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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]

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]

Background: Acute lung injury (ALI) is a fatal respiratory disease caused by overreactive immune reactions (e.g., SARS-CoV-2 infection), with a high mortality rate. Its treatment is often compromised by inefficient drug delivery barriers and insufficient potency of the currently used drugs. Therefore, developing a highly effective lung-targeted drug delivery strategy is a pressing clinical need. Results: In this study, the micro-sized inclusion cocrystal of asiatic acid/γ-cyclodextrin (AA/γCD, with a stoichiometry molar ratio of 2:3 and a mean size of 1.8 μm) was prepared for ALI treatment. The dissolution behavior of the AA/γCD inclusion cocrystals followed a "spring-and-hover" model, which meaned that AA/γCD could dissolve from the cocrystal in an inclusion complex form, thereby promoting a significantly improved water solubility (nine times higher than free AA). This made the cyclodextrin-based inclusion cocrystals an effective solid form for enhanced drug absorption and delivery efficiency. The biodistribution experiments demonstrated AA/γCD accumulated predominantly in the lung (Cmax = 50 µg/g) after systemic administration due to the micron size-mediated passive targeting effect. The AA/γCD group showed an enhanced anti-inflammatory therapeutic effect, as evidenced by reduced levels of pro-inflammatory cytokines in the lung and bronchoalveolar lavage fluids (BALF). Histological examination confirmed that AA/γCD effectively inhibited inflammation reactions. Conclusion: The micro-sized inclusion cocrystals AA/γCD were successfully delivered into the lungs by pulmonary administration and had a significant therapeutic effect on ALI. [ABSTRACT FROM AUTHOR]

Paraquat (PQ) is an irreplaceable insecticide in many countries for the advantage of fast-acting and broad-spectrum. However, PQ was classified as the most prevailing poisoning substance for suicide with no specific antidote. Therefore, it is imperative to develop more effective therapeutic agents for the treatment of PQ poisoning. In the present study, both the RNA-Seq and the application of various cell death inhibitors reflected that ferroptosis exerts a crucial regulatory role in PQ poisoning. Moreover, we found PQ strengthens lipid peroxidation as evidenced by different experimental approaches. Of note, pretreatment of iron chelation agent DFO could ameliorate the ferroptotic cell death and alleviate the ferroptosis-related events. Mechanistically, PQ treatment intensively impaired mitochondrial homeostasis, enhanced phosphorylation of AMPK, accelerated the autophagy flux and triggered the activation of Nuclear receptor coactivator 4-ferritin heavy chain (NCOA4-FTH) axis. Importantly, the activation of autophagy was observed prior to the degradation of ferritin, and inhibition of autophagy could inhibit the accumulation of iron caused by the ferritinophagy process. Genetic and pharmacological inhibition of ferritinophagy could alleviate the lethal oxidative events, and rescue the ferroptotic cell death. Excitingly, in the mouse models of PQ poisoning, both the administration of DFO and adeno-associated virus-mediated FTH overexpression significantly reduced PQ-induced ferroptosis and improved the pathological characteristics of pulmonary fibrosis. In summary, the current work provides an in-depth study on the mechanism of PQ intoxication, describes a framework for the further understanding of ferroptosis in PQ-associated biological processes, and demonstrates modulation of iron metabolism may act as a promising therapeutic agent for the management of PQ toxicity. [ABSTRACT FROM AUTHOR]

The Iran-Iraq war (1980–1988) was the result of the geopolitical situation in the Middle East after the Islamic revolution in Iran in 1979. Certain longstanding territorial disputes and the absence of mutually recognized state border between the rivalry countries were among the direct pretexts of the war. At the same time neither Iraq, nor Iran were ready to serious war, both did not want it in such scales, and they did not possess chemical weapons (CW). During the war, Iraq enjoyed broad international support. At the same time, revolutionary Iran turned into a pariah state. By 1983, Iraq began to suffer a defeat from Iran, which possessed considerable human resources. Because of that certain Western countries helped Iraq (on the paid basis) to start its own CW program and the industrial production of chemical agents and munitions. Gradually CW became an integral part of the offensive and defensive operations, planned by the Iraqi command. Due to the technologies, equipment and chemicals, supplied by certain foreign, mainly Western firms, Iraq was able to start the industrial production of mustard gas, tabun and sarin/cyclosarin, as well as to start the synthesis of VX. During the war, CW turned from purely defensive into offensive means of warfare. The war ended as chemical. In 1988 all the operations, which led to the end of the war, were carried out by Iraq with the use of CW. At the same time, the war revealed certain weaknesses of chemical protection means, possessed by both sides. Thus, it appeared to be impossible to sort effectively the wounded and affected by CW during the medical evacuation phase. The existing decontamination means turned out to be ineffective in case of mass arrival of the affected into hospitals. Because of that, the secondary contamination of medical stuff took place even in Western hospitals. The protective equipment against blister agents, used by NATO countries, turned out to be insufficient in case of use of «dry yperite» by the Iraqis. The accepted schemes of treatment of the affected by tabun also showed their inefficiency. As we find out, the experience of the Iran-Iraq chemical war is studied actively in the West up to now.

The Iraqis became the first nation to use chemical weapons on the modern battlefield during the IranIraq War (1980-1988). There are no general reviews and research available on this issue in Russian. It also puts the Russian researchers in an unequal position in comparison with their Western and Middle Eastern colleagues, who have such information from a wide range of sources. This lack of knowledge limits our ability to understand the secret mechanisms that trigger modern chemical wars in the Middle East. The analysis in the present study is based on different Western sources, UN and CIA materials. The article shows that Iraq – a third world country with the population of 16,3 million people in 1980-ies and relatively low educational level – could start its chemical weapons program only due to the Western aid and assistance (supplies of the precursors, technologies and technical documentation, education of specialists, diplomatic support ect). Only due to this assistance the Iraqi`s chemical weapons program could become successful. The industrial production of chemical agents and chemical munitions of various tactical purposes was established by the Iraqis in less than 10 years. By the end of the 1980-ies, the Iraqi chemists laid the foundations of the future research in the sphere of toxic chemicals. The industrial base for the production of CW have also been established. For Russia, the success of the Iraq`s chemical weapons program is a warning. It means that technically backward, but oil rich quasi-state can acquire chemical weapons in a few years with the clandestine support of the same «sponsors», and use it both for provocations and for conducting combat operations in the regions, vital for Russia`s interests.

