use in bacterial growth media. • Stereospecific Asp/Asn/Lys deuteration using glucose + fumarate media with oxalate + malonate. • Transaminase inhibitor L-cycloserine improves Ala labeling. • Cys + Met inhibit homoserine dehydrogenase to improve Thr labeling. • Optimal labeling of amino acids demonstrated on model WW domain and PagP membrane protein. Solution NMR studies of large proteins are hampered by rapid signal decay due to short-range dipolar 1H–1H and 1H–13C interactions. These are attenuated by rapid rotation in methyl groups and by deuteration (2H), so selective 1H,13C-isotope labelling of methyl groups in otherwise perdeuterated proteins, combined with methyl transverse relaxation optimized spectroscopy (methyl-TROSY), is now standard for solution NMR of large protein systems > 25 kDa. For non-methyl positions, long-lived magnetization can be introduced as isolated 1H–12C groups. We have developed a cost-effective chemical synthesis for producing selectively deuterated phenylpyruvate and hydroxyphenylpyruvate. Feeding these amino acid precursors to E. coli in D 2 O, along with selectively deuterated anthranilate and unlabeled histidine, results in isolated and long-lived 1H magnetization in the aromatic rings of Phe (HD, HZ), Tyr (HD), Trp (HH2, HE3) and His (HD2 and HE1). We are additionally able to obtain stereoselective deuteration of Asp, Asn, and Lys amino acid residues using unlabeled glucose and fumarate as carbon sources and oxalate and malonate as metabolic inhibitors. Combining these approaches produces isolated 1H–12C groups in Phe, Tyr, Trp, His, Asp, Asn, and Lys in a perdeuterated background, which is compatible with standard 1H–13C labeling of methyl groups in Ala, Ile, Leu, Val, Thr, Met. We show that isotope labeling of Ala is improved using the transaminase inhibitor L-cycloserine, and labeling of Thr is improved through addition of Cys and Met, which are known inhibitors of homoserine dehydrogenase. We demonstrate the creation of long-lived 1H NMR signals in most amino acid residues using our model system, the WW domain of human Pin1, as well as the bacterial outer membrane protein PagP. [ABSTRACT FROM AUTHOR]

Currently, multidrug-resistant Salmonella contamination prevention and control are facing with enormous difficulties and challenges in food contamination management. In this study, two lytic Salmonella phages (SWJM-01 and SWJM-02), belonged to Kuttervirus and Felixounavirus family, respectively, were isolated and characterized. The dsDNA genome sequence of SWJM-01 was 155,472 bp with 44.91% GC content, encoding 206 open reading frames (ORFs), while SWJM-02 was 84,679 bp with 38.98% GC content, encoding 147 ORFs. The latent periods of SWJM-01 and SWJM-02 were both 20 min. Their burst sizes were about 52 and 108 FPU/infected cell, respectively. SWJM-01 and SWJM-02 can lytic19.1% and 95.2% of Salmonella (total 42 strains), respectively, revealing that SWJM-02 is bacteriophage with wide spectrum. In addition, they both maintained relatively high activities in broad environment conditions of pH (4–12) and temperature (30–60 °C). Furthermore, the OD 600 values after treatment with SWJM-01, SWJM-02 and their cocktail declined to 1.037, 0.762 and 0.341, respectively, as well as the bacterial counts in lettuce and milk significantly reduced after treatment with phages and their cocktail at 4 °C for 3 d. All results suggested that these two phages can be used as antibacterial agents to control Salmonella contamination in foods, especially phage cocktail. • Two lytic Salmonella phages (SWJM-01, SWJM-02) were isolated and identified. • SWJM-01 and SWJM-02 can effectively control the growth of Salmonella. • SWJM-02 with a broad host rang was stable in extreme alkaline environment. • Phage cocktail was a potential agent for biocontrol in foods during cold storage. [ABSTRACT FROM AUTHOR]

Much has been written on annual variation of tintinnid assemblages although the mechanism causing the annual variation has been poorly studied either in form of species richness or Lorica Oral Diameter (LOD) size-classes. In the present study, a 10-year (May 2003 to December 2012) survey on species occurrence, abundance, and LOD variation of the tintinnid ciliates was conducted in Jiaozhou Bay, western Pacific. In contrast to previous studies, we found summer peaks in tintinnid species richness in Jiaozhou Bay validated by multi-year investigations. We studied phenology of every tintinnid species and explored the mechanism causing the annual variation. The hypothesis was that tintinnid species richness has a winter baseline, to which warm water species added with the progress of the season. We defined the occurrence types of each species, and found there was only one cold occurrence type species. There was no overlap of cold occurrence type and warm occurrence type in the transitional period between winter and summer. The second aim of this study was to explore annual variations in tintinnid assemblages in form of LOD and redundant species. The species frequency distribution patterns among LOD size-classes were similar all year round. The abundance frequency distribution pattern in LOD size-classes could be divided into two phases: cold phase and warm phase with exception of May and September. The portion of redundant species was about 50% in every month. Our result help understand and predict annual variation of tintinnid assemblages in terms of species richness and LOD in world oceans. [ABSTRACT FROM AUTHOR]

