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The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed. [ABSTRACT FROM AUTHOR]

The malfeasant usage of chemical warfare agents (CWAs) involved in the current world praxis poses a threat to humankind. Owing to their acute lethal toxicity, the pursuit of favorable approaches for their detoxification/degradation is making continuous progress. With this background, a series of UiO-66-NH2 metal–organic frameworks (MOFs) featuring structural defects were synthesized using a solvothermal technique by varying the modulator pKa, HCl modulator concentration, synthesis temperature and ligand ratio. The present study contributes additional evidence that the considered synthesis parameters outweigh the creation of an open framework in its own metrics. By fine tuning the synthesis practices, the formation of structural defects has been greatly induced. Furthermore, the impact of structural defects possessed by the synthesized samples was systematically investigated against methyl-paraoxon (DMNP), a CWA simulant. The coexistence of an amine group (–NH2) representing Brønsted basic sites, and Lewis acid sites of metal clusters in UiO-66-NH2 reveals a maximum conversion efficiency up to 93.6% with an ultrafast transient degradation rate (k) and shorter half-lives of 1.567 min−1 and 0.44 min, respectively. [ABSTRACT FROM AUTHOR]

Pralidoxime salts are important medical countermeasures towards different organophosphorus compounds, either nerve agents or pesticides, as they act as acetylcholinesterase reactivators, avoiding health issues and even death that can result from intoxication with such chemicals. In this work, we present an expeditious study focuses on the optimization of a two‐step continuous‐flow synthesis of 2‐PAM. Initial attempts to replace the solvent composition in the oxime formation reaction with acetonitrile resulted in lower yields, highlighting the significance of a polar protic solvent. Subsequent optimization under continuous‐flow conditions revealed the successful execution of oxime formation at room temperature with a residence time of 20 minutes, achieving an impressive 96 % conversion, surpassing literature‐reported conditions. The methylation step required a high residence time of 60 minutes at 120 °C for a substantial conversion of 78 %. The two‐step continuous‐flow process demonstrated robustness, yielding 75 %, with space‐time yields of 0.32 g/h and 0.18 g/h. Further concentration adjustments increased space‐time yields to 3.2 g/h and 2.2 g/h. Despite solvent incompatibility, a strategic alteration of the reaction sequence allowed for a successful cascade process, integrating the methylation step in acetonitrile and the oxime formation in water. The continuous‐flow system, incorporating a heat exchanger, exhibited stability, maintaining full conversion and a space‐time yield of 0.3 g/h over extended periods. This systematic optimization not only enhances the efficiency of 2‐PAM synthesis but also provides insights into a scalable and practical continuous‐flow cascade process. [ABSTRACT FROM AUTHOR]

Herein, the serendipitous discovery of two water-recyclable and reusable fluorescent sensors IMPC (cyan–blue–cyan) and IMPC-OH (green–blue–green) is reported for sensing nerve agent simulants diethylcyanophosphonate and diethylchlorophosphate, respectively, with high sensitivity, short response time, and low detection limits. The unique features of these probes are their regeneration with the addition of a green and cheap solvent, namely water in CHCl3, and ease of fabrication into a portable paper-strip system that can also be regenerated. Various spectroscopic studies were employed to understand the mechanism of sensing and regeneration of both probes; the results reveal that water plays a critical role in the hydrolysis of the adduct formed with DCNP and DCP, which enables the retrieval of the probe with its original fluorescence. [ABSTRACT FROM AUTHOR]

Organophosphorus nerve agents (OPNA) are hazardous environmental exposures to the civilian population and have been historically weaponized as chemical warfare agents (CWA). OPNA exposure can lead to several neurological, sensory, and motor symptoms that can manifest into chronic neurological illnesses later in life. There is still a large need for technological advancement to better understand changes in brain function following OPNA exposure. The human-relevant in vitro multi-electrode array (MEA) system, which combines the MEA technology with human stem cell technology, has the potential to monitor the acute, sub-chronic, and chronic consequences of OPNA exposure on brain activity. However, the application of this system to assess OPNA hazards and risks to human brain function remains to be investigated. In a concentration-response study, we have employed a humanrelevant MEA system to monitor and detect changes in the electrical activity of engineered neural networks to increasing concentrations of the sarin surrogate 4-nitrophenyl isopropyl methylphosphonate (NIMP). We report a biphasic response in the spiking (but not bursting) activity of neurons exposed to low (i.e., 0.4 and 4 μM) versus high concentrations (i.e., 40 and 100 μM) of NIMP, which was monitored during the exposure period and up to 6 days post-exposure. Regardless of the NIMP concentration, at a network level, communication or coordination of neuronal activity decreased as early as 60 min and persisted at 24 h of NIMP exposure. Once NIMP was removed, coordinated activity was no different than control (0 mM of NIMP). Interestingly, only in the high concentration of NIMP did coordination of activity at a network level begin to decrease again at 2 days post-exposure and persisted on day 6 post-exposure. Notably, cell viability was not affected during or after NIMP exposure. Also, while the catalytic activity of AChE decreased during NIMP exposure, its activity recovered once NIMP was removed. Gene expression analysis suggests that human iPSC-derived neurons and primary human astrocytes resulted in altered genes related to the cell's interaction with the extracellular environment, its intracellular calcium signaling pathways, and inflammation, which could have contributed to how neurons communicated at a network level. [ABSTRACT FROM AUTHOR]

Gulf War Illness (GWI) affects nearly 30% of veterans from the 1990-1991 Gulf War (GW) and is a multi-symptom illness with many neurological effects attributed to in-theater wartime chemical overexposures. Brain-focused studies have revealed persistent structural and functional alterations in veterans with GWI, including reduced volumes, connectivity, and signaling that correlate with poor cognitive and motor performance. GWI symptomology components have been recapitulated in rodent models as behavioral, neurochemical, and neuroinflammatory aberrations. However, preclinical structural imaging studies remain limited. This study aimed to characterize the progression of brain structural alterations over the course of 12 months in two established preclinical models of GWI. In the PB/PM model, male C57BL/6 J mice (8-9 weeks) received daily exposure to the nerve agent prophylactic pyridostigmine bromide (PB) and the pyrethroid insecticide permethrin (PM) for 10 days. In the PB/DEET/CORT/DFP model, mice received daily exposure to PB and the insect repellent DEET (days 1-14) and corticosterone (CORT; days 7-14). On day 15, mice received a single injection of the sarin surrogate diisopropylfluorophosphate (DFP). Using a Varian 7 T Bore MRI System, structural (sagittal T2-weighted) scans were performed at 6-, 9-, and 12-months post GWI exposures. Regions of interest, including total brain, ventricles, cortex, hippocampus, cerebellum, and brainstem were delineated in the open source Aedes Toolbox in MATLAB, followed by brain volumetric and cortical thickness analyses in ImageJ. Limited behavioral testing 1 month after the last MRI was also performed. The results of this study compare similarities and distinctions between these exposure paradigms and aid in the understanding of GWI pathogenesis. Major similarities among the models include relative ventricular enlargement and reductions in hippocampal volumes with age. Key differences in the PB/DEET/CORT/DFP model included reduced brainstem volumes and an early and persistent loss of total brain volume, while the PB/PM model produced reductions in cortical thickness with age. Behaviorally, at 13 months, motor function was largely preserved in both models. However, the GWI mice in the PB/DEET/CORT/DFP model exhibited an elevation in anxiety-like behavior. [ABSTRACT FROM AUTHOR]

