We have profiled promoter DNA methylation alterations in 272 glioblastoma tumors in the context of The Cancer Genome Atlas (TCGA). We found that a distinct subset of samples displays concerted ...hypermethylation at a large number of loci, indicating the existence of a glioma-CpG island methylator phenotype (G-CIMP). We validated G-CIMP in a set of non-TCGA glioblastomas and low-grade gliomas. G-CIMP tumors belong to the proneural subgroup, are more prevalent among lower-grade gliomas, display distinct copy-number alterations, and are tightly associated with
IDH1 somatic mutations. Patients with G-CIMP tumors are younger at the time of diagnosis and experience significantly improved outcome. These findings identify G-CIMP as a distinct subset of human gliomas on molecular and clinical grounds.
► Identification of a CpG island methylator phenotype (G-CIMP) in gliomas ► G-CIMP is tightly associated with
IDH1 mutation ► G-CIMP patients are younger at diagnosis and display improved survival ► G-CIMP is more prevalent among low- and intermediate-grade gliomas
Mercury in seafood is a neurotoxicant that threatens human health. Dynamic rates of mercury emission, re-emission, and atmospheric deposition warrant studies into mercury concentrations in fish ...because many are consumed by humans and can serve as sentinels of mercury levels in the environment. We modeled trends in total mercury content in an apex marine fish predator, Atlantic blue marlin Makaira nigricans, whose muscle tissues were opportunistically sampled from North Carolina (USA) sportfishing tournaments over a discontinuous time period: between 1975 and 77 and 1998–2021 (n = 148). The model-estimated influence of marlin weight on total mercury concentration was constant across years (shared slope) allowing for comparisons of weight-corrected mercury concentrations among years. Weight-corrected total mercury concentrations revealed an inter-decadal decline of approximately 45 % between the 1970s and late 1990s and then variable but relatively stable concentrations through 2021. The mean (SD) wet weight concentration of total mercury was 9.47 (4.11) from 1975 to 77 and 4.17 (2.61) from 2020 to 2021. Methylmercury and selenium were measured on a subset of fish to address questions related to human health and consumption. Methylmercury levels (mean = 0.72 μg/g) were much lower than total mercury (mean = 4.69 μg/g) indicating that total mercury is not a good proxy for methylmercury in Atlantic blue marlin. Selenium, examined as a Se:Hg molar ratio and as a selenium health benefit value (HBVSe), showed high protective value against mercury toxicity. Long-term trends in the concentration of mercury in blue marlin should continue to be monitored to determine whether policies to mitigate anthropogenic contributions to global mercury are achieving their intended goals and to provide information to inform safe human consumption.
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•Long-term studies of offshore marine apex predators are valuable for indexing ambient heavy metal concentrations.•Atlantic blue marlin muscle collected from 1975 to 2021 was analyzed for total mercury, methylmercury, and selenium.•Total mercury concentrations declined from the 1970s to late 1990s, but remained approximately constant during this century.•Methylmercury is a small percentage of total mercury in Atlantic blue marlin, which is not typically observed in fish.•High selenium concentrations in Atlantic blue marlin tissue may substantially offset mercury toxicity in human consumers.
The Iceland and Greenland Seas are a crucial region for the climate system, being the headwaters of the lower limb of the Atlantic Meridional Overturning Circulation. Investigating the ...atmosphere–ocean–ice processes in this region often necessitates the use of meteorological reanalyses—a representation of the atmospheric state based on the assimilation of observations into a numerical weather prediction system. Knowing the quality of reanalysis products is vital for their proper use. Here we evaluate the surface‐layer meteorology and surface turbulent fluxes in winter and spring for the latest reanalysis from the European Centre for Medium‐Range Weather Forecasts, i.e., ERA5. In situ observations from a meteorological buoy, a research vessel, and a research aircraft during the Iceland–Greenland Seas Project provide unparalleled coverage of this climatically important region. The observations are independent of ERA5. They allow a comprehensive evaluation of the surface meteorology and fluxes of these subpolar seas and, for the first time, a specific focus on the marginal ice zone. Over the ice‐free ocean, ERA5 generally compares well to the observations of surface‐layer meteorology and turbulent fluxes. However, over the marginal ice zone, the correspondence is noticeably less accurate: for example, the root‐mean‐square errors are significantly higher for surface temperature, wind speed, and surface sensible heat flux. The primary reason for the difference in reanalysis quality is an overly smooth sea‐ice distribution in the surface boundary conditions used in ERA5. Particularly over the marginal ice zone, unrepresented variability and uncertainties in how to parameterize surface exchange compromise the quality of the reanalyses. A parallel evaluation of higher‐resolution forecast fields from the Met Office's Unified Model corroborates these findings.
