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Sample records for attack complex inhibitor

  1. Combined Heuristic Attack Strategy on Complex Networks

    Directory of Open Access Journals (Sweden)

    Marek Šimon

    2017-01-01

    Full Text Available Usually, the existence of a complex network is considered an advantage feature and efforts are made to increase its robustness against an attack. However, there exist also harmful and/or malicious networks, from social ones like spreading hoax, corruption, phishing, extremist ideology, and terrorist support up to computer networks spreading computer viruses or DDoS attack software or even biological networks of carriers or transport centers spreading disease among the population. New attack strategy can be therefore used against malicious networks, as well as in a worst-case scenario test for robustness of a useful network. A common measure of robustness of networks is their disintegration level after removal of a fraction of nodes. This robustness can be calculated as a ratio of the number of nodes of the greatest remaining network component against the number of nodes in the original network. Our paper presents a combination of heuristics optimized for an attack on a complex network to achieve its greatest disintegration. Nodes are deleted sequentially based on a heuristic criterion. Efficiency of classical attack approaches is compared to the proposed approach on Barabási-Albert, scale-free with tunable power-law exponent, and Erdős-Rényi models of complex networks and on real-world networks. Our attack strategy results in a faster disintegration, which is counterbalanced by its slightly increased computational demands.

  2. The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I-mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly.

    Science.gov (United States)

    Escudero-Esparza, Astrid; Kalchishkova, Nikolina; Kurbasic, Emila; Jiang, Wen G; Blom, Anna M

    2013-12-01

    CUB and Sushi multiple domains 1 (CSMD1) is a transmembrane protein containing 15 consecutive complement control protein (CCP) domains, which are characteristic for complement inhibitors. We expressed a membrane-bound fragment of human CSMD1 composed of the 15 C-terminal CCP domains and demonstrated that it inhibits deposition of C3b by the classical pathway on the surface of Chinese hamster ovary cells by 70% at 6% serum and of C9 (component of membrane attack complex) by 90% at 1.25% serum. Furthermore, this fragment of CSMD1 served as a cofactor to factor I-mediated degradation of C3b. In all functional assays performed, well-characterized complement inhibitors were used as positive controls, whereas Coxsackie adenovirus receptor, a protein with no effect on complement, was a negative control. Moreover, attenuation of expression in human T47 breast cancer cells that express endogenous CSMD1 significantly increased C3b deposition on these cells by 45% at 8% serum compared with that for the controls. Furthermore, by expressing a soluble 17-21 CCP fragment of CSMD1, we found that CSMD1 inhibits complement by promoting factor I-mediated C4b/C3b degradation and inhibition of MAC assembly at the level of C7. Our results revealed a novel complement inhibitor for the classical and lectin pathways.

  3. Protecting complex infrastructures against multiple strategic attackers

    Science.gov (United States)

    Hausken, Kjell

    2011-01-01

    Infrastructures are analysed subject to defence by a strategic defender and attack by multiple strategic attackers. A framework is developed where each agent determines how much to invest in defending versus attacking each of multiple targets. A target can have economic, human and symbolic values, which generally vary across agents. Investment expenditure functions for each agent can be linear in the investment effort, concave, convex, logistic, can increase incrementally, or can be subject to budget constraints. Contest success functions (e.g., ratio and difference forms) determine the probability of a successful attack on each target, dependent on the relative investments of the defender and attackers on each target, and on characteristics of the contest. Targets can be in parallel, in series, interlinked, interdependent or independent. The defender minimises the expected damage plus the defence expenditures. Each attacker maximises the expected damage minus the attack expenditures. The number of free choice variables equals the number of agents times the number of targets, or lower if there are budget constraints. Each agent is interested in how his investments vary across the targets, and the impact on his utilities. Alternative optimisation programmes are discussed, together with repeated games, dynamic games and incomplete information. An example is provided for illustration.

  4. 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...

  5. Sequential defense against random and intentional attacks in complex networks

    Science.gov (United States)

    Chen, Pin-Yu; Cheng, Shin-Ming

    2015-02-01

    Network robustness against attacks is one of the most fundamental researches in network science as it is closely associated with the reliability and functionality of various networking paradigms. However, despite the study on intrinsic topological vulnerabilities to node removals, little is known on the network robustness when network defense mechanisms are implemented, especially for networked engineering systems equipped with detection capabilities. In this paper, a sequential defense mechanism is first proposed in complex networks for attack inference and vulnerability assessment, where the data fusion center sequentially infers the presence of an attack based on the binary attack status reported from the nodes in the network. The network robustness is evaluated in terms of the ability to identify the attack prior to network disruption under two major attack schemes, i.e., random and intentional attacks. We provide a parametric plug-in model for performance evaluation on the proposed mechanism and validate its effectiveness and reliability via canonical complex network models and real-world large-scale network topology. The results show that the sequential defense mechanism greatly improves the network robustness and mitigates the possibility of network disruption by acquiring limited attack status information from a small subset of nodes in the network.

  6. Underestimated Cost of Targeted Attacks on Complex Networks

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    Xiao-Long Ren

    2018-01-01

    Full Text Available The robustness of complex networks under targeted attacks is deeply connected to the resilience of complex systems, which is defined as the ability to make appropriate response to the attack. In this paper, we study robustness of complex networks under a realistic assumption that the cost of removing a node is not constant but rather proportional to the degree of a node or equivalently to the number of removed links a removal action produces. We have investigated the state-of-the-art targeted node removing algorithms and demonstrate that they become very inefficient when the cost of the attack is taken into consideration. For the case when it is possible to attack or remove links, we propose a simple and efficient edge removal strategy named Hierarchical Power Iterative Normalized cut (HPI-Ncut. The results on real and artificial networks show that the HPI-Ncut algorithm outperforms all the node removal and link removal attack algorithms when the same definition of cost is taken into consideration. In addition, we show that, on sparse networks, the complexity of this hierarchical power iteration edge removal algorithm is only On log2+ε⁡n.

  7. 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....

  8. Exploring resting-state EEG complexity before migraine attacks.

    Science.gov (United States)

    Cao, Zehong; Lai, Kuan-Lin; Lin, Chin-Teng; Chuang, Chun-Hsiang; Chou, Chien-Chen; Wang, Shuu-Jiun

    2017-01-01

    Objective Entropy-based approaches to understanding the temporal dynamics of complexity have revealed novel insights into various brain activities. Herein, electroencephalogram complexity before migraine attacks was examined using an inherent fuzzy entropy approach, allowing the development of an electroencephalogram-based classification model to recognize the difference between interictal and preictal phases. Methods Forty patients with migraine without aura and 40 age-matched normal control subjects were recruited, and the resting-state electroencephalogram signals of their prefrontal and occipital areas were prospectively collected. The migraine phases were defined based on the headache diary, and the preictal phase was defined as within 72 hours before a migraine attack. Results The electroencephalogram complexity of patients in the preictal phase, which resembled that of normal control subjects, was significantly higher than that of patients in the interictal phase in the prefrontal area (FDR-adjusted p complexity. Conclusion Entropy-based analytical methods identified enhancement or "normalization" of frontal electroencephalogram complexity during the preictal phase compared with the interictal phase. This classification model, using this complexity feature, may have the potential to provide a preictal alert to migraine without aura patients.

  9. 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

    The initiating mechanisms of migraine attacks are very complex but may involve the cyclic AMP signalling pathway. It is unknown whether intracellular cyclic AMP accumulation induces migraine attacks. We investigated whether administration of cilostazol, which causes cyclic AMP accumulation, may...... 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...

  10. Robustness of Dengue Complex Network under Targeted versus Random Attack

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    Hafiz Abid Mahmood Malik

    2017-01-01

    Full Text Available Dengue virus infection is one of those epidemic diseases that require much consideration in order to save the humankind from its unsafe impacts. According to the World Health Organization (WHO, 3.6 billion individuals are at risk because of the dengue virus sickness. Researchers are striving to comprehend the dengue threat. This study is a little commitment to those endeavors. To observe the robustness of the dengue network, we uprooted the links between nodes randomly and targeted by utilizing different centrality measures. The outcomes demonstrated that 5% targeted attack is equivalent to the result of 65% random assault, which showed the topology of this complex network validated a scale-free network instead of random network. Four centrality measures (Degree, Closeness, Betweenness, and Eigenvector have been ascertained to look for focal hubs. It has been observed through the results in this study that robustness of a node and links depends on topology of the network. The dengue epidemic network presented robust behaviour under random attack, and this network turned out to be more vulnerable when the hubs of higher degree have higher probability to fail. Moreover, representation of this network has been projected, and hub removal impact has been shown on the real map of Gombak (Malaysia.

  11. 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.

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

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    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

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

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    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.

  14. 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.

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

    OpenAIRE

    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 fun...

  16. Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins.

    Science.gov (United States)

    Conde, Jonas Nascimento; da Silva, Emiliana Mandarano; Allonso, Diego; Coelho, Diego Rodrigues; Andrade, Iamara da Silva; de Medeiros, Luciano Neves; Menezes, Joice Lima; Barbosa, Angela Silva; Mohana-Borges, Ronaldo

    2016-11-01

    Dengue virus (DENV) infects millions of people worldwide and is a major public health problem. DENV nonstructural protein 1 (NS1) is a conserved glycoprotein that associates with membranes and is also secreted into the plasma in DENV-infected patients. The present study describes a novel mechanism by which NS1 inhibits the terminal complement pathway. We first identified the terminal complement regulator vitronectin (VN) as a novel DENV2 NS1 binding partner by using a yeast two-hybrid system. This interaction was further assessed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) assay. The NS1-VN complex was also detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the DENV2 NS1 protein, either by itself or by interacting with VN, hinders the formation of the membrane attack complex (MAC) and C9 polymerization. Finally, we showed that DENV2, West Nile virus (WNV), and Zika virus (ZIKV) NS1 proteins produced in mammalian cells inhibited C9 polymerization. Taken together, our results points to a role for NS1 as a terminal pathway inhibitor of the complement system. Dengue is the most important arthropod-borne viral disease nowadays and is caused by dengue virus (DENV). The flavivirus NS1 glycoprotein has been characterized functionally as a complement evasion protein that can attenuate the activation of the classical, lectin, and alternative pathways. The present study describes a novel mechanism by which DENV NS1 inhibits the terminal complement pathway. We identified the terminal complement regulator vitronectin (VN) as a novel DENV NS1 binding partner, and the NS1-VN complex was detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the NS1-VN complex inhibited membrane attack complex (MAC) formation, thus interfering with the complement terminal pathway. Interestingly

  17. 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.

  18. What's Next in Complex Networks? Capturing the Concept of Attacking Play in Invasive Team Sports.

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    Ramos, João; Lopes, Rui J; Araújo, Duarte

    2017-09-16

    The evolution of performance analysis within sports sciences is tied to technology development and practitioner demands. However, how individual and collective patterns self-organize and interact in invasive team sports remains elusive. Social network analysis has been recently proposed to resolve some aspects of this problem, and has proven successful in capturing collective features resulting from the interactions between team members as well as a powerful communication tool. Despite these advances, some fundamental team sports concepts such as an attacking play have not been properly captured by the more common applications of social network analysis to team sports performance. In this article, we propose a novel approach to team sports performance centered on sport concepts, namely that of an attacking play. Network theory and tools including temporal and bipartite or multilayered networks were used to capture this concept. We put forward eight questions directly related to team performance to discuss how common pitfalls in the use of network tools for capturing sports concepts can be avoided. Some answers are advanced in an attempt to be more precise in the description of team dynamics and to uncover other metrics directly applied to sport concepts, such as the structure and dynamics of attacking plays. Finally, we propose that, at this stage of knowledge, it may be advantageous to build up from fundamental sport concepts toward complex network theory and tools, and not the other way around.

  19. Hepatitis C virus suppresses C9 complement synthesis and impairs membrane attack complex function.

    Science.gov (United States)

    Kim, Hangeun; Meyer, Keith; Di Bisceglie, Adrian M; Ray, Ranjit

    2013-05-01

    Hepatitis C virus (HCV) proteins inhibit complement component expression, which may attenuate immunity against infection. In this study, we examined whether HCV regulates the membrane attack complex (MAC) via complement component C9. MAC is composed of C5b to C9 (C5b-9) and mediates cell lysis of invaded pathogens. Liver biopsy specimens from chronically HCV-infected patients exhibited a lower level of C9 mRNA expression than liver biopsy specimens from unrelated disease or healthy control human liver RNA. Hepatocytes infected with cell culture-grown HCV or expressing HCV core protein also displayed significant repression of C9 mRNA and protein levels. Promoter analysis suggested that the T cell factor-4 (TCF-4E) transcription factor is responsible for HCV core-mediated C9 promoter regulation. Sera from chronically HCV-infected patients displayed a lower level of C5b-9 and a reduced antimicrobial effect on model organisms compared to unrelated patient sera or sera from healthy volunteers. Together, these results for C9 regulation by HCV core protein coupled with functional impairment of the membrane attack complex underscore HCV-mediated attenuation of immune mechanisms.

  20. Strong correlation of high EBNA-1-IgG levels with edematous attacks involving upper airway mucosa in hereditary angioedema due to C1-inhibitor deficiency.

    Science.gov (United States)

    Csuka, Dorottya; Varga, Lilian; Farkas, Henriette; Füst, George

    2012-01-01

    Elevated level of IgG-type antibodies against Type 1 nuclear antigen (anti-EBNA-1-IgG) of the Epstein-Barr virus is a strong risk factor for certain autoimmune diseases. We measured anti-EBNA-1 IgG titers in 107 patients with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH). In the sera from 33 longitudinally tested patients, we found a very strong correlation (R>0.75, p=0.0005) between anti-EBNA-1-IgG titers measured in 2004 and 2010, respectively. High (>200 U/ml) anti-EBNA-1 levels were strongly correlated with the frequency of upper airway attacks (p=0.003) and the dose requirement of C1-inhibitor concentrate (p=0.008), while no significant association with the frequency of subcutaneous and abdominal attacks was found. These novel findings indicate that the underlying/triggering mechanisms of upper airway attacks in HAE-C1-INH may differ from that of other types of attacks and measurement of the anti-EBNA-1 IgG levels may be suitable for the prediction of upper airway attacks and C1-inhibitor concentrate requirement in HAE-C1-INH patients. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. Hh signaling inhibitors from Vitex negundo; naturally occurring inhibitors of the GLI1-DNA complex.

    Science.gov (United States)

    Arai, Midori A; Fujimatsu, Teruhisa; Uchida, Kyoko; Sadhu, Samir K; Ahmed, Firoj; Ishibashi, Masami

    2013-05-01

    The hedgehog (Hh) signaling pathway has crucial roles in embryonic development, cell maintenance and proliferation, and is also known to contribute to cancer cell growth. New naturally occurring Hh inhibitors (1, 7 and 9) were isolated from Vitex negundo using our previously constructed cell-based assay. Bioactivity guided isolation provided 9 natural compounds including a new diterpene, nishindanol (9). Compounds 7 and 9 showed cytotoxicity against cancer cell lines in which Hh signaling was aberrantly activated. Vitetrifolin D (7; GLI1 transcriptional inhibition IC50 = 20.2 μM) showed inhibition of Hh related protein (PTCH and BCL2) production. Interestingly, the constructed electrophoresis mobility shift assay revealed that vitetrifolin D (7) disrupted GLI1 binding on its DNA binding domain. epi-Sclareol (8; inactive), possessing a similar structure to 7, did not show inhibition of GLI1–DNA complex formation. This is the first example of naturally occurring inhibitors of GLI1–DNA complex formation.

  2. 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

    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...

  3. 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.

  4. 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.

  5. $k$-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.

  6. Inhibitors

    Science.gov (United States)

    ... and exercise, immune tolerance therapy, and needs of older adults with hemophilia and an inhibitor. For more information, visit https://www.hemophilia.org/Events-Educational-Programs/Inhibitor-Education/Inhibitor-Education-Summits The NHF’s Inhibitor Education Summits ...

  7. Mathematical Attacks on RSA Cryptosystem

    OpenAIRE

    Imad K. Salah; Abdullah Darwish; Saleh Oqeili

    2006-01-01

    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.

  8. A Nicotiana attenuata cell wall invertase inhibitor (NaCWII) reduces growth and increases secondary metabolite biosynthesis in herbivore-attacked plants.

    Science.gov (United States)

    Ferrieri, Abigail P; Arce, Carla C M; Machado, Ricardo A R; Meza-Canales, Ivan D; Lima, Eraldo; Baldwin, Ian T; Erb, Matthias

    2015-10-01

    Plant invertases are sucrolytic enzymes that are essential for the regulation of carbohydrate metabolism and source-sink relationships. While their activity has been well documented during abiotic and biotic stresses, the role of proteinaceous invertase inhibitors in regulating these changes is unknown. Here, we identify a putative Nicotiana attenuata cell wall invertase inhibitor (NaCWII) which is strongly up-regulated in a jasmonate (JA)-dependent manner following simulated attack by the specialist herbivore Manduca sexta. To understand the role of NaCWII in planta, we silenced its expression by RNA interference and measured changes in primary and secondary metabolism and plant growth following simulated herbivory. NaCWII-silenced plants displayed a stronger depletion of carbohydrates and a reduced capacity to increase secondary metabolite pools relative to their empty vector control counterparts. This coincided with the attenuation of herbivore-induced CWI inhibition and growth suppression characteristic of wild-type plants. Together our findings suggest that NaCWII may act as a regulatory switch located downstream of JA accumulation which fine-tunes the plant's balance between growth and defense metabolism under herbivore attack. Although carbohydrates are not typically viewed as key factors in plant growth and defense, our study shows that interfering with their catabolism strongly influences plant responses to herbivory. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

  9. 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...... demonstrated synergistic production of C-X-C (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) and C-C (macrophage inflammatory protein-1alpha and monocyte chemoattractant-1) chemokines. In the absence of the costimulus, C5a or MAC did not induce chemokine generation....... In in vivo studies, C5a and MAC alone caused limited or no intrapulmonary generation of chemokines, but in the presence of a costimulus (IgG immune complexes) C5a and MAC caused synergistic intrapulmonary generation of C-X-C and C-C chemokines but not of tumor necrosis factor alpha. Under these conditions...

  10. 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...

  11. Complex hallucinations and panic attacks in a 13-year-old with migraines: the alice in wonderland syndrome.

    Science.gov (United States)

    George, Dimple; Bernard, Paul

    2013-01-01

    This case report describes a 13-year-old girl whose family requested a referral from the pediatrician for Child and Adolescent Mental Health Services in order to understand her recent onset of bizarre behavior. On assessment, she was found to have episodes of complex audiovisual hallucinations and panic attacks with intervals of complete recovery associated with episodes of migraine headaches. The "Alice in Wonderland Syndrome," which is intimately associated with migraine and epilepsy, as well as a number of other neurological conditions, could explain her episodic neurobehavioral disturbance.

  12. 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.

  13. Structure of a membrane-attack complex/perforin (MACPF) family protein from the human gut symbiont Bacteroides thetaiotaomicron.

    Science.gov (United States)

    Xu, Qingping; Abdubek, Polat; Astakhova, Tamara; Axelrod, Herbert L; Bakolitsa, Constantina; Cai, Xiaohui; Carlton, Dennis; Chen, Connie; Chiu, Hsiu Ju; Clayton, Thomas; Das, Debanu; Deller, Marc C; Duan, Lian; Ellrott, Kyle; Farr, Carol L; Feuerhelm, Julie; Grant, Joanna C; Grzechnik, Anna; Han, Gye Won; Jaroszewski, Lukasz; Jin, Kevin K; Klock, Heath E; Knuth, Mark W; Kozbial, Piotr; Krishna, S Sri; Kumar, Abhinav; Lam, Winnie W; Marciano, David; Miller, Mitchell D; Morse, Andrew T; Nigoghossian, Edward; Nopakun, Amanda; Okach, Linda; Puckett, Christina; Reyes, Ron; Tien, Henry J; Trame, Christine B; van den Bedem, Henry; Weekes, Dana; Wooten, Tiffany; Yeh, Andrew; Zhou, Jiadong; Hodgson, Keith O; Wooley, John; Elsliger, Marc André; Deacon, Ashley M; Godzik, Adam; Lesley, Scott A; Wilson, Ian A

    2010-10-01

    Membrane-attack complex/perforin (MACPF) proteins are transmembrane pore-forming proteins that are important in both human immunity and the virulence of pathogens. Bacterial MACPFs are found in diverse bacterial species, including most human gut-associated Bacteroides species. The crystal structure of a bacterial MACPF-domain-containing protein BT_3439 (Bth-MACPF) from B. thetaiotaomicron, a predominant member of the mammalian intestinal microbiota, has been determined. Bth-MACPF contains a membrane-attack complex/perforin (MACPF) domain and two novel C-terminal domains that resemble ribonuclease H and interleukin 8, respectively. The entire protein adopts a flat crescent shape, characteristic of other MACPF proteins, that may be important for oligomerization. This Bth-MACPF structure provides new features and insights not observed in two previous MACPF structures. Genomic context analysis infers that Bth-MACPF may be involved in a novel protein-transport or nutrient-uptake system, suggesting an important role for these MACPF proteins, which were likely to have been inherited from eukaryotes via horizontal gene transfer, in the adaptation of commensal bacteria to the host environment.

  14. Biochemical Characterization of Complexes with p21, a CDK Inhibitor

    Science.gov (United States)

    1998-08-01

    proteins are necessary for S phase entry (reviewed in Sherr and Roberts , 1995). Cyclin A- and cyclin B- dependent kinases are activated subsequently...inhibitors can promote GI phase arrest when overexpressed in certain tissue culture cell lines (reviewed in Sherr and Roberts , 1995). Second, transforming...Dev. 8, 1772-1786. Dynlacht, B. D., Ngwu, C., Winston, J., Swindell , E. C., Elledge, S. J., Harlow, E., and Harper, J. W. (1997). Purification and

  15. ASSESSMENT OF LOOP RIGIDIFICATION IN ENZYME-INHIBITOR COMPLEXES: A QUANTITATIVE AND PROBABILISTIC STUDY

    Directory of Open Access Journals (Sweden)

    Sudip Majumder

    2014-03-01

    Full Text Available Enzyme-inhibitor interactions are one of the most important protein-protein or protein-ligand interactions in biological systems. During complex formation with its cognate enzyme, many inhibitory loops undergo structural rigidification whereby molecular motion of the atoms around the otherwise flexible loop gets reduced. B-factor or temperature factor is a good indicator of such rigidification. Here we present a quantitative assessment of the extent of rigidification of loop residues in comparison to the rest of the inhibitor molecule comparing B-factor values in free inhibitor structures and in their corresponding enzyme–inhibitor complexes for serine protease inhibitors (SPI. Our study also reveals that crystal packing artefacts might also play a crucial role in determining the B-factor values of individual amino acid residues in a protein.

  16. Performance Analysis with Network-Enhanced Complexities: On Fading Measurements, Event-Triggered Mechanisms, and Cyber Attacks

    Directory of Open Access Journals (Sweden)

    Derui Ding

    2014-01-01

    Full Text Available Nowadays, the real-world systems are usually subject to various complexities such as parameter uncertainties, time-delays, and nonlinear disturbances. For networked systems, especially large-scale systems such as multiagent systems and systems over sensor networks, the complexities are inevitably enhanced in terms of their degrees or intensities because of the usage of the communication networks. Therefore, it would be interesting to (1 examine how this kind of network-enhanced complexities affects the control or filtering performance; and (2 develop some suitable approaches for controller/filter design problems. In this paper, we aim to survey some recent advances on the performance analysis and synthesis with three sorts of fashionable network-enhanced complexities, namely, fading measurements, event-triggered mechanisms, and attack behaviors of adversaries. First, these three kinds of complexities are introduced in detail according to their engineering backgrounds, dynamical characteristic, and modelling techniques. Then, the developments of the performance analysis and synthesis issues for various networked systems are systematically reviewed. Furthermore, some challenges are illustrated by using a thorough literature review and some possible future research directions are highlighted.

  17. Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack

    Directory of Open Access Journals (Sweden)

    Ercan Cacan

    2015-12-01

    Full Text Available Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8+ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity.

  18. 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....

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

    Science.gov (United States)

    2006-02-01

    active site mutant of the Bacillus cereus thermolysin-like neutral protease where albeit in the absence of a charged base some residual activity was...1996) E144S Active-site mutant of the Bacillus cereus thermol- ysin-like neutral protease at 2.8 Å Resolution, Acta Crystallogr. D52, 543-550. 33. Li...the toxin in complex with a potential inhibitor via x-ray crystallography and then analyze the interactions between the inhibitor and the protein

  20. Using AI and Semantic Web Technologies to attack Process Complexity in Open Systems

    Science.gov (United States)

    Thompson, Simon; Giles, Nick; Li, Yang; Gharib, Hamid; Nguyen, Thuc Duong

    Recently many vendors and groups have advocated using BPEL and WS-BPEL as a workflow language to encapsulate business logic. While encapsulating workflow and process logic in one place is a sensible architectural decision the implementation of complex workflows suffers from the same problems that made managing and maintaining hierarchical procedural programs difficult. BPEL lacks constructs for logical modularity such as the requirements construct from the STL [12] or the ability to adapt constructs like pure abstract classes for the same purpose. We describe a system that uses semantic web and agent concepts to implement an abstraction layer for BPEL based on the notion of Goals and service typing. AI planning was used to enable process engineers to create and validate systems that used services and goals as first class concepts and compiled processes at run time for execution.

  1. Subnanomolar Inhibitor of Cytochrome bc1 Complex Designed via Optimizing Interaction with Conformationally Flexible Residues

    Science.gov (United States)

    Zhao, Pei-Liang; Wang, Le; Zhu, Xiao-Lei; Huang, Xiaoqin; Zhan, Chang-Guo; Wu, Jia-Wei; Yang, Guang-Fu

    2009-01-01

    Cytochrome bc1 complex (EC 1.10.2.2, bc1), an essential component of the cellular respiratory chain and the photosynthetic apparatus in photosynthetic bacteria, has been identified as a promising target for new drugs and agricultural fungicides. X-ray diffraction structures of the free bc1 complex and its complexes with various inhibitors revealed that the phenyl group of Phe274 in the binding pocket exhibited significant conformational flexibility upon different inhibitors binding to optimize respective π-π interactions, whereas the side chains of other hydrophobic residues showed conformational stability. Therefore, in the present study, a strategy of optimizing the π-π interaction with conformationally flexible residues was proposed to design and discover new bc1 inhibitors with a higher potency. Eight new compounds were designed and synthesized, among which compound 5c with a Ki value of 570 pM was identified as the most promising drug or fungicide candidate, significantly more potent than the commercially available bc1 inhibitors including azoxystrobin (AZ), kresoxim-methyl (KM), and pyraclostrobin (PY). To our knowledge, this is the first bc1 inhibitor discovered from structure-based design with a potency of subnanomolar Ki value. For all of the compounds synthesized and assayed, the calculated binding free energies correlated reasonably well with the binding free energies derived from the experimental Ki values with a correlation coefficient of r2 = 0.89. The further inhibitory kinetics studies revealed that compound 5c is a non-competitive inhibitor with respect to substrate cytochrome c, but is a competitive inhibitor with respect to substrate ubiquinol. Due to its subnanomolar Ki potency and slow dissociation rate constant (k−0 = 0.00358 s−1), compound 5c could be used as a specific probe for further elucidation of the mechanism of bc1 function and as a new lead compound for future drug discovery. PMID:19928849

  2. Should anti-inhibitor coagulant complex and tranexamic acid be used concomitantly?

    Science.gov (United States)

    Valentino, L A; Holme, P A

    2015-11-01

    Inhibitor development in haemophilia patients is challenging especially when undergoing surgical procedures. The development of an inhibitor precludes using factor VIII (FVIII) therapy thereby requiring a bypassing agent (BPA) for surgical bleeding prophylaxis if the FVIII inhibitor titre >5 BU. Concomitant use of anti-inhibitor coagulant complex (AICC) and tranexamic acid has been reported in the literature as a beneficial treatment for this population. Anti-inhibitor coagulant complex is known to cause an increase in thrombin generation and tranexamic acid inhibits fibrinolysis. Hence, the combined used of AICC and tranexamic acid has been limited due to safety concerns over possibilities of increased risk of thrombotic events and disseminated intravascular coagulation. However, the rationale for concomitant therapy is to obtain a potential synergistic effect and to increase clot stability. We conducted a literature review of past studies and individual case reports of concomitant use of AICC and tranexamic acid, which was extensively used during dental procedures. Evidence also exists for concomitant use of the combined therapy in orthopaedic procedures, control of gastrointestinal bleeding, epistaxis and cerebral haemorrhages. Some patients who received the combined therapy had failed monotherapy with a single BPA prior to combined therapy. There were no reports of thrombotic complications related to the concomitant therapy and haemostasis was achieved in all cases. Anti-inhibitor coagulant complex and tranexamic acid therapy was found to be safe, well-tolerated and effective therapy in haemophilia patients with inhibitors. Additional randomized controlled studies should be performed to confirm these findings. © 2015 John Wiley & Sons Ltd.

  3. 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...

  4. Crystal structures of inhibitor complexes of human T-cell leukemia virus (HTLV-1) protease

    Energy Technology Data Exchange (ETDEWEB)

    Satoh, Tadashi; Li, Mi; Nguyen, Jeffrey-Tri; Kiso, Yoshiaki; Gustchina, Alla; Wlodawer, Alexander (NCI); (Kyoto)

    2010-09-28

    Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with several serious diseases, such as adult T-cell leukemia and tropical spastic paraparesis/myelopathy. For a number of years, the protease (PR) encoded by HTLV-1 has been a target for designing antiviral drugs, but that effort was hampered by limited available structural information. We report a high-resolution crystal structure of HTLV-1 PR complexed with a statine-containing inhibitor, a significant improvement over the previously available moderate-resolution structure. We also report crystal structures of the complexes of HTLV-1 PR with five different inhibitors that are more compact and more potent. A detailed study of structure-activity relationships was performed to interpret in detail the influence of the polar and hydrophobic interactions between the inhibitors and the protease.

  5. Plants under dual attack

    NARCIS (Netherlands)

    Ponzio, C.A.M.

    2016-01-01

    Though immobile, plants are members of complex environments, and are under constant threat from a wide range of attackers, which includes organisms such as insect herbivores or plant pathogens. Plants have developed sophisticated defenses against these attackers, and include chemical responses such

  6. Aspects of preanalytical variation of lactoferrin and elastase/alpha 1-protease inhibitor complexes

    DEFF Research Database (Denmark)

    Antonsen, S; Qvist, N; Wanscher, M

    1993-01-01

    A number of interesting applications of plasma elastase/alpha 1-protease inhibitor complexes (ELA-PI) and lactoferrin (LAC) have recently been suggested. However, the clinical utility of these components often seems to be low. This might be improved by minimizing the preanalytical variation...

  7. Heart Attack

    Science.gov (United States)

    Each year almost 800,000 Americans have a heart attack. A heart attack happens when blood flow to the heart suddenly ... it's important to know the symptoms of a heart attack and call 9-1-1 if you or ...

  8. 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.

  9. Mitochondrial complex I inhibitors and forced oxidative phosphorylation synergize in inducing cancer cell death.

    Science.gov (United States)

    Palorini, Roberta; Simonetto, Tiziana; Cirulli, Claudia; Chiaradonna, Ferdinando

    2013-01-01

    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.

  10. Protonation state and free energy calculation of HIV-1 protease-inhibitor complex based on electrostatic polarisation effect

    Science.gov (United States)

    Yang, Maoyou; Jiang, Xiaonan; Jiang, Ning

    2014-06-01

    The protonation states of catalytic Asp25/25‧ residues remarkably affect the binding mechanism of the HIV-1 protease-inhibitor complex. Here we report a molecular dynamics simulation study, which includes electrostatic polarisation effect, to investigate the influence of Asp25/25‧ protonation states upon the binding free energy of the HIV-1 protease and a C2-symmetric inhibitor. Good agreements are obtained on inhibitor structure, hydrogen bond network, and binding free energy between our theoretical calculations and the experimental data. The calculations show that the Asp25 residue is deprotonated, and the Asp25‧ residue is protonated. Our results reveal that the Asp25/25‧ residues can have different protonation states when binding to different inhibitors although the protease and the inhibitors have the same symmetry. This study offers some insights into understanding the protonation state of HIV-1 protease-inhibitor complex, which could be helpful in designing new inhibitor molecules.

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

    Directory of Open Access Journals (Sweden)

    Alex N Bullock

    2009-10-01

    Full Text Available 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.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.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.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.

  12. 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.

  13. 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....

