The chemical threat agent tetramethylenedisulfotetramine (TETS) is a γ-aminobutyric acid type A receptor (GABA AR) antagonist that causes life threatening seizures. Currently, there is no specific ...antidote for TETS intoxication. TETS-induced seizures are typically treated with benzodiazepines, which function as nonselective positive allosteric modulators (PAMs) of synaptic GABAARs. The major target of TETS was recently identified as the GABAAR α2β3γ2 subtype in electrophysiological studies using recombinantly expressed receptor combinations. Here, we tested whether these in vitro findings translate in vivo by comparing the efficacy of GABAAR subunit-selective PAMs in reducing TETS-induced seizure behavior in larval zebrafish. We tested PAMs targeting α1, α2, α2/3/5, α6, ß2/3, ß1/2/3, and δ subunits and compared their efficacy to the benzodiazepine midazolam (MDZ). The data demonstrate that α2- and α6-selective PAMs (SL-651,498 and SB-205384, respectively) were effective at mitigating TETS-induced seizure-like behavior. Combinations of SB-205384 and MDZ or SL-651,498 and 2–261 (ß2/3-selective) mitigated TETS-induced seizure-like behavior at concentrations that did not elicit sedating effects in a photomotor behavioral assay, whereas MDZ alone caused sedation at the concentration required to stop seizure behavior. Isobologram analyses suggested that SB-205384 and MDZ interacted in an antagonistic fashion, while the effects of SL-651,498 and 2–261 were additive. These results further elucidate the molecular mechanism by which TETS induces seizures and provide mechanistic insight regarding specific countermeasures against this chemical convulsant.
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•A zebrafish assay confirms the GABAAR subtype selectivity of the rodenticide TETS.•α2, α6 or ß2/3 selective PAMs mitigated TETS-induced seizure behavior in zebrafish.•The benzodiazepine midazolam (MDZ) caused sedation in photomotor assay.•Low dose MDZ combined with α6-selective PAM mitigates seizures with less sedation.•Combinations of α2 and ß2/3 selective PAMs mitigate seizures with less sedation.
Threat assessment is the continuous process of monitoring the threats identified in the network of the real-time informational environment of an organisation and the business of the companies. The ...sagacity and security assurance for the system of an organisation and company’s business seem to need that information security exercise to unambiguously and effectively handle the threat agent’s attacks. How is this unambiguous and effective way in the present-day state of information security practice working? Given the prevalence of threats in the modern information environment, it is essential to guarantee the security of national information infrastructure. However, the existing models and methodology are not addressing the attributes of threats like motivation, opportunity, and capability (C, M, O), and the critical threat intelligence (CTI) feed to the threat agents during the penetration process is ineffective, due to which security assurance arises for an organisation and the business of companies. This paper proposes a semi-automatic information security model, which can deal with situational awareness data, strategies prevailing information security activities, and protocols monitoring specific types of the network next to the real-time information environment. This paper looks over analyses and implements the threat assessment of network traffic in one particular real-time informational environment. To achieve this, we determined various unique attributes of threat agents from the Packet Capture Application Programming Interface (PCAP files/DataStream) collected from the network between the years 2012 and 2019. We used hypothetical and real-world examples of a threat agent to evaluate the three different factors of threat agents, i.e., Motivation, Opportunity, and Capability (M, O, C). Based on this, we also designed and determined the threat profiles, critical threat intelligence (CTI), and complexity of threat agents that are not addressed or covered in the existing threat agent taxonomies models and methodologies.
Chlorine gas is a toxic respiratory irritant that is considered a chemical threat agent because of the potential for release in industrial accidents or terrorist attacks. Chlorine inhalation damages ...the respiratory tract, including the airways and distal lung, and can result in acute lung injury. Some individuals exposed to chlorine experience a full recovery from acute injury, whereas others develop persistent adverse effects, such as respiratory symptoms, inflammation, and lung‐function decrements. In animal models, chlorine can produce persistent inflammation, remodeling, and obstruction in large or small airways, depending on species. Airways with pseudostratified epithelia are repaired efficiently, with surviving basal epithelial cells serving as progenitor cells that repopulate the complement of differentiated cell types. Distal airways lacking basal cells are repaired less efficiently, leading to chronic inflammation and fibrosis at these sites. Persistent chlorine‐induced airway disease in humans is treated with asthma medication to relieve symptoms. However, such treatment does not ameliorate the underlying disease pathogenesis, so treatments that are more effective at preventing initial development of airway disease after irritant gas exposure and at reversing established disease are needed.
