US Army Medical Research Institute of Chemical Defense
  • Aberdeen Proving Ground, United States
Recent publications
A rational design of the structure of catalyst layer (CL) is required for proton exchange membrane fuel cells to attain outstanding performance and excellent stability. It is crucial to have a profound comprehension of the correlations existing between the properties (catalyst ink), network structures of CL and proton exchange membrane fuel cells' performance for the rational design of the structure of CL. This study deeply investigates the effects of a series of alcohol solvents on the properties and network structure of CL. The results demonstrate that the CL aggregates in higher ε solution show smaller particle sizes, and the sulfonic acid groups (∼SO3H) tend to extend more outward due to the strong dissociation. A more continuous and homogeneous ionomer distribution around Pt/C aggregates is observed in the CL, which improves the electrochemically active surface area (ECSA) and performance of the electrode. But, the electrode has a poor performance at high current density regions due to the mass transfer resistance. Based on this, a two-step solvent control strategy is proposed to maintain uniform ionomer and aggerates distribution and optimize the mass transfer for CL. The performance of the cell improves from 0.555 V to 0.615 V at 2000 mA·cm-2.
Intercalation-type metal oxides are promising active anode materials for the fabrication of safer rechargeable lithium-ion batteries, as they are capable of minimizing or even eliminating Li plating at low voltages. Due to the excellent cycle performance, high specific capacity and appropriate working potential, TiNb2O7 (TNO) is considered to be the candidate of anode materials. Despite a lot of beneficial characteristics, the slow electrochemical kinetics of the TNO-based anodes limits their wide use. In this paper, TiNb2O7@C was prepared by using the self-polymerization coating characteristics of dopamine to enhance the rate-performance and cycling stability. The TNO@C-2 particles present ideal rate performance with the discharge capacity of 295.6 mA h g−1 at 0.1 C. Moreover, the TNO@C-2 anode materials exhibit initial discharge capacity of 177.4 mA h g−1, providing 91% of capacity retention after 400 cycles at 10 C. The outstanding electrochemical performance can be contributed to the carbon layer, which builds fast lithium ion paths, enhancing the electrical conductivity of TNO. All these results confirm that TNO@C is a valid methodology to enhance rate-performance and cycling stability and is a new way to provide reliable and quickly rechargeable energy storage resources.
Botulinum neurotoxins (BoNTs) are highly potent, select agent toxins that inhibit neurotransmitter release at motor nerve terminals, causing muscle paralysis and death by asphyxiation. Other than post-exposure prophylaxis with antitoxin, the only treatment option for symptomatic botulism is intubation and supportive care until recovery, which can require weeks or longer. In previous studies, we reported the FDA-approved drug 3,4-diaminopyridine (3,4-DAP) reverses early botulism symptoms and prolongs survival in lethally intoxicated mice. However, the symptomatic benefits of 3,4-DAP are limited by its rapid clearance. Here we investigated whether 3,4-DAP could sustain symptomatic benefits throughout the full course of respiratory paralysis in lethally intoxicated rats. First, we confirmed serial injections of 3,4-DAP stabilized toxic signs and prolonged survival in rats challenged with 2.5 LD 50 BoNT/A. Rebound of toxic signs and death occurred within hours after the final 3,4-DAP treatment, consistent with the short half-life of 3,4-DAP in rats. Based on these data, we next investigated whether the therapeutic benefits of 3,4-DAP could be sustained throughout the course of botulism by continuous infusion. To ensure administration of 3,4-DAP at clinically relevant doses, three infusion dose rates (0.5, 1.0 and 1.5 mg/kg∙h) were identified that produced steady-state serum levels of 3,4-DAP consistent with clinical dosing. We then compared dose-dependent effects of 3,4-DAP on toxic signs and survival in rats intoxicated with 2.5 LD 50 BoNT/A. In contrast to saline vehicle, which resulted in 100% mortality, infusion of 3,4-DAP at ≥ 1.0 mg/kg∙h from 1 to 14 d after intoxication produced 94.4% survival and full resolution of toxic signs, without rebound of toxic signs after infusion was stopped. In contrast, withdrawal of 3,4-DAP infusion at 5 d resulted in re-emergence of toxic sign and death within 12 h, confirming antidotal outcomes require sustained 3,4-DAP treatment for longer than 5 d after intoxication. We exploited this novel survival model of lethal botulism to explore neurophysiological parameters of diaphragm paralysis and recovery. While neurotransmission was nearly eliminated at 5 d, neurotransmission was significantly improved at 21 d in 3,4-DAP-infused survivors, although still depressed compared to naïve rats. 3,4-DAP is the first small molecule to reverse systemic paralysis and promote survival in animal models of botulism, thereby meeting a critical treatment need that is not addressed by post-exposure prophylaxis with conventional antitoxin. These data contribute to a growing body of evidence supporting the use of 3,4-DAP to treat clinical botulism.
