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The fungicides strobilurins and succinate dehydrogenase inhibitors (SDHIs) are blockers of the electron transport chain (ETC) in fungi. Here, we show that the exposure for 24 h to kresoxym-methyl, a fungicide from the class of strobilurins, alters the mitochondrial respiration in human HepG2 hepatocytes. In addition, we demonstrate an increase in production of mitochondrial superoxide radical anion, a reduction in ATP level, a decrease in the ratio reduced/oxidized glutathione and a decrease in cell viability (assessed by the LDH assay, Presto Blue assay, and Crystal Violet assay). As kresoxym-methyl is associated to boscalid (SDHI) in commercial formulations, we analyzed a potential exacerbation of the induced mitochondrial dysfunction for this combination. For the highest dose at which kresoxym-methyl (5 µM) and boscalid (0.5 µM) did not induce changes in mitochondrial function when used separately, in contrast, when both fungicides were used in combination at the same concentration, we observed a significant alteration of the mitochondrial function of hepatocytes: there was a decrease in oxygen consumption rate, in the ATP level. In addition, the level of mitochondrial superoxide radical anion was increased leading to a decrease in the ratio reduced/oxidized glutathione, and an increase in viability.

Children’s unequal exposure to nature is associated with the uneven distribution of green and blue infrastructure (GBI) in cities, which often disproportionately affects children living in disadvantaged neighbourhoods. School environments are increasingly recognised, both by scientists and policymakers, as priority areas to increase children’s exposure to GBI. However, studies analysing the spatial and temporal patterns of GBI in school environments are still scarce, especially those considering a cross-city and equity perspective. To contribute to the expanding field of urban environmental justice in the context of children’s geographies, our research aims to assess the (un)equal spatial patterns of school-related GBI across four large European cities (Brussels, Barcelona, Rotterdam, and Paris) and over time (between 2006 and 2018). For this purpose, we used EU-comparable green and blue land cover and tree canopy cover data, together with schools’ socio-economic characteristics (median income and educational attainment) based on local neighbourhood-level data. Through geospatial and statistical analyses on 1259 primary schools, our study reveals significant positive correlations between school-related GBI indicators and socio-economic variables in Brussels and Rotterdam. In contrast, negative correlations were found in Barcelona and Paris. Overall, the four cities show very distinct patterns of school-related socio-environmental inequities and no substantial GBI gains during the period analysed, suggesting that greening initiatives in and around school environments are still to be upscaled at the city level.

Background and purpose: The poor delivery of drugs to infiltrating tumor cells contributes to therapeutic failure in glioblastoma. During the early phase of an anti-angiogenic treatment, a remodeling of the tumor vasculature could occur, leading to a more functional vessel network that could enhance drug delivery. However, the restructuration of blood vessels could increase the proportion of normal endothelial cells that could be a barrier for the free diffusion of drugs. The net balance, in favor or not, of a better delivery of compounds during the course of an antiangiogenic treatment remains to be established. This study explored whether cediranib and thalidomide could modulate perfusion and vessel permeability in the brain U87 tumor mouse model. Methods: The dynamic evolution of the diffusion of agents outside the tumor core using the fluorescent dye Evans Blue in histology and Gd-DOTA using dynamic contrast-enhanced (DCE)-MRI. CD31 labelling of endothelial cells was used to measure the vascular density. Results and interpretation: Cediranib and thalidomide effectively reduced tumor size over time. The accessibility of Evans Blue outside the tumor core continuously decreased over time. The vascular density was significantly decreased after treatment while the proportion of normal vessels remained unchanged over time. In contrast to histological studies, DCE-MRI did not tackle any significant change in hemodynamic parameters, in the core or margins of the tumor, whatever the parameter used or the pharmacokinetic model used. While cediranib and thalidomide were effective in decreasing the tumor size, they were ineffective in transiently increasing the delivery of agents in the core and the margins of the tumor.

(1) Background: Glioblastoma (GB) presents a formidable challenge in neuro-oncology due to its aggressive nature, limited treatment options, and poor prognosis. The blood–brain barrier (BBB) complicates treatment by hindering drug delivery to the tumor site, particularly to the infiltrative cells in the margin of the tumor, which are mainly responsible for tumor recurrence. Innovative strategies are therefore needed to enhance drug delivery in the margins of the tumor. This study explores whether irradiation can enhance BBB permeability by assessing hemodynamic changes and the distribution of contrast agents in the core and the margins of GB tumors. (2) Methods: Mice grafted with U-87MG cells were exposed to increasing irradiation doses. The distribution of contrast agents and hemodynamic parameters was evaluated using both non-invasive magnetic resonance imaging (MRI) techniques with gadolinium–DOTA as a contrast agent and invasive histological analysis with Evans blue, a fluorescent vascular leakage marker. Diffusion–MRI was also used to assess cytotoxic effects. (3) Results: The histological study revealed a complex dose-dependent effect of irradiation on BBB integrity, with increased vascular leakage at 5 Gy but reduced leakage at higher doses (10 and 15 Gy). However, there was no significant increase in the diffusion of Gd-DOTA outside the tumor area by MRI. (4) Conclusions: The increase in BBB permeability could be an interesting approach to enhance drug delivery in glioblastoma margins for low irradiation doses. In this model, DCE-MRI analysis was of limited value in assessing the BBB opening in glioblastoma after irradiation.

