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Sample records for attack complex inhibitor

  1. Membrane attack complex inhibitor CD59a protects against focal cerebral ischemia in mice

    Directory of Open Access Journals (Sweden)

    Nietfeld Wilfried

    2010-03-01

    Full Text Available Abstract Background The complement system is a crucial mediator of inflammation and cell lysis after cerebral ischemia. However, there is little information about the exact contribution of the membrane attack complex (MAC and its inhibitor-protein CD59. Methods Transient focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO in young male and female CD59a knockout and wild-type mice. Two models of MCAO were applied: 60 min MCAO and 48 h reperfusion, as well as 30 min MCAO and 72 h reperfusion. CD59a knockout animals were compared to wild-type animals in terms of infarct size, edema, neurological deficit, and cell death. Results and Discussion CD59a-deficiency in male mice caused significantly increased infarct volumes and brain swelling when compared to wild-type mice at 72 h after 30 min-occlusion time, whereas no significant difference was observed after 1 h-MCAO. Moreover, CD59a-deficient mice had impaired neurological function when compared to wild-type mice after 30 min MCAO. Conclusion We conclude that CD59a protects against ischemic brain damage, but depending on the gender and the stroke model used.

  2. Supported Lipid Bilayer Platform To Test Inhibitors of the Membrane Attack Complex: Insights into Biomacromolecular Assembly and Regulation.

    Science.gov (United States)

    Yorulmaz, Saziye; Jackman, Joshua A; Hunziker, Walter; Cho, Nam-Joon

    2015-11-01

    Complement activation plays an important role in innate immune defense by triggering formation of the membrane attack complex (MAC), which is a biomacromolecular assembly that exhibits membrane-lytic activity against foreign invaders including various pathogens and biomaterials. Understanding the details of MAC structure and function has been the subject of extensive work involving bulk liposome and erythrocyte assays. However, it is difficult to characterize the mechanism of action of MAC inhibitor drug candidates using the conventional assays. To address this issue, we employ a biomimetic supported lipid bilayer platform to investigate how two MAC inhibitors, vitronectin and clusterin, interfere with MAC assembly in a sequential addition format, as monitored by the quartz crystal microbalance-dissipation (QCM-D) technique. Two experimental strategies based on modular assembly were selected, precincubation of inhibitor and C5b-7 complex before addition to the lipid bilayer or initial addition of inhibitor followed by the C5b-7 complex. The findings indicate that vitronectin inhibits membrane association of C5b-7 via a direct interaction with C5b-7 and via competitive membrane association onto the supported lipid bilayer. On the other hand, clusterin directly interacts with C5b-7 such that C5b-7 is still able to bind to the lipid bilayer, and clusterin affects the subsequent binding of other complement proteins involved in the MAC assembly. Taken together, the findings in this study outline a biomimetic approach based on supported lipid bilayers to explore the interactions between complement proteins and inhibitors, thereby offering insight into MAC assembly and regulation.

  3. Longest-path attacks on complex networks

    CERN Document Server

    Pu, Cunlai

    2014-01-01

    We investigate the longest-path attacks on complex networks. Specifically, we remove approximately the longest simple path from a network iteratively until there are no paths left in the network. We propose two algorithms, the random augmenting approach (RPA) and the Hamilton-path based approach (HPA), for finding the approximately longest simple path in a network. Results demonstrate that steps of longest-path attacks increase with network density linearly for random networks, while exponentially increasing for scale-free networks. The more homogeneous the degree distribution is, the more fragile the network, which is totally different from the previous results of node or edge attacks. HPA is generally more efficient than RPA in the longest-path attacks of complex networks. These findings further help us understand the vulnerability of complex systems, better protect complex systems, and design more tolerant complex systems.

  4. Continuous Weight Attack on Complex Network

    Institute of Scientific and Technical Information of China (English)

    YIN Yan-Ping; ZHANG Duan-Ming; TAN Jin; PAN Gui-Jun; HE Min-Hua

    2008-01-01

    We introduce a continuous weight attack strategy and numerically investigate the effect of continuous use a weight coefficient ω to define the attack intensity. The weight coefficient ω increases continuously from 1 to infinity, where 1 represents no attack and infinity represents complete destructive attack. Our results show that the continuous weight attack on two selected nodes with small ω (ω≈ 3) could achieve the same damage of complete elimination of a single selected node on both BA and ER networks. It is found that the continuous weight attack on a single selected edge with small ω (ω≈ 2) can reach the same effect of complete elimination of a single edge on BA network, but on ER network the damage of the continuous weight attack on a single edge is close to but always smaller than that of complete elimination of edge even if ω is very large.

  5. Multiple Partial Attacks on Complex Networks

    Institute of Scientific and Technical Information of China (English)

    YIN Yan-Ping; ZHANG Duan-Ming; TAN Jin; PAN Gui-Jun; HE Min-Hua

    2008-01-01

    We numerically investigate the effect of four kinds of partial attacks of multiple targets on the Barabási-Albert (BA) scale-free network and the Erd(o)s-Rényi (ER) random network.Comparing with the effect of single target complete knockout we find that partial attacks of multiple targets may produce an effect higher than the complete knockout of a single target on both BA scale-free network and ER random network.We also find that the BA ecale-free network seems to be more susceptible to multi-target partial attacks than the ER random network.

  6. Correlations in complex networks under attack

    CERN Document Server

    Srivastava, Animesh; Ganguly, Niloy; Peruani, Fernando; 10.1103/PhysRevE.86.036106

    2013-01-01

    For any initial correlated network after any kind of attack where either nodes or edges are removed, we obtain general expressions for the degree-degree probability matrix and degree distribution. We show that the proposed analytical approach predicts the correct topological changes after the attack by comparing the evolution of the assortativity coefficient for different attack strategies and intensities in theory and simulations. We find that it is possible to turn an initial assortative network into a disassortative one, and vice versa, by fine-tuning removal of either nodes or edges. For an initial uncorrelated network, on the other hand, we discover that only a targeted edge-removal attack can induce such correlations.

  7. Robustness of Complex Networks under Attack and Repair

    Institute of Scientific and Technical Information of China (English)

    HU Bin; LI Fang; ZHOU Hou-Shun

    2009-01-01

    To study the robustness of complex networks under attack and repair,we introduce a repair model of complex networks.Based on the model,we introduce two new quantities,i.e.attack fraction f_a and the maximum degree of the nodes that have never been attacked K_a,to study analytically the critical attack fraction and the relati ve size of the giant component of complex networks under attack and repair,using the method of generating function.We show analytically and numerically that the repair strategy significantly enhances the robustness of the scale-free network and the effect of robustness improvement is better for the scale-free networks with a smaller degree exponent.We discuss the application of our theory in relation to the understanding of robustness of complex networks with reparability.

  8. Why cryptography should not rely on physical attack complexity

    CERN Document Server

    Krämer, Juliane

    2015-01-01

    This book presents two practical physical attacks. It shows how attackers can reveal the secret key of symmetric as well as asymmetric cryptographic algorithms based on these attacks, and presents countermeasures on the software and the hardware level that can help to prevent them in the future. Though their theory has been known for several years now, since neither attack has yet been successfully implemented in practice, they have generally not been considered a serious threat. In short, their physical attack complexity has been overestimated and the implied security threat has been underestimated. First, the book introduces the photonic side channel, which offers not only temporal resolution, but also the highest possible spatial resolution. Due to the high cost of its initial implementation, it has not been taken seriously. The work shows both simple and differential photonic side channel analyses. Then, it presents a fault attack against pairing-based cryptography. Due to the need for at least two indepe...

  9. Recombinant human C1-inhibitor in the treatment of acute angioedema attacks

    NARCIS (Netherlands)

    Choi, Goda; Soeters, Maarten R.; Farkas, Henriette; Varga, Lilian; Obtulowicz, Krystyna; Bilo, Barbara; Porebski, Greg; Hack, C. Erik; Verdonk, Rene; Nuijens, Jan; Levi, Marcel

    2007-01-01

    Background: Patients with hereditary C1-inhibitor deficiency have recurrent attacks of angioedema, preferably treated with C1-inhibitor concentrate. A recombinant human C1-inhibitor (rHuC1INH) was developed, derived from milk from transgenic rabbits. This study was undertaken to investigate the effe

  10. Vulnerability of complex networks under three-level-tree attacks

    Science.gov (United States)

    Hao, Yao-hui; Han, Ji-hong; Lin, Yi; Liu, Lin

    2016-11-01

    We investigate vulnerability of complex networks including model networks and real world networks subject to three-level-tree attack. Specifically, we remove three different three-level-tree structures: RRN (Random Root Node), MaxDRN (Max Degree Root Node) and MinDRN (Min Degree Root Node) from a network iteratively until there is no three-level-tree left. Results demonstrate that random network is more robust than scale-free network against three tree attacks, and the robustness of random network decreases as the increases. And scale-free network shows different characteristics in different tree attack modes. The robustness of scale-free is not affected by the parameters for RRN, but increases as the increases for MinDRN. The important thing is that MaxDRN is the most effective in the three tree attack modes, especially for scale-free network. These findings supplement and extend the previous attack results on nodes and edges, and can thus help us better explain the vulnerability of different networks, and provide an insight into more tolerant real complex systems design.

  11. Managing Complex Battlespace Environments Using Attack the Network Methodologies

    DEFF Research Database (Denmark)

    Mitchell, Dr. William L.

    This paper examines the last 8 years of development and application of Attack the Network (AtN) intelligence methodologies for creating shared situational understanding of complex battlespace environment and the development of deliberate targeting frameworks. It will present a short history....... Including their possible application on a national security level for managing longer strategic endeavors....

  12. Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

    Science.gov (United States)

    Longhurst, Hilary; Cicardi, Marco; Craig, Timothy; Bork, Konrad; Grattan, Clive; Baker, James; Li, Huamin H; Reshef, Avner; Bonner, James; Bernstein, Jonathan A; Anderson, John; Lumry, William R; Farkas, Henriette; Katelaris, Constance H; Sussman, Gordon L; Jacobs, Joshua; Riedl, Marc; Manning, Michael E; Hebert, Jacques; Keith, Paul K; Kivity, Shmuel; Neri, Sergio; Levy, Donald S; Baeza, Maria L; Nathan, Robert; Schwartz, Lawrence B; Caballero, Teresa; Yang, William; Crisan, Ioana; Hernandez, María D; Hussain, Iftikhar; Tarzi, Michael; Ritchie, Bruce; Králíčková, Pavlina; Guilarte, Mar; Rehman, Syed M; Banerji, Aleena; Gower, Richard G; Bensen-Kennedy, Debra; Edelman, Jonathan; Feuersenger, Henrike; Lawo, John-Philip; Machnig, Thomas; Pawaskar, Dipti; Pragst, Ingo; Zuraw, Bruce L

    2017-03-23

    Background Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. Methods We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. Results Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; Phereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

  13. Robustness of Complex Networks against Attacks Guided by Damage

    CERN Document Server

    Wang, Hui; Xu, Xiaomin; Xiao, Yanghua; Wang, Wei

    2011-01-01

    Extensive researches have been dedicated to investigating the performance of real networks and synthetic networks against random failures or intentional attack guided by degree (degree attack). Degree is one of straightforward measures to characterize the vitality of a vertex in maintaining the integrity of the network but not the only one. Damage, the decrease of the largest component size that was caused by the removal of a vertex, intuitively is a more destructive guide for intentional attack on networks since the network functionality is usually measured by the largest component size. However, it is surprising to find that little is known about behaviors of real networks or synthetic networks against intentional attack guided by damage (damage attack), in which adversaries always choose the vertex with the largest damage to attack. In this article, we dedicate our efforts to understanding damage attack and behaviors of real networks as well as synthetic networks against this attack. To this end, existing ...

  14. Ecallantide is a novel treatment for attacks of hereditary angioedema due to C1 inhibitor deficiency

    Directory of Open Access Journals (Sweden)

    Farkas H

    2011-05-01

    Full Text Available Henriette Farkas, Lilian Varga3rd Department of Internal Medicine, Semmelweis University, Budapest, HungaryAbstract: Hereditary angioedema (HAE resulting from the deficiency of the C1 inhibitor protein is a rare disease, characterized by paroxysms of edema formation in the subcutis and in the submucosa. Edema can cause obstruction of the upper airway, which may lead to suffocation. Prompt elimination of edema is necessary to save patients from this life-threatening condition. Essentially, these edematous attacks are related to the activation of the kinin-kallikrein system and the consequent release of bradykinin. Ecallantide (known as DX-88 previously, a potent and specific inhibitor of plasma kallikrein is an innovative medicinal product. This is the only agent approved recently by the FDA for all localizations of edematous HAE attacks. Its advantages include no risk of viral contamination, high selectivity, very rapid onset of action, good tolerability, and straightforward subcutaneous administration. Owing to the risk of anaphylaxis, ecallantide should be administered by a health care professional. A postmarketing survey to improve risk-assessment and risk-minimization has been launched. The results of these studies may lead to the approval of ecallantide for self-administration.Keywords: hereditary angioedema, C1-inhibitor deficiency, treatment, bradykinin, kallikrein inhibitor, subcutaneous administration

  15. Degree-based attacks and defense strategies in complex networks

    Science.gov (United States)

    Yehezkel, Aviv; Cohen, Reuven

    2012-12-01

    We study the stability of random scale-free networks to degree-dependent attacks. We present analytical and numerical results to compute the critical fraction pc of nodes that need to be removed for destroying the network under this attack for different attack parameters. We study the effect of different defense strategies, based on the addition of a constant number of links on network robustness. We test defense strategies based on adding links to either low degree, middegree or high degree nodes. We find using analytical results and simulations that the middegree nodes defense strategy leads to the largest improvement to the network robustness against degree-based attacks. We also test these defense strategies on an internet autonomous systems map and obtain similar results.

  16. Low Complexity Signed Response Based Sybil Attack Detection Mechanism in Wireless Sensor Networks

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    M. Saud Khan

    2016-01-01

    Full Text Available Security is always a major concern in wireless sensor networks (WSNs. Identity based attacks such as spoofing and sybil not only compromise the network but also slow down its performance. This paper proposes a low complexity sybil attack detection scheme, that is, based on signed response (SRES authentication mechanism developed for Global System for Mobile (GSM communications. A probabilistic model is presented which analyzes the proposed authentication mechanism for its probability of sybil attack. The paper also presents a simulation based comparative analysis of the existing sybil attack schemes with respect to the proposed scheme. It is observed that the proposed sybil detection scheme exhibits lesser computational cost and power consumption as compared to the existing schemes for the same sybil detection performance.

  17. A Robustness Model of Complex Networks with Tunable Attack Information Parameter

    Institute of Scientific and Technical Information of China (English)

    WU Jun; TAN Yue-Jin; DENG Hong-Zhong; LI Yong

    2007-01-01

    We introduce a novel model for robustness of complex with a tunable attack information parameter. The random failure and intentional attack known are the two extreme cases of our model. Based on the model, we study the robustness of complex networks under random information and preferential information, respectively. Using the generating function method, we derive the exact value of the critical removal fraction of nodes for the disintegration of networks and the size of the giant component. We show that hiding just a small fraction of nodes randomly can prevent a scale-free network from collapsing and detecting just a small fraction of nodes preferentially can destroy a scale-free network.

  18. C1-inhibitor therapy for hereditary angioedema attacks: prospective patient assessments of health-related quality of life.

    Science.gov (United States)

    Bewtra, Againdra K; Levy, Robyn J; Jacobson, Kraig W; Wasserman, Richard L; Machnig, Thomas; Craig, Timothy J

    2012-01-01

    C1-inhibitor (INH) concentrate, which is recommended as first-line treatment for acute hereditary angioedema (HAE) attacks in many countries, was recently approved in the United States. We sought to solicit patients' feedback about their health-related quality of life (HRQoL) while being treated with C1-INH concentrate for acute HAE attacks under real-world conditions, as well as the personal impact of the availability of C1-INH on lifestyle and mental health domains. Subjects enrolled in an open-label study of C1-INH at 20 U/kg for acute HAE attacks were invited to participate in a prospectively designed survey to solicit "real-time" patient responses that were collected via an interactive voice response service or online with a personal computer. Eighteen subjects submitted 60 quarterly HRQoL and treatment impact survey responses over 29 months. Seventeen of 18 patients responding reported mean short form 12 HRQoL scores that were within a normal range. More than one-half indicated that C1-INH availability made them feel somewhat or much better, and >80% reported having a better outlook on the future and feeling more secure about the danger of life-threatening attacks. These data confirm a high level of HRQoL and a positive impact in lifestyle and emotional domains among patients who were treated for acute attacks of HAE with C1-INH concentrate.

  19. Efficiency of attack strategies on complex model and real-world networks

    CERN Document Server

    Bellingeri, Michele; Vincenzi, Simone

    2013-01-01

    We investigated the efficiency of attack strategies to network nodes when targeting several complex model and real-world networks. We tested 5 attack strategies, 3 of which were introduced in this work for the first time, to attack 3 model (Erdos and Renyi, Barabasi and Albert preferential attachment network, and scale-free network configuration models) and 3 real networks (Gnutella peer-to-peer network, email network of the University of Rovira i Virgili, and immunoglobulin interaction network). Nodes were removed sequentially according to the importance criterion defined by the attack strategy. We used the size of the largest connected component (LCC) as a measure of network damage. We found that the efficiency of attack strategies (fraction of nodes to be deleted for a given reduction of LCC size) depends on the topology of the network, although attacks based on the number of connections of a node and betweenness centrality were often the most efficient strategies. Sequential deletion of nodes in decreasin...

  20. Bush animal attacks: management of complex injuries in a resource-limited setting

    Directory of Open Access Journals (Sweden)

    Mitchell Katrina B

    2011-12-01

    Full Text Available Abstract Introduction Though animal-related injuries and fatalities have been documented throughout the world, the variety of attacks by wild animals native to rural East Africa are less commonly described. Given the proximity of our northwestern Tanzania hospital to Lake Victoria, Lake Tanganyika, and the Serengeti National Park, and presentation of several patients attacked by bush animals and suffering a variety of complex injuries, we sought to report the pattern of attacks and surgical management in a resource-limited setting. Materials and methods Four patients who were admitted to the northwestern Tanzania tertiary referral hospital, Bugando Medical Centre (BMC, in 2010-2011 suffered attacks by different bush animals: hyena, elephant, crocodile, and vervet monkey. These patients were triaged as trauma patients in the Casualty Ward, then admitted for inpatient monitoring and treatment. Their outcomes were followed to discharge. Results The age and gender of the patients attacked was variable, though all but the pediatric patient were participating in food gathering or guarding activities in rural locations at the time of the attacks. All patients required surgical management of their injuries, which included debridement and closure of wounds, chest tube insertion, amputation, and external fixation of an extremity fracture. All patients survived and were discharged home. Discussion Though human injuries secondary to encounters with undomesticated animals such as cows, moose, and camel are reported, they often are indirect traumas resulting from road traffic collisions. Snake attacks are well documented and common. However, this series of unique bush animal attacks describes the initial and surgical management of human injuries in the resource-limited setting of the developing world. Conclusion Animal attacks are common throughout the world, but their pattern may vary in Africa throughout jungle and bush environmental settings. It is

  1. Current topics on inhibitors of respiratory complex I.

    Science.gov (United States)

    Murai, Masatoshi; Miyoshi, Hideto

    2016-07-01

    There are a variety of chemicals which regulate the functions of bacterial and mitochondrial complex I. Some of them, such as rotenone and piericidin A, have been indispensable molecular tools in mechanistic studies on complex I. A large amount of experimental data characterizing the actions of complex I inhibitors has been accumulated so far. Recent X-ray crystallographic structural models of entire complex I may be helpful to carefully interpret this data. We herein focused on recent hot topics on complex I inhibitors and the subjects closely connected to these inhibitors, which may provide useful information not only on the structural and functional aspects of complex I, but also on drug design targeting this enzyme. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.

  2. Identifying Vulnerable Nodes of Complex Networks in Cascading Failures Induced by Node-Based Attacks

    Directory of Open Access Journals (Sweden)

    Shudong Li

    2013-01-01

    Full Text Available In the research on network security, distinguishing the vulnerable components of networks is very important for protecting infrastructures systems. Here, we probe how to identify the vulnerable nodes of complex networks in cascading failures, which was ignored before. Concerned with random attack (RA and highest load attack (HL on nodes, we model cascading dynamics of complex networks. Then, we introduce four kinds of weighting methods to characterize the nodes of networks including Barabási-Albert scale-free networks (SF, Watts-Strogatz small-world networks (WS, Erdos-Renyi random networks (ER, and two real-world networks. The simulations show that, for SF networks under HL attack, the nodes with small value of the fourth kind of weight are the most vulnerable and the ones with small value of the third weight are also vulnerable. Also, the real-world autonomous system with power-law distribution verifies these findings. Moreover, for WS and ER networks under both RA and HL attack, when the nodes have low tolerant ability, the ones with small value of the fourth kind of weight are more vulnerable and also the ones with high degree are easier to break down. The results give us important theoretical basis for digging the potential safety loophole and making protection strategy.

  3. Angioedema Related to Angiotensin-Converting Enzyme Inhibitors: Attack Severity, Treatment, and Hospital Admission in a Prospective Multicenter Study.

    Science.gov (United States)

    Javaud, Nicolas; Achamlal, Jallal; Reuter, Paul-George; Lapostolle, Frédéric; Lekouara, Akim; Youssef, Mustapha; Hamza, Lilia; Karami, Ahmed; Adnet, Frédéric; Fain, Olivier

    2015-11-01

    The number of cases of acquired angioedema related to angiotensin converting enzyme inhibitors induced (ACEI-AAE) is on the increase, with a potential concomitant increase in life-threatening attacks of laryngeal edema. Our objective was to determine the main characteristics of ACEI-AAE attacks and, in doing so, the factors associated with likelihood of hospital admission from the emergency department (ED) after a visit for an attack.A prospective, multicenter, observational study (April 2012-December 2014) was conducted in EDs of 4 French hospitals in collaboration with emergency services (SAMU 93) and a reference center for bradykinin-mediated angioedema. For each patient presenting with an attack, emergency physicians collected demographic and clinical presentation data, treatments, and clinical course. They recorded time intervals from symptom onset to ED arrival and to treatment decision, from ED arrival to specific treatment with plasma-derived C1-inhibitor (C1-INH) or icatibant, and from specific treatment to onset of symptom relief. Attacks requiring hospital admission were compared with those not requiring admission.Sixty-two eligible patients with ACEI-AAE (56% men, median age 63 years) were included. Symptom relief occurred significantly earlier in patients receiving specific treatment than in untreated patients (0.5 [0.5-1.0] versus 3.9 [2.5-7.0] hours; P < 0.0001). Even though icatibant was injected more promptly than plasma-derived C1-INH, there, however, was no significant difference in median time to onset of symptom relief between the 2 drugs (0.5 [0.5-1.3] versus 0.5 [0.4-1.0] hours for C1-INH and icatibant, respectively, P = 0.49). Of the 62 patients, 27 (44%) were admitted to hospital from the ED. In multivariate analysis, laryngeal involvement and progressive swelling at ED arrival were independently associated with admission (Odds ratio [95% confidence interval] = 6.2 [1.3-28.2] and 5.9 [1.3-26.5], respectively). A favorable course

  4. Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase

    DEFF Research Database (Denmark)

    Guo, Song; Olesen, Jes; Ashina, Messoud

    2014-01-01

    and that cilostazol-induced attacks responded to their usual migraine treatment. Median time of medication intake was 6 h (range 4-11 h). The present study suggests that intracellular cyclic AMP accumulation plays a crucial role in migraine induction. This knowledge is a further step in our understanding...

  5. Angiotensin-converting enzyme inhibitor-induced angioedema and hereditary angioedema: a comparison study of attack severity.

    Science.gov (United States)

    Javaud, Nicolas; Charpentier, Stéphane; Lapostolle, Frédéric; Lekouara, Hakim; Boubaya, Marouane; Lenoir, Gilles; Mekinian, Arsène; Adnet, Frédéric; Fain, Olivier

    2015-01-01

    Objective There appears to be differences in the clinical presentation of hereditary angioedema (HAE) and angiotensin-converting enzyme inhibitor-induced (ACE-I) angioedema (AE). The aim of this study was to compare the clinical characteristics of these two AE forms. Methods We conducted a retrospective study of consecutive patients with HAE or ACE-I AE. The attack characteristics experienced by the patients were compared by a logistic regression analysis using generalized estimating equations. Results A total of 56 patients were included in this study (ACE-I AE, n=25; HAE, n=31). A total of 534 attacks were documented. Severe attacks were more common in the patients who had an acute episode of ACE-I AE than HAE. Swelling of the tongue, lips and larynx were significantly associated with ACE-I AE [OR: 8.70 (95% CI, 1.04-73.70), OR: 20.4 (95% CI, 4.9-84.2) and OR: 7.50 (95% CI, 1.20-48.30), respectively]. Conclusion Swelling of the tongue, lips and larynx are significantly more frequent in drug-induced AE than HAE.

  6. Icatibant, an inhibitor of bradykinin receptor 2, for hereditary angioedema attacks: prospective experimental single-cohort study

    Directory of Open Access Journals (Sweden)

    Regis Albuquerque Campos

    Full Text Available CONTEXT AND OBJECTIVE: Hereditary angioedema (HAE with C1 inhibitor deficiency manifests as recurrent episodes of edema involving the skin, upper respiratory tract and gastrointestinal tract. It can be lethal due to asphyxia. The aim here was to evaluate the response to therapy for these attacks using icatibant, an inhibitor of the bradykinin receptor, which was recently introduced into Brazil.DESIGN AND SETTING: Prospective experimental single-cohort study on the efficacy and safety of icatibant for HAE patients.METHODS: Patients with a confirmed HAE diagnosis were enrolled according to symptoms and regardless of the time since onset of the attack. Icatibant was administered in accordance with the protocol that has been approved in Brazil. Symptom severity was assessed continuously and adverse events were monitored.RESULTS: 24 attacks in 20 HAE patients were treated (female/male 19:1; 19-55 years; median 29 years of age. The symptoms were: subcutaneous edema (22/24; abdominal pain (15/24 and upper airway obstruction (10/24. The time taken until onset of relief was: 5-10 minutes (5/24; 20.8%; 10-20 (5/24; 20.8%; 20-30 (8/24; 33.4%; 30-60 (5/24; 20.8%; and 2 hours (1/24; 4.3%. The time taken for complete resolution of symptoms ranged from 4.3 to 33.4 hours. Adverse effects were only reported at injection sites. Mild to moderate erythema and/or feelings of burning were reported by 15/24 patients, itching by 3 and no adverse effects in 6.CONCLUSION: HAE type I patients who received icatibant responded promptly; most achieved improved symptom severity within 30 minutes. Local adverse events occurred in 75% of the patients.

  7. Cobalt (III) complexes as novel matrix metalloproteinase-9 inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jiyoun [Sungshin Women' s Univ., Seoul (Korea, Republic of)

    2012-04-15

    We have synthesized a series of novel MMP-9 inhibitors containing cobalt(III) complexes. The synthesized cobalt(III) complexes are effective as enzyme inhibitors and the attachment of a biphenyl group enhanced the efficiency of enzyme inhibition up to 6-fold. When compared to the reported non-hydroxamate MMP inhibitors, the synthesized complexes showed comparable in vitro potency. The enzyme assay showed that the cobalt(III) complex can disrupt the zinc binding active site of MMP-9 and is proposed to work via a ligand exchange mechanism. Since histidine residues are essential for the catalytic activity of a large percentage of enzymes and zinc finger proteins, these cobalt(III) complexes can serve as a prototype inhibitor towards various zinc containing enzymes and proteins. Matrix metalloproteinases (MMPs) are a family of zinc binding endopeptidases that play crucial roles in various physiological processes and diseases such as embryogenic growth, angiogenesis, arthritis, skin ulceration, liver fibrosis and tumor metastasis. Because of their implications in a wide range of diseases, MMPs are considered as intriguing drug targets. The majority of MMP inhibitors are organic small molecules containing a hydroxamate functionality for the zinc binding group. This hydroxamate group binds to a zinc(II) center in a bidentate fashion and creates a distorted trigonal bipyramidal geometry.

  8. The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

    DEFF Research Database (Denmark)

    Hansen, Cecilie Bo; Csuka, Dorottya; Munthe-Fog, Lea

    2015-01-01

    C1 inhibitor (C1-INH) is known to form complexes with the lectin complement pathway serine proteases MASP-1 and MASP-2. Deficiency of C1-INH is associated with hereditary angioedema (HAE), an autosomal inherited disease characterized by swelling attacks caused by elevated levels of bradykinin. MASP...

  9. Exploring the inhibitor binding pocket of respiratory complex I.

    Science.gov (United States)

    Fendel, Uta; Tocilescu, Maja A; Kerscher, Stefan; Brandt, Ulrich

    2008-01-01

    Numerous hydrophobic and amphipathic compounds including several detergents are known to inhibit the ubiquinone reductase reaction of respiratory chain complex I (proton pumping NADH:ubiquinone oxidoreductase). Guided by the X-ray structure of the peripheral arm of complex I from Thermus thermophilus we have generated a large collection of site-directed mutants in the yeast Yarrowia lipolytica targeting the proposed ubiquinone and inhibitor binding pocket of this huge multiprotein complex at the interface of the 49-kDa and PSST subunits. We could identify a number of residues where mutations changed I(50) values for representatives from all three groups of hydrophobic inhibitors. Many mutations around the domain of the 49-kDa subunit that is homologous to the [NiFe] centre binding region of hydrogenase conferred resistance to DQA (class I/type A) and rotenone (class II/type B) indicating a wider overlap of the binding sites for these two types of inhibitors. In contrast, a region near iron-sulfur cluster N2, where the binding of the n-alkyl-polyoxyethylene-ether detergent C(12)E(8) (type C) was exclusively affected, appeared comparably well separated. Taken together, our data provide structure-based support for the presence of distinct but overlapping binding sites for hydrophobic inhibitors possibly extending into the ubiquinone reduction site of mitochondrial complex I.

  10. Formation of complement membrane attack complex in mammalian cerebral cortex evokes seizures and neurodegeneration.

    Science.gov (United States)

    Xiong, Zhi-Qi; Qian, Weihua; Suzuki, Katsuaki; McNamara, James O

    2003-02-01

    The complement system consists of >30 proteins that interact in a carefully regulated manner to destroy invading bacteria and prevent the deposition of immune complexes in normal tissue. This complex system can be activated by diverse mechanisms proceeding through distinct pathways, yet all converge on a final common pathway in which five proteins assemble into a multimolecular complex, the membrane attack complex (MAC). The MAC inserts into cell membranes to form a functional pore, resulting in ion flux and ultimately osmotic lysis. Immunohistochemical evidence of the MAC decorating neurons in cortical gray matter has been identified in multiple CNS diseases, yet the deleterious consequences, if any, of MAC deposition in the cortex of mammalian brain in vivo are unknown. Here we demonstrate that the sequential infusion of individual proteins of the membrane attack pathway (C5b6, C7, C8, and C9) into the hippocampus of awake, freely moving rats induced both behavioral and electrographic seizures as well as cytotoxicity. The onset of seizures occurred during or shortly after the infusion of C8/C9. Neither seizures nor cytotoxicity resulted from the simultaneous infusion of all five proteins premixed in vitro. The requirement for the sequential infusion of all five proteins together with the temporal relationship of seizure onset to infusions of C8/C9 implies that the MAC was formed in vivo and triggered both seizures and cytotoxicity. Deposition of the complement MAC in cortical gray matter may contribute to epileptic seizures and cell death in diverse diseases of the human brain.

  11. Structure of the poly-C9 component of the complement membrane attack complex.

    Science.gov (United States)

    Dudkina, Natalya V; Spicer, Bradley A; Reboul, Cyril F; Conroy, Paul J; Lukoyanova, Natalya; Elmlund, Hans; Law, Ruby H P; Ekkel, Susan M; Kondos, Stephanie C; Goode, Robert J A; Ramm, Georg; Whisstock, James C; Saibil, Helen R; Dunstone, Michelle A

    2016-02-04

    The membrane attack complex (MAC)/perforin-like protein complement component 9 (C9) is the major component of the MAC, a multi-protein complex that forms pores in the membrane of target pathogens. In contrast to homologous proteins such as perforin and the cholesterol-dependent cytolysins (CDCs), all of which require the membrane for oligomerisation, C9 assembles directly onto the nascent MAC from solution. However, the molecular mechanism of MAC assembly remains to be understood. Here we present the 8 Å cryo-EM structure of a soluble form of the poly-C9 component of the MAC. These data reveal a 22-fold symmetrical arrangement of C9 molecules that yield an 88-strand pore-forming β-barrel. The N-terminal thrombospondin-1 (TSP1) domain forms an unexpectedly extensive part of the oligomerisation interface, thus likely facilitating solution-based assembly. These TSP1 interactions may also explain how additional C9 subunits can be recruited to the growing MAC subsequent to membrane insertion.

  12. Synergistic enhancement of chemokine generation and lung injury by C5a or the membrane attack complex of complement

    DEFF Research Database (Denmark)

    Czermak, B J; Lentsch, A B; Bless, N M;

    1999-01-01

    Complement plays an important role in many acute inflammatory responses. In the current studies it was demonstrated that, in the presence of either C5a or sublytic forms of the complement-derived membrane attack complex (MAC), rat alveolar macrophages costimulated with IgG immune complexes...... increased neutrophil accumulation occurred, as did lung injury. These observations suggest that C5a and MAC function synergistically with a costimulus to enhance chemokine generation and the intensity of the lung inflammatory response....

  13. Value of Plasmatic Membrane Attack Complex as a Marker of Severity in Acute Kidney Injury

    Directory of Open Access Journals (Sweden)

    Eva Rodríguez

    2014-01-01

    Full Text Available The aim of this study was to determine if complement pathway is activated in AKI; for this purpose, we measured, through ELISA sandwich, the terminal lytic fraction of the complement system, called membrane attack complex (C5b-C9, in AKI patients compared with patients with similar clinical conditions but normal renal function. Our data showed that complement system is activated in AKI. Plasmatic MAC concentrations were significantly higher in AKI patients than in those with normal renal function; this difference is maintained independently of the AKI etiology and is proportional to the severity of AKI, measured by ADQI classification. In addition, we found that plasmatic MAC concentrations were significantly higher in patients who did not recover renal function at time of hospitalization discharge, in patients who died during the acute process, and in patients who need renal replacement therapy during hospitalization, but in this last group, the differences did not reach statistical significance. In conclusion, plasmatic MAC concentration seems valuable as a marker of AKI severity.

  14. Value of plasmatic membrane attack complex as a marker of severity in acute kidney injury.

    Science.gov (United States)

    Rodríguez, Eva; Riera, Marta; Barrios, Clara; Pascual, Julio

    2014-01-01

    The aim of this study was to determine if complement pathway is activated in AKI; for this purpose, we measured, through ELISA sandwich, the terminal lytic fraction of the complement system, called membrane attack complex (C5b-C9), in AKI patients compared with patients with similar clinical conditions but normal renal function. Our data showed that complement system is activated in AKI. Plasmatic MAC concentrations were significantly higher in AKI patients than in those with normal renal function; this difference is maintained independently of the AKI etiology and is proportional to the severity of AKI, measured by ADQI classification. In addition, we found that plasmatic MAC concentrations were significantly higher in patients who did not recover renal function at time of hospitalization discharge, in patients who died during the acute process, and in patients who need renal replacement therapy during hospitalization, but in this last group, the differences did not reach statistical significance. In conclusion, plasmatic MAC concentration seems valuable as a marker of AKI severity.

  15. $k$-core percolation on complex networks: Comparing random, localized and targeted attacks

    CERN Document Server

    Yuan, Xin; Stanley, H Eugene; Havlin, Shlomo

    2016-01-01

    The type of malicious attack inflicting on networks greatly influences their stability under ordinary percolation in which a node fails when it becomes disconnected from the giant component. Here we study its generalization, $k$-core percolation, in which a node fails when it loses connection to a threshold $k$ number of neighbors. We study and compare analytically and by numerical simulations of $k$-core percolation the stability of networks under random attacks (RA), localized attacks (LA) and targeted attacks (TA), respectively. By mapping a network under LA or TA into an equivalent network under RA, we find that in both single and interdependent networks, TA exerts the greatest damage to the core structure of a network. We also find that for Erd\\H{o}s-R\\'{e}nyi (ER) networks, LA and RA exert equal damage to the core structure whereas for scale-free (SF) networks, LA exerts much more damage than RA does to the core structure.

  16. Mathematical Attacks on RSA Cryptosystem

    Directory of Open Access Journals (Sweden)

    Imad K. Salah

    2006-01-01

    Full Text Available In this paper some of the most common attacks against Rivest, Shamir, and Adleman (RSA cryptosystem are presented. We describe the integer factoring attacks, attacks on the underlying mathematical function, as well as attacks that exploit details in implementations of the algorithm. Algorithms for each type of attacks are developed and analyzed by their complexity, memory requirements and area of usage.

  17. Structural Studies on Intact Clostridium botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design

    Science.gov (United States)

    2008-02-01

    Clostridium botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design PRINCIPAL INVESTIGATOR: Subramanyam Swaminathan...Inhibitors Leading to Drug Design 5b. GRANT NUMBER DAMD17-02-2-0011 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Subramanyam Swaminathan, Ph.D. 5d...on Intact Clostridium botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design Annual Report for the Period ending January 2008

  18. Generation of plasmin during acute attacks of hereditary angioedema.

    Science.gov (United States)

    Cugno, M; Hack, C E; de Boer, J P; Eerenberg, A J; Agostoni, A; Cicardi, M

    1993-01-01

    Hereditary angioedema is caused by a genetic deficiency of C1-inhibitor, a serine protease inhibitor that regulates activation of complement, contact, and fibrinolytic systems. Symptoms (bouts of subcutaneous and mucous swelling) depend on the release of a vasoactive mediator, probably through activation of these three systems. We studied the interrelationship among complement, contact, and fibrinolytic activation in 23 patients with hereditary angiodema, 18 during remission and five during an attack, by measuring plasma levels of C1-C1 inhibitor, factor XIIa-C1 inhibitor, kallikrein-C1 inhibitor, and plasmin-alpha 2-antiplasmin complexes, tissue plasminogen activator, and urokinase plasminogen activator. In addition, cleavage of high-molecular weight kininogen was detected by sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis and quantified by densitometry. During remission, plasma levels of C1-C1 inhibitor complexes were elevated (p = 0.0002), whereas the other parameters were within the normal range. During acute attacks, not only plasma levels of C1-C1 inhibitor complexes but also those of plasmin-alpha 2-antiplasmin complexes (P = 0.0009) and cleaved high-molecular weight kininogen were elevated. A positive correlation between plasmin-alpha 2-antiplasmin complexes and cleaved high-molecular weight kininogen was observed (r = 0.75, p attacks is associated with the activation of the fibrinolytic system.

  19. Predator attack rate evolution in space: the role of ecology mediated by complex emergent spatial structure and self-shading.

    Science.gov (United States)

    Messinger, Susanna M; Ostling, Annette

    2013-11-01

    Predation interactions are an important element of ecological communities. Population spatial structure has been shown to influence predator evolution, resulting in the evolution of a reduced predator attack rate; however, the evolutionary role of traits governing predator and prey ecology is unknown. The evolutionary effect of spatial structure on a predator's attack rate has primarily been explored assuming a fixed metapopulation spatial structure, and understood in terms of group selection. But endogenously generated, emergent spatial structure is common in nature. Furthermore, the evolutionary influence of ecological traits may be mediated through the spatial self-structuring process. Drawing from theory on pathogens, the evolutionary effect of emergent spatial structure can be understood in terms of self-shading, where a voracious predator limits its long-term invasion potential by reducing local prey availability. Here we formalize the effects of self-shading for predators using spatial moment equations. Then, through simulations, we show that in a spatial context self-shading leads to relationships between predator-prey ecology and the predator's attack rate that are not expected in a non-spatial context. Some relationships are analogous to relationships already shown for host-pathogen interactions, but others represent new trait dimensions. Finally, since understanding the effects of ecology using existing self-shading theory requires simplifications of the emergent spatial structure that do not apply well here, we also develop metrics describing the complex spatial structure of the predator and prey populations to help us explain the evolutionary effect of predator and prey ecology in the context of self-shading. The identification of these metrics may provide a step towards expansion of the predictive domain of self-shading theory to more complex spatial dynamics.

  20. Detrended Fluctuation Analysis on Correlations of Complex Networks Under Attack and Repair Strategy

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    We analyze the correlation properties of the Erdos-Rényi random graph (RG) and the Barabási-Albert scale-free network (SF) under the attack and repair strategy with detrended fluctuation analysis (DFA). The maximum degree k representing the local property of the system, shows similar scaling behaviors for random graphs and scale-free networks. The fluctuations are quite random at short time scales but display strong anticorrelation at longer time scales under the same system size N and different repair probability pre. The average degree , revealing the statistical property of the system, exhibits completely different scaling behaviors for random graphs and scale-free networks. Random graphs display long-range power-law correlations. Scale-free networks are uncorrelated at short time scales; while anticorrelated at longer time scales and the anticorrelation becoming stronger with the increase of pre.

  1. Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Nielsen, Tine Kragh [Abteilung für Molekulare Strukturbiologie, Institut für Mikrobiologie und Genetik and GZMB, Justus-von-Liebig Weg 11, 37077 Göttingen (Germany); Hildmann, Christian; Riester, Daniel; Wegener, Dennis; Schwienhorst, Andreas [Abteilung für Molekulare Genetik und Präparative Molekularbiologie, Institut für Mikrobiologie und Genetik, Grisebachstrasse 8, 37077 Göttingen (Germany); Ficner, Ralf, E-mail: rficner@gwdg.de [Abteilung für Molekulare Strukturbiologie, Institut für Mikrobiologie und Genetik and GZMB, Justus-von-Liebig Weg 11, 37077 Göttingen (Germany)

    2007-04-01

    The crystal structure of HDAH FB188 in complex with a trifluoromethylketone at 2.2 Å resolution is reported and compared to a previously determined inhibitor complex. Histone deacetylases (HDACs) have emerged as attractive targets in anticancer drug development. To date, a number of HDAC inhibitors have been developed and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA). Not surprisingly, structural information that can greatly enhance the design of novel HDAC inhibitors is so far only available for hydroxamic acids in complex with HDAC or HDAC-like enzymes. Here, the first structure of an enzyme complex with a nonhydroxamate HDAC inhibitor is presented. The structure of the trifluoromethyl ketone inhibitor 9,9,9-trifluoro-8-oxo-N-phenylnonanamide in complex with bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) has been determined. HDAH reveals high sequential and functional homology to human class 2 HDACs and a high structural homology to human class 1 HDACs. Comparison with the structure of HDAH in complex with SAHA reveals that the two inhibitors superimpose well. However, significant differences in binding to the active site of HDAH were observed. In the presented structure the O atom of the trifluoromethyl ketone moiety is within binding distance of the Zn atom of the enzyme and the F atoms participate in interactions with the enzyme, thereby involving more amino acids in enzyme–inhibitor binding.

  2. rhC1INH: a new drug for the treatment of attacks in hereditary angioedema caused by C1-inhibitor deficiency.

    Science.gov (United States)

    Varga, Lilian; Farkas, Henriette

    2011-03-01

    Recombinant human C1 esterase inhibitor (rhC1INH) (Ruconest(®), Pharming) is a new drug developed for the relief of symptoms occurring in patients with angioedema due to C1-inhibitor deficiency. Pertinent results have already been published elsewhere; this article summarizes the progress made since then. Similar to the purified C1-inhibitor derived from human plasma, the therapeutic efficacy of rhC1INH results from its ability to block the actions of enzymes belonging to the overactivated bradykinin-forming pathway, at multiple locations. During clinical trials into the management of acute edema, a total of 190 subjects received recombinant C1-inhibitor by intravenous infusion on 714 occasions altogether. Dose-ranging efficacy studies established 50 U/kg as the recommended dose, and demonstrated the effectiveness of this agent in all localizations of hereditary angioedema attacks. Studies into the safety of rhC1INH based on 300 administrations to healthy subjects or hereditary angioedema patients followed-up for 90 days have not detected the formation of autoantibodies against rhC1INH or IgE antibodies directed against rabbit proteins, even after repeated administration on multiple occasions. These findings met favorable appraisal by the EMA, which granted European marketing authorization for rhC1INH. Pharming is expected to file a biological licence with the US FDA by the end of 2010 to obtain marketing approval in the USA. The launch of rhC1INH onto the pharmaceutical market may represent an important progress in the management of hereditary angioedema patients.

  3. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice.

    Science.gov (United States)

    Fluiter, Kees; Opperhuizen, Anne Loes; Morgan, B Paul; Baas, Frank; Ramaglia, Valeria

    2014-03-01

    Traumatic brain injury (TBI) is the leading cause of disability and death in young adults. The secondary neuroinflammation and neuronal damage that follows the primary mechanical injury is an important cause of disability in affected people. The membrane attack complex (MAC) of the complement system is detected in the traumatized brain early after TBI; however, its role in the pathology and neurologic outcome of TBI has not yet been investigated. We generated a C6 antisense oligonucleotide that blocks MAC formation by inhibiting C6, and we compared its therapeutic effect to that of Ornithodoros moubata complement inhibitor (OmCI), a known inhibitor of C5 activation that blocks generation of the anaphylatoxin C5a and C5b, an essential component of MAC. Severe closed head injury in mice induced abundant MAC deposition in the brain. Treatment with C6 antisense reduced C6 synthesis (85%) and serum levels (90%), and inhibited MAC deposition in the injured brain (91-96%). Treatment also reduced accumulation of microglia/macrophages (50-88%), neuronal apoptosis, axonal loss and weight loss (54-93%), and enhanced neurologic performance (84-92%) compared with placebo-treated controls after injury. These data provide the first evidence, to our knowledge, that inhibition of MAC formation in otherwise complement-sufficient animals reduces neuropathology and promotes neurologic recovery after TBI. Given the importance of maintaining a functional complement opsonization system to fight infections, a critical complication in TBI patients, inhibition of the MAC should be considered to reduce posttraumatic neurologic damage. This work identifies a novel therapeutic target for TBI and will guide the development of new therapy for patients.

  4. Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity.

    Science.gov (United States)

    Charnley, Adam K; Convery, Máire A; Lakdawala Shah, Ami; Jones, Emma; Hardwicke, Philip; Bridges, Angela; Ouellette, Michael; Totoritis, Rachel; Schwartz, Benjamin; King, Bryan W; Wisnoski, David D; Kang, James; Eidam, Patrick M; Votta, Bartholomew J; Gough, Peter J; Marquis, Robert W; Bertin, John; Casillas, Linda

    2015-11-01

    Receptor interacting protein 2 (RIP2) is an intracellular kinase and key signaling partner for the pattern recognition receptors NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins 1 and 2). As such, RIP2 represents an attractive target to probe the role of these pathways in disease. In an effort to design potent and selective inhibitors of RIP2 we established a crystallographic system and determined the structure of the RIP2 kinase domain in an apo form and also in complex with multiple inhibitors including AMP-PCP (β,γ-Methyleneadenosine 5'-triphosphate, a non-hydrolysable adenosine triphosphate mimic) and structurally diverse ATP competitive chemotypes identified via a high-throughput screening campaign. These structures represent the first set of diverse RIP2-inhibitor co-crystal structures and demonstrate that the protein possesses the ability to adopt multiple DFG-in as well as DFG-out and C-helix out conformations. These structures reveal key protein-inhibitor structural insights and serve as the foundation for establishing a robust structure-based drug design effort to identify both potent and highly selective inhibitors of RIP2 kinase.

  5. CR2-mediated activation of the complement alternative pathway results in formation of membrane attack complexes on human B lymphocytes

    DEFF Research Database (Denmark)

    Nielsen, C H; Marquart, H V; Prodinger, W M;

    2001-01-01

    Normal human B lymphocytes activate the alternative pathway of complement via complement receptor type 2 (CR2, CD21), that binds hydrolysed C3 (iC3) and thereby promotes the formation of a membrane-bound C3 convertase. We have investigated whether this might lead to the generation of a C5...... convertase and consequent formation of membrane attack complexes (MAC). Deposition of C3 fragments and MAC was assessed on human peripheral B lymphocytes in the presence of 30% autologous serum containing 4.4 mM MgCl2/20 mM EGTA, which abrogates the classical pathway of complement without affecting...... the alternative pathway. Blockade of the CR2 ligand-binding site with the monoclonal antibody FE8 resulted in 56 +/- 13% and 71 +/- 9% inhibition of the C3-fragment and MAC deposition, respectively, whereas the monoclonal antibody HB135, directed against an irrelevant CR2 epitope, had no effect. Blockade...

  6. Efficient reconfigurable hardware architecture for accurately computing success probability and data complexity of linear attacks

    DEFF Research Database (Denmark)

    Bogdanov, Andrey; Kavun, Elif Bilge; Tischhauser, Elmar

    2012-01-01

    in a vast range of parameters. The new hardware architecture allows us to verify the existing theoretical models for the complexity estimation in linear cryptanalysis. The designed hardware architecture is realized on two Xilinx Virtex-6 XC6VLX240T FPGAs for smaller block lengths, and on RIVYERA platform...... with 128 Xilinx Spartan-3 XC3S5000 FPGAs for larger block lengths....

  7. Crystal structure of a complex of human chymase with its benzimidazole derived inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, Yoshiyuki; Kakuda, Shinji; Koizumi, Masahiro; Mizuno, Tsuyoshi; Muroga, Yumiko; Kawamura, Takashi; Takimoto-Kamimura, Midori, E-mail: m.kamimura@teijin.co.jp [Teijin Institute for Bio-medical Research, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512 (Japan)

    2013-11-01

    The crystal structure of human chymase complexed with a novel benzimidazole inhibitor, TJK002, was determined at 2.8 Å resolution. The present study shows that the benzimidazole ring of the inhibitor takes the stable stacking interaction with the protonated His57 in the catalytic domain of human chymase. The crystal structure of human chymase complexed with a novel benzimidazole inhibitor, TJK002, was determined at 2.8 Å resolution. The X-ray crystallographic study shows that the benzimidazole inhibitor forms a non-covalent interaction with the catalytic domain of human chymase. The hydrophobic fragment of the inhibitor occupies the S1 pocket. The carboxylic acid group of the inhibitor forms hydrogen bonds with the imidazole N(∊) atom of His57 and/or the O(γ) atom of Ser195 which are members of the catalytic triad. This imidazole ring of His57 induces π–π stacking to the benzene ring of the benzimidazole scaffold as P2 moiety. Fragment molecular orbital calculation of the atomic coordinates by X-ray crystallography shows that this imidazole ring of His57 could be protonated with the carboxyl group of Asp102 or hydroxyl group of Ser195 and the stacking interaction is stabilized. A new drug design strategy is proposed where the stacking to the protonated imidazole of the drug target protein with the benzimidazole scaffold inhibitor causes unpredicted potent inhibitory activity for some enzymes.

  8. Comparative kinetics of Qi site inhibitors of cytochrome bc1 complex: picomolar antimycin and micromolar cyazofamid.

    Science.gov (United States)

    Li, Hui; Zhu, Xiao-Lei; Yang, Wen-Chao; Yang, Guang-Fu

    2014-01-01

    Antimycin and cyazofamid are specific inhibitors of the mitochondrial respiratory chain and bind to the Qi site of the cytochrome bc1 complex. With the aim to understand the detailed molecular inhibition mechanism of Qi inhibitors, we performed a comparative investigation of the inhibitory kinetics of them against the porcine bc1 complex. The results showed that antimycin is a slow tight-binding inhibitor of succinate-cytochrome c reductase (SCR) with Ki  = 0.033 ± 0.00027 nm and non-competitive inhibition with respect to cytochrome c. Cyazofamid is a classical inhibitor of SCR with Ki  = 12.90 ± 0.91 μm and a non-competitive inhibitor with respect to cytochrome c. Both of them show competitive inhibition with respect to substrate DBH2 . Further molecular docking and quantum mechanics calculations were performed. The results showed that antimycin underwent significant conformational change upon the binding. The energy barrier between the conformations in the crystal and in the binding pocket is ~13.63 kcal/mol. Antimycin formed an H-bond with Asp228 and two water-bridged H-bonds with Lys227 and His201, whereas cyazofamid formed only one H-bond with Asp228. The conformational change and the different hydrogen bonding network might account for why antimycin is a slow tight-binding inhibitor, whereas cyazofamid is a classic inhibitor.

  9. Soluble form of membrane attack complex independently predicts mortality and cardiovascular events in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention

    DEFF Research Database (Denmark)

    Lindberg, Søren; Pedersen, Sune H; Mogelvang, Rasmus

    2012-01-01

    The complement system is an important mediator of inflammation, which plays a pivotal role in atherosclerosis and acute myocardial infarction (AMI). Animal studies suggest that activation of the complement cascade resulting in the formation of soluble membrane attack complex (sMAC), contributes...

  10. Urinary excretion of the C5b-9 membrane attack complex of complement is a marker of immune disease activity in autologous immune complex nephritis.

    Science.gov (United States)

    Pruchno, C J; Burns, M M; Schulze, M; Johnson, R J; Baker, P J; Alpers, C E; Couser, W G

    1991-01-01

    The urinary excretion of the C5b-9 membrane attack complex of complement correlates with glomerular deposition of antibody in the passive Heymann nephritis (PHN) model of membranous nephropathy (MN). To determine if this parameter can be correlated with antibody deposition in a model of MN induced by an autologous mechanism and thus more analogous to human MN, the relationship of urinary C5b-9 to ongoing glomerular immune complex formation late in autologous immune complex nephritis (AICN) was studied. Based on urinary C5b-9, the animals were divided into two groups at 12 weeks after induction of AICN, those with persistently high urinary C5b-9 excretion and those in whom urinary excretion of C5b-9 returned to undetectable levels. While all rats developed glomerular deposition of rat IgG and significant proteinuria, high C5b-9 excretors had greater proteinuria and prolonged positive staining for glomerular C3. When normal syngeneic kidneys were transplanted into rats (n = 3) from each group, only those with persistent C5b-9 excretion developed subepithelial immune deposits of rat IgG in the transplanted kidney. As in the PHN model of MN, proteinuria was dissociated widely from urinary C5b-9 excretion, glomerular C3 staining, and evidence of circulating antibody. Thus these findings demonstrate that urinary excretion of C5b-9 serves as an index of on-going immunologic disease activity in the AICN model of MN, while proteinuria does not.

  11. An overview of the binding models of FGFR tyrosine kinases in complex with small molecule inhibitors.

    Science.gov (United States)

    Cheng, Weiyan; Wang, Mixiang; Tian, Xin; Zhang, Xiaojian

    2017-01-27

    The fibroblast growth factor receptor (FGFR) family receptor tyrosine kinase (RTK) includes four structurally related members, termed as FGFR1, FGFR2, FGFR3, and FGFR4. Given its intimate role in the progression of several solid tumors, excessive FGFR signaling provides an opportunity for anticancer therapy. Along with extensive pharmacological studies validating the therapeutic potential of targeting the FGFRs for cancer treatment, co-crystal structures of FGFRs/inhibitors are continuously coming up to study the mechanism of actions and explore new inhibitors. Herein, we review the reported co-crystals of FGFRs in complex with the corresponding inhibitors, main focusing our attention on the binding models and the pharmacological activities of the inhibitors.

  12. On the regiochemistry of nucleophilic attack on 2-halo pi-allyl complexes. 4. The effect of silver acetate and nucleophile concentrations in competitive nucleophilic attack with malonate and phenoxide nucleophiles.

    Science.gov (United States)

    Organ, Michael G; Arvanitis, Elena A; Hynes, Stephen J

    2003-05-16

    2,3-Dibromo-1-propene or its allyl carbonate analogue are ionized under Pd catalysis to generate the 2-bromo Pd-pi-allyl complex (triphenylphosphine ligand), which alkylates with malonate nucleophile at the terminal position. The presence of acetate ion in the reaction mixture results in some malonate attack being redirected to the central carbon. The acetate ion can come from the ionization of 1-acetoxy-2-bromo-2-propene or by the addition of silver acetate to the reaction mixture. The addition of phenoxide ion to the reaction also causes the same regiochemical phenomena, although harder anions such as methoxide exert no such effect.

  13. Crystal structure of eukaryotic ribosome and its complexes with inhibitors.

    Science.gov (United States)

    Yusupova, Gulnara; Yusupov, Marat

    2017-03-19

    A high-resolution structure of the eukaryotic ribosome has been determined and has led to increased interest in studying protein biosynthesis and regulation of biosynthesis in cells. The functional complexes of the ribosome crystals obtained from bacteria and yeast have permitted researchers to identify the precise residue positions in different states of ribosome function. This knowledge, together with electron microscopy studies, enhances our understanding of how basic ribosome processes, including mRNA decoding, peptide bond formation, mRNA, and tRNA translocation and cotranslational transport of the nascent peptide, are regulated. In this review, we discuss the crystal structure of the entire 80S ribosome from yeast, which reveals its eukaryotic-specific features, and application of X-ray crystallography of the 80S ribosome for investigation of the binding mode for distinct compounds known to inhibit or modulate the protein-translation function of the ribosome. We also refer to a challenging aspect of the structural study of ribosomes, from higher eukaryotes, where the structures of major distinctive features of higher eukaryote ribosome-the high-eukaryote-specific long ribosomal RNA segments (about 1MDa)-remain unresolved. Presently, the structures of the major part of these high-eukaryotic expansion ribosomal RNA segments still remain unresolved.This article is part of the themed issue 'Perspectives on the ribosome'.

  14. Structural Studies on Intact Clostridium Botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design

    Science.gov (United States)

    2006-02-01

    structure1. Introduction Tetanus neurotoxin (TeNT) produced by Clostridium tetani and the seven antigenically distinct botulinum neurotoxins (BoNT/A-G...2-0011 TITLE: Structural Studies on Intact Clostridium Botulinum Neurotoxins Complexed with Inhibitors Leading to Drug...DATES COVERED (From - To) 28 Jan 2005 – 27 Jan 2006 4. TITLE AND SUBTITLE Structural Studies on Intact Clostridium Botulinum Neurotoxins Complexed

  15. Mitochondrial Complex I Inhibitors and Forced Oxidative Phosphorylation Synergize in Inducing Cancer Cell Death

    Directory of Open Access Journals (Sweden)

    Roberta Palorini

    2013-01-01

    Full Text Available Cancer cells generally rely mostly on glycolysis rather than oxidative phosphorylation (OXPHOS for ATP production. In fact, they are particularly sensitive to glycolysis inhibition and glucose depletion. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. Therefore, combined treatments targeting both glycolysis and mitochondria function, exploiting peculiar tumor features, might be lethal for cancer cells. In this study, we show that glucose deprivation and mitochondrial Complex I inhibitors synergize in inducing cancer cell death. In particular, our results reveal that low doses of Complex I inhibitors, ineffective on immortalized cells and in high glucose growth, become specifically cytotoxic on cancer cells deprived of glucose. Importantly, the cytotoxic effect of the inhibitors on cancer cells is strongly enhanced by forskolin, a PKA pathway activator, that we have previously shown to stimulate OXPHOS. Taken together, we demonstrate that induction in cancer cells of a switch from a glycolytic to a more respirative metabolism, obtained by glucose depletion or mitochondrial activity stimulation, strongly increases their sensitivity to low doses of mitochondrial Complex I inhibitors. Our findings might be a valuable approach to eradicate cancer cells.

  16. Attack surfaces

    DEFF Research Database (Denmark)

    Gruschka, Nils; Jensen, Meiko

    2010-01-01

    The new paradigm of cloud computing poses severe security risks to its adopters. In order to cope with these risks, appropriate taxonomies and classification criteria for attacks on cloud computing are required. In this work-in-progress paper we present one such taxonomy based on the notion...... of attack surfaces of the cloud computing scenario participants. © 2010 IEEE....

  17. Heart Attack

    Science.gov (United States)

    ... a million people in the U.S. have a heart attack. About half of them die. Many people have permanent heart damage or die because they don't get ... It's important to know the symptoms of a heart attack and call 9-1-1 if someone ...

  18. Systemic effects of treatment with mTOR inhibitors in tuberous sclerosis complex: a comprehensive review.

    Science.gov (United States)

    Sadowski, K; Kotulska, K; Schwartz, R A; Jóźwiak, S

    2016-04-01

    Tuberous sclerosis complex (TSC) is a genetic multisystem disorder associated with constitutive overactivation of the mammalian target of rapamycin (mTOR) pathway and characterized by development of benign tumours in various organs. mTOR inhibitors have proven to be effective in the targeted therapy of certain TSC-associated pathologies such as subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas (AMLs). Accumulating experimental and clinical data suggest that mTOR inhibitors might have a systemic, disease-modifying influence on affected individuals. This systematic review provides an analysis of available clinical data concerning systemic effect of mTOR inhibitors and the influence of mTOR inhibition on different manifestations of TSC in individual patients.

  19. Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor.

    Directory of Open Access Journals (Sweden)

    Alex N Bullock

    Full Text Available BACKGROUND: The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2. PRINCIPAL FINDINGS: Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex (inhibition in sub-nanomolar level. Due to its extraordinary shape complementarity this stable organometallic compound is a highly potent inhibitor of PIM kinases. SIGNIFICANCE: The structure of PIM2 revealed several differences to PIM1 which may be explored further to generate isoform selective inhibitors. It has also demonstrated how an organometallic inhibitor can be adapted to the binding site of protein kinases to generate highly potent inhibitors. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.

  20. A preliminary neutron crystallography on the trypsin-bovine pancreatic trypsin inhibitor complex

    Energy Technology Data Exchange (ETDEWEB)

    Kawamura, K; Yamada, T; Kurihara, K; Tamada, T; Kuroki, R; Tanaka, I; Takahashi, H; Niimura, N, E-mail: niimura@mx.ibaraki.ac.jp

    2010-11-01

    Trypsin is one of serine proteases. BPTI (Bovine Pancreatic Trypsin Inhibitor) is a protein inhibitor, which binds trypsin tightly and inhibits cleavage of peptide bonds. X-ray structure determination of trypsin-BPTI complex could make clear the overview of the active site. However, information of hydrogen atoms related to catalytic mechanism has not been satisfied. In this study, the trypsin-BPTI complex structure has been determined by neutron diffraction data at 2.0 A resolution. Deuterium atoms of catalytic triad, hydration structures in the binding pocket of trypsin and hydrogen bonds were observed. We would like to discuss details of hydrogen bonds in the interface between trypsin and BPTI and the adjacent water molecules including hydrogen atoms involved in the enzymatic reaction.

  1. 代价下复杂网络攻击策略有效性研究%Effectiveness of Attack Strategies of Complex Networks with Cost

    Institute of Scientific and Technical Information of China (English)

    覃俊; 吴泓润; 易云飞; 郑波尽

    2013-01-01

    Choosing suitable and validate attack strategies has meaningful significance to smash target networks or collapse criminal groups. To predict the effectiveness of attack strategies, two new measure indexes are proposed in this research: betweenness-centrality compactness index and closeness-centrality compactness index. The relationship of the indexes of average degree, betweenness-centrality compactness and closeness-centrality compactness with the effectiveness of attack strategies was analyzed in theory. To validate the proposed assumption, four types of complex networks were selected as test-beds for simulation. The results show that; the: effectiveness of attack strategy based on node degree is the worst; with the same average degree, the smaller the betweenness-centrality compactness or closeness-centrality compactness, the more effectiveness of the attack strategy base on betweenness-centrality compactness or closeness-centrality compactness is.%为了预测攻击策略的有效性,提出了介数紧致系数、接近度紧致系数2个新的度量指标,并在考虑攻击代价条件下,理论分析了平均度、介数紧致系数、接近度紧致系数3个指标与攻击策略有效性的关系.选取4种复杂网络作为实验网络,对实验网络在度攻击、介数攻击、接近度攻击策略下进行仿真.实验结果表明,针对同一网络,度攻击策略最差;相同平均度下,介数/接近度紧致系数越小,则与此对应的介数/接近度攻击策略越有效.

  2. Structure of catalytic domain of Matriptase in complex with Sunflower trypsin inhibitor-1

    Directory of Open Access Journals (Sweden)

    Huang Mingdong

    2011-06-01

    Full Text Available Abstract Background Matriptase is a type II transmembrane serine protease that is found on the surfaces of epithelial cells and certain cancer cells. Matriptase has been implicated in the degradation of certain extracellular matrix components as well as the activation of various cellular proteins and proteases, including hepatocyte growth factor and urokinase. Sunflower trypsin inhibitor-1 (SFTI-1, a cyclic peptide inhibitor originally isolated from sunflower seeds, exhibits potent inhibitory activity toward matriptase. Results We have engineered and produced recombinant proteins of the matriptase protease domain, and have determined the crystal structures of the protease:SFTI-1 complex at 2.0 Å as well as the protease:benzamidine complex at 1.2 Å. These structures elaborate the structural basis of substrate selectivity of matriptase, and show that the matriptase S1 substrate specificity pocket is larger enough to allow movement of benzamidine inside the S1 pocket. Our study also reveals that SFTI-1 binds to matriptase in a way similar to its binding to trypsin despite the significantly different isoelectric points of the two proteins (5.6 vs. 8.2. Conclusions This work helps to define the structural basis of substrate specificity of matriptase and the interactions between the inhibitor and protease. The complex structure also provides a structural template for designing new SFTI-1 derivatives with better potency and selectivity against matriptase and other proteases.

