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Abstract Self-renewal is a crucial property of glioblastoma cells that is enabled by the choreographed functions of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could therefore represent an important step toward developing effective treatments for this universally lethal cancer. Here we uncover an epigenetic axis of self-renewal mediated by the histone variant macroH2A2. With omics and functional assays deploying patient-derived in vitro and in vivo models, we show that macroH2A2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. macroH2A2 also sensitizes cells to small molecule-mediated cell death via activation of a viral mimicry response. Consistent with these results, our analyses of clinical cohorts indicate that high transcriptional levels of this histone variant are associated with better prognosis of high-grade glioma patients. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest additional treatment approaches for glioblastoma patients.

Patients with advanced cardiogenic shock requiring mechanical circulatory support are uniquely susceptible to clinical deterioration. Limiting physiologic perturbations via avoidance of general anesthesia and endotracheal intubation by awake Impella 5.5 placement is safe and may represent a novel strategy in mechanical circulatory support initiation among patients in cardiogenic shock. (Level of Difficulty: Intermediate.)

Magnetic particle imaging (MPI) provides hotspot tracking and direct quantification of superparamagnetic iron oxide nanoparticle (SPIO)-labelled cells. Bioluminescence imaging (BLI) with the luciferase reporter gene Akaluc can provide complementary information on cell viability. Thus, we explored combining these technologies to provide a more holistic view of cancer cell fate in mice. Akaluc-expressing 4T1Br5 cells were labelled with the SPIO Synomag-D and injected into the mammary fat pads (MFP) of four nude mice. BLI was performed on days 0, 6 and 13, and MPI was performed on days 1, 8 and 14. Ex vivo histology and fluorescence microscopy of MFP and a potential metastatic site was conducted. The BLI signal in the MFP increased significantly from day 0 to day 13 (p < 0.05), mirroring tumor growth. The MPI signal significantly decreased from day 1 to day 14 (p < 0.05) due to SPIO dilution in proliferating cells. Both modalities detected secondary metastases; however, they were visualized in different anatomical regions. Akaluc BLI complemented MPI cell tracking, allowing for longitudinal measures of cell viability and sensitive detection of distant metastases at different locations. We predict this multimodal imaging approach will help to evaluate novel therapeutics and give a better understanding of metastatic mechanisms.

Human activities create threats that have consequences for freshwater ecosystems and, in most watersheds, observed ecological responses are the result of complex interactions among multiple threats and their associated ecological alterations. Here we discuss the value of considering multiple threats in research and management, offer suggestions for filling knowledge gaps, and provide guidance for addressing the urgent management challenges posed by multiple threats in freshwater ecosystems. There is a growing literature assessing responses to multiple alterations, and we build off this background to identify three areas that require greater attention: linking observed alterations to threats, understanding when and where threats overlap, and choosing metrics that best quantify the effects of multiple threats. Advancing science in these areas will help us understand existing ecosystem conditions and predict future risk from multiple threats. Because addressing the complex issues and novel ecosystems that arise from the interaction of multiple threats in freshwater ecosystems represents a significant management challenge, and the risks of management failure include loss of biodiversity, ecological goods, and ecosystem services, we also identify actions that could improve decision-making and management outcomes. These actions include drawing insights from management of individual threats, using threat attributes (e.g., causes and spatio-temporal dynamics) to identify suitable management approaches, testing management strategies that are likely to be successful despite uncertainties about the nature of interactions among threats, avoiding unintended consequences, and maximizing conservation benefits. We also acknowledge the broadly applicable challenges of decision-making within a socio-political and economic framework, and suggest that multidisciplinary teams will be needed to innovate solutions to meet the current and future challenge of interacting threats in freshwater ecosystems.

Pharmaceuticals and personal care products (PPCPs) are ubiquitous in freshwater ecosystems worldwide and are recognized as contaminants of concern. Currently, contaminants of concern are classified for their persistence, bioaccumulation, and toxicity (PBT criteria). PPCPs are not classified as persistent organic pollutants (POPs), although some PPCPs share characteristics similar to POPs. For example, PPCPs are known to be pseudopersistent due to constant discharge into the environment, often at low concentrations. At commonly reported environmental concentrations, PPCPs are rarely toxic, but the ability of these compounds to disrupt ecological processes and functions in freshwater ecosystems is often overlooked. Herein we briefly summarize recent studies highlighting the potential ecological effects of PPCPs, including effects on key ecological processes (e.g. primary productivity and community respiration), and we propose that appropriate screening for harmful effects of PPCPs in surface waters should be expanded to include Ecologically Disrupting Compounds (EcoDC) in addition to the established PBT criteria.