Metal organic frameworks (MOFs) have been explored as adsorption materials owing to their diversity, controllable structure, high specific surface area, and abundant active sites. However, the shaping of MOFs has become a critical issue hindering their commercial application. A binder or high pressure is commonly used in traditional powder shaping, causing pores to be blocked or collapsed and porosity to be decreased, eventually leading to the degradation of adsorption performance. In this paper, Zr-MOFs were in situ grown on a columnar activated carbon (CAC) matrix, and a series of Zr-MOFs/CAC composites were prepared. The adsorption properties for SO2 and NO2 were measured by dynamic adsorption tests, and the Wheel-Jonas model was used to calculate the saturated adsorption capacity. Abundant mesopores can be formed between MOF crystals and activated carbon particles, and the mesoporosity of Zr-MOFs/CAC composites reached over 50%. Owing to the abundant mesoporous, increased activated sites as well as the synergistic effect between MOFs and activated carbon, the as-obtained HP-Zr-MOFs/CAC exhibited the best adsorption performance both for SO2 and NO2, which are 34.2 and 17.4 mg g-1, respectively, while the adsorption capacities of CAC for SO2 and NO2 are 20.9 and 6.6 mg g-1, respectively. The outstanding performance and facile synthesis process of HP-Zr-MOFs/CAC composites could provide ideas to develop other hierarchical porous MOFs/activated carbon composites.
Chloropicrin (CP) is a common agricultural fumigant historically used as a chemical warfare agent and is a concern for potential use in warfare and terrorist applications. Our inability to effectively treat CP-induced injuries makes it essential to better understand CP toxicity. We set out to elucidate variables that must be understood to achieve optimal exposure conditions for in vitro investigations given that such models are important for the study of CP injury and potential therapeutics. To this end, we evaluated the effects of volatility, cell seeding density, and serum concentration of cell culture medium on CP toxicity in an immortalized human corneal epithelial cell line. We found that even with very dilute solutions, CP remained highly volatile, so much so that a 0.0019% CP solution resulted in 90% cell death at time 0, but was nearly nontoxic 45 min later. Not surprisingly, the CP-induced IL-8 response was shown to vary with cell viability in this experiment. After exposure with 0.00115% CP, cells that were 12% confluent experienced over 40% more cell death than cells exposed at 87% confluency. Exposure with the same CP dose in medium containing concentrations of fetal bovine serum (FBS) ranging from 0.1% to 15% exhibited a 17% difference in cell viability. Given that chemical toxicity can be significantly influenced by volatility, cell density, and serum content of cell culture medium, these phenomena should be explored during the development and optimization of toxicant exposure models.