  3. Discovery of Novel Nonactive Site Inhibitors of the Prothrombinase Enzyme Complex.

    Science.gov (United States)

    Kapoor, Karan; McGill, Nicole; Peterson, Cynthia B; Meyers, Harold V; Blackburn, Michael N; Baudry, Jerome

    2016-03-28

    The risk of serious bleeding is a major liability of anticoagulant drugs that are active-site competitive inhibitors targeting the Factor Xa (FXa) prothrombin (PT) binding site. The present work identifies several new classes of small molecule anticoagulants that can act as nonactive site inhibitors of the prothrombinase (PTase) complex composed of FXa and Factor Va (FVa). These new classes of anticoagulants were identified, using a novel agnostic computational approach to identify previously unrecognized binding pockets at the FXa-FVa interface. From about three million docking calculations of 281,128 compounds in a conformational ensemble of FXa heavy chains identified by molecular dynamics (MD) simulations, 97 compounds and their structural analogues were selected for experimental validation, through a series of inhibition assays. The compound selection was based on their predicted binding affinities to FXa and their ability to successfully bind to multiple protein conformations while showing selectivity for particular binding sites at the FXa/FVa interface. From these, thirty-one (31) compounds were experimentally identified as nonactive site inhibitors. Concentration-based assays further identified 10 compounds represented by four small-molecule families of inhibitors that achieve dose-independent partial inhibition of PTase activity in a nonactive site-dependent and self-limiting mechanism. Several compounds were identified for their ability to bind to protein conformations only seen during MD, highlighting the importance of accounting for protein flexibility in structure-based drug discovery approaches.

  4. Structure-based lead discovery for protein kinase C zeta inhibitor design by exploiting kinase-inhibitor complex crystal structure data and potential therapeutics for preterm labour.

    Science.gov (United States)

    Shao, Qing-Chun; Zhang, Cui-Juan; Li, Jie

    2014-10-14

    The protein kinase C (PKC) is a family of serine/threonine kinases with a broad range of cellular targets. Members of the PKC family participate at the diverse biological events involved in cellular proliferation, differentiation and survival. The PKC isoform zeta (PKCζ) is an atypical member that has recently been found to play an essential role in promoting human uterine contractility and thus been raised as a new target for treating preterm labour and other tocolytic diseases. In this study, an integrative protocol was described to graft hundreds of inhibitor ligands from their complex crystal structures with cognate kinases into the active pocket of PKCζ and, based on the modeled structures, to evaluate the binding strength of these inhibitors to the non-cognate PKCζ receptor by using a consensus scoring strategy. A total of 32 inhibitors with top score were compiled, and eight out of them were tested for inhibitory potency against PKCζ. Consequently, five compounds, i.e. CDK6 inhibitor fisetin, PIM1 inhibitor myricetin, CDK9 inhibitor flavopiridol and PknB inhibitor mitoxantrone as well as the promiscuous kinase inhibitor staurosporine showed high or moderate inhibitory activity on PKCζ, with IC50 values of 58 ± 9, 1.7 ± 0.4, 108 ± 17, 280 ± 47 and 0.019 ± 0.004 μM, respectively, while other three compounds, including two marketed drugs dasatinib and sunitinib as well as the Rho inhibitor fasudil, have not been detected to possess observable activity. Next, based on the modeled structure data we modified three flavonoid kinase inhibitors, i.e. fisetin, myricetin and flavopiridol, to generate a number of more potential molecular entities, two of which were found to have a moderately improved activity as compared to their parent compounds.

  5. Crystal structures of HIV-1 reverse transcriptase complexes with thiocarbamate non-nucleoside inhibitors.

    Science.gov (United States)

    Spallarossa, Andrea; Cesarini, Sara; Ranise, Angelo; Ponassi, Marco; Unge, Torsten; Bolognesi, Martino

    2008-01-25

    O-Phthalimidoethyl-N-arylthiocarbamates (TCs) have been recently identified as a new class of potent HIV-1 reverse transcriptase (RT) non-nucleoside inhibitors (NNRTIs), by means of computer-aided drug design techniques [Ranise A. Spallarossa, S. Cesarini, F. Bondavalli, S. Schenone, O. Bruno, G. Menozzi, P. Fossa, L. Mosti, M. La Colla, et al., Structure-based design, parallel synthesis, structure-activity relationship, and molecular modeling studies of thiocarbamates, new potent non-nucleoside HIV-1 reverse transcriptase inhibitor isosteres of phenethylthiazolylthiourea derivatives, J. Med. Chem. 48 (2005) 3858-3873]. To elucidate the atomic details of RT/TC interaction and validate an earlier TC docking model, the structures of three RT/TC complexes were determined at 2.8-3.0A resolution by X-ray crystallography. The conformations adopted by the enzyme-bound TCs were analyzed and compared with those of bioisosterically related NNRTIs.

  6. The classical and alternative pathways of complement activation play distinct roles in spontaneous C3 fragment deposition and membrane attack complex (MAC) formation on human B lymphocytes

    DEFF Research Database (Denmark)

    Leslie, Robert Graham Quinton; Nielsen, Claus Henrik

    2004-01-01

    The contributions of the classical (CP) and alternative (AP) pathways of complement activation to the spontaneous deposition of C3 fragments and the formation of membrane attack complexes (MAC) on human B lymphocytes, were assessed by incubating peripheral blood mononuclear cells with autologous ...... of MAC formation was also found to be highly pathway dependent, with the AP being about 15-fold more efficient at initiating this process than the CP. A model accounting for the effectiveness of the AP in both preserving C3 fragment integrity and initiating MAC is presented....

  7. Free-energy analysis of enzyme-inhibitor binding: aspartic proteinase-pepstatin complexes.

    Science.gov (United States)

    Kalra, P; Das, A; Jayaram, B

    2001-01-01

    Expeditious in silico determinations of the free energies of binding of a series of inhibitors to an enzyme are of immense practical value in structure-based drug design efforts. Some recent advances in the field of computational chemistry have rendered a rigorous thermodynamic treatment of biologic molecules feasible, starting from a molecular description of the biomolecule, solvent, and salt. Pursuing the goal of developing and making available a software for assessing binding affinities, we present here a computationally rapid, albeit elaborate, methodology to estimate and analyze the molecular thermodynamics of enzyme-inhibitor binding with crystal structures as the point of departure. The complexes of aspartic proteinases with seven inhibitors have been adopted for this study. The standard free energy of complexation is considered in terms of a thermodynamic cycle of six distinct steps decomposed into a total of 18 well-defined components. The model we employed involves explicit all-atom accounts of the energetics of electrostatic interactions, solvent screening effects, van der Waals components, and cavitation effects of solvation combined with a Debye-Huckel treatment of salt effects. The magnitudes and signs of the various components are estimated using the AMBER parm94 force field, generalized Born theory, and solvent accessibility measures. Estimates of translational and rotational entropy losses on complexation as well as corresponding changes in the vibrational and configurational entropy are also included. The calculated standard free energies of binding at this stage are within an order of magnitude of the observed inhibition constants and necessitate further improvements in the computational protocols to enable quantitative predictions. Some areas such as inclusion of structural adaptation effects, incorporation of site-dependent amino acid pKa shifts, consideration of the dynamics of the active site for fine-tuning the methodology are easily

  8. Structural and biochemical characterization of the inhibitor complexes of xenotropic murine leukemia virus-related virus protease

    Energy Technology Data Exchange (ETDEWEB)

    Li, Mi; Gustchina, Alla; Matúz, Krisztina; Tözsér, Jozsef; Namwong, Sirilak; Goldfarb, Nathan E.; Dunn, Ben M.; Wlodawer, Alexander (Debrecen); (NCI); (Florida); (Suan Sunandha)

    2012-10-23

    Interactions between the protease (PR) encoded by the xenotropic murine leukemia virus-related virus and a number of potential inhibitors have been investigated by biochemical and structural techniques. It was observed that several inhibitors used clinically against HIV PR exhibit nanomolar or even subnanomolar values of K{sub i}, depending on the exact experimental conditions. Both TL-3, a universal inhibitor of retroviral PRs, and some inhibitors originally shown to inhibit plasmepsins were also quite potent, whereas inhibition by pepstatin A was considerably weaker. Crystal structures of the complexes of xenotropic murine leukemia virus-related virus PR with TL-3, amprenavir and pepstatin A were solved at high resolution and compared with the structures of complexes of these inhibitors with other retropepsins. Whereas TL-3 and amprenavir bound in a predictable manner, spanning the substrate-binding site of the enzyme, two molecules of pepstatin A bound simultaneously in an unprecedented manner, leaving the catalytic water molecule in place.

  9. Shark attack.

    Science.gov (United States)

    Guidera, K J; Ogden, J A; Highhouse, K; Pugh, L; Beatty, E

    1991-01-01

    Shark attacks are rare but devastating. This case had major injuries that included an open femoral fracture, massive hemorrhage, sciatic nerve laceration, and significant skin and muscle damage. The patient required 15 operative procedures, extensive physical therapy, and orthotic assistance. A review of the literature pertaining to shark bites is included.

  10. Terrorist attacks escalate in frequency and fatalities preceding highly lethal attacks.

    Science.gov (United States)

    Martens, Andy; Sainudiin, Raazesh; Sibley, Chris G; Schimel, Jeff; Webber, David

    2014-01-01

    Highly lethal terrorist attacks, which we define as those killing 21 or more people, account for 50% of the total number of people killed in all terrorist attacks combined, yet comprise only 3.5% of terrorist attacks. Given the disproportionate influence of these incidents, uncovering systematic patterns in attacks that precede and anticipate these highly lethal attacks may be of value for understanding attacks that exact a heavy toll on life. Here we examined whether the activity of terrorist groups escalates--both in the number of people killed per attack and in the frequency of attacks--leading up to highly lethal attacks. Analyses of terrorist attacks drawn from a state-of-the-art international terrorism database (The Global Terrorism Database) showed evidence for both types of escalation leading up to highly lethal attacks, though complexities to the patterns emerged as well. These patterns of escalation do not emerge among terrorist groups that never commit a highly lethal attack.

  11. Characterization of Two Classes of Small Molecule Inhibitors of Arp2/3 Complex

    Energy Technology Data Exchange (ETDEWEB)

    Nolen, B.; Tomasevic, N; Russell, A; Pierce, D; Jia, Z; McCormick, C; Hartman, J; Sakowicz, R; Pollard, T

    2009-01-01

    Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements. However, questions remain regarding the relative contributions of Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells. Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2 and Arp3 into their active conformation. CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.

  12. Structures of aminophenol dioxygenase in complex with intermediate, product and inhibitor.

    Science.gov (United States)

    Li, De Feng; Zhang, Jia Yue; Hou, Yan Jie; Liu, Lei; Hu, Yonglin; Liu, Shuang Jiang; Wang, Da Cheng; Liu, Wei

    2013-01-01

    Dioxygen activation by nonhaem Fe(II) enzymes containing the 2-His-1-carboxylate facial triad has been extensively studied in recent years. Here, crystal structures of 2-aminophenol 1,6-dioxygenase, an enzyme that represents a minor group of extradiol dioxygenases and that catalyses the ring opening of 2-aminophenol, in complex with the lactone intermediate (4Z,6Z)-3-iminooxepin-2(3H)-one and the product 2-aminomuconic 6-semialdehyde and in complex with the suicide inhibitor 4-nitrocatechol are reported. The Fe-ligand binding schemes observed in these structures revealed some common geometrical characteristics that are shared by the published structures of extradiol dioxygenases, suggesting that enzymes that catalyse the oxidation of noncatecholic compounds are very likely to utilize a similar strategy for dioxygen activation and the fission of aromatic rings as the canonical mechanism. The Fe-ligation arrangement, however, is strikingly enantiomeric to that of all other 2-His-1-carboxylate enzymes apart from protocatechuate 4,5-dioxygenase. This structural variance leads to the generation of an uncommon O(-)-Fe(2+)-O(-) species prior to O(2) binding, which probably forms the structural basis on which APD distinguishes its specific substrate and inhibitor, which share an analogous molecular structure.

  13. The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.

    Science.gov (United States)

    He, Yupeng; Selvaraju, Sujatha; Curtin, Michael L; Jakob, Clarissa G; Zhu, Haizhong; Comess, Kenneth M; Shaw, Bailin; The, Juliana; Lima-Fernandes, Evelyne; Szewczyk, Magdalena M; Cheng, Dong; Klinge, Kelly L; Li, Huan-Qiu; Pliushchev, Marina; Algire, Mikkel A; Maag, David; Guo, Jun; Dietrich, Justin; Panchal, Sanjay C; Petros, Andrew M; Sweis, Ramzi F; Torrent, Maricel; Bigelow, Lance J; Senisterra, Guillermo; Li, Fengling; Kennedy, Steven; Wu, Qin; Osterling, Donald J; Lindley, David J; Gao, Wenqing; Galasinski, Scott; Barsyte-Lovejoy, Dalia; Vedadi, Masoud; Buchanan, Fritz G; Arrowsmith, Cheryl H; Chiang, Gary G; Sun, Chaohong; Pappano, William N

    2017-04-01

    Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.

  14. Performance of attack strategies on modular networks

    CERN Document Server

    da Cunha, Bruno Requião

    2016-01-01

    Vulnerabilities of complex networks have became a trend topic in complex systems recently due to its real world applications. Most real networks tend to be very fragile to high betweenness adaptive attacks. However, recent contributions have shown the importance of interconnected nodes in the integrity of networks and module-based attacks have appeared promising when compared to traditional malicious non-adaptive attacks. In the present work we deeply explore the trade-off associated with attack procedures, introducing a generalized robustness measure and presenting an attack performance index that takes into account both robustness of the network against the attack and the run-time needed to obtained the list of targeted nodes for the attack. Besides, we introduce the concept of deactivation point aimed to mark the point at which the network stops to function properly. We then show empirically that non-adaptive module-based attacks perform better than high degree and betweenness adaptive attacks in networks ...

  15. Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex.

    Science.gov (United States)

    MacKeigan, Jeffrey P; Krueger, Darcy A

    2015-12-01

    Tuberous sclerosis complex (TSC) is a genetic autosomal dominant disorder characterized by benign tumor-like lesions, called hamartomas, in multiple organ systems, including the brain, skin, heart, kidneys, and lung. These hamartomas cause a diverse set of clinical problems based on their location and often result in epilepsy, learning difficulties, and behavioral problems. TSC is caused by mutations within the TSC1 or TSC2 genes that inactivate the genes' tumor-suppressive function and drive hamartomatous cell growth. In normal cells, TSC1 and TSC2 integrate growth signals and nutrient inputs to downregulate signaling to mammalian target of rapamycin (mTOR), an evolutionarily conserved serine-threonine kinase that controls cell growth and cell survival. The molecular connection between TSC and mTOR led to the clinical use of allosteric mTOR inhibitors (sirolimus and everolimus) for the treatment of TSC. Everolimus is approved for subependymal giant cell astrocytomas and renal angiomyolipomas in patients with TSC. Sirolimus, though not approved for TSC, has undergone considerable investigation to treat various aspects of the disease. Everolimus and sirolimus selectively inhibit mTOR signaling with similar molecular mechanisms, but with distinct clinical profiles. This review differentiates mTOR inhibitors in TSC while describing the molecular mechanisms, pathogenic mutations, and clinical trial outcomes for managing TSC.

  16. Detection of noncovalent complex between alpha-amylase and its microbial inhibitor tendamistat by electrospray ionization mass spectrometry.

    Science.gov (United States)

    Douglas, D J; Collings, B A; Numao, S; Nesatyy, V J

    2001-01-01

    Electrospray ionization mass spectrometry (ESI-MS) is now routinely used for detection of noncovalent complexes. However, detection of noncovalent protein-protein complexes is not a widespread practice and still produces some challenges for mass spectrometrists. Here we demonstrate the detection of a noncovalent protein-protein complex between alpha-amylase and its microbial inhibitor tendamistat using ESI-MS. Crude porcine pancreatic alpha-amylase was purified using a glycogen precipitation method. Noncovalent complexes between porcine pancreatic alpha-amylase and its microbial inhibitor tendamistat are probed and detected using ESI-MS. The atmosphere-vacuum ESI conditions along with solution conditions and the ratio of inhibitor over enzyme strongly affect the detection of noncovalent complexes in the gas phase. ESI mass spectra of alpha-amylase at pH 7 exhibited charge states significantly lower than that reported previously, which is indicative of a native protein conformation necessary to produce a noncovalent complex. Detection of noncovalent complexes in the gas phase suggests that further use of conventional biochemical approaches to provide a qualitative, and in some cases even quantitative, characterization of equilibria of noncovalent complexes in solution is possible.

  17. Platelet degranulation and monocyte-platelet complex formation are increased in the acute and convalescent phases after ischaemic stroke or transient ischaemic attack.

    LENUS (Irish Health Repository)

    McCabe, Dominick J H

    2004-06-01

    Flow cytometric studies suggest that platelets are activated in ischaemic stroke or transient ischaemic attack (TIA). However, few studies have measured circulating leucocyte-platelet complexes in this patient population. Whole blood flow cytometry was used to quantify the expression of CD62P-, CD63-, and PAC1-binding, and the percentages of leucocyte-platelet complexes in acute (1-27 d, n = 79) and convalescent (79-725 d, n = 70) ischaemic cerebrovascular disease (CVD) patients compared with controls without CVD (n = 27). We performed a full blood count, and measured plasma levels of soluble P-selectin, soluble E-selectin, and von Willebrand factor antigen (VWF:Ag) as additional markers of platelet and\\/or endothelial cell activation. The median percentage CD62P expression and the median percentage monocyte-platelet complexes were higher in both acute and convalescent CVD patients than controls (P <\\/= 0.02). The mean white cell count and mean VWF:Ag levels were significantly elevated in the acute and convalescent phases after ischaemic stroke or TIA (P <\\/= 0.02). Otherwise, there was no significant increase in any other marker of platelet or endothelial activation in CVD patients. There was a positive correlation between the percentage expression of CD62P and the percentages of both neutrophil-platelet and monocyte-platelet complexes in the acute phase, and the percentages of all leucocyte-platelet complexes in the convalescent phase after ischaemic CVD. This study provides evidence for ongoing excessive platelet and\\/or endothelial activation in ischaemic CVD patients despite treatment with antithrombotic therapy.

  18. The calcineurin inhibitor cyclosporin A exhibits synergism with antifungals against Candida parapsilosis species complex.

    Science.gov (United States)

    Cordeiro, Rossana de Aguiar; Macedo, Ramila de Brito; Teixeira, Carlos Eduardo Cordeiro; Marques, Francisca Jakelyne de Farias; Bandeira, Tereza de Jesus Pinheiro Gomes; Moreira, José Luciano Bezerra; Brilhante, Raimunda Sâmia Nogueira; Rocha, Marcos Fábio Gadelha; Sidrim, José Júlio Costa

    2014-07-01

    Candida parapsilosis complex comprises three closely related species, C. parapsilosis sensu stricto, Candida metapsilosis and Candida orthopsilosis. In the last decade, antifungal resistance to azoles and caspofungin among C. parapsilosis sensu lato strains has been considered a matter of concern worldwide. In the present study, we evaluated the synergistic potential of antifungals and the calcineurin inhibitor cyclosporin A (Cys) against planktonic and biofilms of C. parapsilosis complex from clinical sources. Susceptibility assays with amphotericin, fluconazole, voriconazole, caspofungin and Cys were performed by microdilution in accordance with Clinical and Laboratory Standards Institute guidelines. Synergy testing against planktonic cells of C. parapsilosis sensu lato strains was assessed by the chequerboard method. Combinations formed by antifungals with Cys were evaluated against mature biofilms in microtitre plates. No differences in the antifungal susceptibility pattern among species were observed, but C. parapsilosis sensu stricto strains were more susceptible to Cys than C. orthopsilosis and C. metapsilosis. Synergism between antifungals and Cys was observed in C. parapsilosis sensu lato strains. Combinations formed by antifungals and Cys were able to prevent biofilm formation and showed an inhibitory effect against mature biofilms of C. parapsilosis sensu stricto, C. metapsilosis and C. orthopsilosis. These results strengthen the potential of calcineurin inhibition as a promising approach to enhance the efficiency of antifungal drugs.

  19. Organic cadmium complexes as proteasome inhibitors and apoptosis inducers in human breast cancer cells.

    Science.gov (United States)

    Zhang, Zhen; Bi, Caifeng; Buac, Daniela; Fan, Yuhua; Zhang, Xia; Zuo, Jian; Zhang, Pengfei; Zhang, Nan; Dong, Lili; Dou, Q Ping

    2013-06-01

    Although cadmium (Cd) is a widespread environmental contaminant and human carcinogen, our studies indicate an organic Cd complex to be a potent inhibitor of proteasomal chymotrypsin-like (CT-like) activity, further capable of inducing apoptosis in a cancer cell-specific manner. It has been reported that the ligands indole-3-butyric acid (L1) and indole-3-propionic acid (L2) have cancer-fighting effects when tested in a rat carcinoma model. In addition, 3, 5-diaminobenzoic acid o-vanillin Schiff bases (L3) have high antimicrobial activity and a large number of Schiff base complexes have been reported to have proteasome-inhibitory activity. We therefore hypothesized that synthetic forms of Cd in combination with L1, L2 and L3 may have proteasome-inhibitory and apoptosis-inducing activities, which would be cancer cell-specific. To test this hypothesis, we have synthesized three novel Cd-containing complexes: [Cd2(C12H12O2N)4(H2O)2]·2H2O (Cd1), [Cd2(C11H10O2N)4(H2O)2]·2H2O (Cd2) and [Cd(C7H4N2O2)(C8H6O2)2]·2H2O (Cd3), by using these three ligands. We sought out to characterize and assess the proteasome-inhibitory and anti-proliferative properties of these three Cd complexes in human breast cancer cells. Cd1, Cd2 and Cd3 were found to effectively inhibit the chymotrypsin-like activity of purified 20S proteasome with IC50 values of 2.6, 3.0 and 3.3 μΜ, respectively. Moreover, inhibition of cancer cell proliferation also correlated with this effect. As a result of proteasomal shutdown, the accumulation of ubiquitinated proteins and the proteasome target IκB-α protein as well as induction of apoptosis were observed. To account for the cancer specificity of this effect, immortalized, non-tumorigenic breast MCF10A cells were used under the same experimental conditions. Our results indicate that MCF10A cells are much less sensitive to the Cd1, Cd2 and Cd3 complexes when compared to MDA MB 231 breast cancer cells. Therefore, our study suggests that these Cd organic

  20. High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design.

    Science.gov (United States)

    Sippel, Katherine H; Robbins, Arthur H; Domsic, John; Genis, Caroli; Agbandje-McKenna, Mavis; McKenna, Robert

    2009-10-01

    The crystal structure of human carbonic anhydrase II (CA II) complexed with the inhibitor acetazolamide (AZM) has been determined at 1.1 A resolution and refined to an R(cryst) of 11.2% and an R(free) of 14.7%. As observed in previous CA II-inhibitor complexes, AZM binds directly to the zinc and makes several key interactions with active-site residues. The high-resolution data also showed a glycerol molecule adjacent to the AZM in the active site and two additional AZMs that are adventitiously bound on the surface of the enzyme. The co-binding of AZM and glycerol in the active site demonstrate that given an appropriate ring orientation and substituents, an isozyme-specific CA inhibitor may be developed.

  1. Neutrophil elastase reduces secretion of secretory leukoproteinase inhibitor (SLPI by lung epithelial cells: role of charge of the proteinase-inhibitor complex

    Directory of Open Access Journals (Sweden)

    Hiemstra Pieter S

    2008-08-01

    Full Text Available Abstract Background Secretory leukoproteinase inhibitor (SLPI is an important inhibitor of neutrophil elastase (NE, a proteinase implicated in the pathogenesis of lung diseases such as COPD. SLPI also has antimicrobial and anti-inflammatory properties, but the concentration of SLPI in lung secretions in COPD varies inversely with infection and the concentration of NE. A fall in SLPI concentration is also seen in culture supernatants of respiratory cells exposed to NE, for unknown reasons. We investigated the hypothesis that SLPI complexed with NE associates with cell membranes in vitro. Methods Respiratory epithelial cells were cultured in the presence of SLPI, varying doses of proteinases over time, and in different experimental conditions. The likely predicted charge of the complex between SLPI and proteinases was assessed by theoretical molecular modelling. Results We observed a rapid, linear decrease in SLPI concentration in culture supernatants with increasing concentration of NE and cathepsin G, but not with other serine proteinases. The effect of NE was inhibited fully by a synthetic NE inhibitor only when added at the same time as NE. Direct contact between NE and SLPI was required for a fall in SLPI concentration. Passive binding to cell culture plate materials was able to remove a substantial amount of SLPI both with and without NE. Theoretical molecular modelling of the structure of SLPI in complex with various proteinases showed a greater positive charge for the complex with NE and cathepsin G than for other proteinases, such as trypsin and mast cell tryptase, that also bind SLPI but without reducing its concentration. Conclusion These data suggest that NE-mediated decrease in SLPI is a passive, charge-dependent phenomenon in vitro, which may correlate with changes observed in vivo.

  2. Structures of Clostridium Botulinum Neurotoxin Serotype A Light Chain Complexed with Small-Molecule Inhibitors Highlight Active-Site Flexibility

    Energy Technology Data Exchange (ETDEWEB)

    Silvaggi,N.; Boldt, G.; Hixon, M.; Kennedy, J.; Tzipori, S.; Janda, K.; Allen, K.

    2007-01-01

    The potential for the use of Clostridial neurotoxins as bioweapons makes the development of small-molecule inhibitors of these deadly toxins a top priority. Recently, screening of a random hydroxamate library identified a small-molecule inhibitor of C. botulinum Neurotoxin Serotype A Light Chain (BoNT/A-LC), 4-chlorocinnamic hydroxamate, a derivative of which has been shown to have in vivo efficacy in mice and no toxicity. We describe the X-ray crystal structures of BoNT/A-LC in complexes with two potent small-molecule inhibitors. The structures of the enzyme with 4-chlorocinnamic hydroxamate or 2,4-dichlorocinnamic hydroxamate bound are compared to the structure of the enzyme complexed with L-arginine hydroxamate, an inhibitor with modest affinity. Taken together, this suite of structures provides surprising insights into the BoNT/A-LC active site, including unexpected conformational flexibility at the S1' site that changes the electrostatic environment of the binding pocket. Information gained from these structures will inform the design and optimization of more effective small-molecule inhibitors of BoNT/A-LC.

  3. The attack navigator

    DEFF Research Database (Denmark)

    Probst, Christian W.; Willemson, Jan; Pieters, Wolter

    2016-01-01

    -technical system, the attack navigator identifies routes to an attacker goal. Specific attacker properties such as skill or resources can be included through attacker profiles. This enables defenders to explore attack scenarios and the effectiveness of defense alternatives under different threat conditions....

  4. Host-guest complexes and pseudorotaxanes of cucurbit[7]uril with acetylcholinesterase inhibitors.

    Science.gov (United States)

    Wyman, Ian W; Macartney, Donal H

    2009-11-06

    Pseudorotaxanes may be assembled in aqueous solution using dicationic acetylcholinesterase inhibitors, such as succinylcholine, BW284c51, and alpha,omega-bis(trialkylammonium)alkane dications (or their phosphonium analogues), as bolaform axles and cucurbit[7]uril (CB[7]) as the wheel. With the exceptions of the shorter [(CH(3))(3)N(CH(2))(n)N(CH(3))(3)](2+) (n = 6, 8) dications, the addition of a second CB[7] results in the translocation of the first CB[7], such that the hydrophobic -NR(3)(+) and -PR(3)(+) end groups (R = Me or Et) are located in the cavities of the wheels, while the central portion of the axles extend through the CB[7] portals into the bulk solvent. In the case of the [Quin(CH(2))(10)Quin](2+) (Quin = quinuclidinium) dication, the CB[7] host(s) resides only on the quinuclidinium end group(s). The 1:1 host-guest stability constants range from 8 x 10(6) to 3 x 10(10) M(-1) and are dependent on both the nature of the end group as well as the length and hydrophobicity of the central linker. The magnitude of the stability constants for the 2:1 complexes closely follow the trend observed previously for CB[7] binding with the NR(4)(+) and PR(4)(+) cations.

  5. Novel Inhibitors Complexed with Glutamate Dehydrogenase: ALLOSTERIC REGULATION BY CONTROL OF PROTEIN DYNAMICS

    Energy Technology Data Exchange (ETDEWEB)

    Li, Ming; Smith, Christopher J.; Walker, Matthew T.; Smith, Thomas J.; (Danforth)

    2009-12-01

    Mammalian glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of L-glutamate to 2-oxoglutarate using NAD(P){sup +} as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GDH is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GDH by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GDH are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GDH complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GDH through aromatic stacking interactions between the drug and GDH as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GDH contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GDH.

  6. Inferring selection in the Anopheles gambiae species complex: an example from immune-related serine protease inhibitors

    Directory of Open Access Journals (Sweden)

    Little Tom J

    2009-06-01

    Full Text Available Abstract Background Mosquitoes of the Anopheles gambiae species complex are the primary vectors of human malaria in sub-Saharan Africa. Many host genes have been shown to affect Plasmodium development in the mosquito, and so are expected to engage in an evolutionary arms race with the pathogen. However, there is little conclusive evidence that any of these mosquito genes evolve rapidly, or show other signatures of adaptive evolution. Methods Three serine protease inhibitors have previously been identified as candidate immune system genes mediating mosquito-Plasmodium interaction, and serine protease inhibitors have been identified as hot-spots of adaptive evolution in other taxa. Population-genetic tests for selection, including a recent multi-gene extension of the McDonald-Kreitman test, were applied to 16 serine protease inhibitors and 16 other genes sampled from the An. gambiae species complex in both East and West Africa. Results Serine protease inhibitors were found to show a marginally significant trend towards higher levels of amino acid diversity than other genes, and display extensive genetic structuring associated with the 2La chromosomal inversion. However, although serpins are candidate targets for strong parasite-mediated selection, no evidence was found for rapid adaptive evolution in these genes. Conclusion It is well known that phylogenetic and population history in the An. gambiae complex can present special problems for the application of standard population-genetic tests for selection, and this may explain the failure of this study to detect selection acting on serine protease inhibitors. The pitfalls of uncritically applying these tests in this species complex are highlighted, and the future prospects for detecting selection acting on the An. gambiae genome are discussed.

  7. Assembly and Regulation of the Membrane Attack Complex Based on Structures of C5b6 and sC5b9

    Directory of Open Access Journals (Sweden)

    Michael A. Hadders

    2012-03-01

    Full Text Available Activation of the complement system results in formation of membrane attack complexes (MACs, pores that disrupt lipid bilayers and lyse bacteria and other pathogens. Here, we present the crystal structure of the first assembly intermediate, C5b6, together with a cryo-electron microscopy reconstruction of a soluble, regulated form of the pore, sC5b9. Cleavage of C5 to C5b results in marked conformational changes, distinct from those observed in the homologous C3-to-C3b transition. C6 captures this conformation, which is preserved in the larger sC5b9 assembly. Together with antibody labeling, these structures reveal that complement components associate through sideways alignment of the central MAC-perforin (MACPF domains, resulting in a C5b6-C7-C8β-C8α-C9 arc. Soluble regulatory proteins below the arc indicate a potential dual mechanism in protection from pore formation. These results provide a structural framework for understanding MAC pore formation and regulation, processes important for fighting infections and preventing complement-mediated tissue damage.

  8. Genetic attack on neural cryptography.

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Naeh, Rivka; Kanter, Ido

    2006-03-01

    Different scaling properties for the complexity of bidirectional synchronization and unidirectional learning are essential for the security of neural cryptography. Incrementing the synaptic depth of the networks increases the synchronization time only polynomially, but the success of the geometric attack is reduced exponentially and it clearly fails in the limit of infinite synaptic depth. This method is improved by adding a genetic algorithm, which selects the fittest neural networks. The probability of a successful genetic attack is calculated for different model parameters using numerical simulations. The results show that scaling laws observed in the case of other attacks hold for the improved algorithm, too. The number of networks needed for an effective attack grows exponentially with increasing synaptic depth. In addition, finite-size effects caused by Hebbian and anti-Hebbian learning are analyzed. These learning rules converge to the random walk rule if the synaptic depth is small compared to the square root of the system size.

  9. Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3

    Directory of Open Access Journals (Sweden)

    Elder John H

    2007-01-01

    Full Text Available Abstract We have obtained the 1.7 Å crystal structure of FIV protease (PR in which 12 critical residues around the active site have been substituted with the structurally equivalent residues of HIV PR (12X FIV PR. The chimeric PR was crystallized in complex with the broad-based inhibitor TL-3, which inhibits wild type FIV and HIV PRs, as well as 12X FIV PR and several drug-resistant HIV mutants 1234. Biochemical analyses have demonstrated that TL-3 inhibits these PRs in the order HIV PR > 12X FIV PR > FIV PR, with Ki values of 1.5 nM, 10 nM, and 41 nM, respectively 234. Comparison of the crystal structures of the TL-3 complexes of 12X FIV and wild-typeFIV PR revealed theformation of additinal van der Waals interactions between the enzyme inhibitor in the mutant PR. The 12X FIV PR retained the hydrogen bonding interactions between residues in the flap regions and active site involving the enzyme and the TL-3 inhibitor in comparison to both FIV PR and HIV PR. However, the flap regions of the 12X FIV PR more closely resemble those of HIV PR, having gained several stabilizing intra-flap interactions not present in wild type FIV PR. These findings offer a structural explanation for the observed inhibitor/substrate binding properties of the chimeric PR.

  10. Effects of rotenone and other mitochondrial complex I inhibitors on the brine shrimp Artemia.

    Science.gov (United States)

    Vehovszky, Agnes; Szabó, Henriette; Acs, A; Gyori, J; Farkas, Anna

    2010-12-01

    (Artemia) nauplii was used to asses the toxicity of rotenone, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), MP+ (1-methyl-4-phenylpyridinium) and the effect of L-DOPA co-treatment with rotenone. Rotenone had a dose dependent effect on mortality (LC₅₀: 0.37 ± 0.04 μM mean ± S E, n = 24), while MPTP and MP+ proved to be toxic in millimolar range (LC₅₀: 0.21 ± 0.09 mM and 0.20 ± 0.08 mM, respectively, n = 4). L-DOPA (50-200 μM) co-treatment increased the survival of the rotenone-treated animals (LC₅₀: 0.51 ± 0.23 μM, 1.03 ± 0.66 μM, and 0.76 ± 0.52 μM, respectively). In the whole body tissue homogenates of Artemia, sublethal (up to 0.3 μM) concentrations of rotenone increased the glutathione S-transferase (GST) activity by up to 50 about percent (LC₅₀: 53.3 ± 6.8 nM/min/mg protein, against 34.7 ± 3.6 nM/min/mg protein, n = 4). Nauplii treated in 100 mM L-DOPA and rotenone together showed further increase of GST activity all across the range of rotenone concentrations. These results on Artemia nauplii show similarities with other animal models, when complex I inhibitors were tested. Biochemical measurements suggest a protective role of L-DOPA by increasing the GST activity as part of the intracellular defences during toxin-evoked oxidative stress.

  11. Pharmacological properties and pathophysiological significance of a Kunitz-type protease inhibitor (Rusvikunin-II) and its protein complex (Rusvikunin complex) purified from Daboia russelii russelii venom.

    Science.gov (United States)

    Mukherjee, Ashis K; Mackessy, Stephen P

    2014-10-01

    A 7.1 kDa basic peptide (Rusvikunin-II) was purified from a previously described protein complex (Rusvikunin complex, consists of Rusvikunin and Rusvikunin-II) of Daboia russelii russelii venom. The N-terminal sequence of Rusvikunin-II was found to be blocked, but peptide mass fingerprinting analysis indicated its identity as Kunitz-type basic protease inhibitor 2, previously reported from Russell's Viper venom. A tryptic peptide sequence of Rusvikunin-II containing the N-terminal sequence HDRPTFCNLFPESGR demonstrated significant sequence homology to venom basic protease inhibitors, Kunitz-type protease inhibitors and trypsin inhibitors. The secondary structure of Rusvikunin-II was dominated by β-sheets (60.4%), followed by random coil (38.2%), whereas α-helix (1.4%) contributes the least to its secondary structure. Both Rusvikunin-II and the Rusvikunin complex demonstrated dose-dependent anticoagulant activity; however, the anticoagulant potency of latter was found to be higher. Both inhibited the amidolytic activity of trypsin > plasmin > FXa, fibrinogen clotting activity of thrombin, and, to a lesser extent, the prothrombin activation property of FXa; however, the inhibitory effect of the Rusvikunin complex was more pronounced. Neither Rusvikunin-II nor Rusvikunin complex inhibited the amidolytic activity of chymotrypsin and thrombin. Rusvikunin-II at 10 μg/ml was not cytotoxic to Colo-205, MCF-7 or 3T3 cancer cells; conversely, Rusvikunin complex showed ∼30% reduction of MCF-7 cells under identical experimental conditions. Rusvikunin-II (5.0 mg/kg body weight, i.p. injection) was not lethal to mice or House Geckos; nevertheless, it showed in vivo anticoagulant action in mice. However, the Rusvikunin complex (at 5.0 mg/kg) was toxic to NSA mice, but not to House Geckos, suggesting it has prey-specific toxicity. Rusvikunin complex-treated mice exhibited dyspnea and hind-limb paresis prior to death. The present study indicates that the Kunitz

  12. Octahedral rhodium(III) complexes as kinase inhibitors: Control of the relative stereochemistry with acyclic tridentate ligands.

    Science.gov (United States)

    Mollin, Stefan; Riedel, Radostan; Harms, Klaus; Meggers, Eric

    2015-07-01

    Octahedral metal complexes are attractive structural templates for the design of enzyme inhibitors as has been demonstrated, for example, with the development of metallo-pyridocarbazoles as protein kinase inhibitors. The octahedral coordination sphere provides untapped structural opportunities but at the same time poses the drawback of dealing with a large number of stereoisomers. In order to address this challenge of controlling the relative metal-centered configuration, the synthesis of rhodium(III) pyridocarbazole complexes with facially coordinating acyclic tridentate ligands was investigated. A strategy for the rapid synthesis of such complexes is reported, the diastereoselectivities of these reactions were investigated, the structure of several complexes were determined by X-ray crystallography, the high kinetic stability of such complexes in thiol-containing solutions was demonstrated in (1)H-NMR experiments, and the protein kinase inhibition ability of this class of complexes was confirmed. It can be concluded that the use of multidentate ligands is currently maybe the most practical strategy to avoid a large number of possible stereoisomers in the course of exploiting octahedral coordination spheres as structural templates for the design of bioactive molecules.

  13. Congenital segmental lymphedema in tuberous sclerosis complex with associated subependymal giant cell astrocytomas treated with Mammalian target of rapamycin inhibitors.

    Science.gov (United States)

    Prato, Giulia; Mancardi, Maria Margherita; Baglietto, Maria Giuseppina; Janis, Sara; Vercellino, Nadia; Rossi, Andrea; Consales, Alessandro; Raso, Alessandro; Garrè, Maria Luisa

    2014-09-01

    Tuberous sclerosis complex is a genetic, multisystemic disorder characterized by circumscribed benign lesions (hamartomas) in several organs, including brain. This is the result of defects in the TSC1 and/or TSC2 tumor suppressor genes, encoding the hamartin-tuberin complex that inhibits the mammalian target of rapamycin pathway. Specific inhibitors of this pathway have been shown to reduce the volume of subependymal giant cell astrocytomas associated with tuberous sclerosis. Congenital lymphedema is rarely seen in association with tuberous sclerosis, with only a few reported cases. Although this association can be coincidental, the dysgenetic lymphatic system can represent a hamartia as a consequence of gene mutation. We describe a child with congenital lymphedema in tuberous sclerosis and associated subependymal giant cell astrocytoma who experienced lymphangitis under treatment with mammalian target of rapamycin inhibitors. Because our patient did not show worsening of lymphedema, congenital lymphedema does not seem to be a contraindication for this therapy.

  14. Crystal Structure of 12-Lipoxygenase Catalytic-Domain-Inhibitor Complex Identifies a Substrate-Binding Channel for Catalysis

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Shu; Mueser, Timothy C.; Marnett, Lawrence J.; Funk, Jr., Max O. (Toledo); (Vanderbilt)

    2014-10-02

    Lipoxygenases are critical enzymes in the biosynthesis of families of bioactive lipids including compounds with important roles in the initiation and resolution of inflammation and in associated diseases such as diabetes, cardiovascular disease, and cancer. Crystals diffracting to high resolution (1.9 {angstrom}) were obtained for a complex between the catalytic domain of leukocyte 12-lipoxygenase and the isoform-specific inhibitor, 4-(2-oxapentadeca-4-yne)phenylpropanoic acid (OPP). In the three-dimensional structure of the complex, the inhibitor occupied a new U-shaped channel open at one end to the surface of the protein and extending past the redox-active iron site that is essential for catalysis. In models, the channel accommodated arachidonic acid, defining the binding site for the substrate of the catalyzed reaction. There was a void adjacent to the OPP binding site connecting to the surface of the enzyme and providing a plausible access channel for the other substrate, oxygen.

  15. Structure of Human G Protein-Coupled Receptor Kinase 2 in Complex with the Kinase Inhibitor Balanol

    Energy Technology Data Exchange (ETDEWEB)

    Tesmer, John J.G.; Tesmer, Valerie M.; Lodowski, David T.; Steinhagen, Henning; Huber, Jochen (Sanofi); (Michigan); (Texas)

    2010-07-19

    G protein-coupled receptor kinase 2 (GRK2) is a pharmaceutical target for the treatment of cardiovascular diseases such as congestive heart failure, myocardial infarction, and hypertension. To better understand how nanomolar inhibition and selectivity for GRK2 might be achieved, we have determined crystal structures of human GRK2 in complex with G{beta}{gamma} in the presence and absence of the AGC kinase inhibitor balanol. The selectivity of balanol among human GRKs is assessed.

  16. Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I.

    Directory of Open Access Journals (Sweden)

    Simmy Thomas

    Full Text Available Verrucosidin (VCD belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78 expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD's anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose, but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin. However, VCD's strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin might act in a similar GRP78-independent fashion will be discussed.

  17. Remarkable Activation of the Complement System and Aberrant Neuronal Localization of the Membrane Attack Complex in the Brain Tissues of Scrapie-Infected Rodents.

    Science.gov (United States)

    Lv, Yan; Chen, Cao; Zhang, Bao-Yun; Xiao, Kang; Wang, Jing; Chen, Li-Na; Sun, Jing; Gao, Chen; Shi, Qi; Dong, Xiao-Ping

    2015-12-01

    As an integral part of the innate immunity, the complement system has been reported to involve in the pathogenesis of prion diseases (PrD). However, the states of expression and activity of complement proteins in experimental models of scrapie infection are still not fully understood. Herein, the state of complement activation, the presence, and distribution as well as localization of C3 and membrane attack complex (MAC) in the brains of several scrapie-infected rodents were comparatively assessed through various methodologies. Our data illustrated a significant increase in the total complement activity (CH50, U/ml) in several scrapie-infected rodent brains at the terminal stage and a time-dependent upregulation of C1q in 263K-infected hamsters during the incubation period, intimating the sustained and progressive activation of the classical pathway during PrD progression. Confocal microscopy revealed robust activation of C3 and its localization to various central nervous system (CNS) cells with differential morphology in the brain tissues of both 263K-infected hamsters and 139A-infected C57BL/6 mice at disease end stages. Dynamic analyses of MAC in the brains of 263K-infected hamsters and 139A-infected C57BL/6 mice demonstrated remarkably time-dependent deposition during the incubation period, which may highlight a persistently activated terminal complement components. Moreover, immunofluorescent assays (IFAs) showed that MAC-specific signals appeared to overlap with morphologically abnormal neurons rather than proliferative astrocytes or activated microglia throughout the CNS of both 263K-infected hamsters and 139A-infected C57BL/6 mice. Overall, these results indicate that the activation of the complement system and the subsequent localization of the complement components to neurons may be a hallmark during prion infection, which ultimately contribute to the neurodegeneration in PrD.

  18. Spatially localized attacks on interdependent networks: the existence of a finite critical attack size

    CERN Document Server

    Berezin, Yehiel; Danziger, Michael M; Li, Daqing; Havlin, Shlomo

    2013-01-01

    Many real world complex systems such as infrastructure, communication and transportation networks are embedded in space, where entities of one system may depend on entities of other systems. These systems are subject to geographically localized failures due to malicious attacks or natural disasters. Here we study the resilience of a system composed of two interdependent spatially embedded networks to localized geographical attacks. We find that if an attack is larger than a finite (zero fraction of the system) critical size, it will spread through the entire system and lead to its complete collapse. If the attack is below the critical size, it will remain localized. In contrast, under random attack a finite fraction of the system needs to be removed to initiate system collapse. We present both numerical simulations and a theoretical approach to analyze and predict the effect of local attacks and the critical attack size. Our results demonstrate the high risk of local attacks on interdependent spatially embedd...

  19. Study of cascading failure-oriented attack on the edges of complex networks%面向相继故障的复杂网络上边袭击策略研究

    Institute of Scientific and Technical Information of China (English)

    王建伟; 荣莉莉

    2011-01-01

    In order to discuss cascading failures on complex networks subject to attacks, this paper adopts a cascading failure model presented in Physical Review E 77, 026101(2008), compares the universal cascading failure phenomena on BA scale-free and WS small-world networks subject to two different attacks on edges,and explores the effects of network structures on edge attack strategies. Both theoretical analysis and numerical simulations indicate that the attack on the edges with the lowest loads is more prone to trigger cascading failures than the attack on the ones with the highest loads in the certain range of the tunable parameter, and the difference network structures have much important effects on attack strategies.%针对复杂网络遭遇蓄意攻击引发的相继故障问题,采用Physical Review E77,026101(2008)所提出的相继故障模型,对比了BA无标度网络和WS小世界网络上遭遇两种边袭击策略导致的全局相继故障现象,并探讨了网络拓扑结构对边袭击策略的影响.理论解析和数值模拟均表明了在模型中可调参数的一定取值内,袭击网络中负荷最小的边比袭击网络中负荷最大的边更易于导致相继故障现象,而且,网络拓扑结构的不同对袭击策略也有着非常重要的影响.

  20. The complex between urokinase (uPA) and its type-1 inhibitor (PAI-1) in pulmonary adenocarcinoma: Relation to prognosis

    DEFF Research Database (Denmark)

    Pappot, Helle; Pedersen, Anders N; Brünner, Nils

    2006-01-01

    In a lung cancer population comprising tumor tissue from 99 pulmonary adenocarcinoma patients, the relationship between tumor tissue level of the complex formed of urokinase (uPA) and its type-1 inhibitor (PAI-1) and survival was studied. The study included patient material previously investigated....... The amounts of uPA-PAI-1 complex measured in pulmonary adenocarcinoma tissue were within the same range as previously reported in breast cancer tissue (0.11-5.74 ng/mg protein). uPA and PAI-1 levels were weakly correlated to the uPA-PAI-1 complex, r = 0.52 and r = 0.47, respectively, and no relation was found...... these interactions and the clinical importance of the tissue levels of uPA, PAI-1 and uPA-PAI-1 complex, the results suggest further exploratory studies of the components in pulmonary adenocarcinomas and other cancers....

  1. The complex between urokinase (uPA) and its type-1 inhibitor (PAI-1) in pulmonary adenocarcinoma

    DEFF Research Database (Denmark)

    Pappot, Helle; Pedersen, Anders N.; Brünner, Nils

    2006-01-01

    In a lung cancer population comprising tumor tissue from 99 pulmonary adenocarcinoma patients, the relationship between tumor tissue level of the complex formed of urokinase (uPA) and its type-1 inhibitor (PAI-1) and survival was studied. The study included patient material previously investigated....... The amounts of uPA-PAI-1 complex measured in pulmonary adenocarcinoma tissue were within the same range as previously reported in breast cancer tissue (0.11-5.74 ng/mg protein). uPA and PAI-1 levels were weakly correlated to the uPA-PAI-1 complex, r = 0.52 and r = 0.47, respectively, and no relation was found...... these interactions and the clinical importance of the tissue levels of uPA, PAI-1 and uPA-PAI-1 complex, the results suggest further exploratory studies of the components in pulmonary adenocarcinomas and other cancers....

  2. A novel dimeric inhibitor targeting Beta2GPI in Beta2GPI/antibody complexes implicated in antiphospholipid syndrome.

    Directory of Open Access Journals (Sweden)

    Alexey Kolyada

    Full Text Available BACKGROUND: β2GPI is a major antigen for autoantibodies associated with antiphospholipid syndrome (APS, an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. Only the dimeric form of β2GPI generated by anti-β2GPI antibodies is pathologically important, in contrast to monomeric β2GPI which is abundant in plasma. PRINCIPAL FINDINGS: We created a dimeric inhibitor, A1-A1, to selectively target β2GPI in β2GPI/antibody complexes. To make this inhibitor, we isolated the first ligand-binding module from ApoER2 (A1 and connected two A1 modules with a flexible linker. A1-A1 interferes with two pathologically important interactions in APS, the binding of β2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of β2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of β2GPI present in human serum, β2GPI purified from human plasma and the individual domain V of β2GPI. We demonstrated that when β2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of β2GPI to cardiolipin, regardless of the source of β2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of β2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-β2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric β2GPI to cardiolipin. CONCLUSIONS: Our results suggest that the approach of using a dimeric inhibitor to block β2GPI in the pathological multivalent β2GPI/antibody complexes holds significant promise. The novel inhibitor A1-A1 may be a starting point in the development of an effective therapeutic for antiphospholipid syndrome.

  3. A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome

    Energy Technology Data Exchange (ETDEWEB)

    A Kolyada; C Lee; A De Biasio; N Beglova

    2011-12-31

    {beta}2GPI is a major antigen for autoantibodies associated with antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. Only the dimeric form of {beta}2GPI generated by anti-{beta}2GPI antibodies is pathologically important, in contrast to monomeric {beta}2GPI which is abundant in plasma. We created a dimeric inhibitor, A1-A1, to selectively target {beta}2GPI in {beta}2GPI/antibody complexes. To make this inhibitor, we isolated the first ligand-binding module from ApoER2 (A1) and connected two A1 modules with a flexible linker. A1-A1 interferes with two pathologically important interactions in APS, the binding of {beta}2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of {beta}2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of {beta}2GPI present in human serum, {beta}2GPI purified from human plasma and the individual domain V of {beta}2GPI. We demonstrated that when {beta}2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of {beta}2GPI to cardiolipin, regardless of the source of {beta}2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of {beta}2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-{beta}2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric {beta}2GPI to cardiolipin. Our results suggest that the approach of using a dimeric inhibitor to block {beta}2GPI in the pathological multivalent {beta}2GPI/antibody complexes holds significant promise. The novel inhibitor A1-A1 may be a starting point in the development of an effective therapeutic for antiphospholipid syndrome.

  4. Crystallization and preliminary X-ray diffraction studies of a catechol-O-methyltransferase/inhibitor complex

    Energy Technology Data Exchange (ETDEWEB)

    Rodrigues, M. L. [Instituto de Tecnologia Química e Biológica (ITQB), Universidade Nova de Lisboa, Av. República, Apt. 127, 2781-901 Oeiras (Portugal); Bonifácio, M. J.; Soares-da-Silva, P. [Department of Research and Development, BIAL, 4785 S. Mamede do Coronado (Portugal); Carrondo, M. A.; Archer, M., E-mail: archer@itqb.unl.pt [Instituto de Tecnologia Química e Biológica (ITQB), Universidade Nova de Lisboa, Av. República, Apt. 127, 2781-901 Oeiras (Portugal)

    2005-01-01

    Catechol-O-methyltransferase has been co-crystallized with a novel inhibitor, which has potential therapeutic application in the Parkinson’s disease therapy. Inhibitors of the enzyme catechol-O-methyltransferase (COMT) are used as co-adjuvants in the therapy of Parkinson’s disease. A recombinant form of the soluble cytosolic COMT from rat has been co-crystallized with a new potent inhibitor, BIA 8-176 [(3,4-dihydroxy-2-nitrophenyl)phenylmethanone], by the vapour-diffusion method using PEG 6K as precipitant. Crystals diffract to 1.6 Å resolution on a synchrotron-radiation source and belong to the monoclinic space group P2{sub 1}, with unit-cell parameters a = 52.77, b = 79.63, c = 61.54 Å, β = 91.14°.

  5. Structural and functional characterization of complex formation between two Kunitz-type serine protease inhibitors from Russell's Viper venom.

    Science.gov (United States)

    Mukherjee, Ashis K; Dutta, Sumita; Kalita, Bhargab; Jha, Deepak K; Deb, Pritam; Mackessy, Stephen P

    2016-01-01

    Snake venom Kunitz-type serine protease inhibitors (KSPIs) exhibit various biological functions including anticoagulant activity. This study elucidates the occurrence and subunit stoichiometry of a putative complex formed between two KSPIs (Rusvikunin and Rusvikunin-II) purified from the native Rusvikunin complex of Pakistan Russell's Viper (Daboia russelii russelii) venom (RVV). The protein components of the Rusvikunin complex were identified by LC-MS/MS analysis. The non-covalent interaction between two major components of the complex (Rusvikunin and Rusvikunin-II) at 1:2 stoichiometric ratio to form a stable complex was demonstrated by biophysical techniques such as spectrofluorometric, classical gel-filtration, equilibrium gel-filtration, circular dichroism (CD), dynamic light scattering (DLS), RP-HPLC and SDS-PAGE analyses. CD measurement showed that interaction between Rusvikunin and Rusvikunin-II did not change their overall secondary structure; however, the protein complex exhibited enhanced hydrodynamic diameter and anticoagulant activity as compared to the individual components of the complex. This study may lay the foundation for understanding the basis of protein complexes in snake venoms and their role in pathophysiology of snakebite.

  6. Bimolecular Complementation to Visualize Filovirus VP40-Host Complexes in Live Mammalian Cells: Toward the Identification of Budding Inhibitors

    Directory of Open Access Journals (Sweden)

    Yuliang Liu

    2011-01-01

    Full Text Available Virus-host interactions play key roles in promoting efficient egress of many RNA viruses, including Ebola virus (EBOV or “e” and Marburg virus (MARV or “m”. Late- (L- domains conserved in viral matrix proteins recruit specific host proteins, such as Tsg101 and Nedd4, to facilitate the budding process. These interactions serve as attractive targets for the development of broad-spectrum budding inhibitors. A major gap still exists in our understanding of the mechanism of filovirus budding due to the difficulty in detecting virus-host complexes and mapping their trafficking patterns in the natural environment of the cell. To address this gap, we used a bimolecular complementation (BiMC approach to detect, localize, and follow the trafficking patterns of eVP40-Tsg101 complexes in live mammalian cells. In addition, we used the BiMC approach along with a VLP budding assay to test small molecule inhibitors identified by in silico screening for their ability to block eVP40 PTAP-mediated interactions with Tsg101 and subsequent budding of eVP40 VLPs. We demonstrated the potential broad spectrum activity of a lead candidate inhibitor by demonstrating its ability to block PTAP-dependent binding of HIV-1 Gag to Tsg101 and subsequent egress of HIV-1 Gag VLPs.

  7. New parameterization approaches of the LIE method to improve free energy calculations of PlmII-Inhibitors complexes.

    Science.gov (United States)

    Valiente, Pedro A; Gil, Alejandro; Batista, Paulo R; Caffarena, Ernesto R; Pons, Tirso; Pascutti, Pedro G

    2010-11-30

    The standard parameterization of the Linear Interaction Energy (LIE) method has been applied with quite good results to reproduce the experimental absolute binding free energies for several protein-ligand systems. However, we found that this parameterization failed to reproduce the experimental binding free energy of Plasmepsin II (PlmII) in complexes with inhibitors belonging to four dissimilar scaffolds. To overcome this fact, we developed three approaches of LIE, which combine systematic approaches to predict the inhibitor-specific values of α, β, and γ parameters, to gauge their ability to calculate the absolute binding free energies for these PlmII-Inhibitor complexes. Specifically: (i) we modified the linear relationship between the weighted nonpolar desolvation ratio (WNDR) and the α parameter, by introducing two models of the β parameter determined by the free energy perturbation (FEP) method in the absence of the constant term γ, and (ii) we developed a new parameterization model to investigate the linear correlation between WNDR and the correction term γ. Using these parameterizations, we were able to reproduce the experimental binding free energy from these systems with mean absolute errors lower than 1.5 kcal/mol.

  8. The attack navigator

    DEFF Research Database (Denmark)

    Probst, Christian W.; Willemson, Jan; Pieters, Wolter

    2016-01-01

    -technical system, the attack navigator identifies routes to an attacker goal. Specific attacker properties such as skill or resources can be included through attacker profiles. This enables defenders to explore attack scenarios and the effectiveness of defense alternatives under different threat conditions....... that are caused by the strategic behaviour of adversaries. Therefore, technology-supported methods are needed to help us identify and manage these risks. In this paper, we describe the attack navigator: a graph-based approach to security risk assessment inspired by navigation systems. Based on maps of a socio...

  9. Collision Attack on the Full Extended MD4 and Pseudo-Preimage Attack on RIPEMD

    Institute of Scientific and Technical Information of China (English)

    Gao-Li Wang

    2013-01-01

    The cryptographic hash functions Extended MD4 and RIPEMD are double-branch hash functions,which consist of two parallel branches.Extended MD4 was proposed by Rivest in 1990,and RIPEMD was devised in the framework of the RIPE project (RACE Integrity Primitives Evaluation,1988~1992).On the basis of differential analysis and meet-in-the-middle attack principle,this paper proposes a collision attack on the full Extended MD4 and a pseudo-preimage attack on the full RIPEMD respectively.The collision attack on Extended MD4 holds with a complexity of 237,and a collision instance is presented.The pseudo-preimage attack on RIPEMD holds with a complexity of 2125,4,which optimizes the complexity order for brute-force attack.The results in this study will also be beneficial to the analysis of other double-branch hash functions such as RIPEMD-160.

  10. Generating IDS Attack Pattern Automatically Based on Attack Tree

    Institute of Scientific and Technical Information of China (English)

    向尕; 曹元大

    2003-01-01

    Generating attack pattern automatically based on attack tree is studied. The extending definition of attack tree is proposed. And the algorithm of generating attack tree is presented. The method of generating attack pattern automatically based on attack tree is shown, which is tested by concrete attack instances. The results show that the algorithm is effective and efficient. In doing so, the efficiency of generating attack pattern is improved and the attack trees can be reused.

  11. Terrorist attacks escalate in frequency and fatalities preceding highly lethal attacks.

    Directory of Open Access Journals (Sweden)

    Andy Martens

    Full Text Available Highly lethal terrorist attacks, which we define as those killing 21 or more people, account for 50% of the total number of people killed in all terrorist attacks combined, yet comprise only 3.5% of terrorist attacks. Given the disproportionate influence of these incidents, uncovering systematic patterns in attacks that precede and anticipate these highly lethal attacks may be of value for understanding attacks that exact a heavy toll on life. Here we examined whether the activity of terrorist groups escalates--both in the number of people killed per attack and in the frequency of attacks--leading up to highly lethal attacks. Analyses of terrorist attacks drawn from a state-of-the-art international terrorism database (The Global Terrorism Database showed evidence for both types of escalation leading up to highly lethal attacks, though complexities to the patterns emerged as well. These patterns of escalation do not emerge among terrorist groups that never commit a highly lethal attack.

  12. Heart attack first aid

    Science.gov (United States)

    First aid - heart attack; First aid - cardiopulmonary arrest; First aid - cardiac arrest ... A heart attack occurs when the blood flow that carries oxygen to the heart is blocked. The heart muscle ...

  13. Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration.

    Science.gov (United States)

    Garcia-Saez, Isabel; DeBonis, Salvatore; Lopez, Roman; Trucco, Fernando; Rousseau, Bernard; Thuéry, Pierre; Kozielski, Frank

    2007-03-30

    Drugs that target mitotic spindle proteins have been proven useful for tackling tumor growth. Eg5, a kinesin-5 family member, represents a potential target, since its inhibition leads to prolonged mitotic arrest through the activation of the mitotic checkpoint and apoptotic cell death. Monastrol, a specific dihydropyrimidine inhibitor of Eg5, shows stereo-specificity, since predominantly the (S)-, but not the (R)-, enantiomer has been shown to be the biologically active compound in vitro and in cell-based assays. Here, we solved the crystal structure (2.7A) of the complex between human Eg5 and a new keto derivative of monastrol (named mon-97), a potent antimitotic inhibitor. Surprisingly, we identified the (R)-enantiomer bound in the active site, and not, as for monastrol, the (S)-enantiomer. The absolute configuration of this more active (R)-enantiomer has been unambiguously determined via chemical correlation and x-ray analysis. Unexpectedly, both the R- and the S-forms inhibit Eg5 ATPase activity with IC(50) values of 110 and 520 nM (basal assays) and 150 nm and 650 nm (microtubule-stimulated assays), respectively. However, the difference was large enough for the protein to select the (R)- over the (S)-enantiomer. Taken together, these results show that in this new monastrol family, both (R)- and (S)-enantiomers can be active as Eg5 inhibitors. This considerably broadens the alternatives for rational drug design.

  14. Two-headed tetraphosphate cap analogs are inhibitors of the Dcp1/2 RNA decapping complex.

    Science.gov (United States)

    Ziemniak, Marcin; Mugridge, Jeffrey S; Kowalska, Joanna; Rhoads, Robert E; Gross, John D; Jemielity, Jacek

    2016-04-01

    Dcp1/2 is the major eukaryotic RNA decapping complex, comprised of the enzyme Dcp2 and activator Dcp1, which removes the 5' m(7)G cap from mRNA, committing the transcript to degradation. Dcp1/2 activity is crucial for RNA quality control and turnover, and deregulation of these processes may lead to disease development. The molecular details of Dcp1/2 catalysis remain elusive, in part because both cap substrate (m(7)GpppN) and m(7)GDP product are bound by Dcp1/2 with weak (mM) affinity. In order to find inhibitors to use in elucidating the catalytic mechanism of Dcp2, we screened a small library of synthetic m(7)G nucleotides (cap analogs) bearing modifications in the oligophosphate chain. One of the most potent cap analogs, m(7)GpSpppSm(7)G, inhibited Dcp1/2 20 times more efficiently than m(7)GpppN or m(7)GDP. NMR experiments revealed that the compound interacts with specific surfaces of both regulatory and catalytic domains of Dcp2 with submillimolar affinities. Kinetics analysis revealed that m(7)GpSpppSm(7)G is a mixed inhibitor that competes for the Dcp2 active site with micromolar affinity. m(7)GpSpppSm(7)G-capped RNA undergoes rapid decapping, suggesting that the compound may act as a tightly bound cap mimic. Our identification of the first small molecule inhibitor of Dcp2 should be instrumental in future studies aimed at understanding the structural basis of RNA decapping and may provide insight toward the development of novel therapeutically relevant decapping inhibitors.

  15. Crystallization and preliminary crystallographic study of Feline infectious peritonitis virus main protease in complex with an inhibitor.

    Science.gov (United States)

    Wang, Jinshan; Wang, Fenghua; Tan, Yusheng; Chen, Xia; Zhao, Qi; Fu, Sheng; Li, Shuang; Chen, Cheng; Yang, Haitao

    2014-12-01

    Feline infectious peritonitis virus (FIPV) causes a lethal systemic granulomatous disease in wild and domestic cats around the world. Currently, no effective vaccines or drugs have been developed against it. As a member of the genus Alphacoronavirus, FIPV encodes two polyprotein precursors required for genome replication and transcription. Each polyprotein undergoes extensive proteolytic processing, resulting in functional subunits. This process is mainly mediated by its genome-encoded main protease, which is an attractive target for antiviral drug design. In this study, the main protease of FIPV in complex with a Michael acceptor-type inhibitor was crystallized. The complex crystals diffracted to 2.5 Å resolution and belonged to space group I422, with unit-cell parameters a = 112.3, b = 112.3, c = 102.1 Å. There is one molecule per asymmetric unit.

  16. Composite Dos Attack Model

    Directory of Open Access Journals (Sweden)

    Simona Ramanauskaitė

    2012-04-01

    Full Text Available Preparation for potential threats is one of the most important phases ensuring system security. It allows evaluating possible losses, changes in the attack process, the effectiveness of used countermeasures, optimal system settings, etc. In cyber-attack cases, executing real experiments can be difficult for many reasons. However, mathematical or programming models can be used instead of conducting experiments in a real environment. This work proposes a composite denial of service attack model that combines bandwidth exhaustion, filtering and memory depletion models for a more real representation of similar cyber-attacks. On the basis of the introduced model, different experiments were done. They showed the main dependencies of the influence of attacker and victim’s properties on the success probability of denial of service attack. In the future, this model can be used for the denial of service attack or countermeasure optimization.