Six novel brominated bis-pyridinium oximes were designed and synthesized to increase their nucleophilicity and reactivation ability of phosphorylated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Their pKa was valuably found lower to parent non-halogenated oximes. Stability tests showed that novel brominated oximes were stable in water, but the stability of di-brominated oximes was decreased in buffer solution and their degradation products were prepared and characterized. The reactivation screening of brominated oximes was tested on AChE and BChE inhibited by organophosphorus surrogates. Two mono-brominated oximes reactivated AChE comparably to non-halogenated analogues, which was further confirmed by reactivation kinetics. The acute toxicity of two selected brominated oximes was similar to commercially available oxime reactivators and the most promising brominated oxime was tested in vivo on sarin- and VX-poisoned rats. This brominated oxime showed interesting CNS distribution and significant reactivation effectiveness in blood. The same oxime resulted with the best protective index for VX-poisoned rats. [ABSTRACT FROM AUTHOR]

In the presented study, an efficient and fast analytical method was developed for the determination of parathion ethyl as sarin simulant by gas chromatography–mass spectrometry (GC–MS). Dispersive solid phase extraction (DSPE) was performed to concentrate parathion ethyl from soil, plant and water samples. Reduced graphene oxide–iron (II, III) oxide (rGO-Fe3O4) nanocomposite was used as an adsorbent to collect the target analyte from the aqueous sample solutions. After the optimization of extraction/preconcentration parameters, optimum conditions for adsorbent amount, eluent type, mixing type/period, eluent volume and initial sample volume were determined as 15 mg, acetonitrile, vortex/30 s, 100 µL and 10 mL, respectively. Under the optimum conditions, analytical performance of the developed DSPE-GC–MS method was evaluated in terms of limit of detection (LOD), limit of quantitation (LOQ) and dynamic range. Dynamic range, LOD and LOQ values were figured out to be 0.94–235.15 µg/kg, 0.41 µg/kg and 1.36 µg/kg (mass based), respectively. Satisfactory percent recovery results (90.3–125% for soil, 93.5–108.7% for plant, 88.5–112.9% for tap water) were achieved for soil, plant and tap water samples which proved the accuracy and applicability of the developed method. It is predicted that the DSPE-GC–MS method can be accurately used for the detection of sarin in soil, plant and water samples taken from war territories. [ABSTRACT FROM AUTHOR]

In a chemical mass casualty incident requiring skin decontamination, dry removal using absorbent materials may be beneficial to enable immediate decontamination. The efficacy of absorbent materials has therefore been evaluated, alone or procedures including both dry and wet decontamination, following skin exposure to two low volatile toxic chemicals using an in vitro human skin penetration model. Additionally, removal using active carbon wipes was evaluated with or without the Dahlgren Decon solution. All dry decontamination procedures resulted in a significantly decreased skin penetration rate of the industrial chemical 2‐butoxyethanol compared to the control without decontamination. Wet decontamination following dry absorption significantly improved the efficacy compared to dry removal alone. Dry decontamination post‐exposure to the chemical warfare nerve agent VX showed no decontamination efficacy. However, dry and wet decontamination resulted in a decreased agent skin penetration rate during the last hour of the experiment. At −15°C, significantly reduced VX skin penetration rates were demonstrated for both dry decontamination alone and the dry and wet decontamination procedure. The Dahlgren Decon solution significantly reduced the amount of VX penetrating the skin, but the active carbon wipe alone did not impact the skin penetration rate. In conclusion, absorbent materials are beneficial for the removal of low‐volatile chemicals from the skin, but the degree of efficacy varies between chemicals. Despite the variability, immediate dry decontamination using available absorbent materials prior to wet decontamination is recommended as a general procedure for skin decontamination. The procedure should also be prioritized in cold‐weather conditions to prevent patient hypothermia. Skin decontamination is important in a chemical mass casualty incident, including toxic, low‐volatile chemicals. In vitro human skin studies displayed the beneficial impact of dry decontamination prior to wet decontamination, however, the degree of efficacy varies post‐exposure to the industrial chemical 2‐butoxyethanol and the nerve agent VX. In cold air temperatures, dry removal was efficient post‐exposure to VX. Immediate dry removal using available absorbent materials prior to wet decontamination is therefore recommended as a general procedure for skin decontamination. [ABSTRACT FROM AUTHOR]

The recent international scenario highlights the importance to protect human health and environmental quality from toxic compounds. In this context, organophosphorous (OP) Nerve Agents (NAs) have received particular attention, due to their use in terrorist attacks. Classical instrumental detection techniques are sensitive and selective, but they cannot be used in real field due to the high cost, specialized personnel requested and huge size. For these reasons, the development of practical, easy and fast detection methods (smart methods) is the future of this field. Indeed, starting from initial sensing research, based on optical and/or electrical sensors, today the development and use of smart strategies to detect NAs is the current state of the art. This review summarizes the smart strategies to detect NAs, highlighting some important parameters, such as linearity, limit of detection and selectivity. Furthermore, some critical comments of the future on this field, and in particular, the problems to be solved before a real application of these methods, are provided. [ABSTRACT FROM AUTHOR]

Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation. [ABSTRACT FROM AUTHOR]

Herein our study, analysis on the adsorption of VX nerve agent on to X12Y12(Al12N12, Al12P12, C12Si12 and Mg12O12) nanocages is done using density functional theory (DFT). All the calculations were performed using DFT/B3LYP-D3/6-31G (d) basis set, to delve into the capability of these nanocages for sensing and adsorption of VX. Various parameters such as adsorption energy (Eads), energies of highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), Fermi energy (EF), work function alteration (%∆Φ), energy gap (Eg), global electron density transfers (GEDT) along with molecular electrostatic potential (MEP) and density of states (DOS) profiles of the isolates and complex were calculated, compared and examined. The findings exhibited O atom of VX to interact with Al, Si and Mg atoms of the respective nanocages, and the nature of interaction was from nearly covalent to van der Waals. Furthermore, the potential for the nanocage to sense the target gas was analyzed by means of Fermi energy (EF), alteration in work function (%∆Φ) and its recovery time (τ). Among the considered nanostructures, Mg12O12 was recorded with the highest adsorption energy of−97.39 kcal/mol, suggesting it to be a promising adsorbent for VX. [ABSTRACT FROM AUTHOR]

Engaging the thinking of Georges Bataille, this article examines the international politics of poison as a category of death-dealing that defies distinctions between war/not war and weapon/not weapon. Refraining from splitting poison into pesticides and chemical weapons, the article analyses political ecologies and affective economies of poison both historically and today, to illuminate which desires and strategies poison, as a technology of death, lends itself to. Taking its departure in Bataille's writing on fascism and ending with his main theory of a general economy, the article weaves through nerve agent assassinations, fumigation, and ideas about gardening, to arrive at the conclusion that poison is not so much an excessive response as it is a response to excess. Following Bataille in viewing ecology as economies of consumption and competition, the article develops a rubric of martial economies of poison to encapsulate how poison, as mode of martial expenditure, makes spaces vacant by death, and room for organisms deemed worthy. [ABSTRACT FROM AUTHOR]

