Nerve Agents Research Articles

Integrating Mathematical and Computational Biochemistry with an Exploration of the Toxicological and Physical Dimensions of Novichok Agents: A QSAR and Molecular Dynamics Investigation

In recent decades, and particularly over the last few years, nerve agents have emerged as an ongoing threat yet to be neutralized. Specifically, Novichok, also known as A-class nerve agents, poses a significant risk to civilization due to the potential for terrorism and asymmetric threats. In the present study, we present results on toxicological properties, including calculated lipophilicity through QSAR analysis, as well as an array of physical and dynamic properties estimated via Molecular Dynamics Simulations.

Combinatorial Pattern Response of Bioelectronic Nose for the Detection of Real Nerve Agents

Combinatorial Pattern Response of Bioelectronic Nose for the Detection of Real Nerve Agents

Classification, Chemical, and Toxicological Properties of Carbamate Nerve Agents

Classification, Chemical, and Toxicological Properties of Carbamate Nerve Agents

Engineering a Mesoporous Silicon Nanoparticle Cage to Enhance Performance of a Phosphotriesterase Enzyme for Degradation of VX Nerve Agent.

The organophosphate (OP)-hydrolyzing enzyme phosphotriesterase (PTE, variant L7ep-3a) immobilized within a partially oxidized mesoporous silicon nanoparticle cage is synthesized and the catalytic performance of the enzyme@nanoparticle construct for hydrolysis of a simulant, dimethyl p-nitrophenyl phosphate (DMNP), and the live nerve agent VX is benchmarked against the free enzyme. In a neutral aqueous buffer, the optimized construct shows a ≈2-fold increase in the rate of DMNP turnover relative to the free enzyme. Enzyme@nanoparticles with more hydrophobic surface chemistry in the interior of the pores show lower catalytic activity, suggesting the importance of hydration of the pore interior on performance. The enzyme@nanoparticle construct is readily separated from the neutralized agent; the nanoparticle is found to retain DMNP hydrolysis activity through seven decontamination/recovery cycles. The nanoparticle cage stabilizes the enzyme against thermal denaturing and enzymatic (trypsin) degradation conditions relative to free enzyme. When incorporated into a topical gel formulation, the PTE-loaded nanoparticles show high activity toward the nerve agent VX in an ex vivo rabbit skin model. In vitro acetylcholinesterase (AChE) assays in human blood show that the enzyme@nanoparticle construct decontaminates VX, preserving the biological function of AChE when exposed to an otherwise incapacitating dose.

Adsorption of sarin on zigzag boron-nitride nanotubes (BNNTs) via DFT

To find a suitable sensitivity sensor for sarin molecule (GB) as a nerve agent, we have compared and contrasted the adsorption behavior of it on the exterior surfaces of the (4,0), (5,0), (6,0), (7,0) and (8,0) BNNTs, at B3LYP/6-311+G*. The equilibrium distances (RGB-BNNT), Eads., FMOs, Eg, DOS, D.M. (μ) and reactivity index are estimated for the adsorption process of GB on these BNNTs. The RGB-BNNT, Eads. and the electronic properties of the BNNTs are depend on the BNNT diameter and orientation of the GB molecule outside BNNTs. The shorter RGB-BNNT of 1.61 Å and Eads. of −12.58 kcal/mol reveals that the 40O conformer is the most favorable configuration in which oxygen atom of PO in GB molecule is situated above a boron atom of (4,0) BNNT. The longer RGB-BNNT of 3.81 Å and Eads. of −2.31 kcal/mol exhibits that the 80F conformer is the least favorable configuration in which florin atom of PF in GB molecule is situated above a boron atom of (8,0) BNNT. However, adsorption process is exothermic. By increasing of the BNNT’s diameter and in going from (4،0) to (8،0) GB-BNNT complex either for the orientated PO or PF site; Eg and D.M. values are increased via the adsorption process. Henceforth, the designed 40O and 80F systems energetically are anticipated as the most and the least favorable complex, via the strong chemisorption and physisorption, respectively.