  17. Cytotoxic gold(I) N-heterocyclic carbene complexes with phosphane ligands as potent enzyme inhibitors

    NARCIS (Netherlands)

    Rubbiani, Riccardo; Salassa, Luca; de Almeida, Andreia; Casini, Angela; Ott, Ingo

    2014-01-01

    Organometallic gold complexes with N-heterocyclic carbene (NHC) ligands have been demonstrating promising properties as novel anticancer agents. Gold(I) NHC complexes containing different phosphanes as secondary ligands were shown to trigger strong cytotoxic effects in cancer cells, and their effect

  18. FAST CORRELATION ATTACKS ON BLUETOOTH COMBINER

    Institute of Scientific and Technical Information of China (English)

    Ma Weiju; Feng Dengguo

    2006-01-01

    A simple fast correlation attack is used to analysis the security of Bluetooth combiner in this paper.This attack solves the tradeoff between the length of the keystream and the computing complexity needed to recover the secret key. We give the computing complexities of the attack algorithm according to different lengths of the known keystream. The result is less time-consuming than before. It is also shown that the security of the modified Bluetooth combiner by Hermelin and Nyberg is not significantly enhanced.

  19. Terrorist Attacks Escalate in Frequency and Fatalities Preceding Highly Lethal Attacks

    Science.gov (United States)

    Martens, Andy; Sainudiin, Raazesh; Sibley, Chris G.; Schimel, Jeff; Webber, David

    2014-01-01

    Highly lethal terrorist attacks, which we define as those killing 21 or more people, account for 50% of the total number of people killed in all terrorist attacks combined, yet comprise only 3.5% of terrorist attacks. Given the disproportionate influence of these incidents, uncovering systematic patterns in attacks that precede and anticipate these highly lethal attacks may be of value for understanding attacks that exact a heavy toll on life. Here we examined whether the activity of terrorist groups escalates–both in the number of people killed per attack and in the frequency of attacks–leading up to highly lethal attacks. Analyses of terrorist attacks drawn from a state-of-the-art international terrorism database (The Global Terrorism Database) showed evidence for both types of escalation leading up to highly lethal attacks, though complexities to the patterns emerged as well. These patterns of escalation do not emerge among terrorist groups that never commit a highly lethal attack. PMID:24755753

  20. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.

    Science.gov (United States)

    Leenen, Frans H H; Nwachuku, Chuke E; Black, Henry R; Cushman, William C; Davis, Barry R; Simpson, Lara M; Alderman, Michael H; Atlas, Steven A; Basile, Jan N; Cuyjet, Aloysius B; Dart, Richard; Felicetta, James V; Grimm, Richard H; Haywood, L Julian; Jafri, Syed Z A; Proschan, Michael A; Thadani, Udho; Whelton, Paul K; Wright, Jackson T

    2006-09-01

    The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker-initiated therapy in older hypertensive individuals. Patients were randomized to amlodipine (n=9048) or lisinopril (n=9054). The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction, analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (CVD), end-stage renal disease (ESRD), cancer, and gastrointestinal bleeding. Mean follow-up was 4.9 years. Blood pressure control was similar in nonblacks, but not in blacks. No significant differences were found between treatment groups for the primary outcome, all-cause mortality, ESRD, or cancer. Stroke rates were higher on lisinopril in blacks (RR=1.51, 95% CI 1.22 to 1.86) but not in nonblacks (RR=1.07, 95% CI 0.89 to 1.28), and in women (RR=1.45, 95% CI 1.17 to 1.79), but not in men (RR=1.10, 95% CI 0.92 to 1.31). Rates of combined CVD were higher (RR=1.06, 95% CI 1.00 to 1.12) because of higher rates for strokes, peripheral arterial disease, and angina, which were partly offset by lower rates for heart failure (RR=0.87, 95% CI 0.78 to 0.96) on lisinopril compared with amlodipine. Gastrointestinal bleeds and angioedema were higher on lisinopril. Patients with and without baseline coronary heart disease showed similar outcome patterns. We conclude that in hypertensive patients, the risks for coronary events are similar, but for stroke, combined CVD, gastrointestinal bleeding, and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy. Some, but not all, of these differences may be explained by less effective blood pressure control in the lisinopril arm.

  1. Stability of the Human Hsp90-p50Cdc37 Chaperone Complex against Nucleotides and Hsp90 Inhibitors, and the Influence of Phosphorylation by Casein Kinase 2

    Directory of Open Access Journals (Sweden)

    Sanne H. Olesen

    2015-01-01

    Full Text Available The molecular chaperone Hsp90 is regulated by co-chaperones such as p50Cdc37, which recruits a wide selection of client protein kinases. Targeted disruption of the Hsp90-p50Cdc37 complex by protein–protein interaction (PPI inhibitors has emerged as an alternative strategy to treat diseases characterized by aberrant Hsp90 activity. Using isothermal microcalorimetry, ELISA and GST-pull down assays we evaluated reported Hsp90 inhibitors and nucleotides for their ability to inhibit formation of the human Hsp90β-p50Cdc37 complex, reconstituted in vitro from full-length proteins. Hsp90 inhibitors, including the proposed PPI inhibitors gedunin and H2-gamendazole, did not affect the interaction of Hsp90 with p50Cdc37 in vitro. Phosphorylation of Hsp90 and p50Cdc37 by casein kinase 2 (CK2 did not alter the thermodynamic signature of complex formation. However, the phosphorylated complex was vulnerable to disruption by ADP (IC50 = 32 µM, while ATP, AMPPNP and Hsp90 inhibitors remained largely ineffective. The differential inhibitory activity of ADP suggests that phosphorylation by CK2 primes the complex for dissociation in response to a drop in ATP/ADP levels. The approach applied herein provides robust assays for a comprehensive biochemical evaluation of potential effectors of the Hsp90-p50Cdc37 complex, such as phosphorylation by a kinase or the interaction with small molecule ligands.

  2. Stability of the human Hsp90-p50Cdc37 chaperone complex against nucleotides and Hsp90 inhibitors, and the influence of phosphorylation by casein kinase 2.

    Science.gov (United States)

    Olesen, Sanne H; Ingles, Donna J; Zhu, Jin-Yi; Martin, Mathew P; Betzi, Stephane; Georg, Gunda I; Tash, Joseph S; Schönbrunn, Ernst

    2015-01-19

    The molecular chaperone Hsp90 is regulated by co-chaperones such as p50Cdc37, which recruits a wide selection of client protein kinases. Targeted disruption of the Hsp90-p50Cdc37 complex by protein-protein interaction (PPI) inhibitors has emerged as an alternative strategy to treat diseases characterized by aberrant Hsp90 activity. Using isothermal microcalorimetry, ELISA and GST-pull down assays we evaluated reported Hsp90 inhibitors and nucleotides for their ability to inhibit formation of the human Hsp90β-p50Cdc37 complex, reconstituted in vitro from full-length proteins. Hsp90 inhibitors, including the proposed PPI inhibitors gedunin and H2-gamendazole, did not affect the interaction of Hsp90 with p50Cdc37 in vitro. Phosphorylation of Hsp90 and p50Cdc37 by casein kinase 2 (CK2) did not alter the thermodynamic signature of complex formation. However, the phosphorylated complex was vulnerable to disruption by ADP (IC50 = 32 µM), while ATP, AMPPNP and Hsp90 inhibitors remained largely ineffective. The differential inhibitory activity of ADP suggests that phosphorylation by CK2 primes the complex for dissociation in response to a drop in ATP/ADP levels. The approach applied herein provides robust assays for a comprehensive biochemical evaluation of potential effectors of the Hsp90-p50Cdc37 complex, such as phosphorylation by a kinase or the interaction with small molecule ligands.

  3. Stability of the Human Hsp90-p50Cdc37 Chaperone Complex against Nucleotides and Hsp90 Inhibitors, and the Influence of Phosphorylation by Casein Kinase 2

    Science.gov (United States)

    Olesen, Sanne H.; Ingles, Donna J.; Zhu, Jin-Yi; Martin, Mathew P.; Betzi, Stephane; Georg, Gunda I.; Tash, Joseph S.; Schönbrunn, Ernst

    2015-01-01

    The molecular chaperone Hsp90 is regulated by co-chaperones such as p50Cdc37, which recruits a wide selection of client protein kinases. Targeted disruption of the Hsp90-p50Cdc37 complex by protein-protein interaction (PPI) inhibitors has emerged as an alternative strategy to treat diseases characterized by aberrant Hsp90 activity. Using isothermal microcalorimetry, ELISA and GST-pull down assays we evaluated reported Hsp90 inhibitors and nucleotides for their ability to inhibit formation of the human Hsp90β-p50Cdc37 complex, reconstituted in-vitro from full-length proteins. Hsp90 inhibitors, including the proposed PPI inhibitors gedunin and H2-gamendazole, did not affect the interaction of Hsp90 with p50Cdc37 in vitro. Phosphorylation of Hsp90 and p50Cdc37 by casein kinase 2 (CK2) did not alter the thermodynamic signature of complex formation. However, the phosphorylated complex was vulnerable to disruption by ADP (IC50 = 32 µM), while ATP, AMPPNP and Hsp90 inhibitors remained largely ineffective. The differential inhibitory activity of ADP suggests that phosphorylation by CK2 primes the complex for dissociation in response to a drop in ATP/ADP levels. The approach applied herein provides robust assays for a comprehensive biochemical evaluation of potential effectors of the Hsp90-p50Cdc37 complex, such as phosphorylation by a kinase or the interaction with small molecule ligands. PMID:25608045

  4. Quantitative Verification and Synthesis of Attack-Defence Scenarios

    DEFF Research Database (Denmark)

    Aslanyan, Zaruhi; Nielson, Flemming; Parker, David

    2016-01-01

    Attack-defence trees are a powerful technique for formally evaluating attack-defence scenarios. They represent in an intuitive, graphical way the interaction between an attacker and a defender who compete in order to achieve conflicting objectives. We propose a novel framework for the formal...... analysis of quantitative properties of complex attack-defence scenarios, using an extension of attack-defence trees which models temporal ordering of actions and allows explicit dependencies in the strategies adopted by attackers and defenders. We adopt a game-theoretic approach, translating attack......-defence trees to two-player stochastic games, and then employ probabilistic model checking techniques to formally analyse these models. This provides a means to both verify formally specified security properties of the attack-defence scenarios and, dually, to synthesise strategies for attackers or defenders...

  5. Resistance of Hepatitis C Virus to Inhibitors: Complexity and Clinical Implications

    Science.gov (United States)

    Perales, Celia; Quer, Josep; Gregori, Josep; Esteban, Juan Ignacio; Domingo, Esteban

    2015-01-01

    Selection of inhibitor-resistant viral mutants is universal for viruses that display quasi-species dynamics, and hepatitis C virus (HCV) is no exception. Here we review recent results on drug resistance in HCV, with emphasis on resistance to the newly-developed, directly-acting antiviral agents, as they are increasingly employed in the clinic. We put the experimental observations in the context of quasi-species dynamics, in particular what the genetic and phenotypic barriers to resistance mean in terms of exploration of sequence space while HCV replicates in the liver of infected patients or in cell culture. Strategies to diminish the probability of viral breakthrough during treatment are briefly outlined. PMID:26561827

  6. An electroblotting, two-step procedure for the detection of proteinases and the study of proteinase/inhibitor complexes in gelatin-containing polyacrylamide gels.

    Science.gov (United States)

    Visal-Shah, S; Vrain, T C; Yelle, T C; Nguyen-Quoc, B; Michaud, D

    2001-08-01

    A two-step gelatin/polyacrylamide gel electrophoresis (gelatin/PAGE) procedure was devised for the detection of proteinases and the study of proteinase/inhibitor interactions in complex biological extracts. The proteins are first resolved by sodium dodecyl sulfate (SDS)-PAGE under reducing or nonreducing conditions, and electrotransferred into a 0.75 mm-thick accompanying polyacrylamide slab gel containing 0.1% w/v porcine gelatin. The active proteinase bands are developed by a gelatin proteolysis step in the accompanying gel in the presence or absence of diagnostic proteinase inhibitors, allowing the assessment of proteinase classes and the visual discrimination of inhibitor-'sensitive' and -'insensitive' proteinases in complex extracts. Alternatively, protein extracts are preincubated with specific reversible inhibitors before electrophoresis, allowing a rapid discrimination of strong and weak interactions implicating proteinases and reversible inhibitors. In comparison with the standard gelatin/PAGE procedure, that involves copolymerization of gelatin with acrylamide in the resolving gel, this new procedure simplifies proteinase patterns, avoids overestimation of proteinase numbers in complex extracts, and allows in certain conditions the estimation of proteinase molecular weights. Stem bromelain (EC 3.4.22.32), bovine trypsin (EC 3.4.21.4), papain (EC 3.4.22.2), and the extracellular (digestive) cysteine proteinases of five herbivorous pests are used as model enzymes to illustrate the usefulness of this approach in detecting proteinases and in studying their interactions with specific proteinaceous inhibitors potentially useful in biotechnology.

  7. The crystal structure of Sporosarcina pasteurii urease in a complex with citrate provides new hints for inhibitor design.

    Science.gov (United States)

    Benini, Stefano; Kosikowska, Paulina; Cianci, Michele; Mazzei, Luca; Vara, Antonio Gonzalez; Berlicki, Łukasz; Ciurli, Stefano

    2013-03-01

    Urease, the enzyme that catalyses the hydrolysis of urea, is a virulence factor for a large number of ureolytic bacterial human pathogens. The increasing resistance of these pathogens to common antibiotics as well as the need to control urease activity to improve the yield of soil nitrogen fertilization in agricultural applications has stimulated the development of novel classes of molecules that target urease as enzyme inhibitors. We report on the crystal structure at 1.50-Å resolution of a complex formed between citrate and urease from Sporosarcina pasteurii, a widespread and highly ureolytic soil bacterium. The fit of the ligand to the active site involves stabilizing interactions, such as a carboxylate group that binds the nickel ions at the active site and several hydrogen bonds with the surrounding residues. The citrate ligand has a significantly extended structure compared with previously reported ligands co-crystallized with urease and thus represents a unique and promising scaffold for the design of new, highly active, stable, selective inhibitors.

  8. Adversary Model: Adaptive Chosen Ciphertext Attack with Timing Attack

    OpenAIRE

    2014-01-01

    We have introduced a novel adversary model in Chosen-Ciphertext Attack with Timing Attack (CCA2-TA) and it was a practical model because the model incorporates the timing attack. This paper is an extended paper for 'A Secure TFTP Protocol with Security Proofs'. Keywords - Timing Attack, Random Oracle Model, Indistinguishabilit, Chosen Plaintext Attack, CPA, Chosen Ciphertext Attack, IND-CCA1, Adaptive Chosen Ciphertext Attack, IND-CCA2, Trivial File Transfer Protocol, TFTP, Security, Trust, P...

  9. Seven Deadliest Microsoft Attacks

    CERN Document Server

    Kraus, Rob; Borkin, Mike; Alpern, Naomi

    2010-01-01

    Do you need to keep up with the latest hacks, attacks, and exploits effecting Microsoft products? Then you need Seven Deadliest Microsoft Attacks. This book pinpoints the most dangerous hacks and exploits specific to Microsoft applications, laying out the anatomy of these attacks including how to make your system more secure. You will discover the best ways to defend against these vicious hacks with step-by-step instruction and learn techniques to make your computer and network impenetrable. Windows Operating System-Password AttacksActive Directory-Escalat

  10. Seven Deadliest Network Attacks

    CERN Document Server

    Prowell, Stacy; Borkin, Mike

    2010-01-01

    Do you need to keep up with the latest hacks, attacks, and exploits effecting networks? Then you need Seven Deadliest Network Attacks. This book pinpoints the most dangerous hacks and exploits specific to networks, laying out the anatomy of these attacks including how to make your system more secure. You will discover the best ways to defend against these vicious hacks with step-by-step instruction and learn techniques to make your computer and network impenetrable. Attacks detailed in this book include: Denial of Service War Dialing Penetration "Testing" Protocol Tunneling Spanning Tree At

  11. Seven deadliest USB attacks

    CERN Document Server

    Anderson, Brian

    2010-01-01

    Do you need to keep up with the latest hacks, attacks, and exploits effecting USB technology? Then you need Seven Deadliest USB Attacks. This book pinpoints the most dangerous hacks and exploits specific to USB, laying out the anatomy of these attacks including how to make your system more secure. You will discover the best ways to defend against these vicious hacks with step-by-step instruction and learn techniques to make your computer and network impenetrable. Attacks detailed in this book include: USB Hacksaw USB Switchblade USB Based Virus/Malicous Code Launch USB Device Overflow RAMdum

  12. Use of the mTOR inhibitor everolimus in a patient with multiple manifestations of tuberous sclerosis complex including epilepsy

    Directory of Open Access Journals (Sweden)

    James W. Wheless

    2015-01-01

    Full Text Available Tuberous sclerosis complex (TSC is a genetic disease in which overactivation of mechanistic target of rapamycin (mTOR signaling leads to the growth of benign hamartomas in multiple organs, including the brain, and is associated with a high rate of epilepsy and neurological deficits. The mTOR inhibitor everolimus has been used in the treatment of subependymal giant cell astrocytomas and renal angiomyolipomas in patients with TSC. This article describes the case of a 13-year-old girl with TSC-associated epilepsy with refractory generalized seizures who initiated treatment with everolimus and experienced subsequent improvement in several TSC manifestations, including a reduction in seizure frequency from clusters of two or three daily to one every 2 to 4 weeks after 1.5 years of treatment.

  13. Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells

    Directory of Open Access Journals (Sweden)

    Nardou Katya

    2008-06-01

    Full Text Available Abstract Background Histone deacetylase inhibitors (HDACi are a new class of promising anti-tumour agent inhibiting cell proliferation and survival in tumour cells with very low toxicity toward normal cells. Neuroblastoma (NB is the second most common solid tumour in children still associated with poor outcome in higher stages and, thus NB strongly requires novel treatment modalities. Results We show here that the HDACi Sodium Butyrate (NaB, suberoylanilide hydroxamic acid (SAHA and Trichostatin A (TSA strongly reduce NB cells viability. The anti-tumour activity of these HDACi involved the induction of cell cycle arrest in the G2/M phase, followed by the activation of the intrinsic apoptotic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the activation of the pro-apoptotic proteins Bid and BimEL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-xL, RIP and survivin, that further enhanced the apoptotic signal. Interestingly, the activity of these apoptosis regulators was modulated by several different mechanisms, either by caspases dependent proteolytic cleavage or by degradation via the proteasome pathway. In addition, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells. Conclusion HDACi are therefore interesting new anti-tumour agents for targeting highly malignant tumours such as NB, as these agents display a strong toxicity toward aggressive NB cells and they may possibly reduce angiogenesis by decreasing VEGF production by NB cells.

  14. Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor.

    Science.gov (United States)

    Guevara, Tibisay; Ksiazek, Miroslaw; Skottrup, Peter Durand; Cerdà-Costa, Núria; Trillo-Muyo, Sergio; de Diego, Iñaki; Riise, Erik; Potempa, Jan; Gomis-Rüth, F Xavier

    2013-05-01

    Karilysin is the only metallopeptidase identified as a virulence factor in the odontopathogen Tannerella forsythia owing to its deleterious effect on the host immune response during bacterial infection. The very close structural and sequence-based similarity of its catalytic domain (Kly18) to matrix metalloproteinases suggests that karilysin was acquired by horizontal gene transfer from an animal host. Previous studies by phage display identified peptides with the consensus sequence XWFPXXXGGG (single-letter amino-acid codes; X represents any residue) as karilysin inhibitors with low-micromolar binding affinities. Subsequent refinement revealed that inhibition comparable to that of longer peptides could be achieved using the tetrapeptide SWFP. To analyze its binding, the high-resolution crystal structure of the complex between Kly18 and SWFP was determined and it was found that the peptide binds to the primed side of the active-site cleft in a substrate-like manner. The catalytic zinc ion is clamped by the α-amino group and the carbonyl O atom of the serine, thus distantly mimicking the general manner of binding of hydroxamate inhibitors to metallopeptidases and contributing, together with three zinc-binding histidines from the protein scaffold, to an octahedral-minus-one metal-coordination sphere. The tryptophan side chain penetrates the deep partially water-filled specificity pocket of Kly18. Together with previous serendipitous product complexes of Kly18, the present results provide the structural determinants of inhibition of karilysin and open the field for the design of novel inhibitory strategies aimed at the treatment of human periodontal disease based on a peptidic hit molecule.

  15. Native plasma-derived FVIII/VWF complex has lower sensitivity to FVIII inhibitors than the combination of isolated FVIII and VWF proteins. Impact on Bethesda assay titration of FVIII inhibitors.

    Science.gov (United States)

    Bravo, M I; Da Rocha-Souto, B; Grancha, S; Jorquera, J I

    2014-11-01

    Sensitivity to FVIII inhibitors of the native plasma-derived (pd) FVIII/VWF complex vs. the complexes formed after exogenous FVIII infusion in the haemophilic patient has not been thoroughly studied. The role of VWF in the interaction of FVIII with inhibitors was studied in vitro using different combinations of VWF and FVIII concentrates. Normal plasma, pdFVIII/VWF and isolated FVIII (recombinant FVIII, B-domain deleted and pdFVIII) were used. Titre (BU) was kinetically determined (up to 2 h) in serial dilutions of inhibitor IgG (purified from a pool of plasmas with inhibitors) mixed with VWF and then incubated with the different FVIII. Inhibitor was also added to previously mixed VWF+FVIII. Residual FVIII:C was determined. TGA assays were performed with FVIII-deficient plasma spiked with the FVIII-VWF mixtures with/without an ESH-8 antibody. Inhibitor titres for plasma and pdFVIII/VWF were comparable at all time points. Titres for all concentrates of isolated FVIII were significantly higher than those for plasma or pdFVIII/VWF (1.4-1.9 fold) even after preincubation with VWF. At t = 0 h, titres for plasma or pdFVIII/VWF were unquantifiable, but were detectable for isolated FVIII (0.6-1.6 BU). In contrast to pdFVIII/VWF, the decrease in thrombin generation parameters by isolated FVIII in the presence of ESH-8 was significant (P isolated proteins. Bethesda assay titration using different FVIII concentrates would be advisable to guide the treatment of inhibitor patients.

  16. A NEW METHOD FOR RESYNCHRONIZATION ATTACK

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    This paper presents a new method for resynchronization attack, which is the combination of the differential cryptanalysis and algebraic attack. By using the new method one gets a system of linear equations or low-degree equations about initial keys, and the solution of the system of equations results in the recovery of the initial keys. This method has a lower computational complexity and better performance of attack in contrast to the known methods. Accordingly, the design of the resynchronization stream generators should be reconsidered to make them strong enough to avoid our attacks. When implemented to the Toyocrypt, our method gains the computational complexity of O(217), and that of O(267) for LILI-128.

  17. Optimizing Decision Tree Attack on CAS Scheme

    Directory of Open Access Journals (Sweden)

    PERKOVIC, T.

    2016-05-01

    Full Text Available In this paper we show a successful side-channel timing attack on a well-known high-complexity cognitive authentication (CAS scheme. We exploit the weakness of CAS scheme that comes from the asymmetry of the virtual interface and graphical layout which results in nonuniform human behavior during the login procedure, leading to detectable variations in user's response times. We optimized a well-known probabilistic decision tree attack on CAS scheme by introducing this timing information into the attack. We show that the developed classifier could be used to significantly reduce the number of login sessions required to break the CAS scheme.

  18. Attack Vulnerability of Network Controllability.

    Science.gov (United States)

    Lu, Zhe-Ming; Li, Xin-Feng

    2016-01-01

    Controllability of complex networks has attracted much attention, and understanding the robustness of network controllability against potential attacks and failures is of practical significance. In this paper, we systematically investigate the attack vulnerability of network controllability for the canonical model networks as well as the real-world networks subject to attacks on nodes and edges. The attack strategies are selected based on degree and betweenness centralities calculated for either the initial network or the current network during the removal, among which random failure is as a comparison. It is found that the node-based strategies are often more harmful to the network controllability than the edge-based ones, and so are the recalculated strategies than their counterparts. The Barabási-Albert scale-free model, which has a highly biased structure, proves to be the most vulnerable of the tested model networks. In contrast, the Erdős-Rényi random model, which lacks structural bias, exhibits much better robustness to both node-based and edge-based attacks. We also survey the control robustness of 25 real-world networks, and the numerical results show that most real networks are control robust to random node failures, which has not been observed in the model networks. And the recalculated betweenness-based strategy is the most efficient way to harm the controllability of real-world networks. Besides, we find that the edge degree is not a good quantity to measure the importance of an edge in terms of network controllability.

  19. Current therapy for chronic cerebrovascular attack

    Directory of Open Access Journals (Sweden)

    A. A. Shmonin

    2015-01-01

    Full Text Available Chronic cerebrovascular attack (CCVA is a brain lesion caused by vascular factors. CCVA appears as cognitive impairments (CIs, affective (emotional disorders and focal syndromes. Treatment for CCVA requires a comprehensive approach. Effective combination therapy for CCVA involves secondary prevention of stroke and CIs; treatment of CIs; treatment of depression and other affective disorders; and neuroprotective therapy. Basic therapy for CCVA includes modification of risk factors, antihypertensive, hypolipidemic, and antithrombotic therapies. Central acetylcholinesterase inhibitors (galantamine, rivastigmine, donepezil and a reversible NMDA receptor blocker (memantine are symptomatically used at a stage of vascular and mixed dementia. There are no unique guidelines for the therapy of mild and moderate vascular nondementia-related CIs. Drug use, based on the neurochemical mechanisms underlying the development of vascular CIs, is substantiated. When choosing psychotropic agents, it is necessary to take into account the causes and clinical manifestations of neuromediator deficiency. Antidepressants are used as essential drugs. Neuroleptics and tranquilizers are additionally administered in complex-pattern syndromes, such as depression with marked anxiety. Prescription of neuroprotectors may be effective in treating both stroke and CCVA. These medicaments are most effective when a damaging factor acts, i.e. neuroprotectors should be given in a risk situation and to reduce damage. Citicoline is one of the most test drugs in a group of neuroprotectors. 

  20. Modelling Social-Technical Attacks with Timed Automata

    DEFF Research Database (Denmark)

    David, Nicolas; David, Alexandre; Hansen, Rene Rydhof

    2015-01-01

    in our model and perform analysis and simulation of both model and attack, revealing details about the specific interaction between attacker and victim. Using timed automata also allows for intuitive modelling of systems, in which quantities like time and cost can be easily added and analysed.......Attacks on a system often exploit vulnerabilities that arise from human behaviour or other human activity. Attacks of this type, so-called socio-technical attacks, cover everything from social engineering to insider attacks, and they can have a devastating impact on an unprepared organisation....... In this paper we develop an approach towards modelling socio-technical systems in general and socio-technical attacks in particular, using timed automata and illustrate its application by a complex case study. Thanks to automated model checking and automata theory, we can automatically generate possible attacks...

  1. Insight to structural subsite recognition in plant thiol protease-inhibitor complexes : Understanding the basis of differential inhibition and the role of water

    Directory of Open Access Journals (Sweden)

    Mukhopadhayay Bishnu P

    2001-09-01

    Full Text Available Abstract Background This work represents an extensive MD simulation / water-dynamics studies on a series of complexes of inhibitors (leupeptin, E-64, E-64-C, ZPACK and plant cysteine proteases (actinidin, caricain, chymopapain, calotropin DI of papain family to understand the various interactions, water binding mode, factors influencing it and the structural basis of differential inhibition. Results The tertiary structure of the enzyme-inhibitor complexes were built by visual interactive modeling and energy minimization followed by dynamic simulation of 120 ps in water environment. DASA study with and without the inhibitor revealed the potential subsite residues involved in inhibition. Though the interaction involving main chain atoms are similar, critical inspection of the complexes reveal significant differences in the side chain interactions in S2-P2 and S3-P3 pairs due to sequence differences in the equivalent positions of respective subsites leading to differential inhibition. Conclusion The key finding of the study is a conserved site of a water molecule near oxyanion hole of the enzyme active site, which is found in all the modeled complexes and in most crystal structures of papain family either native or complexed. Conserved water molecules at the ligand binding sites of these homologous proteins suggest the structural importance of the water, which changes the conventional definition of chemical geometry of inhibitor binding domain, its shape and complimentarity. The water mediated recognition of inhibitor to enzyme subsites (Pn...H2O....Sn of leupeptin acetyl oxygen to caricain, chymopapain and calotropinDI is an additional information and offer valuable insight to potent inhibitor design.

  2. Angioedema attacks in patients with hereditary angioedema : Local manifestations of a systemic activation process

    NARCIS (Netherlands)

    Hofman, Zonne L M; Relan, Anurag; Zeerleeder, Sacha; Drouet, Christian; Zuraw, Bruce; Hack, C. Erik

    2016-01-01

    Hereditary angioedema (HAE) caused by a deficiency of functional C1-inhibitor (C1INH) becomes clinically manifest as attacks of angioedema. C1INH is the main inhibitor of the contact system. Poor control of a local activation process of this system at the site of the attack is believed to lead to th

  3. Crystallization and Preliminary Diffraction Analysis of the CAL PDZ Domain in Complex with a Selective Peptide Inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    J Amacher; P Cushing; J Weiner; D Madden

    2011-12-31

    Cystic fibrosis (CF) is associated with loss-of-function mutations in the CF transmembrane conductance regulator (CFTR), which regulates epithelial fluid and ion homeostasis. The CFTR cytoplasmic C-terminus interacts with a number of PDZ (PSD-95/Dlg/ZO-1) proteins that modulate its intracellular trafficking and chloride-channel activity. Among these, the CFTR-associated ligand (CAL) has a negative effect on apical-membrane expression levels of the most common disease-associated mutant {Delta}F508-CFTR, making CAL a candidate target for the treatment of CF. A selective peptide inhibitor of the CAL PDZ domain (iCAL36) has recently been developed and shown to stabilize apical expression of {Delta}F508-CFTR, enhancing net chloride-channel activity, both alone and in combination with the folding corrector corr-4a. As a basis for structural studies of the CAL-iCAL36 interaction, a purification protocol has been developed that increases the oligomeric homogeneity of the protein. Here, the cocrystallization of the complex in space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 35.9, b = 47.7, c = 97.3 {angstrom}, is reported. The crystals diffracted to 1.4 {angstrom} resolution. Based on the calculated Matthews coefficient (1.96 {angstrom}{sup 3} Da{sup -1}), it appears that the asymmetric unit contains two complexes.

  4. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy.

    LENUS (Irish Health Repository)

    Wander, Seth A

    2011-04-01

    Mammalian target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation, and survival via mTOR complex 1 (mTORC1) and mTORC2. The mTOR pathway is often aberrantly activated in cancers. While hypoxia, nutrient deprivation, and DNA damage restrain mTORC1 activity, multiple genetic events constitutively activate mTOR in cancers. Here we provide a brief overview of the signaling pathways up- and downstream of mTORC1 and -2, and discuss the insights into therapeutic anticancer targets - both those that have been tried in the clinic with limited success and those currently under clinical development - that knowledge of these pathways gives us.

  5. Hepatocyte growth factor activator inhibitor-1 has a complex subcellular itinerary

    DEFF Research Database (Denmark)

    Godiksen, Sine; Selzer-Plon, Joanna; Pedersen, Esben D K;

    2008-01-01

    it is a key regulator of carcinogenesis. HAI-1 is expressed in polarized epithelial cells, which have the plasma membrane divided by tight junctions into an apical and a basolateral domain. In the present study we show that HAI-1 at steady-state is mainly located on the basolateral membrane of both Madin...... in transporting matriptase as a matriptase-HAI-1 complex from the basolateral plama membrane to the apical plasma membrane, as matriptase is known to interact with prostasin, located at the apical plasma membrane....... and then recycles between the basolateral plasma membrane and endosomes for hours until it is transcytosed to the apical plasma membrane. Minor amounts of HAI-1 present at the apical plasma membrane are proteolytically cleaved and released into the apical medium. Full-length membrane-bound HAI-1 has a half...

  6. Structure of the CCR5 Chemokine Receptor-HIV Entry Inhibitor Maraviroc Complex

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Qiuxiang; Zhu, Ya; Li, Jian; Chen, Zhuxi; Han, Gye Won; Kufareva, Irina; Li, Tingting; Ma, Limin; Fenalti, Gustavo; Li, Jing; Zhang, Wenru; Xie, Xin; Yang, Huaiyu; Jiang, Hualiang; Cherezov, Vadim; Liu, Hong; Stevens, Raymond C.; Zhao, Qiang; Wu, Beili [Scripps; (Chinese Aca. Sci.); (UCSD)

    2013-10-21

    The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom–resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor–gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.

  7. Visualizing active enzyme complexes using a photoreactive inhibitor for proximity ligation--application on γ-secretase.

    Directory of Open Access Journals (Sweden)

    Sophia Schedin-Weiss

    Full Text Available Here, we present a highly sensitive method to study protein-protein interactions and subcellular location selectively for active multicomponent enzymes. We apply the method on γ-secretase, the enzyme complex that catalyzes the cleavage of the amyloid precursor protein (APP to generate amyloid β-peptide (Aβ, the major causative agent in Alzheimer disease (AD. The novel assay is based on proximity ligation, which can be used to study protein interactions in situ with very high sensitivity. In traditional proximity ligation assay (PLA, primary antibody recognition is typically accompanied by oligonucleotide-conjugated secondary antibodies as detection probes. Here, we first performed PLA experiments using antibodies against the γ-secretase components presenilin 1 (PS1, containing the catalytic site residues, and nicastrin, suggested to be involved in substrate recognition. To selectively study the interactions of active γ-secretase, we replaced one of the primary antibodies with a photoreactive γ-secretase inhibitor containing a PEG linker and a biotin group (GTB, and used oligonucleotide-conjugated streptavidin as a probe. Interestingly, significantly fewer interactions were detected with the latter, novel, assay, which is a reasonable finding considering that a substantial portion of PS1 is inactive. In addition, the PLA signals were located more peripherally when GTB was used instead of a PS1 antibody, suggesting that γ-secretase matures distal from the perinuclear ER region. This novel technique thus enables highly sensitive protein interaction studies, determines the subcellular location of the interactions, and differentiates between active and inactive γ-secretase in intact cells. We suggest that similar PLA assays using enzyme inhibitors could be useful also for other enzyme interaction studies.

  8. High resolution crystal structure of rat long chain hydroxy acid oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1, 2, 3-thiadiazole. Implications for inhibitor specificity and drug design

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Zhi-wei; Vignaud, Caroline; Jaafar, Adil; Lévy, Bernard; Guéritte, Françoise; Guénard, Daniel; Lederer, Florence; Mathews, F. Scott (CNRS-UMR); (WU-MED)

    2012-05-24

    Long chain hydroxy acid oxidase (LCHAO) is responsible for the formation of methylguanidine, a toxic compound with elevated serum levels in patients with chronic renal failure. Its isozyme glycolate oxidase (GOX), has a role in the formation of oxalate, which can lead to pathological deposits of calcium oxalate, in particular in the disease primary hyperoxaluria. Inhibitors of these two enzymes may have therapeutic value. These enzymes are the only human members of the family of FMN-dependent L-2-hydroxy acid-oxidizing enzymes, with yeast flavocytochrome b{sub 2} (Fcb2) among its well studied members. We screened a chemical library for inhibitors, using in parallel rat LCHAO, human GOX and the Fcb2 flavodehydrogenase domain (FDH). Among the hits was an inhibitor, CCPST, with an IC{sub 50} in the micromolar range for all three enzymes. We report here the crystal structure of a complex between this compound and LCHAO at 1.3 {angstrom} resolution. In comparison with a lower resolution structure of this enzyme, binding of the inhibitor induces a conformational change in part of the TIM barrel loop 4, as well as protonation of the active site histidine. The CCPST interactions are compared with those it forms with human GOX and those formed by two other inhibitors with human GOX and spinach GOX. These compounds differ from CCPST in having the sulfur replaced with a nitrogen in the five-membered ring as well as different hydrophobic substituents. The possible reason for the {approx}100-fold difference in affinity between these two series of inhibitors is discussed. The present results indicate that specificity is an issue in the quest for therapeutic inhibitors of either LCHAO or GOX, but they may give leads for this quest.

  9. Designing inhibitors of cytochrome c/cardiolipin peroxidase complexes: mitochondria-targeted imidazole-substituted fatty acids.

    Science.gov (United States)

    Jiang, Jianfei; Bakan, Ahmet; Kapralov, Alexandr A; Silva, K Ishara; Huang, Zhentai; Amoscato, Andrew A; Peterson, James; Garapati, Venkata Krishna; Saxena, Sunil; Bayir, Hülya; Atkinson, Jeffrey; Bahar, Ivet; Kagan, Valerian E

    2014-06-01

    Mitochondria have emerged as the major regulatory platform responsible for the coordination of numerous metabolic reactions as well as cell death processes, whereby the execution of intrinsic apoptosis includes the production of reactive oxygen species fueling oxidation of cardiolipin (CL) catalyzed by cytochrome (Cyt) c. As this oxidation occurs within the peroxidase complex of Cyt c with CL, the latter represents a promising target for the discovery and design of drugs with antiapoptotic mechanisms of action. In this work, we designed and synthesized a new group of mitochondria-targeted imidazole-substituted analogs of stearic acid TPP-n-ISAs with various positions of the attached imidazole group on the fatty acid (n = 6, 8, 10, 13, and 14). By using a combination of absorption spectroscopy and EPR protocols (continuous wave electron paramagnetic resonance and electron spin echo envelope modulation) we demonstrated that TPP-n-ISAs indeed were able to potently suppress CL-induced structural rearrangements in Cyt c, paving the way to its peroxidase competence. TPP-n-ISA analogs preserved the low-spin hexa-coordinated heme-iron state in Cyt c/CL complexes whereby TPP-6-ISA displayed a significantly more effective preservation pattern than TPP-14-ISA. Elucidation of these intermolecular stabilization mechanisms of Cyt c identified TPP-6-ISA as an effective inhibitor of the peroxidase function of Cyt c/CL complexes with a significant antiapoptotic potential realized in mouse embryonic cells exposed to ionizing irradiation. These experimental findings were detailed and supported by all-atom molecular dynamics simulations. Based on the experimental data and computation predictions, we identified TPP-6-ISA as a candidate drug with optimized antiapoptotic potency.

  10. Synthesis of novel p-tert-butylcalix[4]arene Schiff bases and their complexes with C60, potential HIV-Protease inhibitors

    Science.gov (United States)

    Khadra, Khalid Abu; Mizyed, Shehadeh; Marji, Deeb; Haddad, Salim F.; Ashram, Muhammad; Foudeh, Ayat

    2015-02-01

    Some p-tert-butylcalix[4]arene Schiff base crown ethers were synthesized, characterized using 1H, 13C-NMR, DEPT 135 and Mass spectrometry. Their complexes with C60 were isolated and characterized. The inhibition effect of these complexes on HIVP was studied and found that complexes of 9 and 10 have comparable Ki values to Pepstatine which is known as HIVP inhibitor and used as a control. The synthesis of the ligands, complexes and the inhibition behavior are discussed in this article.

  11. Supply Chain Attack Framework and Attack Patterns

    Science.gov (United States)

    2013-12-01

    Malware is embedded in a replacement server motherboard (e.g., in the flash memory) in order to alter server functionality from that intended. Attack...Slashdot: Dell Ships Infected Motherboards July 21, 2010(c/o Rick Dove) Threat: An adversary with access to hardware procurement, maintenance, or upgrade...control can embed malware in a critical component server motherboard . Vulnerabilities: The control processes and mechanisms for hardware

  12. Nocturnal panic attacks

    Directory of Open Access Journals (Sweden)

    Lopes Fabiana L.

    2002-01-01

    Full Text Available The panic-respiration connection has been presented with increasing evidences in the literature. We report three panic disorder patients with nocturnal panic attacks with prominent respiratory symptoms, the overlapping of the symptoms with the sleep apnea syndrome and a change of the diurnal panic attacks, from spontaneous to situational pattern. The implication of these findings and awareness to the distinct core of the nocturnal panic attacks symptoms may help to differentiate them from sleep disorders and the search for specific treatment.

  13. Cross-resistance risk of the novel complex II inhibitors cyenopyrafen and cyflumetofen in resistant strains of the two-spotted spider mite Tetranychus urticae

    NARCIS (Netherlands)

    Khalighi, M.; Tirry, L.; Van Leeuwen, T.

    2014-01-01

    BACKGROUND: Cyflumetofen and cyenopyrafen are novel acaricides acting as complex II inhibitors. This new mode of action is extremely useful for devising efficient resistance management strategies for mite control. The authors determined the cross-resistance risk of both compounds, using a collection

  14. Transforming Graphical System Models to Graphical Attack Models

    DEFF Research Database (Denmark)

    Ivanova, Marieta Georgieva; Probst, Christian W.; Hansen, Rene Rydhof;

    2016-01-01

    Manually identifying possible attacks on an organisation is a complex undertaking; many different factors must be considered, and the resulting attack scenarios can be complex and hard to maintain as the organisation changes. System models provide a systematic representation of organisations that...

  15. Transforming graphical system models to graphical attack models

    NARCIS (Netherlands)

    Ivanova, Marieta Georgieva; Probst, Christian W.; Hansen, René Rydhof; Kammüller, Florian; Mauw, S.; Kordy, B.

    2015-01-01

    Manually identifying possible attacks on an organisation is a complex undertaking; many different factors must be considered, and the resulting attack scenarios can be complex and hard to maintain as the organisation changes. System models provide a systematic representation of organisations that he

  16. Heart Attack Payment - State

    Data.gov (United States)

    U.S. Department of Health & Human Services — Payment for heart attack patients measure – state data. This data set includes state-level data for payments associated with a 30-day episode of care for heart...

  17. Heart Attack Payment - Hospital

    Data.gov (United States)

    U.S. Department of Health & Human Services — Payment for heart attack patients measure – provider data. This data set includes provider data for payments associated with a 30-day episode of care for heart...

  18. Heart Attack Payment - National

    Data.gov (United States)

    U.S. Department of Health & Human Services — Payment for heart attack patients measure – national data. This data set includes national-level data for payments associated with a 30-day episode of care for heart...

  19. Transient Ischemic Attack

    Medline Plus

    Full Text Available ... TIA , or transient ischemic attack, is a "mini stroke" that occurs when a blood clot blocks an ... a short time. The only difference between a stroke and TIA is that with TIA the blockage ...

  20. Cooperating attackers in neural cryptography.

    Science.gov (United States)

    Shacham, Lanir N; Klein, Einat; Mislovaty, Rachel; Kanter, Ido; Kinzel, Wolfgang

    2004-06-01

    A successful attack strategy in neural cryptography is presented. The neural cryptosystem, based on synchronization of neural networks by mutual learning, has been recently shown to be secure under different attack strategies. The success of the advanced attacker presented here, called the "majority-flipping attacker," does not decay with the parameters of the model. This attacker's outstanding success is due to its using a group of attackers which cooperate throughout the synchronization process, unlike any other attack strategy known. An analytical description of this attack is also presented, and fits the results of simulations.

  1. The Crystal Structure of BRAF in Complex with an Organoruthenium Inhibitor Reveals a Mechanism for Inhibition of an Active Form of BRAF Kinase

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Peng; Streu, Craig; Qin, Jie; Bregman, Howard; Pagano, Nicholas; Meggers, Eric; Marmorstein, Ronen (Wistar); (UPENN)

    2012-06-19

    Substitution mutations in the BRAF serine/threonine kinase are found in a variety of human cancers. Such mutations occur in 70% of human malignant melanomas, and a single hyperactivating V600E mutation is found in the activation segment of the kinase domain and accounts for more than 90% of these mutations. Given this correlation, the molecular mechanism for BRAF regulation as well as oncogenic activation has attracted considerable interest, and activated forms of BRAF, such as BRAF{sup V600E}, have become attractive targets for small molecule inhibition. Here we report on the identification and subsequent optimization of a potent BRAF inhibitor, CS292, based on an organometallic kinase inhibitor scaffold. A cocrystal structure of CS292 in complex with the BRAF kinase domain reveals that CS292 binds to the ATP binding pocket of the kinase and is an ATP competitive inhibitor. The structure of the kinase-inhibitor complex also demonstrates that CS292 binds to BRAF in an active conformation and suggests a mechanism for regulation of BRAF by phosphorylation and BRAF{sup V600E} oncogene-induced activation. The structure of CS292 bound to the active form of the BRAF kinase also provides a novel scaffold for the design of BRAF{sup V600E} oncogene selective BRAF inhibitors for therapeutic application.

  2. Critical neuropsychobiological analysis of panic attack- and anticipatory anxiety-like behaviors in rodents confronted with snakes in polygonal arenas and complex labyrinths: a comparison to the elevated plus- and T-maze behavioral tests

    Directory of Open Access Journals (Sweden)

    Norberto C. Coimbra

    Full Text Available Objective: To compare prey and snake paradigms performed in complex environments to the elevated plus-maze (EPM and T-maze (ETM tests for the study of panic attack- and anticipatory anxiety-like behaviors in rodents. Methods: PubMed was reviewed in search of articles focusing on the plus maze test, EPM, and ETM, as well as on defensive behaviors displayed by threatened rodents. In addition, the authors’ research with polygonal arenas and complex labyrinth (designed by the first author for confrontation between snakes and small rodents was examined. Results: The EPM and ETM tests evoke anxiety/fear-related defensive responses that are pharmacologically validated, whereas the confrontation between rodents and snakes in polygonal arenas with or without shelters or in the complex labyrinth offers ethological conditions for studying more complex defensive behaviors and the effects of anxiolytic and panicolytic drugs. Prey vs. predator paradigms also allow discrimination between non-oriented and oriented escape behavior. Conclusions: Both EPM and ETM simple labyrinths are excellent apparatuses for the study of anxiety- and instinctive fear-related responses, respectively. The confrontation between rodents and snakes in polygonal arenas, however, offers a more ethological environment for addressing both unconditioned and conditioned fear-induced behaviors and the effects of anxiolytic and panicolytic drugs.

  3. Novel bis-(-)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property.

    Science.gov (United States)

    Zheng, Wei; Li, Juan; Qiu, Zhuibai; Xia, Zheng; Li, Wei; Yu, Lining; Chen, Hailin; Chen, Jianxing; Chen, Yan; Hu, Zhuqin; Zhou, Wei; Shao, Biyun; Cui, Yongyao; Xie, Qiong; Chen, Hongzhuan

    2012-10-01

    The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(-)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC(50) values of 9.63μM (for ZLA) and 8.64μM (for ZLB), and prevent AChE-induced amyloid-β (Aβ) aggregation with IC(50) values of 49.1μM (for ZLA) and 55.3μM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Aβ aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD.

  4. Crystallization and preliminary crystallographic analysis of 2-aminophenol 1,6-dioxygenase complexed with substrate and with an inhibitor.

    Science.gov (United States)

    Li, De-Feng; Zhang, Jia-Yue; Hou, Yanjie; Liu, Lei; Liu, Shuang-Jiang; Liu, Wei

    2012-11-01

    Dioxygen activation implemented by nonhaem Fe(II) enzymes containing the 2-His-1-carboxylate facial triad has been extensively studied in recent years. Extradiol dioxygenase is the archetypal member of this superfamily and catalyzes the oxygenolytic ring opening of catechol analogues. Here, the crystallization and preliminary X-ray analysis of 2-aminophenol 1,6-dioxygenase, an enzyme representing a minor subset of extradiol dioxygenases that catalyze the fission of 2-aminophenol rather than catecholic compounds, is reported. Crystals of the holoenzyme with FeII and of complexes with the substrate 2-aminophenol and the suicide inhibitor 4-nitrocatechol were grown using the cocrystallization method under the same conditions as used for the crystallization of the apoenzyme. The crystals belonged to space group C2 and diffracted to 2.3-2.7 Å resolution; the crystal that diffracted to the highest resolution had unit-cell parameters a=270.24, b=48.39, c=108.55 Å, β=109.57°. All X-ray data sets collected from diffraction-quality crystals were suitable for structure determination.

  5. Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim

    Energy Technology Data Exchange (ETDEWEB)

    Heaslet, Holly; Harris, Melissa; Fahnoe, Kelly; Sarver, Ronald; Putz, Henry; Chang, Jeanne; Subramanyam, Chakrapani; Barreiro, Gabriela; Miller, J. Richard; Pfizer

    2010-09-02

    Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites. Because of its importance in multiple cellular functions, DHFR has been the subject of much research targeting the enzyme with anticancer, antibacterial, and antimicrobial agents. Clinically used compounds targeting DHFR include methotrexate for the treatment of cancer and diaminopyrimidines (DAPs) such as trimethoprim (TMP) for the treatment of bacterial infections. DAP inhibitors of DHFR have been used clinically for >30 years and resistance to these agents has become widespread. Methicillin-resistant Staphylococcus aureus (MRSA), the causative agent of many serious nosocomial and community acquired infections, and other gram-positive organisms can show resistance to DAPs through mutation of the chromosomal gene or acquisition of an alternative DHFR termed 'S1 DHFR.' To develop new therapies for health threats such as MRSA, it is important to understand the molecular basis of DAP resistance. Here, we report the crystal structure of the wild-type chromosomal DHFR from S. aureus in complex with NADPH and TMP. We have also solved the structure of the exogenous, TMP resistant S1 DHFR, apo and in complex with TMP. The structural and thermodynamic data point to important molecular differences between the two enzymes that lead to dramatically reduced affinity of DAPs to S1 DHFR. These differences in enzyme binding affinity translate into reduced antibacterial activity against strains of S. aureus that express S1 DHFR.

  6. The role of complement receptors type 1 (CR1, CD35) and 2 (CR2, CD21) in promoting C3 fragment deposition and membrane attack complex formation on normal peripheral human B cells

    DEFF Research Database (Denmark)

    Nielsen, Claus Henrik; Pedersen, Morten Løbner; Marquart, Hanne Vibeke

    2002-01-01

    Normal human B lymphocytes are known to activate the alternative pathway (AP) of complement, leading to C3-fragment deposition and membrane attack complex (MAC) formation. The process is mediated via complement receptor type 2 (CR2, CD21), with complement receptor type 1 (CR1, CD35) playing...... a subsidiary role. In this study, we examine the relative contributions of CR1 and CR2 to the deposition of C3 fragments and MAC on B lymphocytes under circumstances where all complement pathways are operational. C3-fragment deposition and MAC formation were assessed on human peripheral B lymphocytes......) bearing CR1, however, markedly reduced both C3-fragment deposition and MAC formation. Our data suggest that C3-fragment deposition and MAC formation on B lymphocytes in vivo may involve both AP and classical pathway activation, with CR1 contributing significantly to the latter. On the other hand...

  7. Prophylaxis with anti-inhibitor coagulant complex improves health-related quality of life in haemophilia patients with inhibitors: results from FEIBA NF Prophylaxis Study.

    Science.gov (United States)

    Stasyshyn, O; Antunes, S; Mamonov, V; Ye, X; Epstein, J; Xiong, Y; Tangada, S

    2014-09-01

    The Pro-FEIBA study reported health-related quality of life (HRQoL) improved following 6-month of Factor Eight Inhibitor Bypassing Activity (FEIBA) prophylaxis. This study investigates whether 12-month of FEIBA prophylaxis improved HRQoL in haemophilia patients with inhibitors. Thirty-six subjects in a 1-year prospective, randomized, open-label, parallel-design study were randomized to prophylaxis (85 ± 15 U kg(-1) every other day) or on-demand treatment. HRQoL was assessed at screening, 6 and 12-month termination using the EQ-5D, Haem-A-QoL, Haemo-QoL and a general pain visual analog scale (VAS). To evaluate changes, paired t-tests and criteria for minimally important differences were applied. Repeated measures regression tested the association between annualized bleeding rate (ABR) and physical HRQoL. At 6 and 12 months, prophylaxis subjects reported clinically meaningful improvement in EQ-5D index (mean improvement, 0.10 and 0.08, respectively) and both clinically meaningful and statistically significant improvements in EQ-VAS scores (16.9 and 15.7, respectively; P improvement, 20.3 and 23.2, respectively; both P improvements in Haem-A-QoL Total Score and in four domains: Physical Health, Feeling, View, and Work and School (all P improved HRQoL in inhibitor patients. Subjects with lower ABR reported better physical HRQoL.

  8. Crystallisation and preliminary X-ray diffraction analysis of the protease from Southampton norovirus complexed with a Michael-acceptor inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Coates, Leighton [ORNL; Cooper, Jon [University of Southampton, England; Hussey, Robert [University of Southampton, England

    2008-01-01

    Noroviruses are the predominant cause of human epidemic nonbacterial gastroenteritis. Viral replication requires a cysteine protease that cleaves a 200 kDa viral polyprotein into its constituent functional parts. Here, the crystallization of the recombinant protease from the Southampton norovirus is described. While the native crystals were found to diffract only to medium resolution (2.9 {angstrom}), cocrystals of an inhibitor complex diffracted X-rays to 1.7 {angstrom} resolution. The polypeptide inhibitor (Ac-EFQLQ-propenyl ethyl ester) possesses an amino-acid sequence designed to match the substrate specificity of the enzyme, but was synthesized with a reactive Michael acceptor group at the C-terminal end.

  9. Metal Complexes of 1,3,4-Thiadiazole-2,5-Disulfonamide are Strong Dual Carbonic Anhydrase Inhibitors, although the Ligand Possesses very Weak such Properties

    Science.gov (United States)

    Supuran, Claudiu T.

    1995-01-01

    Coordination compounds of Co(II), Ni(II), Cu(II), Zn(II), and Cd(II) with 1,3,4-thiadiazole-2,5-disulfonamide as ligand were synthesized and characterized by IR and UV spectroscopy, conductimetry and thermogravimetry. The parent ligand is a very weak carbonic anhydrase (CA) inhibitor, although it constituted the lead for developing important classes of diuretics. The complex derivatives behave as much stronger CA inhibitors, with IC50 values around 10−8M against isozyme CA II, and 10−7 M against isozyme CAI. PMID:18472784

  10. Metal Complexes of 1,3,4-Thiadiazole-2,5-Disulfonamide are Strong Dual Carbonic Anhydrase Inhibitors, although the Ligand Possesses very Weak such Properties.

    Science.gov (United States)

    Supuran, C T

    1995-01-01

    Coordination compounds of Co(II), Ni(II), Cu(II), Zn(II), and Cd(II) with 1,3,4-thiadiazole-2,5-disulfonamide as ligand were synthesized and characterized by IR and UV spectroscopy, conductimetry and thermogravimetry. The parent ligand is a very weak carbonic anhydrase (CA) inhibitor, although it constituted the lead for developing important classes of diuretics. The complex derivatives behave as much stronger CA inhibitors, with IC(50) values around 10(-8)M against isozyme CA II, and 10(-7) M against isozyme CAI.

  11. Computational analysis of BACE1-ligand complex crystal structures and linear discriminant analysis for identification of BACE1 inhibitors with anti P-glycoprotein binding property.

    Science.gov (United States)

    Manoharan, Prabu; Chennoju, Kiranmai; Ghoshal, Nanda

    2017-01-12

    More than 100 years of research on Alzheimer's disease didn't yield a potential cure for this dreadful disease. Poor Blood Brain Barrier (BBB) permeability and P-glycoprotein binding of BACE1 inhibitors are the major causes for the failure of these molecules during clinical trials. The design of BACE1 inhibitors with a balance of sufficient affinity to the binding site and little or no interaction with P-glycoproteins is indispensable. Identification and understanding of protein-ligand interactions are essential for ligand optimization process. Structure-based drug design (SBDD) efforts led to a steady accumulation of BACE1-ligand crystal complexes in the PDB. This study focuses on analyses of 153 BACE1-ligand complexes for the direct contacts (hydrogen bonds and weak interactions) observed between protein and ligand and indirect contacts (water-mediated hydrogen bonds), observed in BACE1-ligand complex crystal structures. Intraligand hydrogen bonds were analyzed, with focus on ligand P-glycoprotein efflux. The interactions are dissected specific to subsites in the active site and discussed. The observed protein-ligand and intraligand interactions were used to develop the linear discriminant model for the identification of BACE1 inhibitors with less or no P-glycoprotein binding property. Excellent statistical results and model's ability to correctly predict a new data-set with an accuracy of 92% is achieved. The results are retrospectively analyzed to give input for the design of potential BACE1 inhibitors.

  12. High Order Differential Attack and Trace Attack to Block Ciphers

    Institute of Scientific and Technical Information of China (English)

    HU Yupu; CHEN Kai; Xiao Guozhen

    2001-01-01

    In this paper, we prove a high or-der differential property of power function, then giverespectively high order differential attack and traceattack to block ciphers. These attacks depend onlyon block cipher's algebraic shape on GF(2n) and haveno relation with its designing structure. The condi-tions are given for both effective attacks and strengthagainst attacks.

  13. Quantitative Verification and Synthesis of Attack-Defence Scenarios

    DEFF Research Database (Denmark)

    Aslanyan, Zaruhi; Nielson, Flemming; Parker, David

    2016-01-01

    which guarantee or optimise some quantitative property, such as the probability of a successful attack, the expected cost incurred, or some multi-objective trade-off between the two. We implement our approach, building upon the PRISM-games model checker, and apply it to a case study of an RFID goods...... analysis of quantitative properties of complex attack-defence scenarios, using an extension of attack-defence trees which models temporal ordering of actions and allows explicit dependencies in the strategies adopted by attackers and defenders. We adopt a game-theoretic approach, translating attack......-defence trees to two-player stochastic games, and then employ probabilistic model checking techniques to formally analyse these models. This provides a means to both verify formally specified security properties of the attack-defence scenarios and, dually, to synthesise strategies for attackers or defenders...

  14. XQuery Injection Attack and Countermeasures

    Institute of Scientific and Technical Information of China (English)

    谭玉森

    2014-01-01

    As a database that allows data to be stored in XML format, XML database suffers from some similar attacks as traditional relational database does. These attacks include injection attack by XQuey function in application software. These include BaseX, eXist and MarkLogic. In order to defeat these attacks, countermeasures are proposed.

  15. Seven Deadliest Wireless Technologies Attacks

    CERN Document Server

    Haines, Brad

    2010-01-01

    How can an information security professional keep up with all of the hacks, attacks, and exploits? One way to find out what the worst of the worst are is to read the seven books in our Seven Deadliest Attacks Series. Not only do we let you in on the anatomy of these attacks but we also tell you how to get rid of them and how to defend against them in the future. Countermeasures are detailed so that you can fight against similar attacks as they evolve. Attacks featured in this book include:Bluetooth AttacksCredit Card, Access Card, and Passport AttacksBad Encryption

  16. Hsp90 inhibition accelerates cell lysis. Anti-Hsp90 ribozyme reveals a complex mechanism of Hsp90 inhibitors involving both superoxide- and Hsp90-dependent events.

    Science.gov (United States)

    Sreedhar, Amere Subbarao; Mihály, Katalin; Pató, Bálint; Schnaider, Tamás; Steták, Attila; Kis-Petik, Katalin; Fidy, Judit; Simonics, Tibor; Maraz, Anna; Csermely, Péter

    2003-09-12

    The 90 kDa heat shock protein, Hsp90, is an abundant molecular chaperone participating in the cytoprotection of eukaryotic cells. Here we analyzed the involvement of Hsp90 in the maintenance of cellular integrity using partial cell lysis as a measure. Inhibition of Hsp90 by geldanamycin, radicicol, cisplatin, and novobiocin induced a significant acceleration of detergent- and hypotonic shock-induced cell lysis. The concentration and time dependence of cell lysis acceleration was in agreement with the Hsp90 inhibition characteristics of the N-terminal inhibitors, geldanamycin and radicicol. Glutathione and other reducing agents partially blocked geldanamycin-induced acceleration of cell lysis but were largely ineffective with other inhibitors. Indeed, geldanamycin treatment led to superoxide production and a change in membrane fluidity. When Hsp90 content was diminished using anti-Hsp90 hammerhead ribozymes, an accelerated cell lysis was also observed. Hsp90 inhibition-induced cell lysis was more pronounced in eukaryotic (yeast, mouse red blood, and human T-lymphoma) cells than in bacteria. Our results indicate that besides the geldanamycin-induced superoxide production, and a consequent increase in cell lysis, inhibition or lack of Hsp90 alone can also compromise cellular integrity. Moreover, cell lysis after hypoxia and complement attack was also enhanced by any type of Hsp90 inhibition used, which shows that the maintenance of cellular integrity by Hsp90 is important in physiologically relevant lytic conditions of tumor cells.

  17. Differences in complement activation between complement-resistant and complement-sensitive Moraxella (Branhamella) catarrhalis strains occur at the level of membrane attack complex formation.

    OpenAIRE

    Verduin, C.M.; Jansze, M.; Hol, C; Mollnes, T E; Verhoef, J; Van Dijk, H.

    1994-01-01

    The mechanism of resistance to human complement-mediated killing in Moraxella catarrhalis was studied by comparing different complement-sensitive and complement-resistant M. catarrhalis strains in a functional bystander hemolysis assay and an enzyme-linked immunosorbent assay (ELISA) for soluble terminal complement complexes. Complement-resistant stains appeared to activate complement to the same extent as, or even slightly better than, complement-sensitive strains. This indicates that comple...

  18. Palladium and platinum complexes of tellurium-containing imidodiphosphinate ligands: nucleophilic attack of Li[(P(i)Pr2)(TeP(i)Pr2)N] on coordinated 1,5-cyclooctadiene.

    Science.gov (United States)

    Robertson, Stuart D; Ritch, Jamie S; Chivers, Tristram

    2009-10-28

    Homoleptic group 10 complexes of ditellurido PNP (PNP = imidodiphosphinate), heterodichalcogenido PNP and monotellurido PNP ligands, M[(TeP(i)Pr2)2N]2 (1: M = Pd; 2: M = Pt), M[(EP(i)Pr2)(TeP(i)Pr2)N]2 (3: M = Pd, E = Se; 4: M = Pt, E = Se; 5: M = Pd, E = S; 6: M = Pt, E = S) and M[(P(i)Pr2)(TeP(i)Pr2)N]2 (7: M = Pd; 8: M = Pt), respectively, were prepared by metathesis between alkali-metal derivatives of the appropriate ligand and MCl2(COD) in THF. Complexes 1-8 were characterised in solution by multinuclear (31P, 77Se, 125Te and 195Pt) NMR spectroscopy and, in the case of 1, 2, trans-7, cis-7 and trans-8, in the solid state by X-ray crystallography. The square-planar complexes 3-6 are formed as a mixture of cis- and trans-isomers on the basis of NMR data. The cis and trans isomers of 7 were separated by crystallisation from different solvents. In addition to trans-8, the reaction of Li[(P(i)Pr2)(TeP(i)Pr2)N] with MCl2(COD) produced the heteroleptic complex Pt[(P(i)Pr2)(TeP(i)Pr2)N][sigma:eta2-C8H12(P(i)Pr2NP(i)Pr2Te)] (9) resulting from nucleophilic attack on coordinated 1,5-cyclooctadiene. Complex 9 was identified by multinuclear (13C, 31P, 125Te and 195Pt) NMR spectroscopy, which revealed a mixture of geometric isomers, and by X-ray crystallography.

  19. A macrocyclic HCV NS3/4A protease inhibitor interacts with protease and helicase residues in the complex with its full-length target

    Science.gov (United States)

    Schiering, Nikolaus; D’Arcy, Allan; Villard, Frederic; Simić, Oliver; Kamke, Marion; Monnet, Gaby; Hassiepen, Ulrich; Svergun, Dmitri I.; Pulfer, Ruth; Eder, Jörg; Raman, Prakash; Bodendorf, Ursula

    2011-01-01

    Hepatitis C virus (HCV) infection is a global health burden with over 170 million people infected worldwide. In a significant portion of patients chronic hepatitis C infection leads to serious liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. The HCV NS3 protein is essential for viral polyprotein processing and RNA replication and hence viral replication. It is composed of an N-terminal serine protease domain and a C-terminal helicase/NTPase domain. For full activity, the protease requires the NS4A protein as a cofactor. HCV NS3/4A protease is a prime target for developing direct-acting antiviral agents. First-generation NS3/4A protease inhibitors have recently been introduced into clinical practice, markedly changing HCV treatment options. To date, crystal structures of HCV NS3/4A protease inhibitors have only been reported in complex with the protease domain alone. Here, we present a unique structure of an inhibitor bound to the full-length, bifunctional protease-helicase NS3/4A and show that parts of the P4 capping and P2 moieties of the inhibitor interact with both protease and helicase residues. The structure sheds light on inhibitor binding to the more physiologically relevant form of the enzyme and supports exploring inhibitor-helicase interactions in the design of the next generation of HCV NS3/4A protease inhibitors. In addition, small angle X-ray scattering confirmed the observed protease-helicase domain assembly in solution. PMID:22160684

  20. A macrocyclic HCV NS3/4A protease inhibitor interacts with protease and helicase residues in the complex with its full-length target.