The neutralization of organophosphorous (OP) chemical agents used in modern warfare is a growing concern due to their extreme toxicity to human cells. In several previous works, although the capability of several Zr‐MOF‐based catalysts has been showcased to facilitate hydrolysis of OP agents in heterogeneous pathways, their usage appeared to be limited by very slow kinetics at neutral pH. There is still a lack of MOF based catalysts that can detoxify OPs at physiological pH. The recycling ability of MOF‐based catalysts has also not been greatly explored. Thus, herein, we explored a Zr‐based MOF, MOF‐801(Zr) for the detoxification of a series of OP nerve agents and a pesticide with simultaneous adsorption and degradation at pH 7.5 in a buffer solution, close to physiological conditions. This MOF‐based catalyst demonstrates significant hydrolysis activity towards several nerve agents, with up to 99 % conversion within 2 h and an excellent half‐life of less than 5 minutes. In addition, it can be recycled at least 5 times consecutively with a residual activity of at least 90 %. [ABSTRACT FROM AUTHOR]

Imidazo[1,2-a] pyridine-based two probes with different substituents containing oxime and hydroxyl functional groups were synthesised and evaluated for detection of tabun nerve agent simulant diethylcyanophosphonate (DCNP). The nucleophile hydroxyl group present on both the probes can be rapidly phosphorylated by DCNP through a nucleophilic substitution reaction. The probes were fluorescent and on reacting with DCNP underwent fluorescence OFF, which can be visualised under a UV lamp at 365 nm wavelength. The limit of detection for probes 1 and 2 was calculated as 0.66 μM and 0.54 μM, respectively. The mechanism of detection was studied using spectroscopic techniques revealed that the hydroxyl group is involved in the reaction with DCNP. The probes were found selective for the detection of DCNP in presence of other electrophilic interfering agents. Results were obtained in aqueous media and probes can be used directly for the rapid and sensitive detection of DCNP in water without any pretreatment. [ABSTRACT FROM AUTHOR]

In the field of chemical warfare agents (CWAs), ethanolamines are important building blocks for the preparation of nerve agents belonging to the V-series such as VX and VR as well as the nitrogen-based mustards. In this work, the determination of three members in this class of Schedule 2B reportable chemicals, namely N,N-dimethylethanolamine (DMEA), N,N-diethylethanolamine (DEEA), and N,N-diisopropylethanolamine (DIEA) by electron ionization gas chromatography-mass spectrometry (EI-GC-MS) is presented. The three dialkylethanolamines were spiked in a high organic content soil matrix featured during the 45th Organization for the Prohibition of Chemical Weapons (OPCW) proficiency test (PT) at two separate concentrations each (1 and 10 µg/g separately), simulating values often encountered during these tests. The N,N-dialkylethanolamines were O-alkylated using benzyl bromide and sodium carbonate at 55 °C and were detected as their benzylated versions by electron ionization GC-MS. The benzylation of each dialkylethanolamine yielded derivatives with higher molecular weight and therefore different GC-MS profiles such as longer retention times and sharper peak chromatography relative to their unmodified counterparts. These characteristics enable the analytical chemist to detect and confirm these important CWA-related chemicals specifically in instances where they are present in low concentrations (i.e. <10 µg/g) among more abundant interferences. [ABSTRACT FROM AUTHOR]

A promising, but not yet practiced, approach to the treatment of neurotoxic organophosphate poisoning is the administration of a scavenger that rapidly deactivates the nerve agent before it can exert its toxic effects. The detoxification rates required for successful use of this therapy can currently only be achieved with enzymes, but synthetic scavengers, whose mode of action is based on key concepts of supramolecular chemistry, are an attractive alternative. Considerable progress has recently been made in the development of such scavengers, and compounds from several receptor classes are now available that not only bind nerve agents but also degrade them at promising rates. This review provides an overview of the field and highlights recent developments. [ABSTRACT FROM AUTHOR]

Pinacolyl alcohol (PA), a key forensic marker for the nerve agent Soman (GD), is a particularly difficult analyte to detect by various analytical methods. In this work, we have explored the reaction between PA and 1,1′‐carbonyldiimidazole (CDI) to yield pinacolyl 1H‐imidazole‐1‐carboxylate (PIC), a product that can be conveniently detected by gas chromatography–mass spectrometry (GC–MS) and liquid chromatography‐high‐resolution mass spectrometry (LC‐HRMS). Regarding its GC–MS profile, this new carbamate derivative of PA possesses favorable chromatographic features such as a sharp peak and a longer retention time (RT = 16.62 min) relative to PA (broad peak and short retention time, RT = 4.1 min). The derivative can also be detected by LC‐HRMS, providing an avenue for the analysis of this chemical using this technique where PA is virtually undetectable unless present in large concentrations. From a forensic science standpoint, detection of this low molecular weight alcohol signals the past or latent presence of the nerve agent Soman (GD) in a given matrix (i.e., environmental or biological). The efficiency of the protocol was tested separately in the analysis and detection of PA by EI‐GC–MS and LC‐HRMS when present at a 10 μg/mL in a soil matrix featured in the 44th PT and in a glycerol‐rich liquid matrix featured in the 48th Official Organization for the Prohibition of Chemical Weapons (OPCW) Proficiency Test when present at a 5 μg/mL concentration. In both scenarios, PA was successfully transformed into PIC, establishing the protocol as an additional tool for the analysis of this unnatural and unique nerve agent marker by GC–MS and LC‐HRMS. [ABSTRACT FROM AUTHOR]

Chemical warfare agents primarily comprise organophosphorus nerve agents, saliva alkaloids, cyanides, and mustard gas. Exposure to these agents can result in severe respiratory effects, including spasms, edema, and increased secretions leading to breathing difficulties and suffocation. Protecting public safety and national security from such threats has become an urgent priority. Porous metal–organic framework (MOF) materials have emerged as promising candidates for the degradation of chemical warfare agents due to their large surface area, tunable pore size distribution, and excellent catalytic performance. Furthermore, combining MOFs with polymers can enhance their elasticity and processability and improve their degradation performance. In this review, we summarize the literature of the past five years on MOF-based composite materials and their effectiveness in degrading chemical warfare agents. Moreover, we discuss key factors influencing their degradation efficiency, such as MOF structure, pore size, and functionalization strategies. Furthermore, we highlight recent developments in the design of MOF–polymer composites, which offer enhanced degradation performance and stability for practical applications in CWA degradation. These composite materials exhibit good performance in degrading chemical warfare agents, playing a crucial role in protecting public safety and maintaining national security. We can expect to see more breakthroughs in the application of metal–organic framework porous materials for degrading chemical warfare agents. It is hoped that these innovative materials will play a positive role in achieving social stability and security. [ABSTRACT FROM AUTHOR]

Nerve agents, including organophosphorus compounds such as paraoxon, are potent and highly toxic chemicals with grave implications for human health and the environment. In this paper, we present the development of a novel enzyme inhibition-based biosensor for the sensitive and selective detection of paraoxon, which is commonly used as a surrogate for nerve agents. The biosensor employs reduced graphene oxide as a screen-printed electrode surface modification nanomaterial, leading to increased surface electroactivity and, thus, more sensitive detection. The biosensor exhibits a low detection limit of 0.56 pg/ml (limit of detection, LOD) and 1.25 pg/ml (limit of quantification, LOQ), highlighting its high sensitivity for trace-level analysis of nerve agents in complex sample matrices. Our biosensor demonstrates remarkable selectivity for paraoxon, with minimal interference from other non-target chemicals. Stability and repeatability tests reveal that the system maintains its performance integrity over a 45-day period and consistently produces readings with a margin of error of only 5%. Real sample testing in river water, wastewater, and tap water further confirms the biosensor's practical utility, with recovery percentages ranging from 84 to 115%. This biosensor represents a significant advancement in biosensor technology, facilitating the rapid, cost-effective, and reliable detection of toxic substances in real-world scenarios. [ABSTRACT FROM AUTHOR]