Abstract The ecological dynamics of microplastic (

Background. Despite the favourable effects of adiponectin on the vasculature and insulin resistance (IR), levels are increased in patients with end-stage kidney disease (ESKD), in whom both IR and atherosclerosis are prevalent.Methods. To investigate this paradox, we examined the distribution of adiponectin isoforms, the expression of adiponectin receptor (AdipoR) mRNA on peripheral blood mononuclear cells (PBMC) in 41 patients with ESKD on haemodialysis and 41 matched controls, and its function by adenosine monophosphate-activated protein kinase (AMPK) phosphorylation of AdipoR on PBMC. We also compared the expression of AdipoR on PBMC with that on muscle and subcutaneous and visceral fat in 10 patients undergoing elective cholecystectomy.Results. The proportion of the high molecular weight (HMW) isoform of adiponectin was increased in the dialysis group (P = 0.001), even though these patients were significantly insulin resistant compared with controls (P = 0.006). AdipoR1 and AdipoR2 on PBMC were also increased in patients with ESKD (P < 0.05 and P = 0.007, respectively), but levels did not correlate with IR, the HMW isoform or other anthropometric measurements. There was a strong correlation between AdipoR1 and AdipoR2 on PBMC in ESKD and in subcutaneous and visceral fat in controls. However, there was no relationship between AdipoR in PBMC, muscle or visceral fat. Phosphorylation of AMPK by recombinant adiponectin showed that AdipoR on PBMC, from controls and ESKD patients, were equally functional.Conclusions. IR in ESKD is not explained by the change in isoformic distribution, or by AdipoR down-regulation or dysfunction. Rather, this receptor-ligand axis is up-regulated and may be a beneficial response to the inflammatory milieu of ESKD. [ABSTRACT FROM AUTHOR]

Heavy metal contamination in an area immediately surrounding a zinc smelter has resulted in destruction of over 485 hectares of forest. The elevated levels of heavy metals in these soils have had significant impacts on the population size and overall activity of the soil microbial communities. Remediation of these soils has resulted in increases in indicators of biological activity and viable population size, which suggest recovery of the microbial populations. Questions remain as to how the metal contamination and subsequent remediation at this site have impacted the population structure of the soil microbial communities. In the current study, microbial communities from this site were analyzed by the phospholipid fatty acid (PLFA) procedure. Principal component analysis of the PLFA profiles indicated that there were differences in the profiles for soils with different levels of metal contamination, and that soils with higher levels of metal contamination showed decreases in indicator PLFAs for mycorrhizal fungi, Gram-positive bacteria, fungi, and actinomycetes. PLFA profiles for remediated sites indicated that remediated soils showed increases in indicator PLFAs for fungi, actinomycetes, and Gram-positive bacteria, compared to unremediated metal contaminated soils. These data suggest a change in the population structure of the soil microbial communities resulting from metal contamination and a recovery of several microbial populations resulting from remediation. [ABSTRACT FROM AUTHOR]

Microplastics are ubiquitous contaminants in aquatic habitats globally, and wastewater treatment plants (WWTPs) are point sources of microplastics. Within aquatic habitats microplastics are colonized by microbial biofilms, which can include pathogenic taxa and taxa associated with plastic breakdown. Microplastics enter WWTPs in sewage and exit in sludge or effluent, but the role that WWTPs play in establishing or modifying microplastic bacterial assemblages is unknown. We analyzed microplastics and associated biofilms in raw sewage, effluent water, and sludge from two WWTPs. Both plants retained >99% of influent microplastics in sludge, and sludge microplastics showed higher bacterial species richness and higher abundance of taxa associated with bioflocculation (e.g. Xanthomonas) than influent microplastics, suggesting that colonization of microplastics within the WWTP may play a role in retention. Microplastics in WWTP effluent included significantly lower abundances of some potentially pathogenic bacterial taxa (e.g. Campylobacteraceae) compared to influent microplastics; however, other potentially pathogenic taxa (e.g. Acinetobacter) remained abundant on effluent microplastics, and several taxa linked to plastic breakdown (e.g. Klebsiella, Pseudomonas, and Sphingomonas) were significantly more abundant on effluent compared to influent microplastics. These results indicate that diverse bacterial assemblages colonize microplastics within sewage and that WWTPs can play a significant role in modifying the microplastic-associated assemblages, which may affect the fate of microplastics within the WWTPs and the environment.