Enhanced adsorption and sensing properties of Ptn(n=1,3)-doped SnS2 monolayers for warfare toxic gases: A DFT Study

Toxic gases have been extensively employed in warfare, spanning from the deployment of irritant tear gas to fatal nerve gas. These chemical armaments have caused significant damage and casualties in times of conflict. This study explores the adsorption properties and sensing mechanisms of three chemical warfare agents(chlorine Cl2, phosgene COCl2, chloropicrin CCl3NO2) on both pristine SnS2 and doped SnS2 using density functional theory (DFT). The results highlight the superior adsorption energy, charge transfer efficiency, and band structure of doped Ptn/SnS2 (n=1,3) compared to pristine SnS2. Pt/SnS2 exhibits exceptional adsorption capabilities for all three war gases. Under specific conditions, Pt3/SnS2(cluster) emerges as an ideal material for detecting Cl2 and CCl3NO2, while also serving as an effective adsorbent for COCl2 gas. This research serves as a valuable reference for sensor performance studies grounded in first-principles theory, showcasing the potential of doped Pt3/SnS2 as a viable sensor for warfare gases. The insights from this study contribute to the development of advanced poison gas sensors, facilitating improvements in poison gas detection and prevention capabilities.

Erratum: Isoflurane-lipid emulsion injection as an anticonvulsant and neuroprotectant treatment for nerve agent exposure

Erratum: Isoflurane-lipid emulsion injection as an anticonvulsant and neuroprotectant treatment for nerve agent exposure

Computational Analysis of Sarin, Soman, and Their Water Mixtures in NU-1000: Interaction Mechanisms, Distribution Patterns, and Pairing Effects.

Due to their extraordinary structural stability under humid conditions, zirconium-based metal-organic frameworks (Zr-MOFs) have been widely investigated for the hydrolytic degradation of nerve agents. That said, mechanisms of hydrolysis in the solid state and the participation of environmental water are not well understood. This work utilizes computational techniques to evaluate the behavior of water and two organophosphorus nerve agents (sarin and soman) in NU-1000, a Zr-MOF with the characteristic attributes for hydrolytic efficiency under humid conditions. Density functional theory (DFT) calculations reveal that soman binds more favorably to NU-1000 active sites than sarin, resulting in different preferential locations of each nerve agent within the framework. The strength of nerve agent binding is also found to vary depending on the site environment, with more favorable binding of both nerve agents occurring in the c-pores of NU-1000 than in the mesopores. Molecular dynamics (MD) simulation results further illustrate that free water molecules in NU-1000 prioritize interactions with nerve agents. Given the variation in their affinity for active site interactions, the introduction of different nerve agents to the framework results in substantial differences in water distribution and behavior. The results give insight into potential variances in the functionality of NU-1000 toward the hydrolysis of each nerve agent. More importantly, they emphasize the significance of considering the role of environmental water in hydrolysis and the possibility of diverse reaction variables based on the type of nerve agent and the properties of the MOF.

Development of microfibrillated cellulose-reinforced carboxymethyl cellulose dipstick imprinted with benzotrifluoride-bearing hydrazone sensor for colorimetric detection of organophosphonate.

The colorless and odorless nerve agents can cause paralysis and even death. The development of novel composite-based microporous strips has allowed for the rapid and visual detection of diisopropyl phosphorofluoridate (DIPF) nerve agent mimics. The active methyl-containing tricyanofuran and 4-aminobenzotrifluoride diazonium salt were azo-coupled in a straightforward manner to produce a new benzotrifluoride (BFT)-comprising tricyanofuran (TCF) hydrazone colorimetric probe. The molecular structure of the benzotrifluoride-bearing hydrazone (BFTH) was explored by different spectroscopic techniques. Microfibrillated cellulose (MFC) was produced using a green process from sugarcane bagasse, an agriculture waste that is notorious for being a solid pollution. Consequently, discovering a straightforward procedure to convert bagasse into valuable materials has been of utmost importance. MFC displayed diameters of 0.25-2 μm, whereas the sensory films exhibited pore diameters of 0.5-2.25 μm. Various quantities of the BFTH chromophore were used to create benzotrifluoride-bearing hydrazone/microfibrillated cellulose/carboxymethyl cellulose (BFTH/MFC@CMC) composites. The absorbance band of the hydrazone-immobilized composite increased from 435 nm to 580 nm as the content of DIPF was raised. When exposed to DIPF, the dipstick color shifted from orange to pink, according to the CIE Lab measurements. The sensor strip showed a detection limit to DIPF between 5 and 200 ppm.