The third article in the series is dedicated to the medical consequences of the chemical warfare between Iran and Iraq during the war (1980–1988). The UN official documents and materials, declassified CIA documents, as well as other open Western and Iranian sources have been used during its preparation. The chemical war against the Islamic Republic of Iran was waged in the conditions of the increased power of chemical weapons, when the Iraqi army had the opportunity to carry out multiple massive chemical aviation strikes at operational depth and to use multiple launch rocket systems for the massive use of toxic substances in the tactical zone. The mortality from sulfur mustard reached 30 % in some sections of the front, that was impossible during the First World War. The unpreparedness of the Iranian army to chemical warfare led to the serious irretrievable losses among the Iranian military during the war (25 thousand people) and to the grave long-term consequences for the health of the survivors (at least 100 thousand people), despite of the relatively small amount of poisonous substances used by Iraq (2.54 thousand tons). As in World War I, sulfur mustard turned out to be the «king of gases» in this war. The Iranian scientists find out that even after the curing of acute lesions in hospitals the pathological process caused by the action of poisonous substances does not stop. It enters the phase of delayed effects, manifested with the age of the patient. There are the irreversible obstructive processes in the lungs («mustard lung»). In 2014 about 45 thousand Iranians suffered from late respiratory complications caused by sulfur mustard. There are the eczemoid dermatitis, vitiligo, psoriasis and discoid lupus erythematosus. There are the delayed ulcerative keratitis and various lesions in the neurological tissues of the eye and in the ocular fundus of the vascular system. There are other pathologies as well. The article contains a large number of photographs, diagrams and images, never published in Russian medical literature before.

Low-volatility organophosphorus chemical warfare agents (OP CWAs) are cholinesterase inhibitors which easily absorb into the skin, leading to the formation of a dermal depot from which they slowly enter the bloodstream. This leads to sustained cholinergic hyperstimulation, which if untreated may lead to death. However, current available countermeasures are not adequate to neutralize the agent residing in the dermal depot. Accordingly, we evaluated the efficacy of the potassium salt of acetohydroxamic acid (880 mg/ml in DMSO/H2O 1:4, AHAK), as a potential "catch-up" therapy lotion intended to neutralize the dermal depot, by penetrating the skin and decomposing it before it reaches the bloodstream. To that end, we compared the clinical outcome following skin surface decontamination combined with antidotal treatment, to that following the same antidotal treatment combined with dermal application of AHAK at the site of VX exposure, against percutaneous poisoning by a lethal neat dose (4 mg/kg) of the low-volatility nerve agent VX, in an unanesthetized swine model. Following skin surface decontamination and antidotal treatment, recurrence of intoxication signs and a prolonged recovery time were observed. In contrast, similar antidotal treatment combined with dermal application of AHAK significantly reduced intoxication signs recurrences and accordingly medical supervision duration needed, paralleled by a significantly faster recovery of whole blood cholinesterase activity. An initial evaluation demonstrated the safety of prolonged whole-body AHAK application. Hence, the AHAK lotion may act as an efficient "catch-up" therapy against percutaneous poisoning by low-volatility OP CWAs, improving the clinical outcome and reducing the burden on medical staff. [ABSTRACT FROM AUTHOR]

Alloy 800 was subjected to an autogenous welding treatment using two varying techniques, laser beam (LB) welding and tungsten inert gas (TIG) welding. The weldment regions such as weld fusion zone (WFZ), heat-affected zone (HAZ) and base metal were compared using reactivation technique, i.e., double loop electrochemical potentiodynamic reactivation (DL-EPR) test and ASTM G 28 test for intergranular corrosion (IGC) susceptibility. Alloy 800 showed no significant DOS values in WFZ of laser weldment as cooling rates were faster resulting in negligible carbide precipitation and chromium depletion which was ascertained by G28 test. While considerable reactivation was observed in HAZ of TIG and LB weldments as they are exposed to carbide precipitation temperatures during welding procedures as a result of heat input and cooling rates. Magnetic susceptibility measurements on weldments indicated extent of chromium depletion. The DOS values measured for Alloy 800 LB weldments were one order of magnitude less for all regions as compared to TIG weldment and corroborated with depth of attack obtained from IGC tests. The highest DOS values were observed for HAZ of TIG weldment. DOS values are an indirect measurement of chromium depletion in HAZ that will weaken the passive film formation and result in increased corrosion in ASTM G28 test. The increased grain boundary attack and grain dropping suggest decreased IGC resistance of Alloy 800 weldments by TIG welding compared to LB welding. Hence, laser welding technique is a better technique for welding/repair welding of SG tubes to avoid sensitization and reduce its susceptibility to intergranular corrosion/intergranular stress corrosion cracking (IGC/IGSCC) during operations. [ABSTRACT FROM AUTHOR]

Many extensional basins worldwide are modified by subsequent compressional episodes, which lead to inverted structures. The structures associated with the reactivation of pre-existing faults are critically important in the formation of suitable subsurface traps for hydrocarbons. Major concerns regarding inverted structures are the trap integrity and fault seal. In general, the preferred structures have simple four-way closures due to the minor forced folding of the post-rift cover, as opposed to (reverse) fault-related structures, which have a higher risk of breaching. Such reverse-fault-bounded structures have been generally observed in basins with a thick syn-rift fill and a relatively thin post-rift sequence at the time of inversion (Mode I). In contrast, gentle/open forced folds have been described in basins with thicker post-rift sequences than the syn-rift basin fill (Mode II). Five physical sandbox models, coupled with particle image velocimetry (PIV) analysis, have been performed to address the influence of the syn- versus post-rift thickness ratio on the inversion-related structural style of the post-rift cover. The main control on the development of Mode I or Mode II inversion structures within the post-rift sequence appears to be different due to the amount of compressional displacement accommodated by the inherited listric fault and the thickness of the post-rift cover. These observations do have a direct impact on the understanding of the geo-energy systems associated with inverted structures and are broadly comparable with natural data examples from Aotearoa/New Zealand, Israel, Romania, and the Republic of Türkiye. [ABSTRACT FROM AUTHOR]

Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington's disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity. A 30-week time-course investigative study in dogs treated with vehicle control (negative control), neurotoxic pyridoxine (positive control), or branaplam was conducted to assess neuropathology, nerve morphometry, electrophysiological measurements, gene expression profiles, and correlation to NfL serum concentrations. In branaplam-treated animals, a mild to moderate nerve fiber degeneration was observed in peripheral nerves correlating with increased serum NfL concentrations, but there were no observed signs or changes in electrophysiological parameters. Dogs with pyridoxine-induced peripheral axonal degeneration displayed clinical signs and electrophysiological changes in addition to elevated serum NfL. This study suggests that NfL may be useful as an exploratory biomarker to assist in detecting and monitoring treatment-related peripheral nerve injury, with or without clinical signs, associated with administration of branaplam and other compounds bearing a neurotoxic risk. [ABSTRACT FROM AUTHOR]

Flavonoids are a kind of secondary metabolite which widely exist in plants. They contain a lot of active hydroxyls, which can react with toxic chemicals to produce potential exposure biomarkers. In this article, the model plant Arabidopsis thaliana (L.) was exposed to the nerve agent O-Ethyl N,N-dimethyl phosphoramidocyanidate (Tabun). By comparing with the plant not exposed to Tabun, some characteristic ions were identified by quadrupole–time of flight mass spectrometry in the acetonitrile extract of the exposed leaves. These characteristic ions were selected as parent ions to produce product ion mass spectra (PIMS). Some interesting fragmentation pathways were revealed, including neutral loss of glucoside, rhamnose and ethylene. O-Ethyl N,N-dimethyl phosphoryl modified flavonoids were deduced from assignment of the PIMS. The element components and the accurate mass of the product ions from each parent ion matched well with those of the proposed fragmentation pathways. Through comparison with the PIMS of structurally closely related chemical of Isobutyl methylphosphonyl modified flavonoids, the structures and the fragmentation pathways of the O-Ethyl N,N-dimethyl phosphoryl modified flavonoids were finally confirmed. Successfully finding and identifying these three specific exposure biomarkers in plants provided a new strategy for the retrospective analysis of organophosphorus exposure and forensic analysis. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions. [ABSTRACT FROM AUTHOR]