Production of titanium-dioxide nanomaterials (nano-TiO2) is increasing, leading to potential risks associated with unintended release of these materials into aquatic ecosystems. We investigated the acute effects of nano-TiO2 on metabolic activity and viability of algae and cyanobacteria using high-throughput screening. The responses of three diatoms (Surirella angusta, Cocconeis placentula, Achnanthidium lanceolatum), one green alga (Scenedesmus quadricauda), and three cyanobacteria (Microcystis aeruginosa, Gloeocapsa sp., Synechococcus cedrorum) to short-term exposure (15 to 60 min) to a common nano-TiO2 pigment (PW6; average crystallite size 81.5 nm) with simulated solar illumination were assessed. Five concentrations of nano-TiO2 (0.5, 2.5, 5, 10, and 25 mg L-1) were tested and a fluorescent reporter (fluorescein diacetate) was used to assess metabolic activity. Algae were sensitive to nano-TiO2, with all showing decreased metabolic activity after 30-min exposure to the lowest tested concentration. Microscopic observation of algae revealed increased abundance of dead cells with nano-TiO2 exposure. Cyanobacteria were less sensitive to nano-TiO2 than algae, with Gloeocapsa showing no significant decrease in activity with nano-TiO2 exposure and Synechococcus showing an increase in activity. These results suggest that nanomaterial contamination has the potential to alter the distribution of phototrophic microbial taxa within freshwater ecosystems. The higher resistance of cyanobacteria could have significant implications as cyanobacteria represent a less nutritious food source for higher trophic levels and some cyanobacteria can produce toxins and contribute to harmful algal blooms.

The nanotechnology industry is growing rapidly, leading to concerns about the potential ecological consequences of the release of engineered nanomaterials (ENMs) to the environment. One challenge of assessing the ecological risks of ENMs is the incredible diversity of ENMs currently available and the rapid pace at which new ENMs are being developed. High-throughput screening (HTS) is a popular approach to assessing ENM cytotoxicity that offers the opportunity to rapidly test in parallel a wide range of ENMs at multiple concentrations. However, current HTS approaches generally test one cell type at a time, which limits their ability to predict responses of complex microbial communities. In this study toxicity screening via a HTS platform was used in combination with next generation sequencing (NGS) to assess responses of bacterial communities from two aquatic habitats, Lake Michigan (LM) and the Chicago River (CR), to short-term exposure in their native waters to several commercial TiO2 nanomaterials under simulated solar irradiation. Results demonstrate that bacterial communities from LM and CR differed in their sensitivity to nano-TiO2, with the community from CR being more resistant. NGS analysis revealed that the composition of the bacterial communities from LM and CR were significantly altered by exposure to nano-TiO2, including decreases in overall bacterial diversity, decreases in the relative abundance of Actinomycetales, Sphingobacteriales, Limnohabitans, and Flavobacterium, and a significant increase in Limnobacter. These results suggest that the release of nano-TiO2 to the environment has the potential to alter the composition of aquatic bacterial communities, which could have implications for the stability and function of aquatic ecosystems. The novel combination of HTS and NGS described in this study represents a major advance over current methods for assessing ENM ecotoxicity because the relative toxicities of multiple ENMs to thousands of naturally occurring bacterial species can be assessed simultaneously under environmentally relevant conditions.

Pipes that transport drinking water through municipal drinking water distribution systems (DWDS) are challenging habitats for microorganisms. Distribution networks are dark, oligotrophic and contain disinfectants; yet microbes frequently form biofilms attached to interior surfaces of DWDS pipes. Relatively little is known about the species composition and ecology of these biofilms due to challenges associated with sample acquisition from actual DWDS. We report the analysis of biofilms from five pipe samples collected from the same region of a DWDS in Florida, USA, over an 18 month period between February 2011 and August 2012. The bacterial abundance and composition of biofilm communities within the pipes were analyzed by heterotrophic plate counts and tag pyrosequencing of 16S rRNA genes, respectively. Bacterial numbers varied significantly based on sampling date and were positively correlated with water temperature and the concentration of nitrate. However, there was no significant relationship between the concentration of disinfectant in the drinking water (monochloramine) and the abundance of bacteria within the biofilms. Pyrosequencing analysis identified a total of 677 operational taxonomic units (OTUs) (3% distance) within the biofilms but indicated that community diversity was low and varied between sampling dates. Biofilms were dominated by a few taxa, specifically Methylomonas, Acinetobacter, Mycobacterium, and Xanthomonadaceae, and the dominant taxa within the biofilms varied dramatically between sampling times. The drinking water characteristics most strongly correlated with bacterial community composition were concentrations of nitrate, ammonium, total chlorine and monochloramine, as well as alkalinity and hardness. Biofilms from the sampling date with the highest nitrate concentration were the most abundant and diverse and were dominated by Acinetobacter.