Surface acoustic wave platform integrated with ultraviolet activated rGO-SnS2 nanocomposites to achieve ppb-level dimethyl methylphosphonate detection at room-temperature

Dimethyl methylphosphonate (DMMP) is commonly used as an alternative for demonstrating to detect sarin, which is one of the most toxic but odorless chemical nerve agents. Among various types of DMMP sensors, those utilizing surface acoustic wave (SAW) technology provide notable advantages such as wireless/passive monitoring, digital output, and a compact, portable design. However, key challenges for SAW-based DMMP sensors operated at room temperature lies in simultaneous enhancement of sensitivities and reduction of detection limits. In this study, we developed a binary material strategy by combining reduced graphene oxide (rGO) and tin disulfide (SnS2) with (100)-facets orientation as sensing layers of SAW device for DMMP detection utilized at room temperature. Ultraviolet (UV) light was applied to activate the sensitive film and reduce the sensor's response time. The developed SAW DMMP sensor demonstrated a superior sensitivity (−1298.82 Hz/ppm), a low detection limit of 50 ppb, and a hysteresis below 1.5%, along with fast response/recovery time (39.2 s/28.4 s), excellent selectivity, long-term stability and repeatability. The formation of shrub-like rGO-SnS2 heterojunctions with abundant surface defects and large specific surface areas, high-energy (100) crystalline surfaces of SnS2, and photogenerated carriers generated by UV irradiation were pinpointed as the crucial sensing mechanisms. These factors collectively enhanced adsorption and reaction dynamics of DMMP molecules.

On the Nature of HOPG-Supported Pt1Ti2O7 and its Decomposition of a Nerve Agent Simulant: A Cluster Model of a Single Atom Catalyst Active Site.

Chemical weapons, including hyper lethal nerve agents, are a persistently looming threat across the modern geopolitical landscape. There is a pressing need for the design and development of improved protective materials, which can be substantially aided by the cultivation of a fundamental molecular-level understanding of candidate systems and the corresponding decomposition chemistry. The emergence of the exciting new class of single atom catalyst (SAC) materials has enhanced the prospect of subnanoscale design tailoring in the hopes of optimizing activity and selectivity for a variety of chemical applications. Here, we apply our recently developed experimental technique for modeling the active sites of such SAC materials through the preparation of surface supported size-selected single metal-atom doped metal oxide clusters. The propensity for an SAC cluster model system for Pt1/TiO2 materials, Pt1Ti2O7 supported on highly oriented pyrolytic graphite (HOPG), to adsorb and decompose nerve agent simulant dimethyl methylphosphonate (DMMP) was investigated through a combination of temperature-programmed desorption/reaction (TPD/R) and X-ray photoelectron spectroscopy (XPS). XPS measurements of the as-prepared Pt1Ti2O7 clusters supported the successful isolation of single Pt atoms in clusters monodispersed across the HOPG surface. TPD/R experiments showed that the reactivity exhibited by the Pt1Ti2O7 clusters was distinct from that of Ti2O7 clusters lacking the single Pt atom. It was found that DMMP decomposed over Pt1Ti2O7 upon heating to as low as room temperature, and higher temperature treatments evolved exclusively H2O, CO, and H2, while decomposition over Ti2O7 evolved only methanol and formaldehyde at elevated temperatures. This indicated the promotion of C-H and PO-C bond cleavage within DMMP due to the presence of single Pt atoms in the clusters. Further, the Pt1Ti2O7 clusters were found to desorb P-containing decomposition species, preventing active site poisoning; however, a change of reactivity reflecting that of Ti2O7 was observed following a single TPD/R cycle. This suggested the encapsulation of active Pt sites by titanium oxide during high temperature treatment and is thus an issue deserving of serious attention in the study of Pt1/Ti2O7 SAC materials.