  14. Structural characterization of human heme oxygenase-1 in complex with azole-based inhibitors.

    Science.gov (United States)

    Rahman, Mona N; Vlahakis, Jason Z; Roman, Gheorghe; Vukomanovic, Dragic; Szarek, Walter A; Nakatsu, Kanji; Jia, Zongchao

    2010-03-01

    The development of inhibitors specific for heme oxygenases (HO) aims to provide powerful tools in understanding the HO system. Based on the lead structure (2S, 4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-[((4-aminophenyl)thio)methyl]-1,3-dioxolane (azalanstat, QC-1) we have synthesized structural modifications to develop novel and selective HO inhibitors. The structural study of human HO-1 (hHO-1) in complex with a select group of the inhibitors was initiated using X-ray crystallographic techniques. Comparison of the structures of four such compounds each in complex with hHO-1 revealed a common binding mode, despite having different structural fragments. The compounds bind to the distal side of heme through an azole "anchor" which coordinates with the heme iron. An expansion of the distal pocket, mainly due to distal helix flexibility, allows accommodation of the compounds without displacing heme or the critical Asp140 residue. Rather, binding displaces a catalytically critical water molecule and disrupts an ordered hydrogen-bond network involving Asp140. The presence of a triazole "anchor" may provide further stability via a hydrogen bond with the protein. A hydrophobic pocket acts to stabilize the region occupied by the phenyl or adamantanyl moieties of these compounds. Further, a secondary hydrophobic pocket is formed via "induced fit" to accommodate bulky substituents at the 4-position of the dioxolane ring. Copyright 2009 Elsevier Inc. All rights reserved.

  15. Crystal structures of Mycobacterium tuberculosis GlgE and complexes with non-covalent inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lindenberger, Jared J.; Veleti, Sri Kumar; Wilson, Brittney N.; Sucheck, Steven J.; Ronning, Donald R. (Toledo)

    2015-08-06

    GlgE is a bacterial maltosyltransferase that catalyzes the elongation of a cytosolic, branched α-glucan. In Mycobacterium tuberculosis (M. tb), inactivation of GlgE (Mtb GlgE) results in the rapid death of the organism due to a toxic accumulation of the maltosyl donor, maltose-1-phosphate (M1P), suggesting that GlgE is an intriguing target for inhibitor design. In this study, the crystal structures of the Mtb GlgE in a binary complex with maltose and a ternary complex with maltose and a maltosyl-acceptor molecule, maltohexaose, were solved to 3.3 Å and 4.0 Å, respectively. The maltohexaose structure reveals a dominant site for α-glucan binding. To obtain more detailed interactions between first generation, non-covalent inhibitors and GlgE, a variant Streptomyces coelicolor GlgEI (Sco GlgEI-V279S) was made to better emulate the Mtb GlgE M1P binding site. The structure of Sco GlgEI-V279S complexed with α-maltose-C-phosphonate (MCP), a non-hydrolyzable substrate analogue, was solved to 1.9 Å resolution, and the structure of Sco GlgEI-V279S complexed with 2,5-dideoxy-3-O-α-D-glucopyranosyl-2,5-imino-D-mannitol (DDGIM), an oxocarbenium mimic, was solved to 2.5 Å resolution. These structures detail important interactions that contribute to the inhibitory activity of these compounds, and provide information on future designs that may be exploited to improve upon these first generation GlgE inhibitors.

  16. Tuning cobalt(III) Schiff base complexes as activated protein inhibitors.

    Science.gov (United States)

    Heffern, Marie C; Reichova, Viktorie; Coomes, Joseph L; Harney, Allison S; Bajema, Elizabeth A; Meade, Thomas J

    2015-09-21

    Cobalt(III) Schiff base complexes ([Co(acacen)(L)2](+), where L = NH3) inhibit histidine-containing proteins through dissociative exchange of the labile axial ligands (L). This work investigates axial ligand exchange dynamics of [Co(acacen)(L)2](+) complexes toward the development of protein inhibitors that are activated by external triggers such as light irradiation. We sought to investigate ligand exchange dynamics to design a Co(III) complex that is substitutionally inert under normal physiological conditions for selective activation. Fluorescent imidazoles (C3Im) were prepared as axial ligands in [Co(acacen)(L)2](+) to produce complexes (CoC3Im) that could report on ligand exchange and, thus, complex stability. These fluorescent imidazole reporters guided the design of a new dinuclear Co(III) Schiff base complex containing bridging diimidazole ligands, which exhibits enhanced stability to ligand exchange with competing imidazoles and to hydrolysis within a biologically relevant pH range. These studies inform the design of biocompatible Co(III) Schiff base complexes that can be selectively activated for protein inhibition with spatial and temporal specificity.

  17. Crystal structure of an engineered subtilisin inhibitor complexed with bovine trypsin.

    Science.gov (United States)

    Takeuchi, Y; Nonaka, T; Nakamura, K T; Kojima, S; Miura, K; Mitsui, Y

    1992-05-15

    Proteinase specificity of a proteinaceous inhibitor of subtilisin (SSI; Streptomyces subtilisin inhibitor) can be altered so as to strongly inhibit trypsin simply by replacing P1 methionine with lysine (with or without concomitant change of the P4 residue) through site-directed mutagenesis. Now the crystal structure of one such engineered SSI (P1 methionine converted to lysine and P4 methionine converted to glycine) complexed with bovine trypsin has been solved at 2.6 A resolution and refined to a crystallographic R factor of 0.173. Comparing this structure with the previously established structure of the native SSI complexed with subtilisin BPN', it was found that (i) P1 lysine of the mutant SSI is accommodated in the S1 pocket of trypsin as usual, and (ii) upon complex formation, considerable conformation change occurs to the reactive site loop of the mutant SSI. Thus, in this case, flexibility of the reactive site loop seems important for successfully changing the proteinase specificity through mere replacement of the P1 residue.

  18. Modeling of Plasmodium falciparum Telomerase Reverse Transcriptase Ternary Complex: Repurposing of Nucleoside Analog Inhibitors.

    Science.gov (United States)

    Mohanty, Pallavi; Gupta, Akanksha; Bhatnagar, Sonika

    2015-12-01

    The Plasmodium falciparum telomerase reverse transcriptase (PfTERT) is a ribonucleoprotein that assists the maintenance of the telomeric ends of chromosomes by reverse transcription of its own RNA subunit. It represents an attractive therapeutic target for eradication of the plasmodial parasite at the asexual liver stage. Automated modeling using MUSTER and knowledge-based techniques were used to obtain a three-dimensional model of the active site of reverse transcriptase domain of PfTERT, which is responsible for catalyzing the addition of incoming dNTPs to the growing DNA strand in presence of divalent magnesium ions. Further, the ternary complex of the active site of PfTERT bound to a DNA-RNA duplex was also modeled using Haddock server and represents the functional form of the enzyme. Initially, established nucleoside analog inhibitors of PfTERT, AZTTP, and ddGTP were docked in the modeled binding site of the PfTERT ternary complex using AutoDock v4.2. Subsequently, docking studies were carried out with 14 approved nucleoside analog inhibitors. Docking studies predicted that floxuridine, gemcitabine, stavudine, and vidarabine have high affinity for the PfTERT ternary complex. Further analysis on the basis of known side effects led us to propose repositioning of vidarabine as a suitable drug candidate for inhibition of PfTERT.

  19. [Immune tolerance induction in a case of hemophilia B with inhibitor with prothrombin complex concentrate and rituximab].

    Science.gov (United States)

    Xue, F; Liu, W; Cheng, Y F; Liu, X F; Huang, Y T; Fu, R F; Zhang, L; Yang, R C

    2017-09-14

    Objective: To explore the immune tolerance induction (ITI) in a case of severe hemophilia B patient with inhibitor. Methods: The F Ⅸ∶C was detected using a one-stage method and FIX inhibitor was assayed using Bethesda method. ITI was performed with prothrombin complex concentrates (PCC) in combination with rituximab. Results: His past exposure days (ED) with PCC were 20 ED and his peak FⅨ inhibitor titer was 56 BU/ml. When his FIX inhibitor titer decreased to 10.4 BU/ml in Nov. 2015 and after receiving the informed consent from his parents, ITI was started. PCC with low dose rituximab successfully eradicated the high titer inhibitor within 17 months. There was no anaphylaxis, thrombotic event and infection. Conclusion: This is the first case report for successful immune tolerance induction therapy in Chinese hemophilia B patient. ITI using PCC combined with rituximab is an effective choice to induce immune tolerance of hemophilia B with inhibitor.

  20. Zinc-Metalloproteinase Inhibitors: Evaluation of the Complex Role Played by the Zinc-Binding Group on Potency and Selectivity.

    Science.gov (United States)

    Rouanet-Mehouas, Cecile; Czarny, Bertrand; Beau, Fabrice; Cassar-Lajeunesse, Evelyne; Stura, Enrico A; Dive, Vincent; Devel, Laurent

    2017-01-12

    The most exploited strategy to develop potent zinc-metalloprotease inhibitors relies on a core zinc chelator and a peptidic or nonpeptidic scaffold that provides supplementary interactions for optimized potency and selectivity. Applied to matrix metalloproteases (MMPs) with highly conserved catalytic domains, this strategy failed to identify inhibitors with the desired selectivity profiles. To question the precise role of the zinc-binding group (ZBG), we have carried out a study on MMP-12 inhibitors with a common peptidic core but different ZBGs. We find that exchanging the ZBG modifies inhibitor positioning and affects its dynamics and selectivity. The binding properties of these compounds were compared through biochemical, structural, and calorimetric studies, showing a complex interplay between cooperative interactions and dynamics dictated by the ZBG. Improving selectivity will require expanding the ZBG repertoire within inhibitor libraries, since relying on a single ZBG significantly decreases our chance to identify effective inhibitors.

  1. 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.

  2. Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors.

    Science.gov (United States)

    Lazarus, Michael B; Novotny, Chris J; Shokat, Kevan M

    2015-01-16

    Autophagy is a conserved cellular process that involves the degradation of cellular components for energy maintenance and cytoplasmic quality control that has recently gained interest as a novel target for a variety of human diseases, including cancer. A prime candidate to determine the potential therapeutic benefit of targeting autophagy is the kinase ULK1, whose activation initiates autophagy. Here, we report the first structures of ULK1, in complex with multiple potent inhibitors. These structures show features unique to the enzyme and will provide a path for the rational design of selective compounds as cellular probes and potential therapeutics.

  3. Heart Attack

    Science.gov (United States)

    ... pain Fatigue Heart attack Symptoms & causes Diagnosis & treatment Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  4. Heart attack

    Science.gov (United States)

    ... heart attack. A stent is a small, metal mesh tube that opens up (expands) inside a coronary ... e228. PMID: 25260718 www.ncbi.nlm.nih.gov/pubmed/25260718 . Anderson JL. ST segment elevation acute myocardial ...

  5. The attack navigator

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  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......, however, in the nature of the fragments deposited as a result of CP and AP activation: C3b fragments deposited via the CP were extensively ( approximately 90%) converted to the terminal degradation product, C3dg, whereas about 50% of those deposited by the AP persisted as C3b/iC3b fragments. The extent...

  7. Metal II complexes of ethambutol as good enzyme inhibitor and promising antioxidant.

    Science.gov (United States)

    Jahangir, Muhammad; Farwa, Ume; Mazhar, Farhana; Malik, Afza; Ahmad, Ejaz

    2016-09-01

    Ethambutoldihydrogenchloride (EMB) with chemical formula C10H24N2O2.2HCl is ethane-1,2-diamine in which one hydrogen attached to each of the nitrogen is substituted by a 1-hydroxybutan-2-yl group (S,S-configuration). It is an FDA approved drug and has been used for treatment of tuberculosis since 1960's. Prolong use of EMB has a side effect of visual impairment and in literature it is related with the depletion of Zn metal from the body. As it is a good chelating agent, many metal II complexes have been synthesized with anti-tubercular activity. The purpose of this work was to synthesize metal II complexes of EMB and to evaluate their antioxidant activity along with enzyme inhibition activity (acetylcholine esterase and protease). The metals used for complex formation were Co, Zn, Fe, Cu and Ni. IR spectral data and physical parameters supported the complex formation. The obtained results showed the synthesized complexes as notable antioxidants and enzyme inhibitors.

  8. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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. (AbbVie); (Toronto)

    2017-01-30

    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.

  10. Cost-utility analysis of Ruconest® (conestat alfa) compared to Berinert® P (human C1 esterase inhibitor) in the treatment of acute, life-threatening angioedema attacks in patients with hereditary angioedema

    Science.gov (United States)

    Holko, Przemysław; Paszulewicz, Anna

    2013-01-01

    Introduction Administration of human C1 esterase inhibitor (Berinert® P) from target import is the most widespread treatment strategy for patients with hereditary angioedema (HAE). However, a therapeutic health program including Ruconest® (conestat alfa) could shorten a patient's expectancy for a life-saving treatment. Aim To evaluate the cost-utility of Ruconest® (conestat alfa) financed from public funds within the newly introduced therapeutic health program compared with Berinert® P (human C1 esterase inhibitor) in the treatment of acute angioedema attacks in adults with HAE. Material and methods The cost-utility analysis from the Polish healthcare payer's perspective was performed for 1 year (2012). The costs and health outcomes were simulated for three pairs of eligible HAE patient groups (active treatment and corresponding placebo). The incremental costs of each intervention compared with placebo were listed together (direct or indirect comparisons between options were impossible due to limited clinical data available). Results The incremental cost-utility ratios (ICURs) for the evaluated interventions compared with placebo were as follows: EUR 15,226 per QALY (Ruconest®) and EUR 27,786 per QALY (Berinert® P). The probability of cost-utility (ICUR < EUR 24,279 per QALY) assessed for Ruconest® administered in the case of acute angioedema attack was 61% and 41% for Berinert® P. Conclusions The administration of Ruconest® in acute life-threatening angioedema attacks is economically justified from the Polish healthcare payer's perspective, results in lower costs and is characterized by higher cost-utility probability compared with Berinert® P. PMID:24278067

  11. Preventing Mycobacterium avium complex in patients who are using protease inhibitors: a cost-effectiveness analysis.

    Science.gov (United States)

    Bayoumi, A M; Redelmeier, D A

    1998-08-20

    Practice guidelines recommending Mycobacterium avium complex (MAC) prophylaxis for patients with HIV disease were based on clinical trials in which individuals did not receive protease inhibitors. To estimate the cost-effectiveness of strategies for MAC prophylaxis in patients whose treatment regimen includes protease inhibitors. Decision analysis with Markov modelling of the natural history of advanced HIV disease. Five strategies were evaluated: no prophylaxis, azithromycin, rifabutin, clarithromycin and a combination of azithromycin plus rifabutin. Survival, quality of life, quality-adjusted survival, health care costs and marginal cost-effectiveness ratios. Compared with no prophylaxis, rifabutin increased life expectancy from 78 to 80 months, increased quality-adjusted life expectancy from 50 to 52 quality-adjusted months and increased health care costs from $233000 to $239800. Ignoring time discounting and quality of life, the cost-effectiveness of rifabutin relative to no prophylaxis was $44300 per life year. Adjusting for time discounting and quality of life, the cost-effectiveness of rifabutin relative to no prophylaxis was $41500 per quality-adjusted life year (QALY). In comparison with rifabutin, azithromycin was associated with increased survival, increased costs and an incremental cost-effectiveness ratio of $54300 per QALY. In sensitivity analyses, prophylaxis remained economically attractive unless the lifetime chance of being diagnosed with MAC was less than 20%, the rate of CD4 count decline was less than 10 x 10(6) cells/l per year, or the CD4 count was greater than 50 x 10(6) cells/l. MAC prophylaxis increases quality-adjusted survival at a reasonable cost, even in patients using protease inhibitors. When not contraindicated, starting azithromycin or rifabutin when the patient's CD4 count is between 50 and 75 x 10(6) cells/l is the most cost-effective strategy. The main determinants of cost-effectiveness are CD4 count, viral load, place of

  12. About Heart Attacks

    Science.gov (United States)

    ... Artery Disease Venous Thromboembolism Aortic Aneurysm More About Heart Attacks Updated:Jan 27,2017 A heart attack is ... coronary artery damage leads to a heart attack . Heart Attack Questions and Answers What is a heart attack? ...

  13. Network robustness under large-scale attacks

    CERN Document Server

    Zhou, Qing; Liu, Ruifang; Cui, Shuguang

    2014-01-01

    Network Robustness under Large-Scale Attacks provides the analysis of network robustness under attacks, with a focus on large-scale correlated physical attacks. The book begins with a thorough overview of the latest research and techniques to analyze the network responses to different types of attacks over various network topologies and connection models. It then introduces a new large-scale physical attack model coined as area attack, under which a new network robustness measure is introduced and applied to study the network responses. With this book, readers will learn the necessary tools to evaluate how a complex network responds to random and possibly correlated attacks.

  14. Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis.

    Science.gov (United States)

    Begley, Darren W; Edwards, Thomas E; Raymond, Amy C; Smith, Eric R; Hartley, Robert C; Abendroth, Jan; Sankaran, Banumathi; Lorimer, Donald D; Myler, Peter J; Staker, Bart L; Stewart, Lance J

    2011-09-01

    Babesiosis is a tick-borne disease caused by eukaryotic Babesia parasites which are morphologically similar to Plasmodium falciparum, the causative agent of malaria in humans. Like Plasmodium, different species of Babesia are tuned to infect different mammalian hosts, including rats, dogs, horses and cattle. Most species of Plasmodium and Babesia possess an essential bifunctional enzyme for nucleotide synthesis and folate metabolism: dihydrofolate reductase-thymidylate synthase. Although thymidylate synthase is highly conserved across organisms, the bifunctional form of this enzyme is relatively uncommon in nature. The structural characterization of dihydrofolate reductase-thymidylate synthase in Babesia bovis, the causative agent of babesiosis in livestock cattle, is reported here. The apo state is compared with structures that contain dUMP, NADP and two different antifolate inhibitors: pemetrexed and raltitrexed. The complexes reveal modes of binding similar to that seen in drug-resistant malaria strains and point to the utility of applying structural studies with proven cancer chemotherapies towards infectious disease research.

  15. A glutathione-S-transferase (TuGSTd05) associated with acaricide resistance in Tetranychus urticae directly metabolizes the complex II inhibitor cyflumetofen.

    Science.gov (United States)

    Pavlidi, Nena; Khalighi, Mousaalreza; Myridakis, Antonis; Dermauw, Wannes; Wybouw, Nicky; Tsakireli, Dimitra; Stephanou, Euripides G; Labrou, Nikolaos E; Vontas, John; Van Leeuwen, Thomas

    2017-01-01

    Cyflumetofen is a recently introduced acaricide with a novel mode of action, acting as an inhibitor of complex II of mitochondrial electron transport chain. It is activated by hydrolysis and the resulting de-esterified metabolite is a much stronger inhibitor. Cyflumetofen represents a great addition for the control of mite species including Tetranychus urticae, a major agricultural pest, which has the ability to develop resistance to most classes of pesticides rapidly. A resistant strain (Tu008R) was recently described and synergism experiments pointed towards the involvement of GSTs. Here, we conducted genome-wide gene expression analysis, comparing Tu008R with its parental susceptible strain, and identified the delta GST TuGSTd05 as the prime resistance-conferring candidate. Docking analysis suggests that both cyflumetofen and its de-esterified metabolite are potential substrates for conjugation by TuGSTd05. Several amino acids were identified that might be involved in the interaction, with Y107 and N103 possibly having an important role. To further investigate interaction as well as the role of Y107 and N103 in vitro, we recombinantly expressed and kinetically characterized the wild type TuGSTd05, TuGSTd05 Y107F and TuGSTd05 N103L mutants. While cyflumetofen was not found to act as a strong inhibitor, the de-esterified metabolite showed strong affinity for TuGSTd05 (IC50 = 4 μM), which could serve as a mechanism of rapid detoxification. Y107 and N103 might contribute to this interaction. HPLC-MS analysis provided solid indications that TuGSTd05 catalyzes the conjugation of ionized glutathione (GS(-)) to cyflumetofen and/or its de-esterified metabolite and the resulting metabolite and possible site of attack were identified. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Mechanistic Investigations of the Mitochondrial Complex I Inhibitor Rotenone in the Context of Pharmacological and Safety Evaluation.

    Science.gov (United States)

    Heinz, Sabrina; Freyberger, Alexius; Lawrenz, Bettina; Schladt, Ludwig; Schmuck, Gabriele; Ellinger-Ziegelbauer, Heidrun

    2017-04-04

    Inhibitors of the mitochondrial respiratory chain complex I are suggested to exert anti-tumor activity on those tumors relying on oxidative metabolism and are therefore of interest to oncology research. Nevertheless, the safety profile of these inhibitors should be thoroughly assessed. Rotenone, a proven complex I inhibitor, has shown anti-carcinogenic activity in several studies. In this context rotenone was used in this study as a tool compound with the aim to identify suitable biomarker candidates and provide enhanced mechanistic insights into the molecular and cellular effects of complex I inhibitors. Rats were treated with 400 ppm rotenone daily for 1, 3 or 14 consecutive days followed by necropsy. Classical clinical endpoints, including hematology, clinical chemistry and histopathology with supporting investigations (FACS-analysis, enzymatic activity assays) were examined as well as gene expression analysis. Through these investigations, we identified liver, bone marrow and bone as target organs amongst approx. 40 organs evaluated at least histopathologically. Our results suggest blood analysis, bone marrow parameters, assessment of lactate in serum and glycogen in liver, and especially gene expression analysis in liver as useful parameters for an experimental model to help to characterize the profile of complex I inhibitors with respect to a tolerable risk-benefit balance.

  17. Cholinesterase inhibitors improve both memory and complex learning in aged beagle dogs.

    Science.gov (United States)

    Araujo, Joseph A; Greig, Nigel H; Ingram, Donald K; Sandin, Johan; de Rivera, Christina; Milgram, Norton W

    2011-01-01

    Similar to patients with Alzheimer's disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-β (Aβ) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezil on performance of two tasks, a delayed non-matching-to-position task (DNMP) designed to assess working memory, and an oddity discrimination learning task designed to assess complex learning, in aged dogs. Phenserine (0.5 mg/kg; PO) significantly improved performance on the DNMP at the longest delay compared to wash-out and partially attenuated scopolamine-induced deficits (15 μg/kg; SC). Phenserine also improved learning on a difficult version of an oddity discrimination task compared to placebo, but had no effect on an easier version. We also examined the effects of three doses of donepezil (0.75, 1.5, and 6 mg/kg; PO) on performance of the DNMP. Similar to the results with phenserine, 1.5 mg/kg of donepezil improved performance at the longest delay compared to baseline and wash-out, indicative of memory enhancement. These results further extend the findings of cholinergic hypofunction in aged dogs and provide pharmacological validation of the canine model with a cholinesterase inhibitor approved for use in AD. Collectively, these studies support utilizing the aged dog in future screening of therapeutics for AD, as well as for investigating the links among cholinergic function, Aβ pathology, and cognitive decline.

  18. Molecular investigations of the structure and function of the protein phosphatase 1-spinophilin-inhibitor 2 heterotrimeric complex.

    Science.gov (United States)

    Dancheck, Barbara; Ragusa, Michael J; Allaire, Marc; Nairn, Angus C; Page, Rebecca; Peti, Wolfgang

    2011-02-22

    Regulation of the major Ser/Thr phosphatase protein phosphatase 1 (PP1) is controlled by a diverse array of targeting and inhibitor proteins. Though many PP1 regulatory proteins share at least one PP1 binding motif, usually the RVxF motif, it was recently discovered that certain pairs of targeting and inhibitor proteins bind PP1 simultaneously to form PP1 heterotrimeric complexes. To date, structural information for these heterotrimeric complexes and, in turn, how they direct PP1 activity is entirely lacking. Using a combination of NMR spectroscopy, biochemistry, and small-angle X-ray scattering (SAXS), we show that major structural rearrangements in both spinophilin (targeting) and inhibitor 2 (I-2, inhibitor) are essential for the formation of the heterotrimeric PP1-spinophilin-I-2 (PSI) complex. The RVxF motif of I-2 is released from PP1 during the formation of PSI, making the less prevalent SILK motif of I-2 essential for complex stability. The release of the I-2 RVxF motif allows for enhanced flexibility of both I-2 and spinophilin in the heterotrimeric complex. In addition, we used inductively coupled plasma atomic emission spectroscopy to show that PP1 contains two metals in both heterodimeric complexes (PP1-spinophilin and PP1-I-2) and PSI, demonstrating that PSI retains the biochemical characteristics of the PP1-I-2 holoenzyme. Finally, we combined the NMR and biochemical data with SAXS and molecular dynamics simulations to generate a structural model of the full heterotrimeric PSI complex. Collectively, these data reveal the molecular events that enable PP1 heterotrimeric complexes to exploit both the targeting and inhibitory features of the PP1-regulatory proteins to form multifunctional PP1 holoenzymes.

  19. 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.

  20. 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.

  1. 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.

  2. Crystal structures of Mycobacterium tuberculosis S-adenosyl-L-homocysteine hydrolase in ternary complex with substrate and inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Reddy, Manchi C.M.; Kuppan, Gokulan; Shetty, Nishant D.; Owen, Joshua L.; Ioerger, Thomas R.; Sacchettini, James C. (TAM)

    2009-12-01

    S-adenosylhomocysteine hydrolase (SAHH) is a ubiquitous enzyme that plays a central role in methylation-based processes by maintaining the intracellular balance between S-adenosylhomocysteine (SAH) and S-adenosylmethionine. We report the first prokaryotic crystal structure of SAHH, from Mycobacterium tuberculosis (Mtb), in complex with adenosine (ADO) and nicotinamide adenine dinucleotide. Structures of complexes with three inhibitors are also reported: 3{prime}-keto aristeromycin (ARI), 2-fluoroadenosine, and 3-deazaadenosine. The ARI complex is the first reported structure of SAHH complexed with this inhibitor, and confirms the oxidation of the 3{prime} hydroxyl to a planar keto group, consistent with its prediction as a mechanism-based inhibitor. We demonstrate the in vivo enzyme inhibition activity of the three inhibitors and also show that 2-fluoradenosine has bactericidal activity. While most of the residues lining the ADO-binding pocket are identical between Mtb and human SAHH, less is known about the binding mode of the homocysteine (HCY) appendage of the full substrate. We report the 2.0 {angstrom} resolution structure of the complex of SAHH cocrystallized with SAH. The most striking change in the structure is that binding of HCY forces a rotation of His363 around the backbone to flip out of contact with the 5{prime} hydroxyl of the ADO and opens access to a nearby channel that leads to the surface. This complex suggests that His363 acts as a switch that opens up to permit binding of substrate, then closes down after release of the cleaved HCY. Differences in the entrance to this access channel between human and Mtb SAHH are identified.

  3. [Ictal semiology of temporal partial complex seizures: usefulness for localizing and lateralizing the origin of the attacks].

    Science.gov (United States)

    Fernández Torre, J L

    1999-01-01

    To review signs and symptoms associated with temporal complex partial seizures (CPS) and their utility in the localization and lateralization of seizure onset. CPS are particularly resistant to the standard antiepileptic drugs. Since surgical treatment is a therapeutical alternative in patients with intractable seizures, localization and lateralization of seizure origin are the principal aims in the preoperative assessment. Video-EEG monitorization has made possible characterization of ictal behaviour and correlation with cerebral regions generating the epileptic discharge. Therefore, ictal semiology has increased its importance in the localization and lateralization of seizures. The utility of auras, automatisms, motor manifestations, speech disturbances and autonomic features have been reviewed in relation to this approach. Viscerosensorial and experiential auras have been associated with temporal lobe epilepsy. The automatisms are not exclusive of temporal seizures and may be observed in frontal epilepsy and parietal and occipital seizures with spreading to temporal structures. There is not agreement in relation to head turning and version, therefore, this clinical sign should be used in correlation to other clinical manifestations. Distonic posturing, comprehensible ictal speech and postictal dysphasia appear to be the most reliable clinical signs in the lateralisation of temporal lobe seizures.

  4. Complexes of Imidazole with Poly(ethylene glycol) as a Corrosion Inhibitor for Carbon Steel in Sulphuric Acid

    Science.gov (United States)

    Salimi, Saeed; Nasr-Esfahani, Mojtaba; Umoren, Saviour A.; Saebnoori, Ehsan

    2015-12-01

    The inhibiting action of polyethylene glycol and imidazole (PEG/IMZ)) complexes prepared by a simple deprotonation procedure on carbon steel corrosion in 0.5 mol/L sulphuric acid was evaluated using the weight loss, potentiodynamic polarization, and electrochemical impedance spectroscopy techniques complemented by surface analysis using scanning electron microscopy. The inhibiting effect of the PEG/IMZ complexes on carbon steel corrosion was compared with the non-complex forms. Results obtained show that PEG/IMZ complex is a very effective corrosion inhibitor of carbon steel in the acid environment. The inhibition efficiency increased with the increase in the temperature and also with increasing percentage of imidazole in the complex. Corrosion inhibition occurs by virtue of adsorption of PEG/IMZ complexes on the steel surface which was found to follow the Temkin adsorption isotherm model. The PEG/IMZ complexes function as a mixed-type inhibitor. Results from all the methods employed are in a reasonably good agreement.

  5. Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease.

    Science.gov (United States)

    Baddeley, Thomas C; McCaffrey, Jennifer; Storey, John M D; Cheung, John K S; Melis, Valeria; Horsley, David; Harrington, Charles R; Wischik, Claude M

    2015-01-01

    Methylthioninium (MT) is a tau aggregation inhibitor with therapeutic potential in Alzheimer's disease (AD). MT exists in equilibrium between reduced [leucomethylthioninium (LMT)] and oxidized (MT(+)) forms; as a chloride salt [methylthioninium chloride (MTC), "methylene blue"], it is stabilized in its MT(+) form. Although the results of a phase 2 study of MTC in 321 mild/moderate AD subjects identified a 138-mg MT/day dose as the minimum effective dose on cognitive and imaging end points, further clinical development of MT was delayed pending resolution of the unexpected lack of efficacy of the 228-mg MT/day dose. We hypothesized that the failure of dose response may depend on differences known at the time in dissolution in simulated gastric and intestinal fluids of the 100-mg MTC capsules used to deliver the 228-mg dose and reflect previously unsuspected differences in redox processing of MT at different levels in the gut. The synthesis of a novel chemical entity, LMTX (providing LMT in a stable anhydrous crystalline form), has enabled a systematic comparison of the pharmacokinetic properties of MTC and LMTX in preclinical and clinical studies. The quantity of MT released in water or gastric fluid within 60 minutes proved in retrospect to be an important determinant of clinical efficacy. A further factor was a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered in the MT(+) form as MTC. A model is presented to account for the complexity of MT absorption, which may have relevance for other similar redox molecules. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  6. Physalin H from Solanum nigrum as an Hh signaling inhibitor blocks GLI1-DNA-complex formation.

    Science.gov (United States)

    Arai, Midori A; Uchida, Kyoko; Sadhu, Samir K; Ahmed, Firoj; Ishibashi, Masami

    2014-01-13

    Hedgehog (Hh) signaling plays an important role in embryonic development, cell maintenance and cell proliferation. Moreover, Hh signaling contributes to the growth of cancer cells. Physalins are highly oxidized natural products with a complex structure. Physalins (1-7) were isolated from Solanum nigrum (Solanaceae) collected in Bangladesh by using our cell-based assay. The isolated physalins included the previously reported Hh inhibitors 5 and 6. Compounds 1 and 4 showed strong inhibition of GLI1 transcriptional activity, and exhibited cytotoxicity against cancer cell lines with an aberrant activation of Hh signaling. Compound 1 inhibited the production of the Hh-related proteins patched (PTCH) and BCL2. Analysis of the structures of different physalins showed that the left part of the physalins was important for Hh inhibitory activity. Interestingly, physalin H (1) disrupted GLI1 binding to its DNA binding domain, while the weak inhibitor physalin G (2) did not show inhibition of GLI1-DNA complex formation.

  7. 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.

  8. 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.

  9. 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.

  10. A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex.

    Science.gov (United States)

    Dupré, Aude; Boyer-Chatenet, Louise; Sattler, Rose M; Modi, Ami P; Lee, Ji-Hoon; Nicolette, Matthew L; Kopelovich, Levy; Jasin, Maria; Baer, Richard; Paull, Tanya T; Gautier, Jean

    2008-02-01

    The MRN (Mre11-Rad50-Nbs1)-ATM (ataxia-telangiectasia mutated) pathway is essential for sensing and signaling from DNA double-strand breaks. The MRN complex acts as a DNA damage sensor, maintains genome stability during DNA replication, promotes homology-dependent DNA repair and activates ATM. MRN is essential for cell viability, which has limited functional studies of the complex. Small-molecule inhibitors of MRN could circumvent this experimental limitation and could also be used as cellular radio- and chemosensitization compounds. Using cell-free systems that recapitulate faithfully the MRN-ATM signaling pathway, we designed a forward chemical genetic screen to identify inhibitors of the pathway, and we isolated 6-(4-hydroxyphenyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (mirin, 1) as an inhibitor of MRN. Mirin prevents MRN-dependent activation of ATM without affecting ATM protein kinase activity, and it inhibits Mre11-associated exonuclease activity. Consistent with its ability to target the MRN complex, mirin abolishes the G2/M checkpoint and homology-dependent repair in mammalian cells.