Rationale: Carfentanil, an opioid 10K times more potent than morphine, has no licit clinical use. A powerful CNS depressant, it has been identified increasingly as the cause of overdose death in the United States. Because it is highly lipophilic, the law enforcement and medical communities have been concerned that responding personnel could be percutaneously exposed and that exposure could be enhanced with the use of alcohol-containing hand sanitizers. An LC-MS/MS method was developed to evaluate solvent effects on percutaneous absorption of carfentanil in a live human epidermal model. Methods: In this study, a quantitative liquid chromatography/hybrid triple quadrupole-linear ion trap method was developed for carfentanil and for caffeine, a molecule routinely used to monitor epidermal cell culture viability. The method employed reverse-phase liquid chromatography coupled with positive electrospray ionization and multiple reaction monitoring (MRM) to quantify carfentanil and caffeine against calibration curves formulated from authentic standards. Limits of detection (LOD) for the two compounds were determined using 10:1 signal-to-noise requirements for all product ions with relative peak areas within ±20% of those observed for a mid-level calibrator. Precision and accuracy were determined by analyzing positive controls formulated in quintuplicate, by a different analyst, at three concentrations bracketing the method dynamic range. Inter-day precision was evaluated using data collected from three separate days of analyses. Results: Calibration curves for seven formulated replicates of the two compounds met linearity requirements over at least four orders of magnitude concentration range. The accuracy of measured concentration results was within ±20% of the actual, precision across results (%CV) was ≤15%, curve coefficients of determination (r) were ≥0.980 (correlation coefficient r > 0.990), and relative ion ratios of all qualifier ions were within ±20% of those for a mid-level standard. Limits of quantification (LOQs) for carfentanil and caffeine were 230 pg/ml and 12 ng/ml, respectively. Intra-day accuracies (mean concentrations) for carfentanil and caffeine ranged from 90.1% to 100.8% and from 87.1% to 108.9%, respectively; inter-day accuracies ranged from 98.7% to 100.4% and from 97.5% to 101.7%, respectively. Intra-day precision (%CV) over the dynamic range ranged from 1.31 to 8.88 and from 1.49 to 6.72 for carfentanil and caffeine, respectively. Inter-day precision ranged from 4.7 to 9.9 %CV for carfentanil and 7.6-121 %CV for caffeine. Conclusions: The method was used to evaluate the percutaneous absorption kinetics of carfentanil in solution as a function of solvent composition using an in vitro, live human epidermis model. Counterintuitively, as previously reported, the addition of organic solvents to the formulations decreased rather than increased the percutaneous absorption rate of the ultra-potent opioid, carfentanil.
The opioid crisis is a pressing public health issue, exacerbated by the emergence of more potent synthetic opioids, particularly fentanyl and its analogs. While competitive antagonists exist, their efficacy against synthetic opioids is largely unknown. Furthermore, due to the short durations of action of current antagonists, renarcotization remains a concern. In this study, metabolic activity was characterized for fentanyl‐class opioids and common opioid antagonists using multiple in vitro systems, namely, cytochrome P450 (CYP) enzymes and hepatic spheroids, after which an in vitro‐in vivo correlation was applied to convert in vitro metabolic activity to predictive in vivo intrinsic clearance. For all substrates, intrinsic hepatic metabolism was higher than the composite of CYP activities, due to fundamental differences between whole cells and single enzymatic reactions. Of the CYP isozymes investigated, 3A4 yielded the highest absolute and relative metabolism across all substrates, with largely negligible contributions from 2D6 and 2C19. Comparative analysis highlighted elevated lipophilicity and diminished CYP3A4 activity as potential considerations for the development of more efficacious opioid antagonists. Finally, antagonists with a high degree of molecular similarity exhibited comparable clearance, providing a basis for structure‐metabolism relationships. Together, these results provide multiple screening criteria for early stage drug discovery involving opioid countermeasures. This study represents the first characterization of metabolic clearance for multiple common opioid antagonists and fentanyl‐class opioids using the same in vitro systems. The direct comparability enables a thorough understanding of the relative stability of opioids and opioid antagonists for the development of more efficacious countermeasures, and measured metabolic clearances can be incorporated into pharmacokinetic models.
Background ESKAPEE pathogens Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , Enterobacter spp. and Escherichia coli are multi-drug resistant (MDR) bacteria that present increasing treatment challenges for healthcare institutions and public health worldwide. Methods 431 MDR ESKAPEE pathogens were collected from Queen Sirikit Naval Hospital, Chonburi, Thailand between 2017 and 2018. Species identification and antimicrobial resistance (AMR) phenotype were determined following CLSI and EUCAST guidelines on the BD Phoenix System. Molecular identification of antibiotic resistant genes was performed by polymerase chain reaction (PCR), real-time PCR assays, and whole genome sequencing (WGS). Results Of the 431 MDR isolates collected, 1.2% were E. faecium , 5.8% were S. aureus , 23.7% were K. pneumoniae , 22.5% were A. baumannii , 4.6% were P. aeruginosa , 0.9% were Enterobacter spp . , and 41.3% were E. coli . Of the 401 Gram-negative MDR isolates, 51% were carbapenem resistant, 45% were ESBL producers only, 2% were colistin resistance and ESBLs producers (2%), and 2% were non-ESBLs producers. The most prevalent carbapenemase genes were bla OXA-23 (23%), which was only identified in A. baumannii , followed by bla NDM (17%), and bla OXA-48-like (13%). Beta-lactamase genes detected included bla TEM, bla SHV , bla OXA , bla CTX-M , bla DHA , bla CMY , bla PER and bla VEB . Seven E. coli and K. pneumoniae isolates showed resistance to colistin and carried mcr-1 or mcr-3 , with 2 E. coli strains carrying both genes. Among 30 Gram-positive MDR ESKAPEE, all VRE isolates carried the vanA gene (100%) and 84% S. aureus isolates carried the mecA gene. Conclusions This report highlights the prevalence of AMR among clinical ESKAPEE pathogens in eastern Thailand. E. coli was the most common MDR pathogen collected, followed by K. pneumoniae , and A. baumannii . Carbapenem-resistant Enterobacteriaceae (CRE) and extended spectrum beta-lactamases (ESBLs) producers were the most common resistance profiles. The co-occurrence of mcr-1 and mcr-3 in 2 E. coli strains, which did not affect the level of colistin resistance, is also reported. The participation of global stakeholders and surveillance of MDR remain essential for the control and management of MDR ESKAPEE pathogens.