Lentiviral vectors (LVs) have been successfully used in clinical trials showing long term therapeutic benefits. Studying the role of cellular proteins in lentivirus HIV-1 life cycle can help understand virus assembly and budding, leading to improvement of LV production for gene therapy. Lentiviral vectors were purified using size exclusion chromatography (SEC). The cellular protein composition of LVs produced by two different methods was compared: the transient transfection system pseudotyped with the VSV-G envelope, currently used in clinical trials, and a stable producer cell system using a non-toxic envelope derived from cat endogenous retrovirus RD114, RDpro. Proteins of LVs purified by size exclusion chromatography were identified by tandem mass spectrometry (MS/MS). A smaller number of cellular protein species were detected in stably produced vectors compared to transiently produced vector samples. This may be due to the presence of co-purified VSV-G vesicles in transiently produced vectors. AHNAK (Desmoyokin) was unique to RDpro-Env vectors. The potential role in LV particle production of selected proteins identified by MS analysis including AHNAK was assessed using shRNA gene knockdown technique. Down-regulation of the selected host proteins AHNAK, ALIX, and TSG101 in vector producer cells did not result in a significant difference in vector production. [ABSTRACT FROM AUTHOR]

Novel hybrids with MAO and A β (1–42) self-aggregation inhibitory activities were designed and synthesized with the employment of indazole moiety and resveratrol. The biological screening results indicated that most compounds displayed potent inhibitory activity for A β (1–42) self-aggregation, and obvious selective inhibition to MAO-B. Among these compounds, compound 6e was the most potent inhibitor not only for h MAO-B (IC 50  = 1.14 μM) but also for A β (1–42) self-aggregation (58.9% at 20 μM). Molecular modeling and kinetic studies revealed that compound 6e was a competitive MAO-B inhibitor, which can occupy the active site of MAO-B, and interact with A β (1–42) via π - π and cation–π stacking interactions. In addition, compound 6e had no toxicity on PC12 cells and could cross the BBB. Collectively, all these results suggested that compound 6e might be a promising multi-target lead compound worthy of further investigation. [ABSTRACT FROM AUTHOR]

Gastric cancer tissue-derived mesenchymal stem cells (GC-MSCs) are important resident stromal cells in the tumor microenvironment (TME) and have been shown to play a key role in gastric cancer progression. Whether GC-MSCs exert a tumor-promoting function by affecting anti-tumor immunity is still unclear. In this study, we used GC-MSC conditioned medium (GC-MSC-CM) to pretreat peripheral blood mononuclear cells (PBMCs) from healthy donors. We found that GC-MSC-CM pretreatment markedly reversed the inhibitory effect of PBMCs on gastric cancer growth in vivo, but did not affect functions of PBMCs on gastric cancer cell proliferation, cell cycle and apoptosis in vitro . PBMCs pretreated with GC-MSC-CM significantly promoted gastric cancer migration and epithelial-mesenchymal transition in vitro and liver metastases in vivo . Flow cytometry analysis showed that GC-MSC-CM pretreatment increased the proportion of Treg cells and reduced that of Th17 cells in PBMCs. CFSE labeling and naïve CD4 + T cells differentiation analysis revealed that GC-MSC-CM disrupted the Treg/Th17 balance in PBMCs by suppressing Th17 cell proliferation and inducing differentiation of Treg cells. Overall, our collective results indicate that GC-MSCs impair the anti-tumor immune response of PBMCs through disruption of Treg/Th17 balance, thus providing new evidence that gastric cancer tissue-derived MSCs contribute to the immunosuppressive TME. [ABSTRACT FROM AUTHOR]

Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC 50 = 0.336 ± 0.003 μM) significantly suppressed proliferation, induced apoptosis, arrested cell cycle of EC109 cells at G2/M phase, and caused changes of the associated protein markers correspondingly. We also found that compound LPE-1 potently inhibited the migration and invasion of EC-109 cells. Docking studies showed that the cyano group formed hydrogen bonds with Val811 and Thr810. Additionally, the thiophene moiety formed arene-H interaction with Trp761 residue. In vivo studies showed that compound LPE-1 inhibited tumor growth of xenograft models bearing EC-109 without obvious toxicity. Collectively, our findings indicate that LSD1 may be a potential therapeutic target in ESCC, and compound LPE-1 could serve as a lead compound for further development for anti-ESCC drug discovery. [ABSTRACT FROM AUTHOR]

Enterotoxigenic Escherichia coli (ETEC)-induced diarrhea is a complex pathological process, involving ion channel regulation and water efflux. While the mechanism underlying water efflux in ETEC-induced diarrhea is still largely unknown, aquaporins (AQPs) play important roles in transcellular water movement, but their expression profile has not been demonstrated in the murine small intestine. We identified AQP3 expression in the jejunum, but not the duodenum or ileum, using reverse transcription PCR and western blotting. Immunohistochemistry showed that AQP3 localized to the jejunum villi epithelial cells. Using an ETEC-induced murine diarrhea model, we demonstrated that both AQP3 mRNA expression and protein concentration in the jejunum were gradually but significantly decreased over 7 d compared with controls. These results suggested impaired water influx also plays an important role in ETEC-induced diarrhea. [ABSTRACT FROM AUTHOR]