  11. Repositioning of Verrucosidin, a Purported Inhibitor of Chaperone Protein GRP78, as an Inhibitor of Mitochondrial Electron Transport Chain Complex I

    Science.gov (United States)

    Gonzalez, Reyna; Pao, Peng-Wen; Hofman, Florence M.; Chen, Thomas C.; Louie, Stan G.; Pirrung, Michael C.; Schönthal, Axel H.

    2013-01-01

    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. PMID:23755268

  12. 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.

  13. 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.

  14. Crystal Structure of Novel Metallocarboxypeptidase Inhibitor from Marine Mollusk Nerita versicolor in Complex with Human Carboxypeptidase A4*

    Science.gov (United States)

    Covaleda, Giovanni; Alonso del Rivero, Maday; Chávez, María A.; Avilés, Francesc X.; Reverter, David

    2012-01-01

    NvCI is a novel exogenous proteinaceous inhibitor of metallocarboxypeptidases from the marine snail Nerita versicolor. The complex between human carboxypeptidase A4 and NvCI has been crystallized and determined at 1.7 Å resolution. The NvCI structure defines a distinctive protein fold basically composed of a two-stranded antiparallel β-sheet connected by three loops and the inhibitory C-terminal tail and stabilized by three disulfide bridges. NvCI is a tight-binding inhibitor that interacts with the active site of the enzyme in a substrate-like manner. NvCI displays an extended and novel interface with human carboxypeptidase A4, responsible for inhibitory constants in the picomolar range for some members of the M14A subfamily of carboxypeptidases. This makes NvCI the strongest inhibitor reported so far for this family. The structural homology displayed by the C-terminal tails of different carboxypeptidase inhibitors represents a relevant example of convergent evolution. PMID:22294694

  15. Crystal structure of novel metallocarboxypeptidase inhibitor from marine mollusk Nerita versicolor in complex with human carboxypeptidase A4.

    Science.gov (United States)

    Covaleda, Giovanni; del Rivero, Maday Alonso; Chávez, María A; Avilés, Francesc X; Reverter, David

    2012-03-16

    NvCI is a novel exogenous proteinaceous inhibitor of metallocarboxypeptidases from the marine snail Nerita versicolor. The complex between human carboxypeptidase A4 and NvCI has been crystallized and determined at 1.7 Å resolution. The NvCI structure defines a distinctive protein fold basically composed of a two-stranded antiparallel β-sheet connected by three loops and the inhibitory C-terminal tail and stabilized by three disulfide bridges. NvCI is a tight-binding inhibitor that interacts with the active site of the enzyme in a substrate-like manner. NvCI displays an extended and novel interface with human carboxypeptidase A4, responsible for inhibitory constants in the picomolar range for some members of the M14A subfamily of carboxypeptidases. This makes NvCI the strongest inhibitor reported so far for this family. The structural homology displayed by the C-terminal tails of different carboxypeptidase inhibitors represents a relevant example of convergent evolution.

  16. 1-Butyl-1-methylpyrrolidinium chloride as an effective corrosion inhibitor for stainless steel current collectors in magnesium chloride complex electrolytes

    Science.gov (United States)

    Ha, Jung Hoon; Cho, Jae-Hyun; Kim, Jong Hak; Cho, Byung Won; Oh, Si Hyoung

    2017-07-01

    Corrosion of current collectors is one of the most significant issues to tackle in rechargeable magnesium batteries where chloride-abundant electrolytes are commonly used since it can affect the electrochemical performance and the safety of battery system seriously. Here we investigate 1-butyl-1-methylpyrrolidinium chloride ionic liquid as an effective corrosion inhibitor of the current collector in an electrolyte containing magnesium chloride complex. We find that adding just 0.2 wt.% ionic liquid increases the anodic stability of common current collectors by 0.1-0.3 V while maintaining the coulombic efficiencies for Mg deposition and stripping at over 98%. In particular, analytical studies of the passive film formed on 316L stainless steel show that the inhibitor efficiently prevents the formation of corrosion pits and preserves the protective property of the passive film upon repeated anodic scans. Furthermore, the inhibitor enables almost 100% efficiencies in the full cell cycling with Mo6S8 cathode, reflecting higher anodic stability of the current collectors in the electrolyte containing the inhibitor. We propose that the formation of an adsorbed layer of the ionic liquid as a plausible corrosion inhibition mechanism.

  17. 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°.

  18. A 96-well based analysis of replicon elimination with the HCV NS5A replication complex inhibitor daclatasvir.

    Science.gov (United States)

    O'Boyle, Donald R; Nower, Peter T; Sun, Jin-Hua; Fridell, Robert; Wang, Chunfu; Valera, Lourdes; Gao, Min

    2013-10-01

    A 96-well based replicon elimination and colony formation assay is presented for comparing the resistance barrier of the hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (DCV, BMS-790052) on three HCV genotypes (gts) in a proof of concept experimental protocol. The 96-well assay format provides both individual colony as well as population characterization and is readily applicable to other HCV direct-acting antiviral agents (DAAs). The assay provides an assessment of HCV replication levels over a 5log10 range by measuring a luciferase reporter resident in the HCV replicons. Individual colony status can be measured with a separate and compatible resazurin assay to assess relative host cell fitness following inhibitor treatments. The methods employed are non-toxic and leave intact isolatable colonies that can be used for phenotyping and genotyping. The utility of the assay is demonstrated by the identification and isolation of resistant variants as well as in the ranking of the relative resistance barrier for the replication complex inhibitor DCV for gts 1a, 1b and 2a. The format provides a quantitative ranking based upon luciferase activity and has the ability to monitor DAA resistance development over time for large numbers of compounds. Copyright © 2013. Published by Elsevier B.V.

  19. 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.

  20. 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 investigate...... 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.......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...... for the prognostic impact of PAI-1 on survival. Standard clinical parameters were available and the patients had a median survival time of 25 months. An ELISA established to measure preformed uPA-PAI-1 complexes was applied to the tumor extracts and previously measured data on uPA and PAI-1 levels were available...

  1. 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 investigate...... 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.......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...... for the prognostic impact of PAI-1 on survival. Standard clinical parameters were available and the patients had a median survival time of 25 months. An ELISA established to measure preformed uPA-PAI-1 complexes was applied to the tumor extracts and previously measured data on uPA and PAI-1 levels were available...

  2. 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.

  3. The association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS.

    Science.gov (United States)

    de Mos, M; Huygen, F J P M; Stricker, B H Ch; Dieleman, J P; Sturkenboom, M C J M

    2009-04-01

    Antihypertensive drugs interact with mediators that are also involved in complex regional pain syndrome (CRPS), such a neuropeptides, adrenergic receptors, and vascular tone modulators. Therefore, we aimed to study the association between the use of antihypertensive drugs and CRPS onset. We conducted a population-based case-control study in the Integrated Primary Care Information (IPCI) database in the Netherlands. Cases were identified from electronic records (1996-2005) and included if they were confirmed during an expert visit (using IASP criteria), or if they had been diagnosed by a medical specialist. Up to four controls per cases were selected, matched on gender, age, calendar time, and injury. Exposure to angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium channel blockers, and diuretics was assessed from the automated prescription records. Data were analyzed using multivariate conditional logistic regression. A total of 186 cases were matched to 697 controls (102 confirmed during an expert visit plus 84 with a specialist diagnosis). Current use of ACE inhibitors was associated with an increased risk of CRPS (OR(adjusted): 2.7, 95% CI: 1.1-6.8). The association was stronger if ACE inhibitors were used for a longer time period (OR(adjusted): 3.0, 95% CI: 1.1-8.1) and in higher dosages (OR(adjusted): 4.3, 95% CI: 1.4-13.7). None of the other antihypertensive drug classes was significantly associated with CRPS. We conclude that ACE inhibitor use is associated with CRPS onset and hypothesize that ACE inhibitors influence the neuro-inflammatory mechanisms that underlie CRPS by their interaction with the catabolism of substance P and bradykinin.

  4. Effect of β-Lactamase inhibitors on in vitro activity of β-Lactam antibiotics against Burkholderia cepacia complex species

    Directory of Open Access Journals (Sweden)

    Annelien Everaert

    2016-11-01

    Full Text Available Abstract Background Bacteria belonging to the Burkholderia cepacia complex (Bcc are an important cause of chronic respiratory tract infections in cystic fibrosis patients. Intrinsic resistance to a wide range of antimicrobial agents, including a variety of β-lactam antibiotics, is frequently observed in Bcc strains. Resistance to β-lactams is most commonly mediated by efflux pumps, alterations in penicillin-binding proteins or the expression of β-lactamases. β-lactamase inhibitors are able to restore the in vitro activity of β-lactam molecules against a variety of Gram-negative species, but the effect of these inhibitors on the activity of β-lactam treatment against Bcc species is still poorly investigated. Methods In the present study, the susceptibility of a panel of Bcc strains was determined towards the β-lactam antibiotics ceftazidime, meropenem, amoxicillin, cefoxitin, cefepime and aztreonam; alone or in combination with a β-lactamase inhibitor (clavulanic acid, sulbactam, tazobactam and avibactam. Consequently, β-lactamase activity was determined for active β-lactam/β-lactamase inhibitor combinations. Results Clavulanic acid had no effect on minimum inhibitory concentrations, but addition of sulbactam, tazobactam or avibactam to ceftazidime, amoxicillin, cefoxitin, cefepime or aztreonam leads to increased susceptibility (at least 4-fold MIC-decrease in some Bcc strains. The effect of β-lactamase inhibitors on β-lactamase activity is both strain- and/or antibiotic-dependent, and other mechanisms of β-lactam resistance (besides production of β-lactamases appear to be important. Conclusions Considerable differences in susceptibility of Bcc strains to β-lactam antibiotics were observed. Results obtained in the present study suggest that resistance of Bcc strains against β-lactam antibiotics is mediated by both β-lactamases and non-β-lactamase-mediated resistance mechanisms.

  5. The Molecular Structure of Epoxide Hydrolase B From And Its Complex With Urea-Based Inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Biswal, B.K.; Morisseau, C.; Garen, G.; Cherney, M.M.; Garen, C.; Niu, C.; Hammock, B.D.; James, M.N.G.

    2009-05-11

    Mycobacterium tuberculosis (Mtb), the intracellular pathogen that infects macrophages primarily, is the causative agent of the infectious disease tuberculosis in humans. The Mtb genome encodes at least six epoxide hydrolases (EHs A to F). EHs convert epoxides to trans-dihydrodiols and have roles in drug metabolism as well as in the processing of signaling molecules. Herein, we report the crystal structures of unbound Mtb EHB and Mtb EHB bound to a potent, low-nanomolar (IC(50) approximately 19 nM) urea-based inhibitor at 2.1 and 2.4 A resolution, respectively. The enzyme is a homodimer; each monomer adopts the classical alpha/beta hydrolase fold that composes the catalytic domain; there is a cap domain that regulates access to the active site. The catalytic triad, comprising Asp104, His333 and Asp302, protrudes from the catalytic domain into the substrate binding cavity between the two domains. The urea portion of the inhibitor is bound in the catalytic cavity, mimicking, in part, the substrate binding; the two urea nitrogen atoms donate hydrogen bonds to the nucleophilic carboxylate of Asp104, and the carbonyl oxygen of the urea moiety receives hydrogen bonds from the phenolic oxygen atoms of Tyr164 and Tyr272. The phenolic oxygen groups of these two residues provide electrophilic assistance during the epoxide hydrolytic cleavage. Upon inhibitor binding, the binding-site residues undergo subtle structural rearrangement. In particular, the side chain of Ile137 exhibits a rotation of around 120 degrees about its C(alpha)-C(beta) bond in order to accommodate the inhibitor. These findings have not only shed light on the enzyme mechanism but also have opened a path for the development of potent inhibitors with good pharmacokinetic profiles against all Mtb EHs of the alpha/beta type.

  6. Accurate Prediction of Complex Structure and Affinity for a Flexible Protein Receptor and Its Inhibitor.

    Science.gov (United States)

    Bekker, Gert-Jan; Kamiya, Narutoshi; Araki, Mitsugu; Fukuda, Ikuo; Okuno, Yasushi; Nakamura, Haruki

    2017-06-13

    In order to predict the accurate binding configuration as well as the binding affinity for a flexible protein receptor and its inhibitor drug, enhanced sampling with multicanonical molecular dynamics (McMD) simulation and thermodynamic integration (TI) were combined as a general drug docking method. CDK2, cyclin-dependent kinase 2, is involved in the cell cycle regulation. Malfunctions in CDK2 can cause tumorigenesis, and thus it is a potential drug target. Here, we performed a long McMD simulation for docking the inhibitor CS3 to CDK2 starting from the unbound structure. Subsequently, a potential binding/unbinding pathway was given from the multicanonical ensemble, and the binding free energy was readily computed by TI along the pathway. Using this combination, the correct binding configuration of CS3 to CDK2 was obtained, and its affinity coincided well with the experimental value.

  7. Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex.

    Science.gov (United States)

    Ghosh, Arun K; Brindisi, Margherita; Nyalapatla, Prasanth R; Takayama, Jun; Ella-Menye, Jean-Rene; Yashchuk, Sofiya; Agniswamy, Johnson; Wang, Yuan-Fang; Aoki, Manabu; Amano, Masayuki; Weber, Irene T; Mitsuya, Hiroaki

    2017-10-01

    Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Ki of 0.025nM and antiviral IC50 of 69nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27Å resolution. These structures revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. 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 Hansen

    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......, the presence of extrinsic CR1, on E, may serve to limit spontaneous MAC formation and thereby ensure cell survival in the circulation....

  9. Presurgical Administration of mTOR Inhibitors in Patients with Large Subependymal Giant Cell Astrocytoma Associated with Tuberous Sclerosis Complex.

    Science.gov (United States)

    Jiang, Tao; Du, Jiang; Raynald; Wang, Junmei; Li, Chunde

    2017-11-01

    Direct surgical resection remains the standard treatment for patients with tuberous sclerosis complex (TSC) with a large subependymal giant cell astrocytoma (SEGA). Rapamycin or everolimus is seldom used in these patients because of the risk of increased intracranial pressure and possibility of sudden death. Three patients with TSC and a large intracranial SEGA received oral rapamycin (0.5 mg/day) or everolimus (2.5 mg/day) before surgery for tumor resection. After mTOR inhibitor therapy, computed tomography scans and magnetic resonance imaging revealed tumor reduction. Tumor bleeding was easy to control during surgery, and the border between tumor and surrounding brain tissue was clearly differentiated. Analysis of postsurgical tumor specimens showed low blood density and focal necrosis. Preoperative mTOR inhibitors could be a potentially novel treatment modality in large TSC-SEGA with hydrocephalus. In this series, mTOR inhibitors were not only safe and well tolerated, but also beneficial for tumor resection. Copyright © 2017. Published by Elsevier Inc.

  10. Lanthanide(III) complexes are more active inhibitors of the Fenton reaction than pure ligands.

    Science.gov (United States)

    Martin, Jan; Mladěnka, Přemysl; Saso, Luciano; Kostova, Irena

    2016-03-01

    This study is an extension to our finding of direct anti-oxidant activities of lanthanide(III) complexes with the heterocyclic compound, 5-aminoorotic acid (AOA). In this experiment, we used AOA and coumarin-3-carboxylic acid as the two heterocyclic compounds with anti-oxidant potential, to produce the complexes with different lanthanides. Lanthanide(III) complexes were tested on the iron-driven Fenton reaction. The product of this reaction, the hydroxyl radical, was detected by HPLC. All complexes as well as their ligands had positive or neutral effect on the Fenton reaction but their behavior was different. Both pure ligands in low concentration ratio to iron were inefficient in contrast to some of their complexes. Complexes of neodymium, samarium, gadolinium, and partly of cerium blocked the Fenton reaction at very low ratios (in relation to iron) but the effect disappeared at higher ratios. In contrast, lanthanum complexes appeared to be the most promising. Both blocked the Fenton reaction in a dose-dependent manner. Lanthanide(III) complexes were proven to block the iron-driven production of the hydroxyl radical. Second, the lanthanide(III) element appears to be crucial for the anti-oxidant effect. Overall, lanthanum complexes may be promising direct anti-oxidants for future testing.

  11. Antiproliferative effect of complexes of platinum (II) with plasmanyl-(N-acyl)-ethanolamine, an inhibitor of protein kinase C.

    Science.gov (United States)

    Mikhaevich, I S; Vlasenkova, N K; Gerasimova, G K

    1992-10-01

    Antiproliferative activities of combinations of semisynthetic plasmanyl-(N-acyl)-ethanolamine [PNAE(s)], an inhibitor of protein kinase C, with two antitumor complexes of platinum (II) [cisplatin and ammine(cyclopentylamine)-S-(-)-malatoplatinum (cycloplatam)] were investigated. The exposure of human melanoma BRO cells in culture simultaneously with cisplatin (1-10 microM) and PNAE(s) (100 microM-1 mM) in a molar ratio of 1/100 for 24 h induced a considerable decrease in the ability of these cells to incorporate [3H]thymidine into DNA. A considerable antiproliferative synergism of these agents was observed. The effect of cycloplatam/PNAE(s) combination in similar experiments was significantly different from cisplatin/PNAE(s), i.e. interaction of these agents was complex and synergism was not found.

  12. The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2

    DEFF Research Database (Denmark)

    Mølgaard, Anne; Arnau, Jose; Lauritzen, C.

    2007-01-01

    hDDPI (human dipeptidyl peptidase I) is a lysosomal cysteine protease involved in zymogen activation of granule-associated proteases, including granzymes A and B from cytotoxic T-lymphocytes and natural killer cells, cathepsin G and neutrophil elastase, and mast cell tryptase and chymase. In the ......hDDPI (human dipeptidyl peptidase I) is a lysosomal cysteine protease involved in zymogen activation of granule-associated proteases, including granzymes A and B from cytotoxic T-lymphocytes and natural killer cells, cathepsin G and neutrophil elastase, and mast cell tryptase and chymase...... to 2.05 angstrom resolution to resolve apparent discrepancies between the complex structure and the previously published structure of the native enzyme. The new structure of the native enzyme is, within the experimental error, identical with the structure of the enzyme-inhibitor complex presented here...

  13. Structural and dynamical characterization of the pH-dependence of the pectin methylesterase-pectin methylesterase inhibitor complex.

    Science.gov (United States)

    Sénéchal, Fabien; Habrylo, Olivier; Hocq, Ludivine; Domon, Jean-Marc; Marcelo, Paulo; Lefebvre, Valérie; Pelloux, Jérôme; Mercadante, Davide

    2017-12-29

    Pectin methylesterases (PMEs) catalyze the demethylesterification of pectin, one of the main polysaccharides in the plant cell wall, and are of critical importance in plant development. PME activity generates highly negatively charged pectin and mutates the physiochemical properties of the plant cell wall such that remodeling of the plant cell can occur. PMEs are therefore tightly regulated by proteinaceous inhibitors (PMEIs), some of which become active upon changes in cellular pH. Nevertheless, a detailed picture of how this pH-dependent inhibition of PME occurs at the molecular level is missing. Herein, using an interdisciplinary approach that included homology modeling, MD simulations, and biophysical and biochemical characterizations, we investigated the molecular basis of PME3 inhibition by PMEI7 in Arabidopsis thaliana Our complementary approach uncovered how changes in the protonation of amino acids at the complex interface shift the network of interacting residues between intermolecular and intramolecular. These shifts ultimately regulate the stability of the PME3-PMEI7 complex and the inhibition of the PME as a function of the pH. These findings suggest a general model of how pH-dependent proteinaceous inhibitors function. Moreover, they enhance our understanding of how PMEs may be regulated by pH and provide new insights into how this regulation may control the physical properties and structure of the plant cell wall. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2

    Science.gov (United States)

    Morgunova, Ekaterina; Tuuttila, Ari; Bergmann, Ulrich; Tryggvason, Karl

    2002-01-01

    Matrix metalloproteinases (MMPs) are a family of multidomain enzymes involved in the physiological degradation of connective tissue, as well as in pathological states such as tumor invasion and arthritis. Apart from transcriptional regulation, MMPs are controlled by proenzyme activation and a class of specific tissue inhibitors of metalloproteinases (TIMPs) that bind to the catalytic site. TIMP-2 is a potent inhibitor of MMPs, but it has also been implicated in a unique cell surface activation mechanism of latent MMP-2/gelatinase A/type IV collagenase (proMMP-2), through its binding to the hemopexin domain of proMMP-2 on the one hand and to a membrane-type MMP activator on the other. The present crystal structure of the human proMMP-2/TIMP-2 complex reveals an interaction between the hemopexin domain of proMMP-2 and the C-terminal domain of TIMP-2, leaving the catalytic site of MMP-2 and the inhibitory site of TIMP-2 distant and spatially isolated. The interfacial contact of these two proteins is characterized by two distinct binding regions composed of alternating hydrophobic and hydrophilic interactions. This unique structure provides information for how specificity for noninhibitory MMP/TIMP complex formation is achieved. PMID:12032297

  15. 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

  16. 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.

  17. 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.

  18. Efficacy and safety of TNF-α inhibitors in refractory primary complex aphthosis

    DEFF Research Database (Denmark)

    Sand, Freja Lærke; Thomsen, Simon Francis

    2013-01-01

    Otherwise healthy patients with severe recurrent mucocutaneous aphthous ulcerations (complex aphthosis) may require systemic immunomodulatory therapy. However, a subset of patients remain resistant or intolerant to recommended therapeutic agents. Recently, case reports have described that tumor...

  19. L-glutamine Schiff base copper complex as a proteasome inhibitor and an apoptosis inducer in human cancer cells.

    Science.gov (United States)

    Xiao, Yan; Bi, Caifeng; Fan, Yuhua; Cui, Cindy; Zhang, Xia; Dou, Q Ping

    2008-11-01

    Interest in the use of metallic compounds for cancer treatment has been increasing since the discovery of cisplatin. Clinical studies suggest the use of proteasome inhibitors as potential novel anticancer agents. L-glutamine is the most abundant free amino acid in the body, and has been shown to play a regulatory role in several cellular processes, including metabolism, degradation, redox potential and cellular integrity. Although glutamine is reported to play a role in the regulation of apoptosis, the effect of glutamine copper complex on tumor cells and the involved molecular mechanism have not been investigated. Here, for the first time, we report that a newly synthesized L-glutamine-containing copper complex has proteasome-inhibitory activity in human breast cancer and leukemia cells. The inhibition of the tumor proteasomal activity results in the accumulation of ubiquitinated proteins and ubiquitinated form of IkappaB-alpha, a natural proteasome substrate, followed by induction of apoptosis. Furthermore, this glutamine Schiff base copper complex selectively inhibits the proteasomal activity and induces cell death in cultured breast cancer cells, but not normal, immortalized breast cells. Our data suggest that glutamine Schiff base copper complexes have a potential use for to be used in cancer treatment and prevention.

  20. Gas phase noncovalent protein complexes that retain solution binding properties: Binding of xylobiose inhibitors to the beta-1, 4 exoglucanase from cellulomonas fimi.

    Science.gov (United States)

    Tesić, Milica; Wicki, Jacqueline; Poon, David K Y; Withers, Stephen G; Douglas, Donald J

    2007-01-01

    Tandem mass spectrometry has been used to compare gas-phase and solution binding of three small-molecule inhibitors to the wild type and three mutant forms of the catalytic domain of Cex, an enzyme that hydrolyses xylan and xylo-oligosaccharides. The inhibitors, xylobiosyl-deoxynojirimycin, xylobiosyl-isofagomine lactam, and xylobiosyl-isofagomine consist of a common distal xylose linked to different proximal aza-sugars. The three mutant forms of the enzyme contain the substitutions Asn44Ala, Gln87Met, and Gln87Tyr that alter the binding interactions between Cex and the distal sugar of each inhibitor. An electrospray ionization (ESI) triple quadrupole MS/MS system is used to measure the internal energies, DeltaE(int), that must be added to gas-phase ions to cause dissociation of the noncovalent enzyme-inhibitor complexes. Collision cross sections of ions of the apo-enzyme and enzyme-inhibitor complexes, which are required for the calculations of DeltaE(int), have also been measured. The results show that, in the gas phase, enzyme-inhibitor complexes have more compact, folded conformations than the corresponding apo-enzyme ions. With the mutant enzymes, the effects of substituting a single residue can be detected. The energies required to dissociate the gas-phase complexes follow the same trend as the values of DeltaG0 for dissociation of the complexes in solution. This trend is observed both with different inhibitors, which probe binding to the proximal sugar, and with mutants of Cex, which probe binding to the distal sugar. Thus the gas-phase complexes appear to retain much of their solution binding characteristics.

  1. Solidarity under Attack

    DEFF Research Database (Denmark)

    Meret, Susi; Goffredo, Sergio

    2017-01-01

    https://www.opendemocracy.net/can-europe-make-it/susi-meret-sergio-goffredo/solidarity-under-attack......https://www.opendemocracy.net/can-europe-make-it/susi-meret-sergio-goffredo/solidarity-under-attack...

  2. Social engineering attack framework

    CSIR Research Space (South Africa)

    Mouton, F

    2014-07-01

    Full Text Available link. A social engineering attack targets this weakness by; using various manipulation techniques in order to elicit sensitive; information. The field of social engineering is still in its infancy; stages with regards to formal definitions and attack...

  3. Pericarditis - after heart attack

    Science.gov (United States)

    ... include: A previous heart attack Open heart surgery Chest trauma A heart attack that has affected the thickness of your heart muscle Symptoms Symptoms include: Anxiety Chest pain from the swollen pericardium rubbing on the ...

  4. 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 ...

  5. Transient Ischemic Attack

    Medline Plus

    Full Text Available ... Ischemic Attack TIA , or transient ischemic attack, is a "mini stroke" that occurs when a blood clot blocks an artery for a short time. The only difference between a stroke ...

  6. Mammalian Target of Rapamycin Inhibitor Induced Complete Remission of a Recurrent Subependymal Giant Cell Astrocytoma in a Patient Without Features of Tuberous Sclerosis Complex.

    Science.gov (United States)

    Appalla, Deepika; Depalma, Andres; Calderwood, Stanley

    2016-07-01

    The majority of patients with subependymal giant cell astrocytoma (SEGA) have tuberous sclerosis complex (TSC). In such patients, the mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to induce responses. Isolated SEGA have been reported in patients without clinical or genetic features of TSC. The treatment of these patients with everolimus has not previously been reported. We treated a patient with a recurrent isolated SEGA with an mTOR inhibitor. The patient tolerated therapy well and had a sustained complete remission. MTOR inhibitors may be useful for the treatment of isolated SEGA. Further study is warranted. © 2016 Wiley Periodicals, Inc.

  7. SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding.

    Science.gov (United States)

    Curtin, Michael L; Pliushchev, Marina A; Li, Huan-Qiu; Torrent, Maricel; Dietrich, Justin D; Jakob, Clarissa G; Zhu, Haizhong; Zhao, Hongyu; Wang, Ying; Ji, Zhiqin; Clark, Richard F; Sarris, Kathy A; Selvaraju, Sujatha; Shaw, Bailin; Algire, Mikkel A; He, Yupeng; Richardson, Paul L; Sweis, Ramzi F; Sun, Chaohong; Chiang, Gary G; Michaelides, Michael R

    2017-04-01

    Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. A Novel Phenanthridionone Based Scaffold As a Potential Inhibitor of the BRD2 Bromodomain: Crystal Structure of the Complex.

    Directory of Open Access Journals (Sweden)

    Shailesh Tripathi

    Full Text Available Bromodomain containing proteins recognize the level of histone acetylation and regulate epigenetically controlled processes like gene transcription and chromatin modification. The BET (bromodomain and extra-terminal family proteins, which are transcriptional co-regulators, have been implicated in the pathogenesis of cancer, neurodegenerative disorders, and defects in embryonic stem cell differentiation. Inhibitors selectively targeting the BET bromodomains can pave the path for new drug discovery against several forms of major diseases. By a rational structure-based approach, we have identified a new inhibitor (NSC127133 of the second bromodomain (BD2 of the BET family protein BRD2 using the NCI Diversity Set III library. A high-resolution crystal structure of the BRD2-BD2 in complex with this compound and in apo- form is refined to 0.91 and 0.94 Å, respectively. The compound, which is a phenanthridinone derivative, binds well to the acetyl-lysine binding pocket of BD2 and displays significant hydrophobic and hydrophilic interactions. Moreover, the atomic resolution data obtained in this study allowed us to visualize certain structural features of BD2 which remained unobserved so far. We propose that the discovered compound may be a potential molecule to develop a new library for inhibiting the BRD2-BD2 function.

  9. Recent Advances and Challenges of mTOR Inhibitors Use in the Treatment of Patients with Tuberous Sclerosis Complex

    Directory of Open Access Journals (Sweden)

    Filipe Palavra

    2017-01-01

    Full Text Available Tuberous sclerosis complex (TSC is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in the TSC1 and TSC2 genes, leading to the overactivation of the mammalian target of rapamycin (mTOR signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival. The establishment of a connection between TSC and mTOR led to the clinical use of drugs known as mTOR inhibitors (like rapamycin, also known as sirolimus and everolimus, which are becoming an increasingly interesting tool in the management of TSC-associated features, such as subependymal giant cell astrocytomas, renal angiomyolipomas, and also epilepsy. However, the intrinsic characteristics of these drugs and their systemic effects in such a heterogeneous condition pose many challenges in clinical practice, so that some questions remain unanswered. This article provides an overview of the pharmacological aspects of mTOR inhibitors about the clinical trials leading to their approval in TSC-related conditions and exposes current challenges and future directions associated with this promising therapeutic line.

  10. 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.

  11. Generation of complement molecular complex C5b-9 (C5b-9) in response to poly-traumatic hemorrhagic shock and evaluation of C5 cleavage inhibitors in non-human primates.

    Science.gov (United States)

    Paredes, R Madelaine; Reyna, Sarah; Vernon, Philip; Tadaki, Douglas K; Dallelucca, Jurandir J; Sheppard, Forest

    2018-01-01

    Severe trauma initiates a systemic inflammatory cascade and that involves early activation of complement and cleavage of C5 into C5a (anaphylatoxin) and C5b (C5b-9 membrane attack complex). We examined activation of C5 in non-human primate (NHP) models of hemorrhagic shock. Blood plasma concentrations of C5b-9 were significantly increased in NHPs in response to hemorrhage alone and were further increased with the addition of tissue trauma. The onset of increased C5 cleavage was accelerated in NHPs that experienced decompensated poly-traumatic hemorrhagic shock. Next, to identify an effective inhibitor of NHP C5 cleavage in vitro, as a first step in the development of a potential therapy, three inhibitors of human C5 cleavage and hemolysis were tested in vitro. NHP C5 cleavage and complement-mediated hemolysis were successfully inhibited by pre-treatment of serum samples with a small, inhibitory peptide RA101348. Commercially-available C5 inhibitory antibodies were found to exhibit species-specific efficacy in vitro. Quidel's A217 antibody demonstrated dose-dependent inhibition of C5 cleavage and hemolysis in NHP samples, whereas LGM-Eculizumab only inhibited complement-mediated hemolysis in human samples. This study shows that complement activation in NHPs following experimental poly-traumatic hemorrhagic shock is consistent with clinical reports, and that cleavage of C5 and complement-mediated hemolysis can be effectively inhibited in vitro using a small peptide inhibitor. Taken together, these findings offer a clinically-relevant vehicle and a potential strategy for treatment of hemorrhagic shock with poly-traumatic injury. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. RT-21Mre11-Rad50-Nbs1 COMPLEX INHIBITOR MIRIN ENHANCES RADIOSENSITIVITY IN HUMAN GLIOBLASTOMA CELLS

    Science.gov (United States)

    Mishima, Kazuhiko; Mishima-Kaneko, Masayo; Saya, Hideyuki; Ishimaru, Naozumi; Yamada, Kouichi; Fukada, Junichi; Nishikawa, Ryo; Kawata, Tetsuya

    2014-01-01

    PURPOSE: Radiation therapy plays a central part in the treatment of glioblastoma, however, it is not curative due to the high tumor radioresistance. Therefore, increasing the sensitivity of glioblastoma cells to radiation is a promising approach to improve survival in patients with glioblastoma. The Mre11, Rad 50 and Nbs1 proteins form a complex (MRN) that has a critical role in DNA damage detection and signaling. Because defects in MRN enhance radiosensitivity, it has been proposed that small molecule inhibitors targeted to these proteins might be used as radiosensitizers. Here, we investigated the effects of the MRN complex inhibitor, Mirin, on radiation response of human glioma cells. MATERIALS AND METHODS: Glioma cell lines (U251, LN229 and LN428) were irradiated with and without Mirin and then clonogenicity, apoptosis, and cell cycle change were examined. Western blot analysis was performed to determine the relative potency of Mirin to inhibit the radioresistance, through the signaling activity of AKT. We also examined the levels of H2AX phosphorylation (γH2AX), which is a marker of DNA double-strand breaks (DSBs) using Western blot. RESULTS: Glioblastoma cells pretreated with Mirin demonstrated an enhanced sensitivity to radiation. FACS analysis revealed that Mirin and radiation caused the glioma cells to accumulate in the G2/M-phase of the cell cycle and the combination of these two treatments further increased the G2/M fraction of the glioma cells. Mirin significantly enhanced radiation-induced apoptotic cell death. Also, Mirin blocked the basal and increase of radiation-induced AKT phosphorylation. We observed that the combination of Mirin and radiation increased persistence of γH2AX at 24 h suggesting the inhibition of DNA DSBs repair. CONCLUSION: These results indicate that Mirin can effectively enhance glioma cell radiosensitivity. It suggests that Mirin is a potent radiosensitizer for treating glioma cells.

