Allosteric cooperation in a de novo-designed two-domain protein

We describe the de novo design of an allosterically regulated protein, which comprises two tightly coupled domains. One domain is based on the DF (Due Ferri in Italian or two-iron in English) family of de novo proteins, which have a diiron cofactor that catalyzes a phenol oxidase reaction, while the second domain is based on PS1 (Porphyrin-binding Sequence), which binds a synthetic Zn-porphyrin (ZnP). The binding of ZnP to the original PS1 protein induces changes in structure and dynamics, which we expected to influence the catalytic rate of a fused DF domain when appropriately coupled. Both DF and PS1 are four-helix bundles, but they have distinct bundle architectures. To achieve tight coupling between the domains, they were connected by four helical linkers using a computational method to discover the most designable connections capable of spanning the two architectures. The resulting protein, DFP1 (Due Ferri Porphyrin), bound the two cofactors in the expected manner. The crystal structure of fully reconstituted DFP1 was also in excellent agreement with the design, and it showed the ZnP cofactor bound over 12 Å from the dimetal center. Next, a substrate-binding cleft leading to the diiron center was introduced into DFP1. The resulting protein acts as an allosterically modulated phenol oxidase. Its Michaelis-Menten parameters were strongly affected by the binding of ZnP, resulting in a fourfold tighter Km and a 7-fold decrease in kcat These studies establish the feasibility of designing allosterically regulated catalytic proteins, entirely from scratch

Measuring the Effectiveness of Photoresponsive Nanocomposite Coatings on Aircraft Windshields to Mitigate Laser Intensity

In 2004, pilots reported 46 laser illumination events to the Federal Aviation Administration (FAA), with the number increasing to approximately 3,600 in 2011. Since that time, the number of reported laser incidents has ranged from 3,500 to 4,000. Previous studies indicate the potential for flight crewmember distraction from bright laser light being introduced to the cockpit. Compositional variations of the photoresponsive nanocomposite coatings were applied to an aircraft windscreen using a modified liquid dispersion/heating curing process. The attenuating effects of the deposited films on laser light intensity were evaluated using an optical power meter and the resultant laser intensity data through treated and untreated windscreens was collected. Data revealed a reduction in laser intensity (36–88%) in the presence of the engineered photoresponsive nanocomposite films. Results lend support of the view that the addition of transparent laser attenuating films applied to aircraft windscreens may improve flight safety, and reduce the risk from distraction or disruption of flight crewmembers’ vision

Phytotherapeutic effects of Echinacea purpurea in gamma-irradiated mice

Echinacea (E.) purpurea herb is commonly known as the purple coneflower, red sunflower and rudbeckia. In this paper, we report the curative efficacy of an Echinacea extract in γ-irradiated mice. E. purpurea was given to male mice that were divided into five groups (control, treated, irradiated, treated before irradiation & treated after irradiation) at a dose of 30 mg/kg body weight for 2 weeks before and after irradiation with 3 Gy of γ-rays. The results reflected the detrimental reduction effects of γ-rays on peripheral blood hemoglobin and the levels of red blood cells, differential white blood cells, and bone marrow cells. The thiobarbituric acid-reactive substances (TBARs) level, Superoxide dismutase (SOD) and glutathione peroxidase (GSPx) activities and DNA fragmentation were also investigated. FT-Raman spectroscopy was used to explore the structural changes in liver tissues. Significant changes were observed in the microenvironment of the major constituents, including tyrosine and protein secondary structures. E. purpurea administration significantly ameliorated all estimated parameters. The radio-protection effectiveness was similar to the radio-recovery curativeness in comparison to the control group in most of the tested parameters. The radio-protection efficiency was greater than the radio-recovery in hemoglobin level during the first two weeks, in lymphoid cell count and TBARs level at the fourth week and in SOD activity during the first two weeks, as compared to the levels of these parameters in the control group