The fungicides strobilurins and succinate dehydrogenase inhibitors (SDHIs) are blockers of the electron transport chain (ETC) in fungi. Here, we show that the exposure for 24 h to kresoxym-methyl, a fungicide from the class of strobilurins, alters the mitochondrial respiration in human HepG2 hepatocytes. In addition, we demonstrate an increase in production of mitochondrial superoxide radical anion, a reduction in ATP level, a decrease in the ratio reduced/oxidized glutathione and a decrease in cell viability (assessed by the LDH assay, Presto Blue assay, and Crystal Violet assay). As kresoxym-methyl is associated to boscalid (SDHI) in commercial formulations, we analyzed a potential exacerbation of the induced mitochondrial dysfunction for this combination. For the highest dose at which kresoxym-methyl (5 µM) and boscalid (0.5 µM) did not induce changes in mitochondrial function when used separately, in contrast, when both fungicides were used in combination at the same concentration, we observed a significant alteration of the mitochondrial function of hepatocytes: there was a decrease in oxygen consumption rate, in the ATP level. In addition, the level of mitochondrial superoxide radical anion was increased leading to a decrease in the ratio reduced/oxidized glutathione, and an increase in viability. [ABSTRACT FROM AUTHOR]

Fungicides are widely used in agriculture for crop protection. Succinate dehydrogenase inhibitors (SDHIs) and strobilurins inhibit mitochondria electron transport chain (ETC) in fungi, by blocking complex II and complex III, respectively. Questions regarding their selectivity of action for fungi have been raised in the literature, and we previously showed that boscalid and bixafen (SDHIs) alter the mitochondrial function of human hepatocytes. Here, we analyzed the impact of the exposure of human hepatocytes to pyraclostrobin, a fungicide belonging to the class of strobilurins. Using electron paramagnetic resonance (EPR), we observed a decrease in oxygen consumption rate (OCR) and an increase in mitochondrial superoxide levels after 24 h exposure to 0.5 µM concentration. As a consequence, the content in ATP amount in the cells was reduced, the ratio reduced/oxidized glutathione was decreased, and a decrease in cell viability was observed using three different assays (PrestoBlue, crystal violet, and annexin V assays). In addition, as SDHIs and strobilurins are commonly associated in commercial preparations, we evaluated a potential “cocktail” toxic effect. We selected low concentrations of boscalid (0.5 µM) and pyraclostrobin (0.25 µM) that did not induce a mitochondrial dysfunction in liver cells when used separately. In sharp contrast, when both compounds were used in combination at the same concentration, we observed a decrease in OCR, an increase in mitochondrial superoxide production, a decrease in the ratio reduced/oxidized glutathione, and a decrease in cell viability in three different assays.

Nosemosis is caused by two microsporidian species of the genus recently renamed Vairimorpha (=Nosema) that parasitize the midgut of Apis mellifera. Usually, pooled samples of 60 bees are used for diagnosis. Reported differences in the efficiency of treatments against Vairimorpha sp. led us to wonder if the sample size may be one of the causes of these unpredictable results. This study focuses on the distribution of the spore load of V. ceranae among forager bees within a colony using statistical approaches in relation to sample size. Spore counts per bee were used to describe the spore distribution and to test whether they fit different statistical distributions. Standard errors were calculated and two-sided 95% confidence intervals were constructed for the spore count means, using standard (Student's t) and non-parametric bootstrap methods (Percentil and bias-corrected and accelerated-BCa). Bees with a high degree of infection appear in low percentage but are very influential on the mean value. Data showed a poor fit to all of the distributions evaluated. To obtain a relative standard error below 10% of the mean, pooled samples should have more than 1,500 bees. The BCa interval showed better coverage than others being acceptable starting at 100 data of individual foragers. Results show that, when using the traditional sample size (pooled samples n = 60), the accuracy for estimating the mean spore load is low in V. ceranae infected hives, regardless of the statistical method applied. Thus, this work could justify some erratic results reported for treatments with commercial products. [ABSTRACT FROM AUTHOR]