Acute exposure to nerve agents induces status epilepticus (SE), which can cause death or long-term brain damage. Diazepam is approved by the FDA for the treatment of nerve agent-induced SE, and midazolam (MDZ) is currently under consideration to replace diazepam. However, animal studies have raised questions about the neuroprotective efficacy of benzodiazepines. Here, we compared the antiseizure and neuroprotective efficacy of MDZ (5 mg/kg) with that of tezampanel (LY293558; 10 mg/kg), an AMPA/GluK1 receptor antagonist, administered 1 h after injection of the nerve agent, soman (1.2 × LD50), in adult male rats. Both of the anticonvulsants promptly stopped SE, with MDZ having a more rapid effect. However, SE reoccurred to a greater extent in the MDZ-treated group, resulting in a significantly longer total duration of SE within 24 h post-exposure compared with the LY293558-treated group. The neuroprotective efficacy of the two drugs was studied in the basolateral amygdala, 30 days post-exposure. Significant neuronal and inter-neuronal loss, reduced ratio of interneurons to the total number of neurons, and reduction in spontaneous inhibitory postsynaptic currents accompanied by increased anxiety were found in the MDZ-treated group. The rats treated with LY293558 did not differ from the control rats (not exposed to soman) in any of these measurements. Thus, LY293558 has significantly greater efficacy than midazolam in protecting against prolonged seizures and brain damage caused by acute nerve agent exposure.
Corneal injuries induced by various toxicants result in similar clinical presentations such as corneal opacity and neovascularization. Many studies suggest that several weeks post-exposure a convergence of the molecular mechanisms drives these progressive pathologies. However, chemical agents vary in toxicological properties, and early molecular responses are anticipated to be somewhat dissimilar for different toxicants. We chose 3120 targets from the Dharmacon Human Druggable genome to screen for chloropicrin (CP) and hydrogen fluoride (HF) corneal injury as we hypothesized that targets identified in vitro may be effective as therapeutic targets in future studies. Human immortalized corneal epithelial cells (SV40-HCEC) were used for screening. Cell viability and IL-8 were analyzed to down-select hits into validation studies, where multiplex cytokine analysis and high content analysis were performed to understand toxicant effect and target function. Some endpoints were also evaluated in a second human immortalized corneal epithelial cell line, TCEpi. Over 20 targets entered validation studies for CP and HF; of these, only three targets were shared: NR3C1, RELA, and KMT5A. These findings suggest that early molecular responses to different toxicants may be somewhat distinctive and present dissimilar targets for possible early intervention.
