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Despite the formidable treatment challenges of pancreatic ductal adenocarcinoma (PDAC), considerable progress has been made in improving drug delivery via pioneering nanocarriers. These innovations are geared towards overcoming the obstacles presented by dysplastic stroma and fostering anti-PDAC immune reactions. We are currently conducting research aimed at enhancing chemotherapy to stimulate anti-tumor immunity by inducing immunogenic cell death (ICD). This is accomplished using lipid bilayer-coated nanocarriers, which enable the attainment of synergistic results. Noteworthy examples include liposomes and lipid-coated mesoporous silica nanoparticles known as silicasomes. These nanocarriers facilitate remote chemotherapy loading, as well as the seamless integration of immunomodulators into the lipid bilayer. In this communication, we elucidate innovative ways for further improving chemo-immunotherapy. The first is the development of a liposome platform engineered by the remote loading of irinotecan while incorporating a pro-resolving lipoxin in the lipid bilayer. This carrier interfered in stromal collagen deposition, as well as boosting the irinotecan-induced ICD response. The second approach was to synthesize polymer nanoparticles for the delivery of mutated KRAS peptides in conjunction with a TLR7/8 agonist. The dual delivery vaccine particle boosted the generation of antigen-specific cytotoxic T-cells that are recruited to lymphoid structures at the cancer site, with a view to strengthening the endogenous vaccination response achieved by chemo-immunotherapy.

2D boron nitride (BN) and molybdenum disulfide (MoS2 ) materials are increasingly being used for applications due to novel chemical, electronic, and optical properties. Although generally considered biocompatible, recent data have shown that BN and MoS2 could potentially be hazardous under some biological conditions, for example, during, biodistribution of drug carriers or imaging agents to the liver. However, the effects of these 2D materials on liver cells such as Kupffer cells (KCs), liver sinusoidal endothelial cells, and hepatocytes, are unknown. Here, the toxicity of BN and MoS2 , dispersed in Pluronic F87 (designated BN-PF and MoS2 -PF) is compared with aggregated forms of these materials (BN-Agg and MoS2 -Agg) in liver cells. MoS2 induces dose-dependent cytotoxicity in KCs, but not other cell types, while the BN derivatives are non-toxic. The effect of MoS2 could be ascribed to nanosheet dissolution and the release of hexavalent Mo, capable of inducing mitochondrial reactive oxygen species generation and caspases 3/7-mediated apoptosis in KUP5 cells. In addition, the phagocytosis of MoS2 -Agg triggers an independent response pathway involving lysosomal damage, NLRP3 inflammasome activation, caspase-1 activation, IL-1β, and IL-18 production. These findings demonstrate the importance of Mo release and the state of dispersion of MoS2 in impacting KC viability.

The mononuclear phagocyte system in the liver is a frequent target for nanoparticles (NPs). A toxicological profiling of metal-based NPs is performed in Kupffer cell (KC) and hepatocyte cell lines. Sixteen NPs are provided by the Nanomaterial Health Implications Research Consortium of the National Institute of Environmental Health Sciences to study the toxicological effects in KUP5 (KC) and Hepa 1-6 cells. Five NPs (Ag, CuO, ZnO, SiO2 , and V2 O5 ) exhibit cytotoxicity in both cell types, while SiO2 and V2 O5 induce IL-1β production in KC. Ag, CuO, and ZnO induced caspase 3 generated apoptosis in both cell types is accompanied by ion shedding and generation of mitochondrial reactive oxygen species (ROS) in both cell types. However, the cell death response to SiO2 in KC differs by inducing pyroptosis as a result of potassium efflux, caspase 1 activation, NLRP3 inflammasome assembly, IL-1β release, and cleavage of gasdermin-D. This releases pore-performing peptide fragments responsible for pyroptotic cell swelling. Interestingly, although V2 O5 induces IL-1β release and delays caspase 1 activation by vanadium ion interference in membrane Na+ /K+ adenosine triphosphate (ATP)ase activity, the major cell death mechanism in KC (and Hepa 1-6) is caspase 3 mediated apoptosis. These findings improve the understanding of the mechanisms of metal-based engineered nanomaterial (ENM) toxicity in liver cells toward comprehensive safety evaluation.