  13. Daclatasvir: A NS5A Replication Complex Inhibitor for Hepatitis C Infection.

    Science.gov (United States)

    Smith, Michael A; Regal, Randolph E; Mohammad, Rima A

    2016-01-01

    To review the pharmacology, efficacy, and safety of daclatasvir in the treatment of patients with chronic hepatitis C virus (HCV) infection. A literature search through EMBASE and PubMed was conducted (January 1966 to August 2015) using the terms BMS-790052, daclatasvir, and hepatitis C. References from retrieved articles were reviewed for any additional material. Additionally, the new drug application and prescribing information were retrieved. The literature search was limited to human studies published in English. Phase 1, 2, and 3 studies describing the pharmacology, pharmacokinetics, efficacy, and safety of daclatasvir for HCV were identified. Daclatasvir, a nonstructural 5A protein inhibitor, combined with sofosbuvir, is indicated for adult patients with chronic HCV genotype 3 regardless of treatment or cirrhosis status. The phase III ALLY-3 trial (n = 152) demonstrated that daclatasvir taken once daily with sofosbuvir for 12 weeks was effective at achieving sustained virological response (SVR) rates in treatment-naïve (97%) and treatment-experienced (94%) patients without cirrhosis. Patients with cirrhosis had significantly lower SVR rates (58 and 69%, respectively). The most common adverse drug events associated with daclatasvir and sofosbuvir in ALLY-3 were headache (20%), fatigue (19%), and nausea (12%). Daclatasvir, when combined with sofosbuvir, is an effective agent to treat HCV genotype 3, with SVR rates above 90% for patients without cirrhosis who are treatment naïve or experienced. SVR rates for treatment-naïve or -experienced patients with cirrhosis are not as robust (58%-69%). © The Author(s) 2015.

  14. NGS Transcriptomes and Enzyme Inhibitors Unravel Complexity of Picrosides Biosynthesis in Picrorhiza kurroa Royle ex. Benth.

    Directory of Open Access Journals (Sweden)

    Kirti Shitiz

    Full Text Available Picrorhiza kurroa is an important medicinal herb valued for iridoid glycosides, Picroside-I (P-I and Picroside-II (P-II, which have several pharmacological activities. Genetic interventions for developing a picroside production platform would require knowledge on biosynthetic pathway and key control points, which does not exist as of today. The current study reports that geranyl pyrophosphate (GPP moiety is mainly contributed by the non-mevalonate (MEP route, which is further modified to P-I and P-II through phenylpropanoid and iridoid pathways, in total consisting of 41 and 35 enzymatic steps, respectively. The role of the MEP pathway was ascertained through enzyme inhibitors fosmidomycin and mevinolin along with importance of other integrating pathways using glyphosate, aminooxy acetic acid (AOA and actinomycin D, which overall resulted in 17%-92% inhibition of P-I accumulation. Retrieval of gene sequences for enzymatic steps from NGS transcriptomes and their expression analysis vis-à-vis picrosides content in different tissues/organs showed elevated transcripts for twenty genes, which were further shortlisted to seven key genes, ISPD, DXPS, ISPE, PMK, 2HFD, EPSPS and SK, on the basis of expression analysis between high versus low picrosides content strains of P. kurroa so as to eliminate tissue type/ developmental variations in picrosides contents. The higher expression of the majority of the MEP pathway genes (ISPD, DXPS and ISPE, coupled with higher inhibition of DXPR enzyme by fosmidomycin, suggested that the MEP route contributed to the biosynthesis of P-I in P. kurroa. The outcome of the study is expected to be useful in designing a suitable genetic intervention strategy towards enhanced production of picrosides. Possible key genes contributing to picroside biosynthesis have been identified with potential implications in molecular breeding and metabolic engineering of P. kurroa.

  15. NGS Transcriptomes and Enzyme Inhibitors Unravel Complexity of Picrosides Biosynthesis in Picrorhiza kurroa Royle ex. Benth.

    Science.gov (United States)

    Shitiz, Kirti; Sharma, Neha; Pal, Tarun; Sood, Hemant; Chauhan, Rajinder S

    2015-01-01

    Picrorhiza kurroa is an important medicinal herb valued for iridoid glycosides, Picroside-I (P-I) and Picroside-II (P-II), which have several pharmacological activities. Genetic interventions for developing a picroside production platform would require knowledge on biosynthetic pathway and key control points, which does not exist as of today. The current study reports that geranyl pyrophosphate (GPP) moiety is mainly contributed by the non-mevalonate (MEP) route, which is further modified to P-I and P-II through phenylpropanoid and iridoid pathways, in total consisting of 41 and 35 enzymatic steps, respectively. The role of the MEP pathway was ascertained through enzyme inhibitors fosmidomycin and mevinolin along with importance of other integrating pathways using glyphosate, aminooxy acetic acid (AOA) and actinomycin D, which overall resulted in 17%-92% inhibition of P-I accumulation. Retrieval of gene sequences for enzymatic steps from NGS transcriptomes and their expression analysis vis-à-vis picrosides content in different tissues/organs showed elevated transcripts for twenty genes, which were further shortlisted to seven key genes, ISPD, DXPS, ISPE, PMK, 2HFD, EPSPS and SK, on the basis of expression analysis between high versus low picrosides content strains of P. kurroa so as to eliminate tissue type/ developmental variations in picrosides contents. The higher expression of the majority of the MEP pathway genes (ISPD, DXPS and ISPE), coupled with higher inhibition of DXPR enzyme by fosmidomycin, suggested that the MEP route contributed to the biosynthesis of P-I in P. kurroa. The outcome of the study is expected to be useful in designing a suitable genetic intervention strategy towards enhanced production of picrosides. Possible key genes contributing to picroside biosynthesis have been identified with potential implications in molecular breeding and metabolic engineering of P. kurroa.

  16. Proteomic analysis reveals complex metabolic regulation in Saccharomyces cerevisiae cells against multiple inhibitors stress.

    Science.gov (United States)

    Lv, Ya-Jin; Wang, Xin; Ma, Qian; Bai, Xue; Li, Bing-Zhi; Zhang, Weiwen; Yuan, Ying-Jin

    2014-03-01

    Toxic compounds including acids, furans, and phenols (AFP) were generated from the pretreatment of lignocellulose. We cultivated Saccharomyces cerevisiae cells in a batch mode, besides the cell culture of original yeast strain in AFP-free medium which was referred as C0, three independent subcultures were cultivated under multiple inhibitors AFP and were referred as C1, C2, and C3 in time sequence. Comparing to C0, the cell density was lowered while the ethanol yield was maintained stably in the three yeast cultures under AFP stress, and the lag phase of C1 was extended while the lag phases of C2 and C3 were not extended. In proteomic analysis, 194 and 215 unique proteins were identified as differently expressed proteins at lag phase and exponential phase, respectively. Specifically, the yeast cells co-regulated protein folding and protein synthesis process to prevent the generation of misfolded proteins and to save cellular energy, they increased the activity of glycolysis, redirected metabolic flux towards phosphate pentose pathway and the biosynthesis of ethanol instead of the biosynthesis of glycerol and acetic acid, and they upregulated several oxidoreductases especially at lag phase and induced programmed cell death at exponential phase. When the yeast cells were cultivated under AFP stress, the new metabolism homeostasis in favor of cellular energy and redox homeostasis was generated in C1, then it was inherited and optimized in C2 and C3, enabling the yeast cells in C2 and C3 to enter the exponential phase in a short period after inoculation, which thus significantly shortened the fermentation time.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. Synthesis, crystal structure and biological evaluation of a new dasatinib copper(II) complex as telomerase inhibitor.

    Science.gov (United States)

    Qin, Qi-Pin; Meng, Ting; Tan, Ming-Xiong; Liu, Yan-Cheng; Luo, Xu-Jian; Zou, Bi-Qun; Liang, Hong

    2018-01-01

    A new copper(II) complex of dasatinib (DAS) was synthesized and characterized via ESI-MS, UV-Vis, IR, single-crystal X-ray diffraction analysis, 1 H and 13 C NMR spectroscopy, and elemental analysis. The composition of the new complex (1) was found to be [Cu(DAS + H)(NO 3 ) 2 (H 2 O)]NO 3 ·(H 2 O)·(CH 3 OH). Through MTT assay, it was found that 1 had high cytotoxicity towards A549, HeLa, BEL-7402, Hep-G2, NCI-H460, and MGC80-3 tumor cell lines, with IC 50 values in 4.04-13.04 μM. The Hep-G2 cells were the most sensitive to 1. It is worth noting that compared with DAS and cisplatin, 1 not only had higher in vitro anticancer activity but also exhibited greater selective toxicity towards Hep-G2 cells than for normal HL-7702 cells. Experimental results from cell apoptosis analysis, cellular uptake, TRAP-silver staining assay, RT-PCR, western blot, and transfection assays showed that 1 was most likely a telomerase inhibitor that targeted c-myc G-quadruplex DNA. The high cytotoxicity and biological behaviors of 1 could be correlated with the central copper(II) atom in the coordinated mode with DAS. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. 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.

  3. Structures of the Peptidoglycan N-Acetylglucosamine Deacetylase Bc1974 and Its Complexes with Zinc Metalloenzyme Inhibitors.

    Science.gov (United States)

    Giastas, Petros; Andreou, Athena; Papakyriakou, Athanasios; Koutsioulis, Dimitris; Balomenou, Stavroula; Tzartos, Socrates J; Bouriotis, Vassilis; Eliopoulos, Elias E

    2018-01-05

    The cell wall peptidoglycan is recognized as a primary target of the innate immune system, and usually its disintegration results in bacterial lysis. Bacillus cereus, a close relative of the highly virulent Bacillus anthracis, contains 10 polysaccharide deacetylases. Among these, the peptidoglycan N-acetylglucosamine deacetylase Bc1974 is the highest homologue to the Bacillus anthracis Ba1977 that is required for full virulence and is involved in resistance to the host's lysozyme. These metalloenzymes belong to the carbohydrate esterase family 4 (CE4) and are attractive targets for the development of new anti-infective agents. Herein we report the first X-ray crystal structures of the NodB domain of Bc1974, the conserved catalytic core of CE4s, in the unliganded form and in complex with four known metalloenzyme inhibitors and two amino acid hydroxamates that target the active site metal. These structures revealed the presence of two conformational states of a catalytic loop known as motif-4 (MT4), which were not observed previously for peptidoglycan deacetylases, but were recently shown in the structure of a Vibrio clolerae chitin deacetylase. By employing molecular docking of a substrate model, we describe a catalytic mechanism that probably involves initial binding of the substrate in a receptive, more open state of MT4 and optimal catalytic activity in the closed state of MT4, consistent with the previous observations. The ligand-bound structures presented here, in addition to the five Bc1974 inhibitors identified, provide a valuable basis for the design of antibacterial agents that target the peptidoglycan deacetylase Ba1977.

  4. Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf-DAPK Complex by Raf Inhibitor Combination Therapy.

    Science.gov (United States)

    Tsai, Yi-Ta; Chuang, Mei-Jen; Tang, Shou-Hung; Wu, Sheng-Tang; Chen, Yu-Chi; Sun, Guang-Huan; Hsiao, Pei-Wen; Huang, Shih-Ming; Lee, Hwei-Jen; Yu, Cheng-Ping; Ho, Jar-Yi; Lin, Hui-Kuan; Chen, Ming-Rong; Lin, Chung-Chih; Chang, Sun-Yran; Lin, Victor C; Yu, Dah-Shyong; Cha, Tai-Lung

    2015-09-01

    Mitochondria are the powerhouses of cells. Mitochondrial C-Raf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its N-terminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf(S338)) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPK(S308)), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEF(C-Raf-/-) or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity. In the presence of pDAPK(S308), this drug-target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-Raf(S338) and pDAPK(S308) translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPK(S308) to DAPK. PP2A then dissociated from the C-Raf-DAPK complex and induced profound cancer cell death. Increased pDAPK(S308) modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPK(S308) may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation. ©2015 American Association for Cancer Research.

  5. 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. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED.

    Directory of Open Access Journals (Sweden)

    Ling Li

    Full Text Available Polycomb repressive complex 2 (PRC2, a histone H3 lysine 27 methyltransferase, plays a key role in gene regulation and is a known epigenetics drug target for cancer therapy. The WD40 domain-containing protein EED is the regulatory subunit of PRC2. It binds to the tri-methylated lysine 27 of the histone H3 (H3K27me3, and through which stimulates the activity of PRC2 allosterically. Recently, we disclosed a novel PRC2 inhibitor EED226 which binds to the K27me3-pocket on EED and showed strong antitumor activity in xenograft mice model. Here, we further report the identification and validation of four other EED binders along with EED162, the parental compound of EED226. The crystal structures for all these five compounds in complex with EED revealed a common deep pocket induced by the binding of this diverse set of compounds. This pocket was created after significant conformational rearrangement of the aromatic cage residues (Y365, Y148 and F97 in the H3K27me3 binding pocket of EED, the width of which was delineated by the side chains of these rearranged residues. In addition, all five compounds interact with the Arg367 at the bottom of the pocket. Each compound also displays unique features in its interaction with EED, suggesting the dynamics of the H3K27me3 pocket in accommodating the binding of different compounds. Our results provide structural insights for rational design of novel EED binder for the inhibition of PRC2 complex activity.

  7. Structure of the Neisseria Adhesin Complex Protein (ACP) and its role as a novel lysozyme inhibitor

    Science.gov (United States)

    Lian, Lu-Yun

    2017-01-01

    Pathogenic and commensal Neisseria species produce an Adhesin Complex Protein, which was first characterised in Neisseria meningitidis (Nm) as a novel surface-exposed adhesin with vaccine potential. In the current study, the crystal structure of a recombinant (r)Nm-ACP Type I protein was determined to 1.4 Å resolution: the fold resembles an eight-stranded β-barrel, stabilized by a disulphide bond between the first (Cys38) and last (Cys121) β-strands. There are few main-chain hydrogen bonds linking β4-β5 and β8-β1, so the structure divides into two four-stranded anti-parallel β-sheets (β1-β4 and β5-β8). The computed surface electrostatic charge distribution showed that the β1-β4 sheet face is predominantly basic, whereas the β5-β8 sheet is apolar, apart from the loop between β4 and β5. Concentrations of rNm-ACP and rNeisseria gonorrhoeae-ACP proteins ≥0.25 μg/ml significantly inhibited by ~80–100% (PNeisseria ACP sera to block ACP inhibition and restore HL activity. ACP expression conferred tolerance to HL activity, as demonstrated by significant 3–9 fold reductions (PNeisseria lactamica treated with purified ACP-specific rabbit IgG antibodies showed similar fold reductions in bacterial growth, compared with untreated bacteria (PNeisseria ACP proteins show Neisseria ACP adopts a different mode of lysozyme inhibition and that the ability of ACP to inhibit lysozyme activity could be important for host colonization by both pathogenic and commensal Neisseria organisms. Thus, ACP represents a dual target for developing Neisseria vaccines and drugs to inhibit host-pathogen interactions. PMID:28662181

  8. Nocturnal panic attacks

    OpenAIRE

    Lopes Fabiana L.; Nardi Antonio E.; Nascimento Isabella; Valença Alexandre M.; Zin Walter A

    2002-01-01

    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 sle...

  9. 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.

  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. Transient Ischemic Attack

    Medline Plus

    Full Text Available ... stroke symptoms. Popular Topics TIA Cardiac Catheter Cholesterol Heart Attack Stent © 2018, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. ...

  12. 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

  13. 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

  14. 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

  15. Heart attack - discharge

    Science.gov (United States)

    ... attack Heart bypass surgery Heart bypass surgery - minimally invasive Heart pacemaker High blood cholesterol levels High blood pressure Implantable cardioverter-defibrillator Smoking - tips on how to ...

  16. Transient Ischemic Attack

    Medline Plus

    Full Text Available ... stroke symptoms. Popular Topics TIA Cardiac Catheter Cholesterol Heart Attack Stent © 2017, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. ...

  17. Application of Polyelectrolyte Complex Nanoparticles in Increasing the Lifetime of Poly(Vinyl Sulfonate) Scale Inhibitor in Berea Sandstone Rock

    Science.gov (United States)

    Veisi, Masoumeh

    Water flooding is used extensively in oil fields to maintain reservoir pressure and displace oil. However, seawater containing high concentrations of sulfate ion may form scale precipitate when mixed with incompatible formation water containing barium and strontium ions. Formation of scales such as barium sulfate can pose costly operational problems by plugging the injection and production wells. Polymers such as poly(vinyl sulfonate) (PVS) are well-known scale inhibitors which can effectively prevent the formation of barium sulfate. Squeeze treatment is a common method which can be used to inject the PVS in the reservoir. In this process, PVS solution is injected into production wells and the inhibitor is adsorbed on reservoir rocks and released during subsequent production of reservoir fluids. Once inhibitor concentration decreases to its minimum effective concentration (MEC), the process needs to be repeated. However, the low adsorption of PVS onto the rock results in a very short squeeze lifetime rendering the treatment uneconomical. In this research, the application of polyelectrolyte complexes (PECs) to increase the squeeze treatment lifetime of PVS was examined. The objective of the project was to develop PEC nanoparticles (NPs) which would improve the PVS adsorption on the rock through charge alteration. The PECs entrapped the PVS in their structure and released the polymer gradually when pH or ionic strength of the surrounding brine increased. PVS adsorption followed by a slow release of the polymer can maintain the scale inhibitor concentration above MEC for longer, and therefore extend the squeeze treatment lifetime. Positively charged nanoparticles consisting of poly(ethyleneimine) and poly(vinyl sulfonate) (PEI-PVS) were prepared and optimized to maximize PVS entrapment in the PEC structure. The stability of the nanoparticles at different temperatures and over time was confirmed. Their stability in the presence of mono and divalent cations was also

  18. Crystal structures of Leishmania mexicana arginase complexed with α,α-disubstituted boronic amino-acid inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Hai, Yang; Christianson, David W.

    2016-03-16

    Leishmaniaarginase is a potential drug target for the treatment of leishmaniasis because this binuclear manganese metalloenzyme initiatesde novopolyamine biosynthesis by catalyzing the hydrolysis of L-arginine to generate L-ornithine and urea. The product L-ornithine subsequently undergoes decarboxylation to yield putrescine, which in turn is utilized for spermidine biosynthesis. Polyamines such as spermidine are essential for the growth and survival of the parasite, so inhibition of enzymes in the polyamine-biosynthetic pathway comprises an effective strategy for treating parasitic infections. To this end, two X-ray crystal structures ofL. mexicanaarginase complexed with α,α-disubstituted boronic amino-acid inhibitors based on the molecular scaffold of 2-(S)-amino-6-boronohexanoic acid are now reported. Structural comparisons with human and parasitic arginase complexes reveal interesting differences in the binding modes of the additional α-substituents,i.e.the D side chains, of these inhibitors. Subtle differences in the three-dimensional contours of the outer active-site rims among arginases from different species lead to different conformations of the D side chains and thus different inhibitor-affinity trends. The structures suggest that it is possible to maintain affinity while fine-tuning intermolecular interactions of the D side chain of α,α-disubstituted boronic amino-acid inhibitors in the search for isozyme-specific and species-specific arginase inhibitors.

  19. Enzyme-coupled nanoparticles-assisted laser desorption ionization mass spectrometry for searching for low-mass inhibitors of enzymes in complex mixtures.

    Science.gov (United States)

    Salwiński, Aleksander; Da Silva, David; Delépée, Raphaël; Maunit, Benoît

    2014-04-01

    In this report, enzyme-coupled magnetic nanoparticles (EMPs) were shown to be an effective affinity-based tool for finding specific interactions between enzymatic targets and the low-mass molecules in complex mixtures using classic MALDI-TOF apparatus. EMPs used in this work act as nonorganic matrix enabling ionization of small molecules without any interference in the low-mass range (enzyme-coupled nanoparticles-assisted laser desorption ionization MS, ENALDI MS) and simultaneously carry the superficial specific binding sites to capture inhibitors present in a studied mixture. We evaluated ENALDI approach in two complementary variations: 'ion fading' (IF-ENALDI), based on superficial adsorption of inhibitors and 'ion hunting' (IH-ENALDI), based on selective pre-concentration of inhibitors. IF-ENALDI was applied for two sets of enzyme-inhibitor pairs: tyrosinase-glabridin and trypsin-leupeptin and for the real plant sample: Sparrmannia discolor leaf and stem methanol extract. The efficacy of IH-ENALDI was shown for the pair of trypsin-leupeptin. Both ENALDI approaches pose an alternative for bioassay-guided fractionation, the common method for finding inhibitors in the complex mixtures.

  20. A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

    Science.gov (United States)

    Beautrait, Alexandre; Paradis, Justine S.; Zimmerman, Brandon; Giubilaro, Jenna; Nikolajev, Ljiljana; Armando, Sylvain; Kobayashi, Hiroyuki; Yamani, Lama; Namkung, Yoon; Heydenreich, Franziska M.; Khoury, Etienne; Audet, Martin; Roux, Philippe P.; Veprintsev, Dmitry B.; Laporte, Stéphane A.; Bouvier, Michel

    2017-04-01

    In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

  1. Contact activation and factor VII after the use of an activated prothrombin complex concentrate (FEIBA) in hemophiliacs with inhibitors.

    Science.gov (United States)

    Mariani, G; Bouma, B N; Mazzucconi, M G; Avvisati, G; Di Nucci, G D; Corrao, D; Mandelli, F

    1983-08-01

    Administration of a brand of activated prothrombin complex concentrate (FEIBA) to hemophiliacs with high-titre inhibitor to factor VIII, induced a shortening of the prothrombin time and thrombotest clotting time. This effect stems partly from the presence in the concentrate of high amounts of activated factor VII (alpha-VII a) which indeed after the infusion, were detected in the plasma of Hemophiliacs. The attained levels of factor alpha-VII a were shown to be proportional to the dose of concentrate administered. This form of activated factor VII was not generated as a result of activation of the contact activation mechanism, since after the infusion of the concentrate no changes were detected in the components of this system. The infused factor VII was indeed present in an activated form and this was further substantiated by the infusion of the concentrate in factor VII deficient patients. These observations suggest that factor alpha-VII a is not generated in vivo and thus is of exogenous origin. The clinical effect may well be due to the presence of this form of activated factor VII; in this context the alternative pathway involving factors IX and X should be implicated.

  2. Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening

    Science.gov (United States)

    Orr, Adam L.; Ashok, Deepthi; Sarantos, Melissa R.; Shi, Tong; Hughes, Robert E.; Brand, Martin D.

    2013-01-01

    Mitochondrial production of reactive oxygen species is often considered an unavoidable consequence of aerobic metabolism and currently cannot be manipulated without perturbing oxidative phosphorylation. Antioxidants are widely used to suppress effects of reactive oxygen species after formation, but they can never fully prevent immediate effects at the sites of production. To identify site-selective inhibitors of mitochondrial superoxide/H2O2 production that do not interfere with mitochondrial energy metabolism, we developed a robust small-molecule screen and secondary profiling strategy. We describe the discovery and characterization of a compound (N-cyclohexyl-4-(4-nitrophenoxy)benzenesulfonamide; CN-POBS) that selectively inhibits superoxide/H2O2 production from the ubiquinone-binding site of complex I (site IQ) with no effects on superoxide/H2O2 production from other sites or on oxidative phosphorylation. Structure/activity studies identified a core structure that is important for potency and selectivity for site IQ. By employing CN-POBS in mitochondria respiring on NADH-generating substrates, we show that site IQ does not produce significant amounts of superoxide/H2O2 during forward electron transport on glutamate plus malate. Our screening platform promises to facilitate further discovery of direct modulators of mitochondrially-derived oxidative damage and advance our ability to understand and manipulate mitochondrial reactive oxygen species production in both normal and pathological conditions. PMID:23994103

  3. 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. 

  4. 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.

  5. Transient Ischemic Attack

    Medline Plus

    Full Text Available Transient Ischemic Attack TIA , or transient ischemic attack, is a "mini stroke" that occurs when a blood clot blocks an artery for a short time. The only ... TIA is that with TIA the blockage is transient (temporary). TIA symptoms occur rapidly and last a ...

  6. Structure of a Dihydroxycoumarin Active-Site Inhibitor in Complex with the RNase H Domain of HIV-1 Reverse Transcriptase and Structure-Activity Analysis of Inhibitor Analogs

    Science.gov (United States)

    Himmel, Daniel M.; Myshakina, Nataliya S.; Ilina, Tatiana; Van Ry, Alexander; Ho, William C.; Parniak, Michael A.; Arnold, Eddy

    2014-01-01

    HIV encodes four essential enzymes: protease, integrase, reverse transcriptase (RT) associated DNA polymerase, and RT-associated ribonuclease H (RNase H). Current clinically approved anti-AIDS drugs target all HIV enzymatic activities except RNase H, which has proven to be a very difficult target for HIV drug discovery. Our high-throughput screening activities identified the dihydroxycoumarin compound F3284-8495 as a specific inhibitor of RT RNase H, with low micromolar potency in vitro. Optimization of inhibitory potency can be facilitated by structural information about inhibitor-target binding. Here, we report the crystal structure of F3284-8495 bound to the active site of an isolated RNase H domain of HIV-1 RT at a resolution limit of 1.71 Å. From predictions based on this structure, compounds were obtained that showed improved inhibitory activity. Computational analysis suggested structural alterations that could provide additional interactions with RT and thus improve inhibitory potency. These studies established proof-of-concept that F3284-8495 could be used as a favorable chemical scaffold for development of HIV RNase H inhibitors. PMID:24840303

  7. Reactivity trends of hydroxide ion attack on high spin Fe(II complexes including bromosalicylidene amino acid ligands in some mixed aqueous solvents: Gibb’s Free Energy of Transfer and initial-transition state analysis

    Directory of Open Access Journals (Sweden)

    Laila H. Abdel-Rahman

    2017-05-01

    Full Text Available The kinetics of hydroxide ion attack on bis(bromosalicylidene alanateiron (II (bsali, bis(bromosalicylidene phenylalanateiron(II (bsphali, bis(bromosalicylidene aspartateiron(II (bsasi, (bromosalicylidene histidinateiron(II (bshi, bis(bromosalicylidene arginateiron(II (bsari have been reported in different binary aqueous solvent mixtures at 298 K. The observed reactivity trends are discussed in terms of the hydrophilic and hydrophobic forms of the complexes investigated, as well as the transfer chemical potentials of hydroxide ion and the complex. Both the solvent–solute and solvent–solvent interactions have been considered. The hydrophobic character of the complexes studied was manifested by decreasing in reactivity. Solvent effect on reactivity trends of the investigated complexes has been analyzed into initial and transition state components by using the transfer chemical potentials of the reactants and the kinetic data of the studied compounds. The decrease in the observed rate constant values (kobs of the base hydrolysis of the investigated complexes with increasing of solvent % is dominated by the initial state (IS.

  8. 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.

  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

    OpenAIRE

    Claudiu T. Supuran

    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 agai...

  10. 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.

  11. Modelling Social-Technical Attacks with Timed Automata

    DEFF Research Database (Denmark)

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

    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 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...... 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....

  12. 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.

    Science.gov (United States)

    Coimbra, Norberto C; Paschoalin-Maurin, Tatiana; Bassi, Gabriel S; Kanashiro, Alexandre; Biagioni, Audrey F; Felippotti, Tatiana T; Elias-Filho, Daoud H; Mendes-Gomes, Joyce; Cysne-Coimbra, Jade P; Almada, Rafael C; Lobão-Soares, Bruno

    2017-01-01

    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. 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. 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. 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.

  13. Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains.

    Science.gov (United States)

    Williams, Neal K; Bamert, Rebecca S; Patel, Onisha; Wang, Christina; Walden, Patricia M; Wilks, Andrew F; Fantino, Emmanuelle; Rossjohn, Jamie; Lucet, Isabelle S

    2009-03-20

    The Janus kinases (JAKs) are a pivotal family of protein tyrosine kinases (PTKs) that play prominent roles in numerous cytokine signaling pathways, with aberrant JAK activity associated with a variety of hematopoietic malignancies, cardiovascular diseases and immune-related disorders. Whereas the structures of the JAK2 and JAK3 PTK domains have been determined, the structure of the JAK1 PTK domain is unknown. Here, we report the high-resolution crystal structures of the "active form" of the JAK1 PTK domain in complex with two JAK inhibitors, a tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one (CMP6) and (3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile (CP-690,550), and compare them with the corresponding JAK2 PTK inhibitor complexes. Both inhibitors bound in a similar manner to JAK1, namely buried deep within a constricted ATP-binding site, thereby providing a basis for the potent inhibition of JAK1. As expected, the mode of inhibitor binding in JAK1 was very similar to that observed in JAK2, highlighting the challenges in developing JAK-specific inhibitors that target the ATP-binding site. Nevertheless, differences surrounding the JAK1 and JAK2 ATP-binding sites were apparent, thereby providing a platform for the rational design of JAK2- and JAK1-specific inhibitors.

  14. 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.

  15. 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.

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

    DEFF Research Database (Denmark)

    Khovratovich, Dmitry; Rechberger, Christian

    2014-01-01

    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. 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 < 0.05) vs. baseline. General pain was significantly reduced during prophylaxis at each follow-up (mean improvement, 20.3 and 23.2, respectively; both P <0.05). At 12 months, prophylaxis subjects achieved significant improvements in Haem-A-QoL Total Score and in four domains: Physical Health, Feeling, View, and Work and School (all P < 0.05). No statistically significant changes, except for Haem-A-QoL Physical Health at 6 months, were observed with on-demand treatment. ABR was decreased by 72.5% with prophylaxis vs. on-demand treatment (P = 0.0003) and reduced ABR was associated with better physical HRQoL (P < 0.05). FEIBA prophylaxis significantly reduced ABR and improved HRQoL in inhibitor patients. Subjects with lower ABR reported better physical HRQoL. © 2014 John Wiley & Sons Ltd.

  18. 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...

  19. 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...

  20. 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 ...

  1. Transient Ischemic Attack

    Medline Plus

    Full Text Available ... immediately for any stroke symptoms. Popular Topics TIA Cardiac Catheter Cholesterol Heart Attack Stent © 2018, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. ...

  2. 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...

  3. 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.

  4. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Facial Dog Attack Injuries

    OpenAIRE

    Lin, Wei; Patil, Pavan Manohar

    2013-01-01

    The exposed position of the face makes it vulnerable to dog bite injuries. This fact combined with the short stature of children makes them a high-risk group for such attacks. In contrast to wounds inflicted by assaults and accidents, dog bite wounds are deep puncture type wounds compounded by the presence of pathologic bacteria from the saliva of the attacking dog. This, combined with the presence of crushed, devitalized tissue makes these wounds highly susceptible to infection. Key to succe...

  6. Launch under attack

    Energy Technology Data Exchange (ETDEWEB)

    Steinbruner, J.

    1984-01-01

    The strategy of launch under attack calls for launching nuclear weapons on warning that attacking weapons are on their way. The political pressures for adopting this strategy are symptomatic of an increasing instability in the nuclear balance. The author describes a Brookings Institute model, which indicates that the problems of decentralized control and precise timing could lead to failures in retargeting procedures. The major concern is that the strategy imposes powerful incentives for preemption as the most promising means of conducting nuclear war.

  7. 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.

  8. Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2

    OpenAIRE

    Morgunova, Ekaterina; Tuuttila, Ari; Bergmann, Ulrich; Tryggvason, Karl

    2002-01-01

    Matrix metalloproteinases (MMPs) are a family of multidomain enzymes involved in the physiological degradation of connective tissue, as well as in pathological states such as tumor invasion and arthritis. Apart from transcriptional regulation, MMPs are controlled by proenzyme activation and a class of specific tissue inhibitors of metalloproteinases (TIMPs) that bind to the catalytic site. TIMP-2 is a potent inhibitor of MMPs, but it has also been implicated in a unique cell surface activatio...