Background: The Blue Book, published in conjunction with the Military Health System Strategic Partnership with the American College of Surgeons, serves as a reference manual for institutions wishing to establish a military-civilian partnership. In order to evaluate the applicability of the criteria contained in the Blue Book, we created a survey to be distributed to MCP military surgeons and their civilian host champions. Methods: E-mail surveys were sent to MCP military surgeons and civilian host champions. Military surgeons were queried about basic demographic information and aspects of the MCP including type, duration of assignment, onboarding, malpractice coverage, and billing for services. We gathered information on the role of military surgeons at the MCP, workload information, and trauma cases. The civilian host champions survey focused on institutional activities including trauma surgical volume, clinical and educational opportunities for the military surgeons, and exposure to research. MCP military surgeons and civilian host champions were questioned on program attributes: administrative support, budget, and profile of the program within the institution. Results: 10 MCP military surgeons and 7 host champions completed surveys. The majority of military surgeons were assigned to the MCP for a 3-year instructor role (90%) and most were trauma surgeons (80%). Clinical activities for the military surgeon were where 60% spent >/=13 weeks annually on trauma. Military surgeons identified host program support in academic growth, deployment preparation, sense of value at the MCP as positive attributes. Civilian host champions unanimously reported exposure to research, opportunities to lead trauma teams, dedicated ICU time and patient volume were positive program attributes. Conclusion: This preliminary survey demonstrates the criteria put forth in The Blue Book align with experiences of MCP military surgeons and host champions. Continued development of this survey and others like it may be useful in the MCP program selection and evaluation process. Level of evidence: Care Management, Level V.
The weak inherent non-covalent interactions between carbon aerogel backbone nanoparticles obtained by the pyrolysis of conventional organic aerogel can lead to poor mechanical properties. When applied in the thermal protection system of a high-speed spacecraft, the preparation of carbon aerogel insulation materials with excellent formability and high mechanical strength still remains a huge challenge. This work reports an efficient approach for fabricating carbon foam-reinforced carbon aerogel composites by compounding the nanoporous polyimide aerogel into the microporous pre-carbonized phenolic resin-based carbon foam via vacuum impregnation, gelatinizing and co-carbonization. Benefiting from the co-shrinkage caused by co−carbonization, the thermal insulation capacity of the carbon aerogel and the formability of the pre−carbonized foam are efficiently utilized. The shrinkage, density and carbon yield of aerogels, pre-carbonized foams and the composites at different temperatures were measured to analyze the formation of the interfacial gap within the composite. The co-carbonization mechanism of the polyimide aerogels and phenolic resin-based pre-carbonized foams was analyzed through XPS, TG-MS, and FT-IR. Among the prepared samples, CF30-CPI-1000 °C with small interfacial gaps showed the lowest thermal conductivity, which was as low as 0.56 W/(m·K) at 1900 °C, and the corresponding compressive strength and elastic modulus were as high as 0.532 MPa and 9.091 MPa, respectively.
Organophosphorus (OP) nerve agents and pesticides inhibit the enzyme acetylcholinesterase (AChE) via a covalent interaction at the active site, resulting in a buildup of excess acetylcholine in the synaptic cleft. Current reactivators rely exclusively on oxime moieties that can reverse this inhibition via direct nucleophilic attack of the bound OP at the enzyme active site. Absolute molar concentration is a fundamental component of the mechanism of oxime-mediated reactivation and forms the basis of established reactivation kinetics theory and descriptive mathematics. Recently, a non-oxime reactivator (ADOC) was discovered that operates via a general acid-base catalysis mechanism, which calls the fundamental assumptions of established reactivation kinetics theory into question. The objective of this study is to determine if the assumption that reactivation occurs in an absolute concentration-dependent manner holds true for ADOC. An assay was developed to elucidate the effect of reactivator and enzyme concentration relationships as a component of either inherent compound structure-activity or external environment-activity relationships, and this was utilized to evaluate both an oxime and non-oxime reactivator. Initial results suggest that while chemical structure and, therefore, mechanism of reactivation play a role in the reactivator-to-enzyme interaction, environmental factors are suspected to also impact this relationship only for ADOC, likely via activation of an alternate reactivation mechanism. In conclusion, expanding the reactivation kinetics theory to accommodate alternate mechanisms of reactivation may pave new avenues for the development of nerve agent countermeasure therapeutics.