The green alga Aegagropila linnaei often forms spherical aggregates called "marimo" in Lake Akan in Japan. In winter, marimo are exposed to low water temperatures at 1–4 °C but protected from strong sunlight by ice coverage, which may disappear due to global warming. In this study, photoinhibition in marimo was examined at 2 °C using chlorophyll fluorescence and 830 nm absorption. Filamentous cells of A. linnaei dissected from marimo were exposed to strong light at 2 °C. Photosystem II (PSII) was markedly photoinhibited, while photosystem I was unaffected. When the cells with PSII damaged by the 4 h treatment were subsequently illuminated with moderate repair light at 2 °C, the maximal efficiency of PSII was recovered to the level before photoinhibition. However, after the longer photoinhibitory treatments, PSII efficiency did not recover by the repair light. When the cells were exposed to simulated diurnal light for 12 h per day, which was more ecological, the cells died within a few days. Our results showed new findings of the PSII repair at 2 °C and serious damage at the cellular level from prolonged high-light treatments. Further, we provided a clue to what may happen to marimo in Lake Akan in the near future. [ABSTRACT FROM AUTHOR]

In the presence of the tabun mimic diethylcyanophosphonate (DECP), a fluorescent bifunctional coumarin–enamine chemodosimeter is first phosphorylated and subsequently attacked by the released cyanide ions. The reaction is disclosed in both the UV-vis and fluorescence spectra and confirmed by NMR experiments. DFT calculations support that the bis-adduct as the most thermodynamically stable species. The X-ray structure of the chemodosimeter is also reported. [ABSTRACT FROM AUTHOR]

Tabun Cave, located on the slopes of Mount Carmel (Israel), constitutes one of the key Levantine Palaeolithic sites because of its exceptionally long sequence (ca. 25 m) that has yielded a suite of lithic industries spanning the Lower and Middle Palaeolithic periods. This site is also known to have produced human remains found in the Middle Palaeolithic layers: a Neanderthal female skeleton (C1), and a mandible (C2) commonly classified as Homo sapiens but whose attribution is still debated. Determining the chronology of Levantine Palaeolithic caves has often been limited by severe diagenetic processes, affecting the accuracy of age results obtained using trapped-charge dating methods. Characterising the mineralogical composition of the sediments in such conditions is an important step that was done in this study using Fourier transform infrared (FTIR) spectroscopy. We show that most of our sediment samples underwent diagenesis from the decomposition of guano, ash or bones, based on the presence of authigenic phosphates, which may impact the dose rate. Considering this information, we report here age results obtained using post-infrared infrared stimulated luminescence (pIRIR 290) of polymineral fine grains for Tabun Cave. Our pIRIR 290 ages are in overall agreement with thermoluminescence (TL) dating results obtained previously on burnt flints, reinforcing the antiquity of key transitions in the Middle Pleistocene record from Tabun Cave. The ages suggest that the Lower to Middle Palaeolithic transition at Tabun, possibly coinciding with the arrival of Homo sapiens in the Levant, may be constrained between 265 ± 26 ka (late Lower Palaeolithic, Bed 72, Unit X) and 288 ± 29 ka (early Middle Palaeolithic, Beds 63–64, Unit IX), while the age of the base of the overlying mid-Middle Palaeolithic Layer C (Unit I; Beds 22-19) ranges between 204 ± 18 ka and 192 ± 14 ka. Consequently, the Tabun C2 mandible discovered at the base of Layer C may prove to be among the oldest Homo sapiens fossils found outside Africa. [ABSTRACT FROM AUTHOR]

[Display omitted] • There are three structural types of BChE reactivators: bisquaternary, monoquaternary and uncharged oximes. • Establishment of pseudo-catalytic scavenger by joint administration of BChE and its reactivator could protect AChE from inhibition by organophosphates. • Dichlorinated bisquaternary oxime is a promising lead compound with good reactivation of organophosphate-inhibited BChE. • Two monoquaternary oximes are promising reactivators of BChE inhibited by organophosphates. In this review, the current progress in the research and development of butyrylcholinesterase (BChE) reactivators is summarised and the advantages or disadvantages of these reactivators are critically discussed. Organophosphorus compounds such as nerve agents (sarin, tabun, VX) or pesticides (chlorpyrifos, diazinon) cause irreversible inhibition of acetylcholinesterase (AChE) and BChE in the human body. While AChE inhibition can be life threatening due to cholinergic overstimulation and crisis, selective BChE inhibition has presumably no adverse effects. Because BChE is mostly found in plasma, its activity is important for the scavenging of organophosphates before they can reach AChE in the central nervous system. Therefore, this enzyme in combination with its reactivator can be used as a pseudo-catalytic scavenger of organophosphates. Three structural types of BChE reactivators were found, i.e. bisquaternary salts, monoquaternary salts and uncharged compounds. Although the reviewed reactivators have certain limitations, the promising candidates for BChE reactivation were found in each structural group. [ABSTRACT FROM AUTHOR]

A dual-mode chromo-fluorogenic probe BASO has been introduced that can selectively recognize sarin, tabun, and mustard gas mimics diethylchlorophosphate (DCP), diethylcyanophosphonate (DCNP), and 2-chloroethyl ethyl sulfide (2CEES) in a 1:1 water–dimethyl sulfoxide (DMSO) mixture while native one was non-fluorescent. The opening of the spirolactam ring due to the addition of DCP, DCNP, and 2CEES shows a noticeable pink colorimetric and pink color fluorometric change, which is readily detectable by the naked eye in the µM range in neutral medium. [Display omitted] • A dual-mode chromo-fluorogenic probe BASO has been introduced. • BASO can selectively recognize various nerve agents' and mustard gas mimics. • The opening of the spirolactam ring by the various nerve agents' and mustard gas mimics shows a pink colorimetric and fluorometric change, • BASO could detect various nerve agents' and mustard gas mimics in the µM range in the neutral medium by the naked eye. • BASO has been employed for detecting the vapor phase and soil sample analysis as a practical applicability. Nerve agents are becoming serious issues for the healthy and sustainable environment in modern civilization. Strategically, we have designed and introduced a Schiff base triggered dual chromo-fluorogenic probe BASO via condensation reaction between rhodamine B hydrazide and 3-formyl chromone, which can selectively recognize different toxic target analytes helping a reference to a healthy and sustainable environment. The BASO probe displays enhanced pink photoluminescence extraordinarily due to the introduction of sarin, tabun, and mustard gas mimics diethylchlorophosphate (DCP), diethylcyanophosphonate (DCNP), and 2-chloroethyl ethyl sulfide (2CEES), in a 1:1 water–dimethyl sulfoxide (DMSO) mixture while native one was non-fluorescent. The opening of the spirolactam ring owing to the addition of DCP, DCNP, and 2CEES shows a noticeable pink colorimetric and pink color fluorometric change, which is readily detectable by the naked eye in the µM range in neutral medium and found to be better than numerous available chemosensor (Table S1). We have also fabricated simple paper strip-based test kits as portable and displayable handy photonic tools for on-site detection without any expensive instrumental techniques. The probe BASO has also been employed for detecting the vapor phase and soil sample analysis as a practical applicability. The simple, rapid detection techniques make our probe unique and have significant utility for the recognition of DCP, DCNP, and vesicant or blistering agents mimicking 2CEES. [ABSTRACT FROM AUTHOR]