    Science.gov (United States)

    Schiering, Nikolaus; D'Arcy, Allan; Villard, Frederic; Simic, Oliver; Kamke, Marion; Monnet, Gaby; Hassiepen, Ulrich; Svergun, Dmitri I; Pulfer, Ruth; Eder, Jörg; Raman, Prakash; Bodendorf, Ursula

    2011-12-27

    Hepatitis C virus (HCV) infection is a global health burden with over 170 million people infected worldwide. In a significant portion of patients chronic hepatitis C infection leads to serious liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. The HCV NS3 protein is essential for viral polyprotein processing and RNA replication and hence viral replication. It is composed of an N-terminal serine protease domain and a C-terminal helicase/NTPase domain. For full activity, the protease requires the NS4A protein as a cofactor. HCV NS3/4A protease is a prime target for developing direct-acting antiviral agents. First-generation NS3/4A protease inhibitors have recently been introduced into clinical practice, markedly changing HCV treatment options. To date, crystal structures of HCV NS3/4A protease inhibitors have only been reported in complex with the protease domain alone. Here, we present a unique structure of an inhibitor bound to the full-length, bifunctional protease-helicase NS3/4A and show that parts of the P4 capping and P2 moieties of the inhibitor interact with both protease and helicase residues. The structure sheds light on inhibitor binding to the more physiologically relevant form of the enzyme and supports exploring inhibitor-helicase interactions in the design of the next generation of HCV NS3/4A protease inhibitors. In addition, small angle X-ray scattering confirmed the observed protease-helicase domain assembly in solution.

  1. The political attack ad

    Directory of Open Access Journals (Sweden)

    Palma Peña-Jiménez, Ph.D.

    2011-01-01

    Full Text Available During election campaigns the political spot has a clear objective: to win votes. This message is communicated to the electorate through television and Internet, and usually presents a negative approach, which includes a direct critical message against the opponent, rather than an exposition of proposals. This article is focused on the analysis of the campaign attack video ad purposely created to encourage the disapproval of the political opponent among voters. These ads focus on discrediting the opponent, many times, through the transmission of ad hominem messages, instead of disseminating the potential of the political party and the virtues and manifesto of its candidate. The article reviews the development of the attack ad since its first appearance, which in Spain dates back to 1996, when the famous Doberman ad was broadcast, and examines the most memorable campaign attack ads.

  2. Hsp90 C-terminal inhibitors exhibit antimigratory activity by disrupting the Hsp90α/Aha1 complex in PC3-MM2 cells.

    Science.gov (United States)

    Ghosh, Suman; Shinogle, Heather E; Garg, Gaurav; Vielhauer, George A; Holzbeierlein, Jeffrey M; Dobrowsky, Rick T; Blagg, Brian S J

    2015-02-20

    Human Hsp90 isoforms are molecular chaperones that are often up-regulated in malignances and represent a primary target for Hsp90 inhibitors undergoing clinical evaluation. Hsp90α is a stress-inducible isoform of Hsp90 that plays a significant role in apoptosis and metastasis. Though Hsp90α is secreted into the extracellular space under metastatic conditions, its role in cancer biology is poorly understood. We report that Hsp90α associates with the Aha1 co-chaperone and found this complex to localize in secretory vesicles and at the leading edge of migrating cells. Knockdown of Hsp90α resulted in a defect in cell migration. The functional role of Hsp90α/Aha1 was studied by treating the cells with various novobiocin-based Hsp90 C-terminal inhibitors. These inhibitors disrupted the Hsp90α/Aha1 complex, caused a cytoplasmic redistribution of Hsp90α and Aha1, and decreased cell migration. Structure-function studies determined that disruption of Hsp90α/Aha1 association and inhibition of cell migration correlated with the presence of a benzamide side chain, since an acetamide substituted analog was less effective. Our results show that disruption of Hsp90α/Aha1 interactions with novobiocin-based Hsp90 C-terminal inhibitors may limit the metastatic potential of tumors.

  3. A development of chimeric VEGFR2 TK inhibitor based on two ligand conformers from PDB: 1Y6A complex--medicinal chemistry consequences of a TKs analysis.

    Science.gov (United States)

    Lintnerová, Lucia; García-Caballero, Melissa; Gregáň, Fridrich; Melicherčík, Milan; Quesada, Ana R; Dobiaš, Juraj; Lác, Ján; Sališová, Marta; Boháč, Andrej

    2014-01-24

    VEGFR2 is an important mediator of angiogenesis and influences fate of some cancer stem cells. Here we analysed all 34 structures of VEGFR2 TK available from PDB database. From them a complex PDB: 1Y6A has an exceptional AAZ ligand bound to TK in form of two conformers (U- and S-shaped). This observation inspired us to develop three chimeric bispyridyl VEGFR2 inhibitors by combining structural features of both AAZ conformers and/or their relative ligand AAX (PDB: 1Y6B). Our most interesting inhibitor 22SYM has an enzymatic VEGFR2 TK activity (IC50: 15.1 nM) comparable or better to the active compounds from clinical drugs Nexavar and Sutent. 22SYM inhibits growth, migration and tube formation of endothelial cells (EC) and selectively induces EC apoptosis. 22SYM also inhibits in vivo angiogenesis in Zebrafish embryo assay. Additionally to the above results, we proved here that tyrosine kinases in an inactive form possessing Type I inhibitors can adopt both a closed or an opened conformation of kinase A-loop independently on their DFG-out arrangement. We proposed here that an activity of certain Type I inhibitors (e.g. 22SYM-like) in complex with DFG-out TK can be negatively influenced by collisions with a dynamically moving TK A-loop.

  4. The kinase inhibitor SFV785 dislocates dengue virus envelope protein from the replication complex and blocks virus assembly.

    Directory of Open Access Journals (Sweden)

    Azlinda Anwar

    Full Text Available Dengue virus (DENV is the etiologic agent for dengue fever, for which there is no approved vaccine or specific anti-viral drug. As a remedy for this, we explored the use of compounds that interfere with the action of required host factors and describe here the characterization of a kinase inhibitor (SFV785, which has selective effects on NTRK1 and MAPKAPK5 kinase activity, and anti-viral activity on Hepatitis C, DENV and yellow fever viruses. SFV785 inhibited DENV propagation without inhibiting DENV RNA synthesis or translation. The compound did not cause any changes in the cellular distribution of non-structural 3, a protein critical for DENV RNA synthesis, but altered the distribution of the structural envelope protein from a reticulate network to enlarged discrete vesicles, which altered the co-localization with the DENV replication complex. Ultrastructural electron microscopy analyses of DENV-infected SFV785-treated cells showed the presence of viral particles that were distinctly different from viable enveloped virions within enlarged ER cisternae. These viral particles were devoid of the dense nucleocapsid. The secretion of the viral particles was not inhibited by SFV785, however a reduction in the amount of secreted infectious virions, DENV RNA and capsid were observed. Collectively, these observations suggest that SFV785 inhibited the recruitment and assembly of the nucleocapsid in specific ER compartments during the DENV assembly process and hence the production of infectious DENV. SFV785 and derivative compounds could be useful biochemical probes to explore the DENV lifecycle and could also represent a new class of anti-virals.

  5. New trends in Internet attacks: Clickjacking in detail

    OpenAIRE

    Thoresen, Torgeir Dahlqvist

    2009-01-01

    While the complexity of web applications and their functionality continually increase, so do the number of opportunities for an attacker to launch successful attacks against a web application's users. In this thesis we investigate and describe clickjacking in great detail. To our knowledge, this work represent the first systematic scientific approach to assess clickjacking that also consider the attack's social consequences for users' security through an experiment and survey. We address the...

  6. Shark attack in Natal.

    Science.gov (United States)

    White, J A

    1975-02-01

    The injuries in 5 cases of shark attack in Natal during 1973-74 are reviewed. Experience in shark attacks in South Africa during this period is discussed (1965-73), and the value of protecting heavily utilized beaches in Natal with nets is assessed. The surgical applications of elasmobranch research at the Oceanographic Research Institute (Durban) and at the Headquarters of the Natal Anti-Shark Measures Board (Umhlanga Rocks) are described. Modern trends in the training of surf life-guards, the provision of basic equipment for primary resuscitation of casualties on the beaches, and the policy of general and local care of these patients in Natal are discussed.

  7. Silver(I) complexes of 2,4-dihydroxybenzaldehyde-amino acid Schiff bases-Novel noncompetitive α-glucosidase inhibitors.

    Science.gov (United States)

    Zheng, Jingwei; Ma, Lin

    2015-01-01

    A series of silver(I) complexes of 2,4-dihydroxybenzaldehyde-amino acid Schiff bases were designed and tested for α-glucosidase inhibition. Our results indicate that all the silver complexes (4a-18a) possessed strong inhibitory activity at μmolL(-1) level, especially glutamine (12a) and histidine (18a) Schiff base silver(I) complexes exhibited an IC50 value of less than 0.01μmolL(-1). This series of compounds exhibited noncompetitive inhibition characteristics in kinetic studies. In addition, we investigated the mechanism of inhibition and the structure-activity relationships of the amino acid Schiff base silver complexes. Our results reveal that Schiff base silver complexes may be explored for their therapeutic potential as alternatives of α-glucosidase inhibitors.

  8. Distortion of the catalytic domain of tissue-type plasminogen activator by plasminogen activator inhibitor-1 coincides with the formation of stable serpin-proteinase complexes.

    Science.gov (United States)

    Perron, Michel J; Blouse, Grant E; Shore, Joseph D

    2003-11-28

    Plasminogen activator inhibitor-1 (PAI-1) is a typical member of the serpin family that kinetically traps its target proteinase as a covalent complex by distortion of the proteinase domain. Incorporation of the fluorescently silent 4-fluorotryptophan analog into PAI-1 permitted us to observe changes in the intrinsic tryptophan fluorescence of two-chain tissue-type plasminogen activator (tPA) and the proteinase domain of tPA during the inhibition reaction. We demonstrated three distinct conformational changes of the proteinase that occur during complex formation and distortion. A conformational change occurred during the initial formation of the non-covalent Michaelis complex followed by a large conformational change associated with the distortion of the proteinase catalytic domain that occurs concurrently with the formation of stable proteinase-inhibitor complexes. Following distortion, a very slow structural change occurs that may be involved in the stabilization or regulation of the trapped complex. Furthermore, by comparing the inhibition rates of two-chain tPA and the proteinase domain of tPA by PAI-1, we demonstrate that the accessory domains of tPA play a prominent role in the initial formation of the non-covalent Michaelis complex.

  9. Efficient Complex Surfactants from the Type of Fatty Acids as Corrosion Inhibitors for Mild Steel C1018 in CO{sub 2}-Environments

    Energy Technology Data Exchange (ETDEWEB)

    Abbasov, Vagif M.; Abd Ellatee, Hany M.; Aliyeva, Leylufer I.; Ismayilov, Ismayil T.; Qasimov, Elmar E.; Narmin, Mamedova M. [National Academy of Sciences of Azerbaijan, Baku (Azerbaijan)

    2013-02-15

    The efficiency of three complex surfactants based on sunflower oil and nitrogen containing compounds as corrosion inhibitors for mild steel in CO{sub 2}-saturated 1% NaCl solution, has been determined by weight loss and LPR corrosion rate measurements. These compounds inhibit corrosion even at very low concentrations. The inhibition process was attributed to the formation of an adsorbed film on the metal surface that protects the metal against corrosive media. The inhibition efficiency increases with increasing the concentration of the studied inhibitors. Maximum inhibition efficiency of the surfactants is observed at concentrations around its critical micellar concentration (CMC). Adsorption of complex surfactants on the mild steel surface is in agreement with the Langmuir adsorption isotherm model, and the calculated Gibbs free energy values confirm the chemical nature of the adsorption. Energy dispersive X-ray fluorescence microscopy (EDRF) observations of the electrode surface confirmed the existence of such an adsorbed film.

  10. Distinguishing and Second-Preimage Attacks on CBC-Like MACs

    Science.gov (United States)

    Jia, Keting; Wang, Xiaoyun; Yuan, Zheng; Xu, Guangwu

    This paper first presents a new distinguishing attack on the CBC-MAC structure based on block ciphers in cipher block chaining (CBC) mode. This attack detects a CBC-like MAC from random functions. The second result of this paper is a second-preimage attack on the CBC-MAC, which is an extension of the attack of Brincat and Mitchell. The attack also covers MT-MAC, PMAC and MACs with three-key enciphered CBC mode. Instead of exhaustive search, both types of attacks are of birthday attack complexity.

  11. Crystal structures of the fungal pathogen Aspergillus fumigatus protein farnesyltransferase complexed with substrates and inhibitors reveal features for antifungal drug design

    OpenAIRE

    Mabanglo, Mark F.; Hast, Michael A.; Lubock, Nathan B; Hellinga, Homme W.; Beese, Lorena S.

    2014-01-01

    Species of the fungal genus Aspergillus are significant human and agricultural pathogens that are often refractory to existing antifungal treatments. Protein farnesyltransferase (FTase), a critical enzyme in eukaryotes, is an attractive potential target for antifungal drug discovery. We report high-resolution structures of A. fumigatus FTase (AfFTase) in complex with substrates and inhibitors. Comparison of structures with farnesyldiphosphate (FPP) bound in the absence or presence of peptide ...

  12. Improved Impossible Differential Attacks on Large-Block Rijndael

    DEFF Research Database (Denmark)

    Wang, Qingju; Gu, Dawu; Rijmen, Vincent;

    2012-01-01

    . The improvement can lead to 10-round attack on Rijndael-256 as well. With 2198.1 chosen plaintexts, an attack is demonstrated on 9-round Rijndael-224 with 2 195.2 encryptions and 2140.4 bytes memory. Increasing the data complexity to 2216 plaintexts, the time complexity can be reduced to 2130 encryptions...... and the memory requirements to 2 93.6 bytes. For 9-round Rijndael-256, we provide an attack requiring 2229.3 chosen plaintexts, 2194 encryptions, and 2 139.6 bytes memory. Alternatively, with 2245.3 plaintexts, an attack with a reduced time of 2127.1 encryptions and a memory complexity of 290.9 bytes can...... be mounted. With 2244.2 chosen plaintexts, we can attack 10-round Rijndael-256 with 2253.9 encryptions and 2186.8 bytes of memory....

  13. Synergistic Effects between mTOR Complex 1/2 and Glycolysis Inhibitors in Non-Small-Cell Lung Carcinoma Cells.

    Directory of Open Access Journals (Sweden)

    Suhua Jiang

    Full Text Available Cancer metabolism has greatly interested researchers. Mammalian target of rapamycin (mTOR is dysregulated in a variety of cancers and considered to be an appealing therapeutic target. It has been proven that growth factor signal, mediated by mTOR complex 1 (mTORC1, drives cancer metabolism by regulating key enzymes in metabolic pathways. However, the role of mTORC2 in cancer metabolism has not been thoroughly investigated. In this study, by employing automated spectrophotometry, we found the level of glucose uptake was decreased in non-small-cell lung carcinoma (NSCLC A549, PC-9 and SK-MES-1 cells treated with rapamycin or siRNA against Raptor, indicating that the inhibition of mTORC1 attenuated glycolytic metabolism in NSCLC cells. Moreover, the inhibition of AKT reduced glucose uptake in the cells as well, suggesting the involvement of AKT pathway in mTORC1 mediated glycolytic metabolism. Furthermore, our results showed a significant decrease in glucose uptake in rictor down-regulated NSCLC cells, implying a critical role of mTORC2 in NSCLC cell glycolysis. In addition, the experiments for MTT, ATP, and clonogenic assays demonstrated a reduction in cell proliferation, cell viability, and colony forming ability in mTOR inhibiting NSCLC cells. Interestingly, the combined application of mTORC1/2 inhibitors and glycolysis inhibitor not only suppressed the cell proliferation and colony formation, but also induced cell apoptosis, and such an effect of the combined application was stronger than that caused by mTORC1/2 inhibitors alone. In conclusion, this study reports a novel effect of mTORC2 on NSCLC cell metabolism, and reveals the synergistic effects between mTOR complex 1/2 and glycolysis inhibitors, suggesting that the combined application of mTORC1/2 and glycolysis inhibitors may be a new promising approach to treat NSCLC.

  14. Synergistic Effects between mTOR Complex 1/2 and Glycolysis Inhibitors in Non-Small-Cell Lung Carcinoma Cells.

    Science.gov (United States)

    Jiang, Suhua; Zou, Zhengzhi; Nie, Peipei; Wen, Ruiling; Xiao, Yingying; Tang, Jun

    2015-01-01

    Cancer metabolism has greatly interested researchers. Mammalian target of rapamycin (mTOR) is dysregulated in a variety of cancers and considered to be an appealing therapeutic target. It has been proven that growth factor signal, mediated by mTOR complex 1 (mTORC1), drives cancer metabolism by regulating key enzymes in metabolic pathways. However, the role of mTORC2 in cancer metabolism has not been thoroughly investigated. In this study, by employing automated spectrophotometry, we found the level of glucose uptake was decreased in non-small-cell lung carcinoma (NSCLC) A549, PC-9 and SK-MES-1 cells treated with rapamycin or siRNA against Raptor, indicating that the inhibition of mTORC1 attenuated glycolytic metabolism in NSCLC cells. Moreover, the inhibition of AKT reduced glucose uptake in the cells as well, suggesting the involvement of AKT pathway in mTORC1 mediated glycolytic metabolism. Furthermore, our results showed a significant decrease in glucose uptake in rictor down-regulated NSCLC cells, implying a critical role of mTORC2 in NSCLC cell glycolysis. In addition, the experiments for MTT, ATP, and clonogenic assays demonstrated a reduction in cell proliferation, cell viability, and colony forming ability in mTOR inhibiting NSCLC cells. Interestingly, the combined application of mTORC1/2 inhibitors and glycolysis inhibitor not only suppressed the cell proliferation and colony formation, but also induced cell apoptosis, and such an effect of the combined application was stronger than that caused by mTORC1/2 inhibitors alone. In conclusion, this study reports a novel effect of mTORC2 on NSCLC cell metabolism, and reveals the synergistic effects between mTOR complex 1/2 and glycolysis inhibitors, suggesting that the combined application of mTORC1/2 and glycolysis inhibitors may be a new promising approach to treat NSCLC.

  15. Bluetooth security attacks comparative analysis, attacks, and countermeasures

    CERN Document Server

    Haataja, Keijo; Pasanen, Sanna; Toivanen, Pekka

    2013-01-01

    This overview of Bluetooth security examines network vulnerabilities and offers a comparative analysis of recent security attacks. It also examines related countermeasures and proposes a novel attack that works against all existing Bluetooth versions.

  16. The LOCAL attack: Cryptanalysis of the authenticated encryption scheme ALE

    DEFF Research Database (Denmark)

    Khovratovich, Dmitry; Rechberger, Christian

    2014-01-01

    We show how to produce a forged (ciphertext, tag) pair for the scheme ALE with data and time complexity of 2102 ALE encryptions of short messages and the same number of authentication attempts. We use a differential attack based on a local collision, which exploits the availability of extracted...... state bytes to the adversary. Our approach allows for a time-data complexity tradeoff, with an extreme case of a forgery produced after 2119 attempts and based on a single authenticated message. Our attack is further turned into a state recovery and a universal forgery attack with a time complexity...

  17. Enzyme inhibitor studies reveal complex control of methyl-D-erythritol 4-phosphate (MEP pathway enzyme expression in Catharanthus roseus.

    Directory of Open Access Journals (Sweden)

    Mei Han

    Full Text Available In Catharanthus roseus, the monoterpene moiety exerts a strong flux control for monoterpene indole alkaloid (MIA formation. Monoterpene synthesis depends on the methyl-D-erythritol 4-phosphate (MEP pathway. Here, we have explored the regulation of this pathway in response to developmental and environmental cues and in response to specific enzyme inhibitors. For the MEP pathway entry enzyme 1-deoxy-D-xylulose 5-phosphate synthase (DXS, a new (type I DXS isoform, CrDXS1, has been cloned, which, in contrast to previous reports on type II CrDXS, was not transcriptionally activated by the transcription factor ORCA3. Regulation of the MEP pathway in response to metabolic perturbations has been explored using the enzyme inhibitors clomazone (precursor of 5-ketochlomazone, inhibitor of DXS and fosmidomycin (inhibitor of deoxyxylulose 5-phosphate reductoisomerase (DXR, respectively. Young leaves of non-flowering plants were exposed to both inhibitors, adopting a non-invasive in vivo technique. Transcripts and proteins of DXS (3 isoforms, DXR, and hydroxymethylbutenyl diphosphate synthase (HDS were monitored, and protein stability was followed in isolated chloroplasts. Transcripts for DXS1 were repressed by both inhibitors, whereas transcripts for DXS2A&B, DXR and HDS increased after clomazone treatment but were barely affected by fosmidomycin treatment. DXS protein accumulated in response to both inhibitors, whereas DXR and HDS proteins were less affected. Fosmidomycin-induced accumulation of DXS protein indicated substantial posttranscriptional regulation. Furthermore, fosmidomycin effectively protected DXR against degradation in planta and in isolated chloroplasts. Thus our results suggest that DXR protein stability may be affected by substrate binding. In summary, the present results provide novel insight into the regulation of DXS expression in C. roseus in response to MEP-pathway perturbation.

  18. Enzyme inhibitor studies reveal complex control of methyl-D-erythritol 4-phosphate (MEP) pathway enzyme expression in Catharanthus roseus.

    Science.gov (United States)

    Han, Mei; Heppel, Simon C; Su, Tao; Bogs, Jochen; Zu, Yuangang; An, Zhigang; Rausch, Thomas

    2013-01-01

    In Catharanthus roseus, the monoterpene moiety exerts a strong flux control for monoterpene indole alkaloid (MIA) formation. Monoterpene synthesis depends on the methyl-D-erythritol 4-phosphate (MEP) pathway. Here, we have explored the regulation of this pathway in response to developmental and environmental cues and in response to specific enzyme inhibitors. For the MEP pathway entry enzyme 1-deoxy-D-xylulose 5-phosphate synthase (DXS), a new (type I) DXS isoform, CrDXS1, has been cloned, which, in contrast to previous reports on type II CrDXS, was not transcriptionally activated by the transcription factor ORCA3. Regulation of the MEP pathway in response to metabolic perturbations has been explored using the enzyme inhibitors clomazone (precursor of 5-ketochlomazone, inhibitor of DXS) and fosmidomycin (inhibitor of deoxyxylulose 5-phosphate reductoisomerase (DXR)), respectively. Young leaves of non-flowering plants were exposed to both inhibitors, adopting a non-invasive in vivo technique. Transcripts and proteins of DXS (3 isoforms), DXR, and hydroxymethylbutenyl diphosphate synthase (HDS) were monitored, and protein stability was followed in isolated chloroplasts. Transcripts for DXS1 were repressed by both inhibitors, whereas transcripts for DXS2A&B, DXR and HDS increased after clomazone treatment but were barely affected by fosmidomycin treatment. DXS protein accumulated in response to both inhibitors, whereas DXR and HDS proteins were less affected. Fosmidomycin-induced accumulation of DXS protein indicated substantial posttranscriptional regulation. Furthermore, fosmidomycin effectively protected DXR against degradation in planta and in isolated chloroplasts. Thus our results suggest that DXR protein stability may be affected by substrate binding. In summary, the present results provide novel insight into the regulation of DXS expression in C. roseus in response to MEP-pathway perturbation.

  19. Structural Basis for Dual-Inhibition Mechanism of a Non-Classical Kazal-Type Serine Protease Inhibitor from Horseshoe Crab in Complex with Subtilisin

    Energy Technology Data Exchange (ETDEWEB)

    Shenoy, Rajesh T. [National Univ. of Singapore (Singapore); Thangamani, Saravanan [National Univ. of Singapore (Singapore); Univ. of Texas Medical Branch, Galveston, TX (United States); Velazquez-Campoy, Adrian [Univ. of Zaragoza (Spain); Ho, Bow [National Univ. of Singapore (Singapore); Ding, Jeak Ling [National Univ. of Singapore (Singapore); Sivaraman, J. [National Univ. of Singapore (Singapore); Kursula, Petri [Univ. of Oulu (Germany)

    2011-04-26

    Serine proteases play a crucial role in host-pathogen interactions. In the innate immune system of invertebrates, multi-domain protease inhibitors are important for the regulation of host-pathogen interactions and antimicrobial activities. Serine protease inhibitors, 9.3-kDa CrSPI isoforms 1 and 2, have been identified from the hepatopancreas of the horseshoe crab, Carcinoscorpius rotundicauda. The CrSPIs were biochemically active, especially CrSPI-1, which potently inhibited subtilisin (Ki=1.43 nM). CrSPI has been grouped with the non-classical Kazal-type inhibitors due to its unusual cysteine distribution. Here we report the crystal structure of CrSPI-1 in complex with subtilisin at 2.6 Å resolution and the results of biophysical interaction studies. The CrSPI-1 molecule has two domains arranged in an extended conformation. These two domains act as heads that independently interact with two separate subtilisin molecules, resulting in the inhibition of subtilisin activity at a ratio of 1:2 (inhibitor to protease). Each subtilisin molecule interacts with the reactive site loop from each domain of CrSPI-1 through a standard canonical binding mode and forms a single ternary complex. In addition, we propose the substrate preferences of each domain of CrSPI-1. Domain 2 is specific towards the bacterial protease subtilisin, while domain 1 is likely to interact with the host protease, Furin. Elucidation of the structure of the CrSPI-1: subtilisin (1:2) ternary complex increases our understanding of host-pathogen interactions in the innate immune system at the molecular level and provides new strategies for immunomodulation.

  20. Hereditary Angioedema Attacks: Local Swelling at Multiple Sites.

    Science.gov (United States)

    Hofman, Zonne L M; Relan, Anurag; Hack, C Erik

    2016-02-01

    Hereditary angioedema (HAE) patients experience recurrent local swelling in various parts of the body including painful swelling of the intestine and life-threatening laryngeal oedema. Most HAE literature is about attacks located in one anatomical site, though it is mentioned that HAE attacks may also involve multiple anatomical sites simultaneously. A detailed description of such multi-location attacks is currently lacking. This study investigated the occurrence, severity and clinical course of HAE attacks with multiple anatomical locations. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. Visual analog scale scores filled out by the patients for various symptoms at various locations and investigator symptoms scores during the attack were analysed. Data of 219 eligible attacks in 119 patients was analysed. Thirty-three patients (28%) had symptoms at multiple locations in anatomically unrelated regions at the same time during their first attack. Up to five simultaneously affected locations were reported. The observation that severe HAE attacks often affect multiple sites in the body suggests that HAE symptoms result from a systemic rather than from a local process as is currently believed.

  1. The Role of mTOR Inhibitors in the Treatment of Patients with Tuberous Sclerosis Complex: Evidence-based and Expert Opinions.

    Science.gov (United States)

    Curatolo, Paolo; Bjørnvold, Marit; Dill, Patricia E; Ferreira, José Carlos; Feucht, Martha; Hertzberg, Christoph; Jansen, Anna; Jóźwiak, Sergiusz; Kingswood, J Christopher; Kotulska, Katarzyna; Macaya, Alfons; Moavero, Romina; Nabbout, Rima; Zonnenberg, Bernard A

    2016-04-01

    Tuberous sclerosis complex (TSC) is a genetic disorder arising from mutations in the TSC1 or TSC2 genes. The resulting over-activation of the mammalian target of rapamycin (mTOR) signalling pathway leaves patients with TSC susceptible to the growth of non-malignant tumours in multiple organs. Previously, surgery was the main therapeutic option for TSC. However, pharmacological therapy with mTOR inhibitors such as everolimus and sirolimus is now emerging as an alternate approach. Everolimus and sirolimus have already been shown to be effective in treating subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML), and everolimus is currently being evaluated in treating TSC-related epilepsy. In November 2013 a group of European experts convened to discuss the current options and practical considerations for treating various manifestations of TSC. This article provides evidence-based recommendations for the treatment of SEGA, TSC-related epilepsy and renal AML, with a focus on where mTOR inhibitor therapy may be considered alongside other treatment options. Safety considerations regarding mTOR inhibitor therapy are also reviewed. With evidence of beneficial effects in neurological and non-neurological TSC manifestations, mTOR inhibitors may represent a systemic treatment for TSC.

  2. Molecular docking and molecular dynamics simulation study of inositol phosphorylceramide synthase – inhibitor complex in leishmaniasis: Insight into the structure based drug design [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Vineetha Mandlik

    2016-09-01

    Full Text Available Inositol phosphorylceramide synthase (IPCS has emerged as an important, interesting and attractive target in the sphingolipid metabolism of Leishmania. IPCS catalyzes the conversion of ceramide to IPC which forms the most predominant sphingolipid in Leishmania. IPCS has no mammalian equivalent and also plays an important role in maintaining the infectivity and viability of the parasite. The present study explores the possibility of targeting IPCS; development of suitable inhibitors for the same would serve as a treatment strategy for the infectious disease leishmaniasis. Five coumarin derivatives were developed as inhibitors of IPCS protein. Molecular dynamics simulations of the complexes of IPCS with these inhibitors were performed which provided insights into the binding modes of the inhibitors. In vitro screening of the top three compounds has resulted in the identification of one of the compounds (compound 3 which shows little cytotoxic effects. This compound therefore represents a good starting point for further in vivo experimentation and could possibly serve as an important drug candidate for the treatment of leishmaniasis.

  3. The ternary structure of the double-headed arrowhead protease inhibitor API-A complexed with two trypsins reveals a novel reactive site conformation.

    Science.gov (United States)

    Bao, Rui; Zhou, Cong-Zhao; Jiang, Chunhui; Lin, Sheng-Xiang; Chi, Cheng-Wu; Chen, Yuxing

    2009-09-25

    The double-headed arrowhead protease inhibitors API-A and -B from the tubers of Sagittaria sagittifolia (Linn) feature two distinct reactive sites, unlike other members of their family. Although the two inhibitors have been extensively characterized, the identities of the two P1 residues in both API-A and -B remain controversial. The crystal structure of a ternary complex at 2.48 A resolution revealed that the two trypsins bind on opposite sides of API-A and are 34 A apart. The overall fold of API-A belongs to the beta-trefoil fold and resembles that of the soybean Kunitz-type trypsin inhibitors. The two P1 residues were unambiguously assigned as Leu(87) and Lys(145), and their identities were further confirmed by site-directed mutagenesis. Reactive site 1, composed of residues P5 Met(83) to P5' Ala(92), adopts a novel conformation with the Leu(87) completely embedded in the S1 pocket even though it is an unfavorable P1 residue for trypsin. Reactive site 2, consisting of residues P5 Cys(141) to P5' Glu(150), binds trypsin in the classic mode by employing a two-disulfide-bonded loop. Analysis of the two binding interfaces sheds light on atomic details of the inhibitor specificity and also promises potential improvements in enzyme activity by engineering of the reactive sites.

  4. Structure of a small-molecule inhibitor complexed with GlmU from Haemophilus influenzae reveals an allosteric binding site

    Energy Technology Data Exchange (ETDEWEB)

    Mochalkin, Igor; Lightle, Sandra; Narasimhan, Lakshmi; Bornemeier, Dirk; Melnick, Michael; VanderRoest, Steven; McDowell, Laura (Pfizer)

    2008-04-02

    N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) is an essential enzyme in aminosugars metabolism and an attractive target for antibiotic drug discovery. GlmU catalyzes the formation of uridine-diphospho-N-acetylglucosamine (UDP-GlcNAc), an important precursor in the peptidoglycan and lipopolisaccharide biosynthesis in both Gram-negative and Gram-positive bacteria. Here we disclose a 1.9 {angstrom} resolution crystal structure of a synthetic small-molecule inhibitor of GlmU from Haemophilus influenzae (hiGlmU). The compound was identified through a high-throughput screening (HTS) configured to detect inhibitors that target the uridyltransferase active site of hiGlmU. The original HTS hit exhibited a modest micromolar potency (IC{sub 50} - 18 {mu}M in a racemic mixture) against hiGlmU and no activity against Staphylococcus aureus GlmU (saGlmU). The determined crystal structure indicated that the inhibitor occupies an allosteric site adjacent to the GlcNAc-1-P substrate-binding region. Analysis of the mechanistic model of the uridyltransferase reaction suggests that the binding of this allosteric inhibitor prevents structural rearrangements that are required for the enzymatic reaction, thus providing a basis for structure-guided design of a new class of mechanism-based inhibitors of GlmU.

  5. Relating Admissibility Standards for Digital Evidence to Attack Scenario Reconstruction

    Directory of Open Access Journals (Sweden)

    Changwei Liu

    2014-09-01

    Full Text Available Attackers tend to use complex techniques such as combining multi-step, multi-stage attack with anti-forensic tools to make it difficult to find incriminating evidence and reconstruct attack scenarios that can stand up to the expected level of evidence admissibility in a court of law. As a solution, we propose to integrate the legal aspects of evidence correlation into a Prolog based reasoner to address the admissibility requirements by creating most probable attack scenarios that satisfy admissibility standards for substantiating evidence. Using a prototype implementation, we show how evidence extracted by using forensic tools can be integrated with legal reasoning to reconstruct network attack scenarios. Our experiment shows this implemented reasoner can provide pre-estimate of admissibility on a digital crime towards an attacked network.

  6. Key Recovery Attacks on Recent Authenticated Ciphers

    DEFF Research Database (Denmark)

    Bogdanov, Andrey; Dobraunig, Christoph; Eichlseder, Maria

    2014-01-01

    and wireless networks. All these schemes use well-established and secure components such as the AES, Grain-like NFSRs, ChaCha and SipHash as their building blocks. However, we discover key recovery attacks for all three designs, featuring square-root complexities. Using a key collision technique, we can...... recover the secret key of AVALANCHE in 2n/2, where n 2∈ {28; 192; 256} is the key length. This technique also applies to the authentication part of Calico whose 128-bit key can be recovered in 264 time. For RBS, we can recover its full 132-bit key in 265 time with a guess-and-determine attack. All attacks...

  7. When women attack.

    Science.gov (United States)

    McLaughlin, Bryan; Davis, Catasha; Coppini, David; Kim, Young Mie; Knisely, Sandra; McLeod, Douglas

    2015-01-01

    The common assumption that female candidates on the campaign trail should not go on the attack, because such tactics contradict gender stereotypes, has not received consistent support. We argue that in some circumstances gender stereotypes will favor female politicians going negative. To test this proposition, this study examines how gender cues affect voter reactions to negative ads in the context of a political sex scandal, a context that should prime gender stereotypes that favor females. Using an online experiment involving a national sample of U.S. adults (N = 599), we manipulate the gender and partisan affiliation of a politician who attacks a male opponent caught in a sex scandal involving sexually suggestive texting to a female intern. Results show that in the context of a sex scandal, a female candidate going on the attack is evaluated more positively than a male. Moreover, while female participants viewed the female sponsor more favorably, sponsor gender had no effect on male participants. Partisanship also influenced candidate evaluations: the Democratic female candidate was evaluated more favorably than her Republican female counterpart.

  8. Ca2+/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor-kappa B kinase complex activation in Helicobacter pylori infection.

    Science.gov (United States)

    Maubach, Gunter; Sokolova, Olga; Wolfien, Markus; Rothkötter, Hermann-Josef; Naumann, Michael

    2013-09-15

    Helicobacter pylori, a class I carcinogen, induces a proinflammatory response by activating the transcription factor nuclear factor-kappa B (NF-κB) in gastric epithelial cells. This inflammatory condition could lead to chronic gastritis, which is epidemiologically and biologically linked to the development of gastric cancer. So far, there exists no clear knowledge on how H. pylori induces the NF-κB-mediated inflammatory response. In our study, we investigated the role of Ca(2+) /calmodulin-dependent kinase II (CAMKII), calmodulin, protein kinases C (PKCs) and the CARMA3-Bcl10-MALT1 (CBM) complex in conjunction with H. pylori-induced activation of NF-κB via the inhibitor of nuclear factor-kappa B kinase (IKK) complex. We use specific inhibitors and/or RNA interference to assess the contribution of these components. Our results show that CAMKII and calmodulin contribute to IKK complex activation and thus to the induction of NF-κB in response to H. pylori infection, but not in response to TNF-α. Thus, our findings are specific for H. pylori infected cells. Neither the PKCs α, δ, θ, nor the CBM complex itself is involved in the activation of NF-κB by H. pylori. The contribution of CAMKII and calmodulin, but not PKCs/CBM to the induction of an inflammatory response by H. pylori infection augment the understanding of the molecular mechanism involved and provide potential new disease markers for the diagnosis of gastric inflammatory diseases including gastric cancer.

  9. Simulation of Attacks for Security in Wireless Sensor Network

    Directory of Open Access Journals (Sweden)

    Alvaro Diaz

    2016-11-01

    Full Text Available The increasing complexity and low-power constraints of current Wireless Sensor Networks (WSN require efficient methodologies for network simulation and embedded software performance analysis of nodes. In addition, security is also a very important feature that has to be addressed in most WSNs, since they may work with sensitive data and operate in hostile unattended environments. In this paper, a methodology for security analysis of Wireless Sensor Networks is presented. The methodology allows designing attack-aware embedded software/firmware or attack countermeasures to provide security in WSNs. The proposed methodology includes attacker modeling and attack simulation with performance analysis (node’s software execution time and power consumption estimation. After an analysis of different WSN attack types, an attacker model is proposed. This model defines three different types of attackers that can emulate most WSN attacks. In addition, this paper presents a virtual platform that is able to model the node hardware, embedded software and basic wireless channel features. This virtual simulation analyzes the embedded software behavior and node power consumption while it takes into account the network deployment and topology. Additionally, this simulator integrates the previously mentioned attacker model. Thus, the impact of attacks on power consumption and software behavior/execution-time can be analyzed. This provides developers with essential information about the effects that one or multiple attacks could have on the network, helping them to develop more secure WSN systems. This WSN attack simulator is an essential element of the attack-aware embedded software development methodology that is also introduced in this work.

  10. Simulation of Attacks for Security in Wireless Sensor Network.

    Science.gov (United States)

    Diaz, Alvaro; Sanchez, Pablo

    2016-11-18

    The increasing complexity and low-power constraints of current Wireless Sensor Networks (WSN) require efficient methodologies for network simulation and embedded software performance analysis of nodes. In addition, security is also a very important feature that has to be addressed in most WSNs, since they may work with sensitive data and operate in hostile unattended environments. In this paper, a methodology for security analysis of Wireless Sensor Networks is presented. The methodology allows designing attack-aware embedded software/firmware or attack countermeasures to provide security in WSNs. The proposed methodology includes attacker modeling and attack simulation with performance analysis (node's software execution time and power consumption estimation). After an analysis of different WSN attack types, an attacker model is proposed. This model defines three different types of attackers that can emulate most WSN attacks. In addition, this paper presents a virtual platform that is able to model the node hardware, embedded software and basic wireless channel features. This virtual simulation analyzes the embedded software behavior and node power consumption while it takes into account the network deployment and topology. Additionally, this simulator integrates the previously mentioned attacker model. Thus, the impact of attacks on power consumption and software behavior/execution-time can be analyzed. This provides developers with essential information about the effects that one or multiple attacks could have on the network, helping them to develop more secure WSN systems. This WSN attack simulator is an essential element of the attack-aware embedded software development methodology that is also introduced in this work.

  11. High-resolution crystal structure of Streptococcus pyogenes β-NAD{sup +} glycohydrolase in complex with its endogenous inhibitor IFS reveals a highly water-rich interface

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Ji Young; An, Doo Ri; Yoon, Hye-Jin [Seoul National University, Seoul 151-747 (Korea, Republic of); Kim, Hyoun Sook [Seoul National University, Seoul 151-747 (Korea, Republic of); Seoul National University, Seoul 151-742 (Korea, Republic of); Lee, Sang Jae [Seoul National University, Seoul 151-742 (Korea, Republic of); Im, Ha Na; Jang, Jun Young [Seoul National University, Seoul 151-747 (Korea, Republic of); Suh, Se Won, E-mail: sewonsuh@snu.ac.kr [Seoul National University, Seoul 151-747 (Korea, Republic of); Seoul National University, Seoul 151-747 (Korea, Republic of)

    2013-11-01

    The crystal structure of the complex between the C-terminal domain of Streptococcus pyogenes β-NAD{sup +} glycohydrolase and an endogenous inhibitor for SPN was determined at 1.70 Å. It reveals that the interface between the two proteins is highly rich in water molecules. One of the virulence factors produced by Streptococcus pyogenes is β-NAD{sup +} glycohydrolase (SPN). S. pyogenes injects SPN into the cytosol of an infected host cell using the cytolysin-mediated translocation pathway. As SPN is toxic to bacterial cells themselves, S. pyogenes possesses the ifs gene that encodes an endogenous inhibitor for SPN (IFS). IFS is localized intracellularly and forms a complex with SPN. This intracellular complex must be dissociated during export through the cell envelope. To provide a structural basis for understanding the interactions between SPN and IFS, the complex was overexpressed between the mature SPN (residues 38–451) and the full-length IFS (residues 1–161), but it could not be crystallized. Therefore, limited proteolysis was used to isolate a crystallizable SPN{sub ct}–IFS complex, which consists of the SPN C-terminal domain (SPN{sub ct}; residues 193–451) and the full-length IFS. Its crystal structure has been determined by single anomalous diffraction and the model refined at 1.70 Å resolution. Interestingly, our high-resolution structure of the complex reveals that the interface between SPN{sub ct} and IFS is highly rich in water molecules and many of the interactions are water-mediated. The wet interface may facilitate the dissociation of the complex for translocation across the cell envelope.

  12. Localized attack on clustering networks

    CERN Document Server

    Dong, Gaogao; Du, Ruijin; Shao, Shuai; Stanley, H Eugene; Shlomo, Havlin

    2016-01-01

    Clustering network is one of which complex network attracting plenty of scholars to discuss and study the structures and cascading process. We primarily analyzed the effect of clustering coefficient to other various of the single clustering network under localized attack. These network models including double clustering network and star-like NON with clustering and random regular (RR) NON of ER networks with clustering are made up of at least two networks among which exist interdependent relation among whose degree of dependence is measured by coupling strength. We show both analytically and numerically, how the coupling strength and clustering coefficient effect the percolation threshold, size of giant component, critical coupling point where the behavior of phase transition changes from second order to first order with the increase of coupling strength between the networks. Last, we study the two types of clustering network: one type is same with double clustering network in which each subnetwork satisfies ...

  13. Replacement Attack: A New Zero Text Watermarking Attack

    Science.gov (United States)

    Bashardoost, Morteza; Mohd Rahim, Mohd Shafry; Saba, Tanzila; Rehman, Amjad

    2017-03-01

    The main objective of zero watermarking methods that are suggested for the authentication of textual properties is to increase the fragility of produced watermarks against tampering attacks. On the other hand, zero watermarking attacks intend to alter the contents of document without changing the watermark. In this paper, the Replacement attack is proposed, which focuses on maintaining the location of the words in the document. The proposed text watermarking attack is specifically effective on watermarking approaches that exploit words' transition in the document. The evaluation outcomes prove that tested word-based method are unable to detect the existence of replacement attack in the document. Moreover, the comparison results show that the size of Replacement attack is estimated less accurate than other common types of zero text watermarking attacks.

  14. Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor

    DEFF Research Database (Denmark)

    Guevara, Tibisay; Ksiazek, Miroslaw; Skottrup, Peter Durand

    2013-01-01

    ) to matrix metalloproteinases suggests that karilysin was acquired by horizontal gene transfer from an animal host. Previous studies by phage display identified peptides with the consensus sequence XWFPXXXGGG (single-letter amino-acid codes; X represents any residue) as karilysin inhibitors with low...

  15. Structural Learning of Attack Vectors for Generating Mutated XSS Attacks

    Directory of Open Access Journals (Sweden)

    Yi-Hsun Wang

    2010-09-01

    Full Text Available Web applications suffer from cross-site scripting (XSS attacks that resulting from incomplete or incorrect input sanitization. Learning the structure of attack vectors could enrich the variety of manifestations in generated XSS attacks. In this study, we focus on generating more threatening XSS attacks for the state-of-the-art detection approaches that can find potential XSS vulnerabilities in Web applications, and propose a mechanism for structural learning of attack vectors with the aim of generating mutated XSS attacks in a fully automatic way. Mutated XSS attack generation depends on the analysis of attack vectors and the structural learning mechanism. For the kernel of the learning mechanism, we use a Hidden Markov model (HMM as the structure of the attack vector model to capture the implicit manner of the attack vector, and this manner is benefited from the syntax meanings that are labeled by the proposed tokenizing mechanism. Bayes theorem is used to determine the number of hidden states in the model for generalizing the structure model. The paper has the contributions as following: (1 automatically learn the structure of attack vectors from practical data analysis to modeling a structure model of attack vectors, (2 mimic the manners and the elements of attack vectors to extend the ability of testing tool for identifying XSS vulnerabilities, (3 be helpful to verify the flaws of blacklist sanitization procedures of Web applications. We evaluated the proposed mechanism by Burp Intruder with a dataset collected from public XSS archives. The results show that mutated XSS attack generation can identify potential vulnerabilities.

  16. Temporary diazepam responsive apneic attacks and congenital myasthenic syndrome.

    Science.gov (United States)

    Yis, Uluç; Kurul, Semra Hiz; Oztura, Ibrahim; Ozden, Omer; Akinci, Gülçin; Dirik, Eray

    2009-07-01

    Congenital myasthenic syndromes are a genetically and phenotypically heterogeneous group of hereditary disorders affecting neuromuscular junction. Mutations in the gene encoding choline acetyltransferase cause presynaptic defects. The missense mutation I336T has been identified in Turkish population, and most of the cases carrying this mutation present with exercise-induced fatigability and ptosis. Although apneic attacks occur in these cases during febrile illness in childhood, the number of reported respiratory distress episodes during infancy is scarce. Another important feature of these cases is that response to esterase inhibitors is satisfactory. We present a case of congenital myasthenic syndrome with I336T choline acetyltransferase mutation who presented with numerous attacks of respiratory distress in the infancy period. Interestingly, the patient had myopathic findings on electromyography and diazepam decreased severity of apneic attacks. There was also no improvement with esterase inhibitors.

  17. Seven Deadliest Unified Communications Attacks

    CERN Document Server

    York, Dan

    2010-01-01

    Do you need to keep up with the latest hacks, attacks, and exploits effecting Unified Communications technology? Then you need Seven Deadliest Unified Communication Attacks. This book pinpoints the most dangerous hacks and exploits specific to Unified Communications, laying out the anatomy of these attacks including how to make your system more secure. You will discover the best ways to defend against these vicious hacks with step-by-step instruction and learn techniques to make your computer and network impenetrable. Attacks featured in this book include: UC Ecosystem Attacks Insecure Endpo

  18. Structural Learning of Attack Vectors for Generating Mutated XSS Attacks

    CERN Document Server

    Wang, Yi-Hsun; Lee, Hahn-Ming; 10.4204/EPTCS.35.2

    2010-01-01

    Web applications suffer from cross-site scripting (XSS) attacks that resulting from incomplete or incorrect input sanitization. Learning the structure of attack vectors could enrich the variety of manifestations in generated XSS attacks. In this study, we focus on generating more threatening XSS attacks for the state-of-the-art detection approaches that can find potential XSS vulnerabilities in Web applications, and propose a mechanism for structural learning of attack vectors with the aim of generating mutated XSS attacks in a fully automatic way. Mutated XSS attack generation depends on the analysis of attack vectors and the structural learning mechanism. For the kernel of the learning mechanism, we use a Hidden Markov model (HMM) as the structure of the attack vector model to capture the implicit manner of the attack vector, and this manner is benefited from the syntax meanings that are labeled by the proposed tokenizing mechanism. Bayes theorem is used to determine the number of hidden states in the model...

  19. Palladium(II) and zinc(II) complexes of neutral [N2O2] donor Schiff bases derived from furfuraldehyde: synthesis, characterization, fluorescence and corrosion inhibitors of ligands.

    Science.gov (United States)

    Ali, Omyma A M

    2014-11-11

    Metal complexes of Schiff bases derived from furfuraldehyde and 4,5-dimethyl-1,2-phenylendiamine (L1) or 4,5-dichloro-1,2-phenylendiamine (L2) have been reported and characterized based on elemental analyses, IR, 1H NMR, UV-Vis, magnetic moment, molar conductance and thermal analysis. The complexes are found to have the formulae [PdL1-2]Cl2 and [ZnL1-2](AcO)2·H2O. The molar conductance data reveal that Pd(II) and Zn(II) chelates are ionic in nature and are of the type 2:1 electrolytes. The spectral data are consistent with a square planar and tetrahedral geometry around Pd(II) and Zn(II), respectively, in which the ligands act as tetradentate ligands. The thermal behavior of some chelates is studied and the activation thermodynamic parameters are calculated using Coats-Redfern method. The corrosion inhibition of stainless steel types 410 and 304 in 1 M HCl using the synthesized Schiff bases as inhibitors have been studied by weight loss method. The obtained data considered these ligands as efficient corrosion inhibitors. The ligands and their metal complexes exhibited considerable antibacterial activity against Staphylococcusaureus, and Escherichiacoli and antifungal activity against Candida albicans.

  20. Palladium(II) and zinc(II) complexes of neutral [N2O2] donor Schiff bases derived from furfuraldehyde: Synthesis, characterization, fluorescence and corrosion inhibitors of ligands

    Science.gov (United States)

    Ali, Omyma A. M.

    2014-11-01

    Metal complexes of Schiff bases derived from furfuraldehyde and 4,5-dimethyl-1,2-phenylendiamine (L1) or 4,5-dichloro-1,2-phenylendiamine (L2) have been reported and characterized based on elemental analyses, IR, 1H NMR, UV-Vis, magnetic moment, molar conductance and thermal analysis. The complexes are found to have the formulae [PdL1-2]Cl2 and [ZnL1-2](AcO)2·H2O. The molar conductance data reveal that Pd(II) and Zn(II) chelates are ionic in nature and are of the type 2:1 electrolytes. The spectral data are consistent with a square planar and tetrahedral geometry around Pd(II) and Zn(II), respectively, in which the ligands act as tetradentate ligands. The thermal behavior of some chelates is studied and the activation thermodynamic parameters are calculated using Coats-Redfern method. The corrosion inhibition of stainless steel types 410 and 304 in 1 M HCl using the synthesized Schiff bases as inhibitors have been studied by weight loss method. The obtained data considered these ligands as efficient corrosion inhibitors. The ligands and their metal complexes exhibited considerable antibacterial activity against Staphylococcusaureus, and Escherichiacoli and antifungal activity against Candida albicans.

  1. Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3 Single Amino Acid near the Active Site Influences Inhibitor Sensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Bum Soo; Allali-Hassani, Abdellah; Tempel, Wolfram; Finerty, Jr., Patrick J.; MacKenzie, Farrell; Dimov, Svetoslav; Vedadi, Masoud; Park, Hee-Won (Toronto)

    2010-07-06

    Human choline kinase (ChoK) catalyzes the first reaction in phosphatidylcholine biosynthesis and exists as ChoK{alpha} ({alpha}1 and {alpha}2) and ChoK{beta} isoforms. Recent studies suggest that ChoK is implicated in tumorigenesis and emerging as an attractive target for anticancer chemotherapy. To extend our understanding of the molecular mechanism of ChoK inhibition, we have determined the high resolution x-ray structures of the ChoK{alpha}1 and ChoK{beta} isoforms in complex with hemicholinium-3 (HC-3), a known inhibitor of ChoK. In both structures, HC-3 bound at the conserved hydrophobic groove on the C-terminal lobe. One of the HC-3 oxazinium rings complexed with ChoK{alpha}1 occupied the choline-binding pocket, providing a structural explanation for its inhibitory action. Interestingly, the HC-3 molecule co-crystallized with ChoK{beta} was phosphorylated in the choline binding site. This phosphorylation, albeit occurring at a very slow rate, was confirmed experimentally by mass spectroscopy and radioactive assays. Detailed kinetic studies revealed that HC-3 is a much more potent inhibitor for ChoK{alpha} isoforms ({alpha}1 and {alpha}2) compared with ChoK{beta}. Mutational studies based on the structures of both inhibitor-bound ChoK complexes demonstrated that Leu-401 of ChoK{alpha}2 (equivalent to Leu-419 of ChoK{alpha}1), or the corresponding residue Phe-352 of ChoK{beta}, which is one of the hydrophobic residues neighboring the active site, influences the plasticity of the HC-3-binding groove, thereby playing a key role in HC-3 sensitivity and phosphorylation.

  2. Attacks on computer systems

    Directory of Open Access Journals (Sweden)

    Dejan V. Vuletić

    2012-01-01

    Full Text Available Computer systems are a critical component of the human society in the 21st century. Economic sector, defense, security, energy, telecommunications, industrial production, finance and other vital infrastructure depend on computer systems that operate at local, national or global scales. A particular problem is that, due to the rapid development of ICT and the unstoppable growth of its application in all spheres of the human society, their vulnerability and exposure to very serious potential dangers increase. This paper analyzes some typical attacks on computer systems.

  3. Inhibitors of the mitochondrial cytochrome b-c1 complex inhibit the cyanide-insensitive respiration of Trypanosoma brucei.

    Science.gov (United States)

    Turrens, J F; Bickar, D; Lehninger, A L

    1986-06-01

    The cyanide-insensitive respiration of bloodstream trypomastigote forms of Trypanosoma brucei (75 +/- 8 nmol O2 min-1(mg protein)-1) is completely inhibited by the mitochondrial ubiquinone-like inhibitors 2-hydroxy-3-undecyl-1,4-naphthoquinone (UHNQ) and 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT). The Ki values for UHDBT (30 nM) and UHNQ (2 microM) are much lower than the reported Ki for salicylhydroxamic acid (SHAM) (5 microM), a widely used inhibitor of the cyanide-insensitive oxidase. UHNQ also stimulated the glycerol-3-phosphate-dependent reduction of phenazine methosulfate, demonstrating that the site of UHNQ inhibition is on the terminal oxidase of the cyanide-insensitive respiration of T. brucei. These results suggest that a ubiquinone-like compound may act as an electron carrier between the two enzymatic components of the cyanide-insensitive glycerol-3-phosphate oxidase.

  4. L-Ornithine Schiff base-copper and -cadmium complexes as new proteasome inhibitors and apoptosis inducers in human cancer cells.

    Science.gov (United States)

    Zhang, Zhongyu; Bi, Caifeng; Fan, Yuhua; Zhang, Nan; Deshmukh, Rahul; Yan, Xingchen; Lv, Xiuwen; Zhang, Pengfei; Zhang, Xia; Dou, Q Ping

    2015-01-01

    Ubiquitin-proteasome system (UPS) plays a crucial role in many cellular processes such as cell cycle, proliferation and apoptosis. Aberrant activation of UPS may result in cellular transformation or other altered pathological conditions. Previous studies have shown that metal-based complexes could inhibit proteasome activity and induce apoptosis in certain human cancer cells. In the current study, we report that the cadmium and copper complexes with heterocycle-ornithine Schiff base are potent inhibitors of proteasomal chymotrypsin-like (CT-like) activity, leading to induction of apoptosis in cancer cells. Two novel copper-containing complexes and two novel cadmium-containing complexes with different heterocycle-ornithine Schiff base structures as ligands were synthesized and characterized. We found that complexes Cu1, Cd1 and Cd2 show proteasome-inhibitory activities in human breast cancer MDA-MB-231 and human prostate cancer LNCaP cells, resulting in the accumulation of p27, a natural proteasome substrate and other ubiquitinated proteins, followed by the induction of apoptosis. Our results suggest that metal complexes with heterocycle-ornithine Schiff base have proteasome-inhibitory capabilities and have the potential to be developed into novel anticancer drugs.

  5. Progesterone receptor chaperone complex-based highthroughput screening assay: identification of capsaicin as inhibitor of Hsp90 machine

    Science.gov (United States)

    Patwardhan, Chaitanya A.; Alfa, Eyad; Lu, Su; Chadli, Ahmed

    2016-01-01

    Hsp90 and its co-chaperones are known to be important for cancer cell survival. The N-terminal inhibitors of Hsp90 that are in ongoing clinical trials as anti-tumor agents have unfortunately shown disappointing efficacies in the clinic. Thus, novel inhibitors of the Hsp90 machine with different mechanism of action are urgently needed. We report here the development of a novel high-throughput drug-screening (HTS) assay platform to identify small molecule inhibitors of Hsp90 and its co-chaperones. This assay quantitatively measures the ability of Hsp90 and its co-chaperones to refold/protect the progesterone receptor (PR), a physiological client of Hsp90, in 96-well plate format. We screened the NIH clinical collection drug library and identified capsaicin as a hit molecule. Capsaicin is an FDA-approved drug for topical use in pain management. Cell survival assays showed that capsaicin selectively kills cancer cells and destabilizes several Hsp90 client proteins. Thus, our data may explain the seemingly pleotropic effect of capsaicin. PMID:25184514

  6. Molecular dynamics simulations of sonic hedgehog-receptor and inhibitor complexes and their applications for potential anticancer agent discovery.

    Directory of Open Access Journals (Sweden)

    Swan Hwang

    Full Text Available The sonic hedgehog (Shh signaling pathway is necessary for a variety of development and differentiation during embryogenesis as well as maintenance and renascence of diverse adult tissues. However, an abnormal activation of the signaling pathway is related to various cancers. In this pathway, the Shh signaling transduction is facilitated by binding of Shh to its receptor protein, Ptch. In this study, we modeled the 3D structure of functionally important key loop peptides of Ptch based on homologous proteins. Using this loop model, the molecular interactions between the structural components present in the pseudo-active site of Shh and key residues of Ptch was investigated in atomic level through molecular dynamics (MD simulations. For the purpose of developing inhibitor candidates of the Shh signaling pathway, the Shh pseudo-active site of this interface region was selected as a target to block the direct binding between Shh and Ptch. Two different structure-based pharmacophore models were generated considering the key loop of Ptch and known inhibitor-induced conformational changes of the Shh through MD simulations. Finally two hit compounds were retrieved through a series of virtual screening combined with molecular docking simulations and we propose two hit compounds as potential inhibitory lead candidates to block the Shh signaling pathway based on their strong interactions to receptor or inhibitor induced conformations of the Shh.

  7. The design, synthesis and biological evaluation of novel thiamin diphosphate analog inhibitors against the pyruvate dehydrogenase multienzyme complex E1 from Escherichia coli.

    Science.gov (United States)

    Feng, Lingling; He, Junbo; He, Haifeng; Zhao, Lulu; Deng, Lingfu; Zhang, Li; Zhang, Lin; Ren, Yanliang; Wan, Jian; He, Hongwu

    2014-11-28

    Pyruvate dehydrogenase multienzyme complex E1 (PDHc E1) is a potential target enzyme when looking for inhibitors to combat microbial disease. In this study, we designed and synthesized a series of novel thiamin diphosphate (ThDP) analogs with triazole ring and oxime ether moieties as potential inhibitors of PDHc E1. Their inhibitory activities against PDHc E1 were examined both in vitro and in vivo. Most of the tested compounds exhibited moderate inhibitory activities against PDHc E1 (IC50 = 6.1-75.5 μM). The potent inhibitors 4g, 4h and 4j, had strong inhibitory activities with IC50 values of 6.7, 6.9 and 6.1 μM against PDHc E1 in vitro and with inhibition rates of 35%, 50% and 33% at 100 μg mL(-1) against Gibberella zeae in vivo, respectively. The binding mode of 4j to PDHc E1 was analyzed by a molecular docking method. Furthermore, the possible interactions of the important residues of PDHc E1 with compound 4j were examined by site-directed mutagenesis, enzymatic assays and spectral fluorescence studies. The theoretical and experimental results are in good agreement and suggest that compound 4j could be used as a lead compound for further optimization, and may have potential as a new microbicide.

  8. Inhibition effects of PMA/SbBr3 complex inhibitor on copper and copper-nickel alloy in LiBr solutions

    Institute of Scientific and Technical Information of China (English)

    HU Xian-qi; LIANG Cheng-hao; HUANG Nai-bao

    2005-01-01

    The effects of PMA/SbBr3 inhibitor on copper and copper-nickel alloy in 55%LiBr solution were investigated by chemical immersion and electrochemical measurements. The results indicate that in boiling 55% LiBr solution containing PMA/SbBr3 inhibitor, corrosion rates of copper and copper-nickel alloy are 67.48 μm/a and 38. 14μm/a, respectively. Since both anodic and cathodic electrochemical reactions can be inhibited, PMA/SbBr3 belongs to complex inhibitor. PMA has the effect of inhibiting hydrogen evolution and [PMo12 O40]3- , the anion of PMA,has a strong oxidizing effect. Sb3+ also shows an oxidizing effect. It may exist in LiBr solutions stably with PMA.Because of the synergistic effect of PMA and Sb3+ , a protective film, comprising CuO, Cu2O and Sb, formed on copper and copper-nickel alloy surface may prevent Br- from diffusing to the surface of metals. As a result, the anticorrosion performance of copper and copper-nickel alloy may be improved.

  9. Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

    Energy Technology Data Exchange (ETDEWEB)

    Tabackman, Alexa A.; Frankson, Rochelle; Marsan, Eric S.; Perry, Kay; Cole, Kathryn E. (Ithaca); (Cornell)

    2016-10-17

    Histone deacetylases (HDACs) catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins, and play a critical role in the regulation of many biological processes, including cell differentiation, proliferation, senescence, and apoptosis. Aberrant HDAC activity is associated with cancer, making these enzymes important targets for drug design. In general, HDAC inhibitors (HDACi) block the proliferation of tumor cells by inducing cell differentiation, cell cycle arrest, and/or apoptosis, and comprise some of the leading therapies in cancer treatments. To date, four HDACi have been FDA approved for the treatment of cancers: suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®), romidepsin (FK228, Istodax®), belinostat (Beleodaq®), and panobinostat (Farydak®). Most current inhibitors are pan-HDACi, and non-selectively target a number of HDAC isoforms. Six previously reported HDACi were rationally designed, however, to target a unique sub-pocket found only in HDAC8. While these inhibitors were indeed potent against HDAC8, and even demonstrated specificity for HDAC8 over HDACs 1 and 6, there were no structural data to confirm the mode of binding. Here we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98 Å resolution. We also describe the use of molecular docking studies to explore the binding interactions of the other 5 related HDACi. Our studies confirm that the HDACi induce the formation of and bind in the HDAC8-specific subpocket, offering insights into isoform-specific inhibition.

  10. Recent "phishing" attacks

    CERN Multimedia

    IT Department

    2009-01-01

    Over the last few weeks there has been a marked increase in the number of attacks on CERN made by cybercriminals. Typical attacks arrive in the form of e-mail messages purporting to come from the CERN Help Desk, Mail Service, or some similarly official-sounding entity and suggest that there is a problem with your account, such as it being over-quota. They then ask you to click on a link or to reply and give your password. Please don’t! Be cautious of any unexpected messages containing web links even if they appear to come from known contacts. If you happen to click on such a link and if your permission is requested to run or install software, always decline it. NEVER provide your password or other details if these are requested. These messages try to trick you into clicking on Web links which will help them to install malicious software on your computer, and anti-virus software cannot be relied on to detect all cases. In case of questions on this topic, you may contact mailto:helpdesk@cern.ch. CERN Comput...

  11. Attack resilience of the evolving scientific collaboration network.

    Directory of Open Access Journals (Sweden)

    Xiao Fan Liu

    Full Text Available Stationary complex networks have been extensively studied in the last ten years. However, many natural systems are known to be continuously evolving at the local ("microscopic" level. Understanding the response to targeted attacks of an evolving network may shed light on both how to design robust systems and finding effective attack strategies. In this paper we study empirically the response to targeted attacks of the scientific collaboration networks. First we show that scientific collaboration network is a complex system which evolves intensively at the local level--fewer than 20% of scientific collaborations last more than one year. Then, we investigate the impact of the sudden death of eminent scientists on the evolution of the collaboration networks of their former collaborators. We observe in particular that the sudden death, which is equivalent to the removal of the center of the egocentric network of the eminent scientist, does not affect the topological evolution of the residual network. Nonetheless, removal of the eminent hub node is exactly the strategy one would adopt for an effective targeted attack on a stationary network. Hence, we use this evolving collaboration network as an experimental model for attack on an evolving complex network. We find that such attacks are ineffectual, and infer that the scientific collaboration network is the trace of knowledge propagation on a larger underlying social network. The redundancy of the underlying structure in fact acts as a protection mechanism against such network attacks.

  12. Identification of an HIV-1 replication inhibitor which rescues host restriction factor APOBEC3G in Vif-APOBEC3G complex.

