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Background A key aspect of any new material safety assessment is the evaluation of their in vivo genotoxicity. Graphene oxide (GO) has been studied for many promising applications, but there are remaining concerns about its safety profile, especially after inhalation. Herein we tested whether GO lateral dimension, comparing micrometric (LGO) and nanometric (USGO) GO sheets, has a role in the formation of DNA double strand breaks in mouse lungs. We used spatial resolution and differential cell type analysis to measure DNA damages in both epithelial and immune cells, after either single or repeated exposure. Results GO induced DNA damages were size and dose dependent, in both exposure scenario. After single exposure to a high dose, both USGO and LGO induced significant DNA damage in the lung parenchyma, but only during the acute phase response ( p  < 0.05 for USGO; p  < 0.01 for LGO). This was followed by a fast lung recovery at day 7 and 28 for both GOs. When evaluating the chronic impact of GO after repeated exposure, only a high dose of LGO induced long-term DNA damages in lung alveolar epithelia (at 84 days, p  < 0.05). Regardless of size, low dose GO did not induce any significant DNA damage after repeated exposure. A multiparametric correlation analysis of our repeated exposure data revealed that transient or persistent inflammation and oxidative stress were associated to either recovery or persistent DNA damages. For USGO, recovery from DNA damage was correlated to efficient recovery from acute inflammation ( i.e ., significant secretion of SAA3, p  < 0.001; infiltration of neutrophils, p  < 0.01). In contrast, the persistence of LGO in lungs was associated to a long-lasting presence of multinucleated macrophages (up to 84 days, p  < 0.05), an underlying inflammation (IL-1α secretion up to 28 days, p  < 0.05) and the presence of persistent DNA damages at 84 days. Conclusions Overall these results highlight the importance of the exposure scenario used. We showed that LGO was more genotoxic after repeated exposure than single exposure due to persistent lung inflammation. These findings are important in the context of human health risk assessment and toward establishing recommendations for a safe use of graphene based materials in the workplace.

Nanomaterials may be contaminated with bacterial endotoxin during production and handling, which may confound toxicological testing of these materials, not least when assessing for immunotoxicity. In the present study, we evaluated the conventional Limulus amebocyte lysate (LAL) assay for endotoxin detection in graphene based material (GBM) samples, including graphene oxide (GO) and few-layered graphene (FLG). Our results showed that some GO samples interfered with various formats of the LAL assay. To overcome this problem, we developed a TNF-α expression test (TET) using primary human monocyte-derived macrophages incubated in the presence or absence of the endotoxin inhibitor, polymyxin B sulfate, and found that this assay, performed with non-cytotoxic doses of the GBM samples, enabled unequivocal detection of endotoxin with a sensitivity that is comparable to the LAL assay. FLG also triggered TNF-α production in the presence of the LPS inhibitor, pointing to an intrinsic pro-inflammatory effect. Finally, we present guidelines for the preparation of endotoxin-free GO, validated by using the TET.

Understanding how graphene oxide (GO) interacts with cells is crucial for its safe and efficient biomedical applications. Despite extensive research, a systematic investigation using a panel of cell lines, thoroughly characterized label-free nanomaterials, and complementary analytical techniques is lacking. Here, we examined the uptake of thin GO sheets with distinct lateral dimensions in 13 cell lines: 8 cancer (HeLa, A549, PC3, DU-145, LNCaP, SW-480, SH-SY5Y, U87-MG) and 5 non-cancer (BEAS-2B, NIH/3T3, PNT-2, HaCaT, 293T), using confocal microscopy, transmission electron microscopy, and flow cytometry. Our results reveal a striking difference in GO uptake: non-cancer cells internalized GO efficiently, while in cancer cells, GO predominantly interacted with the plasma membrane, showing minimal to no internalization. Comparison to other nanomaterials (polystyrene beads and graphene flakes) confirmed that cancer cells internalize materials similarly to non-cancer cells, indicating GO-specific interactions. We identified that GO’s thinness plays important role in this differential uptake. More importantly, GO disrupts the actin cytoskeleton of cancer cells, impairing the migration in cancer but not in non-cancer cells. We propose that thin GO sheets act as a cue upon interaction with the plasma membrane of cancer cell lines, subsequently inducing actin filaments disruption leading to impaired endocytosis, migration activity, and reduced capacity of cancer cells towards GO uptake.