This work was conducted in an effort to develop medical countermeasures to treat exposure to toxicants that can be utilized in a terrorism or warfare scenario. Chemical injuries to the eyes are true ocular emergencies because of their high potential to inflict rapid and enduring tissue damage. The cornea and other ocular surface tissues are particularly susceptible to chemical exposures such as sulfur mustard (SM), and long-term prognosis can be poor due to progressive corneal pathologies. Chronic and delayed complications include persistent corneal epithelial defects, dry eye, corneal opacification, and corneal neovascularization. Such long-term complications can lead to permanent discomfort and vision deficits or blindness despite the best current treatment regimens. To identify novel therapeutic targets, we had carried out siRNA-mediated high throughput screening (HTS) using human corneal epithelial cell models of SM exposure. Over 3000 genes identified as differentially regulated after SM ocular exposure by previous microarray studies were tested for their functions involved in cell viability and IL-8 production. The current study transitioned eight validated targets from the HTS to a mouse model of SM-induced ocular injury. Interestingly, four out of the eight targets, PSMA1, PSMA2, PSMD7 and FBXO5, were subunits of proteasomes or E3 ubiquitin ligase complexes. The ubiquitin-proteasome pathway maintains protein homeostasis and therefore important cellular functions through the degradation of misfolded, redundant, and damaged proteins. Treatment with the proteasome inhibitor bortezomib in the first two weeks after SM ocular exposure greatly promoted the rate and number of corneal neovascularization, which is a key feature of a delayed injury phase. Such outcomes were also observed with treatment with another proteasome inhibitor, carfilzomib. In addition to proteasome subunits, GABRR1 (GABA type A receptor subunit rho-1) was among the validated targets from the HTS. We learned that muscimol, a GABA type A receptor agonist, significantly decreased corneal neovascularization during 8-week observation periods. Taken together, these outcomes demonstrated the effectiveness of our systemic approach to identify novel molecular signaling pathways implicated in toxicant-induced ocular injuries and future studies for potential drugs. For example, our future studies include investigating proteasome-mediated protein regulation of angiogenic factors in response to SM ocular exposure and testing the therapeutic potential of proteasome agonists. Some small molecule proteasome agonists such as chlorpromazine and imidazoline were identified in recent years and have been studied for their efficacy in treating different diseases such as neurodegeneration, cancer, and autoimmunity.
Sodium fluoroacetate (1080) is a colorless, odorless, tasteless, water-soluble metabolic poison. In the body, fluoroacetate is converted to fluorocitrate (FC) which blocks the citric acid cycle and drastically decreases ATP production. Symptoms of exposure include nausea, vomiting, abdominal pains, salivation, irrational fear, weakness, tachypnea, cyanosis, sweating, increased temperature, and death. Signs and symptoms of 1080 poisoning are nonspecific, further complicating the diagnosis. 1080 is tightly regulated within the United States, but it is commonly used in Australia, New Zealand, Mexico, Japan, South Korea, and Israel as a rodenticide to control invasive and predatory species. An eco-terrorist scare in New Zealand (2015) and findings reported by the CIA (2007) have led 1080 to being identified as a potential terrorist weapon. To identify potential countermeasures against 1080 poisoning, a Saccharomyces cerevisiae (yeast) model was selected to assess the impact of FC on cellular respiration and to screen candidate therapeutics. In response to FC, yeast showed depressed mitochondrial activity as measured by oxygen consumption rate (OCR). Potential treatments, thonzonium bromide, nifuroxazide, pyrvinium pamoate, menadione, mefloquine, clemastine fumarate, bisacodyl, L-ascorbic acid, thiethylperazine and vinpocitine, were examined in this study. All treatments are approved by the Food and Drug Administration. Toxicity of each treatment was also assessed. Assays were performed in yeast extract peptone galactose media, a metabolically restrictive media. To assess the effect of FC on OCR, cells were exposed to 50 µM, 100 µM, and 200 µM FC in liquid culture for 1, 4, or 24 hours. After incubation, mitochondrial respiration was assessed via the MitoXpress assay (Agilent), a fluorescence-based assay that measures OCR. Once established as a viable model, yeasts were then used to screen therapeutics to improve cellular respiration. Yeast was co-incubated with fluorocitrate (200 µM), and potential treatments at three increasing concentrations for 4 hours and the effects on mitochondrial respiration were assessed via the MitoXpress assay. Following the decreased OCR in yeast exposed to FC, 6 of the 10 treatments successfully restored the mitochondrial function of yeast as demonstrated by an increase in OCR. As a result, the compounds nifuroxazide, pyrvinium pamoate, vinpocitine, clemastine fumarate, bisacodyl, and L-ascorbic acid are moving forward for further testing in cardiomyocytes and hepatic spheroids, with potential in vivo assessment, to characterize their effectiveness against 1080 poisoning. Future studies will continue to use yeast as a valuable screening method to identify other potential treatments for sodium fluoroacetate.