Organophosphates (OPs) are a class of neurotoxic acetylcholinesterase inhibitors including widely used pesticides as well as nerve agents such as VX and VR. Current treatment of these toxins relies on reactivating acetylcholinesterase, which remains ineffective. Enzymatic scavengers are of interest for their ability to degrade OPs systemically before they reach their target. Here we describe a library of computationally designed variants of phosphotriesterase (PTE), an enzyme that is known to break down OPs. The mutations G208D, F104A, K77A, A80V, H254G, and I274N broadly improve catalytic efficiency of VX and VR hydrolysis without impacting the structure of the enzyme. The mutation I106 A improves catalysis of VR and L271E abolishes activity, likely due to disruptions of PTE's structure. This study elucidates the importance of these residues and contributes to the design of enzymatic OP scavengers with improved efficiency. [ABSTRACT FROM AUTHOR]

The treatment of organophosphate (OP) anticholinesterases currently lacks an effective oxime reactivator of OP‐inhibited acetylcholinesterase (AChE) which can penetrate the blood‐brain barrier (BBB). Our laboratories have synthesized novel substituted phenoxyalkyl pyridinium oximes and tested them for their ability to promote survival of rats challenged with lethal doses of nerve agent surrogates. These previous studies demonstrated the ability of some of these oximes to promote 24‐h survival to rats challenged with a lethal level of highly relevant surrogates for sarin and VX. The reactivation of OP‐inhibited AChE in peripheral tissues was likely to be a major contributor to their efficacy in survival of lethal OP challenges. In the present study, twenty of these novel oximes were screened in vitro for reactivation ability for AChE in rat skeletal muscle and serum using two nerve agent surrogates: phthalimidyl isopropyl methylphosphonate (PIMP, a sarin surrogate) and 4‐nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate). The oximes demonstrated a range of 23%–102% reactivation of AChE in vitro across both tissue types. Some of the novel oximes tested in the present study demonstrated the ability to more effectively reactivate AChE in serum than the currently approved oxime, 2‐PAM. Therefore, some of these novel oximes have the potential to reverse AChE inhibition in peripheral target tissues and contribute to survival efficacy. [ABSTRACT FROM AUTHOR]

Protein adducts are important biological targets for traceability of organophosphorus nerve agents (OPNAs). Currently, the recognized biomarkers that can be used in actual samples in the field of chemical forensics only include Y411 in albumin and the active nonapeptide in butyrylcholinesterase (BChE). To explore stable and reliable protein adducts and increase the accuracy of OPNAs traceability further, we gradually expanded OPNAs–albumin adducts based on single and group adduct collection. Several stable peptides were found via LC–MS/MS analysis in human serum albumin (HSA) exposed to OPNAs in a large exposure range. These adducts were present in HSA samples exposed to OPNAs of each concentration, which provided data support for the reliability and stability of using adducts to trace OPNAs. Meanwhile, the formation mechanism of OPNAs–cysteine adduct was clarified via computer simulations. Then, these active sites found and modified peptides were used as raw materials for progressive expansion of albumin adducts. We constructed an OPNAs–HSA adducts group, in which a specific agent is the exposure source, and three or more active peptides constitute data sets for OPNAs traceability. Compared with single or scattered protein adducts, the OPNAs–HSA adduct group improves OPNAs identification by mutual verification using active peptides or by narrowing the identity range of the exposure source. We also determined the minimum detectable concentration of OPNAs for the adduct group. Two or more peptides can be detected when there is an exposure of 50 times the molar excess of OPNAs in relation to HSA. This improved the accuracy of OPNAs exposure and identity confirmation. A collection of OPNAs–albumin adducts was also examined. The collection was established by collecting, classifying, and integrating the existing albumin adducts according to the species to which each albumin belongs, the types of agents, and protease. This method can serve as a reference for discovering new albumin adducts, characteristic phosphonylated peptides, and potential biomarkers. In addition, to avoid a false negative for OPNAs traceability using albumin adducts, we explored OPNAs–cholinesterase adducts because cholinesterase is more reactive with OPNAs than albumin. Seven active peptides in red blood cell acetylcholinesterase (RBC AChE) and serum BChE can assist in OPNAs exposure and identity confirmation. [ABSTRACT FROM AUTHOR]

We have successfully synthesized quinoline derivatives that exhibit easy scalability and responsiveness to multiple stimuli. These derivatives are capable of forming self-assembled nanoscopic aggregates in an aqueous medium. Consequently, when placed in an aqueous environment, we observe dual fluorescence originating from both twisted intramolecular charge transfer and aggregation-induced emission. The introduction of nerve gas agents, such as diethyl chlorophosphate (DClP) or diethylcyanophosphate (DCNP), to the probe molecules facilitates the charge-transfer process, resulting in a red-shift in absorption maxima. Notably, when operating in fluorescence mode, both of these analytes produce distinct output signals, making them easily distinguishable. DCNP generates a blue fluorescence, while the addition of DClP yields cyan fluorescence. Our mechanistic investigation reveals that the initial step involves phosphorylation of the quinoline nitrogen end. However, in the case of DCNP, the released cyanide ion subsequently attacks the carbonyl carbon centre, forming a cyanohydrin derivative. The response to these target analytes appears to be influenced by the nucleophilicity of the quinoline nitrogen end and the electrophilic nature of the carbonyl unit. [ABSTRACT FROM AUTHOR]

The removal and detection of harmful gases from contaminated air has received a great deal of attention in the scientific community. In this study the interaction of toxic nerve agent Venomous Agent X (VX) with boron nitride (BN) nanosheet, nanotube and nanocage is investigated using density functional theory (DFT). The findings revealed that the target gas tends to adsorb on to the boron atom through P = O bond for the considered nanostructures. The results suggested that the electronic properties of the boron nitride nanotube (BNNT) are well altered leading to reduced energy gap and thereby resulting in increased conductivity. Among the considered nanostructures the highest adsorption energy is identified for B12N12 nanocage, recording a value of -30.85 kcal/mol which in turn makes desorption an almost impossible process. Similarly, the BN nanosheet is also seen with higher recovery time and less sensitive due to its wide energy gap and henceforth not be an effective sensor. On the other hand, the study also confirms that with a small recovery time of 2.59s in average and hence could be a potentially effective sensor for the detection of the toxic gas. Our findings could deliver a basic interpretation on the behavior of these BN based nanomaterials towards adsorption of VX nerve agent. Thereby, supporting the research community towards new perspectives on the development of gas sensors in nanotechnology. [ABSTRACT FROM AUTHOR]