The aim of this paper is to provide an analysis of German particle verbs with the particle weg- ‘away’ as in Tattoos weglasern (lit. ‘to laser tattoos away’ within the framework of Construction Grammar (Goldberg, 1995, 2006; Ziem & Lasch, 2013). The meaning of German weg-verbs often being non-compositional, morpho-lexical approaches turn out to be unable to properly account for the meaning of weg-constructions. The constructionist approach allows us to shed light on the relationship between morphology and syntax within weg-constructions and to account for both lexicalised and non-lexicalised instances of verbs with weg-. The analysis is based on the distinction between transitive and reflexive weg-constructions, which can occur as caused-motion and resultative constructions. The discussion of various variants of the German weg-construction suggests that the weg-constructions under investigation are linked to each other in a family of constructions.

Background: While the blood–brain barrier (BBB) is often compromised in glioblastoma (GB), the perfusion and consequent delivery of drugs are highly heterogeneous. Moreover, the accessibility of drugs is largely impaired in the margins of the tumor and for infiltrating cells at the origin of tumor recurrence. In this work, we evaluate the value of methods to assess hemodynamic changes induced by a hyperosmolar shock in the core and the margins of a tumor in a GB model. Methods: Osmotic shock was induced with an intracarotid infusion of a hypertonic solution of mannitol in mice grafted with U87-MG cells. The distribution of fluorescent dye (Evans blue) within the brain was assessed via histology. Dynamic contrast-enhanced (DCE)-MRI with an injection of Gadolinium-DOTA as the contrast agent was also used to evaluate the effect on hemodynamic parameters and the diffusion of the contrast agent outside of the tumor area. Results: The histological study revealed that the fluorescent dye diffused much more largely outside of the tumor area after osmotic shock than in control tumors. However, the study of tumor hemodynamic parameters via DCE-MRI did not reveal any change in the permeability of the BBB, whatever the studied MRI parameter. Conclusions: The use of hypertonic mannitol infusion seems to be a promising method to increase the delivery of compounds in the margins of GB. Nevertheless, the DCE-MRI analysis method using gadolinium-DOTA as a contrast agent seems of limited value for determining the efficacy of opening the BBB in GB after osmotic shock.

The burn intensive care unit (ICU) of the Queen Astrid Military Hospital experienced an outbreak with an extensively drug-resistant Acinetobacter baumannii (XDR-Ab) strain, which began when all burn wound patients from all over Belgium were sent there as part of the national COVID-19 action plan. The purpose of this study is to report on the investigation and strategies that were implemented to contain the outbreak. Between October 2020 and May 2021, five of the 72 patients admitted to the ICU met the acute outbreak case definition (attack rate 7%). Their median age was 46 years and their median total body surface area burned was 39%. All patients developed at least one XDR-Ab infection, with in total three pulmonary, three bloodstream and five burn wound infections. One patient died. All XDR-Ab isolates were only susceptible to colistin. Whole genome sequencing of the isolates from the first two patients revealed an identical A. baumannii ST2 genotype, suggesting an outbreak. XDR-Ab-positive patients were cohorted with dedicated staff. The infection control team intensified its training on hand hygiene, excreta management and bio-cleaning procedures. Concurrently, 30 environmental samples were collected, which proved negative for XDRAb. Spatio-temporal associations were found for all XDR-Ab-positive patients, suggesting cross-transmission via staff's hands. We describe an XDR-Ab outbreak in a burn ICU over a seven-month period, in a context of increased workload. This series underlines the importance of a correct staff-to-patient ratio, especially in outbreak situations. [ABSTRACT FROM AUTHOR]