Acute intoxication with picrotoxin or the rodenticide tetramethylenedisulfotetramine (TETS) can cause seizures that rapidly progress to
status epilepticus
and death. Both compounds inhibit ...γ-aminobutyric acid type-A (GABA
A
) receptors with similar potency. However, TETS is approximately 100 × more lethal than picrotoxin. Here, we directly compared the toxicokinetics of the two compounds following intraperitoneal administration in mice. Using LC/MS analysis we found that picrotoxinin, the active component of picrotoxin, hydrolyses quickly into picrotoxic acid, has a short in vivo half-life, and is moderately brain penetrant (brain/plasma ratio 0.3). TETS, in contrast, is not metabolized by liver microsomes and persists in the body following intoxication. Using both GC/MS and a TETS-selective immunoassay we found that mice administered TETS at the LD
50
of 0.2 mg/kg in the presence of rescue medications exhibited serum levels that remained constant around 1.6 μM for 48 h before falling slowly over the next 10 days. TETS showed a similar persistence in tissues. Whole-cell patch-clamp demonstrated that brain and serum extracts prepared from mice at 2 and 14 days after TETS administration significantly blocked heterologously expressed α
2
β
3
γ
2
GABA
A
-receptors confirming that TETS remains pharmacodynamically active in vivo
.
This observed persistence may contribute to the long-lasting and recurrent seizures observed following human exposures. We suggest that countermeasures to neutralize TETS or accelerate its elimination should be explored for this highly dangerous threat agent.
The microorganisms with which we share our world go largely unnoticed. We are, however, beginning to be able to exploit their apparently silent presence as witnesses to events that are of legal ...concern. This information can be used to link forensic samples to criminal events and even perpetrators. Once dead, our bodies are rapidly colonised, internally and externally. The progress of these events can be charted to inform how long and even by what means a person has died. A small number of microbial species could actually be the cause of such deaths as a result of biocrime or bioterrorism. The procedures and techniques to respond to such attacks have matured in the last 20 years. The capability now exists to identify malicious intent, characterise the threat agent to isolate level and potentially link it to perpetrators with a high level of confidence.
Proactive security plays a vital role in preventing the attack before entering active mode. In the modern information environment, it depends on the vulnerability management practitioners of an ...organization in which the critical factor is the prioritization of threats. The existing models and methodology follow the traditional approaches of a Common Vulnerability Scoring System (CVSS) to prioritize threats and vulnerabilities. The CVSS is not able to provide effectiveness to the security of the business of an organization. In contrast, the vulnerability analysis needs a model which can give significance to the prioritization policies. The model depends on the CVSS score of threats and compares various features of vulnerability like threat vectors, inputs, environments used by threat agent’s groups, and potential outputs of threat agents. Therefore, the research aims to design a semi-automatic model for vulnerability analysis of threats for the National Institute of Standards and Technology (NIST) database of cyber-crime. We have developed a semi-automatic model that simulates the CVE (Common Vulnerabilities and Exposures) list of the NIST database between 1999 and 2021, concerning the resources used by the threat agents, pre-requisites input, attack vectors, and dormant results. The semi-automatic approach of the model to perform the vulnerability analysis of threat agent groups identified in a network makes the model more efficient and effective to addresses the profiling of threat agents and evaluating the CTI (Critical Threat intelligence feed). Our experimental results imply that the semi-automatic model implements the vulnerability prioritization based on the CVSS score and uses the comparative analysis based on the threat agent’s vectors identified. It also provides potency and optimized complexity to an organization’s business to mitigate the vulnerability identified in a network.