Graphene has drawn a lot of interest in the material community due to unique physicochemical properties. Owing to a high surface area to volume ratio and free oxygen groups, the oxidized derivative, graphene oxide (GO) has promising potential as a drug delivery system. Here, the lung tolerability of two distinct GO varying in lateral dimensions is investigated, to reveal the most suitable candidate platform for pulmonary drug delivery. Following repeated chronic pulmonary exposure of mice to GO sheet suspensions, the innate and adaptive immune responses are studied. An acute and transient influx of neutrophils and eosinophils in the alveolar space, together with the replacement of alveolar macrophages by interstitial ones and a significant activation toward anti‐inflammatory subsets, are found for both GO materials. Micrometric GO give rise to persistent multinucleated macrophages and granulomas. However, neither adaptive immune response nor lung tissue remodeling are induced after exposure to micrometric GO. Concurrently, milder effects and faster tissue recovery, both associated to a faster clearance from the respiratory tract, are found for nanometric GO, suggesting a greater lung tolerability. Taken together, these results highlight the importance of dimensions in the design of biocompatible 2D materials for pulmonary drug delivery system. This work highlights the need to interrogate both innate and adaptive immunity to understand the impact of materials. Only the innate immunity is involved in the response to chronic pulmonary exposure to graphene oxide (GO) nanosheets, whereas multi‐walled carbon nanotubes activate both innate and adaptive immunity, and lead to fibrosis. Amongst all tested materials, nanometric GO has the safest profile.

Carbon nanostructures are currently fuelling a revolution in science and technology in areas ranging from aerospace engineering to electronics. Oxidised carbon nanomaterials, such as graphene oxide, exhibit dramatically improved water dispersibility compared to their pristine equivalents, allowing their exploration in biology and medicine. Concomitant with these potential healthcare applications, the issue of degradability has been raised and has started to be investigated. The aim of the present study was to assess the potential of hypochlorite, a naturally occurring and industrially used ion, to degrade oxidised carbon nanomaterials within a week. Our main focus was to characterise the physical and chemical changes that occur during degradation of graphene oxide compared to two other oxidised carbon nanomaterials, namely carbon nanotubes and carbon nanohorns. The kinetics of degradation were closely monitored over a week using a battery of techniques including visual observation, UV–Vis spectroscopy, Raman spectroscopy, infra-red spectroscopy, transmission electron microscopy and atomic force microscopy. Graphene oxide was rapidly degraded into a dominantly amorphous structure lacking the characteristic Raman signature and microscopic morphology. Oxidised carbon nanotubes underwent degradation via a wall exfoliation mechanism, yet maintained a large fraction of the sp 2 carbon backbone, while the degradation of oxidised carbon nanohorns was somewhat intermediate. The present study shows the timeline of physical and chemical alterations of oxidised carbon nanomaterials, demonstrating a faster degradation of 2D graphene oxide sheets compared to 1D oxidised carbon nanomaterials over 7 days in the presence of an oxidising species. Carbon nanomaterials: graphene oxide degrades rapidly when exposed to hypochlorite Oxidised carbon nanomaterials degrade into amorphous structures upon exposure to hypochlorite, a naturally occurring anion in human body. A team led by Kostas Kostarelos at the University of Manchester investigated the physical and chemical modifications occurring during degradation of graphene oxide and oxidised carbon nanotubes and nanohorns exposed to sodium hypochlorite, commonly known as bleach. The degradation pathways were followed over a week with the aid of advanced characterisation tools such as transmission electron microscopy, atomic force microscopy, and optical spectroscopy. Graphene oxide underwent a gradual reduction in dimensions followed by agglomeration and disintegration of its structure. Owing to its peculiar physicochemical features, graphene oxide degraded faster than the other two oxidized carbon nanostructures. These findings may help unveiling the toxicological profile of carbon nanomaterials.