The idea of this study was the estimation of the theoretical acute toxicity (t-LD50, rat, oral dose) of organophosphorus-based chemical warfare agents from the G-series (n = 12) using different in silico methods. Initially identified in Germany, the G-type nerve agents include potent compounds such as tabun, sarin, and soman. Despite their historical significance, there is a noticeable gap in acute toxicity data for these agents. This study employs qualitative (STopTox and AdmetSAR) and quantitative (TEST; CATMoS; ProTox-II and QSAR Toolbox) in silico methods to predict LD50 values, offering an ethical alternative to animal testing. Additionally, we conducted quantitative extrapolation from animals, and the results of qualitative tests confirmed the acute toxicity potential of these substances and enabled the identification of toxicophoric groups. According to our estimations, the most lethal agents within this category were GV, soman (GD), sarin (GB), thiosarin (GBS), and chlorosarin (GC), with t-LD50 values (oral administration, extrapolated from rat to human) of 0.05 mg/kg bw, 0.08 mg/kg bw, 0.12 mg/kg bw, 0.15 mg/kg bw, and 0.17 mg/kg bw, respectively. On the contrary, compounds with a cycloalkane attached to the phospho-oxygen linkage, specifically methyl cyclosarin and cyclosarin, were found to be the least toxic, with values of 2.28 mg/kg bw and 3.03 mg/kg bw. The findings aim to fill the knowledge gap regarding the acute toxicity of these agents, highlighting the need for modern toxicological methods that align with ethical considerations, next-generation risk assessment (NGRA) and the 3Rs (replacement, reduction and refinement) principles. [ABSTRACT FROM AUTHOR]

Poisoning with the organophosphorus nerve agent VX can be life-threatening due to limitations of the standard therapy with atropine and oximes. To date, the underlying pathomechanism of VX affecting the neuromuscular junction has not been fully elucidated structurally. Results of recent studies investigating the effects of VX were obtained from cells of animal origin or immortalized cell lines limiting their translation to humans. To overcome this limitation, motor neurons (MN) of this study were differentiated from in-house feeder- and integration-free-derived human-induced pluripotent stem cells (hiPSC) by application of standardized and antibiotic-free differentiation media with the aim to mimic human embryogenesis as closely as possible. For testing VX sensitivity, MN were initially exposed once to 400 µM, 600 µM, 800 µM, or 1000 µM VX and cultured for 5 days followed by analysis of changes in viability and neurite outgrowth as well as at the gene and protein level using µLC-ESI MS/HR MS, XTT, IncuCyte, qRT-PCR, and Western Blot. For the first time, VX was shown to trigger neuronal cell death and decline in neurite outgrowth in hiPSC-derived MN in a time- and concentration-dependent manner involving the activation of the intrinsic as well as the extrinsic pathway of apoptosis. Consistent with this, MN morphology and neurite network were altered time and concentration-dependently. Thus, MN represent a valuable tool for further investigation of the pathomechanism after VX exposure. These findings might set the course for the development of a promising human neuromuscular test model and patient-specific therapies in the future. [ABSTRACT FROM AUTHOR]

Ultraviolet (UV) curing is an efficient and environmentally friendly curing method. In this paper, UV-cured polyurethane acrylates (PUAs) were investigated as potential military coatings to serve as barriers against chemical warfare agents (CWAs). Seven UV-cured PUA coatings were formulated utilizing hydroxyethyl methacrylate-capped hexamethylene diisocyanate trimer (HEMA-Htri) and trimethylolpropane triacrylate-capped polycarbonate prepolymer (PETA-PCDL) as the PUA monomers. Isobornyl acrylate (IBOA) and triethyleneglycol divinyl ether (DVE-3) were employed as reactive diluents. Gas chromatography was utilized to investigate the constitutive relationships between the structures of the PUA coatings and their protective properties against simulant agents for CWAs, including dimethyl methylphosphonate (DMMP), a nerve agent simulant, and 2-chloroethyl ethyl sulfide (CEES), a mustard simulant. The glass transition temperature (Tg) and crosslinking density (υe) of PUAs were found to be crucial factors affecting their ability to serve as barriers against CWAs. The incorporation of IBOA units led to enhanced Tg and barrier performance of the PUAs, resulting in a DMMP retention of less than 0.5% and nearly 0 retention of CEES. However, an excessive introduction of polycarbonate chains decreased the υe and barrier performance of the PUAs. These findings may offer valuable insights for enhancing the protection of UV-cured PU coatings against CWAs. [ABSTRACT FROM AUTHOR]

Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals' resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD50 of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood–brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development. [ABSTRACT FROM AUTHOR]

Over the past fifty years, swine models have been used for organophosphorus intoxication studies. Among these studies and others on the swine model in general, some physiological data, especially cholinesterase activity highly impacted by organophosphorus compounds like nerve agent VX, still need to be completed. To support and compare our model to others, we have published the experimental protocol, the physiological values of 31 juvenile anesthetized pigs, and the 6 h-follow-up of six supplementary anesthetized control animals and 7 VX-intoxicated pigs. We reported hemodynamics and respiratory parameters, blood levels in several biochemical parameters, blood gas, and complete blood count and compared them to the literature. We also focused on tissue and blood cholinesterase activities and detailed them for acetylcholinesterase and butyrylcholinesterase. After establishing a broad physiological data set consistent with the literature, we reported several cardio-respiratory parameters that seem more affected by an organophosphate intoxication, like heart rate, arterial blood pressure, cardiac output, and respiratory rate. Within the blood, oxygen saturation (SpO 2), lactatemia, base excess, and glycemia can also be measured and associated with the other parameters to evaluate the life-threatening status. This swine model is currently used to develop and evaluate medical countermeasures against organophosphate nerve agent intoxications. • Swine are used to study the effects of organophosphate nerve agent intoxication. • The OPNA intoxication swine model helps develop new therapeutic strategies. • A baseline serves as a reasonable and defined starting point for comparison purposes. [ABSTRACT FROM AUTHOR]

Poisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine (ACh) in the synaptic cleft, is a serious problem for which treatment options are currently insufficient. Our approach to broadening the therapeutic spectrum is to use agents that interact directly with desensitized nicotinic acetylcholine receptors (nAChRs) in order to induce functional recovery after ACh overstimulation. Although MB327, one of the most prominent compounds investigated in this context, has already shown positive properties in terms of muscle force recovery, this compound is not suitable for use as a therapeutic agent due to its insufficient potency. By means of in silico studies based on our recently presented allosteric binding pocket at the nAChR, i.e. the MB327-PAM-1 binding site, three promising MB327 analogs with a 4-aminopyridinium ion partial structure (PTM0056, PTM0062, and PTM0063) were identified. In this study, we present the synthesis and biological evaluation of a series of new analogs of the aforementioned compounds with a 4-aminopyridinium ion partial structure (PTM0064-PTM0072), as well as hydroxy-substituted analogs of MB327 (PTMD90–0012 and PTMD90–0015) designed to substitute entropically unfavorable water clusters identified during molecular dynamics simulations. The compounds were characterized in terms of their binding affinity towards the aforementioned binding site by applying the UNC0642 MS Binding Assays and in terms of their muscle force reactivation in rat diaphragm myography. More potent compounds were identified compared to MB327, as some of them showed a higher affinity towards MB327-PAM-1 and also a higher recovery of neuromuscular transmission at lower compound concentrations. To improve the treatment of organophosphate poisoning, direct targeting of nAChRs with appropriate compounds is a key step, and this study is an important contribution to this research. • Novel MB327 analogs with enhanced affinity to MB327-PAM-1 have been developed. • PTMD90–0012 replaces entropically unfavorable water molecules from MB327-PAM-1. • MB327 analogs show improved muscle force restoring activity after soman poisoning. [ABSTRACT FROM AUTHOR]

Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2′-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20 Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR. [Display omitted] • Bispyridinium non-oximes analogues with a trimethylene or 2,2′-diethyloxy linker and various substituents were studied. • Methyl- and ethyl- substituted compounds with a trimethylene linker were able to partially restore muscle force. • The investigated bispyridinium analogues can be used for future studies to optimize structure-based molecular modeling. [ABSTRACT FROM AUTHOR]

Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1–6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4–8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified. • Pharmacokinetics were evaluated in conscious, unrestrained adult male minipigs. • Doctrinal nerve agent countermeasures were studied across a large range of doses. • Physiological measures were also recorded for general safety assessment. • Orderly pharmacokinetic data and expected/minor physiological changes were observed. • The Göttingen minipig may provide a suitable large animal model for pharmacology. [ABSTRACT FROM AUTHOR]

Organophosphorus nerve agents are toxic compounds that disrupt neuromuscular transmission by inhibiting the neurotransmitter enzyme, acetylcholinesterase, leading to rapid death. A hybrid composite was synthesized using a hydrothermal process for the early detection of dimethyl methyl phosphonate (DMMP), a simulant of the G-series nerve agent, sarin. Quartz crystal microbalance (QCM) and surface acoustic wave (SAW) sensors were used as detectors. Nitrogen-doped multiwalled carbon nanotubes (N-MWCNTs), cobalt oxide (Co3O4), and N-MWCNT@Co3O4 were compared to detect DMMP concentrations of 25–150 ppm. At 25 ppm, the differential frequencies (Δf) of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors were 5.8, 2.3, and 99.5 Hz, respectively. The selectivity results revealed a preference for the DMMP rather than potential interference. The coefficients of determination (R2) of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors for detecting 25–150 ppm DMMP were 0.983, 0.986, and 0.999, respectively. The response times of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors for detecting 100 ppm DMMP were 25, 27, and 34 s, respectively, while the corresponding recovery times were 85, 105, and 181 s. The repeatability results revealed the reversible adsorption and desorption phenomena for the fixed DMMP concentration of 100 ppm. These unique findings show that synthesized materials can be used to detect organophosphorus nerve agents. [ABSTRACT FROM AUTHOR]

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes. [ABSTRACT FROM AUTHOR]

Introduction Nerve agents have emerged as a global threat since their discovery in the 1930s, posing severe risks due to their inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine in nerve synapses. Despite the enforcement of the Chemical Weapon Convention to control chemical weapons, including nerve agents, recent events, such as the Novichok attacks on Sergei Skripal and Alexei Navalny, have highlighted the persistent threat. Novichok, a distinct class of nerve agents, raises specific concerns regarding its management due to limited understanding. This article aims to comprehensively analyze existing literature. Materials and Methods A scoping review was employed to comprehensively assess the current state of knowledge on managing patients poisoned with Novichok. Following the PRISMA-ScR guidelines, relevant literature was identified in peer-reviewed journals covering symptoms, diagnosis, treatment, decontamination, and long-term effects. Searches were conducted on February 1, 2023, across four electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) using "Novichok" as a keyword. No restrictions were applied, and additional studies were sought from the references of identified papers. Eligible papers included discussions on Novichok or its specific properties impacting management, regardless of study type, language, or publication date, while those unrelated to the study's conceptual framework were excluded. Results A total of 170 records were identified from the initial database search, with 86 studies screened after removing duplicates. Among these, 28 publications met the eligibility criteria and were included in the analysis. An additional relevant study was identified from the citation lists of included studies, bringing the total to 29. The review encompasses studies published from 2018 onwards, indicating the growing interest in this topic. While most studies are reviews on Novichok or nerve agents in general, several theoretical and experimental investigations were also found. Conclusion This review highlights the significant uncertainties and knowledge gaps surrounding the management of patients poisoned with Novichok. While some aspects align with other nerve agents, limited research likely due to safety and ethical challenges leads to assumptions and uncertainties in patient care. The review identifies areas with ongoing research, such as decontamination and biomarker recognition, while other aspects remain understudied. The possible inefficacy of current treatment options and the need for further research on oximes, bioscavengers, and long-term effects emphasize the necessity for increased research to optimize patient outcomes. More studies are essential to clarify the actual threat and toxicity of Novichok. Moreover, raising awareness among medical staff is crucial for early diagnosis, prompt treatment, and safety. This review offers valuable insights into managing Novichok-poisoned patients and calls for increased research and awareness in this critical area. [ABSTRACT FROM AUTHOR]

The emergence of Novichok agents, potent organophosphorus nerve agents, has spurred the demand for advanced analytical methods and toxicity assessments as a result of their involvement in high-profile incidents. This study focuses on the degradation products of Novichok agents, particularly their potential toxic effects on biological systems. Traditional in vivo methods for toxicity evaluation face ethical and practical constraints, prompting a shift toward in silico toxicology research. In this context, we conducted a comprehensive qualitative and quantitative analysis of acute oral toxicity (AOT) for Novichok degradation products, using various in silico methods, including TEST, CATMoS, ProTox-II, ADMETlab, ACD/Labs Percepta, and QSAR Toolbox. Adopting these methodologies aligns with the 3Rs principle, emphasising Replacement, Reduction, and Refinement in the realm of toxicological studies. Qualitative assessments with STopTox and admetSAR revealed toxic profiles for all degradation products, with predicted toxicophores highlighting structural features responsible for toxicity. Quantitative predictions yielded varied estimates of acute oral toxicity, with the most toxic degradation products being EOPAA, MOPGA, MOPAA, MPGA, EOPGA, and MPAA, respectively. Structural modifications common to all examined hydrolytic degradation products involve substituting the fluorine atom with a hydroxyl group, imparting consequential effects on toxicity. The need for sophisticated analytical techniques for identifying and quantifying Novichok degradation products is underscored due to their inherent reactivity. This study represents a crucial step in unravelling the complexities of Novichok toxicity, highlighting the ongoing need for research into its degradation processes to refine analytical methodologies and fortify readiness against potential threats. [ABSTRACT FROM AUTHOR]

Aggregation‐induced emission (AIE) shows promising performance in chemical sensing relying on the change of the emission behavior of the probe molecule monomers to the aggregated product. However, whether the response contrast could be further boosted by utilizing the emission property of the aggregated probe and the aggregated product remains a big challenge. Here, an exciting AIE probe regulation strategy was proposed by coherently modulating the aggregation behavior and the intramolecular charge transfer (ICT) property of the probes and thus an aggregated‐to‐aggregated colorimetric‐fluorescent dual‐mode detection was achieved. The blue emissive film obtained with the optimal AIE probe has been proven to be effective to recognize the vapor of nerve agent analog DCP in air by emitting a sharp green fluorescence. In addition, a porous polymer‐based wet sensing chip loaded with the probe enables the immediate response to DCP vapor with a limit of detection (LOD) of 1.7 ppb, and it was further integrated into a wearable watch device for long‐term monitoring of DCP vapor up to two weeks. We expect the present probe design strategy would greatly deepen the AIE‐based science and provide new insights for long‐term monitoring sensors toward trace hazardous substances. [ABSTRACT FROM AUTHOR]