Organophosphate (OPs) compounds make up the most common class of pesticides as well as chemical warfare nerve agents (CWNA), all of which covalently inhibit the active site of acetylcholinesterase (AChE), resulting in intoxication via a cholinergic crisis. While the biochemical mechanism of action resulting in acute intoxication of an exposed individual is well understood, less is known about the mechanism of OP intoxication via other exposure routes, particularly prenatal exposure. The clinical effects of non-acute prenatal OP exposure have been previously studied primarily in cases involving diet and agricultural labor, while case studies documenting the effects on conception of acute exposure during chemical warfare attacks (Japan 1995, Syria 2013 and 2017) have also been published. Such exposure events were linked to a range of serious neurodevelopmental anomalies in children, but the underlying mechanism of action as well as the potential benefits of medical countermeasures have not been clearly elucidated. A robust human-relevant animal model to test both is therefore essential for evaluating current and future OP countermeasures. The present study used a novel humanized mouse strain expressing human AChE and an inactivated native serum carboxylesterase to create a prenatal acute exposure and emergency medical countermeasure evaluation model. Pregnant mice were acutely exposed to an OP at a critical point in cholinergic development, generally equivalent to the first trimester in humans. Dams were challenged with either sarin or the pesticide paraoxon, followed by either a saline vehicle control or 2-PAM and an atropine/midazolam cocktail, the currently fielded emergency treatment for OP intoxication. Mice were allowed to carry pups to term, and upon reaching maturity, cortex, cerebellum, bone marrow and gonads were collected from offspring in each exposure group. Phenotypical and histopathological evaluation of tissues and other factors in dams and offspring were evaluated. Gene expression analyses conducted for each tissue generated a detailed profile associated with each OP exposure/treatment group, providing robust criteria for model development. The resulting data demonstrated a significant beneficial impact of medical countermeasures for both sarin and paraoxon exposures, significantly reducing the amount and the scope of gene expression changes induced by OP exposure. This model provides insight into the developmental pathologies resulting from prenatal acute OP exposure as well as serves as an evaluation model for future treatments.
Traumatic peripheral nerve injuries tend to be more common in younger, working age populations and can lead to long-lasting disability. Peripheral nerves have an impressive capacity to regenerate; however, successful recovery after injury depends on a number of factors including the mechanism and severity of the trauma, the distance from injury to the reinnervation target, connective tissue sheath integrity, and delay between injury and treatment. Even though modern surgical procedures have greatly improved the success rate, many peripheral nerve injuries still culminate in persistent neuropathic pain and incomplete functional recovery. Recent studies in animals suggest that botulinum neurotoxin A (BoNT/A) can accelerate nerve regeneration and improve functional recovery after injury to peripheral nerves. Possible mechanisms of BoNT/A action include activation or proliferation of support cells (Schwann cells, mast cells, and macrophages), increased angiogenesis, and improvement of blood flow to regenerating nerves.
Graphene is considered as a promising electrode material for supercapacitors due to its large specific surface area, excellent electrical conductivity and so on. In this paper, few-layer graphene is prepared by self-propagating combustion reaction between CO and metal magnesium, using powder MgO as deposition template. Graphene with a high specific surface area of up to 928 m² g⁻¹ replicates the morphological feature of powder MgO. Raman spectroscopy analysis demonstrates that the graphene layer decreases when the dosage of MgO template is increased. The specific capacitance of as-prepared sample exhibits the highest specific capacitance of 222 F g⁻¹ at the current density of 1 A g⁻¹ in EMI [TFSI] electrolyte. The sample demonstrates a "double high" performance with high specific energy density and high specific power density. A high energy density of 76.3 Wh kg⁻¹ can be achieved at a specific power density of 1.75 kW kg⁻¹, and it can still remain 48.6 Wh kg⁻¹ when the specific power density reaches a high level of 35 kW kg⁻¹.
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51 members
James F Dillman
  • Science Program Analysis and Integration Office
Radharaman Ray
  • Cellular and Molecular Biology Branch
Ernest Braue
  • Analytical Toxicology
Michael Adler
  • Analytical Toxicology
Douglas M Cerasoli
  • Agent Mitigation
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Aberdeen Proving Ground, United States