    Science.gov (United States)

    Zhang, Shaoyang; Zhong, Limei; Chen, Bing; Pan, Ting; Zhang, Xue; Liang, Liting; Li, Qianwen; Zhang, Ziying; Chen, Hui; Zhou, Jie; Luo, Haihua; Zhang, Hui; Bai, Chuan

    2015-10-01

    HIV-1 Vif protein is one of the most crucial accessory proteins for viral replication. It efficiently counteracts the important host restriction factor APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G, A3G) which is lethal to HIV-1 by causing G to A mutation of viral genome. Vif protein mediates degradation of APOBEC3G via the complicated protein-protein interactions of Vif, APOBEC3G, Elongin C/B and Cullin 5. The importance of Vif-APOBEC3G complex makes it a good potential target to develop new therapeutics of HIV-1. We identified a potent HIV-1 replication inhibitor (ZBMA-1, IC50 = 1.01 μM) that efficiently protected APOBEC3G protein by targeting Vif-APOBEC3G complex. The co-immunoprecipitation and docking studies indicated that compound ZBMA-1 affected the binding of Elongin C with Vif protein.

  13. Substance P induces localization of MIF/α1-inhibitor-3 complexes to umbrella cells via paracellular transit through the urothelium in the rat bladder

    Directory of Open Access Journals (Sweden)

    Vera Pedro L

    2006-09-01

    Full Text Available Abstract Background Macrophage migration inhibitory factor (MIF is released into the intraluminal fluid during bladder inflammation in the rat complexed to α1-inhibitor-3 (A1-I3; a rodent proteinase inhibitor in the α-macroglobulin family. The location of A1-I3 in the bladder had not been investigated. Therefore, we examined the location of A1-I3 and MIF/A1-I3 complexes in the bladder and changes due to experimental inflammation. Methods Anesthetized male rats had bladders removed with no treatment (intact or were injected with Substance P (SP; s.c.; saline vehicle. After one hour intraluminal fluid was removed, bladder was excised and MIF and A1-I3 levels were determined using ELISA and/or western-blotting. MIF co-immunoprecipitation determined MIF/A1-I3 complexes in the bladder. Bladder sections were immunostained for A1-I3 and MIF/A1-I3. Results A1-I3 immunostaining was observed in interstitial spaces throughout the bladder (including submucosa but not urothelium in intact and saline-treated rats. RT-PCR showed that the bladder does not synthesize A1-I3, therefore, A1-I3 in the interstitial space of the bladder must be plasma derived. In SP-treated rats, A1-I3 in the bladder increased and A1-I3 was observed traversing through the urothelium. Umbrella cells that do not show MIF and/or A1-I3 immunostaining in intact or saline-treated rats, showed co-localization of MIF and A1-I3 after SP-treatment. Western blotting demonstrated that in the bladder MIF formed non-covalent interactions and also binds covalently to A1-I3 to form high molecular weight MIF/A1-I3 complexes (170, 130 and 75-kDa, respectively, verified by co-immunoprecipitation. SP-induced inflammation selectively reduced 170-kDa MIF/A1-I3 in the bladder while increasing 170 and 130-kDa MIF/A1-I3 in the intraluminal fluid. Conclusion A1-I3 and MIF/A1-I3 complexes are resident in bladder interstitium. During SP-induced inflammation, MIF/A1-I3 complexes are released from the bladder

  14. Energetics of dendrimer binding to HIV-1 gp120-CD4 complex and mechanismic aspects of its role as an entry-inhibitor

    Science.gov (United States)

    Saurabh, Suman; Sahoo, Anil Kumar; Maiti, Prabal K.

    2016-10-01

    Experiments and computational studies have established that de-protonated dendrimers (SPL7013 and PAMAM) act as entry-inhibitors of HIV. SPL7013 based Vivagel is currently under clinical development. The dendrimer binds to gp120 in the gp120-CD4 complex, destabilizes it by breaking key contacts between gp120 and CD4 and prevents viral entry into target cells. In this work, we provide molecular details and energetics of the formation of the SPL7013-gp120-CD4 ternary complex and decipher modes of action of the dendrimer in preventing viral entry. It is also known from experiments that the dendrimer binds weakly to gp120 that is not bound to CD4. It binds even more weakly to the CD4-binding region of gp120 and thus cannot directly block gp120-CD4 complexation. In this work, we examine the feasibility of dendrimer binding to the gp120-binding region of CD4 and directly blocking gp120-CD4 complex formation. We find that the process of the dendrimer binding to CD4 can compete with gp120-CD4 binding due to comparable free energy change for the two processes, thus creating a possibility for the dendrimer to directly block gp120-CD4 complexation by binding to the gp120-binding region of CD4.

  15. Structures of ceftazidime and its transition-state analogue in complex with AmpC beta-lactamase: Implications for resistance mutations and inhibitor design

    Energy Technology Data Exchange (ETDEWEB)

    Powers, R.A.; Caselli, E.; Focia, P.J.; Prati, F.; Shoichet, B.K.

    2010-03-08

    Third-generation cephalosporins are widely used {beta}-lactam antibiotics that resist hydrolysis by {beta}-lactamases. Recently, mutant {beta}-lactamases that rapidly inactivate these drugs have emerged. To investigate why third-generation cephalosporins are relatively stable to wild-type class C {beta}-lactamases and how mutant enzymes might overcome this, the structures of the class C {beta}-lactamase AmpC in complex with the third-generation cephalosporin ceftazidime and with a transition-state analogue of ceftazidime were determined by X-ray crystallography to 2.0 and 2.3 {angstrom} resolution, respectively. Comparison of the acyl-enzyme structures of ceftazidime and loracarbef, a {beta}-lactam substrate, reveals that the conformation of ceftazidime in the active site differs from that of substrates. Comparison of the structures of the acyl-enzyme intermediate and the transition-state analogue suggests that ceftazidime blocks formation of the tetrahedral transition state, explaining why it is an inhibitor of AmpC. Ceftazidime cannot adopt a conformation competent for catalysis due to steric clashes that would occur with conserved residues Val211 and Tyr221. The X-ray crystal structure of the mutant {beta}-lactamase GC1, which has improved activity against third-generation cephalosporins, suggests that a tandem tripeptide insertion in the {Omega} loop, which contains Val211, has caused a shift of this residue and also of Tyr221 that would allow ceftazidime and other third-generation cephalosporins to adopt a more catalytically competent conformation. These structural differences may explain the extended spectrum activity of GC1 against this class of cephalosporins. In addition, the complexed structure of the transition-state analogue inhibitor (K{sub i} 20 nM) with AmpC reveals potential opportunities for further inhibitor design.

  16. Aqueous Molecular Dynamics Simulations of the M. tuberculosis Enoyl-ACP Reductase-NADH System and Its Complex with a Substrate Mimic or Diphenyl Ethers Inhibitors

    Directory of Open Access Journals (Sweden)

    Camilo Henrique da Silva Lima

    2015-10-01

    Full Text Available Molecular dynamics (MD simulations of 12 aqueous systems of the NADH-dependent enoyl-ACP reductase from Mycobacterium tuberculosis (InhA were carried out for up to 20–40 ns using the GROMACS 4.5 package. Simulations of the holoenzyme, holoenzyme-substrate, and 10 holoenzyme-inhibitor complexes were conducted in order to gain more insight about the secondary structure motifs of the InhA substrate-binding pocket. We monitored the lifetime of the main intermolecular interactions: hydrogen bonds and hydrophobic contacts. Our MD simulations demonstrate the importance of evaluating the conformational changes that occur close to the active site of the enzyme-cofactor complex before and after binding of the ligand and the influence of the water molecules. Moreover, the protein-inhibitor total steric (ELJ and electrostatic (EC interaction energies, related to Gly96 and Tyr158, are able to explain 80% of the biological response variance according to the best linear equation, pKi = 7.772 − 0.1885 × Gly96 + 0.0517 × Tyr158 (R2 = 0.80; n = 10, where interactions with Gly96, mainly electrostatic, increase the biological response, while those with Tyr158 decrease. These results will help to understand the structure-activity relationships and to design new and more potent anti-TB drugs.

  17. Strengthening Crypto-1 Cipher Against Algebraic Attacks

    Directory of Open Access Journals (Sweden)

    Farah Afianti

    2015-08-01

    Full Text Available In the last few years, several studies addressed the problem of data security in Mifare Classic. One of its weaknesses is the low random number quality. This causes SAT solver attacks to have lower complexity. In order to strengthen Crypto-1 against SAT solver attacks, a modification of the feedback function with better cryptographic properties is proposed. It applies a primitive polynomial companion matrix. SAT solvers cannot directly attack the feedback shift register that uses the modified Boolean feedback function, the register has to be split into smaller groups. Experimental testing showed that the amount of memory and CPU time needed were highest when attacking the modified Crypto-1 using the modified feedback function and the original filter function. In addition, another modified Crypto-1, using the modified feedback function and a modified filter function, had the lowest percentage of revealed variables. It can be concluded that the security strength and performance of the modified Crypto-1 using the modified feedback function and the modified filter function are better than those of the original Crypto-1.

  18. Tracing Technique for Blaster Attack

    CERN Document Server

    S., Siti Rahayu; S., Shahrin; A., Faizal M; M, Mohd Zaki; R, Irda

    2009-01-01

    Blaster worm of 2003 is still persistent, the infection appears to have successfully transitioned to new hosts as the original systems are cleaned or shut off, suggesting that the Blaster worm, and other similar worms, will remain significant Internet threats for many years after their initial release. This paper is to propose technique on tracing the Blaster attack from various logs in different OSI layers based on fingerprint of Blaster attack on victim logs, attacker logs and IDS alert log. The researchers intended to do a preliminary investigation upon this particular attack so that it can be used for further research in alert correlation and computer forensic investigation.

  19. Seven Deadliest Web Application Attacks

    CERN Document Server

    Shema, Mike

    2010-01-01

    Do you need to keep up with the latest hacks, attacks, and exploits effecting web applications? Then you need Seven Deadliest Web Application Attacks. This book pinpoints the most dangerous hacks and exploits specific to web applications, laying out the anatomy of these attacks including how to make your system more secure. You will discover the best ways to defend against these vicious hacks with step-by-step instruction and learn techniques to make your computer and network impenetrable. .. .. Attacks detailed in this book include: ..: ..; Cross-Site Scripting (XSS) ..; Cross-Site Request Fo

  20. The Timing of Terrorist Attacks

    DEFF Research Database (Denmark)

    Jensen, Thomas

    2016-01-01

    I use a simple optimal stopping model to derive policy relevant insights on the timing of one-shot attacks by small autonomous terrorist units or “lone wolf” individuals. A main insight is that an increase in proactive counterterrorism measures can lead to a short term increase in the number...... of attempted terrorist attacks because it makes it more risky for existing terrorist units to pursue further development of capabilities. This is consistent with the events in London in 2005 where a terrorist attack on 7 July was followed by a similar but unsuccessful attack two weeks later....

  1. Seven Deadliest Social Network Attacks

    CERN Document Server

    Timm, Carl

    2010-01-01

    Do you need to keep up with the latest hacks, attacks, and exploits effecting social networks? Then you need Seven Deadliest Social Network Attacks. This book pinpoints the most dangerous hacks and exploits specific to social networks like Facebook, Twitter, and MySpace, laying out the anatomy of these attacks including how to make your system more secure. You will discover the best ways to defend against these vicious hacks with step-by-step instruction and learn techniques to make your computer and network impenetrable. Attacks detailed in this book include: Social Networking Infrastruct

  2. Binding Energy Calculation of Patchouli Alcohol Isomer Cyclooxygenase Complexes Suggested as COX-1/COX-2 Selective Inhibitor

    Directory of Open Access Journals (Sweden)

    Sentot Joko Raharjo

    2014-01-01

    Full Text Available To understand the structural features that dictate the selectivity of the two isoforms of the prostaglandin H2 synthase (PGHS/COX, the three-dimensional (3D structure of COX-1/COX-2 was assessed by means of binding energy calculation of virtual molecular dynamic with using ligand alpha-Patchouli alcohol isomers. Molecular interaction studies with COX-1 and COX-2 were done using the molecular docking tools by Hex 8.0. Interactions were further visualized by using Discovery Studio Client 3.5 software tool. The binding energy of molecular interaction was calculated by AMBER12 and Virtual Molecular Dynamic 1.9.1 software. The analysis of the alpha-Patchouli alcohol isomer compounds showed that all alpha-Patchouli alcohol isomers were suggested as inhibitor of COX-1 and COX-2. Collectively, the scoring binding energy calculation (with PBSA Model Solvent of alpha-Patchouli alcohol isomer compounds (CID442384, CID6432585, CID3080622, CID10955174, and CID56928117 was suggested as candidate for a selective COX-1 inhibitor and CID521903 as nonselective COX-1/COX-2.

  3. Crystallization of a Nonclassical Kazal-type Carcinoscorpius Rotundicauda Serine Protease Inhibitor, CrSPI-1, Complexed with Subtilisin

    Energy Technology Data Exchange (ETDEWEB)

    Tulsidas, S.; Thangamani, S; Ho, B; Sivaraman, J; Ding, J

    2009-01-01

    Serine proteases play a major role in host-pathogen interactions. The innate immune system is known to respond to invading pathogens in a nonspecific manner. The serine protease cascade is an essential component of the innate immune system of the horseshoe crab. The serine protease inhibitor CrSPI isoform 1 (CrSPI-1), a unique nonclassical Kazal-type inhibitor of molecular weight 9.3 kDa, was identified from the hepatopancreas of the horseshoe crab Carcinoscorpius rotundicauda. It potently inhibits subtilisin and constitutes a powerful innate immune defence against invading microbes. Here, the cloning, expression, purification and cocrystallization of CrSPI-1 with subtilisin are reported. The crystals diffracted to 2.6 {angstrom}resolution and belonged to space group P2{sub 1}, with unit-cell parameters a = 73.8, b = 65.0, c = 111.9 {angstrom}, {beta} = 95.4. The Matthews coefficient (VM = 2.64 {angstrom}3 Da-1, corresponding to 53% solvent content) and analysis of the preliminary structure solution indicated the presence of one heterotrimer (1:2 ratio of CrSPI-1:subtilisin) and one free subtilisin molecule in the asymmetric unit.

  4. Corrosion Inhibitors for Reinforced Concrete

    OpenAIRE

    ECT Team, Purdue

    2007-01-01

    Steel corrosion in reinforced concrete structures has been a major problem across the U.S. Steel-reinforced concrete structures are continually subject to attack by corrosion brought on by naturally occurring environmental conditions. FerroGard, a corrosion inhibitor, developed by Sika Corporation, penetrates hardened concrete to dramatically reduce corrosion by 65% and extend the structure's service life.

  5. Detonation nanodiamond complexes with cancer stem cells inhibitors or paracrine products of mesenchymal stem cells as new potential medications

    Science.gov (United States)

    Konoplyannikov, A. G.; Alekseenskiy, A. E.; Zlotin, S. G.; Smirnov, B. B.; Kalsina, S. Sh.; Lepehina, L. A.; Semenkova, I. V.; Agaeva, E. V.; Baboyan, S. B.; Rjumshina, E. A.; Nosachenko, V. V.; Konoplyannikov, M. A.

    2015-09-01

    Combined use of complexes of the most active chemotherapeutic drugs and detonation nanodiamonds (DND) is a new trend in cancer therapy, which is probably related to selective chemotherapeutic drug delivery by DND to the zone of so-called cancer stem cells (CSC). Stable DND complexes of 4-5 nm size with salinomycin—a strong CSC inhibitor—have been obtained (as a suspension). It has been demonstrated that a complex administration considerably increases the drug antitumor effect on the transplantable tumor of LLC mice. A similar effect has been observed in CSC models in vivo, obtained by exposure of stem cells of normal mice tissues to a carcinogen 1,2-dimethylhydrazine. It has also been found out, that administration of DND complexes with the conditioned medium from mesenchymal stem cells (MSC) cultures to mice results in a considerable stimulation of stem cell pools in normal mice tissues, which can be used in regenerative medicine.

  6. The versatile binding mode of transition-state analogue inhibitors of tyrosinase towards dicopper(II) model complexes: experimental and theoretical investigations.

    Science.gov (United States)

    Orio, Maylis; Bochot, Constance; Dubois, Carole; Gellon, Gisèle; Hardré, Renaud; Jamet, Hélène; Luneau, Dominique; Philouze, Christian; Réglier, Marius; Serratrice, Guy; Belle, Catherine

    2011-11-25

    We describe 2-mercaptopyridine-N-oxide (HSPNO) as a new and efficient competitive inhibitor of mushroom tyrosinase (K(IC) =3.7 μM). Binding studies of HSPNO and 2-hydroxypyridine-N-oxide (HOPNO) on dinuclear copper(II) complexes [Cu(2)(BPMP)(μ-OH)](ClO(4))(2) (1; HBPMP=2,6-bis[bis(2-pyridylmethyl)aminomethyl]-4-methylphenol) and [Cu(2)(BPEP)(μ-OH)](ClO(4))(2)) (2; HBPEP=2,6-bis{bis[2-(2-pyridyl)ethyl]aminomethyl}-4-methylphenol), known to be functional models for the tyrosinase diphenolase activity, have been performed. A combination of structural data, spectroscopic studies, and DFT calculations evidenced the adaptable binding mode (bridging versus chelating) of HOPNO in relation to the geometry and chelate size of the dicopper center. For comparison, binding studies of HSPNO and kojic acid (5-hydroxy-2-(hydroxymethyl)-4-pyrone) on dinuclear complexes were performed. A theoretical approach has been developed and validated on HOPNO adducts to compare the binding mode on the model complexes. It has been applied for HSPNO and kojic acid. Although results for HSPNO were in line with those obtained with HOPNO, thus reflecting their chemical similarity, we showed that the bridging mode was the most preferential binding mode for kojic acid on both complexes.

  7. The Staphylococcus aureus protein Sbi acts as a complement inhibitor and forms a tripartite complex with host complement Factor H and C3b.

    Directory of Open Access Journals (Sweden)

    Katrin Haupt

    2008-12-01

    Full Text Available The Gram-positive bacterium Staphylococcus aureus, similar to other pathogens, binds human complement regulators Factor H and Factor H related protein 1 (FHR-1 from human serum. Here we identify the secreted protein Sbi (Staphylococcus aureus binder of IgG as a ligand that interacts with Factor H by a-to our knowledge-new type of interaction. Factor H binds to Sbi in combination with C3b or C3d, and forms tripartite SbiratioC3ratioFactor H complexes. Apparently, the type of C3 influences the stability of the complex; surface plasmon resonance studies revealed a higher stability of C3d complexed to Sbi, as compared to C3b or C3. As part of this tripartite complex, Factor H is functionally active and displays complement regulatory activity. Sbi, by recruiting Factor H and C3b, acts as a potent complement inhibitor, and inhibits alternative pathway-mediated lyses of rabbit erythrocytes by human serum and sera of other species. Thus, Sbi is a multifunctional bacterial protein, which binds host complement components Factor H and C3 as well as IgG and beta(2-glycoprotein I and interferes with innate immune recognition.

  8. From indole to pyrrole, furan, thiophene and pyridine: Search for novel small molecule inhibitors of bacterial transcription initiation complex formation.

    Science.gov (United States)

    Thach, Oscar; Mielczarek, Marcin; Ma, Cong; Kutty, Samuel K; Yang, Xiao; Black, David StC; Griffith, Renate; Lewis, Peter J; Kumar, Naresh

    2016-03-15

    The search for small molecules capable of inhibiting transcription initiation in bacteria has resulted in the synthesis of N,N'-disubstituted hydrazines and imine-carbohydrazides comprised of indole, pyridine, pyrrole, furan and thiophene using the respective trichloroacetyl derivatives, carbohydrazides and aldehydes. Replacement of the indole moiety by smaller heterocycles linked by CONHNC linkers afforded a broad variety of compounds efficiently targeting the RNA polymerase-σ(70)/σ(A) interaction as determined by ELISA and exhibiting increased inhibition of the growth of Escherichia coli compared to Bacillus subtilis in culture. The structural features of the synthesized transcription initiation inhibitors needed for antibacterial activity were identified employing molecular modelling and structure-activity relationship (SAR) studies.

  9. Role of the Renin-Angiotensin-Aldosterone System and Its Pharmacological Inhibitors in Cardiovascular Diseases: Complex and Critical Issues.

    Science.gov (United States)

    Borghi, Claudio; Rossi, Francesco

    2015-12-01

    Hypertension is one of the major risk factor able to promote development and progression of several cardiovascular diseases, including left ventricular hypertrophy and dysfunction, myocardial infarction, stroke, and congestive heart failure. Also, it is one of the major driven of high cardiovascular risk profile in patients with metabolic complications, including obesity, metabolic syndrome and diabetes, as well as in those with renal disease. Thus, effective control of hypertension is a key factor for any preventing strategy aimed at reducing the burden of hypertension-related cardiovascular diseases in the clinical practice. Among various regulatory and contra-regulatory systems involved in the pathogenesis of cardiovascular and renal diseases, renin-angiotensin system (RAS) plays a major role. However, despite the identification of renin and the availability of various assays for measuring its plasma activity, the specific pathophysiological role of RAS has not yet fully characterized. In the last years, however, several notions on the RAS have been improved by the results of large, randomized clinical trials, performed in different clinical settings and in different populations treated with RAS inhibiting drugs, including angiotensin converting enzyme (ACE) inhibitors and antagonists of the AT1 receptor for angiotensin II (ARBs). These findings suggest that the RAS should be considered to have a central role in the pathogenesis of different cardiovascular diseases, for both therapeutic and preventive purposes, without having to measure its level of activation in each patient. The present document will discuss the most critical issues of the pathogenesis of different cardiovascular diseases with a specific focus on RAS blocking agents, including ACE inhibitors and ARBs, in the light of the most recent evidence supporting the use of these drugs in the clinical management of hypertension and hypertension-related cardiovascular diseases.

  10. Improved Linear Attacks on the Chinese Block Cipher Standard

    Institute of Scientific and Technical Information of China (English)

    刘明洁; 陈佳哲

    2014-01-01

    The block cipher used in the Chinese Wireless LAN Standard (WAPI), SMS4, was recently renamed as SM4, and became the block cipher standard issued by the Chinese government. This paper gives a method for finding the linear approximations of SMS4. With this method, 19-round one-dimensional approximations are given, which are used to improve the previous linear cryptanalysis of SMS4. The 19-round approximations hold with bias 2−62.27; we use one of them to leverage a linear attack on 23-round SMS4. Our attack improves the previous 23-round attacks by reducing the time complexity. Furthermore, the data complexity of our attack is further improved by the multidimensional linear approach.

  11. 一种复合型无磷缓蚀阻垢剂的研制%Research on a complex phosphate-free corrosion and scale inhibitor

    Institute of Scientific and Technical Information of China (English)

    曾德芳; 严欢

    2012-01-01

    A complex phosphate-free corrosion and scale inhibitors is made from 2 - acrylamido - 2 - methylpropane sulfonic acid (AMPS), inhibitor A, zinc salt , ascorbic acid. The formulations is se- lected from the static scale inhibition experiments and rotation coupon corrosion test. The results show when the quality of each component: 2 -acrylamido -2 -methylpropane sulfonic acid (AMPS) : BTA: zinc salts: inhibitor A = 5: 0. 3: 1.2:4 and when the dosage of the phosphate-free corrosion and scale inhibitor was 40 mg/L, the maximum inhibition and scale inhibition exceeded 92. 89% and 95.12% , respectively . Compared with the traditional corrosion and scale inhibitors , the corrosion inhibition ef- ficiency of this complex phosphate-free corrosion and scale inhibitors is almost the same, the inhibi- tion rate increased by 1.91%, and cost reduced by 16.67%. Since the recipe is Phosphate-free, it does not cause environmental eutrophication, so it has obvious environmental and economic benefits.%以2-丙烯酰胺基-2-甲基丙磺酸(AMPS)、缓蚀剂A、锌盐、抗坏血酸为原料进行复配,开发出一种复合型无磷缓蚀阻垢剂。通过静态阻垢实验、旋转挂片腐蚀实验、动电位电化学测试实验对配方进行筛选和测定。结果表明在各组分质量比为:2-丙烯酰胺基-2-甲基丙磺酸(AMPS):苯并三氮唑:锌盐:缓蚀剂A=5:0.3:1.2:4,复合型无磷缓蚀阻垢剂质量浓度为40mg/L时,缓蚀率达到92.89%,阻垢率达到95.12%。通过与传统含磷配方对比,该复合型无磷缓蚀阻垢剂与传统含磷配方缓蚀率相当,阻垢率提高1.91%,成本降低16.67%。由于该配方无磷,不会造成环境富营养化,具有明显环境与经济效益。

  12. Mitigation of Malicious Attacks on Networks

    CERN Document Server

    Schneider, Christian M; Andrade, Jose S; Havlin, Shlomo; Herrmann, Hans J; 10.1073/pnas.1009440108

    2011-01-01

    Terrorist attacks on transportation networks have traumatized modern societies. With a single blast, it has become possible to paralyze airline traffic, electric power supply, ground transportation or Internet communication. How and at which cost can one restructure the network such that it will become more robust against a malicious attack? We introduce a unique measure for robustness and use it to devise a method to mitigate economically and efficiently this risk. We demonstrate its efficiency on the European electricity system and on the Internet as well as on complex networks models. We show that with small changes in the network structure (low cost) the robustness of diverse networks can be improved dramatically while their functionality remains unchanged. Our results are useful not only for improving significantly with low cost the robustness of existing infrastructures but also for designing economically robust network systems.

  13. Vasoactivity of rucaparib, a PARP-1 inhibitor, is a complex process that involves myosin light chain kinase, P2 receptors, and PARP itself.

    Directory of Open Access Journals (Sweden)

    Cian M McCrudden

    Full Text Available Therapeutic inhibition of poly(ADP-ribose polymerase (PARP, as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699, induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.

  14. Interaction proteins of invertase and invertase inhibitor in cold-stored potato tubers suggested a protein complex underlying post-translational regulation of invertase.

    Science.gov (United States)

    Lin, Yuan; Liu, Jun; Liu, Xun; Ou, Yongbin; Li, Meng; Zhang, Huiling; Song, Botao; Xie, Conghua

    2013-12-01

    The activity of vacuolar invertase (VI) is vital to potato cold-induced sweetening (CIS). A post-translational regulation of VI activity has been proposed which involves invertase inhibitor (VIH), but the mechanism for the interaction between VI and VIH has not been fully understood. To identify the potential partners of VI and VIH, two cDNA libraries were respectively constructed from CIS-resistant wild potato species Solanum berthaultii and CIS-sensitive potato cultivar AC035-01 for the yeast two-hybrid analysis. The StvacINV1 (one of the potato VIs) and StInvInh2B (one of the potato VIHs), previously identified to be associated with potato CIS, were used as baits to screen the two libraries. Through positive selection and sequencing, 27 potential target proteins of StvacINV1 and eight of StInvInh2B were clarified. The Kunitz-type protein inhibitors were captured by StvacINV1 in both libraries and the interaction between them was confirmed by bimolecular fluorescence complementation assay in tobacco cells, reinforcing a fundamental interaction between VI and VIH. Notably, a sucrose non-fermenting-1-related protein kinase 1 was captured by both the baits, suggesting that a protein complex could be necessary for fine turning of the invertase activity. The target proteins clarified in present research provide a route to elucidate the mechanism by which the VI activity can be subtly modulated.

  15. A New Guess-and-Determine Attack on the A5/1

    CERN Document Server

    Shah, Jay

    2012-01-01

    In Europe and North America, the most widely used stream cipher to ensure privacy and confidentiality of conversations in GSM mobile phones is the A5/1. In this paper, we present a new attack on the A5/1 stream cipher with a minimum time complexity of around 2^(40) and an average complexity of 2^(48.5), which is much less than the brute-force attack with a complexity of 2^(64). The attack has a 100% success rate and requires about 5.65GB storage. We provide a detailed description of our new attack along with its implementation and results.

  16. Biological activities of Zn(II)-S-methyl-cysteine complex as antiradical, inhibitor of acid phosphatase enzyme and in vivo antidepressant effects.

    Science.gov (United States)

    Escudero, Graciela E; Martini, Nancy; Jori, Khalil; Jori, Nadir; Maresca, Nahuel R; Laino, Carlos H; Naso, Luciana G; Williams, Patricia A M; Ferrer, Evelina G

    2016-12-01

    The antidepressant effect of simple Zn(II) salts has been proved in several animal models of depression. In this study, a coordination metal complex of Zn(II) having a sulfur containing ligand is tested as antidepressant for the first time. Forced swimming test method on male Wistar rats shows a decrease in the immobility and an increase in the swimming behavior after treatment with [Zn(S-Met)2] (S-Met=S-methyl-l-cysteine) being more effective and remarkable than ZnCl2. The thiobarbituric acid and the pyranine consumption (hydroxyl and peroxyl radicals, respectively) methods were applied to evaluate the antioxidant activity of S-Met and [Zn(S-Met)2] showing evidence of attenuation of hydroxyl but not peroxyl radicals activities. UV-vis studies on the inhibition of acid phosphatase enzyme (AcP) demonstrated that S-methyl-l-cysteine did not produce any effect but, in contrast, [Zn(S-Met)2] complex behaved as a moderate inhibitor. Finally, bioavailability studies were performed by fluorescence spectroscopy denoting the ability of the albumin to transport the complex.

  17. The effect of mitochondrial complex I inhibitor on longevity of short-lived and long-lived seed beetles and its mitonuclear hybrids.

    Science.gov (United States)

    Jovanović, Darka Šešlija; Dorđević, Mirko; Savković, Uroš; Lazarević, Jelica

    2014-01-01

    Mitochondria are suggested to play a central role in ageing and evolution of longevity. Gradual decline in mitochondrial function during ageing and concomitant increase in production of reactive oxygen species (ROS) leads to oxidative damage of macromolecules and impairment of ATP synthesis. To assess relationship between ageing and oxidative stress resistance we exposed different longevity lines of the seed beetle (Acanthoscelides obtectus) to four concentrations of tebufenpyrad, mitochondrial complex I inhibitor. Complex I is one of main sites of ROS production during normal respiration and its inhibition elevates oxidative stress. Our results showed that 24 h of exposure to tebufenpyrad decreased survival and post-stress longevity due to increased baseline mortality. Higher resistance was recorded in beetles from lines selected for late reproduction and extended longevity (L) than in early reproducing beetles (E). Also, females were more resistant than males. Since complex I is under dual genetic control, our second aim was to disentangle relative contribution of nuclear and mitochondrial genes to the variation in longevity. We used crossed combinations of distinct mitochondrial and nuclear genotypes (E × L, L × E) and compared them to control hybrids where mitochondrial genome was "transplanted" onto the original background (E × E, L × L). Our study revealed significant effect of nucleus, i.e. higher survival and post-stress longevity in beetles harbouring L nucleus. Mitochondrion effect was significant only within L nuclear background where E mitochondrion gave advantage.

  18. Binding of the Respiratory Chain Inhibitor Antimycin to theMitochondrial bc1 Complex: A New Crystal Structure Reveals an AlteredIntramolecular Hydrogen-Bonding Pattern

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Li-shar; Cobessi, David; Tung, Eric Y.; Berry, Edward A.

    2005-05-10

    Antimycin A (antimycin), one of the first known and most potent inhibitors of the mitochondrial respiratory chain, binds to the quinone reduction site of the cytochrome bc1 complex.Structure-activity-relationship studies have shown that the N-formylamino-salicyl-amide group is responsible for most of the binding specificity, and suggested that a low pKa for the phenolic OH group and an intramolecular H-bond between that OH and the carbonyl O of the salicylamide linkage are important. Two previous X-ray structures of antimycin bound to vertebrate bc1 complex gave conflicting results. A new structure reported here of the bovine mitochondrial bc1 complex at 2.28Angstrom resolution with antimycin bound, allows us for the first time to reliably describe the binding of antimycin and shows that the intramolecular hydrogen bond described in solution and in the small-molecule structure is replaced by one involving the NH rather than carbonyl O of the amide linkage, with rotation of the amide group relative to the aromatic ring. The phenolic OH and formylamino N form H-bonds with conserved Asp228 of cyt b, and the formylamino O H-bonds via a water molecule to Lys227. A strong density the right size and shape for a diatomic molecule is found between the other side of the dilactone ring and the alpha-A helix.

  19. Refsum's Disease—Use of the Intestinal Lipase Inhibitor, Orlistat, as a Novel Therapeutic Approach to a Complex Disorder

    Directory of Open Access Journals (Sweden)

    Nimalie J. Perera

    2011-01-01

    Full Text Available Refsum's Disease is an inherited metabolic disorder in which a metabolite of branched chain fatty acids accumulates due to lack of appropriate oxidative enzymes. Patients have elevated plasma phytanic acid levels and high concentrations of phytanic acid in a variety of tissues leading to progressive tissue damage. Besides retinal degeneration or retinal dystrophy associated with adult onset retinitis pigmentosa, additional symptoms include chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, anosmia, ichthyosis, as well as skeletal, cardiac, hepatic, and renal abnormalities. Current management includes avoidance of dietary sources of branched chain fatty acids and regular plasmapheresis to prevent accumulation of these compounds to ameliorate progressive neurological deficits. Two brothers with Refsum's disease who experienced progressive symptoms despite optimal diet and plasmapheresis were commenced on a novel therapy. We report the effect of the intestinal lipase inhibitor, Orlistat, which led to significant reduction (P-value <0.001 on 2-sample unpaired t-test of mean preplasmapheresis phytanic acid levels with retardation of the progression of most of their dermatological and neurological symptoms.

  20. Assessing Terrorist Motivations for Attacking Critical Infrastructure

    Energy Technology Data Exchange (ETDEWEB)

    Ackerman, G; Abhayaratne, P; Bale, J; Bhattacharjee, A; Blair, C; Hansell, L; Jayne, A; Kosal, M; Lucas, S; Moran, K; Seroki, L; Vadlamudi, S

    2006-12-04

    Certain types of infrastructure--critical infrastructure (CI)--play vital roles in underpinning our economy, security and way of life. These complex and often interconnected systems have become so ubiquitous and essential to day-to-day life that they are easily taken for granted. Often it is only when the important services provided by such infrastructure are interrupted--when we lose easy access to electricity, health care, telecommunications, transportation or water, for example--that we are conscious of our great dependence on these networks and of the vulnerabilities that stem from such dependence. Unfortunately, it must be assumed that many terrorists are all too aware that CI facilities pose high-value targets that, if successfully attacked, have the potential to dramatically disrupt the normal rhythm of society, cause public fear and intimidation, and generate significant publicity. Indeed, revelations emerging at the time of this writing about Al Qaida's efforts to prepare for possible attacks on major financial facilities in New York, New Jersey, and the District of Columbia remind us just how real and immediate such threats to CI may be. Simply being aware that our nation's critical infrastructure presents terrorists with a plethora of targets, however, does little to mitigate the dangers of CI attacks. In order to prevent and preempt such terrorist acts, better understanding of the threats and vulnerabilities relating to critical infrastructure is required. The Center for Nonproliferation Studies (CNS) presents this document as both a contribution to the understanding of such threats and an initial effort at ''operationalizing'' its findings for use by analysts who work on issues of critical infrastructure protection. Specifically, this study focuses on a subsidiary aspect of CI threat assessment that has thus far remained largely unaddressed by contemporary terrorism research: the motivations and related factors that

  1. The Scale of Social Vulnerability to Terrorist Attack upon Large Complicated Commercial Complex:An Empirical Research on the Shanghai IFC Mall%大型复杂商业综合体恐袭社会脆弱性量表--基于上海国金中心商场IFC Mall的实证研究

    Institute of Scientific and Technical Information of China (English)

    刘霞; 李佩兵

    2016-01-01

    . Stream of people of high density, internal complex structure of large complex commercial complexes are often faced with more serious potential threat of terrorist attacks, but for large complicated commercial complex terrorist attacks social vulnerability research is rare. According to the classical cases from foreign complicated commercial complex terrorist attacks, we chose Shanghai IFC Mall as the research sample, collecting social measurement data and social survey data,by the methods of typical event expert interview, we extract the characteristic variables of terrorist attacks social vulnerability, and then set up the scale of IFC Mall terrorist attacks social vulnerability , measure the large complicated commercial complex terrorist attacks social vulnerability, and test the scale construct validity, content validity and reliability, the factor analysis results indicate that, for large complicated commercial complex,its terrorist attacks social vulnerability is mainly high exposure and low sensitivity for high density and high traffic shopping malls crowd and packing goods and dangerous goods. The research and development of large complicated commercial complex terrorist attacks social vulnerable volume table, can be used to measure the actual potential terrorist attacks of exposure and sensitivity, to provide scientific support for the terrorist attacks of risk management for Shanghai urban security management decision-making departments.

  2. Matrix metalloproteinases during and outside of migraine attacks without aura

    DEFF Research Database (Denmark)

    Ashina, M.; Tvedskov, J.F.; Thiesen, Kerstin Lipka

    2010-01-01

    Ashina M, Tvedskov JF, Lipka K, Bilello J, Penkowa M & Olesen J. Matrix metalloproteinases during and outside of migraine attacks without aura. Cephalalgia 2009. London. ISSN 0333-1024To test the hypothesis that permeability of the blood-brain barrier (BBB) is altered during migraine attack due...... to enhanced activation of matrix metalloproteinases (MMPs), we investigated MMP-3, MMP-9 and tissue inhibitor of metalloproteases (TIMP)-1 in the external jugular vein during and outside of migraine attacks in 21 patients with migraine without aura. In addition, we measured plasma levels of several other...... and interictal plasma levels of MMP-7, -8, -10 and TIMP-2 (P > 0.05). Our data suggest that plasma MMP-9 cannot be used as a biomarker of BBB disruption in migraine without aura. Decreased MMP-3 levels are an interesting and unexpected finding warranting further investigation....

  3. WILD PIG ATTACKS ON HUMANS

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, J.

    2013-04-12

    Attacks on humans by wild pigs (Sus scrofa) have been documented since ancient times. However, studies characterizing these incidents are lacking. In an effort to better understand this phenomenon, information was collected from 412 wild pig attacks on humans. Similar to studies of large predator attacks on humans, data came from a variety of sources. The various attacks compiled occurred in seven zoogeographic realms. Most attacks occurred within the species native range, and specifically in rural areas. The occurrence was highest during the winter months and daylight hours. Most happened under non-hunting circumstances and appeared to be unprovoked. Wounded animals were the chief cause of these attacks in hunting situations. The animals involved were typically solitary, male and large in size. The fate of the wild pigs involved in these attacks varied depending upon the circumstances, however, most escaped uninjured. Most human victims were adult males traveling on foot and alone. The most frequent outcome for these victims was physical contact/mauling. The severity of resulting injuries ranged from minor to fatal. Most of the mauled victims had injuries to only one part of their bodies, with legs/feet being the most frequent body part injured. Injuries were primarily in the form of lacerations and punctures. Fatalities were typically due to blood loss. In some cases, serious infections or toxemia resulted from the injuries. Other species (i.e., pets and livestock) were also accompanying some of the humans during these attacks. The fates of these animals varied from escaping uninjured to being killed. Frequency data on both non-hunting and hunting incidents of wild pig attacks on humans at the Savannah River Site, South Carolina, showed quantitatively that such incidents are rare.

  4. Superposition Attacks on Cryptographic Protocols

    DEFF Research Database (Denmark)

    Damgård, Ivan Bjerre; Funder, Jakob Løvstad; Nielsen, Jesper Buus

    2011-01-01

    Attacks on classical cryptographic protocols are usually modeled by allowing an adversary to ask queries from an oracle. Security is then defined by requiring that as long as the queries satisfy some constraint, there is some problem the adversary cannot solve, such as compute a certain piece...... of information. In this paper, we introduce a fundamentally new model of quantum attacks on classical cryptographic protocols, where the adversary is allowed to ask several classical queries in quantum superposition. This is a strictly stronger attack than the standard one, and we consider the security...

  5. Multiculturalism & The Charlie Hebdo Attack

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2016-01-01

    The attack on Charlie Hebdo has by many been linked to multiculturalism. But it is unclear exactly how the connection between multiculturalism and the attack should be understood and whether there indeed is such a connection. The article discusses this by distinguishing between different senses o...... of multiculturalism and different ways in which one might think that there is a link between multiculturalism and the attack. On this basis the resulting claims are discussed as to whether they are in fact plausible, which many of them turn out not to be....

  6. The Cyber-Physical Attacker

    DEFF Research Database (Denmark)

    Vigo, Roberto

    2012-01-01

    The world of Cyber-Physical Systems ranges from industrial to national interest applications. Even though these systems are pervading our everyday life, we are still far from fully understanding their security properties. Devising a suitable attacker model is a crucial element when studying...... the security properties of CPSs, as a system cannot be secured without defining the threats it is subject to. In this work an attacker scenario is presented which addresses the peculiarities of a cyber-physical adversary, and we discuss how this scenario relates to other attacker models popular in the security...

  7. Multiculturalism & The Charlie Hebdo Attack

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2016-01-01

    The attack on Charlie Hebdo has by many been linked to multiculturalism. But it is unclear exactly how the connection between multiculturalism and the attack should be understood and whether there indeed is such a connection. The article discusses this by distinguishing between different senses...... of multiculturalism and different ways in which one might think that there is a link between multiculturalism and the attack. On this basis the resulting claims are discussed as to whether they are in fact plausible, which many of them turn out not to be....

  8. Insights into the complex formed by matrix metalloproteinase-2 and alloxan inhibitors: molecular dynamics simulations and free energy calculations.

    Directory of Open Access Journals (Sweden)

    Ilenia Giangreco

    Full Text Available Matrix metalloproteinases (MMP are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell-surface receptors. Hence, the development of potent and selective inhibitors targeting these enzymes continues to be eagerly sought. In this paper, a number of alloxan-based compounds, initially conceived to bias other therapeutically relevant enzymes, were rationally modified and successfully repurposed to inhibit MMP-2 (also named gelatinase A in the nanomolar range. Importantly, the alloxan core makes its debut as zinc binding group since it ensures a stable tetrahedral coordination of the catalytic zinc ion in concert with the three histidines of the HExxHxxGxxH metzincin signature motif, further stabilized by a hydrogen bond with the glutamate residue belonging to the same motif. The molecular decoration of the alloxan core with a biphenyl privileged structure allowed to sample the deep S(1' specificity pocket of MMP-2 and to relate the high affinity towards this enzyme with the chance of forming a hydrogen bond network with the backbone of Leu116 and Asn147 and the side chains of Tyr144, Thr145 and Arg149 at the bottom of the pocket. The effect of even slight structural changes in determining the interaction at the S(1' subsite of MMP-2 as well as the nature and strength of the binding is elucidated via molecular dynamics simulations and free energy calculations. Among the herein presented compounds, the highest affinity (pIC(50 = 7.06 is found for BAM, a compound exhibiting also selectivity (>20 towards MMP-2, as compared to MMP-9, the other member of the gelatinases.

  9. The Attack Navigator

    NARCIS (Netherlands)

    Probst, Christian W.; Willemson, Jan; Pieters, Wolter; Mauw, Sjouke; Kordy, Barbara; Jajodia, Sushil

    2016-01-01

    The need to assess security and take protection decisions is at least as old as our civilisation. However, the complexity and develop-ment speed of our interconnected technical systems have surpassed our capacity to imagine and evaluate risk scenarios. This holds in particular for risks that are cau

  10. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes.

    Science.gov (United States)

    Hightower, Kendra E; Wang, Ruolan; Deanda, Felix; Johns, Brian A; Weaver, Kurt; Shen, Yingnian; Tomberlin, Ginger H; Carter, H Luke; Broderick, Timothy; Sigethy, Scott; Seki, Takahiro; Kobayashi, Masanori; Underwood, Mark R

    2011-10-01

    The integrase inhibitor (INI) dolutegravir (DTG; S/GSK1349572) has significant activity against HIV-1 isolates with raltegravir (RAL)- and elvitegravir (ELV)-associated resistance mutations. As an initial step in characterizing the different resistance profiles of DTG, RAL, and ELV, we determined the dissociation rates of these INIs with integrase (IN)-DNA complexes containing a broad panel of IN proteins, including IN substitutions corresponding to signature RAL and ELV resistance mutations. DTG dissociates slowly from a wild-type IN-DNA complex at 37°C with an off-rate of 2.7 × 10(-6) s(-1) and a dissociative half-life (t(1/2)) of 71 h, significantly longer than the half-lives for RAL (8.8 h) and ELV (2.7 h). Prolonged binding (t(1/2), at least 5 h) was observed for DTG with IN-DNA complexes containing E92, Y143, Q148, and N155 substitutions. The addition of a second substitution to either Q148 or N155 typically resulted in an increase in the off-rate compared to that with the single substitution. For all of the IN substitutions tested, the off-rate of DTG from IN-DNA complexes was significantly slower (from 5 to 40 times slower) than the off-rate of RAL or ELV. These data are consistent with the potential for DTG to have a higher genetic barrier to resistance, provide evidence that the INI off-rate may be an important component of the mechanism of INI resistance, and suggest that the slow dissociation of DTG may contribute to its distinctive resistance profile.

  11. The Nogo-C2/Nogo receptor complex regulates the morphogenesis of zebrafish lateral line primordium through modulating the expression of dkk1b, a Wnt signal inhibitor.

    Directory of Open Access Journals (Sweden)

    Hao-Wei Han

    Full Text Available The fish lateral line (LL is a mechanosensory system closely related to the hearing system of higher vertebrates, and it is composed of several neuromasts located on the surface of the fish. These neuromasts can detect changes in external water flow, to assist fish in maintaining a stationary position in a stream. In the present study, we identified a novel function of Nogo/Nogo receptor signaling in the formation of zebrafish neuromasts. Nogo signaling in zebrafish, like that in mammals, involves three ligands and four receptors, as well as three co-receptors (TROY, p75, and LINGO-1. We first demonstrated that Nogo-C2, NgRH1a, p75, and TROY are able to form a Nogo-C2 complex, and that disintegration of this complex causes defective neuromast formation in zebrafish. Time-lapse recording of the CldnB::lynEGFP transgenic line revealed that functional obstruction of the Nogo-C2 complex causes disordered morphogenesis, and reduces rosette formation in the posterior LL (PLL primordium during migration. Consistent with these findings, hair-cell progenitors were lost from the PLL primordium in p75, TROY, and Nogo-C2/NgRH1a morphants. Notably, the expression levels of pea3, a downstream marker of Fgf signaling, and dkk1b, a Wnt signaling inhibitor, were both decreased in p75, TROY, and Nogo-C2/NgRH1a morphants; moreover, dkk1b mRNA injection could rescue the defects in neuromast formation resulting from knockdown of p75 or TROY. We thus suggest that a novel Nogo-C2 complex, consisting of Nogo-C2, NgRH1a, p75, and TROY, regulates Fgf signaling and dkk1b expression, thereby ensuring stable organization of the PLL primordium.

  12. Synthesis and evaluation of the complex-forming ability of hydroxypyranones and hydroxypyridinones with Ni (II) as possible inhibitors for urease enzyme in Helicobacter pylori.

    Science.gov (United States)

    Palizban, Abbasali; Saghaie, Lotfollah

    2016-07-01

    The complex-forming ability of 2-methyl-3-hydroxypyran-4-one (1a), 2-ethyl-3-hydroxypyran-4-one (1b), 1,2-dimethyl-3-hydroxypyridin-4-one (4a) and 1-ethyl-2-methyl-3-hydroxypyridin-4-one (4b) with nickel(Ni(II)) were characterized by infrared, ultraviolet, proton nuclear magnetic resonance spectroscopy and melting point. The mole-ratio of nickel:ligands was analyzed by atomic-absorption-spectrometry. The partition-coefficients (KOW) of the compounds were also determined. The binding of ligands with Ni(II) are through deprotonated hydroxyl group (-O(-), disapeared at 3259 cm(-1)) and ioan-pairs of carbonyl group (=CO(.), shifted from 1650 to 1510-1515 cm(-1)). The characterization of complex geometry for bis-(2-methyl-3-hydroxypyranonato)Ni(II) (5a) and bis-(2-ethyl-3-hydroxypyranonato)Ni(II) (5b) predicted to be square-planer while for bis-(1,2-dimethyl-3-hydroxypyridinonato)Ni(II) (5c) and bis-(1-ethyl-2-methyl-3-hydroxypyridinonato)Ni(II) (5d) distorted to tetrahedral-geometry. Inhibitors of Helicobacter pylori urease are nickel chelators. The compounds 1a, 4a and 4b are likely suitable ligands with complex forming-ability to make complexes of 5a, 5c and 5d with nickel. The KOW values show the compound 5c with low partition-coefficient is more suitable ligand with lower penetration from GI lumen. Future studies demand to find out the biological activity of developed compounds on H. pylori.

  13. Synthesis and evaluation of the complex-forming ability of hydroxypyranones and hydroxypyridinones with Ni (II as possible inhibitors for urease enzyme in Helicobacter pylori

    Directory of Open Access Journals (Sweden)

    Abbasali Palizban

    2016-01-01

    Full Text Available The complex-forming ability of 2-methyl-3-hydroxypyran-4-one ( 1a , 2-ethyl-3-hydroxypyran-4-one ( 1b , 1,2-dimethyl-3-hydroxypyridin-4-one ( 4a and 1-ethyl-2-methyl-3- hydroxypyridin-4-one ( 4b with nickel(Ni(II were characterized by infrared, ultraviolet, proton nuclear magnetic resonance spectroscopy and melting point. The mole-ratio of nickel:ligands was analyzed by atomic-absorption-spectrometry. The partition-coefficients (K OW of the compounds were also determined. The binding of ligands with Ni(II are through deprotonated hydroxyl group (-O - , disapeared at 3259 cm -1 and ioan-pairs of carbonyl group (=CO . , shifted from 1650 to 1510-1515 cm -1 . The characterization of complex geometry for bis-(2-methyl-3-hydroxypyranonatoNi(II ( 5a and bis-(2-ethyl-3-hydroxypyranonatoNi(II ( 5b predicted to be square-planer while for bis-(1,2-dimethyl-3-hydroxypyridinonatoNi(II ( 5c and bis-(1-ethyl-2-methyl-3-hydroxypyridinonatoNi(II ( 5d distorted to tetrahedral-geometry. Inhibitors of Helicobacter pylori urease are nickel chelators. The compounds 1a , 4a and 4b are likely suitable ligands with complex forming-ability to make complexes of 5a , 5c and 5d with nickel. The K OW values show the compound 5c with low partition-coefficient is more suitable ligand with lower penetration from GI lumen. Future studies demand to find out the biological activity of developed compounds on H. pylori.

  14. An Enhanced SYN Cookie Defence Method for TCP DDoS Attack

    Directory of Open Access Journals (Sweden)

    Bo Hang

    2011-08-01

    Full Text Available With the development of network, the issues of network security are rapidly becoming a serious problem, and the Denial of Service (DoS attack has already become the greatest threat to the network. SYN Flood attack is one of the most common distributed denial of service attack way (DDoS. This paper presents an improved SYN Cookie method, designing a novel attack detector processing and a enhanced attack respondor with a new cookie verification algorithm and changing the definition of cookie field, to reduce algorithm complexity with the ensurance of security. The experiment results show that the proposed method provided an average computational complexity reduction of 30% compared with the traditional method. The new method can be an effective defense against the TCP SYN Flood attack with a lower complexity.

  15. Social Engineering:A Partial Technical attack

    Directory of Open Access Journals (Sweden)

    P. S. Maan

    2012-03-01

    Full Text Available This paper suggests the crystal clear concept behind the social engineering attack. Basically social engineering is a non technical attack. But social engineering attack is an attack on human psychology to get the information, but using what? Basically it is an attack on human psychology by using some technical skills or technology. Social engineering attack has many types like fake mail, telephonic cheat etc. which are impossible without any technical skills, so in this paper we suggest that , it is a partial technical attack and can be divided in human based and typical computer based social engineering attack.

  16. Impossible Differential Attacks on 13-Round CLEFIA-128

    Institute of Scientific and Technical Information of China (English)

    Hamid Mala; Mohammad Dakhilalian; Mohsen Shakiba

    2011-01-01

    CLEFIA,a new 128-bit block cipher proposed by Sony Corporation,is increasingly attracting cryptanalysts'attention.In this paper,we present two new impossible differential attacks on 13 rounds of CLEFIA-128.The proposed attacks utilize a variety of previously known techniques,in particular the hash table technique and redundancy in the key schedule of this block cipher.The first attack does not consider the whitening layers of CLEFIA,requires 2109.5 chosen plaintexts,and has a running time equivalent to about 2112.9 encryptions.The second attack preserves the whitening layers,requires 2117.8 chosen plaintexts,and has a total time complexity equivalent to about 2121.2 encryptions.

  17. Positive Mode LC-MS/MS Analysis of Chondroitin Sulfate Modified Glycopeptides Derived from Light and Heavy Chains of The Human Inter-α-Trypsin Inhibitor Complex.

    Science.gov (United States)

    Gomez Toledo, Alejandro; Nilsson, Jonas; Noborn, Fredrik; Sihlbom, Carina; Larson, Göran

    2015-12-01

    The inter-α-trypsin inhibitor complex is a macromolecular arrangement of structurally related heavy chain proteins covalently cross-linked to the chondroitin sulfate (CS) chain of the proteoglycan bikunin. The inter-α-trypsin inhibitor complex is abundant in plasma and associated with inflammation, kidney diseases, cancer and diabetes. Bikunin is modified at Ser-10 by a single low-sulfated CS chain of 23-55 monosaccharides with 4-9 sulfate groups. The innermost four monosaccharides (GlcAβ3Galβ3Galβ4Xylβ-O-) compose the linkage region, believed to be uniform with a 4-O-sulfation to the outer Gal. The cross-linkage region of the bikunin CS chain is located in the nonsulfated nonreducing end, (GalNAcβ4GlcAβ3)(n), to which heavy chains (H1-H3) may be bound in GalNAc to Asp ester linkages. In this study we employed a glycoproteomics protocol to enrich and analyze light and heavy chain linkage and cross-linkage region CS glycopeptides derived from the IαI complex of human plasma, urine and cerebrospinal fluid samples. The samples were trypsinized, enriched by strong anion exchange chromatography, partially depolymerized with chondroitinase ABC and analyzed by LC-MS/MS using higher-energy collisional dissociation. The analyses demonstrated that the CS linkage region of bikunin is highly heterogeneous. In addition to sulfation of the Gal residue, Xyl phosphorylation was observed although exclusively in urinary samples. We also identified novel Neu5Ac and Fuc modifications of the linkage region as well as the presence of mono- and disialylated core 1 O-linked glycans on Thr-17. Heavy chains H1 and H2 were identified cross-linked to GalNAc residues one or two GlcA residues apart and H1 was found linked to either the terminal or subterminal GalNAc residues. The fragmentation behavior of CS glycopeptides under variable higher-energy collisional dissociation conditions displays an energy dependence that may be used to obtain complementary structural details. Finally

  18. Crystal structures of the fungal pathogen Aspergillus fumigatus protein farnesyltransferase complexed with substrates and inhibitors reveal features for antifungal drug design.

    Science.gov (United States)

    Mabanglo, Mark F; Hast, Michael A; Lubock, Nathan B; Hellinga, Homme W; Beese, Lorena S

    2014-03-01

    Species of the fungal genus Aspergillus are significant human and agricultural pathogens that are often refractory to existing antifungal treatments. Protein farnesyltransferase (FTase), a critical enzyme in eukaryotes, is an attractive potential target for antifungal drug discovery. We report high-resolution structures of A. fumigatus FTase (AfFTase) in complex with substrates and inhibitors. Comparison of structures with farnesyldiphosphate (FPP) bound in the absence or presence of peptide substrate, corresponding to successive steps in ordered substrate binding, revealed that the second substrate-binding step is accompanied by motions of a loop in the catalytic site. Re-examination of other FTase structures showed that this motion is conserved. The substrate- and product-binding clefts in the AfFTase active site are wider than in human FTase (hFTase). Widening is a consequence of small shifts in the α-helices that comprise the majority of the FTase structure, which in turn arise from sequence variation in the hydrophobic core of the protein. These structural effects are key features that distinguish fungal FTases from hFTase. Their variation results in differences in steady-state enzyme kinetics and inhibitor interactions and presents opportunities for developing selective anti-fungal drugs by exploiting size differences in the active sites. We illustrate the latter by comparing the interaction of ED5 and Tipifarnib with hFTase and AfFTase. In AfFTase, the wider groove enables ED5 to bind in the presence of FPP, whereas in hFTase it binds only in the absence of substrate. Tipifarnib binds similarly to both enzymes but makes less extensive contacts in AfFTase with consequently weaker binding.

  19. Complexity

    CERN Document Server

    Gershenson, Carlos

    2011-01-01

    The term complexity derives etymologically from the Latin plexus, which means interwoven. Intuitively, this implies that something complex is composed by elements that are difficult to separate. This difficulty arises from the relevant interactions that take place between components. This lack of separability is at odds with the classical scientific method - which has been used since the times of Galileo, Newton, Descartes, and Laplace - and has also influenced philosophy and engineering. In recent decades, the scientific study of complexity and complex systems has proposed a paradigm shift in science and philosophy, proposing novel methods that take into account relevant interactions.

  20. A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts.

    Science.gov (United States)

    Han, Jinbin; Liu, Luming; Yue, Xiaoqiang; Chang, Jinjia; Shi, Weidong; Hua, Yongqiang

    2013-12-15

    It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF-Cu complex. DSF-Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC-Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC-Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC-Cu(I)-treated group. Our data indicates that DDTC-Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer.

  1. Lipophilic Cationic Cyanines Are Potent Complex I Inhibitors and Specific in Vitro Dopaminergic Toxins with Mechanistic Similarities to Both Rotenone and MPP(.).

    Science.gov (United States)

    Kadigamuwa, Chamila C; Mapa, Mapa S T; Wimalasena, Kandatege

    2016-09-19

    We have recently reported that simple lipophilic cationic cyanines are specific and potent dopaminergic toxins with a mechanism of toxicity similar to that of the Parkinsonian toxin MPP(+). In the present study, a group of fluorescent lipophilic cyanines have been used to further exploit the structure-activity relationship of the specific dopaminergic toxicity of cyanines. Here, we report that all cyanines tested were highly toxic to dopaminergic MN9D cells with IC50s in the range of 60-100 nM and not toxic to non-neuronal HepG2 cells parallel to that previously reported for 2,2'- and 4,4'-cyanines. All cyanines nonspecifically accumulate in the mitochondria of both MN9D and HepG2 cells at high concentrations, inhibit the mitochondrial complex I with the inhibition potencies similar to the potent complex I inhibitor, rotenone. They increase the reactive oxygen species (ROS) production specifically in dopaminergic cells causing apoptotic cell death. These and other findings suggest that the complex I inhibition, the expression of low levels of antioxidant enzymes, and presence of high levels of oxidatively labile radical propagator, dopamine, could be responsible for the specific increase in ROS production in dopaminergic cells. Thus, the predisposition of dopaminergic cells to produce high levels of ROS in response to mitochondrial toxins together with their inherent greater demand for energy may contribute to their specific vulnerability toward these toxins. The novel findings that cyanines are an unusual class of potent mitochondrial toxins with specific dopaminergic toxicity suggest that their presence in the environment could contribute to the etiology of PD similar to that of MPP(+) and rotenone.

  2. X-ray structure of the ternary MTX·NADPH complex of the anthrax dihydrofolate reductase: A pharmacophore for dual-site inhibitor design

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, Brad C.; Wan, Qun; Ahmad, Md Faiz; Langan, Paul; Dealwis, Chris G.; (Case Western); (LANL)

    2009-11-18

    For reasons of bioterrorism and drug resistance, it is imperative to identify and develop new molecular points of intervention against anthrax. Dihydrofolate reductase (DHFR) is a highly conserved enzyme and an established target in a number of species for a variety of chemotherapeutic programs. Recently, the crystal structure of B. anthracis DHFR (baDHFR) in complex with methotrexate (MTX) was determined and, based on the structure, proposals were made for drug design strategies directed against the substrate binding site. However, little is gleaned about the binding site for NADPH, the cofactor responsible for hydride transfer in the catalytic mechanism. In the present study, X-ray crystallography at 100 K was used to determine the structure of baDHFR in complex with MTX and NADPH. Although the NADPH binding mode is nearly identical to that seen in other DHFR ternary complex structures, the adenine moiety adopts an off-plane tilt of nearly 90 deg. and this orientation is stabilized by hydrogen bonds to functionally conserved Arg residues. A comparison of the binding site, focusing on this region, between baDHFR and the human enzyme is discussed, with an aim at designing species-selective therapeutics. Indeed, the ternary model, refined to 2.3{angstrom} resolution, provides an accurate template for testing the feasibility of identifying dual-site inhibitors, compounds that target both the substrate and cofactor binding site. With the ternary model in hand, using in silico methods, several compounds were identified which could potentially form key bonding contacts in the substrate and cofactor binding sites. Ultimately, two structurally distinct compounds were verified that inhibit baDHFR at low {mu}M concentrations. The apparent K{sub d} for one of these, (2-(3-(2-(hydroxyimino)-2-(pyridine-4-yl)-6,7-dimethylquinoxalin-2-yl)-1-(pyridine-4-yl)ethanone oxime), was measured by fluorescence spectroscopy to be 5.3 {mu}M.

  3. Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus

    Directory of Open Access Journals (Sweden)

    Melendez DP

    2015-08-01

    Full Text Available Dante P Melendez,1,2 Raymund R Razonable1,2 1Division of Infectious Diseases, 2William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA Abstract: Infection with cytomegalovirus is prevalent in immunosuppressed patients. In solid organ transplant and hematopoietic stem cell transplant recipients, cytomegalovirus infection is associated with high morbidity and preventable mortality. Prevention and treatment of cytomegalovirus with currently approved antiviral drugs is often associated with side effects that sometimes preclude their use. Moreover, cytomegalovirus has developed mutations that confer resistance to standard antiviral drugs. During the last decade, there have been calls to develop novel antiviral drugs that could provide better options for prevention and treatment of cytomegalovirus. Letermovir (AIC246 is a highly specific antiviral drug that is currently undergoing clinical development for the management of cytomegalovirus infection. It acts by inhibiting the viral terminase complex. Letermovir is highly potent in vitro and in vivo against cytomegalovirus. Because of a distinct mechanism of action, it does not exhibit cross-resistance with other antiviral drugs. It is predicted to be active against strains that are resistant to ganciclovir, foscarnet, and cidofovir. To date, early-phase clinical trials suggest a very low incidence of adverse effects. Herein, we present a comprehensive review on letermovir, from its postulated novel mechanism of action to the results of most recent clinical studies. Keywords: cytomegalovirus, letermovir, AIC246, terminase, antivirals, transplantation 

  4. Inhibition of Human Steroid 5-Reductase (AKR1D1) by Finasteride and Structure of the Enzyme-Inhibitor Complex

    Energy Technology Data Exchange (ETDEWEB)

    Drury, J.; Di Costanzo, L; Penning, T; Christianson, D

    2009-01-01

    The {Delta}{sup 4}-3-ketosteroid functionality is present in nearly all steroid hormones apart from estrogens. The first step in functionalization of the A-ring is mediated in humans by steroid 5{alpha}- or 5{beta}-reductase. Finasteride is a mechanism-based inactivator of 5{alpha}-reductase type 2 with subnanomolar affinity and is widely used as a therapeutic for the treatment of benign prostatic hyperplasia. It is also used for androgen deprivation in hormone-dependent prostate carcinoma, and it has been examined as a chemopreventive agent in prostate cancer. The effect of finasteride on steroid 5{beta}-reductase (AKR1D1) has not been previously reported. We show that finasteride competitively inhibits AKR1D1 with low micromolar affinity but does not act as a mechanism-based inactivator. The structure of the AKR1D1 {center_dot} NADP{sup +} {center_dot} finasteride complex determined at 1.7 {angstrom} resolution shows that it is not possible for NADPH to reduce the {Delta}{sup 1-2}-ene of finasteride because the cofactor and steroid are not proximal to each other. The C3-ketone of finasteride accepts hydrogen bonds from the catalytic residues Tyr-58 and Glu-120 in the active site of AKR1D1, providing an explanation for the competitive inhibition observed. This is the first reported structure of finasteride bound to an enzyme involved in steroid hormone metabolism.

  5. Detecting Multi-ChannelWireless Microphone User Emulation Attacks in White Space with Noise

    Directory of Open Access Journals (Sweden)

    Dan Shan

    2014-07-01

    Full Text Available Cognitive radio networks (CRNs are susceptible to primary user emulation (PUE attacks. Conventional PUE attack detection approaches consider television broadcasting as the primary user. In this work, however, we study a special kind of PUE attack named wireless microphone user emulation (WMUE attack. Existing work on WMUE attack detection deals with single channel senario. Although multi-channelWM(MCWM systems are common, detecting WMUE attacks under a multi-channel setting in noisy environments has not been well studied. In this work, we propose a novelmulti-channelWMUEattack detection scheme which operates in low signal-to-noise ratio (SNR environments with low computational complexity, thanks to the first 1.5-bit FM demodulator whose outputs are represented by only 0, 1 and -1. Experimental results show that, the proposed scheme can effectively detect multi-channel WMUE attacks within 0.25 second when SNR is lower than 6 dB.

  6. Inhibition of localized attack on the aluminium alloy AA 6351 in glycol/water solutions

    Energy Technology Data Exchange (ETDEWEB)

    Monticelli, C.; Brunoro, G.; Zucchi, F.; Fagioli, F.