Spatial maps of sea‐ice distribution from 8 March 2018 with sensible heat flux (W·m−2) overplotted as dots. The top panel shows satellite‐derived sea‐ice fraction contours from AMSR2 with aircraft observations. The bottom panel shows sea‐ice fraction contours from OSTIA with ERA5 output. Note that the OSTIA sea‐ice distribution is used in ERA5 and is, incorrectly, too smooth across the marginal ice zone, which has an impact on the accuracy of surface‐layer meteorology and turbulent fluxes.
The bioavailability of 38 individual polycyclic aromatic hydrocarbon (PAH) compounds was determined through calculation of biota−sediment-accumulation factors (BSAF). BSAF values were calculated from ...individual PAH concentrations in freshwater mussel, marine clam, and sediment obtained from field and laboratory bioaccumulation studies. Sediment that was amended with different types of soot carbon (SC) was used in some of the bioaccumulation experiments. BSAF values for petrogenic PAH were greater than those for pyrogenic PAH (e.g., 1.57 ± 0.53 vs 0.25 ± 0.23, respectively), indicating that petrogenic PAH are more bioavailable than pyrogenic PAH (p < 0.05). This trend was consistent among marine and freshwater sites. Increased SC content of sediment resulted in a linear decrease in the bioavailability of pyrogenic PAHs (r 2 = 0.85). The effect of increasing SC content on petrogenic PAH was negligible. SC was considered as an additional sorptive phase when calculating BSAF values, and using PAH−SC partition coefficients from the literature, we obtained unreasonably large BSAF values for all petrogenic PAH and some pyrogenic PAH. This led us to conclude that a quantitative model to assess bioavailability through a combination of organic carbon and soot carbon sorption is not applicable among field sites with a wide range of soot carbon fractions and PAH sources, at least given our current knowledge of PAH−SC partitioning. Our data offer evidence that many factors including analysis of a full suite of PAH analytes, PAH hydrophobicity, sediment organic carbon content, sediment soot carbon content, and PAH source are important to adequately assess PAH bioavailability in the environment.
ABSTRACT
Hereditary spastic paraplegia (HSP) is a group of degenerative neurological disorders. We identified a variant in human kinesin light chain 4 (KLC4) that is suspected to be associated with ...autosomal-dominant HSP. How this and other variants relate to pathologies is unknown. We created a humanized Caenorhabditis elegans model in which klc-2 was replaced by human KLC4 (referred to as hKLC4) and assessed the extent to which hKLC4 retained function in the worm. We observed a slight decrease in motility but no nuclear migration defects in the humanized worms, suggesting that hKLC4 retains much of the function of klc-2. Five hKLC4 variants were introduced into the humanized model. The clinical variant led to early lethality, with significant defects in nuclear migration when homozygous and a weak nuclear migration defect when heterozygous, possibly correlating with the clinical finding of late-onset HSP when the proband was heterozygous. Thus, we were able to establish humanized C. elegans as an animal model for HSP and to use it to test the significance of five variants of uncertain significance in the human gene KLC4.
