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In the present review, we synthesize information on the mechanisms of chronic copper (Cu) toxicity using an adverse outcome pathway framework and identify three primary pathways for chronic Cu toxicity: disruption of sodium homeostasis, effects on bioenergetics, and oxidative stress. Unlike acute Cu toxicity, disruption of sodium homeostasis is not a driving mechanism of chronic toxicity, but compensatory responses in this pathway contribute to effects on organism bioenergetics. Effects on bioenergetics clearly contribute to chronic Cu toxicity with impacts at multiple lower levels of biological organization. However, quantitatively translating these impacts into effects on apical endpoints such as growth, amphibian metamorphosis, and reproduction remains elusive and requires further study. Copper-induced oxidative stress occurs in most tissues of aquatic vertebrates and is clearly a significant driver of chronic Cu toxicity. Although antioxidant responses and capacities differ among tissues, there is no clear indication that specific tissues are more sensitive than others to oxidative stress. Oxidative stress leads to increased apoptosis and cellular damage in multiple tissues, including some that contribute to bioenergetic effects. This also includes oxidative damage to tissues involved in neuroendocrine axes and this damage likely alters the normal function of these tissues. Importantly, Cu-induced changes in hormone concentrations and gene expression in endocrine-mediated pathways such as reproductive steroidogenesis and amphibian metamorphosis are likely the result of oxidative stress-induced tissue damage and not endocrine disruption. Overall, we conclude that oxidative stress is likely the primary driver of chronic Cu toxicity in aquatic vertebrates, with bioenergetic effects and compensatory response to disruption of sodium homeostasis contributing to some degree to observed effects on apical endpoints. Environ Toxicol Chem 2022;00:1-18. (c) 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

The primary objective of the present study was to examine the influence of early systemic toxicity resulting from copper (Cu) exposure on metamorphic processes in Xenopus laevis. A 28-day exposure study with copper, initiated at developmental stage 10, was performed using test concentrations of 3.0, 9.0, 27.2, 82.5, and 250 μg Cu/L. The primary endpoints included mortality, developmental stage, embryo-larval malformation, behavioral effects, hindlimb length (HLL), growth (snout-vent length [SVL] and wet body weight), and histopathology. The 28-day LC50 value with 95% confidence intervals was 61.2 (51.4-72.9) μg Cu/L with 250 μg Cu/L resulting in complete lethality. Developmental arrest in the 82.5 and delay in the 27.2 μg Cu/L treatments was observed as early as study day 10 continuing throughout the remainder of exposure. SVL-normalized HLL, body weight, and SVL in the 27.2 and 82.5 μg Cu/L treatments were significantly decreased relative to control. At 82.5 μg Cu/L, and thyroid gland size was markedly reduced when compared with controls consistent with the stage of developmental and growth arrest. Concentration-dependent findings in the intestine, liver, gills, eyes, and pharyngeal mucosa were consistent with non-endocrine systemic toxicity. These were prevalent in the 9.0 and 27.2 μg Cu/L treatment groups but were minimally evident or absent in the 82.5 μg/L group, which was attributed to developmental arrest. In conclusion, developmental delay in larvae exposed to 27.2 and 82.5 μg Cu/L was the result of systemic toxicity occurring in early development prior hypothalomo-pituitary-thyroid axis (HPT)-driven metamorphosis and was not indicative of endocrine disruption.

Background The Colorado potato beetle (CPB) is a worldwide devastating pest of potato plants and other Solanaceae characterized by its remarkable ability to evolve resistance to insecticides. Bacillus thuringiensis (Bt) Cry3Aa toxin represents an environmentally-safe alternative for CPB control but larvae susceptibility to this toxin has been reported to vary depending on the host plant on which larvae feed. To gain more insight into how nutrition mediates Bt tolerance through effects on gene expression here we explored the post-transcriptional regulation by miRNAs of the CPB-ADAM10 gene encoding the Cry3Aa toxin functional receptor ADAM10. Results The lower CPB-ADAM10 gene expression in CPB larvae fed on potato plants cv. Vivaldi than those fed on potato cv. Monalisa or tomato plants was inversely related to Cry3Aa toxicity. By high-throughput sequencing we identified seven CPB miRNAs and one potato miRNA predicted to base pair with the CPB-ADAM10 mRNA. No differential expression of the endogenous lde-miR1175-5p was found in larvae feeding on any of the two potato plant varieties. However, statistically significant increased amounts of potato stu-miR171c-5p were detected in CPB larvae fed on potato cv. Vivaldi compared to larvae fed on potato cv. Monalisa. Conclusion Our results support a role for dietary miRNAs in Bt toxicity by regulating CPB-ADAM10 gene encoding the Cry3Aa toxin receptor ADAM10 in CPB larvae and open up the possibility of exploiting plant natural variation in miRNAs to provide more sustainable potato crops protection against CPB. This article is protected by copyright. All rights reserved.