The role of morphine in regulation of cancer cell growth

Morphine is considered the “gold standard” for relieving pain and is currently one of the most effective drugs available clinically for the management of severe pain associated with cancer. In addition to its use in the treatment of pain, morphine appears to be important in the regulation of neoplastic tissue. Although morphine acts directly on the central nervous system to relieve pain, its activities on peripheral tissues are responsible for many of the secondary complications. Therefore, understanding the impact, other than pain control, of morphine on cancer treatment is extremely important. The effect of morphine on tumor growth is still contradictory, as both growth-promoting and growth-inhibiting effects have been observed. Accumulating evidence suggests that morphine can affect proliferation and migration of tumor cells as well as angiogenesis. Various signaling pathways have been suggested to be involved in these extra-analgesic effects of morphine. Suppression of immune system by morphine is an additional complication. This review provides an update on the influence of morphine on the growth and migration potential of tumor cells

Modélisation formelle et analyse quantitative de la sécurité à l'aide d'arbres d'attaque et de défense

Risk analysis is a very complex process. It requires rigorous representation and in-depth assessment of threats and countermeasures. This thesis focuses on the formal modelling of security using attack and defence trees. These are used to represent and quantify potential attacks in order to better understand the security issues that the analyzed system may face. They therefore make it possible to guide an expert in the choice of countermeasures to be implemented to secure their system. The main contributions of this thesis are as follows: - The enrichment of the attack and defence tree model allowing the analysis of real security scenarios. In particular, we have developed the theoretical foundations and quantitative evaluation algorithms for the model where an attacker's action can contribute to several attacks and a countermeasure can prevent several threats. - The development of a methodology based on Pareto dominance and allowing several quantitative aspects to be taken into account simultaneously (e.g., cost, time, probability, difficulty, etc.) during a risk analysis. - The design of a technique, using linear programming methods, for selecting an optimal set of countermeasures, taking into account the budget available for protecting the analyzed system. It is a generic technique that can be applied to several optimization problems, for example, maximizing the attack surface coverage, or maximizing the attacker's investment. To ensure their practical applicability, the model and mathematical algorithms developed were implemented in a freely available open source tool. All the results were also validated with a practical study on an industrial scenario of alteration of electricity consumption meters.L'analyse de risque est un processus très complexe. Elle nécessite une représentation rigoureuse et une évaluation approfondie des menaces et de leur contre-mesures. Cette thèse porte sur la modélisation formelle de la sécurité à l'aide d'arbres d'attaque et de défense. Ces derniers servent à représenter et à quantifier les attaques potentielles afin de mieux comprendre les enjeux de sécurité auxquels le système analysé peut être confronté. Ils permettent donc de guider un expert dans le choix des contre-mesures à implémenter pour sécuriser son système. - Le développement d'une méthodologie basée sur la dominance de Pareto et permettant de prendre en compte plusieurs aspects quantitatifs simultanément (e.g., coût, temps, probabilité, difficulté, etc.) lors d'une analyse de risques. - La conception d'une technique, utilisant les méthodes de programmation linéaire, pour sélectionner un ensemble de contre-mesures optimal, en tenant compte du budget destiné à la protection du système analysé. C'est une technique générique qui peut être appliquée à plusieurs problèmes d'optimisation, par exemple, la maximisation de la couverture de surface d'attaque, Les principales contributions de cette thèse sont les ou encore la maximisation du investissement de suivantes : l'attaquant. - L'enrichissement du modèle des arbres d'attaque et de défense permettant d'analyser des scénarios de Pour garantir leur applicabilité pratique, le modèle et sécurité réels. Nous avons notamment développé les les algorithmes mathématiques développés ont été fondements théoriques et les algorithmes d'évaluation implémentés dans un outil informatique à source quantitative pour le modèle où une action de ouverte et accès gratuit. Tous les résultats ont l'attaquant peut contribuer à plusieurs attaques et où également été validés lors d'une étude pratique une contre-mesure peut prévenir plusieurs menaces. portant sur un scénario industriel d'altération de compteurs de consommation d'électricité

Efficient Attack-Defense Tree Analysis using Pareto Attribute Domains

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