Various predators are known to have ubiquitously contributed to the accumulation of fossil microvertebrate assemblages in Quaternary depositional settings. Deciphering the taxonomic identity of the predator responsible for each such assemblage through detailed taphonomic analysis has become a prerequisite for paleoecological research to gain insight into their prey and foraging habitat preferences. However, this flourishing field of research builds on the assumption that the pristine taxon-specific taphonomic signal of various predators could have become preserved in the fossil record, unbiased or only negligibly biased by a wide array of destructive post-depositional processes, which could introduce noise into the preservational system. Here we evaluate the likelihood that the predator taphonomic imprint could have been entirely obliterated by such post-depositional action within an especially large assemblage of the remains of micromammals (Rodentia, Eulipotyphla, and Chiroptera; N = 25,810) from Middle Paleolithic Layer C of Tabun Cave, Mount Carmel, Israel. The microfauna from this major stratigraphic unit (c. 2.5 m thick; uniquely yielding the fossils of both Homo sapiens and Neanderthals), with a mean chronometric age of c. 165 ka, has no contemporary analogues in the regional record, indicating exceptional paleoecological conditions for its timespan. We took advantage of the fact that Layer C (aka a major stratigraphic unit) was subdivided in more recent excavations into as many as 26 separate layers (aka beds), featuring relatively nuanced differences in sedimentary, diagenetic, and anthropogenic characteristics, to both independently assess the possibility that Layer C as a whole is isotaphonomic and evaluate the extent of taphonomic variation from bed to bed within it. While substantial variation and bias were revealed in a broad array of standard taphonomic indices of skeletal element fragmentation and differential representation, one index—the grading of digested molars according to the severity of digestion—proved robust against post-depositional distortions of the predatory signal. We discuss the implications of these findings for reliable taphonomic and paleoecological assessment in research with microvertebrate fossil remains. • Taphonomy of a large assemblage of Middle Paleolithic microvertebrates analyzed. • Variation in multiple taphonomic indices evaluated through one thick layer. • Most taphonomic indices demonstrated wide error ranges and low diagnostic value. • Molar digestion grading proved robust for identifying the accumulating predator. • Reliable and economic taphonomic assessment of microvertebrate remains discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] • Analysis of HOMO, LUMO, and ESP confirmed the adsorption capability of Carbon Nano CNCs toward GB and GA, indicating their potential as carriers for targeted nerve agents. • The inner region (P1) of CNCs exhibits superior adsorption efficacy than the outer one. • A greater affinity is evidenced at a higher concentration of adsorbent/adsorbate ratio. • The interaction nature (van der Waals forces.) was proved via the Non-Covalent Interaction (NCI) plots. • MC and MD simulations provided molecular insights into adsorption of nerve agents. Carbon NanoCones (CNCs), distinguished by their conical shape and large surface area, are evaluated for their potential application in nerve gas [tabun (GA) and sarin (GB)] adsorption. Density Functional Theory (DFT) calculations, Molecular Dynamics (MD), and Monte Carlo (MC) simulations are employed to investigate this phenomenon comprehensively. The study findings indicate that tabun (GA) and sarin (GB) undergo spontaneous adsorption, characterized by significant negative energy values. Density Functional Theory (DFT) calculations indicate electron donation tendencies of nerve agents to CNC surfaces. Computational analysis shows higher adsorption efficiency in the inner portion (P1) of CNCs. Molecular Dynamics (MD) and Monte Carlo (MC) simulations confirm planar adsorption configurations parallel to CNC surfaces. The DFT calculations show that GA has a far greater adsorption energy on a Carbon Nanocone compared to GB (−44.96 kcal/mol for GA, whereas GB has an adsorption energy of −35.95 kcal/mol). Furthermore, the analysis reveals significant differences between Sarin and Tabun nerve agents. Sarin exhibits higher global hardness, indicating increased stability, while Tabun shows higher overall softness, suggesting greater reactivity. Despite similar electronegativities, Sarin's greater ionization energy and electron affinity imply enhanced stability and reactivity. Differences in HOMO and LUMO energies highlight unique reactivity profiles, with Sarin being more susceptible to nucleophilic attacks and Tabun to electrophilic attack. Sarin's larger energy gap between HOMO and LUMO orbitals signifies its superior stability under electronic disturbances. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is the primary cause of death among patients with acute paraquat (PQ) poisoning, whereby peroxidative damage is an important mechanism underlying PQ-induced lung injury. There is a lack of effective interventional drugs for patients with PQ poisoning. Oxaloacetic acid (OAA) participates in multiple in vivo metabolic processes, whereby it facilitates the clearance of reactive oxygen species (ROS) and improves mitochondrial function. The study aimed to assess the protective effects of OAA on PQinduced ALI and elucidate the underlying molecular mechanism. Our data demonstrated that OAA treatment significantly alleviated PQ-induced ALI and improved the survival rate of PQ-poisoned mice, and also alleviated PQ-induced cellular oxidative stress and mitochondrial dysfunction. OAAmediated alleviation of PQ-induced mitochondrial dysfunction depends on the following mechanisms which may explain the above findings: 1) OAA effectively cleared intracellular ROS, inhibited ROS accumulation, and mitochondrial depolarization; 2) OAA inhibited the downregulation of L-OPA1 and MFN2 caused by PQ and promoted a dynamic balance of mitochondrial fusion and fission, and 3) the expression of PGC-1a, TFAM, COX2, and COX4I1, increased significantly following OAA intervention which improved mitochondrial respiratory functions and promoted its biogenesis and energy metabolism in damaged cells. In conclusion, OAA effectively cleared ROS and improved mitochondrial dysfunction, thereby significantly improving ALI caused by PQ poisoning and the animal survival rate. Therefore, OAA may be a potential drug for the treatment of PQ poisoning. [ABSTRACT FROM AUTHOR]