  9. A forward chemical genetic screen reveals an inhibitor of the Mre11–Rad50–Nbs1 complex

    Science.gov (United States)

    Dupré, Aude; Boyer-Chatenet, Louise; Sattler, Rose M; Modi, Ami P; Lee, Ji-Hoon; Nicolette, Matthew L; Kopelovich, Levy; Jasin, Maria; Baer, Richard; Paull, Tanya T; Gautier, Jean

    2009-01-01

    The MRN (Mre11-Rad50-Nbs1)-ATM (ataxia-telangiectasia mutated) pathway is essential for sensing and signaling from DNA double-strand breaks. The MRN complex acts as a DNA damage sensor, maintains genome stability during DNA replication, promotes homology-dependent DNA repair and activates ATM. MRN is essential for cell viability, which has limited functional studies of the complex. Small-molecule inhibitors of MRN could circumvent this experimental limitation and could also be used as cellular radio- and chemosensitization compounds. Using cell-free systems that recapitulate faithfully the MRN-ATM signaling pathway, we designed a forward chemical genetic screen to identify inhibitors of the pathway, and we isolated Z-5-(4-hydroxybenzylidene)-2-imino-1,3-thiazolidin-4-one (mirin, 1) as an inhibitor of MRN. Mirin prevents MRN-dependent activation of ATM without affecting ATM protein kinase activity, and it inhibits Mre11-associated exonuclease activity. Consistent with its ability to target the MRN complex, mirin abolishes the G2/M checkpoint and homology-dependent repair in mammalian cells. PMID:18176557

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. Robustness of non-interdependent and interdependent networks against dependent and adaptive attacks

    Science.gov (United States)

    Tyra, Adam; Li, Jingtao; Shang, Yilun; Jiang, Shuo; Zhao, Yanjun; Xu, Shouhuai

    2017-09-01

    Robustness of complex networks has been extensively studied via the notion of site percolation, which typically models independent and non-adaptive attacks (or disruptions). However, real-life attacks are often dependent and/or adaptive. This motivates us to characterize the robustness of complex networks, including non-interdependent and interdependent ones, against dependent and adaptive attacks. For this purpose, dependent attacks are accommodated by L-hop percolation where the nodes within some L-hop (L ≥ 0) distance of a chosen node are all deleted during one attack (with L = 0 degenerating to site percolation). Whereas, adaptive attacks are launched by attackers who can make node-selection decisions based on the network state in the beginning of each attack. The resulting characterization enriches the body of knowledge with new insights, such as: (i) the Achilles' Heel phenomenon is only valid for independent attacks, but not for dependent attacks; (ii) powerful attack strategies (e.g., targeted attacks and dependent attacks, dependent attacks and adaptive attacks) are not compatible and cannot help the attacker when used collectively. Our results shed some light on the design of robust complex networks.

  15. Cyber Attacks, Information Attacks, and Postmodern Warfare

    Directory of Open Access Journals (Sweden)

    Valuch Jozef

    2017-06-01

    Full Text Available The aim of this paper is to evaluate and differentiate between the phenomena of cyberwarfare and information warfare, as manifestations of what we perceive as postmodern warfare. We describe and analyse the current examples of the use the postmodern warfare and the reactions of states and international bodies to these phenomena. The subject matter of this paper is the relationship between new types of postmodern conflicts and the law of armed conflicts (law of war. Based on ICJ case law, it is clear that under current legal rules of international law of war, cyber attacks as well as information attacks (often performed in the cyberspace as well can only be perceived as “war” if executed in addition to classical kinetic warfare, which is often not the case. In most cases perceived “only” as a non-linear warfare (postmodern conflict, this practice nevertheless must be condemned as conduct contrary to the principles of international law and (possibly a crime under national laws, unless this type of conduct will be recognized by the international community as a “war” proper, in its new, postmodern sense.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. False Positive and False Negative Effects on Network Attacks

    Science.gov (United States)

    Shang, Yilun

    2017-11-01

    Robustness against attacks serves as evidence for complex network structures and failure mechanisms that lie behind them. Most often, due to detection capability limitation or good disguises, attacks on networks are subject to false positives and false negatives, meaning that functional nodes may be falsely regarded as compromised by the attacker and vice versa. In this work, we initiate a study of false positive/negative effects on network robustness against three fundamental types of attack strategies, namely, random attacks (RA), localized attacks (LA), and targeted attack (TA). By developing a general mathematical framework based upon the percolation model, we investigate analytically and by numerical simulations of attack robustness with false positive/negative rate (FPR/FNR) on three benchmark models including Erdős-Rényi (ER) networks, random regular (RR) networks, and scale-free (SF) networks. We show that ER networks are equivalently robust against RA and LA only when FPR equals zero or the initial network is intact. We find several interesting crossovers in RR and SF networks when FPR is taken into consideration. By defining the cost of attack, we observe diminishing marginal attack efficiency for RA, LA, and TA. Our finding highlights the potential risk of underestimating or ignoring FPR in understanding attack robustness. The results may provide insights into ways of enhancing robustness of network architecture and improve the level of protection of critical infrastructures.

  2. False Positive and False Negative Effects on Network Attacks

    Science.gov (United States)

    Shang, Yilun

    2018-01-01

    Robustness against attacks serves as evidence for complex network structures and failure mechanisms that lie behind them. Most often, due to detection capability limitation or good disguises, attacks on networks are subject to false positives and false negatives, meaning that functional nodes may be falsely regarded as compromised by the attacker and vice versa. In this work, we initiate a study of false positive/negative effects on network robustness against three fundamental types of attack strategies, namely, random attacks (RA), localized attacks (LA), and targeted attack (TA). By developing a general mathematical framework based upon the percolation model, we investigate analytically and by numerical simulations of attack robustness with false positive/negative rate (FPR/FNR) on three benchmark models including Erdős-Rényi (ER) networks, random regular (RR) networks, and scale-free (SF) networks. We show that ER networks are equivalently robust against RA and LA only when FPR equals zero or the initial network is intact. We find several interesting crossovers in RR and SF networks when FPR is taken into consideration. By defining the cost of attack, we observe diminishing marginal attack efficiency for RA, LA, and TA. Our finding highlights the potential risk of underestimating or ignoring FPR in understanding attack robustness. The results may provide insights into ways of enhancing robustness of network architecture and improve the level of protection of critical infrastructures.

  3. 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.

  4. Human kallikrein 2 (hK2), but not prostate-specific antigen (PSA), rapidly complexes with protease inhibitor 6 (PI-6) released from prostate carcinoma cells.

    Science.gov (United States)

    Saedi, M S; Zhu, Z; Marker, K; Liu, R S; Carpenter, P M; Rittenhouse, H; Mikolajczyk, S D

    2001-11-01

    Human kallikrein 2 (hK2) is a secreted, trypsin-like protease that shares 80% amino acid sequence identity with prostate-specific antigen (PSA). hK2 has been shown to be a serum marker for prostate cancer and may also play a role in cancer progression and metastasis. We have previously identified a novel complex between human kallikrein 2 (hK2) and protease inhibitor 6 (PI-6) in prostate cancer tissue. PI-6 is an intracellular serine protease inhibitor with both antitrypsin and antichymotrypsin activity. In the current study we have shown that PI-6 forms a rapid in vitro complex with hK2 but does not complex with PSA. Recombinant mammalian cells expressing both hK2 and PI-6 showed hK2-PI-6 complex in the spent media only after cell death and lysis. Similarly, LNCaP cells expressing endogenous hK2 and PI-6 showed extracellular hK2-PI-6 complex formation concurrently with cell death. Immunostaining of prostate cancer tissues with PI-6 monoclonal antibodies showed a marked preferential staining pattern in cancerous epithelial cells compared with noncancerous tissue. These results indicate that the hK2-PI-6 complex may be a naturally occurring marker of tissue damage and necrosis associated with neoplasia. Both hK2 and PI-6 were shed into the lumen of prostate cancer glands as granular material that appeared to be cellular necrotic debris. The differential staining pattern of PI6 in tissues suggests a complex regulation of PI-6 expression that may play a role in other aspects of neoplastic progression. Copyright 2001 Wiley-Liss, Inc.

  5. Heart Attack Recovery FAQs

    Science.gov (United States)

    ... smolder — that can be destructive. If you think counseling would help your family deal with your heart attack more ... your lifestyle habits through exercise training, education and counseling to ... or with the help of your doctor, nurse, dietitian or other healthcare ...

  6. Fatal crocodile attack.

    Science.gov (United States)

    Chattopadhyay, Saurabh; Shee, Biplab; Sukul, Biswajit

    2013-11-01

    Attacks on human beings by various animals leading to varied types of injuries and even death in some cases are not uncommon. Crocodile attacks on humans have been reported from a number of countries across the globe. Deaths in such attacks are mostly due to mechanical injuries or drowning. Bites by the crocodiles often cause the limbs to be separated from the body. The present case refers to an incident of a fatal attack by a crocodile on a 35 years old female where only the mutilated head of the female was recovered. Multiple lacerated wounds over the face and scalp along with fracture of the cranial bones was detected on autopsy. Two distinct bite marks in the form of punched in holes were noted over the parietal and frontal bones. Injuries on the head with its traumatic amputation from the body were sufficient to cause death. However, the presence of other fatal injuries on the unrecovered body parts could not be ruled out. Copyright © 2013 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

  7. Temporal Cyber Attack Detection.

    Energy Technology Data Exchange (ETDEWEB)

    Ingram, Joey Burton [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Draelos, Timothy J. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Galiardi, Meghan [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Doak, Justin E. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2017-11-01

    Rigorous characterization of the performance and generalization ability of cyber defense systems is extremely difficult, making it hard to gauge uncertainty, and thus, confidence. This difficulty largely stems from a lack of labeled attack data that fully explores the potential adversarial space. Currently, performance of cyber defense systems is typically evaluated in a qualitative manner by manually inspecting the results of the system on live data and adjusting as needed. Additionally, machine learning has shown promise in deriving models that automatically learn indicators of compromise that are more robust than analyst-derived detectors. However, to generate these models, most algorithms require large amounts of labeled data (i.e., examples of attacks). Algorithms that do not require annotated data to derive models are similarly at a disadvantage, because labeled data is still necessary when evaluating performance. In this work, we explore the use of temporal generative models to learn cyber attack graph representations and automatically generate data for experimentation and evaluation. Training and evaluating cyber systems and machine learning models requires significant, annotated data, which is typically collected and labeled by hand for one-off experiments. Automatically generating such data helps derive/evaluate detection models and ensures reproducibility of results. Experimentally, we demonstrate the efficacy of generative sequence analysis techniques on learning the structure of attack graphs, based on a realistic example. These derived models can then be used to generate more data. Additionally, we provide a roadmap for future research efforts in this area.

  8. 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....

  9. BIRD ATTACK OCULAR INJURIES.

    Science.gov (United States)

    Tabatabaei, Seyed Ali; Soleimani, Mohammad; Behrouz, Mahmoud Jabbarvand

    2017-03-29

    To report 30 patients with bird attack-related eye injuries. This study was performed among patients coming to Farabi Eye Hospital, Tehran, Iran, from 2010 to 2015 with a history of bird attack causing eye injury. The inclusion criteria were a history of bird attack by pecking causing eye injury and having treatment and follow-up record for at least 6 months after treatment. The primary eye examinations included a full ophthalmic examination including evaluation of uncorrected visual acuity and best-corrected visual acuity (BCVA), anterior segment slit lamp biomicroscopy, and photography. For all patients with penetrating injury, primary repair was undertaken. Thirty patients (10 females and 20 males) with a mean age of 23.3 ± 18.5 years entered the study. The most common zone of injury was zone 1 (P < 0.001), and lensectomy was not needed in majority of patients (P < 0.001). The most common bird causing the injury was mynah (P < 0.001). Those patients with baseline BCVA of less than 20/200 or those with endophthalmitis had statistically worse final BCVA after treatment. Patients attacked by mynah bird had significantly better pretreatment uncorrected visual acuity and BCVA. The most common bird causing the eye injury among the sample of patients from Iran was mynah, which differs with previous studies indicating the rooster attack as the most common cause of eye injury. The authors also found that the most common zone of injury was zone 1, and the presence of endophthalmitis and lower baseline BCVA were significant risk factors for worse visual outcomes.

  10. 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.

  11. Balance between matrix metalloproteinases (MMP and tissue inhibitors of metalloproteinases (TIMP in the cervical mucus plug estimated by determination of free non-complexed TIMP

    Directory of Open Access Journals (Sweden)

    Uldbjerg Niels

    2008-09-01

    Full Text Available Abstract Background The cervical mucus plug (CMP is a semi-solid structure with antibacterial properties positioned in the cervical canal during pregnancy. The CMP contains high concentrations of matrix metalloproteinase 8 and 9 (MMP-8, MMP-9 and tissue inhibitor of metalloproteinase 1 (TIMP-1. This indicates a potential to degrade extracellular matrix components depending on the balance between free non-complexed inhibitors and active enzymes. Methods Thirty-two CMPs collected during active labor at term were analyzed. Twelve CMPs were separated into a cellular and an extracellular/fluid phase and analyzed by gelatin and reverse zymography to reveal MMP and TIMP location. Twenty samples were homogenized, extracted and studied by the TIMP activity assay based on gelatin zymography. Enzyme-linked immunosorbent assay (ELISA was used to determine TIMP-1, MMP-8 and MMP-9 protein concentrations, and gelatin and reverse zymography used to identify gelatinases and TIMPs, respectively. The Western blotting technique was applied for semi-quantification of alpha2-macroglobulin. An ELISA activity assay was used to detect MMP-8 and MMP-9 activity. Results ProMMP-2, proMMP-9, TIMP-1 and TIMP-2 were almost exclusively located in the fluid phase compared to the cellular phase of the CMP. All the extracted samples contained MMP-8, MMP-9, TIMP-1, TIMP-2 and alpha2-macroglobulin. Free non-complexed TIMP was detected in all the samples analyzed by the TIMP activity assay and was associated with TIMP-1 protein (R = 0.71, p Conclusion Due to their extracellular location, potential proteolytic activity from neutrophil-derived MMPs in the CMP could exert a biological impact on cervical dilatation and fetal membrane rupture at term. The functional TIMP activity assay, revealing excess non-complexed TIMP, and a molar inhibitor/enzyme ratio above unity, indicate that refined MMP control prevents CMP-originated proteolytic activity in the surrounding tissue.

  12. RFA: R-Squared Fitting Analysis Model for Power Attack

    Directory of Open Access Journals (Sweden)

    An Wang

    2017-01-01

    Full Text Available Correlation Power Analysis (CPA introduced by Brier et al. in 2004 is an important method in the side-channel attack and it enables the attacker to use less cost to derive secret or private keys with efficiency over the last decade. In this paper, we propose R-squared fitting model analysis (RFA which is more appropriate for nonlinear correlation analysis. This model can also be applied to other side-channel methods such as second-order CPA and collision-correlation power attack. Our experiments show that the RFA-based attacks bring significant advantages in both time complexity and success rate.

  13. 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); (Christopher Newport U)

    2016-11-04

    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.

  14. 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.

  15. Algebraic Side-Channel Attack on Twofish

    Directory of Open Access Journals (Sweden)

    Chujiao Ma

    2017-05-01

    Full Text Available While algebraic side-channel attack (ASCA has been successful in breaking simple cryptographic algorithms, it has never been done on larger or more complex algorithms such as Twofish. Compared to other algorithms that ASCA has been used on, Twofish is more difficult to attack due to the key-dependent S-boxes as well as the complex key scheduling. In this paper, we propose the first algebraic side-channel attack on Twofish, and examine the importance of side-channel information in getting past the key-dependent S-boxes and the complex key scheduling. The cryptographic algorithm and side-channel information are both expressed as boolean equations and a SAT solver is used to recover the key. While algebraic attack by itself is not sufficient to break the algorithm, with the help of side-channel information such as Hamming weights, we are able to correctly solve for 96 bits of the 128 bits key in under 2 hours with known plaintext/ciphertext.

  16. Life After a Heart Attack

    Science.gov (United States)

    ... been stable for a few weeks. Anxiety and Depression After a Heart Attack After a heart attack, ... 2009, this project provided six awards at five academic institutions to identify genetic connections to heart, lung, ...

  17. Rising Trend: Complex and sophisticated attack methods

    Indian Academy of Sciences (India)

    Large scale booking of domain names. Hundred thousands of domains registered in short duration via few registrars; Single registrant; Most of the domains kept unresolved; Mostly being used for spamming and malware distribution; Many domains are listed as malicious; Poor process control by Domain Registrars.

  18. 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.

  19. 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

    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...

  20. 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.

  1. Attack Trees with Sequential Conjunction

    NARCIS (Netherlands)

    Jhawar, Ravi; Kordy, Barbara; Mauw, Sjouke; Radomirović, Sasa; Trujillo-Rasua, Rolando

    2015-01-01

    We provide the first formal foundation of SAND attack trees which are a popular extension of the well-known attack trees. The SAND at- tack tree formalism increases the expressivity of attack trees by intro- ducing the sequential conjunctive operator SAND. This operator enables the modeling of

  2. Copper(II) complexes of methimazole, an anti Grave's disease drug. Synthesis, characterization and its potential biological behavior as alkaline phosphatase inhibitor.

    Science.gov (United States)

    Urquiza, Nora M; Manca, Silvia G; Moyano, María A; Dellmans, Raquel Arrieta; Lezama, Luis; Rojo, Teófilo; Naso, Luciana G; Williams, Patricia A M; Ferrer, Evelina G

    2010-04-01

    Methimazole (MeimzH) is an anti-thyroid drug and the first choice for patients with Grave's disease. Two new copper(II) complexes of this drug: [Cu(MeimzH)(2)(NO(3))(2)]*0.5H(2)O and [Cu(MeimzH)(2)(H(2)O)(2)](NO(3))(2)*H(2)O were synthesized and characterized by elemental analysis, dissolution behavior, thermogravimetric analysis and UV-vis, diffuse reflectance, FTIR and EPR spectroscopies. As it is known that copper(II) cation can act as an inhibitor of alkaline phosphatase (ALP), the inhibitory effect of methimazole and its copper(II) complexes on ALP activity has also been investigated.

  3. 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.

  4. Structural insights on the pamoic acid and the 8 kDa domain of DNA polymerase beta complex: Towards the design of higher-affinity inhibitors

    Directory of Open Access Journals (Sweden)

    Ciais Marion

    2008-04-01

    Full Text Available Abstract Background DNA polymerase beta (pol beta, the error-prone DNA polymerase of single-stranded DNA break repair as well as base excision repair pathways, is overexpressed in several tumors and takes part in chemotherapeutic agent resistance, like that of cisplatin, through translesion synthesis. For this reason pol beta has become a therapeutic target. Several inhibitors have been identified, but none of them presents a sufficient affinity and specificity to become a drug. The fragment-based inhibitor design allows an important improvement in affinity of small molecules. The initial and critical step for setting up the fragment-based strategy consists in the identification and structural characterization of the first fragment bound to the target. Results We have performed docking studies of pamoic acid, a 9 micromolar pol beta inhibitor, and found that it binds in a single pocket at the surface of the 8 kDa domain of pol beta. However, docking studies provided five possible conformations for pamoic acid in this site. NMR experiments were performed on the complex to select a single conformation among the five retained. Chemical Shift Mapping data confirmed pamoic acid binding site found by docking while NOESY and saturation transfer experiments provided distances between pairs of protons from the pamoic acid and those of the 8 kDa domain that allowed the identification of the correct conformation. Conclusion Combining NMR experiments on the complex with docking results allowed us to build a three-dimensional structural model. This model serves as the starting point for further structural studies aimed at improving the affinity of pamoic acid for binding to DNA polymerase beta.

  5. 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.

  6. 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.

  7. 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.

  8. SUMO expression shortens the lag phase of Saccharomyces cerevisiae yeast growth caused by complex interactive effects of major mixed fermentation inhibitors found in hot-compressed water-treated lignocellulosic hydrolysate.

    Science.gov (United States)

    Jayakody, Lahiru N; Kadowaki, Masafumi; Tsuge, Keisuke; Horie, Kenta; Suzuki, Akihiro; Hayashi, Nobuyuki; Kitagaki, Hiroshi

    2015-01-01

    The complex inhibitory effects of inhibitors present in lignocellulose hydrolysate suppress the ethanol fermentation of Saccharomyces cerevisiae. Although the interactive inhibitory effects play important roles in the actual hydrolysate, few studies have investigated glycolaldehyde, the key inhibitor of hot-compressed water-treated lignocellulose hydrolysate. Given this challenge, we investigated the interactive effects of mixed fermentation inhibitors, including glycolaldehyde. First, we confirmed that glycolaldehyde was the most potent inhibitor in the hydrolysate and exerted interactive inhibitory effects in combination with major inhibitors. Next, through genome-wide analysis and megavariate data modeling, we identified SUMOylation as a novel potential mechanism to overcome the combinational inhibitory effects of fermentation inhibitors. Indeed, overall SUMOylation was increased and Pgk1, which produces an ATP molecule in glycolysis by substrate-level phosphorylation, was SUMOylated and degraded in response to glycolaldehyde. Augmenting the SUMO-dependent ubiquitin system in the ADH1-expressing strain significantly shortened the lag phase of growth, released cells from G2/M arrest, and improved energy status and glucose uptake in the inhibitor-containing medium. In summary, our study was the first to establish SUMOylation as a novel platform for regulating the lag phase caused by complex fermentation inhibitors.

  9. 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.

  10. 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.

  11. 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.

  12. Game Theoretic Solutions to Cyber Attack and Network Defense Problems

    National Research Council Canada - National Science Library

    Shen, Dan; Chen, Genshe; Cruz, Jr., , Jose B; Blasch, Erik; Kruger, Martin

    2007-01-01

    .... The protection and defense against cyber attacks to computer network is becoming inadequate as the hacker knowledge sophisticates and as the network and each computer system become more complex...

  13. 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

  14. Practical Attacks on AES-like Cryptographic Hash Functions

    DEFF Research Database (Denmark)

    Kölbl, Stefan; Rechberger, Christian

    2015-01-01

    Despite the great interest in rebound attacks on AES-like hash functions since 2009, we report on a rather generic, albeit keyschedule-dependent, algorithmic improvement: A new message modification technique to extend the inbound phase, which even for large internal states makes it possible...... to drastically reduce the complexity of attacks to very practical values for reduced-round versions. Furthermore, we describe new and practical attacks on Whirlpool and the recently proposed GOST R hash function with one or more of the following properties: more rounds, less time/memory complexity, and more...

  15. 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.

  16. 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.

  17. 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.

  18. Can You Recognize a Heart Attack? Quiz

    Science.gov (United States)

    ... Peripheral Artery Disease Venous Thromboembolism Aortic Aneurysm More Can You Recognize a Heart Attack? Updated:Sep 16, ... a Heart Attack Heart Attack Symptoms in Women “Can you recognize a heart attack?” Quiz • Understand Your ...

  19. Platinum(IV) complexes conjugated with phenstatin analogue as inhibitors of microtubule polymerization and reverser of multidrug resistance.

    Science.gov (United States)

    Huang, Xiaochao; Huang, Rizhen; Gou, Shaohua; Wang, Zhimei; Liao, Zhixin; Wang, Hengshan

    2017-09-01

    Pt(IV) complexes comprising a phenstatin analogue, as dual-targeting Pt(IV) prodrug, were designed and synthesized. They were found not only to carry the DNA binding platinum warhead into the tumor cells, but also to have a small molecular unit to inhibit tubulin polymerization. In vitro evaluation results revealed that Pt(IV) complexes showed better and more potent activity against the test human cancer cells including cisplatin resistant cell lines than their corresponding Pt(II) counterparts. In addition, the Pt(IV) derivative of cisplatin, complex 10, exhibited highly selective inhibition in human cancer cells and displayed no obvious toxicity to two human normal cell lines, respectively. Mechanism study suggested that complex 10 induced cell-cycle arrest at the G2/M phase and caused apoptotic cell death of human lung cancer NCI-H460 cells through the mitochondrial mediated pathway. Moreover, complex 10 effectively inhibited the tumor growth in the NCI-H460 xenograft model. Copyright © 2017. Published by Elsevier Ltd.

  20. Fast WEP-Key Recovery Attack Using Only Encrypted IP Packets

    Science.gov (United States)

    Teramura, Ryoichi; Asakura, Yasuo; Ohigashi, Toshihiro; Kuwakado, Hidenori; Morii, Masakatu

    Conventional efficient key recovery attacks against Wired Equivalent Privacy (WEP) require specific initialization vectors or specific packets. Since it takes much time to collect the packets sufficiently, any active attack should be performed. An Intrusion Detection System (IDS), however, will be able to prevent the attack. Since the attack logs are stored at the servers, it is possible to prevent such an attack. This paper proposes an algorithm for recovering a 104-bit WEP key from any IP packets in a realistic environment. This attack needs about 36, 500 packets with a success probability 0.5, and the complexity of our attack is equivalent to about 220 computations of the RC4 key setups. Since our attack is passive, it is difficult for both WEP users and administrators to detect our attack.

  1. Characterization of nineteen antimony(III) complexes as potent inhibitors of photosystem II, carbonic anhydrase, and glutathione reductase.

    Science.gov (United States)

    Karacan, Mehmet Sayım; Rodionova, Margarita V; Tunç, Turgay; Venedik, Kübra Begüm; Mamaş, Serhat; Shitov, Alexandr V; Zharmukhamedov, Sergei K; Klimov, Vyacheslav V; Karacan, Nurcan; Allakhverdiev, Suleyman I

    2016-12-01

    Nineteen antimony(III) complexes were obtained and examined as possible herbicides. Six of these were synthesized for the first time, and their structures were identified using elemental analyses, (1)H-NMR, (13)C-NMR, FTIR, LCMS, magnetic susceptibility, and conductivity measurement techniques. For the nineteen examined antimony(III) complexes their most-stable forms were determined by DFT/B3LYP/LanL2DZ calculation method. These compounds were examined for effects on photosynthetic electron transfer and carbonic anhydrase activity of photosystem II, and glutathione reductase from chloroplast as well were investigated. Our results indicated that all antimony(III) complexes inhibited glutathione reductase activity of chloroplast. A number of these also exhibited good inhibitory efficiency of the photosynthetic and carbonic anhydrase activity of Photosystem II.

  2. Comparing Alternatives to Measure the Impact of DDoS Attack Announcements on Target Stock Prices

    NARCIS (Netherlands)

    Abhishta,; Joosten, Reinoud; Nieuwenhuis, Lambert J.M.

    2017-01-01

    Distributed denial of service (DDoS) attacks are responsible for creating unavailability of online resources. Botnets based on internet of things (IOT) devices are now being used to conduct DDoS attacks. The estimation of direct and indirect economic damages caused by these attacks is a complex

  3. A Stochastic Framework for Quantitative Analysis of Attack-Defense Trees

    NARCIS (Netherlands)

    Jhawar, Ravi; Lounis, Karim; Mauw, Sjouke

    2016-01-01

    Cyber attacks are becoming increasingly complex, practically sophisticated and organized. Losses due to such attacks are important, varying from the loss of money to business reputation spoilage. Therefore, there is a great need for potential victims of cyber attacks to deploy security solutions

  4. 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...

  5. 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. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  6. 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.

  7. Crystal structure of SPSB2 in complex with a rational designed RGD-containing cyclic peptide inhibitor of SPSB2-iNOS interaction.

    Science.gov (United States)

    You, Tingting; Wang, Yuhui; Li, Kefa; Zhang, Danting; Wei, Huan; Luo, Yanhong; Li, Hua; Lu, Yongzhi; Su, Xunchen; Kuang, Zhihe

    2017-07-29

    SPRY domain-containing SOCS box protein 2 (SPSB2) is a negative regulator of inducible nitric oxide synthase (iNOS) that modulates the lifetime of iNOS and thus the levels of nitric oxide (NO) production. Inhibitors that can disrupt the endogenous SPSB2-iNOS interaction and augment NO production have potential as novel antimicrobial and anticancer drugs. In this study, we have designed a cyclic peptide (cR8), containing an RGD motif and the SPSB2 binding motif (DINNNV). ITC and chemical shift perturbation showed that cR8 binds to the iNOS binding site on SPSB2 with a Kd of 671 nM, and saturation transfer difference NMR showed that cR8 binds to αvβ3 integrin-expressing cells. Moreover, we determined the crystal structure of SPSB2 in complex with cR8, at a resolution of 1.34 Å. cR8 forms extensive hydrogen bonding with SPSB2 residues, but loss of an intramolecular hydrogen bond that is present in SPSB2-bound iNOS peptide may destabilize the bound conformation of cR8 and lead to a gentle reduction in SPSB2 binding affinity. These results serve as a useful basis for designing site-directed SPSB2 inhibitors in the future. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Crystal Structure of Thrombin in Complex with S-Variegin: Insights of a Novel Mechanism of Inhibition and Design of Tunable Thrombin Inhibitors

    Science.gov (United States)

    Koh, Cho Yeow; Kumar, Sundramurthy; Kazimirova, Maria; Nuttall, Patricia A.; Radhakrishnan, Uvaraj P.; Kim, Seongcheol; Jagadeeswaran, Pudur; Imamura, Takayuki; Mizuguchi, Jun; Iwanaga, Sadaaki; Swaminathan, Kunchithapadam; Kini, R. Manjunatha

    2011-01-01

    The inhibition of thrombin is one of the important treatments of pathological blood clot formation. Variegin, isolated from the tropical bont tick, is a novel molecule exhibiting a unique ‘two-modes’ inhibitory property on thrombin active site (competitive before cleavage, noncompetitive after cleavage). For the better understanding of its function, we have determined the crystal structure of the human α-thrombin:synthetic-variegin complex at 2.4 Å resolution. The structure reveals a new mechanism of thrombin inhibition by disrupting the charge relay system. Based on the structure, we have designed 17 variegin variants, differing in potency, kinetics and mechanism of inhibition. The most active variant is about 70 times more potent than the FDA-approved peptidic thrombin inhibitor, hirulog-1/bivalirudin. In vivo antithrombotic effects of the variegin variants correlate well with their in vitro affinities for thrombin. Our results encourage that variegin and the variants show strong potential for the development of tunable anticoagulants. PMID:22053189

  9. 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.

  10. Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 2. Computational titration and pH effects in molecular models of neuraminidase-inhibitor complexes.

    Science.gov (United States)

    Fornabaio, Micaela; Cozzini, Pietro; Mozzarelli, Andrea; Abraham, Donald J; Kellogg, Glen E

    2003-10-09

    One factor that can strongly influence predicted free energy of binding is the ionization state of functional groups on the ligands and at the binding site at which calculations are performed. This analysis is seldom performed except in very detailed computational simulations. In this work, we address the issues of (i) modeling the complexity resulting from the different ionization states of ligand and protein residues involved in binding, (ii) if, and how, computational methods can evaluate the pH dependence of ligand inhibition constants, and (iii) how to score the protonation-dependent models. We developed a new and fairly rapid protocol called "computational titration" that enables parallel modeling of multiple ionization ensembles for each distinct protonation level. Models for possible protonation combinations for site/ligand ionizable groups are built, and the free energy of interaction for each of them is quantified by the HINT (Hydropathic INTeractions) software. We applied this procedure to the evaluation of the binding affinity of nine inhibitors (six derived from 2,3-didehydro-2-deoxy-N-acetylneuraminic acid, DANA) of influenza virus neuraminidase (NA), a surface glycoprotein essential for virus replication and thus a pharmaceutically relevant target for the design of anti-influenza drugs. The three-dimensional structures of the NA enzyme-inhibitor complexes indicate considerable complexity as the ligand-protein recognition site contains several ionizable moieties. Each computational titration experiment reveals a peak HINT score as a function of added protons. This maximum HINT score indicates the optimum pH (or the optimum protonation state of each inhibitor-protein binding site) for binding. The pH at which inhibition is measured and/or crystals were grown and analyzed can vary from this optimum. A protonation model is proposed for each ligand that reconciles the experimental complex structure with measured inhibition and the free energy of binding

  11. Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma.

    Science.gov (United States)

    Demosthenous, Christos; Han, Jing Jing; Stenson, Mary J; Maurer, Matthew J; Wellik, Linda E; Link, Brian; Hege, Kristen; Dogan, Ahmet; Sotomayor, Eduardo; Witzig, Thomas; Gupta, Mamta

    2015-04-20

    Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients.

  12. Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1.

    Science.gov (United States)

    Nettles, Richard E; Gao, Min; Bifano, Marc; Chung, Ellen; Persson, Anna; Marbury, Thomas C; Goldwater, Ronald; DeMicco, Michael P; Rodriguez-Torres, Maribel; Vutikullird, Apinya; Fuentes, Ernesto; Lawitz, Eric; Lopez-Talavera, Juan Carlos; Grasela, Dennis M

    2011-12-01

    The antiviral activity, resistance profile, pharmacokinetics (PK), safety, and tolerability of BMS-790052, a nonstructural protein 5A (NS5A) replication complex inhibitor, were evaluated in a double-blind, placebo-controlled, sequential panel, multiple ascending dose study. Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14-day course of BMS-790052 (1, 10, 30, 60, or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1. The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log(10) IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the in vitro replicon system. The PK profile was supportive of once-daily dosing with median peak plasma concentrations at 1-2 hours postdose and mean terminal half-life of 12-15 hours. Steady state was achieved following 3-4 days of daily dosing. BMS-790052 was well tolerated in all dose groups, with adverse events occurring with a similar frequency in BMS-790052- and placebo-treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters. BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic. At doses of 1-100 mg daily, BMS-790052 was well tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV-RNA levels in patients chronically infected with HCV genotype 1. Copyright © 2011 American Association for the Study of Liver Diseases.

