Liver toxicity is a leading systemic toxicity of drugs and chemicals demanding more human-relevant, high throughput, cost effective in vitro solutions. In addition to contributing to animal welfare, ...in vitro techniques facilitate exploring and understanding the molecular mechanisms underlying toxicity. New ‘omics technologies can provide comprehensive information on the toxicological mode of action of compounds, as well as quantitative information about the multi-parametric metabolic response of cellular systems in normal and patho-physiological conditions. Here, we combined mass-spectroscopy metabolomics with an in vitro liver toxicity model. Metabolite profiles of HepG2 cells treated with 35 test substances resulted in 1114 cell supernatants and 3556 intracellular samples analyzed by metabolomics. Control samples showed relative standard deviations of about 10–15%, while the technical replicates were at 5–10%. Importantly, this procedure revealed concentration–response effects and patterns of metabolome changes that are consistent for different liver toxicity mechanisms (liver enzyme induction/inhibition, liver toxicity and peroxisome proliferation). Our findings provide evidence that identifying organ toxicity can be achieved in a robust, reliable, human-relevant system, representing a non-animal alternative for systemic toxicology.
Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing ...the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.
Taking the advantage of sun glitter (SG) observed from high-resolution satellites Gaofen-1 (GF-1) and Gaofen-6 (GF-6), a new method named Shield and Vortex 1-2 (SAV1-2) for extracting spatial texture ...information from sun glitter was established. Sea surface texture detail information around Diaoyu Dao and its affiliated islands was extracted using SAV1-2. Meanwhile, the dynamic characteristics of the water environment were analyzed by combining the water color, temperature and dynamic data. The results show the following information. (1) Stable westward shield effect and eastward Karman vortex streets, extracted from SG, appear upstream (westward) and downstream (eastward) of the Diaoyu Dao and its affiliated islands respectively. (2) The dominant direction of the Kuroshio Current in the Diaoyu Dao and its affiliated islands area is east, the Diaoyu Dao and its affiliated islands interacting with Kuroshio, inducing western shield and eastern shelter and wake. Furthermore, wave intervals of the shield in front of the island range from hundreds to thousands of metres, and extend wider than the island itself. (3) Combining with high-resolution sea surface temperature (SST) and chlorophyll
a
(Chl
a
) concentration, the directional changes of water color elements are mutually supported and proved with the stable shield (wave packet) effect in the west and vortex street effect in the east. The change of SST upstream of the island (western shield area) is not significant, the temperature in the downstream shelter area decreases slightly, and the SST in the downstream wake area shows a general trend of obvious decrease. The wake area is dominated by Karman vortex streets in shape, supplementing by vortices. The concentration of Chl
a
in the west shield of island is as low as that in downstream shelter area, while it increases significantly in the downstream wake area with shape in eddy or ribbon. (4) The SAV methods of extracting sea surface texture detail using SG can be widely used in different sea areas and water quality. This paper can provide reference for the protection and development of Diaoyu Dao and its affiliated islands and its surrounding waters. It is suggested that some kind of current buffer, such as marine wind farm, should be established in the western waters of Diaoyu Dao and its affiliated islands to protect the islands, and marine pasture should be developed in the downstream of eastern waters of Diaoyu Dao and its affiliated islands.
Water hyacinth ( Pontederia crassipes Mart.) is a monocotyledonous aquatic plant renowned for its rapid growth, extensive proliferation, biological invasiveness, and ecological resilience to ...variations in pH, nutrients, and temperature. The International Union for Conservation of Nature (IUCN) has listed P. crassipes among the top 100 invasive species. However, comprehensive genomic information, particularly concerning its mitochondrial genome (mitogenome), remains surprisingly limited. In this study, the complete mitogenome of P. crassipes was analyzed using bioinformatics approaches. The mitogenome is 399,263 bp long and contains 38 protein-coding genes (PCGs), 24 tRNA genes, and 3 rRNA genes. Sequence analysis revealed that the complete mitogenome of the species contains 3,289 dispersed repeats, and 765 RNA editing sites in protein-coding genes. The P. crassipes mitogenome possessed un-conserved structures, including extensive sequence transfer between its chloroplasts and mitochondria. Our study on the mitogenome of P. crassipes offers critical insights into its evolutionary patterns and phylogenetic relationships with related taxa. This research enhances our understanding of this invasive species, known for its significant biomass and rapid overgrowth in aquatic environments.