Ambidextrous approach in action: Mg(OMe)2-doped hierarchical porous zirconium MOFs for decontaminating toxic chemical agents in nonbuffered systems

Utilizing a ligand-truncation strategy, a hierarchically porous structure was engineered within MOF-808, designated as HP-MOF-808. Furthermore, Mg(OMe)2 doping yielded HP-MOF-808@Mg(OMe)2, materials with both hierarchical porosity and basic character, for decontamination of two types of toxic chemical agents in nonbuffered solutions. In aqueous solution, the HP-808-2 exhibited decontamination rate constants for dimethyl-4-nitrophenyl phosphate (DMNP) and the nerve agent soman (GD) that were 3.13 and 1.98 times higher than MOF-808, respectively. The decontamination half-lives of HP-808-2@Mg(OMe)2 1:2 for DMNP and GD were further reduced by 13.87 and 36.82 times compared to HP-808-2. The material retains its decontamination efficacy for DMNP even after 60-days exposure in air and maintains structural integrity in solvents devoid of labile hydrogen for at least 24 h. In methanol, HP-808-2@Mg(OMe)2 achieved 100% DMNP decontamination in 25 min, outperforming HP-808-2 at 31.8%, marking it as the fastest DMNP decontamination material in methanol. Theoretical simulations confirmed the experimental findings, clearly demonstrating the energy changes during reactions with various nucleophiles and revealing the degradation process and mechanism of DMNP on the active sites of MOFs. Moreover, these materials rapidly degraded 2-chloroethyl ethyl sulfide (CEES) through hydrolysis, dehydrohalogenation, and heterolytic cleavage, demonstrating great potential for dual decontamination of toxic chemical agents in unbuffered systems.

Emergency evacuation risk assessment for toxic gas attacks in airport terminals: Model, algorithm, and application

Transportation infrastructure has often been the target of terrorist attacks, and mitigation of the risk of toxic gas attacks is a challenging task in the design of indoor emergency evacuation systems. Considering multiple emergency response modes, we propose an agent-based risk assessment model and its algorithm to integrate gas diffusion and pedestrian movement data for emergency response, quickly assessing average individual exposure risk. We assessed the exposure status of individuals with respect to their emergency response actions following a toxic gas attack in an airport terminal. The results indicate that in the event of a general gas attack on an airport terminal, ventilation must be immediately ceased along with early evacuation. In areas with a shelter-in-place environment, the ventilation mode and shelter-in-place time should be determined based on the concentration of indoor and outdoor gases. In areas with nerve gas exposure and high population density, a new exit must be established at evacuation bottlenecks, and pedestrians must be guided to evacuate while promptly closing ventilation. These results offer suggestions and strategies for emergency response and decision-making in airport terminals during such incidents.

Organophosphorus Hydrolase-like Nanozyme with an Activity-Quenched Aggregation-Induced Emission Effect: A Self-Reporting and Specific Assay of Nerve Agents.

Given the promising prospect of aggregation-induced emission luminogens (AIEgens) in fluorescence assays, it is interesting and significant to endow AIEgens with molecular recognition capability (such as enzyme-like activity). Here, an AIE nanomaterial with intrinsic enzyme-like activity (named as "AIEzyme") is designed and synthesized via a facile coordination polymerization of Zr4+ and AIE ligands. AIEzyme possesses enhanced and stable fluorescence in different solvents because of the AIE effect of ligands in the rigid structure of a coordination polymer. On the other hand, the organophosphorus hydrolase (OPH)-mimicking activity of AIEzyme exhibits excellent affinity and specific activity. Interestingly, the OPH-like activity can quench the inherent fluorescence of AIEzyme by the hydrolysate of a typical organophosphorus nerve agent (OPNA), diethyl-4-nitrophenylphosphate. Due to the sensitive activity-induced quenching effect for AIE, the self-reporting fluorescence assay method based on AIEzyme was established, which shows ultrahigh sensitivity, high selectivity, good storage stability, and acceptable reliability for a real sample assay. Moreover, the simultaneous colorimetric method broadens the detection range and the application scenarios. The proposed assay method avoided the interference of O2 during detection because the OPH-like activity does not derive from the generation of ROS. As a bonus, AIEzyme can also be used for the degradation of OPNAs by OPH-like activity, and the process can be self-monitored by AIE quenching. This work would provide a new opportunity for expanding the application of AIEgens and artificial enzymes by endowing AIEgens with enzyme-like activity.