    1989-06-01

    The objective of this work was to examine the feasibility of enhancing pitting resistance of AA 6351 (nominal composition: 1% Si, 0.6% Mg, 0.3% Mn, balance Al) by adding suitable inhibitors to the solutions. The compounds used were two inorganic salts: sodium molybdate and sodium tungstate and two derivatives of pyrimidine: 2-aminopyrimidine (2AP) and 2-hydroxypyrimidine (2HP). The inhibiting efficiencies of these substances were tested by both short-time electrochemical tests (galvanic coupling tests and polarization curves) and long-time immersions under experimental conditions causing the localized attack. Molybdate, tungstate and, to some extent, also 2AP efficiently inhibit AA 6351 localized corrosion in degraded solutions at 80/sup 0/C and in pure boiling solutions, for long exposure periods. The short-time electrochemical tests suggest that molybdate and tungstate are able to retard the electrochemical processes occurring on both the aluminium alloy and the small copper cathodic area produced by copper deposition. On the other hand, the 2AP efficiency is attributed to some complexing capability of this pyrimidine derivative towards dissolved copper ions, that are stabilized in solution. 2HP does not prevent AA 6351 localized attack. (orig./MM).

  7. Analytical Characterization of Internet Security Attacks

    Science.gov (United States)

    Sellke, Sarah H.

    2010-01-01

    Internet security attacks have drawn significant attention due to their enormously adverse impact. These attacks includes Malware (Viruses, Worms, Trojan Horse), Denial of Service, Packet Sniffer, and Password Attacks. There is an increasing need to provide adequate defense mechanisms against these attacks. My thesis proposal deals with analytical…

  8. Binding mode of CA074, a specific irreversible inhibitor, to bovine cathepsin B as determined by X-ray crystal analysis of the complex.

    Science.gov (United States)

    Yamamoto, A; Hara, T; Tomoo, K; Ishida, T; Fujii, T; Hata, Y; Murata, M; Kitamura, K

    1997-05-01

    The binding mode of CA074 [N-(L-3-trans-propylcarbamoyl-oxirane-2-carbonyl)-L-isoleucyl-L-pr oline], a specific irreversible inhibitor, to bovine spleen cathepsin B was elucidated by X-ray crystal structure analysis of the complex at 2.2 A resolution (conventional R=0.185). Inconsistently with our model used for the development of CA074, the L-isoleucyl-L-proline and propylcarbamoyl moieties are located at the S' and S subsites, respectively. This unexpected binding is primarily due to (i) similar extended chain conformations (due to the same S configurations) at the oxirane C2 and C3 atoms of CA074 and (ii) the just fit formation of double hydrogen bonds between the carboxyl oxygens of L-proline and the imidazole nitrogens of His-110 and His-111 residues (these residues are missing in papain, the tertiary structure of which was used for the design of CA074). The oxirane C3 atom possessing the P' substituent is covalently bound to the Cys-29 Sgamma atom (C3-Sgamma=1.79 A) and the S configuration is maintained. The present result will provide useful information for characterizing the substrate-specificity of cathepsin B.

  9. Crystal Structure of the Homo sapiens Kynureninase-3-Hydroxyhippuric Acid Inhibitor Complex: Insights into the Molecular Basis Of Kynureninase Substrate Specificity

    Energy Technology Data Exchange (ETDEWEB)

    Lima,Santiago; Kumar,Sunil; Gawandi,Vijay; Momany,Cory; Phillips,Robert S.; (Georgia)

    2009-02-23

    Homo sapiens kynureninase is a pyridoxal-5'-phosphate dependent enzyme that catalyzes the hydrolytic cleavage of 3-hydroxykynurenine to yield 3-hydroxyanthranilate and L-alanine as part of the tryptophan catabolic pathway leading to the de novo biosynthesis of NAD{sup +}. This pathway results in quinolinate, an excitotoxin that is an NMDA receptor agonist. High levels of quinolinate have been correlated with the etiology of neurodegenerative disorders such as AIDS-related dementia and Alzheimer's disease. We have synthesized a novel kynureninase inhibitor, 3-hydroxyhippurate, cocrystallized it with human kynureninase, and solved the atomic structure. On the basis of an analysis of the complex, we designed a series of His-102, Ser-332, and Asn-333 mutants. The H102W/N333T and H102W/S332G/N333T mutants showed complete reversal of substrate specificity between 3-hydroxykynurenine and L-kynurenine, thus defining the primary residues contributing to substrate specificity in kynureninases.

  10. Automated Generation of Attack Trees

    DEFF Research Database (Denmark)

    Vigo, Roberto; Nielson, Flemming; Nielson, Hanne Riis

    2014-01-01

    Attack trees are widely used to represent threat scenarios in a succinct and intuitive manner, suitable for conveying security information to non-experts. The manual construction of such objects relies on the creativity and experience of specialists, and therefore it is error-prone and impractica......Attack trees are widely used to represent threat scenarios in a succinct and intuitive manner, suitable for conveying security information to non-experts. The manual construction of such objects relies on the creativity and experience of specialists, and therefore it is error...

  11. 膜攻击复合物在特发性炎性肌肉病的表达研究%Expression of membrane attack complex in common idiopathic inflammatory myopathy

    Institute of Scientific and Technical Information of China (English)

    赵亚雯; 徐春晓; 刘靖; 左越焕; 张巍; 王朝霞; 袁云

    2015-01-01

    目的 总结膜攻击复合物在不同类型特发性炎性肌肉病的表达规律.方法 收集2011-2014年在北京大学第一医院收集的57例皮肌炎、37例多发性肌炎、9例散发性包涵体肌炎及15例抗信号识别颗粒(SRP)抗体免疫性坏死性肌病患者的肌肉活体组织标本,对其肌纤维和肌内衣毛细血管膜攻击复合物的表达率进行检测,采用x2检验或Fisher精确概率法进行统计学分析.结果 皮肌炎、多发性肌炎、散发性包涵体肌炎及抗SRP抗体免疫性坏死性肌病的肌肉膜攻击复合物表达总阳性率分别为75.4%(43/57)、86.5%(32/37)、4/9和13/15.肌纤维膜攻击复合物表达阳性率分别为50.9%(29/57)、81.1%(30/37)、3/9和13/15,肌内衣毛细血管膜攻击复合物表达阳性率分别为49.1% (28/57)、24.3%(9/37)、1/9和6/15.散发性包涵体肌炎的肌纤维和肌内衣毛细血管膜攻击复合物表达均低于其他类型炎性肌肉病,多发性肌炎和抗SRP抗体免疫性坏死性肌病的肌纤维膜攻击复合物表达阳性率差异无统计学意义,但均显著高于皮肌炎和散发性包涵体肌炎,皮肌炎和抗SRP抗体免疫性坏死性肌病的肌内衣毛细血管膜攻击复合物表达阳性率差异无统计学意义(x2=0.397,P=0.574),但均高于多发性肌炎和散发性包涵体肌炎.所有类型特发性炎性肌肉病的膜攻击复合物均存在区域性分布特点,其中11.6% (5/43)的皮肌炎患者出现束周分布.结论 膜攻击复合物在各种类型特发性炎性肌肉病的表达存在差异,抗SRP抗体免疫性坏死性肌病的膜攻击复合物表达兼具皮肌炎和多发性肌炎的特点.%Objective To analyze membrane attack complex (MAC) expression in different types of idiopathic inflammtory myopathy (IIM).Methods We enrolled 57 cases of dermatomyositis (DM) , 37 cases of polymyositis (PM) ,9 cases of sporadic inclusion body myositis (sIBM) and 15 cases of autoimmune necrotizing

  12. New Message Differences for Collision Attacks on MD4 and MD5

    Science.gov (United States)

    Sasaki, Yu; Wang, Lei; Kunihiro, Noboru; Ohta, Kazuo

    In 2005, collision resistance of several hash functions was broken by Wang et al. The strategy of determining message differences is the most important part of collision attacks against hash functions. So far, many researchers have tried to analyze Wang et al.'s method and proposed improved collision attacks. Although several researches proposed improved attacks, all improved results so far were based on the same message differences proposed by Wang et al. In this paper, we propose new message differences for collision attacks on MD4 and MD5. Our message differences of MD4 can generate a collision with complexity of less than two MD4 computations, which is faster than the original Wang et al.'s attack, and moreover, than the all previous attacks. This is the first result that improves the complexity of collision attack by using different message differences from Wang et al.'s. Regarding MD5, so far, no other message difference from Wang et al.'s is known. Therefore, study for constructing method of other message differences on MD5 should be interesting. Our message differences of MD5 generates a collision with complexity of 242 MD5 computations, which is slower than the latest best attack. However, since our attack needs only 1 bit difference, it has some advantages in terms of message freedom of collision messages.

  13. Impact of Degree Heterogeneity on Attack Vulnerability of Interdependent Networks

    Science.gov (United States)

    Sun, Shiwen; Wu, Yafang; Ma, Yilin; Wang, Li; Gao, Zhongke; Xia, Chengyi

    2016-09-01

    The study of interdependent networks has become a new research focus in recent years. We focus on one fundamental property of interdependent networks: vulnerability. Previous studies mainly focused on the impact of topological properties upon interdependent networks under random attacks, the effect of degree heterogeneity on structural vulnerability of interdependent networks under intentional attacks, however, is still unexplored. In order to deeply understand the role of degree distribution and in particular degree heterogeneity, we construct an interdependent system model which consists of two networks whose extent of degree heterogeneity can be controlled simultaneously by a tuning parameter. Meanwhile, a new quantity, which can better measure the performance of interdependent networks after attack, is proposed. Numerical simulation results demonstrate that degree heterogeneity can significantly increase the vulnerability of both single and interdependent networks. Moreover, it is found that interdependent links between two networks make the entire system much more fragile to attacks. Enhancing coupling strength between networks can greatly increase the fragility of both networks against targeted attacks, which is most evident under the case of max-max assortative coupling. Current results can help to deepen the understanding of structural complexity of complex real-world systems.

  14. FLOODING ATTACK AWARE SECURE AODV

    Directory of Open Access Journals (Sweden)

    S. Madhavi

    2013-01-01

    Full Text Available Providing security in a Mobile Ad hoc Network (MANET is a challenging task due to its inherent nature. Flooding is a type of Denial of Service (DoS attack in MANET. Intentional flooding may lead to disturbances in the networking operation. This kind of attack consumes battery power, storage space and bandwidth. Flooding the excessive number of packets may degrade the performance of the network. This study considers hello flooding attack. As the hello packets are continuously flooded by the malicious node, the neighbor node is not able to process other packets. The functioning of the legitimate node is diverted and destroys the networking operation. Absence of hello packet during the periodical hello interval may lead to wrong assumption that the neighbor node has moved away. So one of the intermediate neighbor nodes sends Route Error (RERR message and the source node reinitiates the route discovery process. In a random fashion the hello interval values are changed and convey this information to other nodes in the network in a secured manner. This study identifies and prevents the flooding attack. This methodology considers the performance parameters such as packet delivery ratio, delay and throughput. This algorithm is implemented in Secure AODV and tested in ad hoc environment. The result of the proposed algorithm decreases the control overhead by 2%.

  15. Mitigating Higher Ed Cyber Attacks

    Science.gov (United States)

    Rogers, Gary; Ashford, Tina

    2015-01-01

    In this presentation we will discuss the many and varied cyber attacks that have recently occurred in the higher ed community. We will discuss the perpetrators, the victims, the impact and how these institutions have evolved to meet this threat. Mitigation techniques and defense strategies will be covered as will a discussion of effective security…

  16. Television journalism during terror attacks

    DEFF Research Database (Denmark)

    Mogensen, Kirsten

    2008-01-01

    This article views television news coverage of ongoing terrorist attacks and their immediate aftermath as a special genre within journalism, and describes norms connected with the genre. The description is based on qualitative analyses of the coverage on major American networks the first 24 hours...

  17. Television Journalism During Terror Attacks

    DEFF Research Database (Denmark)

    Mogensen, Kirsten

    This article views television news coverage of ongoing terrorist attacks and their immediate aftermath as a special genre within journalism, and describes norms connected with the genre. The description is based on qualitative analyses of the coverage on the major American networks in the fi rst ...

  18. A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Han, Jinbin, E-mail: hanjinbin@gmail.com [Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032 (China); Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Shanghai Clinical Center, Chinese Academy of Sciences/Xuhui Central Hospital, Shanghai 200031 (China); Liu, Luming, E-mail: llm1010@163.com [Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032 (China); Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Yue, Xiaoqiang [Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Chang, Jinjia [Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032 (China); Shi, Weidong; Hua, Yongqiang [Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032 (China); Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032 (China)

    2013-12-15

    It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF–Cu complex. DSF–Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC–Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC–Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC–Cu(I)-treated group. Our data indicates that DDTC–Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer. - Highlights: • A new structure of DDTC–Cu(I) was reported for the first time. • DDTC–Cu(I) dissolved directly in water was for in vitro and in vivo uses. • DDTC–Cu(I) demonstrated significant anticancer effect in vitro and in vivo. • DDTC–Cu(I) is capable of inhibiting proteasome activity in vitro and in vivo.

  19. Assessing Terrorist Motivations for Attacking Critical Infrastructure

    Energy Technology Data Exchange (ETDEWEB)

    Ackerman, G; Abhayaratne, P; Bale, J; Bhattacharjee, A; Blair, C; Hansell, L; Jayne, A; Kosal, M; Lucas, S; Moran, K; Seroki, L; Vadlamudi, S

    2006-12-04

    Certain types of infrastructure--critical infrastructure (CI)--play vital roles in underpinning our economy, security and way of life. These complex and often interconnected systems have become so ubiquitous and essential to day-to-day life that they are easily taken for granted. Often it is only when the important services provided by such infrastructure are interrupted--when we lose easy access to electricity, health care, telecommunications, transportation or water, for example--that we are conscious of our great dependence on these networks and of the vulnerabilities that stem from such dependence. Unfortunately, it must be assumed that many terrorists are all too aware that CI facilities pose high-value targets that, if successfully attacked, have the potential to dramatically disrupt the normal rhythm of society, cause public fear and intimidation, and generate significant publicity. Indeed, revelations emerging at the time of this writing about Al Qaida's efforts to prepare for possible attacks on major financial facilities in New York, New Jersey, and the District of Columbia remind us just how real and immediate such threats to CI may be. Simply being aware that our nation's critical infrastructure presents terrorists with a plethora of targets, however, does little to mitigate the dangers of CI attacks. In order to prevent and preempt such terrorist acts, better understanding of the threats and vulnerabilities relating to critical infrastructure is required. The Center for Nonproliferation Studies (CNS) presents this document as both a contribution to the understanding of such threats and an initial effort at ''operationalizing'' its findings for use by analysts who work on issues of critical infrastructure protection. Specifically, this study focuses on a subsidiary aspect of CI threat assessment that has thus far remained largely unaddressed by contemporary terrorism research: the motivations and related factors that

  20. Crystal structure of the Bowman-Birk Inhibitor from Vigna unguiculata seeds in complex with beta-trypsin at 1.55 A resolution and its structural properties in association with proteinases.

    Science.gov (United States)

    Barbosa, João Alexandre R G; Silva, Luciano P; Teles, Rozeni C L; Esteves, Gisele F; Azevedo, Ricardo B; Ventura, Manuel M; de Freitas, Sonia M

    2007-03-01

    The structure of the Bowman-Birk inhibitor from Vigna unguiculata seeds (BTCI) in complex with beta-trypsin was solved and refined at 1.55 A to a crystallographic R(factor) of 0.154 and R(free) of 0.169, and represents the highest resolution for a Bowman-Birk inhibitor structure to date. The BTCI-trypsin interface is stabilized by hydrophobic contacts and hydrogen bonds, involving two waters and a polyethylene glycol molecule. The conformational rigidity of the reactive loop is characteristic of the specificity against trypsin, while hydrophobicity and conformational mobility of the antichymotryptic subdomain confer the self-association tendency, indicated by atomic force microscopy, of BTCI in complex and free form. When BTCI is in binary complexes, no significant differences in inhibition constants for producing a ternary complex with trypsin and chymotrypsin were detected. These results indicate that binary complexes present no conformational change in their reactive site for both enzymes confirming that these sites are structurally independent. The free chymotrypsin observed in the atomic force microscopy assays, when the ternary complex is obtained from BTCI-trypsin binary complex and chymotrypsin, could be related more to the self-association tendency between chymotrypsin molecules and the flexibility of the reactive site for this enzyme than to binding-related conformational changes.

  1. Using attack-defense trees to analyze threats and countermeasures in an ATM: a case study

    NARCIS (Netherlands)

    Fraile, Marlon; Ford, Margaret; Gadyatskaya, Olga; Kumar, Rajesh; Stoelinga, Mariëlle; Trujillo-Rasua, Rolando

    2016-01-01

    Securing automated teller machines (ATMs), as critical and complex infrastructure, requires a precise understanding of the associated threats. This paper reports on the application of attack-defense trees to model and analyze the security of ATMs.We capture the most dangerous multi-stage attack scen

  2. Finding multi-step attacks in computer networks using heuristic search and mobile ambients

    NARCIS (Netherlands)

    Franqueira, Virginia Nunes Leal

    2009-01-01

    An important aspect of IT security governance is the proactive and continuous identification of possible attacks in computer networks. This is complicated due to the complexity and size of networks, and due to the fact that usually network attacks are performed in several steps. This thesis proposes

  3. On Linear Hulls, Statistical Saturation Attacks, PRESENT and a Cryptanalysis of PUFFIN

    DEFF Research Database (Denmark)

    Leander, Gregor

    2011-01-01

    We discuss complexities of advanced linear attacks. In particular, we argue why it is often more appropriate to examine the median of the complexity than the average value. Moreover, we apply our methods to the block ciphers PUFFIN and PRESENT. For PUFFIN, a 128 bit key cipher, we present an attack...... which breaks the cipher for at least a quarter of the keys with a complexity less than 258. In the case of PRESENT we show that the design is sound. The design criteria are sufficient to ensure the resistance against linear attacks, taking into account the notion of linear hulls. Finally, we show...

  4. New related-key rectangle attacks on reduced AES-192 and AES-256

    Institute of Scientific and Technical Information of China (English)

    WEI YongZhuang; HU YuPu

    2009-01-01

    In this paper, we examine the security of reduced AES-192 and AES-256 against related-key rectangle attacks by exploiting the weakness in the AES key schedule. We find the following two new attacks: 9-round reduced AES-192 with 4 related keys, and 10-round reduced AES-256 with 4 related keys. Our results show that related-key rectangle attack with 4 related keys on 9-round reduced AES-192 requires a data complexity of about 2101 chosen plaintexts and a time complexity of about 2174.8 encryptions, and moreover, related-key rectangle attack with 4 related keys on 10-round reduced AES-256 requires a data complexity of about 297.5 chosen plaintexts and a time complexity of about 2254 encryptions. These attacks are the first known attacks on 9-round reduced AES-192 and 10-round reduced AES-256 with only 4 related keys. Furthermore, we give an improvement of the 10-round reduced AES-192 attack presented at FSE2007, which reduces both the data complexity and the time complexity.

  5. A simple coherent attack and practical security of differential phase shift quantum cryptography

    Science.gov (United States)

    Kronberg, D. A.

    2014-02-01

    The differential phase shift quantum key distribution protocol reveals good security against such powerful attacks as unambiguous state discrimination and beam splitting attacks. Its complete security analysis is complex due to high dimensions of the supposed spaces and density operators. In this paper, we consider a particular and conceptually simple coherent attack, available in practical implementations. The main condition for this attack is the length of used coherent state tuples of order 8-12. We show that under this condition, no high level of practical distance between legitimate users can be achieved.

  6. Jaguar attack on a child: case report and literature review.

    Science.gov (United States)

    Iserson, Kenneth V; Francis, Adama M

    2015-03-01

    Jaguar attacks on humans rarely occur in the wild. When they do, they are often fatal. We describe a jaguar attack on a three-year-old girl near her home deep in a remote area of the Guyanese jungle. The patient had a complex but, relatively, rapid transport to a medical treatment facility for her life-threatening injuries. The child, who suffered typical jaguar-inflicted injury patterns and survived, is highlighted. We review jaguar anatomy, environmental status, hunting and killing behaviors, and discuss optimal medical management, given the resource-limited treatment environment of this international emergency medicine case.

  7. Perfection of Recent Attacks using IP

    Directory of Open Access Journals (Sweden)

    A. RENGARAJAN

    2012-02-01

    Full Text Available The Internet threat monitoring (ITM systems have been deployed to detect widespread attacks on the Internet in recent years. However, the effectiveness of ITM systems critically depends on the confidentiality of the location of their monitors. If adversaries learn the monitor locations of an ITM system, they can bypass the monitors and focus on the uncovered IP address space without being detected. In this paper, we study a new class of attacks, the invisible LOCalization (iLOC attack. The iLOC attack can accurately and invisibly localize monitors of ITM systems. In the iLOC attack, the attacker launches low-rate port-scan traffic, encoded with a selected pseudo noise code (PN-code, to targeted networks. While the secret PN-code is invisible to others, the attacker can accurately determine the existence of monitors in the targeted networks based on whether the PN-code is embedded in the report data queried from the data center of the ITM system. We formally analyze the impact of various parameters on attack effectiveness. We implement the iLOC attack and conduct the performance evaluation on a real-world ITM system to demonstrate the possibility of such attacks. We also conduct extensive simulations on the iLOC attack using real-world traces. Our data show that the iLOC attack can accurately identify monitors while being invisible to ITM systems. Finally, we present a set of guidelines to counteract the iLOC attack.

  8. Trypanosoma cruzi trans-sialidase in complex with a neutralizing antibody: structure/function studies towards the rational design of inhibitors.

    Directory of Open Access Journals (Sweden)

    Alejandro Buschiazzo

    2012-01-01

    Full Text Available Trans-sialidase (TS, a virulence factor from Trypanosoma cruzi, is an enzyme playing key roles in the biology of this protozoan parasite. Absent from the mammalian host, it constitutes a potential target for the development of novel chemotherapeutic drugs, an urgent need to combat Chagas' disease. TS is involved in host cell invasion and parasite survival in the bloodstream. However, TS is also actively shed by the parasite to the bloodstream, inducing systemic effects readily detected during the acute phase of the disease, in particular, hematological alterations and triggering of immune cells apoptosis, until specific neutralizing antibodies are elicited. These antibodies constitute the only known submicromolar inhibitor of TS's catalytic activity. We now report the identification and detailed characterization of a neutralizing mouse monoclonal antibody (mAb 13G9, recognizing T. cruzi TS with high specificity and subnanomolar affinity. This mAb displays undetectable association with the T. cruzi superfamily of TS-like proteins or yet with the TS-related enzymes from Trypanosoma brucei or Trypanosoma rangeli. In immunofluorescence assays, mAb 13G9 labeled 100% of the parasites from the infective trypomastigote stage. This mAb also reduces parasite invasion of cultured cells and strongly inhibits parasite surface sialylation. The crystal structure of the mAb 13G9 antigen-binding fragment in complex with the globular region of T. cruzi TS was determined, revealing detailed molecular insights of the inhibition mechanism. Not occluding the enzyme's catalytic site, the antibody performs a subtle action by inhibiting the movement of an assisting tyrosine (Y₁₁₉, whose mobility is known to play a key role in the trans-glycosidase mechanism. As an example of enzymatic inhibition involving non-catalytic residues that occupy sites distal from the substrate-binding pocket, this first near atomic characterization of a high affinity inhibitory molecule

  9. Novel bis-(−)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Wei [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 (China); Li, Juan [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Qiu, Zhuibai [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Xia, Zheng [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Li, Wei [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Yu, Lining; Chen, Hailin; Chen, Jianxing [NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 (China); Chen, Yan; Hu, Zhuqin; Zhou, Wei; Shao, Biyun; Cui, Yongyao [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Xie, Qiong, E-mail: xiejoanxq@gmail.com [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Chen, Hongzhuan, E-mail: yaoli@shsmu.edu.cn [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)

    2012-10-01

    The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(−)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC{sub 50} values of 9.63 μM (for ZLA) and 8.64 μM (for ZLB), and prevent AChE-induced amyloid-β (Aβ) aggregation with IC{sub 50} values of 49.1 μM (for ZLA) and 55.3 μM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Aβ aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD. -- Highlights: ► Two novel bis-(−)-nor-meptazinol derivatives are designed and synthesized. ► ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency. ► They are potential leads for disease-modifying treatment of Alzheimer's disease.

  10. Conestat alfa for the treatment of angioedema attacks

    Directory of Open Access Journals (Sweden)

    Davis B

    2011-07-01

    Full Text Available Benjamin Davis, Jonathan A BernsteinUniversity of Cincinnati College of Medicine, Department of Internal Medicine, Division of Immunology/Allergy Section, Cincinnati, OH, USAAbstract: Recently, multiple C1 inhibitor (C1-INH replacement products have been approved for the treatment of hereditary angioedema (HAE. This review summarizes HAE and its current treatment modalities and focuses on findings from bench to bedside trials of a new C1-INH replacement, conestat alfa. Conestat alfa is unique among the other C1-INH replacement products because it is produced from transgenic rabbits rather than derived from human plasma donors, which can potentially allow an unlimited source of drug without any concern of infectious transmission. The clinical trial data generated to date indicate that conestat alfa is safe and effective for the treatment of acute HAE attacks.Keywords: androgens, adverse events, patients, HAE attacks 

  11. Ontology based Intrusion Detection System in Wireless Sensor Network for Active Attacks

    Directory of Open Access Journals (Sweden)

    Naheed Akhter

    2016-06-01

    Full Text Available WSNs are vulnerable to attacks and have deemed special attention for developing mechanism for securing against various threats that could effect the overall infrastructure. WSNs are open to miscellaneous classes of attacks and security breaches are intolerable in WSNs. Threats like untrusted data transmissions, settlement in open and unfavorable environments are still open research issues. Safekeeping is an essential and complex requirement in WSNs. These issues raise the need to develop a security-based mechanism for Wireless Sensor Network to categorize the different attacks based on their relevance. A detailed survey of active attacks is highlighted based on the nature and attributes of those attacks. An Ontology based mechanism is developed and tested for active attack in WSNs.

  12. Protecting Cryptographic Memory against Tampering Attack

    DEFF Research Database (Denmark)

    Mukherjee, Pratyay

    In this dissertation we investigate the question of protecting cryptographic devices from tampering attacks. Traditional theoretical analysis of cryptographic devices is based on black-box models which do not take into account the attacks on the implementations, known as physical attacks....... In practice such attacks can be executed easily, e.g. by heating the device, as substantiated by numerous works in the past decade. Tampering attacks are a class of such physical attacks where the attacker can change the memory/computation, gains additional (non-black-box) knowledge by interacting...... with the faulty device and then tries to break the security. Prior works show that generically approaching such problem is notoriously difficult. So, in this dissertation we attempt to solve an easier question, known as memory-tampering, where the attacker is allowed tamper only with the memory of the device...

  13. Zika Attacks Nerves, Muscles, Other Tissues

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_164010.html Zika Attacks Nerves, Muscles, Other Tissues Monkey study may ... 2017 (HealthDay News) -- Scientists have learned where the Zika virus attacks the body in monkeys. In their ...

  14. Stochastic Model of TCP SYN Attacks

    Directory of Open Access Journals (Sweden)

    Simona Ramanauskaitė

    2011-08-01

    Full Text Available A great proportion of essential services are moving into internet space making the threat of DoS attacks even more actual. To estimate the real risk of some kind of denial of service (DoS attack in real world is difficult, but mathematical and software models make this task easier. In this paper we overview the ways of implementing DoS attack models and offer a stochastic model of SYN flooding attack. It allows evaluating the potential threat of SYN flooding attacks, taking into account both the legitimate system flow as well as the possible attack power. At the same time we can assess the effect of such parameters as buffer capacity, open connection storage in the buffer or filte­ring efficiency on the success of different SYN flooding attacks. This model can be used for other type of memory depletion denial of service attacks.Article in Lithuanian

  15. Attacks and countermeasures on AES and ECC

    DEFF Research Database (Denmark)

    Tange, Henrik; Andersen, Birger

    2013-01-01

    is foreseeable while the rounds are performed. ECC (Elliptic Curve Cryptography) is used as a public key crypto system with the key purpose of creating a private shared between two participants in a communication network. Attacks on ECC include the Pohlig-Hellman attack and the Pollard's rho attack. Furthermore......AES (Advanced Encryption Standard) is widely used in LTE and Wi-Fi communication systems. AES has recently been exposed to new attacks which have questioned the overall security of AES. The newest attack is a so called biclique attack, which is using the fact that the content of the state array...... side-channels attacks can be applied to ECC. This paper reflects an ongoing research in the field of countermeasures against the attacks mentioned above....

  16. Computing Preferred Extensions for Argumentation Systems with Sets of Attacking

    DEFF Research Database (Denmark)

    Nielsen, Søren Holbech; Parsons, Simon

    2006-01-01

    The hitherto most abstract, and hence general, argumentation system, is the one described by Dung in a paper from 1995. This framework does not allow for joint attacks on arguments, but in a recent paper we adapted it to support such attacks, and proved that this adapted framework enjoyed the same...... formal properties as that of Dung. One problem posed by Dung's original framework, which was neglected for some time, is how to compute preferred extensions of the argumentation systems. However, in 2001, in a paper by Doutre and Mengin, a procedure was given for enumerating preferred extensions...... for these systems. In this paper we propose a method for enumerating preferred extensions of the potentially more complex systems, where joint attacks are allowed. The method is inspired by the one given by Doutre and Mengin....

  17. A Case Of Transient Ischemic Attack Presenting As Hemichroea

    Directory of Open Access Journals (Sweden)

    Hasan Hüseyin Özdemir

    2013-12-01

    Full Text Available Chorea is defined as; involuntary movements of the distal parts of limbs which have arrhythmic, rapid, bouncing or smooth, simple or complex properties. Choreiform movements occur when putamen, globus pallidus and subthalamic nucleus are affected. Chorea can be observed during the course of metabolic and vascular diseases, neurodegenerative or hereditary diseases. Chorea may be a rare symptom of cerebral hypoperfusion. Transient ischemic attack is an event that occurs in short term characterized by a temporary ischemia of brain. A wide variety of symptoms can be seen depending on the localization of cerebral hypoperfusion. Hemichorea is a very rare finding observed during transient ischemic attacks. In this article hemichorea in a case of symptomatic transient ischemic attack is discussed with relevant literature.

  18. Inhibitors for Androgen Receptor Activation Surfaces

    Science.gov (United States)

    2007-09-01

    mortality after heart attack (6), and RU486, which is used as emergency birth control (7). New NR inhibitors would most likely be useful for...mifepristone and levonorgestrel when used for emergency contraception. Hum Reprod Update 10:341-348 8. Webb P NN, Chiellini G, Yoshihara HA, Cunha Lima ST

  19. Biomechanics of knife stab attacks.

    Science.gov (United States)

    Chadwick, E K; Nicol, A C; Lane, J V; Gray, T G

    1999-10-25

    Equipment, materials and methods for the measurement of the biomechanical parameters governing knife stab attacks have been developed and data have been presented that are relevant to the improvement of standards for the testing of stab-resistant materials. A six-camera Vicon motion analysis system was used to measure velocity, and derive energy and momentum during the approach phase of the attack and a specially developed force-measuring knife was used to measure three-dimensional forces and torque during the impact phase. The body segments associated with the knife were modelled as a series of rigid segments: trunk, upper arm, forearm and hand. The velocities of these segments, together with knowledge of the mass distribution from biomechanical tables, allowed the calculation of the individual segment energy and momentum values. The instrumented knife measured four components of load: axial force (along the length of the blade), cutting force (parallel to the breadth of the blade), lateral force (across the blade) and torque (twisting action) using foil strain gauges. Twenty volunteers were asked to stab a target with near maximal effort. Three styles of stab were used: a short thrust forward, a horizontal style sweep around the body and an overhand stab. These styles were chosen based on reported incidents, providing more realistic data than had previously existed. The 95th percentile values for axial force and energy were 1885 N and 69 J, respectively. The ability of current test methods to reproduce the mechanical parameters measured in human stab attacks has been assessed. It was found that current test methods could reproduce the range of energy and force values measured in the human stab attacks, although the simulation was not accurate in some respects. Non-axial force and torque values were also found to be significant in the human tests, but these are not reproduced in the standard mechanical tests.

  20. Sybil attack in Wireless Sensor Network

    Directory of Open Access Journals (Sweden)

    Abirami.K

    2013-04-01

    Full Text Available Wireless network is very susceptible to different types of attack. The main attack is Sybil attack, which allows forming other attacks on the network. Security is very important to the wireless network. In wireless sensor network, to verify node identities by cryptographic authentication but this is not easy because sensor node which contains limited resources. Therefore the current research is going on how to handling the situation of different traffic levels and transmission power for security.

  1. New Multi-step Worm Attack Model

    OpenAIRE

    Robiah, Y.; Rahayu, S. Siti; Shahrin , S.; M. FAIZAL A.; Zaki, M. Mohd; Marliza, R.

    2010-01-01

    The traditional worms such as Blaster, Code Red, Slammer and Sasser, are still infecting vulnerable machines on the internet. They will remain as significant threats due to their fast spreading nature on the internet. Various traditional worms attack pattern has been analyzed from various logs at different OSI layers such as victim logs, attacker logs and IDS alert log. These worms attack pattern can be abstracted to form worms' attack model which describes the process of worms' infection. Fo...

  2. Measurement of homonuclear three-bond J(HNH{alpha}) coupling constants in unlabeled peptides complexed with labeled proteins: Application to a decapeptide inhibitor bound to the proteinase domain of the NS3 protein of hepatitis C virus (HCV)

    Energy Technology Data Exchange (ETDEWEB)

    Cicero, Daniel O.; Barbato, Gaetano; Koch, Uwe; Ingallinella, Paolo; Bianchi, Elisabetta; Sambucini, Sonia; Neddermann, Petra; De Francesco, Raffaele; Pessi, Antonello; Bazzo, Renzo

    2001-05-15

    A new isotope-filtered experiment has been designed to measure homonuclear three-bond J(H{sup N}H{sup {alpha}}) coupling constants of unlabeled peptides complexed with labeled proteins. The new experiment is based on the 3D HNHA pulse scheme, and belongs to the 'quantitative J-correlation' type. It has been applied to a decapeptide inhibitor bound to the proteinase domain of the NS3 protein of human hepatitis C virus (HCV)

  3. Timing and hamming weight attacks on minimal cost encryption scheme

    Institute of Scientific and Technical Information of China (English)

    YUAN Zheng; WANG Wei; ZHANG Hua; WEN Qiao-yan

    2009-01-01

    The timing and Hamming weight attacks on the data encryption standard (DES) cryptosystem for minimal cost encryption scheme is presented in this article. In the attack, timing information on encryption processing is used to select and collect effective plaintexts for attack. Then the collected plaintexts are utilized to infer the expanded key differences of the secret key, from which most bits of the expanded secret key are recovered. The remaining bits of the expanded secret key are deduced by the correlations between Hamming weight values of the input of the S-boxes in the first-round. Finally, from the linear relation of the encryption time and the secret key's Hamming weight, the entire 56 bits of the secret key are thoroughly recovered. Using the attack, the minimal cost encryption scheme can be broken with 223 known plaintexts and about 221 calculations at a success rate a>99%. The attack has lower computing complexity, and the method is more effective than other previous methods.

  4. 47 CFR 76.1612 - Personal attack.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 4 2010-10-01 2010-10-01 false Personal attack. 76.1612 Section 76.1612... CABLE TELEVISION SERVICE Notices § 76.1612 Personal attack. (a) When, during origination cablecasting of issues of public importance, an attack is made upon the honesty, character, integrity, or like...

  5. Cyberprints: Identifying Cyber Attackers by Feature Analysis

    Science.gov (United States)

    Blakely, Benjamin A.

    2012-01-01

    The problem of attributing cyber attacks is one of increasing importance. Without a solid method of demonstrating the origin of a cyber attack, any attempts to deter would-be cyber attackers are wasted. Existing methods of attribution make unfounded assumptions about the environment in which they will operate: omniscience (the ability to gather,…

  6. Attack Tree Generation by Policy Invalidation

    DEFF Research Database (Denmark)

    Ivanova, Marieta Georgieva; Probst, Christian W.; Hansen, Rene Rydhof;

    2015-01-01

    through brainstorming of experts. In this work we formalize attack tree generation including human factors; based on recent advances in system models we develop a technique to identify possible attacks analytically, including technical and human factors. Our systematic attack generation is based...

  7. On Mitigating Distributed Denial of Service Attacks

    Science.gov (United States)

    Gao, Zhiqiang

    2006-01-01

    Denial of service (DoS) attacks and distributed denial of service (DDoS) attacks are probably the most ferocious threats in the Internet, resulting in tremendous economic and social implications/impacts on our daily lives that are increasingly depending on the well-being of the Internet. How to mitigate these attacks effectively and efficiently…

  8. Postangioedema attack skin blisters: an unusual presentation of hereditary angioedema.

    Science.gov (United States)

    Wiesen, Jonathan; Gonzalez-Estrada, Alexei; Auron, Moises

    2014-04-10

    Hereditary angioedema (HAE) is an autosomal dominant disorder characterised by attacks of self-limited swelling affecting extremities, face and intra-abdominal organs, most often caused by mutations in the C1-inhibitor gene with secondary Bradykinin-mediated increased vascular permeability. We describe a 36-year-old man with a history of HAE who presented with painful interdigital bullae secondary to an acute oedema exacerbation. Biopsy and cultures of the lesions were negative and they resolved spontaneously. It is important to highlight and recognise the development of oedema blisters after resolution of a flare of HAE (only 1 previous case report), and hence avoid unnecessary dermatological diagnostic workup and treatment.

  9. Methods of Identifying and Preventing SQL Attacks

    Directory of Open Access Journals (Sweden)

    Bojken Shehu

    2012-11-01

    Full Text Available The paper begins by identifying the organizations which are vulnerable to the SQL attack referred to as an SQL injection attack. The term SQL injection attack is defined and a diagram is used to illustrate the way that attack occurs. In another section, the paper identifies the methods used to detect an attack to SQL, whereby the techniques are discussed extensively using relevant diagrams for illustration. The other sections cover the preventive methods, where the methods are also discussed with an illustration using diagrams.

  10. Lightweight Distance Bounding Protocol against Relay Attacks

    Science.gov (United States)

    Kim, Jin Seok; Cho, Kookrae; Yum, Dae Hyun; Hong, Sung Je; Lee, Pil Joong

    Traditional authentication protocols are based on cryptographic techniques to achieve identity verification. Distance bounding protocols are an enhanced type of authentication protocol built upon both signal traversal time measurement and cryptographic techniques to accomplish distance verification as well as identity verification. A distance bounding protocol is usually designed to defend against the relay attack and the distance fraud attack. As there are applications to which the distance fraud attack is not a serious threat, we propose a streamlined distance bounding protocol that focuses on the relay attack. The proposed protocol is more efficient than previous protocols and has a low false acceptance rate under the relay attack.

  11. Identification of quercitrin as an inhibitor of the p90 S6 ribosomal kinase (RSK): structure of its complex with the N-terminal domain of RSK2 at 1.8 Å resolution

    Energy Technology Data Exchange (ETDEWEB)

    Derewenda, Urszula; Artamonov, Mykhaylo; Szukalska, Gabriela; Utepbergenov, Darkhan; Olekhnovich, Natalya [University of Virginia, Charlottesville, VA 22908-0736 (United States); Parikh, Hardik I.; Kellogg, Glen E. [Virginia Commonwealth University, Richmond, VA 23298-0540 (United States); Somlyo, Avril V.; Derewenda, Zygmunt S., E-mail: zsd4n@virginia.edu [University of Virginia, Charlottesville, VA 22908-0736 (United States)

    2013-02-01

    The crystal structure of quercitrin, a naturally occurring flavonol glycoside, has been determined in a complex with the N-terminal kinase domain of murine RSK2. The structure revealed that quercitrin inhibits the RSK2 kinase in the same fashion as another known inhibitor, SL0101. Members of the RSK family of kinases constitute attractive targets for drug design, but a lack of structural information regarding the mechanism of selective inhibitors impedes progress in this field. The crystal structure of the N-terminal kinase domain (residues 45–346) of mouse RSK2, or RSK2{sup NTKD}, has recently been described in complex with one of only two known selective inhibitors, a rare naturally occurring flavonol glycoside, kaempferol 3-O-(3′′,4′′-di-O-acetyl-α-l-rhamnopyranoside), known as SL0101. Based on this structure, it was hypothesized that quercitrin (quercetin 3-O-α-l-rhamnopyranoside), a related but ubiquitous and inexpensive compound, might also act as an RSK inhibitor. Here, it is demonstrated that quercitrin binds to RSK2{sup NTKD} with a dissociation constant (K{sub d}) of 5.8 µM as determined by isothermal titration calorimetry, and a crystal structure of the binary complex at 1.8 Å resolution is reported. The crystal structure reveals a very similar mode of binding to that recently reported for SL0101. Closer inspection shows a number of small but significant differences that explain the slightly higher K{sub d} for quercitrin compared with SL0101. It is also shown that quercitrin can effectively substitute for SL0101 in a biological assay, in which it significantly suppresses the contractile force in rabbit pulmonary artery smooth muscle in response to Ca{sup 2+}.

  12. Whispering through DDoS attack

    Directory of Open Access Journals (Sweden)

    Miralem Mehic

    2016-03-01

    Full Text Available Denial of service (DoS attack is an attempt of the attacker to disable victim's machine by depleting network or computing resources. If this attack is performed with more than one machine, it is called distributed denial of service (DDoS attack. Covert channels are those channels which are used for information transmission even though they are neither designed nor intended to transfer information at all. In this article, we investigated the possibility of using of DDoS attack for purposes of hiding data or concealing the existing covert channel. In addition, in this paper we analyzed the possibility of detection of such covert communication with the well-known statistical method. Also, we proposed the coordination mechanisms of the attack which may be used. A lot of research has been done in order to describe and prevent DDoS attacks, yet research on steganography on this field is still scarce.

  13. Network Protection Against DDoS Attacks

    Directory of Open Access Journals (Sweden)

    Petr Dzurenda

    2015-03-01

    Full Text Available The paper deals with possibilities of the network protection against Distributed Denial of Service attacks (DDoS. The basic types of DDoS attacks and their impact on the protected network are presented here. Furthermore, we present basic detection and defense techniques thanks to which it is possible to increase resistance of the protected network or device against DDoS attacks. Moreover, we tested the ability of current commercial Intrusion Prevention Systems (IPS, especially Radware DefensePro 6.10.00 product against the most common types of DDoS attacks. We create five scenarios that are varied in type and strength of the DDoS attacks. The attacks intensity was much greater than the normal intensity of the current DDoS attacks.

  14. NETWORK SECURITY ATTACKS. ARP POISONING CASE STUDY

    Directory of Open Access Journals (Sweden)

    Luminiţa DEFTA

    2010-12-01

    Full Text Available Arp poisoning is one of the most common attacks in a switched network. A switch is a network device that limits the ability of attackers that use a packet sniffer to gain access to information from internal network traffic. However, using ARP poisoning the traffic between two computers can be intercepted even in a network that uses switches. This method is known as man in the middle attack. With this type of attack the affected stations from a network will have invalid entries in the ARP table. Thus, it will contain only the correspondence between the IP addresses of the stations from the same network and a single MAC address (the station that initiated the attack. In this paper we present step by step the initiation of such an attack in a network with three computers. We will intercept the traffic between two stations using the third one (the attacker.

  15. Attack Tree Generation by Policy Invalidation

    DEFF Research Database (Denmark)

    Ivanova, Marieta Georgieva; Probst, Christian W.; Hansen, Rene Rydhof

    2015-01-01

    Attacks on systems and organisations increasingly exploit human actors, for example through social engineering, complicating their formal treatment and automatic identification. Formalisation of human behaviour is difficult at best, and attacks on socio-technical systems are still mostly identifi...... on invalidating policies in the system model by identifying possible sequences of actions that lead to an attack. The generated attacks are precise enough to illustrate the threat, and they are general enough to hide the details of individual steps....... through brainstorming of experts. In this work we formalize attack tree generation including human factors; based on recent advances in system models we develop a technique to identify possible attacks analytically, including technical and human factors. Our systematic attack generation is based...

  16. SQL Injection Attacks and Defense

    CERN Document Server

    Clarke, Justin

    2012-01-01

    SQL Injection Attacks and Defense, First Edition: Winner of the Best Book Bejtlich Read Award "SQL injection is probably the number one problem for any server-side application, and this book unequaled in its coverage." -Richard Bejtlich, Tao Security blog SQL injection represents one of the most dangerous and well-known, yet misunderstood, security vulnerabilities on the Internet, largely because there is no central repository of information available for penetration testers, IT security consultants and practitioners, and web/software developers to turn to for help. SQL Injection Att

  17. Attack Coverage in High-Level Men’s Volleyball: Organization on the Edge of Chaos?

    Directory of Open Access Journals (Sweden)

    Laporta Lorenzo

    2015-09-01

    Full Text Available Change is pervasive, but emerging patterns are occasionally detectable through analysis of systemic behaviors. Match analysis uses these patterns in order to reduce the degree of improvisation and to optimize the training process. However, it is possible that certain game phases elude systematic patterning. In this vein, our aim was to analyze the case of attack coverage in men’s volleyball, as we suspected it would elude systematic patterning and has received negligible attention in scientific research. We analyzed the occurrence of attack coverage in 4544 plays of the 2011 Volleyball World League. A Chi-square test with residual adjusted values was applied to explore significant associations between variables. A Monte Carlo correction was applied, as some cells had n<5. Effect sizes were determined using Cramer’s V. Overall, attack coverage occurred in 3.89% of ball possessions, and 23 distinct structures emerged. These structures lacked significant associations with the game complex, setting zone, and effect of attack coverage. Conversely, attack coverage structures showed significant associations with the attack zone and tempo, with very strong effect sizes (V=0.472 and V=0.521, respectively. As certain attack zones are deeply associated with attack tempo, it is apparent that quicker attack plays affect attack coverage structuring, promoting the formation of less complex structures. Ultimately, attack coverage structures seem to depend on momentary constraints, thereby rendering rigid systematization impracticable. Still, we contended that a principle-based approach might be suitable. This invites researchers to rethink how to interpret game regularities.

  18. Migraine attacks the Basal Ganglia

    Directory of Open Access Journals (Sweden)

    Bigal Marcelo

    2011-09-01

    Full Text Available Abstract Background With time, episodes of migraine headache afflict patients with increased frequency, longer duration and more intense pain. While episodic migraine may be defined as 1-14 attacks per month, there are no clear-cut phases defined, and those patients with low frequency may progress to high frequency episodic migraine and the latter may progress into chronic daily headache (> 15 attacks per month. The pathophysiology of this progression is completely unknown. Attempting to unravel this phenomenon, we used high field (human brain imaging to compare functional responses, functional connectivity and brain morphology in patients whose migraine episodes did not progress (LF to a matched (gender, age, age of onset and type of medication group of patients whose migraine episodes progressed (HF. Results In comparison to LF patients, responses to pain in HF patients were significantly lower in the caudate, putamen and pallidum. Paradoxically, associated with these lower responses in HF patients, gray matter volume of the right and left caudate nuclei were significantly larger than in the LF patients. Functional connectivity analysis revealed additional differences between the two groups in regard to response to pain. Conclusions Supported by current understanding of basal ganglia role in pain processing, the findings suggest a significant role of the basal ganglia in the pathophysiology of the episodic migraine.

  19. Where can an Insider attack?

    DEFF Research Database (Denmark)

    Probst, Christian W.; Hansen, René Rydhof; Nielson, Flemming

    2006-01-01

    By definition, an insider has better access, is more trusted, and has better information about internal procedures, high-value targets, and potential weak spots in the security, than an outsider. Consequently, an insider attack has the potential to cause significant, even catastrophic, damage to ...... of the modelled systems. Our analysis of processes identifies which actions may be performed by whom, at which locations, accessing which data. This allows to compute a superset of audit results---before an incident occurs.......By definition, an insider has better access, is more trusted, and has better information about internal procedures, high-value targets, and potential weak spots in the security, than an outsider. Consequently, an insider attack has the potential to cause significant, even catastrophic, damage...... to the targeted organisation. While the problem is well recognised in the security community as well as in law-enforcement and intelligence communities, the main resort still is to audit log files \\$\\backslash\\$emph{after the fact}. There has been little research into developing models, automated tools...

  20. ACTIVITY ATTACK ON REDUCED VARIANTS OF RIJNDAEL

    Institute of Scientific and Technical Information of China (English)

    Wei Baodian; Liu Dongsu; Wang Xinmei

    2004-01-01

    The famous Square attacks against the Rijndael algorithm have taken advantage of the change of the balance of some bytes. Further study shows that the change of activity always happens before the change of balance, which builds the foundation for a new activity attack presented in this paper. In the activity attack, the round in which the activity changes is executed in an equivalent form to avoid the obstructive restriction of the subkeys of that round.The existence of the birthday paradox guarantees much fewer plaintexts necessary for activity attacks comparing with that for corresponding Square attacks. But no benefit may result from the new attacks performed independently because the activity attacks guess four instead of one key byte once. Only when both the balance property and the activity property are exploited at the same time can much better performance be obtained. The better performance in the simulation shows that the consuming time and chosen plaintexts necessary are both reduced to one tenth of those of the corresponding Square attacks. So the activity attacks could be viewed as an efficient supplement to the Square attacks.

  1. [Hereditary angioedema. Treatment of acute attacks in Argentina].

    Science.gov (United States)

    Malbrán, Alejandro; Malbrán, Eloisa; Menéndez, Alejandra; Fernández Romero, Diego S

    2014-01-01

    In the world, hereditary angioedema (HAE) affects 1 every 50000 persons. It is characterized by highly disabling and recurrent episodes of cutaneous, abdominal and laryngeal episodes of angioedema. Asphyxia related mortality ranges from 15 to 50%. In Argentina a plasma derived C1 inhibitor concentrate (pdC1INH) has been available for the treatment of acute attacks for many decades, however, only15 (26%) out of 58 patients had received pdC1INH at least once until 2008, and only2 (3.4%) had used it regularly. After worldwide approval of the new drugs for the treatment of acute HAE attacks, adding icatibant to pdC1INH in Argentina, and after publication of the therapeutic guide for the country, 42 (82%) out of 51 patients from the original group has pdC1INH available to treat their next attack. However, 16 (18%) patients continue without access to medication and other 15 (35.7%) obtain their therapy spuriously through some other affected relative in their environment. Only 12 (28.6%) patients of the group self-treated at home. Access to treatment has greatly improved, but needs to be extended to all patients and self-treatment at home should be encouraged.

  2. Management of acute attacks of hereditary angioedema: role of ecallantide

    Directory of Open Access Journals (Sweden)

    Duffey H

    2015-04-01

    Full Text Available Hannah Duffey,1 Rafael Firszt1,2 1Department of Pediatrics, 2Division of Allergy, Immunology and Rheumatology, University of Utah, Salt Lake City, UT, USA Abstract: Hereditary angioedema (HAE is characterized as an episodic swelling disorder with autosomal dominant inheritance. Clinical features include nonpitting edema of external or mucosal body surfaces, and patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can lead to asphyxiation. Patients with HAE classically have no associated urticaria, which is often referred to as nonhistaminergic angioedema. Treatment for HAE involves long-term prophylaxis, short-term prophylaxis, and management of acute attacks. Up until the past few years, acute HAE episodes were predominately treated with supportive measures. Three classes of medications have recently been approved by the US Food and Drug Administration (FDA for the management of acute HAE attacks. Ecallantide, a recombinant protein that acts as a reversible inhibitor of kallikrein, is currently indicated for acute attacks of HAE in those aged 12 years. In two randomized, double-blind, placebo-controlled, multicenter trials, EDEMA3 and EDEMA4, patients treated with 30 mg of ecallantide demonstrated statistically significant improvement in symptoms compared to those on placebo. In addition to its use as treatment for HAE, ecallantide has been used off label in the management of nonhistaminergic angioedema, not due to HAE. Ecallantide has shown promise in the treatment of these other forms; however, data are limited to mainly case reports at this time. Ecallantide is generally a safe and well-tolerated medication; however, based on reports of anaphylaxis, ecallantide does contain a black box warning. Due to the risk of anaphylaxis, ecallantide cannot be self-administered and must be given by a health care professional. Overall, ecallantide is a safe and effective medication for the

  3. Substitutions at NS3 Residue 155, 156, or 168 of Hepatitis C Virus Genotypes 2 to 6 Induce Complex Patterns of Protease Inhibitor Resistance

    DEFF Research Database (Denmark)

    Jensen, Sanne B.; Serre, Stephanie B. N.; Humes, Daryl G.

    2015-01-01

    Various protease inhibitors (PIs) are currently becoming available for treatment of hepatitis C virus (HCV). For genotype 1, substitutions at NS3 protease positions 155, 156, and 168 are main determinants of PI resistance. For other genotypes, similar substitutions were selected during PI treatme...

  4. Detection of Denial-of-service Attacks

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Denial-of-service (DOS) is a type of computer attack, which can essentially disable computers and networks.Resource consumption type of DOS attack could not be detected by the traditional misuse detection technique. This paper presents a new method of support vector mchine (SVM) to detect these attacks. We find that a DOS attack to a host is related to the activities within an impact data set of the host. The SVM method is used to classify the subsets of an impact data set to estimate its anomalism. The experiment result shows that this method can detect resource consumption type of DOS attacks, such as SYNflood, Smurf and UDP-storm. A receiver operating characteristic curve is plotted to determine performance for any possible operating point of the DOS attacks detection.

  5. Cyber attacks against state estimation in power systems: Vulnerability analysis and protection strategies

    Science.gov (United States)

    Liu, Xuan

    Power grid is one of the most critical infrastructures in a nation and could suffer a variety of cyber attacks. With the development of Smart Grid, false data injection attack has recently attracted wide research interest. This thesis proposes a false data attack model with incomplete network information and develops optimal attack strategies for attacking load measurements and the real-time topology of a power grid. The impacts of false data on the economic and reliable operations of power systems are quantitatively analyzed in this thesis. To mitigate the risk of cyber attacks, a distributed protection strategies are also developed. It has been shown that an attacker can design false data to avoid being detected by the control center if the network information of a power grid is known to the attacker. In practice, however, it is very hard or even impossible for an attacker to obtain all network information of a power grid. In this thesis, we propose a local load redistribution attacking model based on incomplete network information and show that an attacker only needs to obtain the network information of the local attacking region to inject false data into smart meters in the local region without being detected by the state estimator. A heuristic algorithm is developed to determine a feasible attacking region by obtaining reduced network information. This thesis investigates the impacts of false data on the operations of power systems. It has been shown that false data can be designed by an attacker to: 1) mask the real-time topology of a power grid; 2) overload a transmission line; 3) disturb the line outage detection based on PMU data. To mitigate the risk of cyber attacks, this thesis proposes a new protection strategy, which intends to mitigate the damage effects of false data injection attacks by protecting a small set of critical measurements. To further reduce the computation complexity, a mixed integer linear programming approach is also proposed to

  6. Fault Attack on the Balanced Shrinking Generator

    Institute of Scientific and Technical Information of China (English)

    GAO Juntao; LI Xuelian; HU Yupu

    2006-01-01

    Fault analysis, belonging to indirect attack, is a cryptanalysis technique for the physical implementation of cryptosystem. In this paper, we propose a fault attack on the Balanced Shrinking Generator. The results show that the attacker can obtain the secret key by analyzing faulty output sequences which is produced by changing control clock of one of Linear Feedback Shift Registers (LFSR). Therefore, the balanced shrinking generator has a trouble in hardware implementation.

  7. Impact of Alleged Russian Cyber Attacks

    Science.gov (United States)

    2009-05-01

    March 14, 2009). 96 Ivan Buranov, Vladimir Vodo, and Seda Yegikyan, Pro-Kremlin Activist Admits Attack on Estonian Websites, Denies Criminal...Vladimir Vodo, and Seda Yegikyan, Pro-Kremlin Activist Admits Attack on Estonian Websites, Denies Criminal Wrongdoing, Translated by Open Source...Buranov, Ivan; Vodo, Vladimir; and Yegikyan, Seda Pro-Kremlin Activist Admits Attack on Estonian Websites, Denies Criminal Wrongdoing, Translated

  8. Abnormal brain processing of cutaneous pain in migraine patients during the attack.

    Science.gov (United States)

    de Tommaso, Marina; Guido, Marco; Libro, Giuseppe; Losito, Luciana; Sciruicchio, Vittorio; Monetti, Carlo; Puca, Francomichele

    2002-11-15

    We examined cutaneous pain thresholds using CO(2) laser stimuli during migraine attacks, and defined the evoked cortical potential characteristics. Ten patients without aura were studied during attacks and for at least 72 h subsequently. Pain stimuli were generated on the dorsum of both hands and the right and left supraorbital zones, using pulses from a CO(2) laser. Absolute latencies of scalp potentials were measured at the highest peak of each response component, and the peak-to-peak amplitudes of N2a-P2 components were recorded. Cutaneous pain thresholds were significantly reduced on both the symptomatic and non-symptomatic sides during the attack, in comparison with the headache-free phase. The N2a-P2 complexes also increased in amplitude during attacks in comparison with the pain-free side. Thus, cutaneous hyperalgesia occurs during migraine attack, and is subtended by central sensitization phenomena, probably involving the cortex.

  9. Attacks on Local Searching Tools

    CERN Document Server

    Nielson, Seth James; Wallach, Dan S

    2011-01-01

    The Google Desktop Search is an indexing tool, currently in beta testing, designed to allow users fast, intuitive, searching for local files. The principle interface is provided through a local web server which supports an interface similar to Google.com's normal web page. Indexing of local files occurs when the system is idle, and understands a number of common file types. A optional feature is that Google Desktop can integrate a short summary of a local search results with Google.com web searches. This summary includes 30-40 character snippets of local files. We have uncovered a vulnerability that would release private local data to an unauthorized remote entity. Using two different attacks, we expose the small snippets of private local data to a remote third party.

  10. Improved Collision Attack on Hash Function MD5

    Institute of Scientific and Technical Information of China (English)

    Jie Liang; Xue-Jia Lai

    2007-01-01

    In this paper, we present a fast attack algorithm to find two-block collision of hash function MD5.The algorithm is based on the two-block collision differential path of MD5 that was presented by Wang et al.In the Conference EUROCRYPT 2005.We found that the derived conditions for the desired collision differential path were not sufficient to guarantee the path to hold and that some conditions could be modified to enlarge the collision set.By using technique of small range searching and omitting the computing steps to check the characteristics in the attack algorithm, we can speed up the attack of MD5 efficiently.Compared with the Advanced Message Modification technique presented by Wang et al.,the small range searching technique can correct 4 more conditions for the first iteration differential and 3 more conditions for the second iteration differential, thus improving the probability and the complexity to find collisions.The whole attack on the MD5 can be accomplished within 5 hours using a PC with Pentium4 1.70GHz CPU.

  11. Hello Flood Attack and its Countermeasures in Wireless Sensor Networks

    Directory of Open Access Journals (Sweden)

    Virendra Pal Singh

    2010-05-01

    Full Text Available Wireless sensor network have emerged as an important application of the ad-hoc networks paradigm, such as for monitoring physical environment. These sensor networks have limitations of system resources like battery power, communication range and processing capability. Low processing power and wireless connectivity make such networks vulnerable to various types of network attacks. One of them is hello flood attack, in which an adversary, which is not a legal node in the network, can flood hello request to any legitimate node and break the security of WSN. The current solutions for these types of attacks are mainly cryptographic, which suffer from heavy computational complexity. Hence they are less suitable for wireless sensor networks. In this paper a method based on signal strength has been proposed to detect and prevent hello flood attack. Nodes have been classified as friend and stranger based on the signal strength. Short client puzzles that require less computational power and battery power have been used to check the validity of suspicious nodes.

  12. Potential Security Attacks on Wireless Networks and their Countermeasure

    Directory of Open Access Journals (Sweden)

    Sreedhar. C

    2010-10-01

    Full Text Available The security of wireless networks has been a constant topic in the recent years. With the advance ofwireless networks, building reliable and secured communication is becoming extremely important.Wireless security is a mechanism of preventing unauthorized access or damage to computers usingwireless networks. A mobile ad-hoc network (MANET is a self-organizing system of mobile nodes thatcommunicate with each other through wireless links with no fixed infrastructure or centralizedadministration. This paper presents potential security attacks on Ad-hoc On-demand Distance Vector(AODV routing protocol and their countermeasure. IETF standardized AODV and considered as one ofthe most popular and promising on-demand routing protocols because of its lower network overhead andalgorithm complexity. AODV protocol does not store all the routing information in its routing table andthis causes potential security threat to the wireless networks. In this paper, we consider various knownsecurity attacks and in- specific blackhole attack on AODV and propose a countermeasure to thwartblackhole attack.

  13. Evaluation of Hypervisor Stability towards Insider Attacks

    Institute of Scientific and Technical Information of China (English)

    Roman Kulikov; Svetlana Kolesnikova

    2016-01-01

    Virtualization technology plays a key role in cloud computing. Thus, the security issues of virtualization tools (hypervisors, emulators, etc.) should be under precise consideration. However, threats of insider attacks are underestimated. The virtualization tools and hypervisors have been poorly protected from this type of attacks. Furthermore, hypervisor is one of the most critical elements in cloud computing infrastructure. Firstly, hypervisor vulnerabilities analysis is provided. Secondly, a formal model of insider attack on hypervisor is developed. Consequently, on the basis of the formal attack model, we propose a new methodology of hypervisor stability evaluation. In this paper, certain security countermeasures are considered that should be integrated in hypervisor software architecture.

  14. Colluding attacks on a group signature scheme

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Xie and Yu (2005) proposed a group signature scheme and claimed that it is the most efficient group signature scheme so far and secure. In this paper, we show that two dishonest group members can collude to launch two attacks on the scheme. In the first attack they can derive the group secret key and then generate untraceable group signatures. In the second attack, they can impersonate other group members once they see their signatures. Therefore we conclude that the signature scheme is not secure.We show that some parameters should be carefully selected in the scheme to resist our attacks.

  15. Off-Path Attacking the Web

    CERN Document Server

    Gilad, Yossi

    2012-01-01

    We show how an off-path (spoofing-only) attacker can perform cross-site scripting (XSS), cross-site request forgery (CSRF) and site spoofing/defacement attacks, without requiring vulnerabilities in either web-browser or server and circumventing known defenses. Attacker can also launch devastating denial of service (DoS) attacks, even when the connection between the client and the server is secured with SSL/TLS. The attacks are practical and require a puppet (malicious script in browser sandbox) running on a the victim client machine, and attacker capable of IP-spoofing on the Internet. Our attacks use a technique allowing an off-path attacker to learn the sequence numbers of both client and server in a TCP connection. The technique exploits the fact that many computers, in particular those running Windows, use a global IP-ID counter, which provides a side channel allowing efficient exposure of the connection sequence numbers. We present results of experiments evaluating the learning technique and the attacks ...

  16. Corrosion inhibitor development for slightly sour environments with oxygen intrusion

    Energy Technology Data Exchange (ETDEWEB)

    Wylde, J.; Wang, H.; Li, J. [Clariant Oil Services North America, Calgary, AB (Canada)

    2009-07-01

    This presentation reported on a study that examined the effect of oxygen on the inhibition of carbon steel in slightly sour corrosion, and the initiation and propagation of localized attack. Oxygen can enter sour water injection systems through the vapor space in storage tanks and process system. Oxygen aggravates the corrosion attack by participating in the cathodic reaction under full or partial diffusion control. Laboratory testing results were reported in this presentation along with the development of corrosion inhibitors for such a slightly sour system. Bubble testing cells were used with continuous H{sub 2}/CO{sub 2} mixture gas sparging and occasional oxygen intrusion of 2 to 4 hours during a week long test. Linear polarization resistance (LPR) measurements and weight loss corrosion coupons were used to quantify the corrosion attack. The findings were presented in terms of the magnitude of localized attacks at different oxygen concentrations and intrusion periods, with and without the presence of corrosion inhibitors. tabs., figs.

  17. Pediatric hereditary angioedema due to C1-inhibitor deficiency

    Directory of Open Access Journals (Sweden)

    Farkas Henriette

    2010-07-01

    Full Text Available Abstract Hereditary angioedema (HAE resulting from the deficiency of the C1 inhibitor (C1-INH is a rare, life-threatening disorder. It is characterized by attacks of angioedema involving the skin and/or the mucosa of the upper airways, as well as the intestinal mucosa. In approximately 50 per cent of cases, clinical manifestations may appear during childhood. The complex management of HAE in pediatric patients is in many respects different from the management of adults. Establishing the diagnosis early, preferably before the onset of clinical symptoms, is essential in cases with a positive family history. Complement studies usually afford accurate diagnosis, whereas molecular genetics tests may prove helpful in uncertain cases. Appropriate therapy, supported by counselling, suitable modification of lifestyle, and avoidance of triggering factors (which primarily include mechanical trauma, mental stress and airway infections in children may spare the patient unnecessary surgery and may prevent mortality. Prompt control of edematous attacks, short-term prophylaxis and intermittent therapy are recommended as the primary means for the management of pediatric cases. Medicinal products currently used for the treatment of children with hereditary angioedema include antifibrinolytics, attenuated androgens, and C1-INH replacement therapy. Current guidelines favour antifibrinolytics for long-term prophylaxis because of their favorable safety profile but efficacy may be lacking. Attenuated androgens administered in the lowest effective dose are another option. C1-INH replacement therapy is also an effective and safe agent for children. Regular monitoring and follow-up of patients are necessary.