Nanocellulose is increasingly considered for applications; however, the fibrillar nature, crystalline phase, and surface reactivity of these high aspect ratio nanomaterials need to be considered for safe biomedical use. Here a comprehensive analysis of the impact of cellulose nanofibrils (CNF) and nanocrystals (CNC) is performed using materials provided by the Nanomaterial Health Implications Research Consortium of the National Institute of Environmental Health Sciences. An intermediary length of nanocrystals is also derived by acid hydrolysis. While all CNFs and CNCs are devoid of cytotoxicity, 210 and 280 nm fluorescein isothiocyanate (FITC)-labeled CNCs show higher cellular uptake than longer and shorter CNCs or CNFs. Moreover, CNCs in the 200-300 nm length scale are more likely to induce lysosomal damage, NLRP3 inflammasome activation, and IL-1β production than CNFs. The pro-inflammatory effects of CNCs are correlated with higher crystallinity index, surface hydroxyl density, and reactive oxygen species generation. In addition, CNFs and CNCs can induce maturation of bone marrow-derived dendritic cells and CNCs (and to a lesser extent CNFs) are found to exert adjuvant effects in ovalbumin (OVA)-injected mice, particularly for 210 and 280 nm CNCs. All considered, the data demonstrate the importance of length scale, crystallinity, and surface reactivity in shaping the innate immune response to nanocellulose.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The pine pitch canker fungus, Fusarium circinatum, has caused large-scale mortality of Pinus patula crops in South African nurseries and high in-field post-planting mortality. Tree breeders have identified selection and breeding of tolerant material as the likely long-term solution to this disease. In this study, the greenhouse artificial inoculation screening method was employed to investigate the genetic control of F. circinatum tolerance in a factorial mating design of Pinus patula × P. tecunumanii low elevation (PPTL) and high elevation (PPTH) hybrid families and their parental species. Results indicated that F. circinatum tolerance is under moderate genetic control (h2 between 0.13 and 0.36) as assessed in a hybrid factorial mating design with a large number of PPTL and PPTH families. The PPTL hybrid displayed the highest level of tolerance, followed by pure P. tecunumanii LE, then the PPTH hybrid, pure P. tecunumanii HE and lastly pure P. patula. A general hybridising ability (GHA) and specific hybridising ability (SHA) analysis was also conducted to rank parent families as well as hybrid families. These breeding values can be used to identify superior families for commercial production and further breeding. A poor correlation between frost tolerance and F. circinatum tolerance was also found when compared to a previous frost tolerance study utilising the same hybrid families. The results from this study indicated that it is possible for breeders to cross selected P. patula seed parents with selected P. tecunumanii pollen parents to develop F. circinatum tolerant hybrid families for commercial production. [ABSTRACT FROM AUTHOR]

Applying BEAST v1.10.4, we constructed a Bayesian Inference tree comprising 322 taxa, primarily representing Paleoptera (Odonata and Ephemeroptera; Pterygota), Zygentoma and Archaeognatha (Apterygota; paraphyly), and Neoptera (Plecoptera; Pterygota), based on a 2685 bp sequence dataset. Our analyses revealed that robust dating required the incorporation of both Quaternary and pre‐Quaternary dates. To achieve this, our dating incorporated a 1.55 Ma (Quaternary) geological event (the formation of the Ryukyu Islands) and a set of chronologically well‐founded fossil dates, spanning from up to 400 Ma (Devonian) for the stem Archaeognatha, 320 Ma (Carboniferous) for the crown of Paleoptera, 300 Ma (Carboniferous) for the crown Ephemeroptera, and 280 Ma (Permian) for the crown Odonata, down to 1.76 Ma (Quaternary) for Calopteryx japonica, encompassing a total of 22 calibration points (events: 6, fossils: 16; Quaternary: 7, pre‐Quaternary: 15). The resulting dated tree aligns with previous research, albeit with some dates being overestimated. This overestimation was mainly due to the lack of Quaternary calibration and the exclusive dependence on pre‐Quaternary calibration, though the application of maximum age constraints also played a role. Our minimum age dating demonstrates that the molecular clock did not uniformly progress, rendering rate dating an inapplicable approach. We observed that the base substitution rate is time‐dependent, with an exponential increase evident from around 20 Ma (Miocene) to the present time, exceeding an order of magnitude. The extensive radiation and speciation of Insecta and Paleoptera, potentially resulting from the severe climatic changes associated with the Quaternary, including the commencement of glacial and interglacial cycles, may have significantly contributed to this increase in base substitution rates. Additionally, we identified a potential peak in base substitution rates during the Carboniferous period, around 320 million years ago, possibly corresponding to the Late Paleozoic Ice Age. [ABSTRACT FROM AUTHOR]