The gut microbiome produces metabolites that interact with the aryl hydrocarbon receptor (AhR), a key regulator of immune homoeostasis in the gut 1 , 2 . Here we show that oral exposure to graphene oxide (GO) modulates the composition of the gut microbiome in adult zebrafish, with significant differences in wild-type versus ahr2 -deficient animals. Furthermore, GO was found to elicit AhR-dependent induction of cyp1a and homing of lck + cells to the gut in germ-free zebrafish larvae when combined with the short-chain fatty acid butyrate. To obtain further insights into the immune responses to GO, we used single-cell RNA sequencing to profile cells from whole germ-free embryos as well as cells enriched for lck . These studies provided evidence for the existence of innate lymphoid cell (ILC)-like cells 3 in germ-free zebrafish. Moreover, GO endowed with a ‘corona’ of microbial butyrate triggered the induction of ILC2-like cells with attributes of regulatory cells. Taken together, this study shows that a nanomaterial can influence the crosstalk between the microbiome and immune system in an AhR-dependent manner. Although the toxicity of graphene‐based nanomaterials on human health has been extensively studied, their impact on the microbiome remains poorly understood. Using zebrafish as a model, we show that graphene oxide modulates the immune system in a microbiome‐dependent manner through a mechanism mediated by the aryl hydrocarbon receptor. The study suggests an interplay among graphene‐based nanomaterials, microbiome and innate immune system.

Graphene oxide nanomaterials are being developed for wide-ranging applications but are associated with potential safety concerns for human health. We conducted a double-blind randomized controlled study to determine how the inhalation of graphene oxide nanosheets affects acute pulmonary and cardiovascular function. Small and ultrasmall graphene oxide nanosheets at a concentration of 200 μg m − 3 or filtered air were inhaled for 2 h by 14 young healthy volunteers in repeated visits. Overall, graphene oxide nanosheet exposure was well tolerated with no adverse effects. Heart rate, blood pressure, lung function and inflammatory markers were unaffected irrespective of graphene oxide particle size. Highly enriched blood proteomics analysis revealed very few differential plasma proteins and thrombus formation was mildly increased in an ex vivo model of arterial injury. Overall, acute inhalation of highly purified and thin nanometre-sized graphene oxide nanosheets was not associated with overt detrimental effects in healthy humans. These findings demonstrate the feasibility of carefully controlled human exposures at a clinical setting for risk assessment of graphene oxide, and lay the foundations for investigating the effects of other two-dimensional nanomaterials in humans. Clinicaltrials.gov ref: NCT03659864. Assessment of the health risks of exposure to anthropogenic nanomaterials is crucial to maximize their potential applications. This double-blind, randomized controlled study in healthy humans evaluates the impact of inhalation of graphene oxide nanosheets on acute pulmonary and cardiovascular functions.