Projected potential of 2.5–4.0 Å cryo-EM structures for structure-based drug design is not well realized yet. Here we show that a 3.1 Å structure of PRMT5 is suitable for selecting computed poses of a chemical inhibitor and its analogs for enhanced potency. PRMT5, an oncogenic target for various cancer types, has many inhibitors manifesting little cooperativity with MTA, a co-factor analog accumulated in MTAP−/− cells. To achieve MTA-synergic inhibition, a pharmacophore from virtual screen leads to a specific inhibitor (11-2 F). Cryo-EM structures of 11-2 F / MTA-bound human PRMT5/MEP50 complex and its apo form resolved at 3.1 and 3.2 Å respectively show that 11-2 F in the catalytic pocket shifts the cofactor-binding pocket away by ~2.0 Å, contributing to positive cooperativity. Computational analysis predicts subtype specificity of 11-2 F among PRMTs. Structural analysis of ligands in the binding pockets is performed to compare poses of 11-2 F and its redesigned analogs and identifies three new analogs predicted to have significantly better potency. One of them, after synthesis, is ~4 fold more efficient in inhibiting PRMT5 catalysis than 11-2 F, with strong MTA-synergy. These data suggest the feasibility of employing near-atomic resolution cryo-EM structures and computational analysis of ligand poses for small molecule therapeutics. Cryo-EM map-guided drug design and computational comparison of ligand poses yield a PRMT5 inhibitor or derivatives that are MTA-synergic and show enhanced potency. [ABSTRACT FROM AUTHOR]

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Selective optical detection of highly toxic nerve agents and their mimics like diethyl cyanophosphate (DCNP) is of paramount importance for armed forces and first responders in order to decide the suitable medical countermeasures. The reported optical chemical sensors for DCNP suffered from poor selectivity due to their single point covalent interaction with analyte. To overcome this limitation, we herein, report a novel protocol utilizing a ditopic chemodosimeter which, in presence of tetrabutylammonium hydroxide (TBAOH), underwent dual interaction with reactive subunits of DCNP, viz., electrophilic phosphorus and cyanide, to induce unique changes in its fluorescence as well as colorimetric properties. Other interfering analytes could not trigger the similar optical response in the sensing probe due to the absence of electrophilic phosphorus and cyanide. A truth table was constructed to reveal that only DCNP but not other analytes could induce changes in both fluorescence as well as colorimetric properties of sensing probe. The linearity range of the proposed method was found to be 30–70 μM while chromogenic limit of detection (LOD) was calculated to be 99 nM which are comparable to the reported methods. Thus, use of indigenously available 2‐hydroxy‐1‐naphthaldehyde as sensing probe without requiring further chemical manipulation represented a significant improvement over the literature methods for DCNP sensing. [ABSTRACT FROM AUTHOR]

An in-depth survey was conducted by collecting information from web sources, supplemented by interviews with experts and/or bakers, to identify all the flat breads (FBs) produced in the nine Mediterranean countries involved in the FlatBreadMine Project (Croatia, Egypt, France, Greece, Italy, Jordan, Lebanon, Malta and Spain), and to have an insight into their technical and cultural features. A database with information on 143 FB types (51 single-layered, 15 double-layered, 66 garnished, 11 fried) was established. Flours were from soft wheat (67.4%), durum wheat (13.7%), corn (8.6%), rye, sorghum, chickpea, and chestnut (together 5.2%). The raising agents were compressed yeast (55.8%), sourdough (16.7%), baking powder (9.0%), but 18.6% of FBs were unleavened. Sixteen old-style baking systems were recorded, classified into baking plates and vertical ovens (tannur and tabun). Artisanal FBs accounted for 82%, while the industrial ones for 7%. Quality schemes (national, European or global) applied to 91 FBs. Fifteen FBs were rare, prepared only for family consumption: changes in lifestyle and increasing urbanization may cause their disappearance. Actions are needed to prevent the reduction of biodiversity related to FBs. Information in the database will be useful for the selection of FBs suitable to promotional activities and technical or nutritional improvement. [ABSTRACT FROM AUTHOR]

In this paper, the stability and stabilization are investigated for continuous-time switched systems with admissible edge-dependent average dwell time (AED-ADT). The core idea is to propose new-type Lyapunov functions (LFs), i.e., switching-dependent convex Lyapunov function (CLF) and switching-dependent LF, to achieve the less conservative stability criteria. Corresponding to the novel LFs, two controller design approaches are built to stabilize the underlying system, which are switching-dependent convex controller under an innovative switching scheme and switching-dependent traditional controller under AED-ADT. In the end, a numerical example is provided to verify the effectiveness of the designed LFs in the aspect of stability analysis; a tunnel diode circuit is employed to unfold the potency of the above controller design approaches in optimizing control performances, such as settling time and overshoot. [ABSTRACT FROM AUTHOR]

Yeast particles (YPs) are 3–5 µm hollow and porous microspheres, a byproduct of some food grade yeast (Saccharomyces cerevisiae) extract manufacturing processes. Terpenes can be efficiently encapsulated inside YPs by passive diffusion through the porous cell walls. As previously published, this YP terpene encapsulation approach has been successfully implemented (1) to develop and commercialize fungicide and nematicide products for agricultural applications, (2) to co-load high potency agrochemical actives dissolved in terpenes or suitable solvents, and (3) to identify YP terpenes with broad-acting anthelmintic activity for potential pharmaceutical applications. These first-generation YP terpene materials were developed with a <2:1 terpene: YP weight ratio. Here we report methods to increase the terpene loading capacity in YPs up to 5:1 terpene: YP weight ratio. Hyper-loaded YP terpenes extend the kinetics of payload release up to three-fold compared to the commercialized YP terpene formulations. Hyper-loaded YP-terpene compositions were further optimized to achieve high terpene storage encapsulation stability from −20 °C to 54 °C. The development of hyper-loaded YP terpenes has a wide range of potential agricultural and pharmaceutical applications with terpenes and other compatible active substances that could benefit from a delivery system with a high payload loading capacity combined with increased payload stability and sustained release properties. [ABSTRACT FROM AUTHOR]

Background capacitor-current-sensor (CCS) calibration (CAL) is proposed for dc–dc converters to achieve fast load-transient response for small undershoot $V_{\mathrm {US}}$ , overshoot $V_{\mathrm {OS}}$ , and short settling time $t_{\mathrm {S}}$ in the output voltage $V_{\mathrm {O}}$. The CCS’ impedance $Z_{\mathrm {Cs}}$ is calibrated to a scaled replica of the output capacitor’s impedance $Z_{\mathrm {Co}}$ , which varies with printed-circuit-board parasitics, process-voltage-temperature variations, and aging. Thus, the CCS shunts a current $I_{\mathrm {Cs}}$ equal to a scaled output-capacitor current $I_{\mathrm {Co}}$ , which instantly and accurately reflects load-current $I_{\mathrm {load}}$ transients. The CAL operates at a fixed switching frequency $f_{\mathrm {SW}}$. At this $f_{\mathrm {SW}}$ , although $Z_{\mathrm {Cs}}$ is dominated by its inductive part, this work can still calibrate its capacitive and resistive parts based on the time derivatives dVO/dt and dICs/dt, respectively. This fixed- $f_{\mathrm {SW}}$ CAL overcomes the bottleneck of the prior state-of-the-art CCS CAL, which must hop $f_{\mathrm {SW}}$ to lower values to calibrate $Z_{\mathrm {Cs}}$ capacitive and resistive parts, thereby enlarging $V_{\mathrm {O}}$ steady-state ripples and transient fluctuations during CAL. Thus, only this fixed- $f_{\mathrm {SW}}$ CAL is suitable for background operation. Moreover, this CAL can be interrupted by a load-transient or dynamic-voltage-scaling event and be reactivated in quasi-steady state. The shortest CAL period is 8.8 $\mu \text{s}$ at $f_{\mathrm {SW}} = 30$ MHz without interruption. A buck converter with this CCS CAL is fabricated in 0.18- $\mu \text{m}$ CMOS process and occupies 2.25 mm2. Under a 2-A/4-ns step-up (step-down) load transient, the measured $V_{\mathrm {US}}$ ($V_{\mathrm {OS}}$) and $t_{\mathrm {S}}$ are 36 mV (29 mV) and 56 ns (45 ns), respectively. Compared with prior state of the arts, this work achieves much smaller $V_{\mathrm {O}}$ ripples and fluctuations during CAL, shorter CAL period, and faster load-transient response. [ABSTRACT FROM AUTHOR]