  13. Cyber Attacks and Combat Behavior

    Directory of Open Access Journals (Sweden)

    Carataș Maria Alina

    2017-01-01

    Full Text Available Cyber terrorism is an intangible danger, a real over the corner threat in the life of individuals,organizations, and governments and is getting harder to deal with its damages. The motivations forthe cyber-attacks are different, depending on the terrorist group, from cybercrime to hacktivism,attacks over the authorities’ servers. Organizations constantly need to find new ways ofstrengthening protection against cyber-attacks, assess their cyber readiness, expand the resiliencecapacity and adopts international security regulations.

  14. Tracing Technique for Blaster Attack

    OpenAIRE

    S., Siti Rahayu; Y., Robiah; 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...

  15. Attacks on RFID Identification Systems

    Directory of Open Access Journals (Sweden)

    D. M. Mikhaylov

    2010-09-01

    Full Text Available This article is about attacks on RFID systems. Currently antivirus developers are not developing systems that protect from viruses that could exist on RFID tags. Such viruses are considered as not existing because the RFID tag memory is very small. Unfortunately such viruses exist. This article is concerned to such viruses and attacks that hackers could do using such viruses. Based on this article methods to prevent RFID-viruses attacks could be developed.

  16. RT-21Mre11-Rad50-Nbs1 COMPLEX INHIBITOR MIRIN ENHANCES RADIOSENSITIVITY IN HUMAN GLIOBLASTOMA CELLS

    OpenAIRE

    Mishima, Kazuhiko; Mishima-Kaneko, Masayo; Saya, Hideyuki; Ishimaru, Naozumi; Yamada, Kouichi; Fukada, Junichi; Nishikawa, Ryo; Kawata, Tetsuya

    2014-01-01

    PURPOSE: Radiation therapy plays a central part in the treatment of glioblastoma, however, it is not curative due to the high tumor radioresistance. Therefore, increasing the sensitivity of glioblastoma cells to radiation is a promising approach to improve survival in patients with glioblastoma. The Mre11, Rad 50 and Nbs1 proteins form a complex (MRN) that has a critical role in DNA damage detection and signaling. Because defects in MRN enhance radiosensitivity, it has been proposed that smal...

  17. 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.

  18. 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.

  19. Survival of child after lion attack

    Science.gov (United States)

    Dabdoub, Carlos F.; Dabdoub, Carlos B.; Chavez, Mario; Molina, Felipe

    2013-01-01

    Background: Injuries to humans caused by attacks from large predators are very rare, especially in the United States, Europe, or Latin America. A few cases were reported on accidents in zoos or animal farms, being very uncommon in children. The purposes of this report include describing the case of a child who sustained an attack by a lion named “Bang-Bang”, which resulted in injuries to the head, chest, and abdomen, as well as the subsequent neurosurgical treatment and providing a review of the literature. Case Description: We report the case of an 8-year-old boy who was attacked by a lion during a circus show. The patient underwent an emergent neurosurgical procedure, including parietal craniectomy, cleaning, and extensive surgical debridement of the wounds. Despite open severe head trauma with brain damage as well as thorax and abdomen trauma, the child survived, with minimal neurological sequelae. Conclusions: Human injury resulting from encounters with nondomesticated animals is increasingly rising throughout the world. This case highlights the potentially violent and aggressive nature of wild mammals held in captivity. Unusual wild animal attacks and the complex injuries that result may pose a challenge to surgeons practicing in resource-limited settings. In this sense, the best treatment in the mentioned case is the prevention of human injuries by these animals. In addition, to attend to these infrequent cases, the authors emphasize the importance of a multidisciplinary approach to achieve the best cosmetic and functional results. PMID:23869277

  20. 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

  1. 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

  2. Attacker profiling in quantitative security assessment based on attack trees

    NARCIS (Netherlands)

    Lenin, Aleksandr; Willemson, Jan; Sari, Dyan Permata

    2014-01-01

    We present the results of research of limiting adversarial budget in attack games, and, in particular, in the failure-free attack tree models presented by Buldas-Stepanenko in 2012 and improved in 2013 by Buldas and Lenin. In the previously presented models attacker’s budget was assumed to be

  3. Crystal structure of a polyhistidine-tagged recombinant catalytic subunit of cAMP-dependent protein kinase complexed with the peptide inhibitor PKI(5-24) and adenosine.

    Science.gov (United States)

    Narayana, N; Cox, S; Shaltiel, S; Taylor, S S; Xuong, N

    1997-04-15

    The crystal structure of the hexahistidine-tagged mouse recombinant catalytic subunit (H6-rC) of cAMP-dependent protein kinase (cAPK), complexed with a 20-residue peptide inhibitor from the heat-stable protein kinase inhibitor PKI(5-24) and adenosine, was determined at 2.2 A resolution. Novel crystallization conditions were required to grow the ternary complex crystals. The structure was refined to a final crystallographic R-factor of 18.2% with good stereochemical parameters. The "active" enzyme adopts a "closed" conformation as found in rC:PKI(5-24) [Knighton et al. (1991a,b) Science 253, 407-414, 414-420] and packs in a similar manner with the peptide providing a major contact surface. This structure clearly defines the subsites of the unique nucleotide binding site found in the protein kinase family. The adenosine occupies a mostly hydrophobic pocket at the base of the cleft between the two lobes and is completely buried. The missing triphosphate moiety of ATP is filled with a water molecule (Wtr 415) which replaces the gamma-phosphate of ATP. The glycine-rich loop between beta1 and beta2 helps to anchor the phosphates while the ribose ring is buried beneath beta-strand 2. Another ordered water molecule (Wtr 375) is pentacoordinated with polar atoms from adenosine, Leu 49 in beta-strand 1, Glu 127 in the linker strand between the two lobes, Tyr 330, and a third water molecule, Wtr 359. The conserved nucleotide fold can be defined as a lid comprised of beta-strand 1, the glycine-rich loop, and beta-strand 2. The adenine ring is buried beneath beta-strand 1 and the linker strand (120-127) that joins the small and large lobes. The C-terminal tail containing Tyr 330, a segment that lies outside the conserved core, covers this fold and anchors it in a closed conformation. The main-chain atoms of the flexible glycine-rich loop (residues 50-55) in the ATP binding domain have a mean B-factor of 41.4 A2. This loop is quite mobile, in striking contrast to the other

  4. A holistic approach to dissecting SPARC family protein complexity reveals FSTL-1 as an inhibitor of pancreatic cancer cell growth.

    Science.gov (United States)

    Viloria, Katrina; Munasinghe, Amanda; Asher, Sharan; Bogyere, Roberto; Jones, Lucy; Hill, Natasha J

    2016-11-25

    SPARC is a matricellular protein that is involved in both pancreatic cancer and diabetes. It belongs to a wider family of proteins that share structural and functional similarities. Relatively little is known about this extended family, but evidence of regulatory interactions suggests the importance of a holistic approach to their study. We show that Hevin, SPOCKs, and SMOCs are strongly expressed within islets, ducts, and blood vessels, suggesting important roles for these proteins in the normal pancreas, while FSTL-1 expression is localised to the stromal compartment reminiscent of SPARC. In direct contrast to SPARC, however, FSTL-1 expression is reduced in pancreatic cancer. Consistent with this, FSTL-1 inhibited pancreatic cancer cell proliferation. The complexity of SPARC family proteins is further revealed by the detection of multiple cell-type specific isoforms that arise due to a combination of post-translational modification and alternative splicing. Identification of splice variants lacking a signal peptide suggests the existence of novel intracellular isoforms. This study underlines the importance of addressing the complexity of the SPARC family and provides a new framework to explain their controversial and contradictory effects. We also demonstrate for the first time that FSTL-1 suppresses pancreatic cancer cell growth.

  5. 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.

  6. Invisible Trojan-horse attack

    DEFF Research Database (Denmark)

    Sajeed, Shihan; Minshull, Carter; Jain, Nitin

    2017-01-01

    We demonstrate the experimental feasibility of a Trojan-horse attack that remains nearly invisible to the single-photon detectors employed in practical quantum key distribution (QKD) systems, such as Clavis2 from ID Quantique. We perform a detailed numerical comparison of the attack performance...

  7. Heart Attack Symptoms in Women

    Science.gov (United States)

    ... and Conditions and Privacy Policy Go Red For Women® presents: View our first-ever short film (opens in new window) by Elizabeth Banks and share with the women you love. Heart Attack • Home • About Heart Attacks ...

  8. [Heart-attack in pregnancy].

    Science.gov (United States)

    Výtisková, T; Suchá, D; Fučíková, Z

    To describe hear-attack on crystal meth addicted pregnant woman. Case report. Acute heart-attack during pregnancy means unexpected obstetric complication. The consequences could be fatal for the mother and the fetus. Although good delivery management and treatment could reduce morbidity and mortality to a minimum.

  9. Crystal structure of human cyclin-dependent kinase-2 complex with MK2 inhibitor TEI-I01800: insight into the selectivity

    Energy Technology Data Exchange (ETDEWEB)

    Fujino, Aiko; Fukushima, Kei; Kubota, Takaharu; Kosugi, Tomomi; Takimoto-Kamimura, Midori, E-mail: m.kamimura@teijin.co.jp [Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino-shi, Tokyo 191-8512 (Japan)

    2013-11-01

    The Gly-rich loop of cyclin-dependent kinase 2 (CDK2) bound to TEI-I01800 as an MK2 specific inhibitor forms a β-sheet which is a common structure in CDK2–ligand complexes. Here, the reason why TEI-I01800 does not become a strong inhibitor against CDK2 based on the conformation of TEI-I01800 is presented. Mitogen-activated protein kinase-activated protein kinase 2 (MK2 or MAPKAP-K2) is a Ser/Thr kinase from the p38 mitogen-activated protein kinase signalling pathway and plays an important role in inflammatory diseases. The crystal structure of the MK2–TEI-I01800 complex has been reported; its Gly-rich loop was found to form an α-helix, not a β-sheet as has been observed for other Ser/Thr kinases. TEI-I01800 is 177-fold selective against MK2 compared with CDK2; in order to understand the inhibitory mechanism of TEI-I01800, the cyclin-dependent kinase 2 (CDK2) complex structure with TEI-I01800 was determined at 2.0 Å resolution. Interestingly, the Gly-rich loop of CDK2 formed a β-sheet that was different from that of MK2. In MK2, TEI-I01800 changed the secondary structure of the Gly-rich loop from a β-sheet to an α-helix by collision between Leu70 and a p-ethoxyphenyl group at the 7-position and bound to MK2. However, for CDK2, TEI-I01800 bound to CDK2 without this structural change and lost the interaction with the substituent at the 7-position. In summary, the results of this study suggest that the reason for the selectivity of TEI-I01800 is the favourable conformation of TEI-I01800 itself, making it suitable for binding to the α-form MK2.

  10. Persistence of resistant variants in hepatitis C virus-infected patients treated with the NS5A replication complex inhibitor daclatasvir.

    Science.gov (United States)

    Wang, Chunfu; Sun, Jin-Hua; O'Boyle, Donald R; Nower, Peter; Valera, Lourdes; Roberts, Susan; Fridell, Robert A; Gao, Min

    2013-05-01

    Daclatasvir (DCV; BMS-790052) is a hepatitis C virus (HCV) NS5A replication complex inhibitor (RCI) with picomolar to low nanomolar potency and broad genotypic coverage in vitro. Viral RNA declines have been observed in the clinic for both alpha interferon-ribavirin (IFN-α-RBV) and IFN-RBV-free regimens that include DCV. Follow-up specimens (up to 6 months) from selected subjects treated with DCV in 14-day monotherapy studies were analyzed for genotype and phenotype. Variants were detected by clonal sequencing in specimens from baseline and were readily detected by population sequencing following viral RNA breakthrough and posttreatment. The major amino acid substitutions generating resistance in vivo were at residues M28, Q30, L31, and Y93 for genotype 1a (GT-1a) and L31 and Y93 for GT-1b, similar to the resistance substitutions observed with the in vitro replicon system. The primary difference in the resistance patterns observed in vitro and in vivo was the increased complexity of linked variant combinations observed in clinical specimens. Changes in the percentage of individual variants were observed during follow-up; however, the overall percentage of variants in the total population persisted up to 6 months. Our results suggest that during the 14-day monotherapy, most wild-type virus was eradicated by DCV. After the end of DCV treatment, viral fitness, rather than DCV resistance, probably determines which viral variants emerge as dominant in populations.

  11. The crystal structures of native hydroquinone 1,2-dioxygenase from Sphingomonas sp. TTNP3 and of substrate and inhibitor complexes.

    Science.gov (United States)

    Ferraroni, Marta; Da Vela, Stefano; Kolvenbach, Boris A; Corvini, Philippe F X; Scozzafava, Andrea

    2017-05-01

    The crystal structure of hydroquinone 1,2-dioxygenase, a Fe(II) ring cleaving dioxygenase from Sphingomonas sp. strain TTNP3, which oxidizes a wide range of hydroquinones to the corresponding 4-hydroxymuconic semialdehydes, has been solved by Molecular Replacement, using the coordinates of PnpCD from Pseudomonas sp. strain WBC-3. The enzyme is a heterotetramer, constituted of two subunits α and two β of 19 and 38kDa, respectively. Both the two subunits fold as a cupin, but that of the small α subunit lacks a competent metal binding pocket. Two tetramers are present in the asymmetric unit. Each of the four β subunits in the asymmetric unit binds one Fe(II) ion. The iron ion in each β subunit is coordinated to three protein residues, His258, Glu264, and His305 and a water molecule. The crystal structures of the complexes with the substrate methylhydroquinone, obtained under anaerobic conditions, and with the inhibitors 4-hydroxybenzoate and 4-nitrophenol were also solved. The structures of the native enzyme and of the complexes present significant differences in the active site region compared to PnpCD, the other hydroquinone 1,2-dioxygenase of known structure, and in particular they show a different coordination at the metal center. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Hepatitis B virus X protein up-regulates C4b-binding protein α through activating transcription factor Sp1 in protection of hepatoma cells from complement attack.

    Science.gov (United States)

    Feng, Guoxing; Li, Jiong; Zheng, Minying; Yang, Zhe; Liu, Yunxia; Zhang, Shuqin; Ye, Lihong; Zhang, Weiying; Zhang, Xiaodong

    2016-05-10

    Hepatitis B virus X protein (HBx) plays crucial roles in the development of hepatocellular carcinoma (HCC). We previously showed that HBx protected hepatoma cells from complement attack by activation of CD59. Moreover, in this study we found that HBx protected hepatoma cells from complement attack by activation of C4b-binding protein α (C4BPα), a potent inhibitor of complement system. We observed that HBx were positively correlated with those of C4BPα in clinical HCC tissues. Mechanistically, HBx activated the promoter core region of C4BPα, located at -1199/-803nt, through binding to transcription factor Sp1. In addition, chromatin immunoprecipitation (ChIP) assays showed that HBx was able to bind to the promoter of C4BPα, which could be blocked by Sp1 silencing. Functionally, knockdown of C4BPα obviously increased the deposition of C5b-9, a complex of complement membrane attack, and remarkably abolished the HBx-induced resistance of hepatoma cells from complement attack in vitro and in vivo. Thus, we conclude that HBx up-regulates C4BPα through activating transcription factor Sp1 in protection of liver cancer cells from complement attack. Our finding provides new insights into the mechanism by which HBx enhances protection of hepatoma cells from complement attack.

  13. Invisible Trojan-horse attack.

    Science.gov (United States)

    Sajeed, Shihan; Minshull, Carter; Jain, Nitin; Makarov, Vadim

    2017-08-21

    We demonstrate the experimental feasibility of a Trojan-horse attack that remains nearly invisible to the single-photon detectors employed in practical quantum key distribution (QKD) systems, such as Clavis2 from ID Quantique. We perform a detailed numerical comparison of the attack performance against Scarani-Ac´ın-Ribordy-Gisin (SARG04) QKD protocol at 1924 nm versus that at 1536 nm. The attack strategy was proposed earlier but found to be unsuccessful at the latter wavelength, as reported in N. Jain et al., New J. Phys. 16, 123030 (2014). However at 1924 nm, we show experimentally that the noise response of the detectors to bright pulses is greatly reduced, and show by modeling that the same attack will succeed. The invisible nature of the attack poses a threat to the security of practical QKD if proper countermeasures are not adopted.

  14. Superposition Attacks on Cryptographic Protocols

    DEFF Research Database (Denmark)

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

    2011-01-01

    string model. While our protocol is classical, it is sound against a cheating unbounded quantum prover and computational zero-knowledge even if the verifier is allowed a superposition attack. Finally, we consider multiparty computation and show that for the most general type of attack, simulation based......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...

  15. Assessment of pharmacokinetic interactions of the HCV NS5A replication complex inhibitor daclatasvir with antiretroviral agents: ritonavir-boosted atazanavir, efavirenz and tenofovir.

    Science.gov (United States)

    Bifano, Marc; Hwang, Carey; Oosterhuis, Berend; Hartstra, Jan; Grasela, Dennis; Tiessen, Renger; Velinova-Donga, Maria; Kandoussi, Hamza; Sevinsky, Heather; Bertz, Richard

    2013-01-01

    Approximately one-third of all HIV-infected individuals are coinfected with HCV, many of whom will receive concomitant treatment for both infections. With the advent of direct-acting antivirals (DAAs) for HCV, potential drug interactions between antiretrovirals and DAAs require evaluation prior to co-therapy. Three open-label studies were conducted in healthy subjects to assess potential interactions between the investigational first-in-class HCV NS5A replication complex inhibitor daclatasvir and representative antiretrovirals atazanavir/ritonavir, efavirenz and tenofovir disoproxil fumarate. Target exposure was that of 60 mg daclatasvir alone. Dose-normalized (60 mg) geometric mean ratios of daclatasvir AUCτ for 20 mg ± atazanavir/ritonavir (2.10 [90% CI 1.95, 2.26]) and 120 mg ± efavirenz (0.68 [0.60, 0.78]) showed less than the three-fold elevation and two-fold reduction, respectively, in systemic exposure predicted by prior interaction studies with potent inhibitors/inducers of CYP3A4. Daclatasvir dose adjustment to 30 mg once daily with atazanavir/ritonavir and 90 mg once daily with efavirenz is predicted to normalize AUCτ relative to the target exposure (geometric mean ratios 1.05 [0.98, 1.13] and 1.03 [0.90, 1.16], respectively). Atazanavir exposure (Cmax, AUCτ and C24 trough) and efavirenz Ctrough under coadministration were similar to historical data without daclatasvir. No clinically relevant interactions between daclatasvir and tenofovir disoproxil fumarate were observed for either drug, and no dosing adjustments were indicated. Daclatasvir was well tolerated in all three studies. The pharmacokinetic data support coadministration of daclatasvir with atazanavir/ritonavir, efavirenz and/or tenofovir. A Phase III study in HIV-HCV coinfection has commenced using the described dose modifications.

  16. Loss of Tuberous Sclerosis Complex 2 (TSC2 as a Predictive Biomarker of Response to mTOR Inhibitor Treatment in Patients with Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Jinhyun Cho

    2016-10-01

    Full Text Available BACKGROUND: Hepatocellular carcinoma (HCC is a leading cause of cancer-related death globally. Mechanistic target of rapamycin (mTOR is frequently up-regulated in HCC and plays an important role in HCC tumorigenesis. Tumors with loss of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTOR signaling, tend to respond well to mTOR inhibitors. We analyzed TSC2 expression status in Korean patients with HCC and evaluated the correlation between TSC2 loss and response to the mTOR inhibitor, everolimus. METHODS: We retrospectively assessed 36 patients with advanced HCC who had received sorafenib at a single center in Korea between 2008 and 2014, and for whom tumor specimens were available for TSC2 immunohistochemical analysis (IHC. Three patient-derived tumor cell lines (PDCs were analyzed by western blotting to determine TSC2 expression and drug sensitivity to mTOR. RESULTS: Twelve of 36 patients (33.3% showed low to undetectable levels of TSC2 expression. No significant differences were observed in progression-free survival (PFS or overall survival with sorafenib treatment based on TSC2 expression status. Two patients were treated with everolimus after sorafenib failure; one patient, with moderate TSC2 expression, experienced stable disease with a PFS of 5.8 months; the other, with high TSC2 expression, experienced rapid progression. PDC models demonstrated that the TSC2-low HCC PDC line was significantly more sensitive to everolimus than the TSC2-high HCC PDC lines. CONCLUSION: Loss of TSC2 may predict improved response to everolimus in HCC patients, but further studies are needed to confirm the predictive role of TSC2 expression for everolimus treatment.

  17. 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.

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

    Science.gov (United States)

    Melendez, Dante P; Razonable, Raymund R

    2015-01-01

    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.

  19. 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 

  20. Khyâl attacks: a key idiom of distress among traumatized cambodia refugees.

    Science.gov (United States)

    Hinton, Devon E; Pich, Vuth; Marques, Luana; Nickerson, Angela; Pollack, Mark H

    2010-06-01

    Traumatized Cambodian refugees with PTSD often complain of khyâl attacks. The current study investigates khyâl attacks from multiple perspectives and examines the validity of a model of how khyâl attacks are generated. The study found that khyâl attacks had commonly been experienced in the previous 4 weeks and that their severity was strongly correlated with the severity of PTSD (PTSD Checklist). It was found that khyâl attacks were triggered by various processes--such as worry, trauma recall, standing up, going to a mall--and that khyâl attacks almost always met panic attack criteria. It was also found that during a khyâl attack there was great fear that death might occur from bodily dysfunction. It was likewise found that a complex nosology of khyâl attacks exists that rates the attacks on a scale of severity, that the severity determines how the khyâl attacks should be treated and that those treatments are often complex. As illustrated by the article, khyâl attacks constitute a key aspect of trauma ontology in this group, a culturally specific experiencing of anxiety and trauma-related disorder. The article also contributes to the study of trauma somatics, that is, to the study of how trauma results in specific symptoms in a specific cultural context, showing that a key part of the trauma-somatic reticulum is often a cultural syndrome.

  1. 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.

  2. 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. © 2013. Published by Elsevier Inc. All rights reserved.

  3. Complexity

    Indian Academy of Sciences (India)

    Rahul Pandit

    2008-10-31

    Oct 31, 2008 ... ”The more complex a thing is, the more you can talk about it.” - attributed to Giorgio Parisi. ▻ ”C'est magnifique, mais ce n'est pas de la science.” (It is magnificent, but not all of it is science.) - attributed ... Earliest examples: theoretical computer science, algorithmic complexity, etc. ▻ Rapid progress after the ...

  4. 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....

  5. Allergens might trigger migraine attacks.

    Science.gov (United States)

    Bektas, Hesna; Karabulut, Hayriye; Doganay, Beyza; Acar, Baran

    2017-03-01

    Migraine is a common primary headache disorder. The mechanisms underlying the onset of a migraine attack are not completely understood. Environmental changes and a number of other factors could induce migraine attacks. The aim of this study was to investigate the relationship between the frequency of migraine attacks and allergens. Migraine patients without aura, and healthy individuals similar in age and gender without a history of headache and allergy were prospectively included in the study. The duration of migraine, the frequency of migraine attacks, the medication history, and the symptoms during attacks were questioned. Migraine disability assessment score (MIDAS) and visual analog scale (VAS) scores were obtained. Allergen extracts including dust, fungi, insect, animal epithelium, pollens, and food allergens were applied for allergy tests. 49 migraine patients and 49 healthy individuals were enrolled in the study. There was no significant difference in terms of age and gender. The median migraine disease duration, the number of attacks in a month, and the duration of attacks were, respectively, 5.5 years (1-44), 4 (1-10) day/month, and 24 (4-72) h. The mean MIDAS grade was 2.45 ± 0.14 (1-4), and mean VAS score was 7.89 ± 0.27 (4-10). The positivity of allergy tests was 55.1 % (27/49) in the migraine group and 32.7 % (16/49) in the control group (p < 0.05). The allergy tests were positive for house dust, red birch, hazel tree, olive tree, nettle, and wheat. The frequency of migraine attacks was higher in allergy-test-positive patients than in negative ones in the migraine group (p = 0.001). The migraine patients who had frequent attacks should be examined for allergies.

  6. 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.

  7. Shark Attack Project - Marine Attack at Towed Hydrophone Arrays

    National Research Council Canada - National Science Library

    Kalmijn, Adrianus J

    2005-01-01

    The original objective of the SIO Marine Attack project was to identify the electric and magnetic fields causing sharks to inflict serious damage upon the towed hydrophone arrays of US Navy submarines...

  8. Several Novel N-Donor Tridentate Ligands Formed in Chemical Studies of New fac-Re(CO)3 Complexes Relevant to fac-99mTc(CO)3 Radiopharmaceuticals. Attack of a Terminal Amine on Coordinated Acetonitrile

    Science.gov (United States)

    Perera, Theshini; Marzilli, Patricia A.; Fronczek, Frank R.; Marzilli, Luigi G.

    2010-01-01

    Synopsis A novel ligand was discovered in which acetonitrile appears to have inserted between the two protons and the nitrogen of a primary amine. A proposed pathway for this process involves a putative seven-membered chelate ring (formed by attack of a primary amine on coordinated acetonitrile) that undergoes proton transfer and rearrangement. The pathway is supported by the structure of a related compound that has a methyl group in place of one of the protons. PMID:20104873

  9. 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....

  10. Automated Generation of Attack Trees

    DEFF Research Database (Denmark)

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

    2014-01-01

    -prone and impracticable for large systems. Nonetheless, the automated generation of attack trees has only been explored in connection to computer networks and levering rich models, whose analysis typically leads to an exponential blow-up of the state space. We propose a static analysis approach where attack trees...... interesting quantitative problems, that can be solved through an encoding into Satisfiability Modulo Theories. The flexibility and effectiveness of the approach is demonstrated on the study of a national-scale authentication system, whose attack tree is computed thanks to a Java implementation...

  11. 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...

  12. Some legal challenges posed by remote attack

    National Research Council Canada - National Science Library

    William Boothby

    2012-01-01

      Abstract Attacking from a distance is nothing new, but with the advent of certain new technologies, attacks can be undertaken in which the attacker remains very remote from the scene where force will be employed...

  13. Social Engineering Attack Detection Model: SEADMv2

    CSIR Research Space (South Africa)

    Mouton, F

    2015-10-01

    Full Text Available and is only able to cater for social engineering attacks that use bidirectional communication. Previous research discovered that social engineering attacks can be classified into three different categories, namely attacks that utilise bidirectional...

  14. Survey on attacks in image and video watermarking

    Science.gov (United States)

    Vassaux, Boris; Nguyen, Philippe; Baudry, Severine; Bas, Patrick; Chassery, Jean-Marc

    2002-11-01

    Watermarking techniques have been considerably improved for the last past years, aiming at being always more resistant to attacks. In fact, if the main goal of watermarking at the beginning was to secure digital data (audio, image and video), numerous attacks are still now able to cast doubts on the owner's authenticity ; we can distinguish three different groups of attacks : these one which consist to remove the watermark, these one which aim at impairing the data sufficiently to falsify the detection, and finally these one which try to alter the detection process so that another person becomes the apparent owner of the data. By considering the growing development of always more efficient attacks, this paper firstly presents a recent and exhaustive review of attacks in image and video watermarking. In a second part, the consequences of still image watermarking attacks on video sequences will be outlined and a particular attention will be given to the recently created benchmarks : Stirmark, the benchmark proposed by the University of Geneva Vision Group, this one proposed by the Department of Informatics of the University of Thessaloniki and finally we will speak of the current work of the European Project Certimark ; we will present a comparison of these various benchmarks and show how difficult it is to develop a self-sufficient benchmark, especially because of the complexity of intentional attacks.

  15. Robust continuous-variable quantum key distribution against practical attacks

    Science.gov (United States)

    Huang, Peng; Huang, Jingzheng; Wang, Tao; Li, Huasheng; Huang, Duan; Zeng, Guihua

    2017-05-01

    Recently, several practical attacks on continuous-variable quantum key distribution (CVQKD) were proposed based on faking the estimated value of channel excess noise to hide the intercept-and-resend eavesdropping strategy, including the local oscillator (LO) fluctuation, calibration, wavelength, and saturation attacks. However, the known countermeasures against all these practical attacks will inevitably increase the complexity of the implementation of CVQKD and affect its performance. We develop here an asynchronous countermeasure strategy without structural modifications of the conventional CVQKD scheme. In particular, two robust countermeasures are proposed by adding peak-valley seeking and Gaussian postselection steps in conventional data postprocessing procedure. The analysis shows that the peak-valley seeking method naturally make the schemes immune to all known types of calibration attacks even when Eve simultaneously performs wavelength or LO fluctuation attacks and exhibit simpler implementation and better performance than the known countermeasures. Meanwhile, since the Gaussian postselection is able to resist the saturation attacks, the proposed schemes are secure against all known types of practical attacks.

  16. Microwave-assisted synthesis of ruthenium(II) complexes with alkynes as potential inhibitor by selectively recognizing c-myc G-quadruplex DNA.

    Science.gov (United States)

    Zhang, Shuangyan; Wu, Qiong; Zhang, Hao; Wang, Qi; Wang, Xicheng; Mei, Wenjie; Wu, Xiaohui; Zheng, Wenjie

    2017-11-01

    Herein, two polypyridyl ruthenium(II) complexes with alkynes, [Ru(bpy)2L](ClO4)2 (L=p-TEPIP (1) and p-BEPIP (2); bpy=2,2'-bipyridine; p-TEPIP=2-(4-trimethylsilylpropargyl)-1H-imidazo[4,5f][1,10]phenanthroline; p-BEPIP=2-(4-phenyacetylenephenyl)-1H-imidazo[4,5f][1,10]phenanthroline) have been successfully achieved in yields of 32%-89% by a Sonogashira coupling reaction under microwave irradiation. We studied these complexes as potential stabilizers of c-myc G-quadruplex DNA. Observations revealed that both complexes could selectively bind to and stabilize c-myc G-quadruplex DNA with a constant of approximately 1.61±0.78 and 9.47±4.20×10(3)M(-1), respectively, as determined from ITC (isothermal ttitration calorimetry) experiments, FRET (fluorescence resonance energy ttransfer) assay and competitive FRET assay. Moreover, the melting point (Tm) of the c-myc G-quadruplex DNA increased in the presence of 1 and 2 ([Ru]=0.2μM) by approximately 9 and 19.9°C, respectively. It is noteworthy that the conformation of the c-myc G-quadruplex DNA appeared to change when titrated with 1 and 2, which was accompanied by a negative-induced CD (circular dichroism) signal that appeared at a wavelength of 295nm. Furthermore, the conformational change in c-myc G-quadruplex DNA induced by 1 and 2have also been confirmed by TEM (transmission electron microscopy) and AFM (atomic force microscopy). Consequently, the replication of c-myc DNA was blocked by 1 and 2, and especially by 2, as verified by PCR (polymerase chain reaction) -stop assay and Western-blot assay. Thus, these ruthenium(II) complexes can be developed as potential inhibitors in chemotherapy through their binding and stabilization of c-myc G-quadruplex DNA. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. The attack navigator

    NARCIS (Netherlands)

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

    2016-01-01

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

  18. The Attack Navigator (Invited)

    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

  19. A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers.

    Science.gov (United States)

    Sugino, N; Kawahara, M; Tatsumi, G; Kanai, A; Matsui, H; Yamamoto, R; Nagai, Y; Fujii, S; Shimazu, Y; Hishizawa, M; Inaba, T; Andoh, A; Suzuki, T; Takaori-Kondo, A

    2017-11-01

    Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDSs) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells. NCD38 elevated H3K27ac level on enhancers of these LSD1 signature genes and newly activated ~500 super-enhancers. Upregulated genes with super-enhancer activation in erythroleukemia cells were enriched in leukocyte differentiation. Eleven genes including GFI1 and ERG, but not CEBPA, were identified as the LSD1 signature with super-enhancer activation. Super-enhancers of these genes were activated prior to induction of the transcripts and myeloid differentiation. Depletion of GFI1 attenuated myeloid differentiation by NCD38. Finally, a single administration of NCD38 causes the in vivo eradication of primary MDS-related leukemia cells with a complex karyotype. Together, NCD38 derepresses super-enhancers of hematopoietic regulators that are silenced abnormally by LSD1, attenuates leukemogenic programs and consequently exerts anti-leukemic effect against MDS-related leukemia with adverse outcome.