Role of paraoxonase 1 in organophosphate G-series nerve agent poisoning and future therapeutic strategies.

Chemical warfare nerve agents (CWNA) are neurotoxic chemicals unethically used as agents of mass destruction by terrorist outfits and during war. The available antidote against CWNA-mediated toxicity is not sufficiently effective and possesses several limitations. As a countermeasure, paraoxonase 1 (PON1), a catalytic bioscavenger, is being developed as a prophylactic treatment. However, the catalytic activity and substrate specificity of human PON1 are insufficient to be used as a potential antidote. Several laboratories have made different approaches to enhance the CWNA hydrolytic activity against various nerve agents. This review explores the holistic view of PON1 as a potential prophylactic agent against G-series CWNA poisoning, from its initial development to recent advancements and limitations. Apart from this, the review also provides an overview of all available PON1 variants that could be used as a potential prophylactic agent and discusses several possible ways to counteract immunogenicity.

Isoflurane-lipid emulsion injection as an anticonvulsant and neuroprotectant treatment for nerve agent exposure.

We have shown that briefly inhaled isoflurane rapidly halts convulsions and protects the central nervous system (CNS) from organophosphate-induced neuronal loss when administered at 5% for 5min, even as late as 1h after organophosphate exposure. In the current study we investigated if an injectable form of isoflurane was as effective as inhaled isoflurane. We used a mixture of 10% isoflurane dissolved in an IV-compatible lipid-water emulsion for intravenous administration. Rats with an implanted jugular vein cannula were infused with 1,000μL of the 10% isoflurane-lipid emulsion (ILE) mixture at a rate of 200μL per minute, which achieved full anesthesia lasting approximately 10min. When administered 30min after a highly lethal dose of the organophosphate insecticide paraoxon (POX), the short-duration administration halted convulsions over the course of the study and prevented the great majority of neuronal loss as shown by Fluoro-Jade B staining (FJB). Our results indicate that injectable isoflurane is very effective for treating organophosphate poisoning, negating the need for vaporizer equipment and enabling intravenous therapy.

Designing a one-dimensional photonic crystal sensor for dimethyl methylphosphonate detection leveraging a hydrogen-bonding-based acidic strategy

Chemical warfare agents (CWAs) are extremely toxic chemicals, necessitating rapid, easy-to-use, sensitive and selective sensors for detection. Dimethyl methylphosphonate (DMMP) serves as a simulant of nerve agents and is commonly used to evaluate the efficacy of sensors in detecting these hazardous compounds. In this context, this paper proposes a one-dimensional (1D) photonic crystal (PC) gas sensor functionalised with UIO-66-COOH, leveraging a hydrogen-bonding-based acidic strategy, for rapid and sensitive DMMP detection. To optimise DMMP uptake, the organic ligand, UIO-66, is functionalised by grafting additional carboxyl groups to facilitate hydrogen-bonding interactions with the PO groups of organophosphorus gases such as DMMP. Subsequently, attenuated total reflection surface-enhanced infrared absorption spectroscopy is performed to quantitatively monitor the impact of strong interactions between the PC bonds and PO bonds of DMMP and the adsorption sites of metal–organic frameworks (MOFs) during adsorption. The results reveal an increase in the number of hydrogen-bonding sites available for DMMP adsorption, thus promoting hydrogen-bonding interactions. Furthermore, density functional theory calculations are employed to analyse the presence and strength of hydrogen bonds between the MOFs and DMMP. The results reveal that the chemisorption energy of UIO-66-COOH exceeds those of its variants, corroborating the findings of sensing experiments. Overall, the developed 1D PC gas sensor comprising UIO-66-COOH/TiO2 demonstrates excellent stability and reproducibility, with a limit of detection of 0.3 ppm. This sensor also demonstrates enhanced selectivity towards organophosphorus gases compared to volatile organic compounds.