• A selective chromo-fluorogenic probe (AMP) has been introduced to detect sarin & tabun mimics. • A ratiometric UV–visible absorption spectral and colorimetric change from yellow to bright pink is observed. • A "turn-off" photoluminescence from yellow color to non-fluorescence is noticed in the presence of both mimics. • The spectral and chromo-fluorgenic behavior is reversed in the presence of triethyl amine (TEA). • The sensitivity of AMP towards the detection is found in the μM range. The abuse of nerve agents has become a severe threat to peaceful modern civilization. Hence, it is of paramount importance to the scientific communities to detect and degrade them for a modern society. In the present contribution, we have introduced a selective chromo-fluorogenic probe (AMP) based on neutral red dye for visual detection of the solution and vapor phase of sarin & tabun mimics, namely diethyl chlorophosphate (DCP) and diethyl cyanophosphonate (DCNP), respectively. A ratiometric UV–visible absorption spectral change with colorimetric visualization from yellow to bright pink is observed in the presence of both mimics. A "turn-off" photoluminescence from yellow color to non-fluorescence is observed in the presence of both mimics. The spectral and chromo-fluorgenic behavior is reversed in the presence of triethylamine (TEA). The sensitivity of AMP towards the detection of targeted analytes is recorded in the μM range. Additionally, filter paper-based strips are fabricated for the actual applicability of the current probe to identify trace amounts of both analytes in the presence of various types of analogous target analytes. The vapor phase sensing and two types of soil analysis are also employed to check the sensor's potential in real-life applications. The present report has revealed prompt, sensitive, selective, in-situ, accurate sample detectors of sarin & tabun gas in actual threatening situations. A selective chromo-fluorogenic probe (AMP) based on neutral red dye has been introduced for visual detection of the solution and vapor phase of sarin & tabun mimics, namely diethyl chlorophosphate (DCP) and diethyl cyanophosphate (DCNP), respectively displaying a colorimetric change from yellow to bright pink and "turn-off" photoluminescence behavior. [Display omitted] [ABSTRACT FROM AUTHOR]

Flavonoids are a kind of secondary metabolite which widely exist in plants. They contain a lot of active hydroxyls, which can react with toxic chemicals to produce potential exposure biomarkers. In this article, the model plant Arabidopsis thaliana (L.) was exposed to the nerve agent O-Ethyl N,N-dimethyl phosphoramidocyanidate (Tabun). By comparing with the plant not exposed to Tabun, some characteristic ions were identified by quadrupole–time of flight mass spectrometry in the acetonitrile extract of the exposed leaves. These characteristic ions were selected as parent ions to produce product ion mass spectra (PIMS). Some interesting fragmentation pathways were revealed, including neutral loss of glucoside, rhamnose and ethylene. O-Ethyl N,N-dimethyl phosphoryl modified flavonoids were deduced from assignment of the PIMS. The element components and the accurate mass of the product ions from each parent ion matched well with those of the proposed fragmentation pathways. Through comparison with the PIMS of structurally closely related chemical of Isobutyl methylphosphonyl modified flavonoids, the structures and the fragmentation pathways of the O-Ethyl N,N-dimethyl phosphoryl modified flavonoids were finally confirmed. Successfully finding and identifying these three specific exposure biomarkers in plants provided a new strategy for the retrospective analysis of organophosphorus exposure and forensic analysis.

The therapeutic efficacy of treatments for acute intoxication with highly toxic organophosphorus compounds, called nerve agents, usually involves determination of LD50 values 24 h after nerve agent challenge without and with a single administration of the treatment. Herein, the LD50 values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated intoxication were investigated in mice for experimental end points of 6 and 24 h. The LD50 values of the nerve agents were evaluated by probit-logarithmical analysis of deaths within 6 and 24 h of i.m. challenge of the nerve agent at five different doses, using six mice per dose. The efficiency of atropine alone or atropine in combination with an oxime was practically the same at 6 and 24 h. The therapeutic efficacy of the higher dose of the antinicotinic compound MB327 was slightly higher at the 6 h end point compared to the 24 h end point for soman and tabun intoxication. A higher dose of MB327 increased the therapeutic efficacy of atropine alone for sarin, soman and tabun intoxication, and that of the standard antidotal treatment (atropine and oxime) for sarin and tabun intoxication. The therapeutic efficacy of MB327 was lower than the oxime-based antidotal treatment. To compare the 6 and 24 h end points, the influence of the experimental end point was not observed, with the exception of the higher dose of MB327. In addition, only a negligible beneficial impact of the compound MB327 was observed. Nevertheless, antinicotinics may offer an additional avenue for countering poisoning by nerve agents that are difficult to treat, and synthetic and biological studies towards the development of such novel drugs based on the core bispyridinium structure or other molecular scaffolds should continue. [ABSTRACT FROM AUTHOR]

Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. In severe cases, subsequent desensitisation of the receptors results in hypoxia, vasodepression, and respiratory arrest, followed by death. Prompt action is therefore critical to improve the chances of victim’s survival and recovery. Standard therapy of NA poisoning generally involves administration of anticholinergic atropine and an oxime reactivator of phosphylated AChE. Anticholinesterase compounds or NA bioscavengers can also be applied to preserve native AChE from inhibition. With this review of 70 years of research we aim to present current and potential approaches to counteracting NA poisoning.