  20. 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.

  1. Regulation of the Action of Early Mitotic Inhibitor 1 on the Anaphase-promoting Complex/Cyclosome by Cyclin-dependent Kinases*

    Science.gov (United States)

    Moshe, Yakir; Bar-On, Ortal; Ganoth, Dvora; Hershko, Avram

    2011-01-01

    Cell cycle regulation is characterized by alternating activities of cyclin-dependent kinases (CDKs) and of the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). During S-phase APC/C is inhibited by early mitotic inhibitor 1 (Emi1) to allow the accumulation of cyclins A and B and to prevent re-replication. Emi1 is degraded at prophase by a Plk1-dependent pathway. Recent studies in which the degradation pathway of Emi1 was disrupted have shown that APC/C is activated at mitotic entry despite stabilization of Emi1. These results suggested the possibility of additional mechanisms other than degradation of Emi1, which release APC/C from inhibition by Emi1 upon entry into mitosis. In this study we report one such mechanism, by which the ability of Emi1 to inhibit APC/C is negatively regulated by CDKs. We show that in Plk1-inhibited cells Emi1 is stabilized and phosphorylated, that Emi1 is phosphorylated by CDKs in mitotic but not S-phase cell extracts, and that Emi1 phosphorylation by mitotic cell extracts or purified CDKs markedly reduces the ability of Emi1 to bind and to inhibit APC/C. Finally, we show that the addition of extracts from S-phase cells to extracts from mitotic cells protects Emi1 from CDK-mediated inactivation. PMID:21454540

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

    Science.gov (United States)

    Khalighi, Mousaalreza; Tirry, Luc; Van Leeuwen, Thomas

    2014-03-01

    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 of well-characterised resistant strains of Tetranychus urticae, and also selected for cyflumetofen resistance in the laboratory. Cross-resistance to cyflumetofen and cyenopyrafen was detected in field strains, with LC50 values exceeding the registered field dose. Synergism experiments suggested that P450 monooxygenases are involved in resistance, and that the activation mechanism of the two compounds most likely differs. Laboratory selection with cyflumetofen resulted in a highly resistant T. urticae strain that displayed negative cross-resistance to cyenopyrafen. The cross-resistance risk of cyflumetofen and cyenopyrafen documented in this study needs to be integrated in resistance management strategies, especially in regions or crops with a history of frequent acaricide applications, in order to safeguard the efficacy of these compounds with a valuable new mode of action. © 2013 Society of Chemical Industry.

  3. What Causes a Heart Attack?

    Science.gov (United States)

    ... heart attack at age 36, it stopped her "dead in her tracks." Jennifer reminds us how heart disease takes too many of our moms, sisters, and friends from us every day. The more we share our stories, the faster ...

  4. What Is a Heart Attack?

    Science.gov (United States)

    ... blood pressure and excess protein in the urine. Preeclampsia is linked to an increased lifetime risk of heart disease, including CHD, heart attack, heart failure , and high blood pressure. Screening and Prevention Lowering your risk factors for coronary heart disease ...

  5. CAS, interdiction, and attack helicopters

    OpenAIRE

    Groenke, Andrew S.

    2005-01-01

    Within days of a major failed strike by attack helicopters during Operation Iraqi Freedom (OIF) analysts were questioning the value of such platforms on the modern battlefield. As OIF moved from combat to stability operations, helicopter losses from enemy action actually increased seemingly strengthening the argument of those who see the helicopter as unsuitable to some combat operations. Attack helicopter operations have diverged into two distinct categories, interdiction and close air sup...

  6. Software-based Microarchitectural Attacks

    OpenAIRE

    Gruss, Daniel

    2017-01-01

    Modern processors are highly optimized systems where every single cycle of computation time matters. Many optimizations depend on the data that is being processed. Software-based microarchitectural attacks exploit effects of these optimizations. Microarchitectural side-channel attacks leak secrets from cryptographic computations, from general purpose computations, or from the kernel. This leakage even persists across all common isolation boundaries, such as processes, containers, and virtual ...

  7. A computer network attack taxonomy and ontology

    CSIR Research Space (South Africa)

    Van Heerden, RP

    2012-01-01

    Full Text Available of attacks, means that an attack could be mitigated accordingly. The authors extend a previous, initial taxonomy of computer network attacks which forms the basis of a proposed network attack ontology in this paper. The objective of this ontology...

  8. 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…

  9. Time-dependent analysis of attacks

    NARCIS (Netherlands)

    Arnold, Florian; Hermanns, H.; Pulungan, Reza; Stoelinga, Mariëlle Ida Antoinette

    The success of a security attack crucially depends on time: the more time available to the attacker, the higher the probability of a successful attack; when given enough time, any system can be compromised. Insight in time-dependent behaviors of attacks and the evolution of the attacker’s success as

  10. RESIST SRP AGAINST WORMHOLE ATTACK

    Directory of Open Access Journals (Sweden)

    Marjan Kuchaki Rafsanjani

    2013-06-01

    Full Text Available Ad-hoc networks refer to temporary or interim networks which form for special purposes. Actually they are wireless networks with mobile nodes. These networks use no network assisting element for path routing and in these networks available nodes are responsible for path routing. Therefore when malicious nodes want to find a way to interfere with the path routing then the existence of a secure route protocol (SRP can prevent the interference. SRP protocol is one of the secure algorithms of path routing protocol but it is notresistant against wormhole attack. Wormhole attack is considered as a subtle attack in which two malicious nodes make a short connection in network's topology through private or implicit connection and represent two non neighbor nodes as neighbors and prevent the correctoperation of path routing protocol by using this method. One of the methods of preventing wormhole attack is by using packet leashes. We try to decrease the wormhole attack occurrence in this routing protocol by a kind of packet leashes called temporal leashes. We alsowill minimize problems resulting from using temporal leashes by different methods and modifications in its structure.

  11. Subtle Regulation of Potato Acid Invertase Activity by a Protein Complex of Invertase, Invertase Inhibitor, and SUCROSE NONFERMENTING1-RELATED PROTEIN KINASE.

    Science.gov (United States)

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

    2015-08-01

    Slowing down cold-induced sweetening (CIS) of potato (Solanum tuberosum) tubers is of economic importance for the potato industry to ensure high-quality products. The conversion of sucrose to reducing sugars by the acid invertase StvacINV1 is thought to be critical for CIS. Identification of the specific StvacINV1 inhibitor StInvInh2B and the α- and β-subunits of the interacting protein SUCROSE NONFERMENTING1-RELATED PROTEIN KINASE from the wild potato species Solanum berthaultii (SbSnRK1) has led to speculation that invertase activity may be regulated via a posttranslational mechanism that remains to be elucidated. Using bimolecular fluorescence complementation assays, this study confirmed the protein complex by pairwise interactions. In vitro kinase assays and protein phosphorylation analysis revealed that phosphorylation of SbSnRK1α is causal for StvacINV1 activity and that its active form blocks the inhibition of StInvInh2B by SbSnRK1β, whereas its inactive form restores the function of SbSnRK1β that prevents StInvInh2B from repressing StvacINV1. Overexpression of SbSnRK1α in CIS-sensitive potato confirmed that SbSnRK1α has significant effects on acid invertase-associated sucrose degradation. A higher level of SbSnRK1α expression was accompanied by elevated SbSnRK1α phosphorylation, reduced acid invertase activity, a higher sucrose-hexose ratio, and improved chip color. Our results lend new insights into a subtle regulatory mode of invertase activity and provide a novel approach for potato CIS improvement. © 2015 American Society of Plant Biologists. All Rights Reserved.

  12. Subtle Regulation of Potato Acid Invertase Activity by a Protein Complex of Invertase, Invertase Inhibitor, and SUCROSE NONFERMENTING1-RELATED PROTEIN KINASE1

    Science.gov (United States)

    Liu, Tengfei; Zhang, Huiling; Li, Meng; Song, Botao

    2015-01-01

    Slowing down cold-induced sweetening (CIS) of potato (Solanum tuberosum) tubers is of economic importance for the potato industry to ensure high-quality products. The conversion of sucrose to reducing sugars by the acid invertase StvacINV1 is thought to be critical for CIS. Identification of the specific StvacINV1 inhibitor StInvInh2B and the α- and β-subunits of the interacting protein SUCROSE NONFERMENTING1-RELATED PROTEIN KINASE from the wild potato species Solanum berthaultii (SbSnRK1) has led to speculation that invertase activity may be regulated via a posttranslational mechanism that remains to be elucidated. Using bimolecular fluorescence complementation assays, this study confirmed the protein complex by pairwise interactions. In vitro kinase assays and protein phosphorylation analysis revealed that phosphorylation of SbSnRK1α is causal for StvacINV1 activity and that its active form blocks the inhibition of StInvInh2B by SbSnRK1β, whereas its inactive form restores the function of SbSnRK1β that prevents StInvInh2B from repressing StvacINV1. Overexpression of SbSnRK1α in CIS-sensitive potato confirmed that SbSnRK1α has significant effects on acid invertase-associated sucrose degradation. A higher level of SbSnRK1α expression was accompanied by elevated SbSnRK1α phosphorylation, reduced acid invertase activity, a higher sucrose-hexose ratio, and improved chip color. Our results lend new insights into a subtle regulatory mode of invertase activity and provide a novel approach for potato CIS improvement. PMID:26134163

  13. 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

  14. 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.

  15. Directional Migration in Esophageal Squamous Cell Carcinoma (ESCC is Epigenetically Regulated by SET Nuclear Oncogene, a Member of the Inhibitor of Histone Acetyltransferase Complex

    Directory of Open Access Journals (Sweden)

    Xiang Yuan

    2017-11-01

    Full Text Available Directional cell migration is of fundamental importance to a variety of biological events, including metastasis of malignant cells. Herein, we specifically investigated SET oncoprotein, a subunit of the recently identified inhibitor of acetyltransferases (INHAT complex and identified its role in the establishment of front–rear cell polarity and directional migration in Esophageal Squamous Cell Carcinoma (ESCC. We further define the molecular circuits that govern these processes by showing that SET modulated DOCK7/RAC1 and cofilin signaling events. Moreover, a detailed analysis of the spatial distribution of RAC1 and cofilin allowed us to decipher the synergistical contributions of the two in coordinating the advancing dynamics by measuring architectures, polarities, and cytoskeletal organizations of the lamellipodia leading edges. In further investigations in vivo, we identified their unique role at multiple levels of the invasive cascade for SET cell and indicate the necessity for their functional balance to enable efficient invasion as well. Additionally, SET epigenetically repressed miR-30c expression by deacetylating histones H2B and H4 on its promoter, which was functionally important for the biological effects of SET in our cell-context. Finally, we corroborated our findings in vivo by evaluating the clinical relevance of SET signaling in the metastatic burden in mice and a large series of patients with ESCC at diagnosis, observing it's significance in predicting metastasis formation. Our findings uncovered a novel signaling network initiated by SET that epigenetically modulated ESCC properties and suggest that targeting the regulatory axis might be a promising strategy to inhibit migration and metastasis.

  16. Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals.

    Science.gov (United States)

    Olajuyigbe, Folasade M; Demitri, Nicola; De Zorzi, Rita; Geremia, Silvano

    2016-10-31

    Protease inhibitors are key components in the chemotherapy of HIV infection. However, the appearance of viral mutants routinely compromises their clinical efficacy, creating a constant need for new and more potent inhibitors. Recently, a new class of epoxide-based inhibitors of HIV-1 protease was investigated and the configuration of the epoxide carbons was demonstrated to play a crucial role in determining the binding affinity. Here we report the comparison between three crystal structures at near-atomic resolution of HIV-1 protease in complex with the epoxide-based inhibitor, revealing an in-situ epoxide ring opening triggered by a pH change in the mother solution of the crystal. Increased pH in the crystal allows a stereospecific nucleophile attack of an ammonia molecule onto an epoxide carbon, with formation of a new inhibitor containing amino-alcohol functions. The described experiments open a pathway for the development of new stereospecific protease inhibitors from a reactive lead compound.

  17. Towards Synthesis of Attack Trees for Supporting Computer-Aided Risk Analysis

    OpenAIRE

    Pinchinat, Sophie; Acher, Mathieu; Vojtisek, Didier

    2014-01-01

    International audience; Attack trees are widely used in the fields of defense for the analysis of risks (or threats) against electronics systems, computer control systems or physical systems. Based on the analysis of attack trees, practitioners can define actions to engage in order to reduce or annihilate risks. A major barrier to support computer-aided risk analysis is that attack trees can become largely complex and thus hard to specify. This paper is a first step towards a methodology, for...

  18. Further Insight into Crystal Structures of Escherichia coli IspH/LytB in Complex with Two Potent Inhibitors of the MEP Pathway: A Starting Point for Rational Design of New Antimicrobials.

    Science.gov (United States)

    Borel, Franck; Barbier, Elodie; Krasutsky, Sergiy; Janthawornpong, Karnjapan; Chaignon, Philippe; Poulter, C Dale; Ferrer, Jean-Luc; Seemann, Myriam

    2017-11-02

    IspH, also called LytB, a protein involved in the biosynthesis of isoprenoids through the methylerythritol phosphate pathway, is an attractive target for the development of new antimicrobial drugs. Here, we report crystal structures of Escherichia coli IspH in complex with the two most potent inhibitors: (E)-4-mercapto-3-methylbut-2-en-1-yl diphosphate (TMBPP) and (E)-4-amino-3-methylbut-2-en-1-yl diphosphate (AMBPP) at 1.95 and 1.7 Å resolution, respectively. The structure of the E. coli IspH:TMBPP complex exhibited two conformers of the inhibitor. This unexpected feature was exploited to design and evolve new antimicrobial candidates in silico. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Fault Attack on the Authenticated Cipher ACORN v2

    Directory of Open Access Journals (Sweden)

    Xiaojuan Zhang

    2017-01-01

    Full Text Available Fault attack is an efficient cryptanalysis method against cipher implementations and has attracted a lot of attention in recent public cryptographic literatures. In this work we introduce a fault attack on the CAESAR candidate ACORN v2. Our attack is done under the assumption of random fault injection into an initial state of ACORN v2 and contains two main steps: fault locating and equation solving. At the first step, we first present a fundamental fault locating method, which uses 99-bit output keystream to determine the fault injected location with probability 97.08%. And then several improvements are provided, which can further increase the probability of fault locating to almost 1. As for the system of equations retrieved at the first step, we give two solving methods at the second step, that is, linearization and guess-and-determine. The time complexity of our attack is not larger than c·2179.19-1.76N at worst, where N is the number of fault injections such that 31≤N≤88 and c is the time complexity of solving linear equations. Our attack provides some insights into the diffusion ability of such compact stream ciphers.

  20. 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…

  1. 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 24...

  2. 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...

  3. 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...

  4. Complex Patterns of Protease Inhibitor Resistance among Antiretroviral Treatment-Experienced HIV-2 Patients from Senegal: Implications for Second-Line Therapy

    Science.gov (United States)

    Smith, Robert A.; Ba, Selly; Toure, Macoumba; Traore, Fatou; Sall, Fatima; Pan, Charlotte; Blankenship, Lindsey; Montano, Alexandra; Olson, Julia; Dia Badiane, Ndeye Mery; Mullins, James I.; Kiviat, Nancy B.; Hawes, Stephen E.; Sow, Papa Salif; Gottlieb, Geoffrey S.

    2013-01-01

    Protease inhibitor (PI)-based antiretroviral therapy (ART) can effectively suppress HIV-2 plasma load and increase CD4 counts; however, not all PIs are equally active against HIV-2, and few data exist to support second-line therapy decisions. To identify therapeutic options for HIV-2 patients failing ART, we evaluated the frequency of PI resistance-associated amino acid changes in HIV-2 sequences from a cohort of 43 Senegalese individuals receiving unboosted indinavir (n = 18 subjects)-, lopinavir/ritonavir (n = 4)-, or indinavir and then lopinavir/ritonavir (n = 21)-containing ART. Common protease substitutions included V10I, V47A, I54M, V71I, I82F, I84V, L90M, and L99F, and most patients harbored viruses containing multiple changes. Based on genotypic data, we constructed a panel of 15 site-directed mutants of HIV-2ROD9 containing single- or multiple-treatment-associated amino acid changes in the protease-encoding region of pol. We then quantified the susceptibilities of the mutants to the HIV-2 “active” PIs saquinavir, lopinavir, and darunavir using a single-cycle assay. Relative to wild-type HIV-2, the V47A mutant was resistant to lopinavir (6.3-fold increase in the mean 50% effective concentration [EC50]), the I54M variant was resistant to darunavir and lopinavir (6.2- and 2.7-fold increases, respectively), and the L90M mutant was resistant to saquinavir (3.6-fold increase). In addition, the triple mutant that included I54M plus I84V plus L90M was resistant to all three PIs (31-, 10-, and 3.8-fold increases in the mean EC50 for darunavir, saquinavir, and lopinavir, respectively). Taken together, our data demonstrate that PI-treated HIV-2 patients frequently harbor viruses that exhibit complex patterns of PI cross-resistance. These findings suggest that sequential PI-based regimens for HIV-2 treatment may be ineffective. PMID:23571535

  5. FSHR and LHR Expression and Signaling as Well as Maturation and Apoptosis of Cumulus-Oocyte Complexes Following Treatment with FSH Receptor Binding Inhibitor in Sheep

    Directory of Open Access Journals (Sweden)

    Suocheng Wei

    2017-09-01

    Full Text Available Background/Aims: Currently, it remains unknown whether FSH receptor binding inhibitor (FRBI influences follicular development and reproduction functions in humans and animals. The present study aimed to investigate FRBI effects on in vitro maturation (IVM and apoptosis of cumulus-oocyte complexes (COCs of sheep, to determine the effect of FRBI on mRNA and protein levels of FSHR and LHR in COCs, and to elucidate the signal pathway of FRBI effects. Methods: COCs were in vitro cultured for 24h in the IVM media supplemented with varying concentrations of FRBI (0, 10, 20, 30 and 40µg/mL and FSH (10IU/mL. The harvested COCs were observed under an inverted microscope and maturation rates of COCs were determined. Real time RT-PCR and Western blotting were utilized to detect mRNA and protein levels of FSHR and LHR. The concentrations of FSH, LH and caspase-3 were determined using especial ELISA kits for sheep, respectively. Results: Maturation rates of COCs decreased gradually as FRBI concentrations increased from 0 to 40µg/mL, reaching a bottom value of 23.76% of the FRBI-4 group. The maximal apoptosis rate was detected in the FRBI-4 group. IP3 contents of FRBI-3 and FRBI-4 groups were reduced as compared to control group (CG and FSH groups (P<0.05. Levels of FSHR protein of FRBI-3 and FRBI-4 groups as well as LHR protein of FRBI-4 group were significantly less than that of CG and FSH group. FSH contents of four FRBI treatment groups were gradually decreased along with the supplementation doses of FRBI. Caspase-3 contents of FRBI groups were reduced with a maximum reduction of the FRBI-2 group. Conclusion: Our results revealed supplement of FRBI into IVM media could dose-dependently decrease the maturation rate and increase apoptosis rate of sheep COCs. A lower dose of FRBI treatment slightly promoted IP3 production, but a higher dose of FRBI reduced IP3 production. FRBI suppressed the mRNA and protein expression levels of FSHR and LHR in sheep COCs

  6. 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

  7. Trojan Horse Attacking Strategy on Quantum Cryptography

    Science.gov (United States)

    Zeng, Guihua

    2003-08-01

    Trojan horse attacking strategy on quantum cryptography is investigated, three aspects are involved. First, the mechanism for the Trojan horse attacking strategy on quantum cryptography as well as classic cryptography is studied. Then the fragility of the quantum cryptographic algorithm employing EPR pairs as key against the Trojan horse attacking strategy is analyzed. To prevent the Trojan horse attacking strategy, an improvement scheme which makes use of non-orthogonal entangled states is proposed, results show the improvement scheme is robust to the Trojan horse attacking strategy without reducing the security on other kinds of attacking strategies.

  8. DAG-based attack and defense modeling: don’t miss the forest for the attack trees

    NARCIS (Netherlands)

    Kordy, Barbara; Piètre-Cambacédès, Ludovic; Schweitzer, Patrick

    2015-01-01

    This paper presents the current state of the art on attack and defense modeling approaches that are based on directed acyclic graphs (DAGs). DAGs allow for a hierarchical decomposition of complex scenarios into simple, easily understandable and quantifiable actions. Methods based on threat trees and

  9. Finding Multi-step Attacks in Computer Networks using Heuristic Search and Mobile Ambients

    NARCIS (Netherlands)

    Nunes Leal Franqueira, V.

    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

  10. 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 Ida Antoinette; 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

  11. Crony Attack: Strategic Attack’s Silver Bullet

    Science.gov (United States)

    2006-11-01

    by distributing a large amount of private goods to the selectorate—the cronies—can be termed kleptocracies . Many govern- ments do indeed resemble...where the high-private goods kleptocracy is a good model. Furthermore, while not an example of crony attack to affect policy change (as opposed to...information about those nearest to the leader. The relationships part is only the start. Kleptocracies , like orga- nized crime leaders, are clever

  12. Situational panic attacks in social anxiety disorder.

    Science.gov (United States)

    Potter, Carrie M; Wong, Judy; Heimberg, Richard G; Blanco, Carlos; Liu, Shang-Min; Wang, Shuai; Schneier, Franklin R

    2014-01-01

    Panic attacks (PAs) are common in many psychiatric disorders other than panic disorder, especially social anxiety disorder (SAD). PAs have been associated with increased severity, comorbidity, and impairment in many disorders; therefore, PAs can now be used as a descriptive specifier across all DSM-5 disorders. However, the clinical implications of PAs in SAD remain unclear. The aim of the present investigation was to examine demographic and clinical characteristics associated with SAD-related situational panic attacks in a large, representative epidemiological sample of individuals with SAD (N=1138). We compared individuals with SAD who did and did not endorse situational PAs in terms of demographic factors, fear/avoidance of social situations, distress, impairment, and diagnostic comorbidity. Being male, black, Asian, or over 65 years old was associated with a decreased likelihood of experiencing situational PAs, whereas being unemployed was associated with an increased likelihood. Individuals with situational PAs also exhibited greater fear and avoidance of social situations, impairment, coping-oriented substance use, treatment utilization, and concurrent and longitudinal psychiatric comorbidity. Consistent with most epidemiologic studies, the information collected relied on self-report, and not all participants were available for both waves of assessment. The present findings suggest that SAD-related situational PAs are associated with more severe and complex presentations of SAD. Implications for the assessment and treatment of SAD, as well as for the use of PAs as a descriptive specifier for SAD, are discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Security Analysis of Zipper Hash Against Multicollisions Attacks

    Directory of Open Access Journals (Sweden)

    N. Bagheri

    2012-06-01

    Full Text Available In this paper, the existence of multicollisions in Zipper Hash structure, a new Hash structure which was introduced to strengthen the iterated Hash structures, is presented. This study shows that finding multicollisions, i.e. 2k-way collision, in this Hash structure is not much harder than finding such multicollisions in ordinary Merkle - Damgard (MD structure. In fact, the complexity of the attacks is approximately n/2 times harder than what has been found for MD structures. Then, these large multicollisions are used as a tool to find D-way preimage for this structure. The complexity of finding 2K-way multicollisions and 2k-way preimages are (eq and (eq respectively. Similar to what has been proved by Joux for MD, it is shown in this paper that this structure could not be used to create a Hash function with 2n-bit length by concatenating this structure with any other Hash structure by Hash’s output length of n-bite. It is also shown that time complexity of finding a collision for this concatenated structure is (eq which is much smaller than what was expected from generic-birthday attack which would be (eq . In addition, it is shown that increasing the number of rounds of this Hash function can not improve its security against this attack significantly and the attacker can find multicollisions on this Hash function which means that this Hash function has a structural flaw.

  14. Timing Is Everything with Heart Attacks

    Science.gov (United States)

    ... and certain time periods. The study was published online recently in the American Heart Journal . Previous research has suggested that highly stressful events, such as earthquakes and World Cup soccer games, may trigger heart attacks. Stress-related heart attacks ...

  15. 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

  16. Lifestyle Changes for Heart Attack Prevention

    Science.gov (United States)

    ... help prevent your first heart attack. Heart-Healthy Lifestyle Changes A heart-healthy lifestyle can help prevent ... to flow to the heart muscle. Heart-Healthy Lifestyle Changes Treatment for a heart attack usually includes ...

  17. Social engineering attack examples, templates and scenarios

    CSIR Research Space (South Africa)

    Mouton, Francois

    2016-06-01

    Full Text Available link. A social engineering attack targets this weakness by using various manipulation techniques to elicit sensitive information. The field of social engineering is still in its early stages with regard to formal definitions, attack frameworks...

  18. Being active after a heart attack (image)

    Science.gov (United States)

    ... best activity when you start exercising after a heart attack. Start slowly, and increase the amount of time ... best activity when you start exercising after a heart attack. Start slowly, and increase the amount of time ...

  19. Intermittent hypoendorphinaemia in migraine attack.

    Science.gov (United States)

    Baldi, E; Salmon, S; Anselmi, B; Spillantini, M G; Cappelli, G; Brocchi, A; Sicuteri, F

    1982-06-01

    Beta-endorphin (RIA method, previous chromatographic extraction) was evaluated in plasma of migraine sufferers in free periods and during attacks. Decreased levels of the endogenous opioid peptide were found in plasma sampled during the attacks but not in free periods. Even chronic headache sufferers exhibited significantly lowered levels of beta-endorphin, when compared with control subjects with a negative personal and family history of head pains. The mechanism of the hypoendorphinaemia is unknown: lowered levels of the neuropeptide, which controls nociception, vegetative functions and hedonia, could be important in a syndrome such as migraine, characterized by pain, dysautonomia and anhedonia. The impairment of monoaminergic synapses ("empty neuron" condition) constantly present in sufferers from serious headaches, could be due to the fact that opioid neuropeptides, because of a receptoral or metabolic impairment, poorly modulate the respective monoaminergic neurons, resulting in imbalance of synaptic neurotransmission.

  20. Network Attack Reference Data Set

    Science.gov (United States)

    2004-12-01

    fingerprinting tools include QueSO [10] (literally translates to “what OS”) and nmap [11], however there are a number of additional tools available for...Network Attack Reference Data Set J. McKenna and J. Treurniet Defence R&D Canada √ Ottawa TECHNICAL...collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources

  1. Joint Direct Attack Munition (JDAM)

    Science.gov (United States)

    2015-12-01

    Selected Acquisition Report (SAR) RCS: DD-A&T(Q&A)823-503 Joint Direct Attack Munition (JDAM) As of FY 2017 President’s Budget Defense Acquisition...Mission and Description 6 Executive Summary 7 Threshold Breaches 8 Schedule 9 Performance 12 Track to Budget 14 Cost and Funding...15 Low Rate Initial Production 26 Foreign Military Sales 27 Nuclear Costs 29 Unit Cost 30 Cost Variance 33 Contracts 36

  2. Dual Stage SQL Injection Attacks

    OpenAIRE

    Eve, Martin Paul

    2009-01-01

    I came across quite an interesting SQL Injection scenario today. The software in which the vulnerability resides will remain anonymous until fixed, but an abstracted version of the scenario can safely be outlined below.\\ud \\ud The objective of the software is to restrict user accounts to certain IP addresses when accessing a bulletin board. This shows how this can be bypassed using a dual-stage SQL injection attack.

  3. New Multi-step Worm Attack Model

    OpenAIRE

    Robiah, Y.; Rahayu, S. Siti; 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. Fo...

  4. Classifying network attack scenarios using an ontology

    CSIR Research Space (South Africa)

    Van Heerden, RP

    2012-03-01

    Full Text Available ). ?Spear Phishing? refers to targeted social engineering-type email attacks (Jagatic, 2007). ?Physical? refers to manual methods to gain access, for example physically removing the hard drive or breaking the access door to enter a secure server room... the size and utility of the target. The "Target" class is the physical device or entity targeted by an attack. The "Vulnerability" class describes a target vulnerability used by the attacker. The "Phase" class represents an attack model that subdivides...

  5. Terror attacks influence driving behavior in Israel

    Science.gov (United States)

    Stecklov, Guy; Goldstein, Joshua R.

    2004-01-01

    Terror attacks in Israel produce a temporary lull in light accidents followed by a 35% spike in fatal accidents on Israeli roads 3 days after the attack. Our results are based on time-series analysis of Israeli traffic flows, accidents, and terror attacks from January 2001 through June 2002. Whereas prior studies have focused on subjective reports of posttraumatic stress, our study shows a population-level behavioral response to violent terror attacks. PMID:15448203

  6. Attack Graph Construction for Security Events Analysis

    Directory of Open Access Journals (Sweden)

    Andrey Alexeevich Chechulin

    2014-09-01

    Full Text Available The paper is devoted to investigation of the attack graphs construction and analysis task for a network security evaluation and real-time security event processing. Main object of this research is the attack modeling process. The paper contains the description of attack graphs building, modifying and analysis technique as well as overview of implemented prototype for network security analysis based on attack graph approach.

  7. Distance hijacking attacks on distance bounding protocols

    OpenAIRE

    Cremers, Cas; Rasmussen, Kasper Bonne; Čapkun, Srdjan

    2011-01-01

    Distance bounding protocols are typically analyzed with respect to three types of attacks: Distance Fraud, Mafia Fraud, and Terrorist Fraud. We define a fourth main type of attacks on distance bounding protocols, called Distance Hijacking attacks. We show that many proposed distance bounding protocols are vulnerable to these attacks, and we propose solutions to make these protocols resilient to Distance Hijacking. Additionally, we generalize Distance Hijacking to Location Hijacking, to which ...

  8. Cathepsin D inhibitors

    Directory of Open Access Journals (Sweden)

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  9. 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,…

  10. 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...

  11. Attacks and countermeasures on AES and ECC

    DEFF Research Database (Denmark)

    Tange, Henrik; Andersen, Birger

    2013-01-01

    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...

  12. Automated classification of computer network attacks

    CSIR Research Space (South Africa)

    Van Heerden, R

    2013-11-01

    Full Text Available In this paper we demonstrate how an automated reasoner, HermiT, is used to classify instances of computer network based attacks in conjunction with a network attack ontology. The ontology describes different types of network attacks through classes...

  13. 47 CFR 76.1612 - Personal attack.

    Science.gov (United States)

    2010-10-01

    ... 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 personal... 47 Telecommunication 4 2010-10-01 2010-10-01 false Personal attack. 76.1612 Section 76.1612...

  14. Calculating Adversarial Risk from Attack Trees: Control Strength and Probabilistic Attackers

    NARCIS (Netherlands)

    Pieters, Wolter; Davarynejad, Mohsen

    2015-01-01

    Attack trees are a well-known formalism for quantitative analysis of cyber attacks consisting of multiple steps and alternative paths. It is possible to derive properties of the overall attacks from properties of individual steps, such as cost for the attacker and probability of success. However, in

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. Coronary Artery Dissection: Not Just a Heart Attack

    Science.gov (United States)

    ... Aneurysm More Coronary Artery Dissection: Not Just a Heart Attack Updated:Oct 4,2016 Sometimes a heart attack ... Disease Go Red For Women Types of aneurysms Heart Attack • Home • About Heart Attacks Acute Coronary Syndrome (ACS) ...

  1. [ALK inhibitor].

    Science.gov (United States)

    Mano, Hiroyuki

    2011-01-01

    While lung cancer is the leading cause of cancer deaths worldwide, the molecular mechanism underlying its carcinogenesis is mainly unknown. We have discovered a small, fusion-type tyrosine kinase EML4-ALK that is generated through a tiny inversion within the short arm of human chromosome 2. Transgenic mice expressing EML4-ALK in lung developed hundreds of lung cancer nodules soon after birth, but such nodules were readily eradicated upon treatment with an ALK inhibitor. Clinical trials for EML4-ALK-positive lung cancer with an ALK inhibitor is ongoing, with its interim results being highly promising.

  2. Shoulder injuries from attacking motion

    Science.gov (United States)

    Yanagi, Shigeru; Nishimura, Tetsu; Itoh, Masaru; Wada, Yuhei; Watanabe, Naoki

    1997-03-01

    Sports injuries have bothered professional players. Although many medical doctors try to treat injured players, to prevent sports injuries is more important. Hence, it is required to clear a kinematic mechanism of the sport injuries. A shoulder of volleyball attacker or baseball pitcher is often inured by playing motion. The injuries are mainly caused at the end of long head tendon, which is located in the upper side of scapula. Generally, a muscle and tendon have enough strength against tensile force, however, it seems that they are sometimes defeated by the lateral force. It is imagined that the effect of the lateral force has a possibility of injuring the tendon. If we find the influence of the lateral force on the injured portion, the mechanism of injuries must be cleared. In our research, volleyball attacking motion is taken by high speed video cameras. We analyze the motion as links system and obtain an acceleration of an arm and a shoulder from video image data. The generated force at a shoulder joint is calculated and resolved into the lateral and longitudinal forces. Our final goal is to discuss a possibility that the lateral force causes the injuries.

