Oxime antidotes regenerate organophosphate‐inhibited acetylcholinesterase (AChE). Although they share a common mechanism of AChE reactivation, the rate and amount of oxime that enters the brain are critical to the efficacy, a process linked to the oxime structure and charge. Using a platform based on the organophosphate [18F]‐VXS as a positron emission tomography tracer for active AChE, the
Xenoestrogens are chemicals found in plant products, such as genistein (GEN), and in industrial chemicals, e.g., bisphenol A (BPA), present in plastics and other products that are prevalent in the environment. Early exposure to such endocrine disrupting chemicals (EDC) may affect brain development by directly disrupting neural programming and/or through the microbiome-gut-brain axis. To test this hypothesis, California mice (
- NSF-PAR ID:
- 10167474
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 10
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract in vivo distribution of [18F]‐VXS was evaluated after an LD50dose (250 μg/kg) of the organophosphate paraoxon (POX) and following oximes as antidotes. Rats given [18F]‐VXS tracer alone had significantly higher radioactivity (two‐ to threefold) in the heart and lung than rats given LD50POX at 20 or 60 min prior to [18F]‐VXS. When rats were given LD50POX followed by 2‐PAM (cationic), RS194b (ionizable), or monoisonitrosoacetone (MINA) (neutral), central nervous system (CNS) radioactivity returned to levels at or above untreated naive rats (no POX), whereas CNS radioactivity did not increase in rats given the dication oximes HI‐6 or MMB‐4. MINA showed a significant, pairwise increase in CNS brain radioactivity compared with POX‐treated rats. This newin vivo dynamic platform using [18F]‐VXS tracer measures and quantifies peripheral and CNS relative changes in AChE availability after POX exposure and is suitable for comparing oxime delivery and AChE reactivation in rats. -
null (Ed.)Accurate chromosome segregation relies on correct chromosome-microtubule interactions within a stable bipolar spindle apparatus. Thus, exposure to spindle disrupting compounds can impair meiotic division and genomic stability in oocytes. The endocrine disrupting activity of bisphenols such as bisphenol A (BPA) is well recognized, yet their damaging effects on spindle microtubules (MTs) is poorly understood. Here, we tested the effect(s) of acute exposure to BPA and bisphenol F (BPF) on assembled spindle stability in ovulated oocytes. Brief (4 h) exposure to increasing concentrations (5, 25, and 50 µg/mL) of BPA or BPF disrupted spindle organization in a dose-dependent manner, resulting in significantly shorter spindles with highly unfocused poles and fragmented pericentrin. The chromosomes remained congressed in an abnormally elongated metaphase-like configuration, yet normal end-on chromosome-MT attachments were reduced in BPF-treated oocytes. Live-cell imaging revealed a rapid onset of bisphenol-mediated spindle MT disruption that was reversed upon compound removal. Moreover, MT stability and regrowth were impaired in BPA-exposed oocytes, with few cold-stable MTs and formation of multipolar spindles upon MT regrowth. MT-associated kinesin-14 motor protein (HSET/KIFC1) labeling along the spindle was also lower in BPA-treated oocytes. Conversely, cold stable MTs and HSET labeling persisted after BPF exposure. Notably, inhibition of Aurora Kinase A limited bisphenol-mediated spindle pole widening, revealing a potential interaction. These results demonstrate rapid MT disrupting activity by bisphenols, which is highly detrimental to meiotic spindle stability and organization. Moreover, we identify an important link between these defects and altered distribution of key spindle associated factors as well as Aurora Kinase A activity.more » « less
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ABSTRACT Climate change and an increase in endangered species, are examples of technological advances negatively impacting the environment. As technology demands increase, an earnest effort to reduce the environmental impact of processing and manufacturing related activities is critical. From a business perspective, minimizing or removing toxic process chemicals is a high impact area that can increase work environment safety and decrease waste management costs. This work presents processing considerations when transitioning to greener alternative polymer resist solvents, for applications in nanomanufacturing with sustainability considerations. Within government contracting, process modifications that change product form, fit, or function require qualification and at minimum justification. This