The lack of animal models for some human diseases precludes our understanding of disease mechanisms and our ability to test prospective therapies in vivo. Generation of kidney organoids from Tuberous Sclerosis Complex (TSC) patient-derived-hiPSCs allows us to recapitulate a rare kidney tumor called angiomyolipoma (AML). Organoids derived from TSC2−/− hiPSCs but not from isogenic TSC2+/− or TSC2+/+ hiPSCs share a common transcriptional signature and a myomelanocytic cell phenotype with kidney AMLs, and develop epithelial cysts, replicating two major TSC-associated kidney lesions driven by genetic mechanisms that cannot be consistently recapitulated with transgenic mice. Transplantation of multiple TSC2−/− renal organoids into the kidneys of immunodeficient rats allows us to model AML in vivo for the study of tumor mechanisms, and to test the efficacy of rapamycin-loaded nanoparticles as an approach to rapidly ablate AMLs. Collectively, our experimental approaches represent an innovative and scalable tissue-bioengineering strategy for modeling rare kidney disease in vivo. The lack of animal models for some human diseases precludes our understanding of disease mechanisms and our ability to test new therapies in vivo. Here the authors present a tissue bioengineering strategy for the study of a rare kidney tumor called angiomyolipoma, in vitro and in vivo, using patient-derived hiPSCs. [ABSTRACT FROM AUTHOR]

After the defeat of Iraqi army in Kuwait in February 1991, on April 3, the UN Security Council (UN Security Council) adopted Resolution 687, that «decides that Iraq shall unconditionally accept the destruction, removal, or rendering harmless, under international supervision, of: (a) All chemical and biological weapons and all stocks of agents and all related subsystems and components and all research, development, support and manufacturing facilities». This UN operation was not the first forced disarmament of vanquished by victors, but it gave great impetus to the completion of the work on the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on Their Destruction, i.e. the destruction of an entire class of weapons of mass destruction. The aim of this article was to show the process of Iraqi`s chemical weapons destruction. The destruction of Iraqi chemical weapons included the formation of legal basis (United Nations Security Council Resolution 687); the establishment of the United Nations Special Commission (UNSCOM) to inspect and oversee the destruction or elimination of Iraq’s chemical weapons directly on Iraqi territory; certain measures of political, economic (UN sanctions) and military coercion (the US and the UK military operation «Desert Fox»). In summer 1991, UNSCOM formed a Destruction Advisory Panel to develop technologies for the destruction of chemical weapons, toxic substances and their precursors. Their destruction was carried out in the period October 1992 to May 1994 on the territory of the Muthanna State Establishment. Sarin, cyclosarin, tabun and their precursors were destroyed by hydrolysis in aqueous alkaline solution using a repurposed production facility. Thus 76 tons of sarin and sarin/cyclosarin mixture, as well as 40 tons of tabun were destroyed. For the sulfur mustard, the high-temperature direct burning method was used at the special factory, established under the project of the Destruction Advisory Panel. Thus were destroyed around 400 tons of liquid sulfur mustard. Chemical munitions and containers, after the extraction of poisonous agents, were destroyed using a specially developed technique of explosive ventilation and burning. 30 chemical warheads for Al-Hussein ballistic missiles, 12,8 thousand 155-mm mustard shells, 40,5 thousand 122 mm rockets for MLRS, filled with sarin/cyclosarin, were destroyed. In general, UNSCOM managed to solve the problem of chemical disarmament of Iraq. The article describes in details the Iraq’s chemical weapons destruction technologies.

The review considers and summarizes separation and preconcentration methods used in the determination of toxicants of the 1st hazard class, namely, organophosphorus nerve agents (a group of Vx isomers, sarin, cyclosarin, soman, and tabun) and blister agents (sulfur mustard). [ABSTRACT FROM AUTHOR]

In this study, we reported sensitivity of (6,0), (7,0), and (8,0) boron nitride nanotubes (BNNTs) toward tabun by using DFT method at the B3LYP/6-311G(d,p) level of the theory. Adsorption energies, DOS, HOMO/LUMO energy gaps, charge transfer, dipole moments, NBO, QTAIM, and second order perturbation energy (E2) were calculated. The most adsorption energy was obtained from the interaction of tabun and (6,0) BNNT. By evaluation of the energies we concluded that (6,0), (7,0), and (8,0) BN nanotubes are not suitable sensors for detecting tabun molecule. The obtained topological data confirmed the calculated adsorption energies. [ABSTRACT FROM AUTHOR]

Density functional theory (DFT) studies were performed to evaluate the adsorption behavior and electronic response of (4,4) carbon nanotubes (CNTs) to the organophosphorus nerve agents 3,3-dimethylbutan-2-yl methyl phosphono fluoridate (Soman), pinacolyl methyl phosphonate (SOS), diethyl fluorophosphates (SAS-F) and diethyl chlorophosphate (SAS-Cl). The calculations were performed using the triple numerical plus polarization (TNP) as the basis set with an orbital cutoff of 4.5 Å. The electronic exchange and correlation effects were analyzed by generalized gradient approximation (GGA) with the BLYP parameterization. The studied systems were fully optimized and adsorption energy (Ead), interaction distances, geometric and electronic structures were investigated. According to the obtained relatively high Ead, it was shown that Soman, SOS, SAS-Cl and SAS-F more likely to be absorbed on the CNTs surfaces, introducing an interesting candidate for chemisorption of the nerve agent gas molecules. As a result, the order of increasing of the Ead values of the studied systems were |Ead SAS-F/CNT| > |Ead SAS-Cl/CNT| > |Ead SOS/CNT| > |Ead Soman/CNT| systems. The calculated partial density of states (PDOS) of the adsorption systems confirmed the strong electrons interaction between the nerve agent molecules and the CNTs surfaces. The obtained results indicated the potential application of CNTs in the design and fabrication of protective low-cost gas filters against toxic odorless nerve agent gases. [ABSTRACT FROM AUTHOR]

Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. In severe cases, subsequent desensitisation of the receptors results in hypoxia, vasodepression, and respiratory arrest, followed by death. Prompt action is therefore critical to improve the chances of victim's survival and recovery. Standard therapy of NA poisoning generally involves administration of anticholinergic atropine and an oxime reactivator of phosphylated AChE. Anticholinesterase compounds or NA bioscavengers can also be applied to preserve native AChE from inhibition. With this review of 70 years of research we aim to present current and potential approaches to counteracting NA poisoning. [ABSTRACT FROM AUTHOR]

The mechanism for the hydrolysis and aminolysis reactions of potential nerve agent tabun have been investigated both at DFT/M062X level and at ab initio MP2 level of theory. Effect of solvent water has also been incorporated using Minnesota SMD model. Based on leaving groups, there are three probable dissociation pathways of tabun: (1) elimination of HCN, (2) elimination of dimethyl amine and (3) elimination of ethanol. Each of the pathways follows a stepwise neutral route through two transition states. From the mechanism, it has been established that the HCN removal pathway is most favorable than the other two due to greater leaving tendency of the cyanide group. The reaction possesses two four-membered transition state in each path, i.e., for the addition of ammonia/water and for the release of leaving groups. As the four-membered cyclic TSs are not so favorable, the investigated reactions were found quite a bit high energetic. The first addition step of the H2O or NH3 is found as the rate-determining step. The reactivity of ammonia toward tabun has been found highly favorable (by ~ 7.6 kcal mol−1) than the water. This can be easily explained using the fact that the nucleophilicity of NH3 is higher than the H2O. Further, we have seen that water can be a very effective catalyst in the aminolysis reaction as it reduces the barrier of activation of the RDS by ~ 10 kcal mol−1. Self-catalyzed hydrolysis of water has also been performed, and it decreases the activation of ~ 11 kcal mol−1 than the uncatalyzed pathways. The significant reduction of energy of activation takes place due to the formation of six-membered transition states that makes much easier hydrogen transfer compared to the four-membered transition state formed in case of uncatalyzed aminolysis reactions. [ABSTRACT FROM AUTHOR]