Valgus cantalensis sp. nov., second fossil species of the scarabaeid subfamily Valginae, is described from the Upper Miocene Konservat-Laggerstätte of Sainte-Reine (France). The fossil is compared to the extant valgine genera and Valgus spp., showing it is a new species. But its exact affinities in the genus Valgus remain undetermined because of the lacking of a recent morphological phylogenetic analysis of the Valgus spp. [ABSTRACT FROM AUTHOR]

The family of two-dimensional (2D) materials is comprised of a continually expanding palette of unique compositions and properties with potential applications in electronics, optoelectronics, energy capture and storage, catalysis, and nanomedicine. To accelerate the implementation of 2D materials in widely disseminated technologies, human health and environmental implications need to be addressed. While extensive research has focused on assessing the toxicity and environmental fate of graphene and related carbon nanomaterials, the potential hazards of other 2D materials have only recently begun to be explored. Herein, the toxicity and environmental fate of postcarbon 2D materials, such as transition metal dichalcogenides, hexagonal boron nitride, and black phosphorus, are reviewed as a function of their preparation methods and surface functionalization. Specifically, we delineate how the hazard potential of 2D materials is directly related to structural parameters and physicochemical properties and how experimental design is critical to the accurate elucidation of the underlying toxicological mechanisms. Finally, a multidisciplinary approach for streamlining the hazard assessment of emerging 2D materials is outlined, thereby providing a pathway for accelerating their safe use in a range of technologically relevant contexts.

Carbon nanotubes (CNTs) exhibit a number of physicochemical properties that contribute to adverse biological outcomes. However, it is difficult to define the independent contribution of individual properties without purified materials. A library of highly purified single-walled carbon nanotubes (SWCNTs) of different lengths is prepared from the same base material by density gradient ultracentrifugation, designated as short (318 nm), medium (789 nm), and long (1215 nm) SWCNTs. In vitro screening shows length-dependent interleukin-1β (IL-1β) production, in order of long > medium > short. However, there are no differences in transforming growth factor-β1 production in BEAS-2B cells. Oropharyngeal aspiration shows that all the SWCNTs induce profibrogenic effects in mouse lung at 21 d postexposure, but there are no differences between tube lengths. In contrast, these SWCNTs demonstrate length-dependent antibacterial effects on Escherichia coli, with the long SWCNT exerting stronger effects than the medium or short tubes. These effects are reduced by Pluronic F108 coating or supplementing with glucose. The data show length-dependent effects on proinflammatory response in macrophage cell line and antibacterial effects, but not on collagen deposition in the lung. These data demonstrate that over the length scale tested, the biological response to highly purified SWCNTs is dependent on the complexity of the nano/bio interface.

The liver and the mononuclear phagocyte system are a frequent target for engineered nanomaterials, either as a result of particle uptake and spread from primary exposure sites or systemic administration of therapeutic and imaging nanoparticles. In this study, we performed a comparative analysis of the toxicological impact of 29 metal oxide nanoparticles (NPs), some commonly used in consumer products, in transformed or primary Kupffer cells (KCs) and hepatocytes. We not only observed differences between KCs and hepatocytes, but also differences in the toxicological profiles of transition-metal oxides (TMOs, e. g., Co3O4) versus rare-earth oxide (REO) NPs ( e. g., Gd2O3). While pro-oxidative TMOs induced the activation of caspases 3 and 7, resulting in apoptotic cell death in both cell types, REOs induced lysosomal damage, NLRP3 inflammasome activation, caspase 1 activation, and pyroptosis in KCs. Pyroptosis was accompanied by cell swelling, membrane blebbing, IL-1β release, and increased membrane permeability, which could be reversed by knockdown of the pore forming protein, gasdermin D. Though similar features were not seen in hepatocytes, the investigation of the cytotoxic effects of REO NPs could also be seen to affect macrophage cell lines such as J774A.1 and RAW 264.7 cells as well as bone marrow-derived macrophages. These phagocytic cell types also demonstrated features of pyroptosis and increased IL-1β production. Collectively, these findings demonstrate important mechanistic considerations that can be used for safety evaluation of metal oxides, including commercial products that are developed from these materials.