  18. Theoretical studies on the interaction between the nitrile-based inhibitors and the catalytic triad of Cathepsin K.

    Science.gov (United States)

    Pitchumani Violet Mary, C; Shankar, R; Vijayakumar, S

    2017-02-20

    Computational studies on the interaction of novel inhibitor compounds with the Cathepsin K protease have been performed to study the inhibition properties of the inhibitor compounds. The quantum chemical calculations have been performed to analyze the molecular geometries, structural stability, reactivity, nature of interaction, and the charge transfer properties using B3LYP level of theory by implementing 6-311g(d,p) basis set. The calculated C-S and N-H…N bond lengths of the inhibitor-triad complexes are found to agree well with the previous literature results. The chemical reactivity of the inhibitors and catalytic triad are analyzed through frontier molecular orbital analysis and found that the inhibitors are subjected to nucleophilic attack by the catalytic triad. The nature of inhibition of the inhibitor compounds is examined using the quantum theory of Atoms in Molecules analysis and found to be partially covalent. The NBO stabilization energy for the Cys - inhibitor are found to be most stable than the other interactions. The molecular dynamic simulations were performed to study the influence of dynamic of the active site on the QM results. The many body decomposition interaction energy calculated for the final results of MD simulation reveals that the dynamic of the active site induces significant changes in the interaction energy and occupancy of H-bonds plays a major role in the stabilizing the active site inhibitor interactions. The present study reveals that the inhibitor compounds can inhibit the proteolytic activity of the proteases on binding with the catalytic active site.

  19. Chiral gold(I vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK-hepatitis C virus inhibitor

    Directory of Open Access Journals (Sweden)

    María Martín-Rodríguez

    2011-07-01

    Full Text Available The synthesis of a GSK 2nd generation inhibitor of the hepatitis C virus, by enantioselective 1,3-dipolar cycloaddition between a leucine derived iminoester and tert-butyl acrylate, was studied. The comparison between silver(I and gold(I catalysts in this reaction was established by working with chiral phosphoramidites or with chiral BINAP. The best reaction conditions were used for the total synthesis of the hepatitis C virus inhibitor by a four step procedure affording this product in 99% ee and in 63% overall yield. The origin of the enantioselectivity of the chiral gold(I catalyst was justified according to DFT calculations, the stabilizing coulombic interaction between the nitrogen atom of the thiazole moiety and one of the gold atoms being crucial.

  20. Ternary complex structures of human farnesyl pyrophosphate synthase bound with a novel inhibitor and secondary ligands provide insights into the molecular details of the enzyme’s active site closure

    Directory of Open Access Journals (Sweden)

    Park Jaeok

    2012-12-01

    Full Text Available Abstract Background Human farnesyl pyrophosphate synthase (FPPS controls intracellular levels of farnesyl pyrophosphate, which is essential for various biological processes. Bisphosphonate inhibitors of human FPPS are valuable therapeutics for the treatment of bone-resorption disorders and have also demonstrated efficacy in multiple tumor types. Inhibition of human FPPS by bisphosphonates in vivo is thought to involve closing of the enzyme’s C-terminal tail induced by the binding of the second substrate isopentenyl pyrophosphate (IPP. This conformational change, which occurs through a yet unclear mechanism, seals off the enzyme’s active site from the solvent environment and is essential for catalysis. The crystal structure of human FPPS in complex with a novel bisphosphonate YS0470 and in the absence of a second substrate showed partial ordering of the tail in the closed conformation. Results We have determined crystal structures of human FPPS in ternary complex with YS0470 and the secondary ligands inorganic phosphate (Pi, inorganic pyrophosphate (PPi, and IPP. Binding of PPi or IPP to the enzyme-inhibitor complex, but not that of Pi, resulted in full ordering of the C-terminal tail, which is most notably characterized by the anchoring of the R351 side chain to the main frame of the enzyme. Isothermal titration calorimetry experiments demonstrated that PPi binds more tightly to the enzyme-inhibitor complex than IPP, and differential scanning fluorometry experiments confirmed that Pi binding does not induce the tail ordering. Structure analysis identified a cascade of conformational changes required for the C-terminal tail rigidification involving Y349, F238, and Q242. The residues K57 and N59 upon PPi/IPP binding undergo subtler conformational changes, which may initiate this cascade. Conclusions In human FPPS, Y349 functions as a safety switch that prevents any futile C-terminal closure and is locked in the “off” position in the

  1. Identification and Development of 2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one Inhibitors Targeting Bromodomains within the Switch/Sucrose Nonfermenting Complex.

    Science.gov (United States)

    Sutherell, Charlotte L; Tallant, Cynthia; Monteiro, Octovia P; Yapp, Clarence; Fuchs, Julian E; Fedorov, Oleg; Siejka, Paulina; Müller, Suzanne; Knapp, Stefan; Brenton, James D; Brennan, Paul E; Ley, Steven V

    2016-05-26

    Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these proteins and display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a KD of 124 nM, SMARCA2B and SMARCA4 with KD values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4.

  2. Angioedema attacks in patients with hereditary angioedema: Local manifestations of a systemic activation process.

    Science.gov (United States)

    Hofman, Zonne L M; Relan, Anurag; Zeerleder, Sacha; Drouet, Christian; Zuraw, Bruce; Hack, C Erik

    2016-08-01

    Hereditary angioedema (HAE) caused by a deficiency of functional C1-inhibitor (C1INH) becomes clinically manifest as attacks of angioedema. C1INH is the main inhibitor of the contact system. Poor control of a local activation process of this system at the site of the attack is believed to lead to the formation of bradykinin (BK), which increases local vasopermeability and mediates angioedema on interaction with BK receptor 2 on the endothelium. However, several observations in patients with HAE are difficult to explain from a pathogenic model claiming a local activation process at the site of the angioedema attack. Therefore we postulate an alternative model for angioedema attacks in patients with HAE, which assumes a systemic, fluid-phase activation of the contact system to generate BK and its breakdown products. Interaction of these peptides with endothelial receptors that are locally expressed in the affected tissues rather than with receptors constitutively expressed by the endothelium throughout the whole body explains that such a systemic activation process results in local manifestations of an attack. In particular, BK receptor 1, which is induced on the endothelium by inflammatory stimuli, such as kinins and cytokines, meets the specifications of the involved receptor. The pathogenic model discussed here also provides an explanation for why angioedema can occur at multiple sites during an attack and why HAE attacks respond well to modest increases of circulating C1INH activity levels because inhibition of fluid-phase Factor XIIa and kallikrein requires lower C1INH levels than inhibition of activator-bound factors.

  3. Development of an Attack-Resistant and Secure SCADA System using WSN, MANET, and Internet

    Directory of Open Access Journals (Sweden)

    N. Rajesh kumar

    2014-06-01

    Full Text Available Industrial Control Systems (ICS are open to security attacks when they are integrated with IT systems and wireless technologies for enhanced processing and remote control. These Critical Infrastructures (CIs are highly important as they provide service for an entire nation and causes serious danger even when interrupted for a while. Some of the common SCADA (Supervisory Control and Data Acquisition systems involve energy and water distribution systems. In this paper, the energy distribution SCADA system comprising several substations is considered. A secure framework is proposed that combines the energy control system with Wireless Sensor Networks (WSNs, Mobile Ad hoc Networks (MANETs, and the Internet, providing anomaly prevention and status management. SCADA attacks occur at the state estimators of the power systems which are used to route power flows and detect faulty devices. These estimators are located in the SCADA control center which is a sensitive area and measurements must be transmitted over a secure communication channel. The attack-resistance of the SCADA system is enhanced by increasing the hardness and complexity of the attack problem. The Attack-Resistant and Secure (ARS SCADA system is evaluated against existing techniques like NAMDIA (Network-Aware Mitigation of Data Integrity Attacks, Retrofit IDS (Intrusion Detection System, and CSBF (Critical State-Based Filtering for enhancing the attack-resistance and security of SCADA systems. It is found that the performance of ARS SCADA system is good compared to the existing methods in terms of maximum normalized attack impact and latency.

  4. Proto-cooperation: group hunting sailfish improve hunting success by alternating attacks on grouping prey.

    Science.gov (United States)

    Herbert-Read, James E; Romanczuk, Pawel; Krause, Stefan; Strömbom, Daniel; Couillaud, Pierre; Domenici, Paolo; Kurvers, Ralf H J M; Marras, Stefano; Steffensen, John F; Wilson, Alexander D M; Krause, Jens

    2016-11-16

    We present evidence of a novel form of group hunting. Individual sailfish (Istiophorus platypterus) alternate attacks with other group members on their schooling prey (Sardinella aurita). While only 24% of attacks result in prey capture, multiple prey are injured in 95% of attacks, resulting in an increase of injured fish in the school with the number of attacks. How quickly prey are captured is positively correlated with the level of injury of the school, suggesting that hunters can benefit from other conspecifics' attacks on the prey. To explore this, we built a mathematical model capturing the dynamics of the hunt. We show that group hunting provides major efficiency gains (prey caught per unit time) for individuals in groups of up to 70 members. We also demonstrate that a free riding strategy, where some individuals wait until the prey are sufficiently injured before attacking, is only beneficial if the cost of attacking is high, and only then when waiting times are short. Our findings provide evidence that cooperative benefits can be realized through the facilitative effects of individuals' hunting actions without spatial coordination of attacks. Such 'proto-cooperation' may be the pre-cursor to more complex group-hunting strategies.

  5. Taxonomies for Reasoning About Cyber-physical Attacks in IoT-based Manufacturing Systems

    Directory of Open Access Journals (Sweden)

    Yao Pan

    2017-03-01

    Full Text Available The Internet of Things (IoT has transformed many aspects of modern manufacturing, from design to production to quality control. In particular, IoT and digital manufacturing technologies have substantially accelerated product development- cycles and manufacturers can now create products of a complexity and precision not heretofore possible. New threats to supply chain security have arisen from connecting machines to the Internet and introducing complex IoT-based systems controlling manufacturing processes. By attacking these IoT-based manufacturing systems and tampering with digital files, attackers can manipulate physical characteristics of parts and change the dimensions, shapes, or mechanical properties of the parts, which can result in parts that fail in the field. These defects increase manufacturing costs and allow silent problems to occur only under certain loads that can threaten safety and/or lives. To understand potential dangers and protect manufacturing system safety, this paper presents two taxonomies: one for classifying cyber-physical attacks against manufacturing processes and another for quality control measures for counteracting these attacks. We systematically identify and classify possible cyber-physical attacks and connect the attacks with variations in manufacturing processes and quality control measures. Our taxonomies also provide a scheme for linking emerging IoT-based manufacturing system vulnerabilities to possible attacks and quality control measures.

  6. Optimal space-time attacks on system state estimation under a sparsity constraint

    Science.gov (United States)

    Lu, Jingyang; Niu, Ruixin; Han, Puxiao

    2016-05-01

    System state estimation in the presence of an adversary that injects false information into sensor readings has attracted much attention in wide application areas, such as target tracking with compromised sensors, secure monitoring of dynamic electric power systems, secure driverless cars, and radar tracking and detection in the presence of jammers. From a malicious adversary's perspective, the optimal strategy for attacking a multi-sensor dynamic system over sensors and over time is investigated. It is assumed that the system defender can perfectly detect the attacks and identify and remove sensor data once they are corrupted by false information injected by the adversary. With this in mind, the adversary's goal is to maximize the covariance matrix of the system state estimate by the end of attack period under a sparse attack constraint such that the adversary can only attack the system a few times over time and over sensors. The sparsity assumption is due to the adversary's limited resources and his/her intention to reduce the chance of being detected by the system defender. This becomes an integer programming problem and its optimal solution, the exhaustive search, is intractable with a prohibitive complexity, especially for a system with a large number of sensors and over a large number of time steps. Several suboptimal solutions, such as those based on greedy search and dynamic programming are proposed to find the attack strategies. Examples and numerical results are provided in order to illustrate the effectiveness and the reduced computational complexities of the proposed attack strategies.

  7. Internal differential collision attacks on the reduced-round Grøstl-0 hash function

    DEFF Research Database (Denmark)

    Ideguchi, Kota; Tischhauser, Elmar Wolfgang; Preneel, Bart

    2014-01-01

    . This results in collision attacks and semi-free-start collision attacks on the Grøstl-0 hash function and compression function with reduced rounds. Specifically, we show collision attacks on the Grøstl-0-256 hash function reduced to 5 and 6 out of 10 rounds with time complexities 248 and 2112 and on the Grøstl......-0-512 hash function reduced to 6 out of 14 rounds with time complexity 2183. Furthermore, we demonstrate semi-free-start collision attacks on the Grøstl-0-256 compression function reduced to 8 rounds and the Grøstl-0-512 compression function reduced to 9 rounds. Finally, we show improved...

  8. Evaluation of Crosstalk Attacks in Access Networks

    DEFF Research Database (Denmark)

    Wagner, Christoph; Eiselt, Michael; Grobe, Klaus

    2016-01-01

    WDM-PON systems regained interest as low-cost solution for metro and access networks. We present a comparative analysis of resilience of wavelength-selective and wavelength-routed architectures against crosstalk attackers. We compare the vulnerability of these architectures against attacks...

  9. Fast Collision Attack on MD5

    NARCIS (Netherlands)

    Stevens, M.M.J.

    2006-01-01

    In this paper, we present an improved attack algorithm to find two-block collisions of the hash function MD5. The attack uses the same differential path of MD5 and the set of sufficient conditions that was presented by Wang et al. We present a new technique which allows us to deterministically fulfi

  10. Minimization and Reliability Analyses of Attack Graphs

    Science.gov (United States)

    2002-02-01

    they model only attacks. Since we have a generic state machine model , we can simultaneously model not just attacks, but also seemingly benign system...Finite State Machine Model The Network We model the network as a set of facts, each represented as a relational predicate. The state of the network

  11. Quantifying Shannon's work function for cryptanalytic attacks

    NARCIS (Netherlands)

    van Son, R.J.J.H.

    2010-01-01

    Attacks on cryptographic systems are limited by the available computational resources. A theoretical understanding of these resource limitations is needed to evaluate the security of cryptographic primitives and procedures. This study uses an Attacker versus Environment game formalism based on compu

  12. British used Congreve Rockets to Attack Napoleon

    Science.gov (United States)

    2004-01-01

    Sir William Congreve developed a rocket with a range of about 9,000 feet. The incendiary rocket used black powder, an iron case, and a 16-foot guide stick. In 1806, British used Congreve rockets to attack Napoleon's headquarters in France. In 1807, Congreve directed a rocket attack against Copenhagen.

  13. Attack tree generation by policy invalidation

    NARCIS (Netherlands)

    Ivanova, Marieta Georgieva; Probst, Christian W.; Hansen, René Rydhof; Kammüller, Florian; Naeem Akram, R.; Jajodia, S.

    2015-01-01

    Attacks on systems and organisations increasingly exploit human actors, for example through social engineering, complicating their formal treatment and automatic identification. Formalisation of human behaviour is difficult at best, and attacks on socio-technical systems are still mostly identified th

  14. Quantum private query with perfect user privacy against a joint-measurement attack

    Science.gov (United States)

    Yang, Yu-Guang; Liu, Zhi-Chao; Li, Jian; Chen, Xiu-Bo; Zuo, Hui-Juan; Zhou, Yi-Hua; Shi, Wei-Min

    2016-12-01

    The joint-measurement (JM) attack is the most powerful threat to the database security for existing quantum-key-distribution (QKD)-based quantum private query (QPQ) protocols. Wei et al. (2016) [28] proposed a novel QPQ protocol against the JM attack. However, their protocol relies on two-way quantum communication thereby affecting its real implementation and communication efficiency. Moreover, it cannot ensure perfect user privacy. In this paper, we present a new one-way QPQ protocol in which the special way of classical post-processing of oblivious key ensures the security against the JM attack. Furthermore, it realizes perfect user privacy and lower complexity of communication.

  15. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.;

    2004-01-01

    Proteins that inhibit alpha-amylases have been isolated from plants and microorganisms. These inhibitors can have natural roles in the control of endogenous a-amylase activity or in defence against pathogens and pests; certain inhibitors are reported to be antinutritional factors. The alpha-amylase...... inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha-amylases...... in complex with inhibitors from five families. These structures indicate major diversity but also some similarity in the structural basis of alpha-amylase inhibition. Mutational analysis of the mechanism of inhibition was performed in a few cases and various protein engineering and biotechnological...

  16. New Multi-step Worm Attack Model

    CERN Document Server

    Robiah, Y; Shahrin, S; Faizal, M A; Zaki, M Mohd; Marliza, R

    2010-01-01

    The traditional worms such as Blaster, Code Red, Slammer and Sasser, are still infecting vulnerable machines on the internet. They will remain as significant threats due to their fast spreading nature on the internet. Various traditional worms attack pattern has been analyzed from various logs at different OSI layers such as victim logs, attacker logs and IDS alert log. These worms attack pattern can be abstracted to form worms' attack model which describes the process of worms' infection. For the purpose of this paper, only Blaster variants were used during the experiment. This paper proposes a multi-step worm attack model which can be extended into research areas in alert correlation and computer forensic investigation.

  17. Use of Attack Graphs in Security Systems

    Directory of Open Access Journals (Sweden)

    Vivek Shandilya

    2014-01-01

    Full Text Available Attack graphs have been used to model the vulnerabilities of the systems and their potential exploits. The successful exploits leading to the partial/total failure of the systems are subject of keen security interest. Considerable effort has been expended in exhaustive modeling, analyses, detection, and mitigation of attacks. One prominent methodology involves constructing attack graphs of the pertinent system for analysis and response strategies. This not only gives the simplified representation of the system, but also allows prioritizing the security properties whose violations are of greater concern, for both detection and repair. We present a survey and critical study of state-of-the-art technologies in attack graph generation and use in security system. Based on our research, we identify the potential, challenges, and direction of the current research in using attack graphs.

  18. Automatic Classification of Attacks on IP Telephony

    Directory of Open Access Journals (Sweden)

    Jakub Safarik

    2013-01-01

    Full Text Available This article proposes an algorithm for automatic analysis of attack data in IP telephony network with a neural network. Data for the analysis is gathered from variable monitoring application running in the network. These monitoring systems are a typical part of nowadays network. Information from them is usually used after attack. It is possible to use an automatic classification of IP telephony attacks for nearly real-time classification and counter attack or mitigation of potential attacks. The classification use proposed neural network, and the article covers design of a neural network and its practical implementation. It contains also methods for neural network learning and data gathering functions from honeypot application.

  19. Rotational Rebound Attacks on Reduced Skein

    DEFF Research Database (Denmark)

    Khovratovich, Dmitry; Nikolić, Ivica; Rechberger, Christian

    2014-01-01

    ciphers, including the new standard SHA-3 (Keccak). The rebound attack is a start-from-the-middle approach for finding differential paths and conforming pairs in byte-oriented designs like Substitution-Permutation networks and AES. We apply our new compositional attack to the reduced version of the hash......In this paper we combine two powerful methods of symmetric cryptanalysis: rotational cryptanalysis and the rebound attack. Rotational cryptanalysis was designed for the analysis of bit-oriented designs like ARX (Addition-Rotation-XOR) schemes. It has been applied to several hash functions and block...... function Skein, a finalist of the SHA-3 competition. Our attack penetrates more than two thirds of the Skein core—the cipher Threefish, and made the designers to change the submission in order to prevent it. The rebound part of our attack has been significantly enhanced to deliver results on the largest...

  20. CompChall: Addressing Password Guessing Attacks

    CERN Document Server

    Goyal, Vipul; Singh, Mayank; Abraham, Ajith; Sanyal, Sugata

    2011-01-01

    Even though passwords are the most convenient means of authentication, they bring along themselves the threat of dictionary attacks. Dictionary attacks may be of two kinds: online and offline. While offline dictionary attacks are possible only if the adversary is able to collect data for a successful protocol execution by eavesdropping on the communication channel and can be successfully countered using public key cryptography, online dictionary attacks can be performed by anyone and there is no satisfactory solution to counter them. This paper presents a new authentication protocol which is called CompChall (computational challenge). The proposed protocol uses only one way hash functions as the building blocks and attempts to eliminate online dictionary attacks by implementing a challenge-response system. This challenge-response system is designed in a fashion that it does not pose any difficulty to a genuine user but is time consuming and computationally intensive for an adversary trying to launch a large n...

  1. SURVEY OF PACKET DROPPING ATTACK IN MANET

    Directory of Open Access Journals (Sweden)

    A.Janani

    2014-03-01

    Full Text Available Mobile Ad-hoc NETwork (MANET is an application of wireless network with self-configuring mobile nodes. MANET does not require any fixed infrastructure. Its development never has any threshold range. Nodes in MANET can communicate with each other if and only if all the nodes are in the same range. This wide distribution of nodes makes MANET vulnerable to various attacks, packet dropping attack or black hole attack is one of the possible attack. It is very hard to detect and prevent. To prevent from packet dropping attack, detection of misbehavior links and selfish nodes plays a vital role in MANETs. In this paper, a omprehensive investigation on detection of misbehavior links and malicious nodes is carried out.

  2. Combating Memory Corruption Attacks On Scada Devices

    Science.gov (United States)

    Bellettini, Carlo; Rrushi, Julian

    Memory corruption attacks on SCADA devices can cause significant disruptions to control systems and the industrial processes they operate. However, despite the presence of numerous memory corruption vulnerabilities, few, if any, techniques have been proposed for addressing the vulnerabilities or for combating memory corruption attacks. This paper describes a technique for defending against memory corruption attacks by enforcing logical boundaries between potentially hostile data and safe data in protected processes. The technique encrypts all input data using random keys; the encrypted data is stored in main memory and is decrypted according to the principle of least privilege just before it is processed by the CPU. The defensive technique affects the precision with which attackers can corrupt control data and pure data, protecting against code injection and arc injection attacks, and alleviating problems posed by the incomparability of mitigation techniques. An experimental evaluation involving the popular Modbus protocol demonstrates the feasibility and efficiency of the defensive technique.

  3. Evaluating Deterioration of Concrete by Sulfate Attack

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Effects of factors such as water to cement ratio, fly ash and silica fume on the resistance of concrete to sulfate attack were investigated by dry-wet cycles and immersion method. The index of the resistance to sulfate attack was used to evaluate the deterioration degree of concrete damaged by sulfate. The relationship between the resistance of concrete to sulfate attack and its permeability/porosity were analyzed as well as its responding mechanism. Results show that the depth of sulfate crystal attack from surface to inner of concrete can be reduced by decreasing w/c and addition of combining fly ash with silica fume. The variation of relative elastic modulus ratio and relative flexural strength ratio of various specimens before and after being subjected to sulfate attack was compared.

  4. Quantum attack-resistent certificateless multi-receiver signcryption scheme.

    Directory of Open Access Journals (Sweden)

    Huixian Li

    Full Text Available The existing certificateless signcryption schemes were designed mainly based on the traditional public key cryptography, in which the security relies on the hard problems, such as factor decomposition and discrete logarithm. However, these problems will be easily solved by the quantum computing. So the existing certificateless signcryption schemes are vulnerable to the quantum attack. Multivariate public key cryptography (MPKC, which can resist the quantum attack, is one of the alternative solutions to guarantee the security of communications in the post-quantum age. Motivated by these concerns, we proposed a new construction of the certificateless multi-receiver signcryption scheme (CLMSC based on MPKC. The new scheme inherits the security of MPKC, which can withstand the quantum attack. Multivariate quadratic polynomial operations, which have lower computation complexity than bilinear pairing operations, are employed in signcrypting a message for a certain number of receivers in our scheme. Security analysis shows that our scheme is a secure MPKC-based scheme. We proved its security under the hardness of the Multivariate Quadratic (MQ problem and its unforgeability under the Isomorphism of Polynomials (IP assumption in the random oracle model. The analysis results show that our scheme also has the security properties of non-repudiation, perfect forward secrecy, perfect backward secrecy and public verifiability. Compared with the existing schemes in terms of computation complexity and ciphertext length, our scheme is more efficient, which makes it suitable for terminals with low computation capacity like smart cards.

  5. Quantum attack-resistent certificateless multi-receiver signcryption scheme.

    Science.gov (United States)

    Li, Huixian; Chen, Xubao; Pang, Liaojun; Shi, Weisong

    2013-01-01

    The existing certificateless signcryption schemes were designed mainly based on the traditional public key cryptography, in which the security relies on the hard problems, such as factor decomposition and discrete logarithm. However, these problems will be easily solved by the quantum computing. So the existing certificateless signcryption schemes are vulnerable to the quantum attack. Multivariate public key cryptography (MPKC), which can resist the quantum attack, is one of the alternative solutions to guarantee the security of communications in the post-quantum age. Motivated by these concerns, we proposed a new construction of the certificateless multi-receiver signcryption scheme (CLMSC) based on MPKC. The new scheme inherits the security of MPKC, which can withstand the quantum attack. Multivariate quadratic polynomial operations, which have lower computation complexity than bilinear pairing operations, are employed in signcrypting a message for a certain number of receivers in our scheme. Security analysis shows that our scheme is a secure MPKC-based scheme. We proved its security under the hardness of the Multivariate Quadratic (MQ) problem and its unforgeability under the Isomorphism of Polynomials (IP) assumption in the random oracle model. The analysis results show that our scheme also has the security properties of non-repudiation, perfect forward secrecy, perfect backward secrecy and public verifiability. Compared with the existing schemes in terms of computation complexity and ciphertext length, our scheme is more efficient, which makes it suitable for terminals with low computation capacity like smart cards.

  6. Detection Block Model for SQL Injection Attacks

    Directory of Open Access Journals (Sweden)

    Diksha G. Kumar

    2014-10-01

    Full Text Available With the rapid development of Internet, more and more organizations connect their databases to the Internet for resource sharing. However, due to developers' lack of knowledge of all possible attacks, web applications become vulnerable to multiple attacks. Thus the network databases could face multiple threats. Web applications generally consist of a three tier architecture where database is in the third pole, which is the most valuable asset in any organization. SQL injection is an attack technique in which specially crafted input string is entered in user input field. It is submitted to server and result is returned to the user. In SQL injection vulnerability, the database server is forced to execute malicious operations which may cause the data loss or corruption, denial of access, and unauthentic access to sensitive data by crafting specific inputs. An attacker can directly compromise the database, and that is why this is a most threatening web attack. SQL injection attack occupies first position in top ten vulnerabilities as specified by Open Web Application Security Project. It is probably the most common Website vulnerability today. Current scenarios which provide solutions to SQL injection attack either have limited scope i.e. can’t be implemented across all platforms, or do not cover all types of SQL injection attacks. In this work we implement Message Authentication Code (MAC based solution against SQL injection attacks. The model works both on client and server side. Client side implements a filter function and server side is based on information theory. MAC of static and dynamic queries is compared to detect SQL injection attack.

  7. Trp[superscript 2313]-His[superscript 2315] of Factor VIII C2 Domain Is Involved in Membrane Binding Structure of a Complex Between the C[subscript 2] Domain and an Inhibitor of Membrane Binding

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Zhuo; Lin, Lin; Yuan, Cai; Nicolaes, Gerry A.F.; Chen, Liqing; Meehan, Edward J.; Furie, Bruce; Furie, Barbara; Huang, Mingdong (Harvard-Med); (UAH); (Maastricht); (Chinese Aca. Sci.)

    2010-11-03

    Factor VIII (FVIII) plays a critical role in blood coagulation by forming the tenase complex with factor IXa and calcium ions on a membrane surface containing negatively charged phospholipids. The tenase complex activates factor X during blood coagulation. The carboxyl-terminal C2 domain of FVIII is the main membrane-binding and von Willebrand factor-binding region of the protein. Mutations of FVIII cause hemophilia A, whereas elevation of FVIII activity is a risk factor for thromboembolic diseases. The C2 domain-membrane interaction has been proposed as a target of intervention for regulation of blood coagulation. A number of molecules that interrupt FVIII or factor V (FV) binding to cell membranes have been identified through high throughput screening or structure-based design. We report crystal structures of the FVIII C2 domain under three new crystallization conditions, and a high resolution (1.15 {angstrom}) crystal structure of the FVIII C2 domain bound to a small molecular inhibitor. The latter structure shows that the inhibitor binds to the surface of an exposed {beta}-strand of the C2 domain, Trp{sup 2313}-His{sup 2315}. This result indicates that the Trp{sup 2313}-His{sup 2315} segment is an important constituent of the membrane-binding motif and provides a model to understand the molecular mechanism of the C2 domain membrane interaction.

  8. Preparation data of the bromodomains BRD3(1, BRD3(2, BRD4(1, and BRPF1B and crystallization of BRD4(1-inhibitor complexes

    Directory of Open Access Journals (Sweden)

    Martin Hügle

    2016-06-01

    Full Text Available This article presents detailed purification procedures for the bromodomains BRD3(1, BRD3(2, BRD4(1, and BRPF1B. In addition we provide crystallization protocols for apo BRD4(1 and BRD4(1 in complex with numerous inhibitors. The protocols described here were successfully applied to obtain affinity data by isothermal titration calorimetry (ITC and by differential scanning fluorimetry (DSF as well as structural characterizations of BRD4(1 inhibitor complexes (PDB codes: PDB: 4LYI, PDB: 4LZS, PDB: 4LYW, PDB: 4LZR, PDB: 4LYS, PDB: 5D24, PDB: 5D25, PDB: 5D26, PDB: 5D3H, PDB: 5D3J, PDB: 5D3L, PDB: 5D3N, PDB: 5D3P, PDB: 5D3R, PDB: 5D3S, PDB: 5D3T. These data have been reported previously and are discussed in more detail elsewhere [1,2].

  9. Jaguar Attack on a Child: Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Iserson, Kenneth V.

    2015-02-01

    Full Text Available Jaguar attacks on humans rarely occur in the wild. When they do, they are often fatal. We describe a jaguar attack on a three-year-old girl near her home deep in a remote area of the Guyanese jungle. The patient had a complex but, relatively, rapid transport to a medical treatment facility for her life-threatening injuries. The child, who suffered typical jaguar-inflicted injury patterns and survived, is highlighted. We review jaguar anatomy, environmental status, hunting and killing behaviors, and discuss optimal medical management, given the resource-limited treatment environment of this international emergency medicine case. [West J Emerg Med. 2015;16(2:303–309.

  10. An Intrusion Detection System Against UDP Flood Attack and Ping of Death Attack (DDOS in MANET

    Directory of Open Access Journals (Sweden)

    Ankur Ashok Acharya

    2016-04-01

    Full Text Available DDoS is one of the serious attacks in the ad hoc network. Among lot many DDoS attacks, UDP flood attack and Ping of death attack are considered to be important as these two attacks may cause severe damage to the network. To provide better security to the network, efficient intrusion detection (IDS system is required to monitor the network continuously, keeping track of malicious activities and policy violations and produce report to the network administrator. UDP flood attack and ping of death attack are given importance in this paper as they are not well addressed in the existing research works. Packet capture and packet decoder is used to identify the packets and retrieve the packet details. A threshold is set for each node that is connected to the network. If the packet flow into the node exceeds the threshold that is set then the administrator is notified about the same.

  11. An Entropy Architecture for Defending Distributed Denial-of-service Attacks

    Directory of Open Access Journals (Sweden)

    S. K. Srivatsa

    2009-10-01

    Full Text Available The goal of intrusion detection is to identify entities attempting to destabilize the security controls. Network based intrusion detection techniques are used to identify unauthorized, illicit and anomalous behavior based on the network traffic. Identifying the network intruders is the most significant problem for network administrators and network security experts. Intrusion detection systems are an important component of defensive measures protecting computer systems and networks from abuse. New threats are emerging at an increasing rate. Distributed Denial-of-Service (DDoS attacks have emerged as a popular means of causing mass damage. The impacts of DoS attack will cause greater collateral damage. DoS attacks remain a serious threat to the users, organizations, and infrastructures of the Internet. The approaches used in the existing defense techniques are based on traffic characteristics such as traffic deviation, attack pattern matching etc, which may not yield accurate detection and involves high complexity. In this paper, the router based entropy algorithm has been designed to improve the performance and protection from the distributed denial-of-service attacks. This work includes attack tree construction, attacks detection and clustering of alerts. By calculating the predicted entropy for a router, alerts are raised for flows in which the predicted entropy is more than a threshold value. Then the alerts are grouped into different clusters according to their source, target, time and attack-type. It helps to avoid group redundant alerts and to associate alerts that are of the same nature. By Simulation results, it has been shown that the proposed architecture improves the detection accuracy and throughput while reducing the alert overhead. In this paper, we have explored the current research potential in terms of security, throughput performance of the router and impact of DoS attack technology based on intruder activity and attack tools.

  12. Forensics Investigation of Web Application Security Attacks

    Directory of Open Access Journals (Sweden)

    Amor Lazzez

    2015-02-01

    Full Text Available Nowadays, web applications are popular targets for security attackers. Using specific security mechanisms, we can prevent or detect a security attack on a web application, but we cannot find out the criminal who has carried out the security attack. Being unable to trace back an attack, encourages hackers to launch new attacks on the same system. Web application forensics aims to trace back and attribute a web application security attack to its originator. This may significantly reduce the security attacks targeting a web application every day, and hence improve its security. The aim of this paper is to carry out a detailed overview about the web application forensics. First, we define the web applications forensics, and we present a taxonomic structure of the digital forensics. Then, we present the methodology of a web application forensics investigation. After that, we illustrate the forensics supportive tools for a web application forensics investigation. After that, we present a detailed presentation of a set of the main considered web application forensics tools. Finally, we provide a comparison of the main considered web application forensics tools.

  13. Utilizing Probabilistic Linear Equations in Cube Attacks

    Institute of Scientific and Technical Information of China (English)

    Yuan Yao; Bin Zhang; Wen-Ling Wu

    2016-01-01

    Cube attacks, proposed by Dinur and Shamir at EUROCRYPT 2009, have shown huge power against stream ciphers. In the original cube attacks, a linear system of secret key bits is exploited for key recovery attacks. However, we find a number of equations claimed linear in previous literature actually nonlinear and not fit into the theoretical framework of cube attacks. Moreover, cube attacks are hard to apply if linear equations are rare. Therefore, it is of significance to make use of probabilistic linear equations, namely nonlinear superpolys that can be approximated by linear expressions effectively. In this paper, we suggest a way to test out and utilize these probabilistic linear equations, thus extending cube attacks to a wider scope. Concretely, we employ the standard parameter estimation approach and the sequential probability ratio test (SPRT) for linearity test in the preprocessing phase, and use maximum likelihood decoding (MLD) for solving the probabilistic linear equations in the online phase. As an application, we exhibit our new attack against 672 rounds of Trivium and reduce the number of key bits to search by 7.

  14. Rotational Rebound Attacks on Reduced Skein

    DEFF Research Database (Denmark)

    Khovratovich, Dmitry; Nikolic, Ivica; Rechberger, Christian

    2010-01-01

    In this paper we combine a recent rotational cryptanalysis with the rebound attack, which results in the best cryptanalysis of Skein, a candidate for the SHA-3 competition. The rebound attack approach was so far only applied to AES-like constructions. For the first time, we show that this approac...... inside-out computations and neutral bits in the inbound phase of the rebound attack, and give well-defined rotational distinguishers as certificates of weaknesses for the compression functions and block ciphers.......In this paper we combine a recent rotational cryptanalysis with the rebound attack, which results in the best cryptanalysis of Skein, a candidate for the SHA-3 competition. The rebound attack approach was so far only applied to AES-like constructions. For the first time, we show that this approach...... and the Threefish cipher. The new techniques include an analytical search for optimal input values in the rotational cryptanalysis, which allows to extend the outbound phase of the attack with a precomputation phase, an approach never used in any rebound-style attack before. Further we show how to combine multiple...

  15. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency

    NARCIS (Netherlands)

    Levi, M; Choi, G; Picavet, C; Hack, CE

    2006-01-01

    Background: Administration of C1-inhibitor concentrate is effective for prophylaxis and treatment of severe angioedema attacks caused by Cl-inhibitor deficiency. The concentrate should be administered intravenously and hence needs to be administered by health care professionals, which might cause co

  16. Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal.

    Science.gov (United States)

    Lipski, Samuel Michael; Casimir, Georges; Vanlommel, Martine; Jeanmaire, Mathieu; Dolhen, Pierre

    2015-02-01

    C1 esterase inhibitor (Berinert®) is generally used to treat severe attack of hereditary angioedema. We describe here the case of a patient who presented with a severe angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) endangering her life. It could be successfully treated with that medicine.

  17. Measuring a System’s Attack Surface

    Science.gov (United States)

    2004-01-01

    fold: • In terms of a state machine model of the system, we present formal definitions of attack, attack surface, and attack class. Our definitions are...versions. The rest of this paper is organized as follows. In Section 2, we introduce our state machine model and point out the key differences from...approach in Section 6 and compare it to related work in Section 7. We conclude in Section 8. 2 State Machine Model We use a state machine to model the

  18. Unique Pattern of Component Gene Disruption in the NRF2 Inhibitor KEAP1/CUL3/RBX1 E3-Ubiquitin Ligase Complex in Serous Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Victor D. Martinez

    2014-01-01

    Full Text Available The NFE2-related factor 2 (NRF2 pathway is critical to initiate responses to oxidative stress; however, constitutive activation occurs in different cancer types, including serous ovarian carcinomas (OVCA. The KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is a regulator of NRF2 levels. Hence, we investigated the DNA-level mechanisms affecting these genes in OVCA. DNA copy-number loss (CNL, promoter hypermethylation, mRNA expression, and sequence mutation for KEAP1, CUL3, and RBX1 were assessed in a cohort of 568 OVCA from The Cancer Genome Atlas. Almost 90% of cases exhibited loss-of-function alterations in any components of the NRF2 inhibitory complex. CNL is the most prominent mechanism of component disruption, with RBX1 being the most frequently disrupted component. These alterations were associated with reduced mRNA expression of complex components, and NRF2 target gene expression was positively enriched in 90% of samples harboring altered complex components. Disruption occurs through a unique DNA-level alteration pattern in OVCA. We conclude that a remarkably high frequency of DNA and mRNA alterations affects components of the KEAP1/CUL3/RBX1 complex, through a unique pattern of genetic mechanisms. Together, these results suggest a key role for the KEAP1/CUL3/RBX1 complex and NRF2 pathway deregulation in OVCA.

  19. What Are the Symptoms of a Heart Attack?

    Science.gov (United States)

    ... from the NHLBI on Twitter. What Are the Symptoms of a Heart Attack? Not all heart attacks ... symptoms are called silent heart attacks. Most Common Symptoms The most common warning symptoms of a heart ...

  20. Detecting Pulsing Denial-of-Service Attacks with Nondeterministic Attack Intervals

    Directory of Open Access Journals (Sweden)

    Xiapu Luo

    2009-01-01

    Full Text Available This paper addresses the important problem of detecting pulsing denial of service (PDoS attacks which send a sequence of attack pulses to reduce TCP throughput. Unlike previous works which focused on a restricted form of attacks, we consider a very broad class of attacks. In particular, our attack model admits any attack interval between two adjacent pulses, whether deterministic or not. It also includes the traditional flooding-based attacks as a limiting case (i.e., zero attack interval. Our main contribution is Vanguard, a new anomaly-based detection scheme for this class of PDoS attacks. The Vanguard detection is based on three traffic anomalies induced by the attacks, and it detects them using a CUSUM algorithm. We have prototyped Vanguard and evaluated it on a testbed. The experiment results show that Vanguard is more effective than the previous methods that are based on other traffic anomalies (after a transformation using wavelet transform, Fourier transform, and autocorrelation and detection algorithms (e.g., dynamic time warping.

  1. ATTACK DETECTION AND CLASSIFICATION OF HETEROGENEOUS WIRELESS SENSORS USING CO-CLUSTERING

    Directory of Open Access Journals (Sweden)

    K.V.RAMANA

    2012-02-01

    Full Text Available In a Wireless Sensor Network a large number of sensors are deployed for the purpose of sensing data and then to bring the data back securely to nearby base stations. The base stations then perform thecostly computation on behalf of the sensors to analyze the data sensed by the sensors. Due to resource limitations of the nodes and also due to the vulnerability of physical captures of the nodes, the traditional cryptographic techniques are very complex and should not fit for energy constrained environments. Data mining techniques can be applied to find the malicious behavior of the nodes of the SensorNetwork. By analyzing the traffic patterns one can differentiate the normal behavior from malicious behaviour.Those techniques are used to identify various attacks. This paper addresses the issue of Attacks using data mining techniques. There exist two types of attacks: (i external and (ii internal. External attacks are those in which an attacker manipulates the communication between pairs of trusted nodes and causes the nodes to de-synchronize. Internal attacks are those in which internal attackers report false clock references to their neighboring nodes proposed an approach to develop a protocol. The protocol not only finds malicious node(s but also counts them withinthe group using data mining clustering techniques.

  2. Password-only authenticated three-party key exchange proven secure against insider dictionary attacks.

    Science.gov (United States)

    Nam, Junghyun; Choo, Kim-Kwang Raymond; Paik, Juryon; Won, Dongho

    2014-01-01

    While a number of protocols for password-only authenticated key exchange (PAKE) in the 3-party setting have been proposed, it still remains a challenging task to prove the security of a 3-party PAKE protocol against insider dictionary attacks. To the best of our knowledge, there is no 3-party PAKE protocol that carries a formal proof, or even definition, of security against insider dictionary attacks. In this paper, we present the first 3-party PAKE protocol proven secure against both online and offline dictionary attacks as well as insider and outsider dictionary attacks. Our construct can be viewed as a protocol compiler that transforms any 2-party PAKE protocol into a 3-party PAKE protocol with 2 additional rounds of communication. We also present a simple and intuitive approach of formally modelling dictionary attacks in the password-only 3-party setting, which significantly reduces the complexity of proving the security of 3-party PAKE protocols against dictionary attacks. In addition, we investigate the security of the well-known 3-party PAKE protocol, called GPAKE, due to Abdalla et al. (2005, 2006), and demonstrate that the security of GPAKE against online dictionary attacks depends heavily on the composition of its two building blocks, namely a 2-party PAKE protocol and a 3-party key distribution protocol.

  3. Taxonomy of SSL/TLS Attacks

    Directory of Open Access Journals (Sweden)

    Keerthi Vasan K.

    2016-02-01

    Full Text Available Secure Socket Layer (SSL and Transport Layer Security (TLS protocols use cryptographic algorithms to secure data and ensure security goals such as Data Confidentiality and Integrity in networking. They are used along with other protocols such as HTTP, SMTP, etc. in applications such as web browsing, electronic mail, and VoIP. The existing versions of the protocols as well as the cryptographic algorithms they use have vulnerabilities and is not resistant towards Man-In-The- Middle (MITM attacks. Exploiting these vulnerabilities, several attacks have been launched on SSL/TLS such as session hijacking, version degradation, heart bleed, Berserk etc. This paper is a comprehensive analysis of the vulnerabilities in the protocol, attacks launched by exploiting the vulnerabilities and techniques to mitigate the flaws in protocols. A novel taxonomy of the attacks against SSL/TLS has been proposed in this paper.

  4. Women's Heart Disease: Heart Attack Symptoms

    Science.gov (United States)

    ... this page please turn JavaScript on. Feature: Women's Heart Disease Heart Attack Symptoms Past Issues / Winter 2014 Table ... NHLBI has uncovered some of the causes of heart diseases and conditions, as well as ways to prevent ...

  5. Diabetes - preventing heart attack and stroke

    Science.gov (United States)

    Diabetes complications - heart; Coronary artery disease - diabetes; CAD - diabetes; Cerebrovascular disease - diabetes ... People with diabetes have a higher chance of having heart attacks and strokes. Smoking and having high blood pressure and high ...

  6. AN APPROACH OF DEFENDING AGAINST DDOS ATTACK

    Institute of Scientific and Technical Information of China (English)

    Wu Zhijun; Duan Haixin; Li Xing

    2006-01-01

    An approach of defending against Distributed Denial of Service (DDoS) attack based on flow model and flow detection is presented. The proposed approach can protect targets from DDoS attacking, and allow targets to provide good service to legitimate traffic under DDoS attacking, with fast reaction. This approach adopts the technique of dynamic comb filter, yields a low level of false positives of less than 1.5%,drops similar percentage of good traffic, about 1%, and passes neglectable percentage of attack bandwidth to the victim, less than 1.5%. The prototype of commercial product, D-fighter, is developed by implementing this proposed approach on Intel network processor platform IXP 1200.

  7. SECURING MANET FROM BLACKHOLE AND WORMHOLE ATTACKS

    Directory of Open Access Journals (Sweden)

    C.M.Vidhyapathi

    2013-06-01

    Full Text Available Mobile Ad-Hoc networks are self-configuring and self-organizing multi-hop wireless networks. They do not have any fixed infrastructure or centralized management. Due to this, the ad hoc networks are vulnerable to attacks. The routing protocol for MANET considered in this paper is AODV(Ad hoc On-demand Distance Vector Routing Protocol. Blackhole and Wormhole nodes are malicious nodeswhich degrade the performance of the network. They actively participate in the network and conform to forward packets to the destination. The Watchdog Mechanism is used to correct the network from both blackhole and wormhole attacks. The networks originally, with the attacks and after being prevented from attacks are compared on the basis of packets received, throughput, end-to-end delay and packet delivery ratio. ns2 software is used for the simulation.

  8. How Is a Heart Attack Treated?

    Science.gov (United States)

    ... medicines also keep existing clots from getting larger. Beta blockers . Beta blockers decrease your heart’s workload. These medicines also are ... discomfort and to help prevent another heart attack. Beta blockers also are used to treat arrhythmias (irregular heartbeats). ...

  9. Preventing Coordinated Attacks Via Distributed Alert Exchange

    CERN Document Server

    Garcia-Alfaro, Joaquin; Muehl, Gero; Borrell, Joan

    2008-01-01

    Attacks on information systems followed by intrusions may cause large revenue losses. The prevention of both is not always possible by just considering information from isolated sources of the network. A global view of the whole system is necessary to recognize and react to the different actions of such an attack. The design and deployment of a decentralized system targeted at detecting as well as reacting to information system attacks might benefit from the loose coupling realized by publish/subscribe middleware. In this paper, we present the advantages and convenience in using this communication paradigm for a general decentralized attack prevention framework. Furthermore, we present the design and implementation of our approach based on existing publish/subscribe middleware and evaluate our approach for GNU/Linux systems.

  10. The role of sleep in migraine attacks

    Directory of Open Access Journals (Sweden)

    Elaine Inamorato

    1993-11-01

    Full Text Available Migraine attacks may be precipitated by sleep deprivation or excessive sleep and sleep is also associated with relief of migraine attacks. In view of this variable relationship we studied the records of 159 consecutive outpatients of our Headache Unit. In 121 records there was reference to sleep involvement, in 55% by a single form and in 45% by more than one form. When only one form was related, relief was most common (70%. 30% of that group of patients had the migraine attack precipitated by sleep, 24% by deprivation and 6% by sleep excess. When the effects of sleep were multiple, these effects were as expected logically in 65%: «in accordance» group (e.g attack precipitated by sleep deprivation and relieved by sleep onset. In a second group, («conflicting» where the involvement was not logical, there were three different combinations of sleep involvement, possibly due to more than one pathophysiological mechanism.

  11. Study Shows How Zika Attacks Infant Brain

    Science.gov (United States)

    ... gov/news/fullstory_162514.html Study Shows How Zika Attacks Infant Brain Virus can copy itself thousands ... New research paints a chilling portrait of how Zika ravages the infant brain. Scientists from the U.S. ...

  12. Thatcher condemns attacks on abortion mp.

    Science.gov (United States)

    1987-12-19

    The Prime Minister, Mrs Margaret Thatcher, has stepped in to condemn a series of violent attacks on Liberal MP David Alton who is trying to reduce the [Illegible word] limit on abortions from 28 to 18 weeks.

  13. Twisted Polynomials and Forgery Attacks on GCM

    DEFF Research Database (Denmark)

    Abdelraheem, Mohamed Ahmed A. M. A.; Beelen, Peter; Bogdanov, Andrey;

    2015-01-01

    nonce misuse resistance, such as POET. The algebraic structure of polynomial hashing has given rise to security concerns: At CRYPTO 2008, Handschuh and Preneel describe key recovery attacks, and at FSE 2013, Procter and Cid provide a comprehensive framework for forgery attacks. Both approaches rely...... heavily on the ability to construct forgery polynomials having disjoint sets of roots, with many roots (“weak keys”) each. Constructing such polynomials beyond naïve approaches is crucial for these attacks, but still an open problem. In this paper, we comprehensively address this issue. We propose to use...... in an improved key recovery algorithm. As cryptanalytic applications of our twisted polynomials, we develop the first universal forgery attacks on GCM in the weak-key model that do not require nonce reuse. Moreover, we present universal weak-key forgeries for the nonce-misuse resistant AE scheme POET, which...

  14. Prevention of Routing Attacks In Manet

    Directory of Open Access Journals (Sweden)

    N.Rajesh

    2013-01-01

    Full Text Available Mobile Ad hoc Networks (MANET are easily prone to attacks due to its network infrastructure. In previous routing attacks the malicious node is isolated using naive fuzzy response decisions. In this paper a new technology of broadcasting the awareness information about attacker node to all the existing nodes in the network is discussed. The awareness approach is based on an extended Dempster-Shafer mathematical theory(D-S Theory. Dempster-Shafer mathematical theory is used to collect the evidence notion of importance factors. The adaptiveness of the mechanism allows to systematically cope with the identified MANET routing attacks. The intrusion response action in MANET was addressed by isolating uncooperative nodes based on the node reputation derived from their behaviors. Here the effectiveness of the approach with the consideration of the packet delivery ratio and routing cost were demonstrated using java swing concepts

  15. Structure of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase in complex with the feedback inhibitor CoA reveals only one active-site conformation

    Energy Technology Data Exchange (ETDEWEB)

    Wubben, T.; Mesecar, A.D. (Purdue); (UIC)

    2014-10-02

    Phosphopantetheine adenylyltransferase (PPAT) catalyzes the penultimate step in the coenzyme A (CoA) biosynthetic pathway, reversibly transferring an adenylyl group from ATP to 4'-phosphopantetheine to form dephosphocoenzyme A (dPCoA). To complement recent biochemical and structural studies on Mycobacterium tuberculosis PPAT (MtPPAT) and to provide further insight into the feedback regulation of MtPPAT by CoA, the X-ray crystal structure of the MtPPAT enzyme in complex with CoA was determined to 2.11 {angstrom} resolution. Unlike previous X-ray crystal structures of PPAT-CoA complexes from other bacteria, which showed two distinct CoA conformations bound to the active site, only one conformation of CoA is observed in the MtPPAT-CoA complex.

  16. To mitigate Black-hole attack with CBDS in MANET

    Directory of Open Access Journals (Sweden)

    Navjot

    2015-06-01

    Full Text Available Mobile ad-hoc network is self configured network that consist of mobile nodes which communicate with each other. Distributed self-organized nature of this network makes it venerable to various attacks likes DOS attack, Black hole attack, wormhole attack and jamming attack etc. Blackhole attack is one of the serious attack in network in which information loss occur which degrades the performance of network. In this work black hole attack is detected with the help of CBDS (cooperative Bait Detection Algorithm and MD5 is used for the security purpose. This work is implemented in Network simulator and performance is checked on the bases of network parameters.

  17. Randomized, controlled trial of telcagepant over four migraine attacks

    DEFF Research Database (Denmark)

    Ho, Andrew P; Dahlöf, Carl Gh; Silberstein, Stephen D

    2010-01-01

    This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with migraine were randomized, double-blind, to telcagepant 140 mg, telcagepant 280 mg, or control treatment...... sequences to treat four moderate-to-severe migraine attacks. Control patients received placebo for three attacks and telcagepant 140 mg for one attack. Efficacy for the first attack (Attack 1) and consistency of efficacy over multiple attacks were assessed. For an individual patient, consistent efficacy...

  18. Heart Attack Prediction System Based Neural Arbitration

    OpenAIRE

    Helwan, Abdulkader

    2015-01-01

    Heart attack is an asymptomatic and epidemic medical condition that may suddenly occur and causes “death”. Therefore, it is a life-threatening condition and it should be detected before it occurs. Heart attack is so far predicted using the conventional ways of doctor’s examination and by performing some medical tests such as stress test, ECG, and heart CTScan etc. The coronary vessels constriction, the cholesterol levels in the arteries, and other attributes can be good indicators for making ...

  19. Cyber Security Audit and Attack Detection Toolkit

    Energy Technology Data Exchange (ETDEWEB)

    Peterson, Dale

    2012-05-31

    This goal of this project was to develop cyber security audit and attack detection tools for industrial control systems (ICS). Digital Bond developed and released a tool named Bandolier that audits ICS components commonly used in the energy sector against an optimal security configuration. The Portaledge Project developed a capability for the PI Historian, the most widely used Historian in the energy sector, to aggregate security events and detect cyber attacks.

  20. High angle of attack aerodynamics subsonic, transonic, and supersonic flows

    CERN Document Server

    Rom, Josef

    1992-01-01

    The aerodynamics of aircraft at high angles of attack is a subject which is being pursued diligently, because the modern agile fighter aircraft and many of the current generation of missiles must perform well at very high incidence, near and beyond stall. However, a comprehensive presentation of the methods and results applicable to the studies of the complex aerodynamics at high angle of attack has not been covered in monographs or textbooks. This book is not the usual textbook in that it goes beyond just presenting the basic theoretical and experimental know-how, since it contains reference material to practical calculation methods and technical and experimental results which can be useful to the practicing aerospace engineers and scientists. It can certainly be used as a text and reference book for graduate courses on subjects related to high angles of attack aerodynamics and for topics related to three-dimensional separation in viscous flow courses. In addition, the book is addressed to the aerodynamicist...

  1. Identifying optimal targets of network attack by belief propagation

    Science.gov (United States)

    Mugisha, Salomon; Zhou, Hai-Jun

    2016-07-01

    For a network formed by nodes and undirected links between pairs of nodes, the network optimal attack problem aims at deleting a minimum number of target nodes to break the network down into many small components. This problem is intrinsically related to the feedback vertex set problem that was successfully tackled by spin-glass theory and an associated belief propagation-guided decimation (BPD) algorithm [Zhou, Eur. Phys. J. B 86, 455 (2013), 10.1140/epjb/e2013-40690-1]. In the present work we apply the BPD algorithm (which has approximately linear time complexity) to the network optimal attack problem and demonstrate that it has much better performance than a recently proposed collective information algorithm [Morone and Makse, Nature 524, 65 (2015), 10.1038/nature14604] for different types of random networks and real-world network instances. The BPD-guided attack scheme often induces an abrupt collapse of the whole network, which may make it very difficult to defend.

  2. Affect Response to Simulated Information Attack during Complex Task Performance

    Science.gov (United States)

    2014-12-02

    analyses (Saucier, 1997), which include Extraversion, Openness, Neuroticism , Agreeableness, and Conscientiousness. The model was developed and...Five-Factor Markers, to include the BFI (Big Five Inventory), NEO-FFI/PI-R ( Neuroticism , Extraversion, Openness Five-Factor Inventory/Personality...Institutional Review Board MATB Multi-Attribute Task Battery NASA National Aeronautics and Space Agency NEO Neuroticism , Extraversion, Openness PANAS-X

  3. Kinetic and structural analysis of enzyme sliding on a substrate: multiple attack in beta-amylase.

    Science.gov (United States)

    Ishikawa, Kazuhiko; Nakatani, Hiroshi; Katsuya, Yoshio; Fukazawa, Chikafusa

    2007-01-23

    Beta-amylase (EC 3.2.1.2) is starch-hydrolyzing exo-type enzyme that can catalyze the successive liberation of beta-maltose from the nonreducing ends of alpha-1,4-linked glucopyranosyl polymers. There is a well-known phenomenon called multiple or repetitive attack where the enzyme releases several maltose molecules in a single enzyme-substrate complex. In order to understand it further, we examined the beta-amylase-catalyzed reaction using maltooligosaccharides. The Monte Carlo method was applied for simulation of the beta-amylase-catalyzed reaction including the multiple attack mechanism. Through site-directed mutagenesis, we have successfully prepared a mutant enzyme which may be simulated as a multiple attack action reduced one with retaining significant hydrolytic activity. From the results of X-ray structure analysis of the mutant enzyme, it was clarified that one carboxyl residue plays a very important role in the multiple attack. The multiple attack action needs the force of enzyme sliding on the substrate. In addition, it is important for the multiple attack that the enzyme and substrate have the characteristics of a stable productive substrate-enzyme complex through a hydrogen bond between the nonreducing end of the substrate and the carboxyl residue of the enzyme.

  4. 3-Nitropropionic Acid is a Suicide Inhibitor of MitochondrialRespiration that, Upon Oxidation by Complex II, Forms a Covalent AdductWith a Catalytic Base Arginine in the Active Site of the Enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Li-shar; Sun, Gang; Cobessi, David; Wang, Andy C.; Shen,John T.; Tung, Eric Y.; Anderson, Vernon E.; Berry, Edward A.

    2005-12-01

    We report three new structures of mitochondrial respiratory Complex II (succinate ubiquinone oxidoreductase, E.C. 1.3.5.1) at up to 2.1 {angstrom} resolution, with various inhibitors. The structures define the conformation of the bound inhibitors and suggest the residues involved in substrate binding and catalysis at the dicarboxylate site. In particular they support the role of Arg297 as a general base catalyst accepting a proton in the dehydrogenation of succinate. The dicarboxylate ligand in oxaloacetate-containing crystals appears to be the same as that reported for Shewanella flavocytochrome c treated with fumarate. The plant and fungal toxin 3-nitropropionic acid, an irreversible inactivator of succinate dehydrogenase, forms a covalent adduct with the side chain of Arg297. The modification eliminates a trypsin cleavage site in the flavoprotein, and tandem mass spectroscopic analysis of the new fragment shows the mass of Arg 297 to be increased by 83 Da and to have potential of losing 44 Da, consistent with decarboxylation, during fragmentation.

  5. Multidimensional zero-correlation attacks on lightweight block cipher HIGHT: Improved cryptanalysis of an ISO standard

    DEFF Research Database (Denmark)

    Wen, Long; Wang, Meiqin; Bogdanov, Andrey

    2014-01-01

    HIGHT is a block cipher designed in Korea with the involvement of Korea Information Security Agency. It was proposed at CHES 2006 for usage in lightweight applications such as sensor networks and RFID tags. Lately, it has been adopted as ISO standard. Though there is a great deal of cryptanalytic...... results on HIGHT, its security evaluation against the recent zero-correlation linear attacks is still lacking. At the same time, the Feistel-type structure of HIGHT suggests that it might be susceptible to this type of cryptanalysis. In this paper, we aim to bridge this gap. We identify zero......-correlation linear approximations over 16 rounds of HIGHT. Based upon those, we attack 27-round HIGHT (round 4 to round 30) with improved time complexity and practical memory requirements. This attack of ours is the best result on HIGHT to date in the classical single-key setting. We also provide the first attack...

  6. Blocking of SQL Injection Attacks by Comparing Static and Dynamic Queries

    Directory of Open Access Journals (Sweden)

    Raman Kumar

    2013-02-01

    Full Text Available Due to internet expansion web applications have now become a part of everyday life. As a result a number of incidents which exploit web application vulnerabilities are increasing. A large number of these incidents are SQL Injection attacks which are a serious security threat to databases which contain sensitive information, the leakage of which cause a large amount of loss. SQL Injection Attacks occur when an intruder changes the query structure by inserting any malicious input. There are a number of methods available to detect and prevent SQL Injection Attacks. But these are too complex to use. This paper proposes a very simple, effective and time saving technique to detect SQLIAs which uses combined static and dynamic analysis and also defines an attack other than existing classification of SQLIAs.

  7. Copper(II) complexes with highly water-soluble L- and D-proline-thiosemicarbazone conjugates as potential inhibitors of Topoisomerase IIα.

    Science.gov (United States)

    Bacher, Felix; Enyedy, Éva A; Nagy, Nóra V; Rockenbauer, Antal; Bognár, Gabriella M; Trondl, Robert; Novak, Maria S; Klapproth, Erik; Kiss, Tamás; Arion, Vladimir B

    2013-08-05

    Two proline-thiosemicarbazone bioconjugates with excellent aqueous solubility, namely, 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone [L-Pro-FTSC or (S)-H2L] and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone [D-Pro-FTSC or (R)-H2L], have been synthesized and characterized by elemental analysis, one- and two-dimensional (1)H and (13)C NMR spectroscopy, and electrospray ionization mass spectrometry. The complexation behavior of L-Pro-FTSC with copper(II) in an aqueous solution and in a 30% (w/w) dimethyl sulfoxide/water mixture has been studied via pH potentiometry, UV-vis spectrophotometry, electron paramagnetic resonance, (1)H NMR spectroscopy, and spectrofluorimetry. By the reaction of copper(II) acetate with (S)-H2L and (R)-H2L in water, the complexes [Cu(S,R)-L] and [Cu(R,S)-L] have been synthesized and comprehensively characterized. An X-ray diffraction study of [Cu(S,R)-L] showed the formation of a square-pyramidal complex, with the bioconjugate acting as a pentadentate ligand. Both copper(II) complexes displayed antiproliferative activity in CH1 ovarian carcinoma cells and inhibited Topoisomerase IIα activity in a DNA plasmid relaxation assay.

  8. Effect of the ATPase inhibitor protein IF{sub 1} on H{sup +} translocation in the mitochondrial ATP synthase complex

    Energy Technology Data Exchange (ETDEWEB)

    Zanotti, Franco [Dept. of Medical Biochemistry, Biology and Physics, University of Bari (Italy); Inst. of Biomembranes and Bioenergetics, CNR, Bari (Italy); Gnoni, Antonio; Mangiullo, Roberto [Dept. of Medical Biochemistry, Biology and Physics, University of Bari (Italy); Papa, Sergio, E-mail: papabchm@cimedoc.uniba.it [Dept. of Medical Biochemistry, Biology and Physics, University of Bari (Italy); Inst. of Biomembranes and Bioenergetics, CNR, Bari (Italy)

    2009-06-19

    The H{sup +} F{sub o}F{sub 1}-ATP synthase complex of coupling membranes converts the proton-motive force into rotatory mechanical energy to drive ATP synthesis. The F{sub 1} moiety of the complex protrudes at the inner side of the membrane, the F{sub o} sector spans the membrane reaching the outer side. The IF{sub 1} component of the mitochondrial complex is a basic 10 kDa protein, which inhibits the F{sub o}F{sub 1}-ATP hydrolase activity. The mitochondrial matrix pH is the critical factor for the inhibitory binding of the central segment of IF{sub 1} (residue 42-58) to the F{sub 1}-{alpha}/{beta} subunits. We have analyzed the effect of native purified IF{sub 1} the IF{sub 1}-(42-58) synthetic peptide and its mutants on proton conduction, driven by ATP hydrolysis or by [K{sup +}] gradients, in bovine heart inside-out submitochondrial particles and in liposome-reconstituted F{sub o}F{sub 1} complex. The results show that IF{sub 1}, and in particular its central 42-58 segment, displays different inhibitory affinity for proton conduction from the F{sub 1} to the F{sub o} side and in the opposite direction. Cross-linking of IF{sub 1} to F{sub 1}-{alpha}/{beta} subunits inhibits the ATP-driven H{sup +} translocation but enhances H{sup +} conduction in the reverse direction. These observation are discussed in terms of the rotary mechanism of the F{sub o}F{sub 1} complex.

  9. Classification of HTTP Attacks: A Study on the ECML/PKDD 2007 Discovery Challenge

    Energy Technology Data Exchange (ETDEWEB)

    Gallagher, Brian [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Eliassi-Rad, Tina [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2009-07-08

    As the world becomes more reliant on Web applications for commercial, financial, and medical transactions, cyber attacks on the World Wide Web are increasing in frequency and severity. Web applications provide an attractive alternative to traditional desktop applications due to their accessibility and ease of deployment. However, the accessibility of Web applications also makes them extremely vulnerable to attack. This inherent vulnerability is intensified by the distributed nature ofWeb applications and the complexity of configuring application servers. These factors have led to a proliferation of Web-based attacks, in which attackers surreptitiously inject code into HTTP requests, allowing them to execute arbitrary commands on remote systems and perform malicious activities such as reading, altering, or destroying sensitive data. One approach for dealing with HTTP-based attacks is to identify malicious code in incoming HTTP requests and eliminate bad requests before they are processed. Using machine learning techniques, we can build a classifier to automatically label requests as “Valid” or “Attack.” For this study, we develop a simple, but effective HTTP attack classifier, based on the vector space model used commonly for Information Retrieval. Our classifier not only separates attacks from valid requests, but can also identify specific attack types (e.g., “SQL Injection” or “Path Traversal”). We demonstrate the effectiveness of our approach through experiments on the ECML/PKDD 2007 Discovery Challenge data set. Specifically, we show that our approach achieves higher precision and recall than previous methods. In addition, our approach has a number of desirable characteristics, including robustness to missing contextual information, interpretability of models, and scalability.