This review presents recent studies of the chemical and molecular regulators of acetylcholine (ACh) signaling and the complexity of the small molecule and RNA regulators of those mechanisms that control cholinergic functioning in health and disease. The underlying structural, neurochemical, and transcriptomic concepts, including basic and translational research and clinical studies, shed new light on how these processes inter‐change under acute states, age, sex, and COVID‐19 infection; all of which modulate ACh‐mediated processes and inflammation in women and men and under diverse stresses. The aspect of organophosphorus (OP) compound toxicity is discussed based on the view that despite numerous studies, acetylcholinesterase (AChE) is still a vulnerable target in OP poisoning because of a lack of efficient treatment and the limitations of oxime‐assisted reactivation of inhibited AChE. The over‐arching purpose of this review is thus to discuss mechanisms of cholinergic signaling dysfunction caused by OP pesticides, OP nerve agents, and anti‐cholinergic medications; and to highlight new therapeutic strategies to combat both the acute and chronic effects of these chemicals on the cholinergic and neuroimmune systems. Furthermore, OP toxicity was examined in view of cholinesterase inhibition and beyond in order to highlight improved small molecules and RNA therapeutic strategies and assess their predicted pitfalls to reverse the acute toxicity and long‐term deleterious effects of OPs. [ABSTRACT FROM AUTHOR]

Millions of individuals globally suffer from inadvertent, occupational or self‐harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post‐exposure therapeutic countermeasures generally include administration of atropine with an oxime to reactivate the OP‐inhibited AChE. However, animal model studies and recent clinical trials using insecticide‐poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the blood–brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure, for example RS194B, have been developed that efficiently cross the BBB resulting in reactivation of OP‐inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticides or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms, and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these findings and assess the ability of post‐exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1–2 h was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non‐invasive treatment, especially in isolated rural settings. [ABSTRACT FROM AUTHOR]

A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound. [ABSTRACT FROM AUTHOR]

Thermocatalytic decomposition is an efficient purification technology that is potentially applicable to degrading chemical warfare agents and industrial toxic gases. In particular, ZrO2 has attracted attention as a catalyst for the thermocatalytic decomposition of dimethyl methylphosphonate (DMMP), which is a simulant of the nerve gas sarin. However, the influence of the crystal phase and morphology on the catalytic performance of ZrO2 requires further exploration. In this study, monoclinic- and tetragonal-phase ZrO2 (m- and t-ZrO2, respectively) with nanoparticle, flower-like shape and hollow microsphere morphologies were prepared via hydrothermal and solvothermal methods, and their thermocatalytic decomposition of DMMP was systematically investigated. For a given morphology, m-ZrO2 performed better than t-ZrO2. For a given crystalline phase, the morphology of hollow microspheres resulted in the longest protection time. The exhaust gases generated by the thermocatalytic decomposition of DMMP mainly comprised H2, CO2, H2O and CH3OH, and the by-products were phosphorus oxide species. Thus, the deactivation of ZrO2 was attributed to the deposition of these phosphorous oxide species on the catalyst surface. These results are expected to help guide the development of catalysts for the safe disposal of chemical warfare agents. [ABSTRACT FROM AUTHOR]

Organophosphorus compounds have a wide range of applications; they are commonly used as drugs or pesticides or in the production of ion batteries. However, some organophosphorus compounds, which were developed as warfare nerve agents, are neurotoxic and potentially lethal to living organisms. On the basis of the literature search, certain properties of these compounds are not well known. Knowledge of thermodynamic properties and the availability of reliable data are fundamental in the development of methods for detecting, treating, and safely analyzing decontamination. For research purposes, substitutes, called simulants, which have similar molecular structures and properties but are less toxic, are often employed. This work presents a thermodynamic study of four organophosphorus nerve agent simulants: trimethyl phosphate, triethyl phosphate, dimethyl methylphosphonate, and diethyl methylphosphonate. Differential scanning calorimeter and a Tian–Calvet type calorimeter were used to analyze their phase behavior and measure the liquid heat capacities, respectively. Vapor pressures were experimentally determined with the static method. Ideal-gas heat capacities were calculated using the R1SM approach, which combines the rigid rotor–harmonic oscillator model, the one-dimensional hindered rotor model, and the mixing model. The results obtained were compared with the data from the literature and simultaneously correlated to obtain a highly reliable thermodynamic description. [ABSTRACT FROM AUTHOR]

Nerve agents are the most notorious substances, which can be fatal to an individual because they block the activity of acetylcholinesterase. Fighting against unpredictable terrorist assaults and wars requires the simple and quick detection of chemical warfare agent vapor. In the present contribution, we have introduced a rhodamine-based chemosensor, BDHA, for the detection of nerve gas-mimicking agents diethylchlorophosphate (DCP) and diethylcyanophosphonate (DCNP) and mustard gas-mimicking agent 2-chloroethyl ethyl sulfide (CEES), both in the liquid and vapor phase. Probe BDHA provides the ability for detection by the naked eye in terms of colorimetric and fluorometric changes. It has been revealed that the interaction between nerve agents mimics and probe BDHA facilitates spirolactam ring opening due to the phosphorylation process. Thus, the highly fluorescent and colored species developed while probe BDHA is colorless and non-fluorescent due to the intramolecular spirolactam ring. Moreover, probe BDHA can effectively recognize DCP, DCNP, and CEES in the µM range despite many toxic analytes and could be identified based on the response times and quantum yield values. Inexpensive, easily carried paper strips-based test kits were developed for the quick, on-location solid and vapor phase detection of these mustard gas imitating agents (CEES) and nerve gas mimicking agents (DCP and DCNP) without needing expensive equipment or skilled personnel. More remarkably, the test strips' color and fluorescence can be rapidly restored, exposing them to triethyl amine (TEA) for cyclic use, suggesting a potential application in the real-time identification of chemical warfare agents. To accomplish the on-location application of BDHA, we have experimented with soil samples to find traces of DCP. Therefore, the chromo-fluorogenic probe BDHA is a promising, instantaneous, and on-the-spot monitoring tool for the selective detection of DCP, DCNP, and CEES in the presence of others. [ABSTRACT FROM AUTHOR]

Wearable military chemical gas sensors were realized using 19 types of color-changeable functional dyes with great aggregative characteristics, and the optimal wearable sensor with the best detection performance was selected. The wearable sensor was designed to demonstrate color change, which exhibited high sensitivity to low concentrations of chemical warfare agent vapors at room temperature. The dyes were applied to textile substrates (cotton fabrics) of the wearable chemical gas sensors, and their sensing properties, performance, and mechanisms were examined for an organophosphorus simulant of nerve agents, dimethyl methyl phosphonate (DMMP). A color difference of almost 5 was obtained at 3 ppm within 10 min, and the spectrum exhibited hypsochromic and hyperchromic shifts. The sensing mechanism was found to depend on solvatochromism, aggregative characteristics of the dye molecules, and the adsorption amount of DMMP vapor on textile substrates. In addition, the reusability of the wearable sensor was tested for ten repeat cycles. [ABSTRACT FROM AUTHOR]