Nerve agent exposure and physiological stress alter brain microstructure and immune profiles after inflammatory challenge in a long-term rat model of Gulf War Illness

Gulf War Illness (GWI) is a disorder experienced by many veterans of the 1991 Gulf War, with symptoms including fatigue, chronic pain, respiratory and memory problems. Exposure to toxic chemicals during the war, such as oil well fire smoke, pesticides, physiological stress, and nerve agents, is thought to have triggered abnormal neuroinflammatory responses that contribute to GWI. Previous studies have examined the acute effects of combined physiological stress and chemical exposures using GWI rodent models and presented findings related to neuroinflammation and changes in diffusion magnetic resonance imaging (MRI) measures, suggesting a neuroimmune basis for GWI. In the current study, using ex vivo MRI, cytokine mRNA expression, and immunohistological analyses of brain tissues, we examined the brain structure and immune function of a chronic rat model of GWI. Our data showed that a combination of long-term corticosterone treatment (to mimic high physiological stress) and diisopropyl fluorophosphate exposure (to mimic sarin exposure) primed the response to subsequent systemic immune challenge with lipopolysaccharide resulting in elevations of multiple cytokine mRNAs, an increased activated glial population, and disrupted brain microstructure in the cingulate cortex and hippocampus compared to control groups. Our findings support the critical role of neuroinflammation, dysregulated glial activation, and their relationship to disrupted brain microstructural integrity in the pathophysiology of GWI and highlight the unique consequences of long-term combined exposures on brain biochemistry and structural connectivity.

SERS-integrated centrifugal microfluidic platform for the detection and quantification of Chemical Warfare Agents in single-component solution and mixtures

Chemical Warfare Agents (CWAs) are toxic chemicals. Among CWAs, nerve agents are lethal compounds at low concentrations, and, thus, there is the need to detect and quantify the danger. The combination of Surface-Enhanced Raman Spectroscopy (SERS) with centrifugal microfluidic (CM) systems is a possibility for a safer handling and a fast analysis of nerve agents.In this work, the SERS signal from single-component solutions and mixtures of Tabun (GA) and VX were analyzed with Au-capped silicon nanopillar (NP) SERS substrates integrated on a CM platform and recorded with a custom-built Raman System (RS). Univariate and multivariate analysis methods were applied for the quantification. Both GA and VX were detected and quantified individually with Partial Least Squares regression (PLSR) models, with LoD and LoQ values of 7.39 ppm and 22.17 ppm respectively for GA, and 7.13 ppm and 21.39 ppm for VX. Detection and quantification of GA and VX in mixtures was achieved with Supported Vector Machine (SVM), obtaining R2 of the prediction 0.87 and 0.95, respectively.The results obtained show the potential of the SERS-integrated CM platform combined with machine learning analysis as a reliable method for CWAs on-site detection and quantification and for national security applications in real-case scenarios.

Highly Mesoporous Zr‐Based MOF‐Fabric Composites: A Benign Approach for Expeditious Degradation of Chemical Warfare Agents and Simulants

AbstractRecent research has demonstrated the degradation of organophosphonates through hydrolysis using microporous UiO–66–NH2‐fabric composites. Yet, challenges remain due to the limitations of organophosphonates accessing active sites in large, engineered granules. To address this, an innovative approach to integrate mesoporous UiO–66–NH2 onto various fabrics is provided, thereby overcoming previous mass transfer limitations. Mesoporosity in the UiO–66–NH2‐fabric is attributed to the amphoteric cocamidopropylbetaine (CAPB) surfactant which templates the mesochannel construction. Unexpectedly, because the synthesis is aqueous, benign, low temperature (60°C), and avoids strong acids and toxic solvents, it is compatible with fragile supports such as untreated cotton. The UiO–66–NH2‐fabric composite formed using treated polypropylene (PP) attains a BET specific surface area of 360 m2 g−1comp. Remarkably, the mesoporous UiO–66–NH2‐composites exhibit a pore volume as large as 0.2 cm3 g−1comp, 33% in the mesoporous range, which is higher than other previous reports. Practically, the mesoporous UiO–66–NH2‐treated PP composite enhances the rate of methyl paraoxon (DMNP) degradation, showing a t1/2 value that is 15 times faster than microporous UiO–66–NH2 composites measured under the same conditions. Similar trends are observed in the degradation of actual nerve agents. These composites hold significant potential across diverse applications, including filtration, protection, and catalysis.