Stargazer: Long-Term and Multiregional Measurement of Timing/ Geolocation-Based Cloaking

Malicious hosts have come to play a significant and varied role in today's cyber attacks. Some of these hosts are equipped with a technique called cloaking, which discriminates between access from potential victims and others and then returns malicious content only to potential victims. This is a serious threat because it can evade detection by security vendors and researchers and cause serious damage. As such, cloaking is being extensively investigated, especially for phishing sites. We are currently engaged in a long-term cloaking study of a broader range of threats. In the present study, we implemented Stargazer, which actively monitors malicious hosts and detects geographic and temporal cloaking, and collected 30,359,410 observations between November 2019 and February 2022 for 18,397 targets from 13 sites where our sensors are installed. Our analysis confirmed that cloaking techniques are widely abused, i.e., not only in the context of specific threats such as phishing. This includes geographic and time-based cloaking, which is difficult to detect with single-site or one-shot observations. Furthermore, we found that malicious hosts that perform cloaking include those that survive for relatively long periods of time, and those whose contents are not present in VirusTotal. This suggests that it is not easy to observe and analyze the cloaking malicious hosts with existing technologies. The results of this study have deepened our understanding of various types of cloaking, including geographic and temporal ones, and will help in the development of future cloaking detection methods

Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics

Cysteine hydropersulfide (CysSSH) occurs in abundant quantities in various organisms, yet little is known about its biosynthesis and physiological functions. Extensive persulfide formation is apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is believed to result from post-translational processes involving hydrogen sulfide-related chemistry. Here we demonstrate effective CysSSH synthesis from the substrate l-cysteine, a reaction catalyzed by prokaryotic and mammalian cysteinyl-tRNA synthetases (CARSs). Targeted disruption of the genes encoding mitochondrial CARSs in mice and human cells shows that CARSs have a crucial role in endogenous CysSSH production and suggests that these enzymes serve as the principal cysteine persulfide synthases in vivo. CARSs also catalyze co-translational cysteine polysulfidation and are involved in the regulation of mitochondrial biogenesis and bioenergetics. Investigating CARS-dependent persulfide production may thus clarify aberrant redox signaling in physiological and pathophysiological conditions, and suggest therapeutic targets based on oxidative stress and mitochondrial dysfunction

Protein S-guanylation by the biological signal 8-nitroguanosine 3\u27,5\u27-cyclic monophosphate

The signaling pathway of nitric oxide (NO) depends mainly on guanosine 3′,5′-cyclic monophosphate (cGMP, 1). Here we report the formation and chemical biology of a nitrated derivative of cGMP, 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP, 2), in NO-mediated signal transduction. Immunocytochemistry demonstrated marked 8-nitro-cGMP production in various cultured cells in an NO-dependent manner. This finding was confirmed by HPLC plus electrochemical detection and tandem mass spectrometry. 8-Nitro-cGMP activated cGMP-dependent protein kinase and showed unique redox-active properties independent of cGMP activity. Formation of protein Cys-cGMP adducts by 8-nitro-cGMP was identified as a new post-translational modification, which we call protein S-guanylation. 8-Nitro-cGMP seems to regulate the redox-sensor signaling protein Keap1, via S-guanylation of the highly nucleophilic cysteine sulfhydryls of Keap1. This study reveals 8-nitro-cGMP to be a second messenger of NO and sheds light on new areas of the physiology and chemical biology of signal transduction by NO

Cell signaling mediated by nitrated cyclic guanine nucleotide

We recently clarified the physiological formation of 8-nitroguanosine 3\u27,5\u27-cyclic monophosphate (8-nitro-cGMP) and its critical roles in nitric oxide (NO) signal transductions. This discovery of 8-nitro-cGMP is the first demonstration of a nitrated cyclic nucleotide functioning as a new second messenger in mammals since the identification of cGMP more than 40. years ago. By means of chemical analyses, e.g., liquid chromatography-tandem mass spectrometry, we unequivocally identified 8-nitro-cGMP formation, which depended on NO production, in several types of cultured cells, including macrophages and glial cells. Most important, we previously showed that 8-nitro-cGMP as an electrophile reacted with particular sulfhydryls of proteins to generate a unique post-translational modification that we called protein S-guanylation. In fact, certain specific intracellular proteins, such as the redox-sensor protein Keap1, readily underwent S-guanylation induced by 8-nitro-cGMP. 8-Nitro-cGMP activated the Nrf2 signaling pathway by triggering dissociation of Keap1, via S-guanylation of its highly nucleophilic cysteine sulfhydryls. We also determined that S-guanylation of Keap1 was involved in cytoprotective actions of NO and 8-nitro-cGMP by inducing oxidative stress response genes such as heme oxygenase-1. Such unique chemical properties of 8-nitro-cGMP shed light on new areas of NO and cGMP signal transduction. Protein S-guanylation induced by 8-nitro-cGMP may thus have important implications in NO-related physiology and pathology, pharmaceutical chemistry, and development of therapeutics for many diseases

3-layer modelling method to improve the cyber resilience in Industrial Control Systems

Cyberattacks against Industrial Control Systems (ICS), which play a crucial role in many industrial domains, could bring environmental and safety damages as well as huge economic loss. To decrease such cybersecurity risks, it is needed to improve the cyber resilience, that is the capability to respond to and recover from the threat in case cyberattacks occur. To this end, we propose the 3-layer modelling method that reproduces ICS by the actor, asset, and process models. The modelling approach based on Petri-Nets is used to express the state of all models in time series and quantify the availability of ICS influenced by cyberattacks, considering the behavior of personnel involving both cybersecurity and industrial operations. To demonstrate the effectiveness, resilience curves, which draw the availability as a function of time, are finally calculated for multiple cases of cyberattacks, assuming a hypothetical manufacturing factory. As a result, the production rate, which represents the availability of the manufacturing industry, is calculated in time series. The resilience curve can be used to determine what and when to do to minimize the impact of cyberattacks, which leads to the improvement of the cyber resilience