Rita Sofia Garcia Ribeiro,1,* Sarah Belderbos,1,* Pierre Danhier,2 Juan Gallo,2 Bella B Manshian,1 Bernard Gallez,2 Manuel Bañobre,3 Marcel de Cuyper,4 Stefaan J Soenen,1 Willy Gsell,1 Uwe Himmelreich11Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, Leuven B-3000, Belgium; 2Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique De Louvain, Brussels B-1200, Belgium; 3Diagnostic Tools and Methods/Advanced (Magnetic) Theranostic Nanostructures Lab, International Iberian Nanotechnology Laboratory (INL), PT-Braga 4715-330, Portugal; 4Laboratory of Bionanocolloids, Interdisciplinary Research Centre, KULAK/KU Leuven, Kortrijk B-8500, Belgium*These authors contributed equally to this workPurpose: Magnetoliposomes (MLs) have shown great potential as magnetic resonance imaging contrast agents and as delivery vehicles for cancer therapy. Targeting the MLs towards the tumor cells or neovascularization could ensure delivery of drugs at the tumor site. In this study, we evaluated the potential of MLs targeting the αvβ3 integrin overexpressed on tumor neovascularization and different tumor cell types, including glioma and ovarian cancer.Methods: MLs functionalized with a Texas Red fluorophore (anionic MLs), and with the fluorophore and the cyclic Arginine-Glycine-Aspartate (cRGD; cRGD-MLs) targeting the αvβ3 integrin, were produced in-house. Swiss nude mice were subcutaneously injected with 107 human ovarian cancer SKOV-3 cells. Tumors were allowed to grow for 3 weeks before injection of anionic or cRGD-MLs. Biodistribution of MLs was followed up with a 7T preclinical magnetic resonance imaging (MRI) scanner and fluorescence imaging (FLI) right after injection, 2h, 4h, 24h and 48h post injection. Ex vivo intratumoral ML uptake was confirmed using FLI, electron paramagnetic resonance spectroscopy (EPR) and histology at different time points post injection.Results: In vivo, we visualized a higher uptake of cRGD-MLs in SKOV-3 xenografts compared to control, anionic MLs with both MRI and FLI. Highest ML uptake was seen after 4h using MRI, but only after 24h using FLI indicating the lower sensitivity of this technique. Furthermore, ex vivo EPR and FLI confirmed the highest tumoral ML uptake at 4 h. Last, a Perl’s stain supported the presence of our iron-based particles in SKOV-3 xenografts.Conclusion: Uptake of cRGD-MLs can be visualized using both MRI and FLI, even though the latter was less sensitive due to lower depth penetration. Furthermore, our results indicate that cRGD-MLs can be used to target SKOV-3 xenograft in Swiss nude mice. Therefore, the further development of this particles into theranostics would be of interest.Keywords: tumor targeting, SKOV-3, cRGD, magnetoliposomes, MRI, FLI

Background: Because statins were found to decrease the oxygen consumption rate (OCR) of a variety of normal cells, our hypothesis was that statins may also decrease the OCR of cancer cells, alleviate tumor hypoxia and radiosensitize tumors. Methods: OCR was assessed using the Seahorse XF96 technology and EPR respirometry in PC-3 prostate cancer cells. Mitochondrial superoxide production was measured by EPR with mitoTEMPO-H as a sensing probe. Tumor pO2 was measured in vivo using low-frequency EPR oximetry to define the optimal window of reoxygenation, the time at which tumors were irradiated with a single 6 Gy dose with a Cesium-137 irradiator. Results: 24-h exposure to simvastatin and fluvastatin significantly decreased the OCR of PC-3 cancer cells. An increase in mitochondrial superoxide levels was also observed after fluvastatin exposure. The PC-3 prostate cancer model was found highly hypoxic at the basal level. When mice were treated with simvastatin or fluvastatin (daily injection of 20 mg/kg), tumor oxygenation increased 48 and 72 h after initiation of the treatment. However, despite reoxygenation, simvastatin did not sensitize the PC-3 tumor model to RT. Conclusions: exposure to statins affect tumor metabolism and tumor oxygenation, however, with limited impact on tumor growth with or without irradiation.

Background: Mito-metformin10 (MM10), synthesized by attaching a triphenylphosphonium cationic moiety via a 10-carbon aliphatic side chain to metformin, is a mitochondria-targeted analog of metformin that was recently demonstrated to alter mitochondrial function and proliferation in pancreatic ductal adenocarcinoma. Here, we hypothesized that this compound may decrease the oxygen consumption rate (OCR) in prostate cancer cells, increase the level of mitochondrial ROS, alleviate tumor hypoxia, and radiosensitize tumors. Methods: OCR and mitochondrial superoxide production were assessed by EPR (9 GHz) in vitro in PC-3 and DU-145 prostate cancer cells. Reduced and oxidized glutathione were assessed before and after MM10 exposure. Tumor oxygenation was measured in vivo using 1 GHz EPR oximetry in PC-3 tumor model. Tumors were irradiated at the time of maximal reoxygenation. Results: 24-hours exposure to MM10 significantly decreased the OCR of PC-3 and DU-145 cancer cells. An increase in mitochondrial superoxide levels was observed in PC-3 but not in DU-145 cancer cells, an observation consistent with the differences observed in glutathione levels in both cancer cell lines. In vivo, the tumor oxygenation significantly increased in the PC-3 model (daily injection of 2 mg/kg MM10) 48 and 72 h after initiation of the treatment. Despite the significant effect on tumor hypoxia, MM10 combined to irradiation did not increase the tumor growth delay compared to the irradiation alone. Conclusions: MM10 altered the OCR in prostate cancer cells. The effect of MM10 on the superoxide level was dependent on the antioxidant capacity of cell line. In vivo, MM10 alleviated tumor hypoxia, yet without consequence in terms of response to irradiation.