This editorial is written on the occasion of the 25th anniversary of the infamous sarin and VX terrorist attacks in Japan, in order to increase the awareness of the potential terrorist use of nerve agents and to urge the preparedness to cope with its consequences. Nerve agents are extremely toxic organophosphorus acetylcholinesterase inhibitors, divided in three known groups: G-, Vand A-agents. G-agents tabun, sarin and soman were synthesised in Nazi Germany (1938-1944), V-agents including VX by the British in the 1950s and A-agents or Novichok agents between 1971 and 1993 in the Soviet Union. The use or alleged use of tabun and sarin was mentioned in connection with the Iraq-Iran war (1980-1988) and the Syrian conflict in 2013 and 2017. Sarin and VX were used for terrorist purposes by the Japanese religious sect AUM Shinrikyo in 1994 and 1995. The assassination of Kim Jong NAM with VX took place in Kuala Lumpur, Malesia in 2017, while the 2018 Salisbury and Amesbury poisonings in the UK were ascribed to the so-called Novichok agent A234. Milder cases of poisoning with nerve agents is accompanied by predominantly muscarinic symptomatology and more massive intoxications with mainly nicotinic and central symptoms. Treatment consists of use of atropine, oximes and anticonvulsants.

Organophosphorus agents (OP) are widely used as pesticides due to their cost effectiveness, yet they present a significant public health risk owing to their high toxicity, especially in cases of occupational exposure in agriculture, during suicide attempts using pesticides, and as nerve agents in warfare. Their vigorous permeability through inhalation, ingestion, and dermal exposure results in a high number of reported OP poisoning cases and alarming mortality rates. Initial first-aid management involves decontamination, ventilation, and hemodialysis. Additionally, current treatment guidelines recommend prompt administration of atropine as a first-line antidote, oximes as a follow-up, benzodiazepines for seizure control, and pyridostigmine for prophylaxis. Nevertheless, current treatment options are associated with several challenges. Thus, recent research has focused on investigating novel approaches for their potential in improving current management strategies. This article intends to review recent advances in OP poisoning treatment, including agents investigated for their use as an alternative or adjunctive therapy, novel formulations such as nasal drops or sublingual tablets for emergency administration of atropine, as well as innovative strategies for enhanced oximes delivery and overall efficacy. However, two major barriers may limit these innovations, ethical issues associated with their clinical assessment in emergencies, and limited profitability in countries where most cases occur. [ABSTRACT FROM AUTHOR]

Tabun (ethyl N,N‐dimethylphosphoramidocyanidate), or GA, is a chemical warfare nerve agent produced during the World War II. The synthesis of its analogs is rather simple; thus, it is a significant threat. Furthermore, experiments with tabun and other nerve agents are greatly limited by the involved life risks and the severe restrictions imposed by the Chemical Weapons Convention. For these reasons, accurate theoretical assignment of fragmentation pathways can be especially important. In this work, we employ the Quantum Chemistry Electron Ionization Mass Spectra method, which combines molecular dynamics, quantum chemistry methods, and stochastic approaches, to accurately investigate the electron ionization/mass spectrometry (EI/MS) fragmentation spectrum and pathways of the tabun molecule. We found that different rearrangement reactions occur including a McLafferty involving the nitrile group. An essential and characteristic pathway for identification of tabun and analogs, a two‐step fragmentation producing the m/z 70 ion, was confirmed. The present results will be also useful to predict EI/MS spectrum and fragmentation pathways of other members of the tabun family, namely, the O‐alkyl/cycloalkyl N,N‐dialkyl (methyl, ethyl, isopropyl, or propyl) phosphoramidocyanidates. [ABSTRACT FROM AUTHOR]

• The binding properties of tabun-subtype nerve agents were investigated. • The binding mechanism with selectivity to lysine residues were studied. • K525 and K414 can serve as the primary biomarkers for traceability of GAs exposure in humans. Upon entering the body, nerve agents can bind active amino acid residues to form phosphonylated adducts. Tabun derivatives (O -alkyl- N,N- dialkyl phosphoroamidocyanidates) have strikingly different structural features from other G-series nerve agents, such as sarin and soman. Here, we investigate the binding mechanism for the phosphonylated adducts of nerve agents of tabun derivatives. Binding sites for three tabun derivatives, O -ethyl- N,N - dimethyl phosphoramidocyanidate (GA), O -ethyl- N,N -ethyl(methyl) phosphoramidocyanidate, and O -ethyl- N,N -diethylphosphoramidocyanidate were studied. Quadrupole-orbitrap mass spectrometry (Q-Orbitrap-MS) coupled to proteomics was used to screen adducts between tabun derivatives and albumin, immunoglobulin, and hemoglobin. The results reveal that all three tabun derivatives exhibit robust selectivity to lysine residues, rather than other amino acid residue types. A set of 10 lysine residues on human serum albumin are labeled by tabun derivatives in vitro , with K525 (K*QTALVELVK) and K199 (LK*CASLQK) peptides displaying the most reactivity. Tabun derivatives formed stable adducts on K525 and K414 (K*VPQVSTPTLVEVSR) for at least 7 days and on K351 (LAK*TYETTLEK) for at least 5 days in a rabbit model. Three of these peptides—K525, K414, and K351—have the highest homology with human serum albumin of all 5 lysine residues that bound to examined rabbit blood proteins in vivo. Molecular simulation of the tabun-albumin interaction using structural analysis and molecular docking provided theoretical evidence supporting lysine residue reactivity to phosphonylation by tabun derivatives. K525 has the lowest free binding energy and the strongest hydrogen bonding to human albumin. In summary, these findings identify unique binding properties for tabun derivatives to blood proteins. [ABSTRACT FROM AUTHOR]

Both DCNP (nerve gas Tabun mimic) and Cd2+ are extremely toxic to mankind. We have focused our research on quantitative estimation of DCNP and Cd2+ in given water samples. A carbazole–pyrrole conjugate CPC has been designed and synthesized which possesses a unique characteristic feature of detecting two hazardous analytes DCNP and Cd2+ by giving two different optical responses i.e. visual color changes and fluorescence "turn-on" respectively. The PET based chemosensor CPC produces a new compound CPC-1 and a highly fluorescent CPC–Cd2+ complex upon addition of DCNP and Cd2+, respectively. The detection limit of CPC for DCNP and Cd2+ has been estimated to be 7.75 nM and 0.27 μM, respectively, at pH 7.0. Quantum chemical calculations have been executed to demonstrate the electronic properties and the mechanism of the receptor–donor interactions. The concentrations of DCNP and Cd2+ ions in various water samples have been estimated with the help of standard absorbance and fluorescence curves. [ABSTRACT FROM AUTHOR]