Soluble fragments of peptidoglycan called muropeptides are released from the cell wall of bacteria as part of their metabolism or as a result of biological stresses. These compounds trigger immune responses in mammals and plants. In bacteria, they play a major role in the induction of antibiotic resistance. The development of efficient methods to produce muropeptides is, therefore, desirable both to address their mechanism of action and to design new antibacterial and immunostimulant agents. Herein, we engineered the peptidoglycan recycling pathway of Escherichia coli to produce N-acetyl-β-D-glucosaminyl-(1→4)-1,6-anhydro-N-acetyl-β-D-muramic acid (GlcNAc-anhMurNAc), a common precursor of Gram-negative and Gram-positive muropeptides. Inactivation of the hexosaminidase nagZ gene allowed the efficient production of this key disaccharide, providing access to Gram-positive muropeptides through subsequent chemical peptide conjugation. E. coli strains deficient in both NagZ hexosaminidase and amidase activities further enabled the in vivo production of Gram-negative muropeptides containing meso-diaminopimelic acid, a rarely available amino acid.

International audience; Root mechanical traits, including tensile strength (Tr), tensile strain (εr), modulus of elasticity (Er) and tensile toughness (Wr), play a key role in plant functioning (e.g., anchorage and stem stability). Yet, their variability and their relationships with other root traits are poorly known. Here, we characterize Tr, εr, Er and Wr at both intra-and interspecific levels and examine how they covary with other root traits related to root economics space (RES). We used twelve herbaceous species from contrasting taxonomical families grown in controlled plein-air conditions. For each species, we excavated root systems and measured morphological and chemical traits and mechanical traits at two locations (proximal versus distal) for two root types (absorptive versus transport roots). Transport roots tended to show higher mechanical trait values than absorptive roots, especially for εr, while the location where the root was sampled showed a limited effect on root mechanics. The five monocots (Poaceae species) had higher mechanical traits than the seven dicots (including five Fabaceae species) except for Er. Root mechanical traits covaried positively and were strongly positively correlated with specific root length, i.e., a trait related to soil exploration strategy, and negatively with root diameter and root tissue density, i.e. a trait related to root life span. We demonstrate the important role of species category and root type in governing mechanical trait variation at both intra-and inter-specific levels. Our results can be regarded as the first evidence of the link between root mechanical robustness and the RES through a strong association with the 'do-it-yourself' soil exploration strategy.

There are many multiple-stage racing competitions in various sports such as swimming, running, or cycling. The wide availability of affordable tracking devices facilitates monitoring the position along with the race of all participants, even for non-professional contests. Getting real-time information of contenders is useful but also unleashes the possibility of creating more complex visualization systems that ease the understanding of the behavior of all participants during a simple stage or throughout the whole competition. In this paper we focus on bicycle races, which are highly popular, especially in Europe, being the Tour de France its greatest exponent. Current visualizations from TV broadcasting or real-time tracking websites are useful to understand the current stage status, up to a certain extent. Unfortunately, still no current system exists that visualizes a whole multi-stage contest in such a way that users can interactively explore the relevant events of a single stage (e.g. breakaways, groups, virtual leadership...), as well as the full competition. In this paper, we present an interactive system that is useful both for aficionados and professionals to visually analyze the development of multi-stage cycling competitions. This work has been supported in part by project TIN2017-88515-C2-1-R(GEN3DLIVE), from the Spanish Ministerio de Economía y Competitividad, by 839 FEDER (EU) funds and by the Grant No. PID2019-106426RB-C31 / AEI / 10.13039/501100011033 from the Spanish Government.

Background Tyrosine kinase inhibitors (TKI) can be safely discontinued in chronic phase chronic myeloid leukemia (CP‐CML) patients who had achieved a sustained deep molecular response. Based on the results of discontinuation trials, recommendations regarding patient selection for a treatment‐free remission (TFR) attempt had been proposed. The aims of this study were to evaluate the rate of patients eligible for TKI discontinuation and molecular recurrence‐free survival (MRFS) after stop according to recommendations. Methods Over a 10‐year period, newly diagnosed CP‐CML patients and treated with first‐line TKI in the nine French participating centers were included. Eligibility to treatment discontinuation and MRFS were analyzed and compared according to selection criteria defined by recommendations and first‐line treatments. Results From January 2006 to December 2015, 398 patients were considered. Among them, 73% and 27% of patients received imatinib or either second or third generation tyrosine kinase inhibitors as frontline treatment, respectively. Considering the selection criteria defined by recommendations, up to 55% of the patients were selected as optimal candidates for treatment discontinuation. Overall 95/398 (24%) discontinued treatment. MRFS was 51.8% [95% CI 41.41–62.19] at 2 years and 43.8% [31.45–56.15] at 5 years. Patients receiving frontline second‐generation TKI and fulfilling the eligibility criteria suggested by recommendations had the lowest probability of molecular relapse after TKI stop when compare to others. Conclusion One third of CP‐CML patients treated with TKI frontline fulfilled the selection criteria suggested by European LeukemiaNet TFR recommendations. Meeting selection criteria and second‐generation TKI frontline were associated with the highest MRFS., Tyrosine kinase inhibitors (TKI) can be safely discontinued in chronic phase chronic myeloid leukemia patients who had achieved a sustained deep molecular response. Several recommendations regarding the optimal selection of the patients before stop have been proposed. Based on these recommendations, we estimate that one third of the patients treated with frontline TKI will meet these criteria. Moreover, patients treated with frontline second generation TKI and selected as optimal candidate according to these recommendations have the highest probability of molecular recurrence‐free survival when compared to others.