  10. Serum Inter-α-inhibitor activates the Yes tyrosine kinase and YAP/TEAD transcriptional complex in mouse embryonic stem cells.

    Science.gov (United States)

    Pijuan-Galitó, Sara; Tamm, Christoffer; Annerén, Cecilia

    2014-11-28

    We have previously demonstrated that the Src family kinase Yes, the Yes-associated protein (YAP) and TEA domain TEAD2 transcription factor pathway are activated by leukemia inhibitory factor (LIF) and contribute to mouse embryonic stem (mES) cell maintenance of pluripotency and self-renewal. In addition, we have shown that fetal bovine serum (FBS) induces Yes auto-phosphorylation and activation. In the present study we confirm that serum also activates TEAD-dependent transcription in a time- and dose-dependent manner and we identify Inter-α-inhibitor (IαI) as a component in serum capable of activating the Yes/YAP/TEAD pathway by inducing Yes auto-phosphorylation, YAP nuclear localization and TEAD-dependent transcription. The cleaved heavy chain 2 (HC2) sub-component of IαI, is demonstrated to be responsible for this effect. Moreover, IαI is also shown to efficiently increase expression of TEAD-downstream target genes including well-known stem cell factors Nanog and Oct 3/4. IαI is not produced by the ES cells per se but is added to the cells via the cell culture medium containing serum or serum-derived components such as bovine serum albumin (BSA). In conclusion, we describe a novel function of IαI in activating key pluripotency pathways associated with ES cell maintenance and self-renewal.

  11. Crystal Structure of a Cytochrome P450 2B6 Genetic Variant in Complex with the Inhibitor 4-(4-Chlorophenyl)imidazole at 2.0-Å Resolution

    Science.gov (United States)

    Shah, Manish B.; Talakad, Jyothi C.; Maekawa, Keiko; Roberts, Arthur G.; Wilderman, P. Ross; Sun, Ling; Yang, Jane Y.; Huelga, Stephanie C.; Hong, Wen-Xu; Zhang, Qinghai; Stout, C. David; Halpert, James R.

    2010-01-01

    The structure of the K262R genetic variant of human cytochrome P450 2B6 in complex with the inhibitor 4-(4-chlorophenyl)imidazole (4-CPI) has been determined using X-ray crystallography to 2.0-Å resolution. Production of diffraction quality crystals was enabled through a combination of protein engineering, chaperone coexpression, modifications to the purification protocol, and the use of unique facial amphiphiles during crystallization. The 2B6-4-CPI complex is virtually identical to the rabbit 2B4 structure bound to the same inhibitor with respect to the arrangement of secondary structural elements and the placement of active site residues. The structure supports prior P450 2B6 homology models based on other mammalian cytochromes P450 and is consistent with the limited site-directed mutagenesis studies on 2B6 and extensive studies on P450 2B4 and 2B1. Although the K262R genetic variant shows unaltered binding of 4-CPI, altered binding affinity, kinetics, and/or product profiles have been previously shown with several other ligands. On the basis of new P450 2B6 crystal structure and previous 2B4 structures, substitutions at residue 262 affect a hydrogen-bonding network connecting the G and H helices, where subtle differences could be transduced to the active site. Docking experiments indicate that the closed protein conformation allows smaller ligands such as ticlopidine to bind to the 2B6 active site in the expected orientation. However, it is unknown whether 2B6 undergoes structural reorganization to accommodate bulkier molecules, as previously inferred from multiple P450 2B4 crystal structures. PMID:20061448

  12. Crystal structure of a cytochrome P450 2B6 genetic variant in complex with the inhibitor 4-(4-chlorophenyl)imidazole at 2.0-A resolution.

    Science.gov (United States)

    Gay, Sean C; Shah, Manish B; Talakad, Jyothi C; Maekawa, Keiko; Roberts, Arthur G; Wilderman, P Ross; Sun, Ling; Yang, Jane Y; Huelga, Stephanie C; Hong, Wen-Xu; Zhang, Qinghai; Stout, C David; Halpert, James R

    2010-04-01

    The structure of the K262R genetic variant of human cytochrome P450 2B6 in complex with the inhibitor 4-(4-chlorophenyl)imidazole (4-CPI) has been determined using X-ray crystallography to 2.0-A resolution. Production of diffraction quality crystals was enabled through a combination of protein engineering, chaperone coexpression, modifications to the purification protocol, and the use of unique facial amphiphiles during crystallization. The 2B6-4-CPI complex is virtually identical to the rabbit 2B4 structure bound to the same inhibitor with respect to the arrangement of secondary structural elements and the placement of active site residues. The structure supports prior P450 2B6 homology models based on other mammalian cytochromes P450 and is consistent with the limited site-directed mutagenesis studies on 2B6 and extensive studies on P450 2B4 and 2B1. Although the K262R genetic variant shows unaltered binding of 4-CPI, altered binding affinity, kinetics, and/or product profiles have been previously shown with several other ligands. On the basis of new P450 2B6 crystal structure and previous 2B4 structures, substitutions at residue 262 affect a hydrogen-bonding network connecting the G and H helices, where subtle differences could be transduced to the active site. Docking experiments indicate that the closed protein conformation allows smaller ligands such as ticlopidine to bind to the 2B6 active site in the expected orientation. However, it is unknown whether 2B6 undergoes structural reorganization to accommodate bulkier molecules, as previously inferred from multiple P450 2B4 crystal structures.

  13. Presence of C1-Inhibitor Polymers in a Subset of Patients Suffering from Hereditary Angioedema

    DEFF Research Database (Denmark)

    Elenius Madsen, Daniel; Hansen, Søren Werner Karlskov; Gram, Jørgen Brodersen

    2014-01-01

    Hereditary angioedema (HAE) is a potentially life-threatening disease caused by mutations in the gene encoding the serine protease inhibitor (serpin) C1 inhibitor (C1-inh). The mutations cause decreased functional plasma levels of C1-inh, which triggers unpredictable recurrent edema attacks...

  14. Pathologic features of fatal shark attacks.

    Science.gov (United States)

    Byard, R W; Gilbert, J D; Brown, K

    2000-09-01

    To examine the pattern of injuries in cases of fatal shark attack in South Australian waters, the authors examined the files of their institution for all cases of shark attack in which full autopsies had been performed over the past 25 years, from 1974 to 1998. Of the seven deaths attributed to shark attack during this period, full autopsies were performed in only two cases. In the remaining five cases, bodies either had not been found or were incomplete. Case 1 was a 27-year-old male surfer who had been attacked by a shark. At autopsy, the main areas of injury involved the right thigh, which displayed characteristic teeth marks, extensive soft tissue damage, and incision of the femoral artery. There were also incised wounds of the right wrist. Bony injury was minimal, and no shark teeth were recovered. Case 2 was a 26-year-old male diver who had been attacked by a shark. At autopsy, the main areas of injury involved the left thigh and lower leg, which displayed characteristic teeth marks, extensive soft tissue damage, and incised wounds of the femoral artery and vein. There was also soft tissue trauma to the left wrist, with transection of the radial artery and vein. Bony injury was minimal, and no shark teeth were recovered. In both cases, death resulted from exsanguination following a similar pattern of soft tissue and vascular damage to a leg and arm. This type of injury is in keeping with predator attack from underneath or behind, with the most severe injuries involving one leg. Less severe injuries to the arms may have occurred during the ensuing struggle. Reconstruction of the damaged limb in case 2 by sewing together skin, soft tissue, and muscle bundles not only revealed that no soft tissue was missing but also gave a clearer picture of the pattern of teeth marks, direction of the attack, and species of predator.

  15. Modelling social-technical attacks with timed automata

    NARCIS (Netherlands)

    David, Nicolas; David, Alexandre; Hansen, René Rydhof; Larsen, Kim G.; Legay, Axel; Olesen, Mads Chr.; Probst, Christian W.

    2015-01-01

    Attacks on a system often exploit vulnerabilities that arise from human behaviour or other human activity. Attacks of this type, so-called socio-technical attacks, cover everything from social engineering to insider attacks, and they can have a devastating impact on an unprepared organisation. In th

  16. A Game Theoretic Approach to Cyber Attack Prediction

    Energy Technology Data Exchange (ETDEWEB)

    Peng Liu

    2005-11-28

    The area investigated by this project is cyber attack prediction. With a focus on correlation-based prediction, current attack prediction methodologies overlook the strategic nature of cyber attack-defense scenarios. As a result, current cyber attack prediction methodologies are very limited in predicting strategic behaviors of attackers in enforcing nontrivial cyber attacks such as DDoS attacks, and may result in low accuracy in correlation-based predictions. This project develops a game theoretic framework for cyber attack prediction, where an automatic game-theory-based attack prediction method is proposed. Being able to quantitatively predict the likelihood of (sequences of) attack actions, our attack prediction methodology can predict fine-grained strategic behaviors of attackers and may greatly improve the accuracy of correlation-based prediction. To our best knowledge, this project develops the first comprehensive framework for incentive-based modeling and inference of attack intent, objectives, and strategies; and this project develops the first method that can predict fine-grained strategic behaviors of attackers. The significance of this research and the benefit to the public can be demonstrated to certain extent by (a) the severe threat of cyber attacks to the critical infrastructures of the nation, including many infrastructures overseen by the Department of Energy, (b) the importance of cyber security to critical infrastructure protection, and (c) the importance of cyber attack prediction to achieving cyber security.

  17. Panic Attack during Elective Gastrointestinal Endoscopy

    Directory of Open Access Journals (Sweden)

    Charalampos Mitsonis

    2011-01-01

    Full Text Available Background. Esophagogastroduodenoscopy (EGD and colonoscopy (CS can evoke anxiety, embarrassment, and discomfort. These concerns can culminate in panic attacks, which may traumatize patients and significantly decrease their compliance to the procedure. The objective of this study was to evaluate the relationship between preendoscopic anxiety and the possibility of a panic attack during an elective gastrointestinal endoscopy (EGE. Methods. The study population comprised of 79 Greek outpatients. The examination was carried out without the use of conscious sedation. Patients' anxiety levels were assessed before the procedure using the Greek version of the Spielberger State-Trait Anxiety Inventory (STAI-Y. Results. Seventy-nine patients were enrolled: 45 EGD and 34 CS. Females had higher state and trait anxiety levels than males (48.14 ± 7.94 versus 44.17 ± 7.43, <0.05; and 43.68 ± 6.95 versus 39.86 ± 7.46, <0.05. Patients who experienced panic attack had significantly higher levels of both trait and state anxiety, compared to those who were panic-free. There was no significant relationship between panic attacks and sex or type of procedure. Conclusions. Patients who experience panic attacks during endoscopic procedures appear to have significantly higher anxiety levels before the procedure. Administering the STAI questionnaire prior to the endoscopy seems to be a useful screening method for vulnerable patients.

  18. Trace Attack against Biometric Mobile Applications

    Directory of Open Access Journals (Sweden)

    Sanaa Ghouzali

    2016-01-01

    Full Text Available With the exponential increase in the dependence on mobile devices in everyday life, there is a growing concern related to privacy and security issues in the Gulf countries; therefore, it is imperative that security threats should be analyzed in detail. Mobile devices store enormous amounts of personal and financial information, unfortunately without any security. In order to secure mobile devices against different threats, biometrics has been applied and shown to be effective. However, biometric mobile applications are also vulnerable to several types of attacks that can decrease their security. Biometric information itself is considered sensitive data; for example, fingerprints can leave traces in touched objects and facial images can be captured everywhere or accessed by the attacker if the facial image is stored in the mobile device (lost or stolen. Hence, an attacker can easily forge the identity of a legitimate user and access data on a device. In this paper, the effects of a trace attack on the sensitivity of biometric mobile applications are investigated in terms of security and user privacy. Experimental results carried out on facial and fingerprint mobile authentication applications using different databases have shown that these mobile applications are vulnerable to the proposed attack, which poses a serious threat to the overall system security and user privacy.

  19. Performance Evaluation of AODV with Blackhole Attack

    Science.gov (United States)

    Dara, Karuna

    2010-11-01

    A Mobile Ad Hoc Network (MANET) is a temporary network set up by a wireless mobile computers moving arbitrary in the places that have no network infrastructure. These nodes maintain connectivity in a decentralized manner. Since the nodes communicate with each other, they cooperate by forwarding data packets to other nodes in the network. Thus the nodes find a path to the destination node using routing protocols. However, due to security vulnerabilities of the routing protocols, mobile ad-hoc networks are unprotected to attacks of the malicious nodes. One of these attacks is the Black Hole Attack against network integrity absorbing all data packets in the network. Since the data packets do not reach the destination node on account of this attack, data loss will occur. In this paper, we simulated the black hole attack in various mobile ad-hoc network scenarios using AODV routing protocol of MANET and have tried to find a effect if number of nodes are increased with increase in malicious nodes.

  20. Safety and Usage of C1-Inhibitor in Hereditary Angioedema

    DEFF Research Database (Denmark)

    Riedl, Marc A; Bygum, Anette; Lumry, William

    2016-01-01

    BACKGROUND: The plasma-derived, highly purified, nanofiltered C1-inhibitor concentrate (Berinert; "pnfC1-INH") is approved in the United States for treating hereditary angioedema (HAE) attacks and in many European countries for attack treatment and short-term prophylaxis. OBJECTIVE: The objective...... of this study was to describe safety and usage patterns of pnfC1-INH. METHODS: A multicenter, observational, registry was conducted between 2010 and 2014 at 30 United States and 7 European sites to obtain both prospective (occurring after enrollment) and retrospective (occurring before enrollment) safety...... and usage data on subjects receiving pnfC1-INH for any reason. RESULTS: Of 343 enrolled patients, 318 received 1 or more doses of pnfC1-INH for HAE attacks (11,848 infusions) or for prophylaxis (3142 infusions), comprising the safety population. Median dosages per infusion were 10.8 IU/kg (attack treatment...

  1. Cross-site scripting attacks procedure and Prevention Strategies

    Directory of Open Access Journals (Sweden)

    Wang Xijun

    2016-01-01

    Full Text Available Cross-site scripting attacks and defense has been the site of attack and defense is an important issue, this paper, the definition of cross-site scripting attacks, according to the current understanding of the chaos on the cross-site scripting, analyzes the causes and harm cross-site scripting attacks formation of attacks XXS complete process XSS attacks made a comprehensive analysis, and then for the web program includes Mobility there are cross-site scripting filter laxity given from ordinary users browse the web and web application developers two the defense cross-site scripting attacks effective strategy.

  2. Pareto Efficient Solutions of Attack-Defence Trees

    DEFF Research Database (Denmark)

    Aslanyan, Zaruhi; Nielson, Flemming

    2015-01-01

    Attack-defence trees are a promising approach for representing threat scenarios and possible countermeasures in a concise and intuitive manner. An attack-defence tree describes the interaction between an attacker and a defender, and is evaluated by assigning parameters to the nodes, such as proba......Attack-defence trees are a promising approach for representing threat scenarios and possible countermeasures in a concise and intuitive manner. An attack-defence tree describes the interaction between an attacker and a defender, and is evaluated by assigning parameters to the nodes...... on a new and general formalism for attack-defence trees....

  3. Attack Prevention for Collaborative Spectrum Sensing in Cognitive Radio Networks

    CERN Document Server

    Duan, Lingjie; Huang, Jianwei; Shin, Kang G

    2011-01-01

    Collaborative spectrum sensing can significantly improve the detection performance of secondary unlicensed users (SUs). However, the performance of collaborative sensing is vulnerable to sensing data falsification attacks, where malicious SUs (attackers) submit manipulated sensing reports to mislead the fusion center's decision on spectrum occupancy. Moreover, attackers may not follow the fusion center's decision regarding their spectrum access. This paper considers a challenging attack scenario where multiple rational attackers overhear all honest SUs' sensing reports and cooperatively maximize attackers' aggregate spectrum utilization. We show that, without attack-prevention mechanisms, honest SUs are unable to transmit over the licensed spectrum, and they may further be penalized by the primary user for collisions due to attackers' aggressive transmissions. To prevent such attacks, we propose two novel attack-prevention mechanisms with direct and indirect punishments. The key idea is to identify collisions...

  4. Attack-tolerant networked control system: an approach for detection the controller stealthy hijacking attack

    Science.gov (United States)

    Atta Yaseen, Amer; Bayart, Mireille

    2017-01-01

    In this work, a new approach will be introduced as a development for the attack-tolerant scheme in the Networked Control System (NCS). The objective is to be able to detect an attack such as the Stuxnet case where the controller is reprogrammed and hijacked. Besides the ability to detect the stealthy controller hijacking attack, the advantage of this approach is that there is no need for a priori mathematical model of the controller. In order to implement the proposed scheme, a specific detector for the controller hijacking attack is designed. The performance of this scheme is evaluated be connected the detector to NCS with basic security elements such as Data Encryption Standard (DES), Message Digest (MD5), and timestamp. The detector is tested along with networked PI controller under stealthy hijacking attack. The test results of the proposed method show that the hijacked controller can be significantly detected and recovered.

  5. Distributed Denial of Service Attacks: A Review

    Directory of Open Access Journals (Sweden)

    Sonali Swetapadma Sahu

    2014-01-01

    Full Text Available A wireless sensor network (WSN is a wireless network consisting of spatially distributed autonomous devices using sensors to monitor physical or environmental conditions.WSN is a fluorishing network that has numerous applications and could be used in diverse scenarios. DDoS (Distributed Denial of Service is an attack where a number of compromised systems attack a single target, thereby causing denial of service for users of the targeted system. The flood of incoming messages to the target system essentially forces it to shut down, thereby denying service to the system to legitimate users.Not much research work has been done in DDoS in WSN.We are conducting a review on DDoS attack to show its impact on networks and to present various defensive, detection and preventive measures adopted by researchers till now.

  6. Quantifying Mixed Uncertainties in Cyber Attacker Payoffs

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, Samrat; Halappanavar, Mahantesh; Tipireddy, Ramakrishna; Oster, Matthew R.; Saha, Sudip

    2015-04-15

    Representation and propagation of uncertainty in cyber attacker payoffs is a key aspect of security games. Past research has primarily focused on representing the defender’s beliefs about attacker payoffs as point utility estimates. More recently, within the physical security domain, attacker payoff uncertainties have been represented as Uniform and Gaussian probability distributions, and intervals. Within cyber-settings, continuous probability distributions may still be appropriate for addressing statistical (aleatory) uncertainties where the defender may assume that the attacker’s payoffs differ over time. However, systematic (epistemic) uncertainties may exist, where the defender may not have sufficient knowledge or there is insufficient information about the attacker’s payoff generation mechanism. Such epistemic uncertainties are more suitably represented as probability boxes with intervals. In this study, we explore the mathematical treatment of such mixed payoff uncertainties.

  7. A Traceability Attack against e-Passports

    Science.gov (United States)

    Chothia, Tom; Smirnov, Vitaliy

    Since 2004, many nations have started issuing "e-passports" containing an RFID tag that, when powered, broadcasts information. It is claimed that these passports are more secure and that our data will be protected from any possible unauthorised attempts to read it. In this paper we show that there is a flaw in one of the passport's protocols that makes it possible to trace the movements of a particular passport, without having to break the passport's cryptographic key. All an attacker has to do is to record one session between the passport and a legitimate reader, then by replaying a particular message, the attacker can distinguish that passport from any other. We have implemented our attack and tested it successfully against passports issued by a range of nations.

  8. Resistance of the double random phase encryption against various attacks.

    Science.gov (United States)

    Frauel, Yann; Castro, Albertina; Naughton, Thomas J; Javidi, Bahram

    2007-08-06

    Several attacks are proposed against the double random phase encryption scheme. These attacks are demonstrated on computer-generated ciphered images. The scheme is shown to be resistant against brute force attacks but susceptible to chosen and known plaintext attacks. In particular, we describe a technique to recover the exact keys with only two known plain images. We compare this technique to other attacks proposed in the literature.

  9. Enhancing collaborative intrusion detection networks against insider attacks using supervised intrusion sensitivity-based trust management model

    DEFF Research Database (Denmark)

    Li, Wenjuan; Meng, Weizhi; Kwok, Lam-For

    2017-01-01

    To defend against complex attacks, collaborative intrusion detection networks (CIDNs) have been developed to enhance the detection accuracy, which enable an IDS to collect information and learn experience from others. However, this kind of networks is vulnerable to malicious nodes which...... of intrusion sensitivity based on expert knowledge. In the evaluation, we compare the performance of three different supervised classifiers in assigning sensitivity values and investigate our trust model under different attack scenarios and in a real wireless sensor network. Experimental results indicate...... are utilized by insider attacks (e.g., betrayal attacks). In our previous research, we developed a notion of intrusion sensitivity and identified that it can help improve the detection of insider attacks, whereas it is still a challenge for these nodes to automatically assign the values. In this article, we...

  10. Mortality and management of 96 shark attacks and development of a shark bite severity scoring system.

    Science.gov (United States)

    Lentz, Ashley K; Burgess, George H; Perrin, Karen; Brown, Jennifer A; Mozingo, David W; Lottenberg, Lawrence

    2010-01-01

    Humans share a fascination and fear of sharks. We predict that most shark attacks are nonfatal but require skilled, timely medical intervention. The development of a shark bite severity scoring scale will assist communication and understanding of such an injury. We retrospectively reviewed records of the prospectively maintained International Shark Attack File (ISAF) at the University of Florida. The ISAF contains 4409 investigations, including 2979 documented attacks, 96 of which have complete medical records. We developed a Shark-Induced Trauma (SIT) Scale and calculated the level of injury for each attack. Medical records were reviewed for the 96 documented shark attack victims since 1921. Calculated levels of injury in the SIT Scale reveal 40 Level 1 injuries (41.7%), 16 Level 2 injuries (16.7%), 18 Level 3 injuries (18.8%), 14 Level 4 injuries (14.6%), and eight Level 5 injuries (8.3%). The overall mortality of shark attacks was 8.3 per cent. However, SIT Scale Level 1 injuries comprised the greatest percentage of cases at 41.7 per cent. Injury to major vascular structures increases mortality and necessitates immediate medical attention and definitive care by a surgeon. Shark bites deserve recognition with prompt resuscitation, washout, débridement, and follow up for prevention of infection and closure of more complex wounds.

  11. X-ray Crystal Structures of Monomeric and Dimeric Peptide Inhibitors in Complex with the Human Neonatal Fc Receptor, FcRn

    Energy Technology Data Exchange (ETDEWEB)

    Mezo, Adam R.; Sridhar, Vandana; Badger, John; Sakorafas, Paul; Nienaber, Vicki (Zenobia); (Biogen)

    2010-10-28

    The neonatal Fc receptor, FcRn, is responsible for the long half-life of IgG molecules in vivo and is a potential therapeutic target for the treatment of autoimmune diseases. A family of peptides comprising the consensus motif GHFGGXY, where X is preferably a hydrophobic amino acid, was shown previously to inhibit the human IgG:human FcRn protein-protein interaction (Mezo, A. R., McDonnell, K. A., Tan Hehir, C. A., Low, S. C., Palombella, V. J., Stattel, J. M., Kamphaus, G. D., Fraley, C., Zhang, Y., Dumont, J. A., and Bitonti, A. J. (2008) Proc. Natl. Acad. Sci. U.S.A., 105, 2337-2342). Herein, the x-ray crystal structure of a representative monomeric peptide in complex with human FcRn was solved to 2.6 {angstrom} resolution. The structure shows that the peptide binds to human FcRn at the same general binding site as does the Fc domain of IgG. The data correlate well with structure-activity relationship data relating to how the peptide family binds to human FcRn. In addition, the x-ray crystal structure of a representative dimeric peptide in complex with human FcRn shows how the bivalent ligand can bridge two FcRn molecules, which may be relevant to the mechanism by which the dimeric peptides inhibit FcRn and increase IgG catabolism in vivo. Modeling of the peptide:FcRn structure as compared with available structural data on Fc and FcRn suggest that the His-6 and Phe-7 (peptide) partially mimic the interaction of His-310 and Ile-253 (Fc) in binding to FcRn, but using a different backbone topology.

  12. Playing Attack and Defense with Trusted Storage

    DEFF Research Database (Denmark)

    Gonzalez, Javier; Bonnet, Philippe; Bouganim, Luc

    2014-01-01

    It is often convenient to assume in a data management platform that one or several computing devices are trusted, specially when the goal is to provide privacy guarantees over personal data. But what does it take for a computing device to be trusted? More specifically, how can a personal device...... provide trusted storage? This is the question we tackle in this demonstration. We describe how secure devices, equipped with a trusted execution environment, differ from general purpose devices. We illustrate with our demonstration scenario, that it is much more difficult to attack a storage service...... running on a secure device, than to attack the same service running on a general purpose device....

  13. Defending Against Wormhole Attack in OLSR

    Institute of Scientific and Technical Information of China (English)

    HONG Liang; HONG Fan; FU Cai

    2006-01-01

    OLSR (optimal link state routing) is one of the four basic routing protocols used in mobile ad hoc Networks by the MANET working group of IETF(Internet engineering task force). OLSR, a proactive routing protocol, is based on a multipoint relaying flooding technique to reduce the number of topology broadcast. OLSR uses periodic HELLO packets to neighbor detection. As introduced in Reference [1], the wormhole attack can form a serious threat in wireless Networks, especially against many ad hoc Network routing protocols and location-based wireless security systems. Here, a trust model to handle this attack in OLSR is provided and simulated in NS2.

  14. Textual Manipulation for SQL Injection Attacks

    Directory of Open Access Journals (Sweden)

    Hussein AlNabulsi

    2013-11-01

    Full Text Available SQL injection attacks try to use string or text manipulations to access illegally websites and their databases. This is since using some symbols or characters in SQL statements may trick the authentication system to incorrectly allow such SQL statements to be processed or executed. In this paper, we highlighted several examples of such text manipulations that can be successfully used in SQL injection attacks. We evaluated the usage of those strings on several websites and web pages using SNORT open source. We also conducted an extensive comparison study of some relevant papers.

  15. CESA TRAFFICKING INHIBITOR inhibits cellulose deposition and interferes with the trafficking of cellulose synthase complexes and their associated proteins KORRIGAN1 and POM2/CELLULOSE SYNTHASE INTERACTIVE PROTEIN1.

    Science.gov (United States)

    Worden, Natasha; Wilkop, Thomas E; Esteve, Victor Esteva; Jeannotte, Richard; Lathe, Rahul; Vernhettes, Samantha; Weimer, Bart; Hicks, Glenn; Alonso, Jose; Labavitch, John; Persson, Staffan; Ehrhardt, David; Drakakaki, Georgia

    2015-02-01

    Cellulose synthase complexes (CSCs) at the plasma membrane (PM) are aligned with cortical microtubules (MTs) and direct the biosynthesis of cellulose. The mechanism of the interaction between CSCs and MTs, and the cellular determinants that control the delivery of CSCs at the PM, are not yet well understood. We identified a unique small molecule, CESA TRAFFICKING INHIBITOR (CESTRIN), which reduces cellulose content and alters the anisotropic growth of Arabidopsis (Arabidopsis thaliana) hypocotyls. We monitored the distribution and mobility of fluorescently labeled cellulose synthases (CESAs) in live Arabidopsis cells under chemical exposure to characterize their subcellular effects. CESTRIN reduces the velocity of PM CSCs and causes their accumulation in the cell cortex. The CSC-associated proteins KORRIGAN1 (KOR1) and POM2/CELLULOSE SYNTHASE INTERACTIVE PROTEIN1 (CSI1) were differentially affected by CESTRIN treatment, indicating different forms of association with the PM CSCs. KOR1 accumulated in bodies similar to CESA; however, POM2/CSI1 dissociated into the cytoplasm. In addition, MT stability was altered without direct inhibition of MT polymerization, suggesting a feedback mechanism caused by cellulose interference. The selectivity of CESTRIN was assessed using a variety of subcellular markers for which no morphological effect was observed. The association of CESAs with vesicles decorated by the trans-Golgi network-localized protein SYNTAXIN OF PLANTS61 (SYP61) was increased under CESTRIN treatment, implicating SYP61 compartments in CESA trafficking. The properties of CESTRIN compared with known CESA inhibitors afford unique avenues to study and understand the mechanism under which PM-associated CSCs are maintained and interact with MTs and to dissect their trafficking routes in etiolated hypocotyls.

  16. Polymorphic Attacks and Network Topology: Application of Concepts from Natural Systems

    Science.gov (United States)

    Rangan, Prahalad

    2010-01-01

    The growing complexity of interactions between computers and networks makes the subject of network security a very interesting one. As our dependence on the services provided by computing networks grows, so does our investment in such technology. In this situation, there is a greater risk of occurrence of targeted malicious attacks on computers…

  17. Attack Classification Schema for Smart City WSNs.

    Science.gov (United States)

    Garcia-Font, Victor; Garrigues, Carles; Rifà-Pous, Helena

    2017-04-05

    Urban areas around the world are populating their streets with wireless sensor networks (WSNs) in order to feed incipient smart city IT systems with metropolitan data. In the future smart cities, WSN technology will have a massive presence in the streets, and the operation of municipal services will be based to a great extent on data gathered with this technology. However, from an information security point of view, WSNs can have failures and can be the target of many different types of attacks. Therefore, this raises concerns about the reliability of this technology in a smart city context. Traditionally, security measures in WSNs have been proposed to protect specific protocols in an environment with total control of a single network. This approach is not valid for smart cities, as multiple external providers deploy a plethora of WSNs with different security requirements. Hence, a new security perspective needs to be adopted to protect WSNs in smart cities. Considering security issues related to the deployment of WSNs as a main data source in smart cities, in this article, we propose an intrusion detection framework and an attack classification schema to assist smart city administrators to delimit the most plausible attacks and to point out the components and providers affected by incidents. We demonstrate the use of the classification schema providing a proof of concept based on a simulated selective forwarding attack affecting a parking and a sound WSN.

  18. Plant defences against herbivore and insect attack

    Science.gov (United States)

    Plants deploy a number of defences against attack by insects and other herbivores. Direct defence is conferred by plant products and structures that deter or kill the herbivores. Chemical toxins and deterrents vary widely among plant species, and some typical toxins include alkaloids, terpenoids, st...

  19. Why Does Asthma Attack Severely at Night?

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ The rhythmic changes of human physiological activities by day and at night may cause regular change of the patient's condition within one day. The following is the explanation with the theory of Chinese medicine for the reason why asthma attacks severely at night.

  20. Rhode Island School Terrorist Attack Preparedness

    Science.gov (United States)

    Dube, Michael W. M.

    2012-01-01

    This study examined the state of safety and terrorist attack preparedness in Rhode Island Schools as determined by Rhode Island school leader perceptions. The study is descriptive in nature as it gathers data to describe a particular event or situation. Using a researcher generated survey based on terrorist preparedness guidelines and suggestions…

  1. The diagnosis of transient ischemic attacks

    NARCIS (Netherlands)

    P.J. Koudstaal (Peter Jan)

    1989-01-01

    textabstractThe diagnosis of transient ischemic attack (TIA) is fraught with difficulty, since the diagnosis rests entirely upon the history of the patient's symptoms and the neurologist's skill in questioning the patient. The aim of this thesis is to investigate various measures to improve the reli

  2. Persistent cognitive impairment after transient ischemic attack

    NARCIS (Netherlands)

    Rooij, F.G. van; Schaapsmeerders, P.; Maaijwee, N.A.; Duijnhoven, D.A. van; Leeuw, F.E. de; Kessels, R.P.; Dijk, E.J. van

    2014-01-01

    BACKGROUND AND PURPOSE: By definition, the symptoms of a transient ischemic attack (TIA) subside completely within 24 hours. Imaging studies show signs of persistent ischemic tissue damage in a substantial amount of patients with TIA. Cerebral infarction can cause permanent cognitive impairment. Whe

  3. Persistent Cognitive Impairment After Transient Ischemic Attack

    NARCIS (Netherlands)

    Rooij, F.G. van; Schaapsmeerders, P.; Maaijwee, N.A.M.M.; Duijnhoven, D.A. van; de Leeuw, F.E.; Kessels, R.P.C.; Dijk, E.J. van

    2014-01-01

    Background and Purpose—By definition, the symptoms of a transient ischemic attack (TIA) subside completely within 24 hours. Imaging studies show signs of persistent ischemic tissue damage in a substantial amount of patients with TIA. Cerebral infarction can cause permanent cognitive impairment. Whet

  4. Chemical Attack of Malaysian Pozzolans Concrete

    Directory of Open Access Journals (Sweden)

    Mohd Hilton Ahmad

    2011-09-01

    Full Text Available Malaysia produces more than 10 million tonne of by-product from industrial sector per year. As the environmental impact concerns, more than half of the by-product can be recycled to be used as construction materials. One of them is pozzolan, a cement replacing material that can be used to enhance the properties of the concrete. This paper studies the chemical attack to local prozzolans concrete. The parameters studied include weight loss, length change, and residual strength of local pozzolans concrete after been exposed to severe environment. The specimen were tested under normal room temperature, exposed to magnesium sulfate, MgSO4. 2H2O where both sulfate attack and acid attack take place. Two series of pozzolans< which is Pulverized fly ash (PFA and Palm oil fuel ash (POFA were identified. Another series of admixture, Quarry Dust (QD from quarry waste that contain high amount of silica content also been carried out. Each series will study the effect of cement replacement percentage of 5%, 10% and 15%. The parameters were compared to conventional ordinary Portland cement (OPC concrete as control mix. Accelerated testing was conducted at 3, 7, 28, 56 and 90 days. The result shows that the local pozzolans concrete were found to be in good resistance against sulfate attack compared to conventional concrete. Compared to all series conducted, series of PFA replacement gave the best resistance followed by POFA and QD replacement series.

  5. Intrusion-Tolerant Replication under Attack

    Science.gov (United States)

    Kirsch, Jonathan

    2010-01-01

    Much of our critical infrastructure is controlled by large software systems whose participants are distributed across the Internet. As our dependence on these critical systems continues to grow, it becomes increasingly important that they meet strict availability and performance requirements, even in the face of malicious attacks, including those…

  6. Shark Attack! Sinking Your Teeth into Anatomy.

    Science.gov (United States)

    House, Herbert

    2002-01-01

    Presents a real life shark attack story and studies arm reattachment surgery to teach human anatomy. Discusses how knowledge of anatomy can be put to use in the real world and how the arm functions. Includes teaching notes and suggestions for classroom management. (YDS)

  7. Association between Terror Attacks and Suicide Attempts

    Science.gov (United States)

    Weizman, Tal; Yagil, Yaron; Schreiber, Shaul

    2009-01-01

    Based on Durkheim's "Control theory," we explored the association between frequency of terror attacks in Israel and the frequency of suicide attempts admitted to the Emergency Room of a major general hospital in Tel-Aviv (1999-2004). Analysis of the six-year study period as a whole revealed no significant correlation between the…

  8. An Adaptive Approach for Defending against DDoS Attacks

    Directory of Open Access Journals (Sweden)

    Muhai Li

    2010-01-01

    Full Text Available In various network attacks, the Distributed Denial-of-Service (DDoS attack is a severe threat. In order to deal with this kind of attack in time, it is necessary to establish a special type of defense system to change strategy dynamically against attacks. In this paper, we introduce an adaptive approach, which is used for defending against DDoS attacks, based on normal traffic analysis. The approach can check DDoS attacks and adaptively adjust its configurations according to the network condition and attack severity. In order to insure the common users to visit the victim server that is being attacked, we provide a nonlinear traffic control formula for the system. Our simulation test indicates that the nonlinear control approach can prevent the malicious attack packets effectively while making legitimate traffic flows arrive at the victim.

  9. A graph based system for multi-stage attacks recognition

    Institute of Scientific and Technical Information of China (English)

    Safaa O. Al-Mamory; Zhai Jianhong; Zhang Hongli

    2008-01-01

    Building attack scenario is one of the most important aspects in network security. This paper proposed a system which collects intrusion alerts, clusters them as sub-attacks using alerts abstraction, aggregates the similar sub-attacks, and then correlates and generates correlation graphs. The scenarios were represented by alert classes instead of alerts themselves so as to reduce the required rules and have the ability of detecting new variations of attacks. The proposed system is capable of passing some of the missed attacks. To evaluate system effectiveness, it was tested with different datasets which contain multi-step attacks. Compressed and easily understandable correlation graphs which reflect attack scenarios were generated. The proposed system can correlate related alerts, uncover the attack strategies, and detect new variations of attacks.

  10. Recovery of human remains after shark attack.

    Science.gov (United States)

    Byard, Roger W; James, Ross A; Heath, Karen J

    2006-09-01

    Two cases of fatal shark attack are reported where the only tissues recovered were fragments of lung. Case 1: An 18-year-old male who was in the sea behind a boat was observed by friends to be taken by a great white shark (Carcharodon carcharias). The shark dragged him under the water and then, with a second shark, dismembered the body. Witnesses noted a large amount of blood and unrecognizable body parts coming to the surface. The only tissues recovered despite an intensive beach and sea search were 2 fragments of lung. Case 2: A 19-year-old male was attacked by a great white shark while diving. A witness saw the shark swim away with the victim's body in its mouth. Again, despite intensive beach and sea searches, the only tissue recovered was a single piece of lung, along with pieces of wetsuit and diving equipment. These cases indicate that the only tissue to escape being consumed or lost in fatal shark attacks, where there is a significant attack with dismemberment and disruption of the integrity of the body, may be lung. The buoyancy of aerated pulmonary tissue ensures that it rises quickly to the surface, where it may be recovered by searchers soon after the attack. Aeration of the lung would be in keeping with death from trauma rather than from drowning and may be a useful marker in unwitnessed deaths to separate ante- from postmortem injury, using only relatively small amounts of tissues. Early organ recovery enhances the identification of human tissues as the extent of morphologic alterations by putrefactive processes and sea scavengers will have been minimized. DNA testing is also possible on such recovered fragments, enabling confirmation of the identity of the victim.

  11. Role of CD59 in T cell activation induced by non-lethal complement attack

    Institute of Scientific and Technical Information of China (English)

    HAN Gen-cheng; BAI Yun; JIANG Man; LI Wan-ling; ZHU Xi-hua

    2001-01-01

    To study the mechanism ofT-cell activation induced by non-lethal complement attack and the role of CD59 in this process. Methods: Human CD59 and its transmembrane counterpart CD59TM cDNA were transfected into murine thymoma EL-4 cells. Activation and proliferation of EL-4 transfectants were observed with MTT assay.Results: Both CD59 and CD59 TM cDNA expressed on EL-4 cells effectively inhibited complement-mediated membrane damage. Cross-linking of CD59 with antibody induced activation of CD59/EL-4 cells but not CD59TM/EL-4cells. This effect was inhibited by Herbimycin A, a special protein tyrosine kinase (PTK) inhibitor. Non-lethal complement attack induced CD59/EL-4 but not CD59TM/EL-4 cell to proliferate, and this reaction was not blocked by Herbimycin A. Conclusion: CD59 takes part in T cell activation induced by non-lethal complement attack. The mechanisms of T cell activation induced by non-lethal complement attack are different from those by cross-linking of CD59.

  12. A Survey of Mobile Ad Hoc Network Attacks

    Directory of Open Access Journals (Sweden)

    PRADIP M. JAWANDHIYA,

    2010-09-01

    Full Text Available Security is an essential requirement in mobile ad hoc network (MANETs. Compared to wired networks, MANETs are more vulnerable to security attacks due to the lack of a trusted centralized authority and limited resources. Attacks on ad hoc networks can be classified as passive and active attacks, depending on whether the normal operation of the network is disrupted or not. In this paper, we are describing the all prominent attacks described in literature in a consistent manner to provide a concise comparison on attack types. To the best of our knowledge, this is the first paper that studies all the existing attacks on MANETs.

  13. Analysis of the SYN Flood DoS Attack

    Directory of Open Access Journals (Sweden)

    Mitko Bogdanoski

    2013-06-01

    Full Text Available The paper analyzes systems vulnerability targeted by TCP (Transmission Control Protocol segments when SYN flag is ON, which gives space for a DoS (Denial of Service attack called SYN flooding attack or more often referred as a SYN flood attack. The effects of this type of attack are analyzed and presented in OPNET simulation environment. Furthermore, the paper presents two anomaly detection algorithms as an effective mechanism against this type of attack. Finally, practical approaches against SYN flood attack for Linux and Windows environment which are followed by are shown.

  14. Complement, Kinins, and Hereditary Angioedema: Mechanisms of Plasma Instability when C1 Inhibitor is Absent.

    Science.gov (United States)

    Kaplan, Allen P; Joseph, Kusumam

    2016-10-01

    Plasma of patients with types I and II hereditary angioedema is unstable if incubated in a plastic (i.e., inert) vessel at 37 °C manifested by progressively increasing formation of bradykinin. There is also a persistent low level of C4 in 95 % of patients even when they are symptomatic. These phenomena are due to the properties of the C1r subcomponent of C1, factor XII, and the bimolecular complex of prekallikrein with high molecular weight kininogen (HK). Purified C1r auto-activates in physiologic buffers, activates C1s, which in turn depletes C4. This occurs when C1 inhibitor is deficient. The complex of prekallikrein-HK acquires an inducible active site not present in prekallikrein which in Tris-type buffers cleaves HK stoichiometrically to release bradykinin, or in phosphate buffer auto-activates to generate kallikrein and bradykinin. Thus immunologic depletion of C1 inhibitor from factor XII-deficient plasma (phosphate is the natural buffer) auto-activates on incubation to release bradykinin. Normal C1 inhibitor prevents this from occurring. During attacks of angioedema, if factor XII auto-activates on surfaces, the initial factor XIIa formed converts prekallikrein to kallikrein, and kallikrein cleaves HK to release bradykinin. Kallikrein also rapidly activates most remaining factor XII to factor XIIa. Additional cleavages convert factor XIIa to factor XIIf and factor XIIf activates C1r enzymatically so that C4 levels approach zero, and C2 is depleted. There is also a possibility that kallikrein is generated first as a result of activation of the prekallikrein-HK complex by heat shock protein 90 released from endothelial cells, followed by kallikrein activation of factor XII.

  15. New insights on the role of the gamma-herpesvirus uracil-DNA glycosylase leucine loop revealed by the structure of the Epstein-Barr virus enzyme in complex with an inhibitor protein.

    Science.gov (United States)

    Géoui, Thibault; Buisson, Marlyse; Tarbouriech, Nicolas; Burmeister, Wim Pascal

    2007-02-09

    Epstein-Barr virus (EBV) is a human gamma-herpesvirus. Within its 86 open reading frame containing genome, two enzymes avoiding uracil incorporation into DNA can be found: uracil triphosphate hydrolase and uracil-DNA glycosylase (UNG). The latter one excises uracil bases that are due to cytosine deamination or uracil misincorporation from double-stranded DNA substrates. The EBV enzyme belongs to family 1 UNGs. We solved the three-dimensional structure of EBV UNG in complex with the uracil-DNA glycosylase inhibitor protein (Ugi) from bacteriophage PBS-2 at a resolution of 2.3 A by X-ray crystallography. The structure of EBV UNG encoded by the BKRF3 reading frame shows the excellent global structural conservation within the solved examples of family 1 enzymes. Four out of the five catalytic motifs are completely conserved, whereas the fifth one, the leucine loop, carries a seven residue insertion. Despite this insertion, catalytic constants of EBV UNG are similar to those of other UNGs. Modelling of the EBV UNG-DNA complex shows that the longer leucine loop still contacts DNA and is likely to fulfil its role of DNA binding and deformation differently than the enzymes with previously solved structures. We could show that despite the evolutionary distance of EBV UNG from the natural host protein, bacteriophage Ugi binds with an inhibitory constant of 8 nM to UNG. This is due to an excellent specificity of Ugi for conserved elements of UNG, four of them corresponding to catalytic motifs and a fifth one corresponding to an important beta-turn structuring the catalytic site.

  16. Discovering anti-platelet drug combinations with an integrated model of activator-inhibitor relationships, activator-activator synergies and inhibitor-inhibitor synergies.

    Directory of Open Access Journals (Sweden)

    Federica Lombardi

    2015-04-01

    Full Text Available Identifying effective therapeutic drug combinations that modulate complex signaling pathways in platelets is central to the advancement of effective anti-thrombotic therapies. However, there is no systems model of the platelet that predicts responses to different inhibitor combinations. We developed an approach which goes beyond current inhibitor-inhibitor combination screening to efficiently consider other signaling aspects that may give insights into the behaviour of the platelet as a system. We investigated combinations of platelet inhibitors and activators. We evaluated three distinct strands of information, namely: activator-inhibitor combination screens (testing a panel of inhibitors against a panel of activators; inhibitor-inhibitor synergy screens; and activator-activator synergy screens. We demonstrated how these analyses may be efficiently performed, both experimentally and computationally, to identify particular combinations of most interest. Robust tests of activator-activator synergy and of inhibitor-inhibitor synergy required combinations to show significant excesses over the double doses of each component. Modeling identified multiple effects of an inhibitor of the P2Y12 ADP receptor, and complementarity between inhibitor-inhibitor synergy effects and activator-inhibitor combination effects. This approach accelerates the mapping of combination effects of compounds to develop combinations that may be therapeutically beneficial. We integrated the three information sources into a unified model that predicted the benefits of a triple drug combination targeting ADP, thromboxane and thrombin signaling.

  17. Attack diagnosis on binary executables using dynamic program slicing

    Science.gov (United States)

    Huang, Shan; Zheng, Yudi; Zhang, Ruoyu

    2011-12-01

    Nowadays, the level of the practically used programs is often complex and of such a large scale so that it is not as easy to analyze and debug them as one might expect. And it is quite difficult to diagnose attacks and find vulnerabilities in such large-scale programs. Thus, dynamic program slicing becomes a popular and effective method for program comprehension and debugging since it can reduce the analysis scope greatly and drop useless data that do not influence the final result. Besides, most of existing dynamic slicing tools perform dynamic slicing in the source code level, but the source code is not easy to obtain in practice. We believe that we do need some kinds of systems to help the users understand binary programs. In this paper, we present an approach of diagnosing attacks using dynamic backward program slicing based on binary executables, and provide a dynamic binary slicing tool named DBS to analyze binary executables precisely and efficiently. It computes the set of instructions that may have affected or been affected by slicing criterion set in certain location of the binary execution stream. This tool also can organize the slicing results by function call graphs and control flow graphs clearly and hierarchically.

  18. Modified AODV Protocol against Blackhole Attacks in MANET

    Directory of Open Access Journals (Sweden)

    K.Rama,

    2010-12-01

    Full Text Available Mobile Adhoc Network (MANET consists of a collection of wireless mobile hosts without the required intervention of any existing infrastructure or centralized access point such as base station. The dynamic topology of MANET allows nodes to join and leave the network at any point of time. Wireless MANET is particularly vulnerabledue to its fundamental characteristics such as open medium, dynamic topology, distributed cooperation and constrained capability. So security in MANET is a complex issue. There are many routing protocols that establish the routes between the nodes in the network. The control towards the management of the nodes in the MANET is distributed. This features does not give assurance towards the security aspects of the network. There are many routing attacks caused due to lack of security. In this paper, therefore, we attempt to focus on analyzing and improving the security of one of the popularrouting protocol for MANET viz. the Adhoc On Demand Distance Vector (AODV routing protocol. Our focus specifically, is on ensuring the security against the Blackhole Attack. The proposed solution is that capable of detecting and removing black hole nodes in the MANET at the initial stage itself without any delay.

  19. Cyber-Attacks and the Risks for CERN

    CERN Multimedia

    Computer Security Team

    2013-01-01

    In the previous Bulletin, we discussed the cyber-risks for the accelerator complex. However, looking at the broader picture, the cyber-risks for CERN are much more diverse.   Attacks can not only harm the operation of accelerators or experiments, but also impact negatively on the operation of the Organization as a whole and/or its reputation. This would not only hamper and impede our work while making us looking plain stupid, but might also make funding agencies reconsider whether their money is well invested in CERN… Examples? Sure, let’s be imaginative! What would be the consequences, if: a laptop holding sensitive CERN documents is lost or stolen, and ends up on eBay? your password is compromised and your mail account misused to send nasty messages to thousands of external mail addresses? an attacker manages to add photos of naked women/men onto a prominent CERN website, and boasts about this on Twitter? confidential documents like job application forms or passwo...

  20. Fast correlation attack on stream cipher ABC v3

    Institute of Scientific and Technical Information of China (English)

    ZHANG HaiNa; LI Lin; WANG XiaoYun

    2008-01-01

    ABC v3 is a stream cipher submitted to the ECRYPT eStream project and has entered the second evaluation phase.Its key length is 128 bits.In this paper,we find large numbers of new weak keys of ABC family and introduce a method to search for them,and then apply a fast correlation attack to break ABC v3 with weak keys.We show that there are at least 2103.71 new weak keys in ABC v3.Recovering the internal state of a weak key requires 236.05 keystream words and 250.56 operations.The attack can be applied to ABC v1 and v2 with the same complexity as that of ABC v3.However,the number of weak keys of ABC v1 as well as ABC v2 decreases to 297+295.19.It reveals that ABC v3 incurs more weak keys than that of ABC v1 and v2.

  1. Integrated approach for investigating the durability of self-consolidating concrete to sulfate attack

    Science.gov (United States)

    Bassuoni, Mohamed Tamer F.

    The growing use of self-consolidating concrete (SCC) in various infrastructure applications exposed to sulfate-rich environments necessitates conducting comprehensive research to evaluate its durability to external sulfate attack. Since the reliability and adequacy of standard sulfate immersion tests have been questioned, the current thesis introduced an integrated testing approach for assessing the durability of a wide scope of SCC mixtures to external sulfate attack. This testing approach involved progressive levels of complexity from single to multiple damage processes. A new series of sulfate attack tests involving multiple field-like parameters and combined damage mechanisms (various cations, controlled pH, wetting-drying, partial immersion, freezing-thawing, and cyclic cold-hot conditions with or without sustained flexural loading) were designed to evaluate the performance (suitability) of the SCC mixtures under various sulfate attack exposure scenarios. The main mixture design variables of SCC included the type of binder (single, binary, ternary and quaternary), air-entrainment, sand-to-aggregate mass ratio and hybrid fibre reinforcement. The comprehensive database and knowledge obtained from this research were used to develop smart models (fuzzy and neuro-fuzzy inference systems) based on artificial-intelligence to evaluate and predict the performance of the SCC mixtures under various sulfate attack exposure regimes implemented in this study. In full immersion tests involving high concentration sodium and magnesium sulfate solutions with controlled pH, the low penetrability of SCC was responsible for the high durability of specimens. Ternary and quaternary cementitious systems with or without limestone materials provided a passivating layer, with or without acid neutralization capacity, which protected SCC from severe damage in the aggressive sulfuric acid and ammonium sulfate solutions. In contrast to conclusions drawn from the sodium sulfate immersion

  2. Predicting the structures of complexes between phosphoinositide 3-kinase (PI3K) and romidepsin-related compounds for the drug design of PI3K/histone deacetylase dual inhibitors using computational docking and the ligand-based drug design approach.

    Science.gov (United States)

    Oda, Akifumi; Saijo, Ken; Ishioka, Chikashi; Narita, Koichi; Katoh, Tadashi; Watanabe, Yurie; Fukuyoshi, Shuichi; Takahashi, Ohgi

    2014-11-01

    Predictions of the three-dimensional (3D) structures of the complexes between phosphoinositide 3-kinase (PI3K) and two inhibitors were conducted using computational docking and the ligand-based drug design approach. The obtained structures were refined by structural optimizations and molecular dynamics (MD) simulations. The ligands were located deep inside the ligand binding pocket of the p110α subunit of PI3K, and the hydrogen bond formations and hydrophobic effects of the surrounding amino acids were predicted. Although rough structures were obtained for the PI3K-inhibitor complexes before the MD simulations, the refinement of the structures by these simulations clarified the hydrogen bonding patterns of the complexes.

  3. Flooding attack and defence in Ad hoc networks

    Institute of Scientific and Technical Information of China (English)

    Yi Ping; Hou Yafei; Zhong Yiping; Zhang Shiyong; Dai Zhoulin

    2006-01-01

    Mobile ad hoc networks are particularly vulnerable to denial of service (DOS) attacks launched through compromised nodes or intruders. In this paper, we present a new DOS attack and its defense in ad hoc networks. The new DOS attack, called Ad hoc Flooding Attack(AHFA), is that intruder broadcasts mass Route Request packets to exhaust the communication bandwidth and node resource so that the valid communication can not be kept. After analyzed Ad hoc Flooding Attack, we develop Flooding Attack Prevention (FAP), a generic defense against the Ad hoc Flooding Attack. When the intruder broadcasts exceeding packets of Route Request, the immediate neighbors of the intruder record the rate of Route Request. Once the threshold is exceeded, nodes deny any future request packets from the intruder. The results of our implementation show FAP can prevent the Ad hoc Flooding attack efficiently.

  4. Comparative Analysis of Routing Attacks in Ad Hoc Network

    Directory of Open Access Journals (Sweden)

    Bipul Syam Purkayastha

    2012-03-01

    Full Text Available In the mobile ad hoc networks the major role is played by the routing protocols in order to route the data from one mobile node to another mobile node. But in such mobile networks, routing protocols are vulnerable to various kinds of security attacks such as blackhole node attacks. The routing protocols of MANET are unprotected and hence resulted into the network with the malicious mobile nodes in the network. These malicious nodes in the network are basically acts as attacks in the network. In this paper, we modify the existing DSR protocol with the functionality of attacks detection without affecting overall performance of the network. Also, we are considering the various attacks on mobile ad hoc network called blackhole attack, flooding attack and show the comparative analysis of these attacks using network simulator ns-2.

  5. An Attack Modeling Based on Colored Petri Net

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shijie; QIN Zhiguang; ZHANG Feng; LIU Jinde

    2004-01-01

    A color petri net (CPN) based attack modeling approach is addressed.Compared with graph-based modeling,CPN based attack model is fiexible enough to model Intemet intrusions,because of their static and dynamic features.The processes and rules of building CPN based attack model from attack tree are also presented.In order to evaluate the risk of intrusion,some cost elements are added to CPN based attack modeling.This extended model is useful in intrusion detection and risk evaluation.Experiences show that it is easy to exploit CPN based attack modeling approach to provide the controlling functions,such as intrusion response and intrusion defense.A case study given in this paper shows that CPN based attack model has many unique characters which attack tree model hasn't.

  6. Denial of Service Attack Techniques: Analysis, Implementation and Comparison

    Directory of Open Access Journals (Sweden)

    Khaled Elleithy

    2005-02-01

    Full Text Available A denial of service attack (DOS is any type of attack on a networking structure to disable a server from servicing its clients. Attacks range from sending millions of requests to a server in an attempt to slow it down, flooding a server with large packets of invalid data, to sending requests with an invalid or spoofed IP address. In this paper we show the implementation and analysis of three main types of attack: Ping of Death, TCP SYN Flood, and Distributed DOS. The Ping of Death attack will be simulated against a Microsoft Windows 95 computer. The TCP SYN Flood attack will be simulated against a Microsoft Windows 2000 IIS FTP Server. Distributed DOS will be demonstrated by simulating a distribution zombie program that will carry the Ping of Death attack. This paper will demonstrate the potential damage from DOS attacks and analyze the ramifications of the damage.

  7. New attacks on Wi-Fi Protected Setup

    Directory of Open Access Journals (Sweden)

    Hamed Mohtadi

    2015-09-01

    Full Text Available Wi-Fi Protected Setup (WPS is a network security standard that is used to secure networks in home and office, introduced in 2006 by the Wi-Fi Alliance. It provides easier configuration setup and is used in almost all recent Wi-Fi devices. In this paper we propose two attacks on this standard. The first attack is an offline brute force attack that uses imbalance on registration protocol. This attack needs user action, but it is more efficient than previous attacks. The second attack uses weaknesses in the implementation of WPS and provides an improved evil twin attack. This attack shows that even by completely disabling the WPS on the routers, all vulnerabilities are not covered.

  8. Understanding how components of organisations contribute to attacks

    NARCIS (Netherlands)

    Gu, Min; Aslanyan, Zaruhi; Probst, Christian W.

    2016-01-01

    Attacks on organisations today explore many different layers, including buildings infrastructure, IT infrastructure, and human factor – the physical, virtual, and social layer. Identifying possible attacks, understanding their impact, and attributing their origin and contributing factors is difficul

  9. Aspirin to Prevent a First Heart Attack or Stroke

    Science.gov (United States)

    ... Aspirin to Prevent a First Heart Attack or Stroke Also known as aspirin primary prevention. Aspirin is ... taking aspirin to prevent another heart attack or stroke? The information discussed in Who may benefit? only ...

  10. Protection Against DDoS and Data Modification Attack in Computational Grid Cluster Environment

    Directory of Open Access Journals (Sweden)

    Basappa B. Kodada

    2012-07-01

    Full Text Available In the past decades, focus of computation has shifted to high performance computing like Grid Computing and Cloud Computing. In Grid computing, grid server is responsible for managing the all resources like processor, memory and CPU cycles. Grids are basically networks that pool resources, CPU cycles, storage or data from many different nodes used to solve the complex or scientific problem. However in this case, security is a major concern. Even most grid security researches focus on user authentication, authorization and secure communication. This paper presents DDoS and Data Modification attack scenario and also provides the solution to prevent it. In case of data modification attack, it shows how easy to read/forward/modify the data exchanged between a cluster head node and computing nodes. Therefore this paper provides the solution to protect the grid computing environment against Data Modification and DDOS attack.

  11. Machine Learning for Power System Disturbance and Cyber-attack Discrimination

    Energy Technology Data Exchange (ETDEWEB)

    Borges, Raymond Charles [ORNL; Beaver, Justin M [ORNL; Buckner, Mark A [ORNL; Morris, Thomas [Mississippi State University (MSU); Adhikari, Uttam [ORNL; Pan, Shengyi [Mississippi State University (MSU)

    2014-01-01

    Power system disturbances are inherently complex and can be attributed to a wide range of sources, including both natural and man-made events. Currently, the power system operators are heavily relied on to make decisions regarding the causes of experienced disturbances and the appropriate course of action as a response. In the case of cyber-attacks against a power system, human judgment is less certain since there is an overt attempt to disguise the attack and deceive the operators as to the true state of the system. To enable the human decision maker, we explore the viability of machine learning as a means for discriminating types of power system disturbances, and focus specifically on detecting cyber-attacks where deception is a core tenet of the event. We evaluate various machine learning methods as disturbance discriminators and discuss the practical implications for deploying machine learning systems as an enhancement to existing power system architectures.

  12. Quantum Communication Attacks on Classical Cryptographic Protocols

    DEFF Research Database (Denmark)

    Damgård, Ivan Bjerre

    In the literature on cryptographic protocols, it has been studied several times what happens if a classical protocol is attacked by a quantum adversary. Usually, this is taken to mean that the adversary runs a quantum algorithm, but communicates classically with the honest players. In several cases......, one can show that the protocol remains secure even under such an attack. However, there are also cases where the honest players are quantum as well, even if the protocol uses classical communication. For instance, this is the case when classical multiparty computation is used as a “subroutine......” in quantum multiparty computation. Furthermore, in the future, players in a protocol may employ quantum computing simply to improve efficiency of their local computation, even if the communication is supposed to be classical. In such cases, it no longer seems clear that a quantum adversary must be limited...

  13. Making MANET secured against malicious attack

    Science.gov (United States)

    Kush, Ashwani; Taneja, Sunil; Kush, Shagun

    2011-12-01

    A Mobile Adhoc Network (MANET) is characterized by mobile nodes, multihop wireless connectivity, infrastructureless environment and dynamic topology. A recent trend in Ad Hoc network routing is the reactive ondemand philosophy where routes are established only when required. Stable Routing is of major concern in Ad hoc routing. Security and Power efficiency are the major concerns in this field. This paper is an effort to use security to achieve more reliable routing. The ad hoc environment is accessible to both legitimate network users and malicious attackers. The proposed scheme is intended to incorporate security aspect on existing protocols. The study will help in making protocol more robust against attacks to achieve stable routing in routing protocols.

  14. Two fatal tiger attacks in zoos.

    Science.gov (United States)

    Tantius, Britta; Wittschieber, Daniel; Schmidt, Sven; Rothschild, Markus A; Banaschak, Sibylle

    2016-01-01

    Two captive tiger attacks are presented that took place in Cologne and Münster zoos. Both attacks occurred when the handlers, intent on cleaning the enclosures, entered whilst the tigers accidently retained access to the location, and thus defended their territory against the perceived intruders. Both victims suffered fatal neck injuries from the bites. At Münster, colleagues managed to lure the tiger away from its victim to enable treatment, whilst the Cologne zoo tiger had to be shot in order to allow access to be gained. Whilst it was judged that human error led to the deaths of the experienced zookeepers, the investigation in Münster was closed as no third party was found to be at fault, whereas the Cologne zoo director was initially charged with being negligent. These charges were subsequently dismissed as safety regulations were found to be up to date.

  15. GNSS-based positioning: Attacks and Countermeasures

    CERN Document Server

    Papadimitratos, P

    2010-01-01

    Increasing numbers of mobile computing devices, user-portable, or embedded in vehicles, cargo containers, or the physical space, need to be aware of their location in order to provide a wide range of commercial services. Most often, mobile devices obtain their own location with the help of Global Navigation Satellite Systems (GNSS), integrating, for example, a Global Positioning System (GPS) receiver. Nonetheless, an adversary can compromise location-aware applications by attacking the GNSS-based positioning: It can forge navigation messages and mislead the receiver into calculating a fake location. In this paper, we analyze this vulnerability and propose and evaluate the effectiveness of countermeasures. First, we consider replay attacks, which can be effective even in the presence of future cryptographic GNSS protection mechanisms. Then, we propose and analyze methods that allow GNSS receivers to detect the reception of signals generated by an adversary, and then reject fake locations calculated because of ...

  16. Quantifying Shannon's Work Function for Cryptanalytic Attacks

    CERN Document Server

    van Son, R J J H

    2010-01-01

    Attacks on cryptographic systems are limited by the available computational resources. A theoretical understanding of these resource limitations is needed to evaluate the security of cryptographic primitives and procedures. This study uses an Attacker versus Environment game formalism based on computability logic to quantify Shannon's work function and evaluate resource use in cryptanalysis. A simple cost function is defined which allows to quantify a wide range of theoretical and real computational resources. With this approach the use of custom hardware, e.g., FPGA boards, in cryptanalysis can be analyzed. Applied to real cryptanalytic problems, it raises, for instance, the expectation that the computer time needed to break some simple 90 bit strong cryptographic primitives might theoretically be less than two years.

  17. Sharkonomics How to attack market leaders

    CERN Document Server

    Engeseth, Stefan

    2012-01-01

    Sharks are nature's most revered and feared killing machines. But if you study the behaviour of sharks, you will learn they are also highly strategic and efficient in the way they survive and thrive in nature's competitive environment. Inspired by the shark's evolved (over 420 million years) instincts and strategic moves, this book provides businesses with 10 ways on how to attack the market leaders, and take market share, in your sector.

  18. Afghanistan: Green-on-Blue Attacks

    Science.gov (United States)

    2013-05-02

    Afghanistan, December 2012, p 35 15 Yousafzai, Sami and Moreau , Ron, http://www.thedailybeast.com/newsweek/2012/08/26/ afghanistan-green-on-blue-killings...spike-insider-attacks- stress-ramadan-fasting, 24 August 2012 37 Yousafzai, Sami and Moreau , Ron, http://www.thedailybeast.com/newsweek/2012/08/26...afghanistan-green-on-blue-killings- explained.html, Afghanistan: ‘Green on Blue’ Killings Explained, 27 August 2012 38 Yousafzai, Sami and Moreau , Ron

  19. Coal Slag Attack-A Review

    Institute of Scientific and Technical Information of China (English)

    GUO Zongqi

    2004-01-01

    Although slagging coal gasifiers have served the commercial systems of electricity and chemical fertilizer productions for more than ten years, refractory service life still is a critical factor for gasifier availability. Some investigations were attracted, focusing on coal slag attack on high chromia refractories. A general introduction is made in order to have further understanding about slag corrosion in coal gasification environment. Microstructural deterioration and wear process of high chromia refractory in slagging gasifiers are discussed.

  20. Fighting Through a Logistics Cyber Attack

    Science.gov (United States)

    2015-06-19

    cumulative cost of cyber-attacks was more than the combined global black market cost of cocaine, heroin and marijuana. These alarming figures raised...information (in many cases real-time) among many users at a very low cost . The number of networks the DoD uses to execute its mission has increased...the country to its knees. The Luftwaffe was uncontested in the Battle of Britain until radar’s ability to detect inbound aircraft provided the