This study focuses on the detection of ethyl methyl phosphonic acid (EMPA), a metabolite of the banned organophosphorus nerve agent VX. We developed an electrochemical sensor utilizing the molecularly imprinted polymer (MIP) based on 4-aminobenzoic acid (4-ABA) and tetraethyl orthosilicate for the selective detection of EMPA in human plasma and urine samples. The 4-ABA@EMPA/MIP/GCE sensor was constructed by a thermal polymerization process on a glassy carbon electrode and sensor characterization was performed by cyclic voltammetry and electrochemical impedance spectroscopy. The 4-ABA@EMPA/MIP/GCE sensor demonstrated impressive linear ranges 1.0 × 10–10 M–2.5 × 10–9 M for the standard solution, 1.0 × 10–10 M–2.5 × 10–9 M for the urine sample, and 1.0 × 10–10 M–1 × 10–9 M of EMPA for the plasma sample with outstanding detection limits of 2.75 × 10−11 M (standard solution), 2.11 × 10−11 M (urine), and 2.36 × 10−11 M (plasma). The sensor exhibited excellent recovery percentages ranging from 99.86 to 101.30% in urine samples and 100.62 to 101.08% in plasma samples. These findings underscore the effectiveness of the 4-ABA@EMPA/MIP/GCE as a straightforward, highly sensitive, and selective interface capable of detecting the target analyte EMPA in human plasma and urine samples. [ABSTRACT FROM AUTHOR]

Pralidoxime chloride, a highly hydrophilic antidote, cannot be effectively separated by reverse-phase high-performance liquid chromatography (RP-HPLC), unless the mobile-phase composition is varied. However, the use of ion-pairing reagents for pralidoxime separation is hindered by the persistent contamination of the stationary phase or chromatography system inside the HPLC system. Thus, this study aimed to develop a simple, rapid, and robust method based on RP-HPLC to determine pralidoxime chloride in antidote autoinjectors using a chaotropic salt as the mobile-phase additive. The use of UV detection at 270 nm allowed for the simultaneous detection of pralidoxime chloride and the internal standard, pyridine-2-aldoxime. The addition of chaotropic salts (NaPF6, NaBF4, and NaClO4) and an ionic liquid ([EMIM]PF6) increased the retention time of pralidoxime chloride. Among them, NaPF6 exhibited the highest capacity factor in the reverse-phase C18 column. Increasing the salt concentration increased the capacity factor and the number of theoretical plates. Analytical method validation was performed to assess the linearity, accuracy, precision, recovery, and repeatability, according to the Ministry of Food and Drug Safety guidelines. Additionally, this newly developed method exhibits an adequate separation capability, making it a potential substitute for the current method employed in the United States/Korean Pharmacopoeia, and it ensures the necessary durability to maintain the robustness and reliability of the analytical system. [ABSTRACT FROM AUTHOR]

We herein present for the first time the phosphylated (*) tetrapeptide (TP)-adduct GlyGluSer198*Ala generated from butyrylcholinesterase (BChE) with proteinase K excellently suited for the verification of exposure to toxic organophosphorus nerve agents (OPNA). Verification requires bioanalytical methods mandatory for toxicological and legal reasons. OPNA react with BChE by phosphonylation of the active site serine residue (Ser198) forming one of the major target protein adducts for verification. After its enzymatic cleavage with pepsin, the nonapeptide (NP) PheGlyGluSer*AlaGlyAlaAlaSer is typically produced as biomarker. Usually OPNA occur as racemic mixtures of phosphonic acid derivatives with the stereocenter at the phosphorus atom, e.g. (±)-VX. Both enantiomers react with BChE, but the adducted NP does not allow their chromatographic distinction. In contrast, the herein introduced TP-adducts appeared as two peaks when using a stationary reversed phase (1.8 µm) in micro-liquid chromatography–electrospray ionisation tandem-mass spectrometry (µLC–ESI MS/MS) analysis. These two peaks represent diastereomers of the (+)- and (−)-OPNA adducted to the peptide that comprises chiral L-amino acids exclusively. Concentration- and time-dependent effects of adduct formation with (±)-VX and its pure enantiomers (+)- and (−)-VX as well as with (±)-cyclosarin (GF) were investigated in detail characterising enantioselective adduct formation, stability, ageing and spontaneous reactivation. The method was also successfully applied to samples from a real case of pesticide poisoning as well as to samples of biomedical proficiency tests provided by the Organisation for the Prohibition of Chemical Weapons. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke is a serious neurological disorder caused by blockages in cerebral artery. Protein phosphatase 2A (PP2A) is a phosphatase that performs a critical role in cell signaling and growth. PP2A subunit B acts as a neuroprotective agent in the nerve system. Chlorogenic acid, which is mainly found in roasted coffee, has antioxidant, anti-inflammatory, and anti-apoptotic effects. We hypothesized that chlorogenic acid modulates PP2A subunit B expression in ischemic stroke models and glutamate-mediated neurons. Middle artery occlusion (MCAO) surgery was operated and chlorogenic acid (30 mg/kg) or phosphate buffer saline was treated 2 h after MCAO. The cerebral cortex was collected 24 h after surgery and the change of PP2A subunit B expression was analyzed. Glutamate and/or chlorogenic acid were treated in cultured neurons, further study was performed. Results: A decrease in PP2A subunit B expression in MCAO animals was identified. Chlorogenic acid alleviated this decrease due to ischemic injury. Moreover, the number of PP2A subunit B-positive cells in the ischemic cerebral cortex was significantly decreased, chlorogenic acid alleviated this decrease. We also found protective effects of chlorogenic acid in neurons exposed to glutamate. Glutamate decreased the expression of PP2A subunit B and chlorogenic acid mitigated this decrease. Our results elucidated that chlorogenic acid performs neuroprotective functions and attenuates the reduction of PP2A subunit B by brain damage and glutamate-mediated excitotoxicity. Conclusions: We showed that chlorogenic acid attenuated the decrease of PP2A subunit B in ischemic injury and neurons exposed to glutamate. Since PP2A subunit B contributes to the protection of brain tissue, we can suggest that chlorogenic acid preserves neurons by modulating PP2A subunit B during ischemic damage. [ABSTRACT FROM AUTHOR]

Organ-on-a-chip technology is considered a next-generation platform in pharmacology and toxicology. Nevertheless, this novel technology still faces several challenges concerning the respective materials which are used for these microfluidic devices. Currently available organ-chips are most often based on polydimethylsiloxane (PDMS). However, this material has strong limitations regarding compound binding. The current study investigated options to reduce compound absorption of the highly toxic nerve agent VX (1000 µmol/L) in a commercially available organ-chip. In addition, surface effects on degradation products of VX were investigated. The alternative polymer cyclic olefin copolymers (CoC) showed significantly less compound absorption compared to PDMS. Furthermore, a coating of PDMS- and CoC-based chips was investigated. The biocompatible polymer polyethyleneimine (PEI) successfully modified PDMS and CoC surfaces and further reduced compound absorption. A previously examined VX concentration after 72 h of 141 ± 10 µmol/L VX could be increased to 442 ± 54 µmol/L. Finally, the respective concentrations of VX and degradation products accounted for > 90% of the initial concentration of 1000 µmol/L VX. The currently described surface modification might be a first step towards the optimization of organ-on-a-chip surfaces, facilitating a better comparability of different studies and results. • An organ-on-a-chip model facilitating low compound absorption was investigated. • The highly toxic nerve agent VX was studied. • Surface effects and a novel polymer showed less compound absorption than traditional PDMS-based models. [ABSTRACT FROM AUTHOR]