Formaldehyde (CHOH), a common volatile organic compound, causes many adverse effects on human health. The highly exposed TiO2(001) facet possesses a high photodegradation efficiency of CHOH due to ...its excellent ability to trap photogenerated holes and high density of surface unsaturated Ti atoms (Ti5c) to bind CHOH. However, the rapid recombination of photoinduced electron-hole pairs of TiO2(001) limits the photodegradation efficiency. We adopted a strategy of decorating TiO2(001) with g-C3N4 quantum dots (QDs), exploiting the quantum effect of g-C3N4QDs and their combined staggered band structure. This decoration improves the photocatalytic activity of TiO2(001). Moreover, the chemical configuration of g-C3N4QDs/TiO2(001) and the combination mode between the g-C3N4QDs and TiO2(001) support were explored in detail using high-resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS), and density functional theory (DFT) calculations. Following the physiochemical characteristic results, the transport mechanism of photoinduced carriers was further analyzed by ultraviolet photoelectron spectroscopy (UPS), electron paramagnetic resonance (EPR), and Heyd-Scuseria-Ernzerh (HSE) exchange-correlation functional calculations. Finally, the performance and reaction mechanism of the photodegradation of CHOH by TiO2(001) and g-C3N4QDs/TiO2(001) were thoroughly investigated. The results show that the g-C3N4QDs were composed of an N-defect tri-s-triazine supported by TiO2(001) via a strong C-O-Ti chemical bond, which accelerated the separation of photoinduced carriers through a Z-scheme route. The photodegradation and mineralization efficiencies of CHOH were significantly promoted by 30% and 60% for g-C3N4QDs/TiO2(001) compared with those of TiO2(001). The photodegradation mechanism proceeded as CHOH - dioxymethylene - formate - carbonate - CO2. This study provides a surface engineering means to design highly active modified TiO2 for CHOH photodegradation.
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•High exposed TiO2(001) facet is used as a composite catalyst carrier.•The g-C3N4QDs consist of an N-deficient tri-s-triazine structure.•Defective state g-C3N4QDs supported by TiO2(001) via a strong C-O-Ti bond.•Hydroxyl radicals are essential for the photooxidation of CHOH.•Separation of photoinduced carriers by Z-scheme route.
Genetically engineered (GE) rice endogenous epsps (5-enolpyruvoylshikimate-3-phosphate synthase) gene overexpressing EPSPS can increase glyphosate herbicide-resistance of cultivated rice. This type ...of epsps transgene can enhance the fecundity of rice crop-weed hybrid offspring in the absence of glyphosate, stimulating great concerns over undesired environmental impacts of transgene flow to populations of wild relatives. Here, we report the substantial alteration of phenology and fitness traits in F
-F
crop-wild hybrid descendants derived from crosses between an epsps GE rice line and two endangered wild rice (Oryza rufipogon) populations, based on the common-garden field experiments. Under the glyphosate-free condition, transgenic hybrid lineages showed significantly earlier tillering and flowering, as well as increased fecundity and overwintering survival/regeneration abilities. In addition, a negative correlation was observed between the contents of endogenous EPSPS of wild, weedy, and cultivated rice parents and fitness differences caused by the incorporation of the epsps transgene. Namely, a lower level of endogenous EPSPS in the transgene-recipient populations displayed a more pronounced enhancement in fitness. The altered phenology and enhanced fitness of crop-wild hybrid offspring by the epsps transgene may cause unwanted environmental consequences when this type of glyphosate-resistance transgene introgressed into wild rice populations through gene flow.
Spodoptera frugiperda (J.E. Smith) is a highly significant agricultural pest that poses a threat to crop production worldwide. It is polyphagous, has a strong migratory ability, and is difficult to ...control, which makes it a threat not only to crops but also to woody plants. However, research on its adaptability to woody plants is limited. This study compares the feeding adaptations (survival rate, pupation time, pupation rate, weight, length, and daily food consumption), protective enzyme activities, and feeding preferences of S. frugiperda on leaves of six economically important tree species (Areca catechu L., Aquilaria sinensis (Lour.) Spreng, Cocos nucifera L., Camellia oleifera Abel, Dalbergia odorifera T. Chen, and Hevea brasiliensis (Willd. ex A. Juss.) Müll. Arg.), with Zea mays L. used as a control treatment. The results indicate that S. frugiperda did not survive when fed with A. catechu, C. oleifera, and D. odorifera. A. catechu had similar survival rates (83.33%), pupation (86.67%), weight, and length data compared to the maize control. C. nucifera had lower survival rates (46.67%) but no significant differences in pupation (76.67%), weight, and length data of S. frugiperda. H. brasiliensis exhibited significantly lower survival (50.00%) and pupation rates (46.67%) compared to maize. However, there was no significant difference in weight and length data, and its preference index was higher among the six tree species treatments. Therefore, A. sinensis is a vulnerable tree with a high risk, while H. brasiliensis and C. nucifera showed varying degrees of susceptibility. A. catechu, C. oleifera, and D. odorifera were found to be unsuitable hosts for S. frugiperda. In conclusion, this study extensively explores the feeding effects of S. frugiperda on six economically important tree species. It provides insights into the feeding preferences of the pest, thereby informing the potential threat posed by S. frugiperda to economically important trees. It helps to prevent further damage from S. frugiperda and provides a reference for agriculture and forestry to develop effective joint prevention and control measures.