work presents the conversion from a chlorobenzene to anisole based solvent using a 495 kMW polymetheyl methacrylate polymer resin, without impacting form fit or function of the intended device. Resist conversion is of interest as the difference in the substituents of the two solvents, impact the effective toxicity of the polymer resists. Specifically, the oral median lethal dose (LD 50 ) in rats for chlorobenzene is 1110 mg/kg, while anisole is 3700 mg/kg. Therefore, developing a process utilizing anisole and replacing chlorobenzene addresses safety concerns and contributes to green initiatives worldwide. Within this work electron beam lithography fabricated transistor components consisting of a double layered source, and gate were converted from a chlorobenzene to anisole based process; while maintaining process of record specifications. The purpose of this work is to provide a starting platform for individuals seeking to convert from a chlorobenzene solvent to an anisole based resist for sub-micron lithography steps.more » « less
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Abstract It has been previously reported that ursodeoxycholic acid (UDCA), a therapeutic bile acid, reduced risk for advanced colorectal adenoma in men but not women. Interactions between the gut microbiome and fecal bile acid composition as a factor in colorectal cancer neoplasia have been postulated but evidence is limited to small cohorts and animal studies. Using banked stool samples collected as part of a phase III randomized clinical trial of UDCA for the prevention of colorectal adenomatous polyps, we compared change in the microbiome composition after a 3‐year intervention in a subset of participants randomized to oral UDCA at 8‐10 mg/kg of body weight per day (n = 198) or placebo (n = 203). Study participants randomized to UDCA experienced compositional changes in their microbiome that were statistically more similar to other individuals in the UDCA arm than to those in the placebo arm. This reflected a UDCA‐associated shift in microbial community composition (
P < 0.001), independent of sex, with no evidence of a UDCA effect on microbial richness (P > 0.05). These UDCA‐associated shifts in microbial community distance metrics from baseline to end‐of‐study were not associated with risk of any or advanced adenoma (allP > 0.05) in men or women. Separate analyses of microbial networks revealed an overrepresentation ofFaecalibacterium prausnitzii in the post‐UDCA arm and an inverse relationship betweenF prausnitzii andRuminococcus gnavus. In men who received UDCA, the overrepresentation ofF prausnitzii and underrepresentation ofR gnavus were more prominent in those with no adenoma recurrence at follow‐up compared to men with recurrence. This relationship was not observed in women. Daily UDCA use modestly influences the relative abundance of microbial species in stool and affects the microbial network composition with suggestive evidence for sex‐specific effects of UDCA on stool microbial community composition as a modifier of colorectal adenoma risk. -
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Abstract Background Aluminum is the third most prevalent element in the earth’s crust. In most conditions, it is tightly bound to form inaccessible compounds, however in low soil pH, the ionized form of aluminum can be taken up by plant roots and distributed throughout the plant tissue. Following this uptake, nectar and pollen concentrations in low soil pH regions can reach nearly 300 mg/kg. Inhibition of acetylcholinesterase (AChE) has been demonstrated following aluminum exposure in mammal and aquatic invertebrate species. In honey bees, behaviors consistent with AChE inhibition have been previously recorded; however, the physiological mechanism has not been tested, nor has aversive conditioning.
Results This article presents results of ingested aqueous aluminum chloride exposure on AChE as well as acute exposure effects on aversive conditioning in an
Apis mellifera ligustica hive. Contrary to previous findings, AChE activity significantly increased as compared to controls following exposure to 300 mg/L Al3+. In aversive conditioning studies, using an automated shuttlebox, there were time and dose-dependent effects on learning and reduced movement following 75 and 300 mg/L exposures.Conclusions These findings, in comparison to previous studies, suggest that aluminum toxicity in honey bees may depend on exposure period, subspecies, and study metrics. Further studies are encouraged at the moderate-high exposure concentrations as there may be multiple variables that affect toxicity which should be teased apart further.