Ammonia toxicity data for freshwater mussels (Unionidae), a significantly imperiled taxa, were used to derive estimates of concentrations that would not likely be harmful in acute and chronic ...exposures and to assess the protectiveness of current U.S. Environmental Protection Agency (U.S. EPA) water quality criteria to this family of organisms. Thirty acute (24–96‐h) median lethal concentrations (LC50s), covering 10 species in eight unionid genera, were used to calculate genus mean acute values (GMAVs) ranging from 2.56 to 8.97 mg/L total ammonia as N at pH 8. Freshwater mussels are at the sensitive end of the range when added to the GMAVs from the database used to derive the U.S. EPA criteria maximum concentration (CMC). We derived two estimates of acute exposure water quality guidance for the protection of freshwater mussels (CMCFM) by a recalculation of the CMC after adding freshwater mussel GMAVs to the U.S. EPA data set. The CMCFMs of 1.75 and 2.50 mg/L total ammonia as N at pH 8 average 60% less than the U.S. EPA CMC of 5.62 mg/L total ammonia as N at pH 8 for application when salmonids are present. These values average about 75% less than the CMC for application when salmonids are absent. No chronic ammonia exposure data existed for unionids. Thus, we applied a range of estimated acute:chronic ratios to the acute toxicity data set, expanded with the freshwater mussel GMAVs, to estimate continuous ammonia concentrations that may be protective of freshwater mussels. These estimates ranged from 0.3 to 1.0 mg/L total ammonia as N at pH 8, about 20 to 75% less than the U.S. EPA criteria continuous concentration (CCC) of 1.24 mg/L total ammonia as N at pH 8 and 25°C. The current numeric criteria for ammonia may not be protective of mussels, more than half of whose nearly 300 species are in decline in North America. While the CMCFM and CCCFM are not equivalent to revised U.S. EPA criteria, they are offered as interim guidance for the protection of freshwater mussels.
Rapid changes in salinity, as with other environmental stressors, can have detrimental effects on fish and may trigger increased susceptibility to disease. However, the precise mechanisms of these ...effects are not well understood. We examined the effects of sudden increases or decreases in salinity on teleost immune function using Nile tilapia, Oreochromis niloticus (L.), as the fish model in a battery of bioassays of increasing immune system specificity. Two different salinity experiments were performed: one of increasing salinity (0 to 5, 10 and 20 g L−1) and one of decreasing salinity (20 to 15, 10 and 5 g L−1). Histopathology of anterior kidney, gills, gonads, intestines and liver of exposed fish was performed, but no remarkable lesions were found that were attributable to the salinity treatment regimes. The spleen was removed from each fish for analysis of cytokine expression, and peripheral blood was used for haematology, cortisol and phagocytosis assays. In the increasing salinity experiments, no significant changes were observed in any immune system assays. However, in the decreasing salinity experiments, lymphopenia, neutrophilia and monocytosis were observed in the peripheral blood without modification of the packed cell volume, plasma protein or plasma cortisol levels. Phagocytosis was increased in response to decreases in salinity from 20 g L−1 to 15 g L−1, 10 g L−1 and 5 g L−1, whereas phagocytic index was not significantly altered. Transforming growth factor‐β (TGF‐β) transcription increased during the same decreases in salinity. However, the TGF‐β value at 5 g L−1 was less than those in the 15 and 10 g L−1 salinity treatments. Interleukin‐1β (IL‐1β) transcription did not significantly respond to either salinity regime. In total, acute salinity changes appeared to trigger reactive dysregulation of the immune response in tilapia, a situation which, when combined with additional co‐occurring stressors such as sudden changes in temperature and/or dissolved oxygen, could make fish more susceptible to infectious diseases. Accordingly, these findings may help to explain how sudden environmental changes may initiate disease outbreaks and lead to critical declines in cultured or wild fish populations.
Objectives
Silver carbenes may represent novel, broad-spectrum antimicrobial agents that have low toxicity while providing varying chemistry for targeted applications. Here, the bactericidal activity ...of four silver carbene complexes (SCCs) with different formulations, including nanoparticles (NPs) and micelles, was tested against a panel of clinical strains of bacteria and fungi that are the causative agents of many skin and soft tissue, respiratory, wound, blood, and nosocomial infections.