► Concentration–response data are often background corrected and normalized to control. ► A 4-parameter log-logistic function is often fitted to concentration–response data. ► EC50 estimate depends ...on the number of parameters in the log–logistic model. ► Parameters in the log-logistic model should be fixed only with compelling reason. ► Data transformation on does not affect EC50 estimate if the fitting function is kept.
Concentration–response studies are performed to investigate the potency of the substance under investigation. Data are typically evaluated using non-linear regression. A common model is the log-logistic model which includes parameters for lower and upper boundary of mean response, EC50 and Hill slope. Often, response and/or concentration data are transformed before proceeding with the analysis of their relationship. This is motivated by practical reasons, including comparability of results across different assays. We prove mathematically that a linear transformation of data will not change the EC50 and Hill slope estimates and only results in an identical transformation of the estimated parameters for lower and upper boundary of mean response. However, fixing some of the parameters may lead to erroneous estimates. This is of practical relevance when data are corrected for background signal and normalized by background corrected solvent control and a reduced model is used in which the response range is fixed between 100% and 0%. Computer simulations and a real data example are used to illustrate the impact of data transformations on parameter estimation. We further shed light on some common problems arising in the analysis of concentration–response data. Recommendations for practical implementation in concentration–response analysis are provided.
Increased infestation of weedy rice-a noxious agricultural pest has caused significant reduction of grain yield of cultivated rice (Oryza sativa) worldwide. Knowledge on genetic diversity and ...structure of weedy rice populations will facilitate the design of effective methods to control this weed by tracing its origins and dispersal patterns in a given region. To generate such knowledge, we studied genetic diversity and structure of 21 weedy rice populations from Sri Lanka based on 23 selected microsatellite (SSR) loci. Results indicated an exceptionally high level of within-population genetic diversity (He = 0.62) and limited among-population differentiation (Fst = 0.17) for this predominantly self-pollinating weed. UPGMA analysis showed a loose genetic affinity of the weedy rice populations in relation to their geographical locations, and no obvious genetic structure among populations across the country. This phenomenon was associated with the considerable amount of gene flow between populations. Limited admixture from STRUCTURE analyses suggested a very low level of hybridization (pollen-mediated gene flow) between populations. The abundant within-population genetic diversity coupled with limited population genetic structure and differentiation is likely caused by the considerable seed-mediated gene flow of weedy rice along with the long-distance exchange of farmer-saved rice seeds between weedy-rice contaminated regions in Sri Lanka. In addition to other effective weed management strategies, promoting the application of certified rice seeds with no weedy rice contamination should be the immediate action to significantly reduce the proliferation and infestation of this weed in rice ecosystems in countries with similar rice farming styles as in Sri Lanka.
Toxicological responses to chemical insult are largely regulated by transcriptionally activated pathways that may be independent, correlated and partially or fully overlapping. Investigating the ...dynamics of the interactions between stress responsive transcription factors from toxicogenomic data and defining the signature of each of them is an additional step toward a system level understanding of perturbation driven mechanisms. To this end, we investigated the segregation of the genes belonging to the three following transcriptionally regulated pathways: the AhR pathway, the Nrf2 pathway and the ATF4 pathway. Toxicogenomic datasets from three projects (carcinoGENOMICS, Predict-IV and TG-GATEs) obtained in various experimental conditions (in human and rat
liver and kidney models and rat
, with bolus administration and with repeated doses) were combined and consolidated where overlaps between datasets existed. A bioinformatic analysis was performed to refine pathways' signatures and to create chemical activation capacity scores to classify chemicals by their potency and selectivity of activation of each pathway. With some refinement such an approach may improve chemical safety classification and allow biological read across on a pathway level.
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