Resumen: El siguiente artículo pretende identificar posibles espacios comunes entre arte y educación partiendo de la propuesta artística Mapa dels Desitjos[1] del colectivo Cràter[2]. Esta propuesta se llevó a cabo en el contexto de la XVII Mostra d’Art Públic / Universitat Pública de la Universitat de València. Mapa dels Desitjos surgió de la idea de preguntar a la comunidad universitaria cómo organizarían su vida si no tuviesen en cuenta la cuestión económica y de hacer públicas sus respuestas. A partir de esta experiencia, analizamos y reflexionamos en torno a cuatro preguntas que estructuran el análisis: ¿Qué paralelismos existen entre los roles de artista/público y maestro/estudiante? ¿Cómo se utiliza el espacio? ¿Cómo se comporta el factor tiempo? ¿Cuál es el conocimiento que se genera? Siguiendo las relaciones entre estos elementos, presentes tanto en el arte como en la educación, abordamos algunas reflexiones sobre conceptos educativos en permanente desarrollo, tales como educación expandida (Díaz et al., 2012), aprendizajes colaterales (González, del Rincón, Bonilla y Sáez, 2012) y currículum oculto (Freire, 1975).   Palabras Clave: Educación Artística, Investigación Artística, Práctica artística, Educación Superior, Entornos de aprendizaje. Abstract: The following paper aims to identify possible common spaces between art and education, departing from the art project Mapa dels Desitjos1 (Map of Wishes), by the collective Cràter2. The project took place in the framework of the 17 Show of Public Art / Public University at University of Valencia. Mapa dels desitjos emerged from the idea of asking members of the university community about how they would organize their lives if they did not have to consider any economic constraints, and then making their answers public. Based on this experience, we analyze and reflect on four questions that structure our analysis: What paralels are there between the roles of artist/audience and teacher/student? How is the space used? What role does time play? What is the knowledge being generated? Through the relationships between these elements, present both in art as well as in education, we engage in some reflections on educational concepts that are in continuous development, such as expanded education (Díaz et al., 2012), collateral learning (González, del Rincón, Bonilla & Sáez, 2012) and hidden curriculum (Freire, 1975).   Keywords: Artistic Education, Artistic Research, Artistic Practice, Higher Education, Learning Environments.http://dx.doi.org/10.7203/eari.7.8071  [1] http://mapadelsdesitjos.com/ [2] http://lescrater.com

In this paper, we report on a catanionic vesicles-based strategy to reduce the cytotoxicity of the diacyl glycerol arginine-based synthetic surfactants 1,2-dimyristoyl-rac-glycero-3-O-(N α-acetyl-l-arginine) hydrochloride (1414RAc) and 1,2-dilauroyl-rac-glycero-3-O-(N α-acetyl-l-arginine) hydrochloride (1212RAc). The behavior of these surfactants was studied either as pure components or after their formulation as pseudo-tetra-chain catanionic mixtures with phosphatidylglycerol (PG) and as cationic mixtures with 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) used as control. The antimicrobial activity of the negatively charged formulations against Acinetobacter baumannii was maintained with respect to the surfactant alone, while a significant improvement of the antimicrobial activity against Staphylococcus aureus was observed, together with a strong decrease of hemolytic activity. The influence of the net charge of the catanionic vesicles on membrane selectivity was studied using model membranes. The dynamics of surface tension changes induced by the addition of 1414RAc/PG aqueous dispersions into phospholipid monolayers composed of zwitterionic DPPC as model system for mammalian membranes and of negatively charged PG mimicking cytoplasmic membrane of Gram-positive bacteria was followed by tensiometry. Our results constitute a proof of principle that tuning formulation can reduce the cytotoxicity of many surfactants, opening their possible biological applications.

Nanomaterials may be contaminated with bacterial endotoxin during production and handling, which may confound toxicological testing of these materials, not least when assessing for immunotoxicity. In the present study, we evaluated the conventional Limulus amebocyte lysate (LAL) assay for endotoxin detection in graphene based material (GBM) samples, including graphene oxide (GO) and few-layered graphene (FLG). Our results showed that some GO samples interfered with various formats of the LAL assay. To overcome this problem, we developed a TNF-[alpha] expression test (TET) using primary human monocyte-derived macrophages incubated in the presence or absence of the endotoxin inhibitor, polymyxin B sulfate, and found that this assay, performed with non-cytotoxic doses of the GBM samples, enabled unequivocal detection of endotoxin with a sensitivity that is comparable to the LAL assay. FLG also triggered TNF-[alpha] production in the presence of the LPS inhibitor, pointing to an intrinsic pro-inflammatory effect. Finally, we present guidelines for the preparation of endotoxin-free GO, validated by using the TET.