Methods
MIC, MBC and multidose experiments were conducted against a broad range of bacteria and fungi. Time-release and cytotoxicity studies of the compounds were also carried out. Free SCCs and SCC NPs were tested against a panel of medically important pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Acinetobacter baumannii (MRAB), Pseudomonas aeruginosa, Burkholderia cepacia and Klebsiella pneumoniae.
Results
All four SCCs demonstrated strong efficacy in concentration ranges of 0.5-90 mg/L. Clinical bacterial isolates with high inherent resistance to purified compounds were more effectively treated either with an NP formulation of these compounds or by repeated dosing. Overall, the compounds were active against highly resistant bacterial strains, such as MRSA and MRAB, and were active against the biodefence pathogens Bacillus anthracis and Yersinia pestis. All of the medically important bacterial strains tested play a role in many different infectious diseases.
Conclusions
The four SCCs described here, including their development as NP therapies, show great promise for treating a wide variety of bacterial and fungal pathogens that are not easily killed by routine antimicrobial agents.
As concerns mount over the human health risks associated with consumption of fish contaminated with persistent organic pollutants, there exists a need to better evaluate fish body burdens without ...lethally sampling many of the important commercial and sport species of interest. The aim of this study was to investigate two novel methods for estimating organic contaminants in fish that are a concern for both fish and human health. The removal of fish adipose fins, commonly done in mark−recapture studies with salmonid species, was evaluated as a nonlethal sampling technique to estimate concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in flathead catfish (Pylodictis olivaris), relative to those found in muscle fillets of the same fish. We also assessed the efficacy of using poly(dimethylsiloxane) (PDMS) as a mobile passive sampling device (PSD) attached directly to wild flathead catfish for assessing location-specific exposure of the fish to waterborne contaminants. The results of this study have demonstrated for the first time that organic contaminant concentrations in adipose fin were highly correlated (R 2 = 0.87) with muscle fillet concentrations, indicating that the adipose fin of certain fishes may be used to accurately estimate tissue concentrations without the need for lethal sampling. Moreover, mobile PSDs attached directly to fish and used here for the first time accurately estimated ultratrace concentrations of waterborne PCBs and OCPs without any apparent harm to the fish, indicating that there are no practical or physical barriers to the use of mobile passive samplers attached to aquatic organisms. Among the many practical implications of this research, two potential priority items include the analysis of organic contaminants in farm-raised and sport fish intended for human consumption, without the economic and population losses associated with lethally sampling fish to obtain tissues, and identifying specific areas where fish may be accumulating large portions of their contaminant burden.
Zebra mussels (Dreissena polymorpha) were sampled from artificial substrates deployed from May 30 to October 19, 1995, at 19 locks and dams from Minneapolis, MN, to Muscatine, IA. Analyses of ...composite tissue samples of zebra mussels (10−20-mm length) revealed accumulation of mercury (Hg), cadmium (Cd), and polychlorinated biphenyls (PCBs) during a 143-d exposure period. Concentrations of total Hg ranged from 2.6 to 6.1 ng/g wet weight and methylmercury (CH3Hg) from 1.0 to 3.3 ng/g wet weight. About 50% (range 30−70%) of the mean total Hg in zebra mussels was CH3Hg. Cadmium ranged from 76 to 213 ng/g wet weight. Concentrations of total PCBs (Aroclor 1254) in zebra mussels varied longitudinally (range 1000−7330 ng/g lipid weight), but the composition of PCB congeners (total of 21 measured) was similar throughout the river. Chlordane and dieldrin were the only two pesticides detected of the 15 analyzed. Zebra mussels are sentinels of contaminant bioavailability in the Upper Mississippi River and may be an important link in the trophic transfer of contaminants in the river because of their increasing importance in the diets of certain fish and waterfowl.
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