Chlorine is a chemical threat agent that can be harmful to humans. Acute inhalation of high levels of chlorine results in the death of airway epithelial cells and can lead to persistent adverse ...effects on respiratory health, including airway remodeling and hyperreactivity. We previously developed a mouse chlorine exposure model in which animals developed inflammation and fibrosis in large airways. In the present study, examination by laser capture microdissection of developing fibroproliferative lesions in FVB/NJ mice exposed to 240 ppm-h chlorine revealed upregulation of genes related to macrophage function. Treatment of chlorine-exposed mice with the corticosteroid drug budesonide daily for 7 days (30–90 μg/mouse i.m.) starting 1 h after exposure prevented the influx of M2 macrophages and the development of airway fibrosis and hyperreactivity. In chlorine-exposed, budesonide-treated mice 7 days after exposure, large airways lacking fibrosis contained extensive denuded areas indicative of a poorly repaired epithelium. Damaged or poorly repaired epithelium has been considered a trigger for fibrogenesis, but the results of this study suggest that inflammation is the ultimate driver of fibrosis in our model. Examination at later times following 7-day budesonide treatment showed continued absence of fibrosis after cessation of treatment and regrowth of a poorly differentiated airway epithelium by 14 days after exposure. Delay in the start of budesonide treatment for up to 2 days still resulted in inhibition of airway fibrosis. Our results show the therapeutic potential of budesonide as a countermeasure for inhibiting persistent effects of chlorine inhalation and shed light on mechanisms underlying the initial development of fibrosis following airway injury.
•Fibrotic lesions in chlorine-exposed mouse lungs had large gene expression changes.•Pro-inflammatory gene expression suggested benefits of anti-inflammatory therapy.•The corticosteroid budesonide inhibited chlorine-induced airway fibrosis in mice.•Budesonide inhibited fibrosis even in the absence of efficient epithelial repair.•Inflammation rather than epithelial damage may drive fibrogenesis in this model.
The rodenticide tetramethylenedisulfotetramine (TETS) is a potent convulsant (lethal dose in humans 7–10 mg) that is listed as a possible threat agent by the United States Department of Homeland ...Security. TETS has previously been studied in vivo for toxicity and in vitro in binding assays, with the latter demonstrating it to be a non-competitive antagonist on GABA
A
receptors. To determine whether TETS exhibits subtype selectivity for a particular GABA
A
receptor combination, we used whole-cell patch-clamp to determine the potency of TETS on the major synaptic and extrasynaptic GABA
A
receptors associated with convulsant activity. The active component of picrotoxin, picrotoxinin, was used as a control. While picrotoxinin did not differentiate well between 13 GABA
A
receptors, TETS exhibited the highest activity on α2β3γ2 (IC
50
480 nM, 95% CI 320–640 nM) and α6β3γ2 (IC
50
400 nM, 95% CI 290–510 nM). Introducing β1 or β2 subunits into these receptor combinations reduced or abolished TETS sensitivity, suggesting that TETS preferentially affects receptors with α2/β3 or α6/β3 composition. Since α2β3γ2 receptors make up 15–20% of the GABA
A
receptors in the mammalian CNS, we suggest that α2β3γ2 is probably the most important GABA
A
receptor for the seizure-inducing activity of TETS.
Botulinum toxin is the highly toxic substance that causes very dangerous neuroparalytic disease called botulism. It is produced by anaerobic and endospore forming bacteria called C. botulinum. In the ...absence of licensed vaccine against botulism, an immunoproteome-based approach was developed to find immunogenic proteins of C. botulinum type B for development of vaccine against botulism. Extracellular proteins of C. botulinum type B were separated by 2-DE and probed with hyper-immune antisera of extracellular proteins and antisera of live spores of C. botulinum type B to evaluate the reactivity of extracellular proteins by immunoblotting assay. Five proteins reacted with extracellular proteins antisera and one protein reacted with live spores' antisera. These identified immunogenic proteins will be further evaluated as the vaccine candidates against botulism.
The main goal of proactive security is to prevent attacks before they happen. In modern information systems it largely depends on the vulnerability management process, where prioritization is one of ...the key steps. A widely used prioritization policy based only upon a common vulnerability scoring system (CVSS) score is frequently criticised for bad effectiveness. The main reason is that the CVSS score alone is not a good predictor of vulnerability exploitation in the wild. Therefore, the aim of the research in this field is to determine in what way we can improve our prediction abilities. Clearly, software vulnerabilities are commodities used by attackers. Hence, it makes sense considering their characteristics in vulnerability prioritization. In contrast, one should be able to measure and compare the effectiveness of various policies. Therefore, an important goal of this paper was to develop an evaluation model, which would allow such comparisons. For this purpose, we developed an agent-based simulation model which measures the exposure of information system to exploitable vulnerabilities. Besides, some policies which take into account human threats were defined and then compared with the most popular existing methods. Experimental results imply that the proposed policy, which is based on CVSS vectors and attacker characteristics, achieves the highest effectiveness among existing methods.
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