Nanoenabled products (NEPs) have numerous outdoor uses in construction, transportation or consumer scenarios, and there is evidence that their fragments are released in the environment at low rates. We hypothesized that the lower surface availability of NEPs fragment reduced their environmental effects with respect to pristine nanomaterials. This hypothesis was explored by testing fragments generated by intentional micronisation ("the SUN approach"; Nowack et al. Meeting the Needs for Released Nanomaterials Required for Further Testing: The SUN Approach. Environmental Science & Technology, 2016 (50), 2747). The NEPs were composed of four matrices (epoxy, polyolefin, polyoxymethylene, and cement) with up to 5% content of three nanomaterials (carbon nanotubes, iron oxide, and organic pigment). Regardless of the type of nanomaterial or matrix used, it was observed that nanomaterials were only partially exposed at the NEP fragment surface, indicating that mostly the intrinsic and extrinsic properties of the matrix drove the NEP fragment toxicity. Ecotoxicity in multiple assays was done covering relevant media from terrestrial to aquatic, including sewage treatment plant (biological activity), soil worms (Enchytraeus crypticus), and fish (zebrafish embryo and larvae and trout cell lines). We designed the studies to explore the possible modulation of ecotoxicity by nanomaterial additives in plastics/polymer/cement, finding none. The results support NEPs grouping by the matrix material regarding ecotoxicological effect during the use phase. Furthermore, control results on nanomaterial-free polymer fragments representing microplastic had no significant adverse effects up to the highest concentration tested.

Genetic variation constitutes an important variable impacting the susceptibility to inhalable toxic substances and air pollutants, as reflected by epidemiological studies in humans and differences among animal strains. While multiwalled carbon nanotubes (MWCNTs) are capable of causing lung fibrosis in rodents, it is unclear to what extent the genetic variation in different mouse strains influence the outcome. Four inbred mouse strains, including C57Bl/6, Balb/c, NOD/ShiLtJ, and A/J, to test the pro-fibrogenic effects of a library of MWCNTs in vitro and in vivo are chosen. Ex vivo analysis of IL-1β production in bone marrow-derived macrophages (BMDMs) as molecular initiating event (MIE) is performed. The order of cytokine production (Balb/c > A/J > C57Bl/6 > NOD/ShiLtJ) in BMDMs is also duplicated during assessment of IL-1β production in the bronchoalveolar lavage fluid of the same mouse strains 40 h after oropharyngeal instillation of a representative MWCNT. Animal test after 21 d also confirms a similar hierarchy in TGF-β1 production and collagen deposition in the lung. Statistical analysis confirms a correlation between IL-1β production in BMDM and the lung fibrosis. All considered, these data demonstrate that genetic background indeed plays a major role in determining the pro-fibrogenic response to MWCNTs in the lung.

Given increasing use of copper-based nanomaterials, particularly in applications with direct release, it is imperative to understand their human and ecological risks. A comprehensive and systematic approach was used to determine toxicity and fate of several Cu nanoparticles (Cu NPs). When used as pesticides in agriculture, Cu NPs effectively control pests. However, even at low (5–20 mg Cu/plant) doses, there are metabolic effects due to the accumulation of Cu and generation of reactive oxygen species (ROS). Embedded in antifouling paints, Cu NPs are released as dissolved Cu+ 2 and in nano- and micron-scale particles. Once released, Cu NPs can rapidly (hours to weeks) oxidize, dissolve, and form CuS and other insoluble Cu compounds, depending on water chemistry (e.g. salinity, alkalinity, organic matter content, presence of sulfide and other complexing ions). More than 95% of Cu released into the environment will enter soil and aquatic sediments, where it may accumulate to potentially toxic levels (> 50–500 μg/L). Toxicity of Cu compounds was generally ranked by high throughput assays as: Cu+ 2 > nano Cu(0) > nano Cu(OH)2 > nano CuO > micron-scale Cu compounds. In addition to ROS generation, Cu NPs can damage DNA plasmids and affect embryo hatching enzymes. Toxic effects are observed at much lower concentrations for aquatic organisms, particularly freshwater daphnids and marine amphipods, than for terrestrial organisms. This knowledge will serve to predict environmental risks, assess impacts, and develop approaches to mitigate harm while promoting beneficial uses of Cu NPs.