  3. 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.

  4. Differential Fault Attack on KASUMI Cipher Used in GSM Telephony

    Directory of Open Access Journals (Sweden)

    Zongyue Wang

    2014-01-01

    Full Text Available The confidentiality of GSM cellular telephony depends on the security of A5 family of cryptosystems. As an algorithm in this family survived from cryptanalysis, A5/3 is based on the block cipher KASUMI. This paper describes a novel differential fault attack on KAUSMI with a 64-bit key. Taking advantage of some mathematical observations on the FL, FO functions, and key schedule, only one 16-bit word fault is required to recover all information of the 64-bit key. The time complexity is only 232 encryptions. We have practically simulated the attack on a PC which takes only a few minutes to recover all the key bits. The simulation also experimentally verifies the correctness and complexity.

  5. MATHEMATICAL MODEL OF THE MOTION OF A LIGHT ATTACK AIRCRAFT WITH EXTERNAL LOAD SLINGS IN THE EXTREME AREA OF FLIGHT MODES ACCORDING TO THE ANGLE OF ATTACK

    Directory of Open Access Journals (Sweden)

    A. Popov Sergey

    2017-01-01

    Full Text Available For the time being, a combat-capable trainer aircraft has already been used as a light attack aircraft. The quality of mission effectiveness evaluation depends on the degree of relevance of mathematical models used. It is known that the mis- sion efficiency is largely determined by maneuvering capabilities of the aircraft which are realized most fully in extreme angle of attack flight modes. The article presents the study of the effect of Reynolds number, angle of attack and position on the external sling on the parameters characterizing the state of separated-vortex flow, which was conducted using soft- ware complexes such as Solid Works and Ansys Fluent. There given the dependences of the observed parameters for sta- tionary and nonstationary cases of light attack aircraft movement. The article considers the influence of time constants, which characterize the response rate and delaying of separated flow development and attached flow recovery on the state of separated-vortex flow. The author mentions how the speed of angle of attack change influences lift coefficient of a light attack aircraft with external slings due to response rate and delaying of separated flow development and attached flow recovery. The article describes the mathematical model invented by the authors. This is the model of the movements of light attack aircraft with external slings within a vertical flight maneuver, considering the peculiarities of separated-vortex flow. Using this model, there has been obtained the parameters of light attack aircraft output path from the pitch using large an- gles of attack. It is demonstrated that not considering the peculiarities of the separated-vortex flow model of light attack aircraft movements leads to certain increase of height loss at the pullout of the maneuver, which accordingly makes it pos- sible to decrease the height of the beginning of the pullout.

  6. Angiogenesis Inhibitors

    Science.gov (United States)

    ... blood vessels “feed” growing tumors with oxygen and nutrients , allowing the cancer cells to invade nearby tissue , to move throughout ... any angiogenesis inhibitors currently being used to treat cancer in humans? Yes. The U.S. Food and Drug Administration (FDA) has approved bevacizumab to ...

  7. Synthesis, characterization, antimicrobial activity and carbonic anhydrase enzyme inhibitor effects of salicilaldehyde-N-methyl p-toluenesulfonylhydrazone and its Palladium(II), Cobalt(II) complexes

    Science.gov (United States)

    Alyar, Saliha; Adem, Şevki

    2014-10-01

    We report the synthesis of the ligand, salicilaldehyde-N-methyl p-toluenesulfonylhydrazone (salptsmh) derived from p-toluenesulfonicacid-1-methylhydrazide (ptsmh) and its Pd(II) and Co(II) metal complexes were synthesized for the first time. The structure of the ligand and their complexes were investigated using elemental analysis, magnetic susceptibility, molar conductance and spectral (IR, NMR and LC-MS) measurements. Salptsmh has also been characterized by single crystal X-ray diffraction. 1H and 13C shielding tensors for crystal structure were calculated with GIAO/DFT/B3LYP/6-311++G(d,p) methods in CDCl3. The complexes were found to have general composition [ML2]. The results of elemental analysis showed 1:2 (metal/ligand) stoichiometry for all the complex. Magnetic and spectral data indicate a square planar geometry for Pd(II) complex and a distorted tetrahedral geometry for Co(II) complexes. The ligand and its metal chelates have been screened for their antimicrobial activities using the disk diffusion method against the selected Gram positive bacteria: Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, Enterococcus faecalis, Gram negative bacteria: Eschericha coli, Pseudomonas aeruginosa, Klebsiella pneumonia. The inhibition activities of these compounds on carbonic anhydrase II (CA II) and carbonic anhydrase I (CA I) have been investigated by comparing IC50 and Ki values and it has been found that Pd(II) complex have more enzyme inhibition efficiency than salptsmh and Co(II) complex.

  8. 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.

  9. 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].

  10. Ancestry Analysis in the 11-M Madrid Bomb Attack Investigation

    OpenAIRE

    Phillips, Christopher; Prieto, Lourdes; Fondevila, Manuel; Salas, Antonio; G?mez-Tato, Antonio; ?lvarez-Dios, Jos?; Alonso, Antonio; Blanco-Verea, Alejandro; Bri?n, Mar?a; Montesino, Marta; Carracedo, ?ngel; Lareu, Mar?a Victoria

    2009-01-01

    The 11-M Madrid commuter train bombings of 2004 constituted the second biggest terrorist attack to occur in Europe after Lockerbie, while the subsequent investigation became the most complex and wide-ranging forensic case in Spain. Standard short tandem repeat (STR) profiling of 600 exhibits left certain key incriminatory samples unmatched to any of the apprehended suspects. A judicial order to perform analyses of unmatched samples to differentiate European and North African ancestry became a...

  11. Network Design for Reliability and Resilience to Attack

    Science.gov (United States)

    2014-03-01

    nuclear smuggling interdiction, IIE Transactions , vol. 39, no. 1, pp. 314, Jan. 2007. [31] L. V. Snyder, M. P. Scaparra, M. S. Daskin, and R. L. Church...complexity of network reliability analysis: An overview, IEEE Transactions on Reliability, vol. 35, no. 3, pp. 230239, Aug. 1986. [12] L. G. Valiant, The...Kanturska, J.-D. Schmöcker, and A. Fonzone, Attacker-defender models and road network vulnerability. Philosophical transactions . Series A, Math

  12. 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

  13. DDOS ATTACK DETECTION SIMULATION AND HANDLING MECHANISM

    Directory of Open Access Journals (Sweden)

    Ahmad Sanmorino

    2013-11-01

    Full Text Available In this study we discuss how to handle DDoS attack that coming from the attacker by using detection method and handling mechanism. Detection perform by comparing number of packets and number of flow. Whereas handling mechanism perform by limiting or drop the packets that detected as a DDoS attack. The study begins with simulation on real network, which aims to get the real traffic data. Then, dump traffic data obtained from the simulation used for detection method on our prototype system called DASHM (DDoS Attack Simulation and Handling Mechanism. From the result of experiment that has been conducted, the proposed method successfully detect DDoS attack and handle the incoming packet sent by attacker.

  14. Securing internet by eliminating DDOS attacks

    Science.gov (United States)

    Niranchana, R.; Gayathri Devi, N.; Santhi, H.; Gayathri, P.

    2017-11-01

    The major threat caused to the authorised usage of Internet is Distributed Denial of Service attack. The mechanisms used to prevent the DDoS attacks are said to overcome the attack’s ability in spoofing the IP packets source addresses. By utilising Internet Protocol spoofing, the attackers cause a consequential load over the networks destination for policing attack packets. To overcome the IP Spoofing level on the Internet, We propose an Inter domain Packet Filter (IPF) architecture. The proposed scheme is not based on global routing information. The packets with reliable source addresses are not rejected, the IPF frame work works in such a manner. The spoofing capability of attackers is confined by IPF, and also the filter identifies the source of an attack packet by minimal number of candidate network.

  15. Model checking exact cost for attack scenarios

    DEFF Research Database (Denmark)

    Aslanyan, Zaruhi; Nielson, Flemming

    2017-01-01

    Attack trees constitute a powerful tool for modelling security threats. Many security analyses of attack trees can be seamlessly expressed as model checking of Markov Decision Processes obtained from the attack trees, thus reaping the benefits of a coherent framework and a mature tool support....... However, current model checking does not encompass the exact cost analysis of an attack, which is standard for attack trees. Our first contribution is the logic erPCTL with cost-related operators. The extended logic allows to analyse the probability of an event satisfying given cost bounds and to compute...... the exact cost of an event. Our second contribution is the model checking algorithm for erPCTL. Finally, we apply our framework to the analysis of attack trees....

  16. Shooting Alone: The Pre-Attack Experiences and Behaviors of U.S. Solo Mass Murderers.

    Science.gov (United States)

    Gill, Paul; Silver, James; Horgan, John; Corner, Emily

    2017-05-01

    This paper outlines the sociodemographic, developmental, antecedent attack, attack preparation, and commission properties of 115 mass murderers between 1990 and 2014. The results indicate that mass murderer attacks are usually the culmination of a complex mix of personal, political, and social drivers that crystalize at the same time to drive the individual down the path of violent action. We specifically focus upon areas related to prior criminal engagement, leakage, and attack location familiarity. Whether the violence comes to fruition is usually a combination of the availability and vulnerability of suitable targets that suit the heady mix of personal and political grievances and the individual's capability to engage in an attack from both a psychological and technical capability standpoint. Many individual cases share a mixture of unfortunate personal life circumstances coupled with an intensification of beliefs/grievances that later developed into the idea to engage in violence. © 2016 American Academy of Forensic Sciences.

  17. Distance hijacking attacks on distance bounding protocols

    OpenAIRE

    Cremers, Cas; Rasmussen, Kasper Bonne; Čapkun, Srdjan

    2011-01-01

    Distance bounding protocols are typically analyzed with respect to three types of attacks: Distance Fraud, Mafia Fraud, and Terrorist Fraud. We define and analyze a fourth main type of attack on distance bounding protocols, called Distance Hijacking. We show that many proposed distance bounding protocols are vulnerable to this type of attack, and we propose solutions to make these protocols resilient to Distance Hijacking. We further show that verifying distance bounding protocols using exist...

  18. Snow fall and heart attacks.

    Science.gov (United States)

    Persinger, M A; Ballance, S E; Moland, M

    1993-03-01

    Total numbers of daily hospital admissions for cardiac emergencies were obtained from 3 hospitals within the Sudbury Basin in Canada for November through March for each of 4 consecutive years (1983-1986). Major diagnostic categories were also differentiated. No statistically significant correlations were found between the amount of snowfall during the day of or the days before or after admissions for the major categories of cardiac emergency. Specific analyses, conducted to reveal possible recondite associations between extreme or cumulative snowfalls and the most extreme days of cardiac emergencies, indicated a chance association. We conclude that the occurrence of heart attacks is independent of snowfall but that, when they occur, they are attributed to shoveling if there has been a recent major snow storm.

  19. Cache timing attacks on recent microarchitectures

    DEFF Research Database (Denmark)

    Andreou, Alexandres; Bogdanov, Andrey; Tischhauser, Elmar Wolfgang

    2017-01-01

    AES or similar algorithms in virtualized environments. This paper applies variants of this cache timing attack to Intel's latest generation of microprocessors. It enables a spy-process to recover cryptographic keys, interacting with the victim processes only over TCP. The threat model is a logically...... separated but CPU co-located attacker with root privileges. We report successful and practically verified applications of this attack against a wide range of microarchitectures, from a two-core Nehalem processor (i5-650) to two-core Haswell (i7-4600M) and four-core Skylake processors (i7-6700). The attack...

  20. 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 treatment...... to nine PIs (telaprevir, boceprevir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, deldeprevir, and grazoprevir) in Huh7.5 cells. We found that most variants showed decreased fitness compared to original viruses. Overall, R155K-, A156G/S-, and D/Q168A/E/H/N/V-variants showed highest...... resistant. For the remaining PIs, most genotype 2-, 4-, 5-, and 6-, but not genotype 3-variants, showed varying resistance levels. Overall, grazoprevir (MK-5172) had the highest efficacy against original viruses and variants.This is the first comprehensive study revealing the impact of described key PI...

  1. Design, parallel synthesis, and crystal structures of biphenyl antithrombotics as selective inhibitors of tissue factor FVIIa complex. Part 1: Exploration of S2 pocket pharmacophores.

    Science.gov (United States)

    Kotian, Pravin L; Krishnan, Raman; Rowland, Scott; El-Kattan, Yahya; Saini, Surendra K; Upshaw, Ramanda; Bantia, Shanta; Arnold, Shane; Babu, Y Sudhakar; Chand, Pooran

    2009-06-01

    Factor VIIa (FVIIa), a serine protease enzyme, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TF x FVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. We report here a novel series of substituted biphenyl derivatives that are highly potent and selective TF x FVIIa inhibitors. Parallel synthesis coupled with structure-based drug design allowed us to explore the S2 pocket of the enzyme active site. A number of compounds with IC(50) value of ring in the S2 pocket. Compounds with these two substituents are the most potent compounds in this series with good selectivity over related serine proteases. These compounds will be further explored for structure-activity relationship.

  2. Cued Panic Attacks in Body Dysmorphic Disorder

    Science.gov (United States)

    Phillips, Katharine A.; Menard, William; Bjornsson, Andri S.

    2013-01-01

    Background Body dysmorphic disorder (BDD) is a common and often severe disorder. Clinical observations suggest that panic attacks triggered by BDD symptoms may be common. However, to our knowledge, no study has examined such panic attacks in BDD. We investigated the prevalence, clinical features, and correlates of BDD-triggered panic attacks in individuals with this disorder. Methods Panic attacks and other variables were assessed using reliable and valid measures in 76 individuals with lifetime DSM-IV BDD. Results 28.9% (95% CI, 18.5%–39.4%) of participants reported lifetime panic attacks triggered by BDD symptoms. The most common triggers of such attacks were feeling that others were looking at or scrutinizing the perceived appearance defects (61.9%), looking in the mirror at perceived defects (38.1%), and being in bright light where perceived defects would be more visible (23.8%). The most common panic attack symptoms were palpitations (86.4%), sweating (66.7%), shortness of breath (63.6%), trembling or shaking (63.6%), and fear of losing control or going crazy (63.6%). Compared to participants without such panic attacks, those with BDD-triggered panic attacks had more severe lifetime BDD, social anxiety, and depressive symptoms, as well as poorer functioning and quality of life on a number of measures. They were also less likely to be employed and more likely to have been psychiatrically hospitalized and to have had suicidal ideation due to BDD. Conclusions Panic attacks triggered by BDD-related situations appear common in individuals with this disorder. BDD-triggered panic attacks were associated with greater symptom severity and morbidity. PMID:23653076

  3. Robustness and structure of complex networks

    Science.gov (United States)

    Shao, Shuai

    This dissertation covers the two major parts of my PhD research on statistical physics and complex networks: i) modeling a new type of attack -- localized attack, and investigating robustness of complex networks under this type of attack; ii) discovering the clustering structure in complex networks and its influence on the robustness of coupled networks. Complex networks appear in every aspect of our daily life and are widely studied in Physics, Mathematics, Biology, and Computer Science. One important property of complex networks is their robustness under attacks, which depends crucially on the nature of attacks and the structure of the networks themselves. Previous studies have focused on two types of attack: random attack and targeted attack, which, however, are insufficient to describe many real-world damages. Here we propose a new type of attack -- localized attack, and study the robustness of complex networks under this type of attack, both analytically and via simulation. On the other hand, we also study the clustering structure in the network, and its influence on the robustness of a complex network system. In the first part, we propose a theoretical framework to study the robustness of complex networks under localized attack based on percolation theory and generating function method. We investigate the percolation properties, including the critical threshold of the phase transition pc and the size of the giant component Pinfinity. We compare localized attack with random attack and find that while random regular (RR) networks are more robust against localized attack, Erdoḧs-Renyi (ER) networks are equally robust under both types of attacks. As for scale-free (SF) networks, their robustness depends crucially on the degree exponent lambda. The simulation results show perfect agreement with theoretical predictions. We also test our model on two real-world networks: a peer-to-peer computer network and an airline network, and find that the real-world networks

  4. Generating attacks in SysML activity diagrams by detecting attack surfaces

    NARCIS (Netherlands)

    Ouchani, Samir; Lenzini, Gabriele

    In the development process of a secure system is essential to detect as early as possible the system’s vulnerable points, the so called attack surfaces, and to estimate how feasible it would be that known attacks breach through them. Even if attack surfaces can be sometimes detected automatically,

  5. Attack Trees for Practical Security Assessment: Ranking of Attack Scenarios with ADTool 2.0

    NARCIS (Netherlands)

    Gadyatskaya, Olga; Jhawar, Ravi; Kordy, P.T.; Lounis, Karim; Mauw, Sjouke; Trujillo-Rasua, Rolando

    2016-01-01

    In this tool demonstration paper we present the ADTool2.0: an open-source software tool for design, manipulation and analysis of attack trees. The tool supports ranking of attack scenarios based on quantitative attributes entered by the user; it is scriptable; and it incorporates attack trees with

  6. 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.

  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. Quantum private query with perfect user privacy against a joint-measurement attack

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Yu-Guang, E-mail: yangyang7357@bjut.edu.cn [College of Computer Science and Technology, Beijing University of Technology, Beijing 100124 (China); State Key Laboratory of Information Security, Institute of Information Engineering, Chinese Academy of Sciences, Beijing 100093 (China); Liu, Zhi-Chao [College of Computer Science and Technology, Beijing University of Technology, Beijing 100124 (China); Li, Jian [School of Computer, Beijing University of Posts and Telecommunications, Beijing 100876 (China); Chen, Xiu-Bo [Information Security Center, State Key Laboratory of Networking and Switching Technology, Beijing University of Posts and Telecommunications, Beijing, 100876 (China); Zuo, Hui-Juan [College of Mathematics and Information Science, Hebei Normal University, Shijiazhuang 050024 (China); Zhou, Yi-Hua; Shi, Wei-Min [College of Computer Science and Technology, Beijing University of Technology, Beijing 100124 (China)

    2016-12-16

    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. - Highlights: • A special classical post-processing ensures the security against the JM attack. • It ensures perfect user privacy. • It ensures lower complexity of communication. Alice's conclusive key rate is 1/6.

  9. 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.

  10. Playing Attack and Defense with Trusted Storage

    DEFF Research Database (Denmark)

    Gonzalez, Javier; Bonnet, Philippe; Bouganim, Luc

    2014-01-01

    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....

  11. 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...

  12. Micromechanics of high temperature hydrogen attack

    NARCIS (Netherlands)

    Schlögl, Sabine M.; Giessen, Erik van der

    1999-01-01

    Hydrogen attack is a material degradation process that occurs at elevated temperatures in hydrogen-rich environments, such as found in petro-chemical installations. Weldments in components such as reactor vessels are particularly susceptible to hydrogen attack. This paper discusses a multi-scale

  13. Drammer : Deterministic Rowhammer attacks on mobile platforms

    NARCIS (Netherlands)

    Van Der Veen, Victor; Fratantonio, Yanick; Lindorfer, Martina; Gruss, Daniel; Maurice, Clémentine; Vigna, Giovanni; Bos, Herbert; Razavi, Kaveh; Giuffrida, Cristiano

    2016-01-01

    Recent work shows that the Rowhammer hardware bug can be used to craft powerful attacks and completely subvert a system. However, existing efforts either describe probabilistic (and thus unreliable) attacks or rely on special (and often unavailable) memory management features to place victim objects

  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 approach...

  15. Revisiting attacker model for smart vehicles

    NARCIS (Netherlands)

    Petit, Jonathan; Feiri, Michael; Kargl, Frank

    Because of the potential impact on user's life in cooperative automated safety applications, the security of Vehicle-to-X communication (V2X) is mandatory. However, the current attacker model used in literature is often too network-oriented, and it is unclear what realistic attacks could be. In this

  16. 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.

  17. 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.

  18. 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.

  19. Protecting Cryptographic Memory against Tampering Attack

    DEFF Research Database (Denmark)

    Mukherjee, Pratyay

    . 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...... but not the computation. Such weaker model can still be practically useful and moreover, may provide nice building-blocks to tackle full-fledged tampering in future. In this dissertation we study different models of memory-tampering and provide a number of solutions with different flavors. Mainly we took two different...

  20. Two Improved Multiple-Differential Collision Attacks

    Directory of Open Access Journals (Sweden)

    An Wang

    2014-01-01

    Full Text Available In CHES 2008, Bogdanov proposed multiple-differential collision attacks which could be applied to the power analysis attacks on practical cryptographic systems. However, due to the effect of countermeasures on FPGA, there are some difficulties during the collision detection, such as local high noise and the lack of sampling points. In this paper, keypoints voting test is proposed for solving these problems, which can increase the success ratio from 35% to 95% on the example of one implementation. Furthermore, we improve the ternary voting test of Bogdanov, which can improve the experiment efficiency markedly. Our experiments show that the number of power traces required in our attack is only a quarter of the requirement of traditional attack. Finally, some alternative countermeasures against our attacks are discussed.

  1. 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.

  2. Structural Hypervariability of the Two Human Protein Kinase CK2 Catalytic Subunit Paralogs Revealed by Complex Structures with a Flavonol- and a Thieno[2,3-d]pyrimidine-Based Inhibitor

    Directory of Open Access Journals (Sweden)

    Karsten Niefind

    2017-01-01

    Full Text Available Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2α, the catalytic subunit of human protein kinase CK2, or its paralog CK2α′ in complex with two ATP-competitive inhibitors—based on either a flavonol or a thieno[2,3-d]pyrimidine framework—are presented. The structures show examples for extreme structural deformations of the ATP-binding loop and its neighbourhood and of the hinge/helix αD region, i.e., of two zones of the broader ATP site environment. Thus, they supplement our picture of the conformational space available for CK2α and CK2α′. Further, they document the potential of synthetic ligands to trap unusual conformations of the enzymes and allow to envision a new generation of inhibitors that stabilize such conformations.

  3. 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.

  4. Automatically Repairing Web Application Firewalls Based on Successful SQL Injection Attacks

    OpenAIRE

    Appelt, Dennis; Panichella, Annibale; Briand, Lionel

    2017-01-01

    Testing and fixing WAFs are two relevant and complementary challenges for security analysts. Automated testing helps to cost-effectively detect vulnerabilities in a WAF by generating effective test cases, i.e., attacks. Once vulnerabilities have been identified, the WAF needs to be fixed by augmenting its rule set to filter attacks without blocking legitimate requests. However, existing research suggests that rule sets are very difficult to understand and too complex to be manually fixed. In ...

  5. 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.

  6. 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

  7. 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.

  8. Pharmacophore Modelling and 4d-Qsar Study Of Ruthenium(Ii) Arene Complexes As Anticancer Agents (Inhibitors) By Electron Conformational-Genetic Algorithm Method.

    Science.gov (United States)

    Yavuz, Sevtap Çağlar; Sabancı, Nazmiye; Sarıpınar, Emin

    2017-05-28

    The EC-GA method was employed in this study as a 4D-QSAR method, for the identification of the pharmacophore (Pha) of ruthenium(II) arene complex derivatives and quantitative prediction of activity. The arrangement of the computed geometric and electronic parameters for atoms and bonds of each compound occurring in a matrix is known as the electron-conformational matrix of congruity (ECMC). It contains the data from HF/3-21G level calculations. Compounds were represented by a group of conformers for each compound rather than a single conformation, known as fourth dimension to generate the model. ECMCs were compared within a certain range of tolerance values by using the EMRE program and the responsible pharmacophore group for ruthenium(II) arene complex derivatives was found. For selecting the sub-parameter which had the most effect on activity in the series and the calculation of theoretical activity values, the non-linear least square method and genetic algorithm which are included in the EMRE program were used. In addition, compounds were classified as the training and test set and the accuracy of the models was tested by cross-validation statistically. The model for training and test sets attained by the optimum 10 parameters gave highly satisfactory results with R2training= 0.817, q 2=0.718 and SEtraining=0.066, q2ext1 = 0.867, q2ext2 = 0.849, q2ext3 =0.895, ccctr = 0.895, ccctest = 0.930 and cccall = 0.905. Since there is no 4D-QSAR research on metal based organic complexes in the literature, this study is original and supply a powerful tool to the design of novel and selective ruthenium(II) arene complexes. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Synthesis, characterization, antibacterial activities and carbonic anhydrase enzyme inhibitor effects of new arylsulfonylhydrazone and their Ni(II), Co(II) complexes

    Science.gov (United States)

    Özdemir, Ümmühan Özmen; Arslan, Fatma; Hamurcu, Fatma

    2010-01-01

    Ethane sulfonic acide hydrazide ( esh: CH 3CH 2SO 2NHNH 2) derivatives as 5-methylsalicyl-aldehydeethanesulfonylhydrazone ( 5msalesh), 5-methyl-2-hydroxyacetophenoneethane sulfonylhydrazone ( 5mafesh) and their Ni(II), Co(II) complexes have been synthesized for the first time. The structure of these compounds has been investigated by elemental analysis, FT-IR, 1H NMR, 13C NMR, LC/MS, UV-vis spectrophotometric method, magnetic susceptibility, thermal studies and conductivity measurements. The antibacterial activities of synthesized compounds were studied against Gram positive bacteria; Staphylococcus aureus, Bacillus subtilis, Bacillus magaterium and Gram negative bacteria; Salmonella enteritidis, Escherichia coli by using the microdilution broth method. The biological activity screening showed that ligands have more activity than complexes against the tested bacteria. The inhibition activities of these compounds on carbonic anhydrase II (CA II) have been investigated by comparing IC 50 and Ki values and it has been found that 5msalesh and its complexes have more enzyme inhibition efficiency than other compounds.

  10. Evidence synthesis and decision modelling to support complex decisions: stockpiling neuraminidase inhibitors for pandemic influenza usage [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Samuel I. Watson

    2017-03-01

    Full Text Available Objectives: The stockpiling of neuraminidase inhibitor (NAI antivirals as a defence against pandemic influenza is a significant public health policy decision that must be made despite a lack of conclusive evidence from randomised controlled trials regarding the effectiveness of NAIs on important clinical end points such as mortality. The objective of this study was to determine whether NAIs should be stockpiled for treatment of pandemic influenza on the basis of current evidence. Methods: A decision model for stockpiling was designed. Data on previous pandemic influenza epidemiology was combined with data on the effectiveness of NAIs in reducing mortality obtained from a recent individual participant meta-analysis using observational data. Evidence synthesis techniques and a bias modelling method for observational data were used to incorporate the evidence into the model. The stockpiling decision was modelled for adults (≥16 years old and the United Kingdom was used as an example. The main outcome was the expected net benefits of stockpiling in monetary terms. Health benefits were estimated from deaths averted through stockpiling. Results: After adjusting for biases in the estimated effectiveness of NAIs, the expected net benefit of stockpiling in the baseline analysis was £444 million, assuming a willingness to pay of £20,000/QALY ($31,000/QALY. The decision would therefore be to stockpile NAIs. There was a greater probability that the stockpile would not be utilised than utilised. However, the rare but catastrophic losses from a severe pandemic justified the decision to stockpile. Conclusions: Taking into account the available epidemiological data and evidence of effectiveness of NAIs in reducing mortality, including potential biases, a decision maker should stockpile anti-influenza medication in keeping with the postulated decision rule.

  11. 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 atta...

  12. Affect Response to Simulated Information Attack during Complex Task Performance

    Science.gov (United States)

    2014-12-02

    emotion recognition. IEEE International Conference on Multisensor Fusion and Integration for Intelligent Systems, (pp. 114-119). Kim, K. H., Bang, S. W...Disentangling feeling and knowing. Cognition and Emotion, 15, 725-747. Novak, D., Mihelj, M., & Munih, M. (2012). A survey of methods for data fusion ...drawings, specifications, or other data included in this document for any purpose other than Government procurement does not in any way obligate the U.S

  13. Regulation of complement membrane attack complex formation in myocardial infarction.

    OpenAIRE

    Väkevä, A.; Laurila, P; Meri, S.

    1993-01-01

    Recent studies have suggested that the complement (C) system is involved in the development of tissue injury of myocardial infarction. As it is not known why the strictly controlled C system starts to react against autologous heart tissue, we have analyzed the expression of various membrane regulators of C (CR1, DAF, MCP, CD59, C8 binding protein) and the pattern of deposition of C components and plasma C regulators (C4b binding protein and vitronectin) in normal (n = 7) and infarcted (n = 13...

  14. The Increasing Complexity of Hacker Attacks on Personal and ...

    African Journals Online (AJOL)

    Just any one is affected by the services of Information Technology - Transportation Systems, Personal and corporate financial records and systems, Banking and financial institutions, Hospitals and the medical community. The public telephone network, Air Traffic Control, Power systems and other utilities, the government ...

  15. Classification of cyber attacks in South Africa

    CSIR Research Space (South Africa)

    Van Heerden, R

    2016-05-01

    Full Text Available various ATM's throughout South Africa. Two criminals, Motsoane and Masoleng, were arrested in February 2012 and both sentenced to 15 years in jail [36, 37]. 3.10 2013: IOL DDoS Anonymous Africa claimed responsibility for launching a Distributed Denial... of Service (DDoS) attack on the Independent Newspaper web site iol.co.za. The attack was in response to claims that the IOL group supports Zimbabwean president Robert Mugabe. The following taunt was sent to boast about the attack: “IOL bad boys bad boys...

  16. Advanced meet-in-the-middle preimage attacks: First results on full tiger, and improved results on MD4 and SHA-2

    DEFF Research Database (Denmark)

    Guo, Jian; Ling, San; Wang, Huaxiong

    2010-01-01

    We revisit narrow-pipe designs that are in practical use, and their security against preimage attacks. Our results are the best known preimage attacks on Tiger, MD4, and reduced SHA-2, with the result on Tiger being the first cryptanalytic shortcut attack on the full hash function. Our attacks runs...... in time 2188.8 for finding preimages, and 2188.2 for second-preimages. Both have memory requirement of order 28, which is much less than in any other recent preimage attacks on reduced Tiger. Using pre-computation techniques, the time complexity for finding a new preimage or second-preimage for MD4 can...

  17. Warning Signs of Heart Attack, Stroke and Cardiac Arrest

    Science.gov (United States)

    ... Heart Attack WARNING SIGNS OF HEART ATTACK, STROKE & CARDIAC ARREST HEART ATTACK WARNING SIGNS CHEST DISCOMFORT Most heart ... to the hospital immediately. Learn more about stroke CARDIAC ARREST WARNING SIGNS SUDDEN LOSS OF RESPONSIVENESS No response ...

  18. 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.

  19. Binding of AR to SMRT/N-CoR complex and its co-operation with PSA promoter in prostate cancer cells treated with natural histone deacetylase inhibitor NaB.

    Science.gov (United States)

    Trtkova, K; Paskova, L; Matijescukova, N; Strnad, M; Kolar, Z

    2010-01-01

    Signaling through the androgen receptor (AR) plays a critical role in prostate cancer progression. The AR is a classical nuclear receptor (NR) providing a link between signaling molecule and transcription response. Histone deacetylase inhibitors- (HDACI) have antiproliferative and proapoptotic effects on prostate cancer cells and their implication in silence AR signaling may have potential therapeutic use. We aimed to study the inhibitory effects of the corepressor SMRT (Silencing Mediator for Retinoid and Thyroid -hormone receptors) which forms a complex together with nuclear receptor corepressor (N-CoR) and with histone deacetylase 3 (HDAC3) on AR activity.The androgen-sensitive prostate cancer cell line LNCaP and androgen-insensitive prostate cancer cell line C4-2 both AR-positive, and androgen-insensitive DU145 and PC3 prostate cancer cell lines were treated with two HDACIs, sodium butyrate (NaB) and/or trichostatin A (TSA). We amplified immunoprecipitated DNA by conventional PCR and in the -following step we used the chromatin immunoprecipitation (ChIP) analysis coupled with quantitative PCR for monitoring NaB induced formation of AR-SMRT/N-CoR complex binding on the PSA promoter. The co-immunoprecipitation assay revealed increase in AR-SMRT formation in NaB treated cells. Simultaneously, the Western blot analysis showed a significant decrease in AR protein expression. In conclusion, the inhibitory effect of NaB on AR gene expression seems to be specific and unique for prostate cancer AR-positive cell lines and corresponds with its ability to stimulate AR-SMRT complex formation. We suggest that AR and SMRT/N-CoR corepressors may form a stable complex in vitro and NaB may facilitate the interaction between AR nuclear steroid receptor and SMRT corepressor prote.

  20. Structural analysis of human dihydrofolate reductase as a binary complex with the potent and selective inhibitor 2,4-diamino-6-{2'-O-(3-carboxypropyl)oxydibenz[b,f]-azepin-5-yl}methylpteridine reveals an unusual binding mode.

    Science.gov (United States)

    Cody, Vivian; Pace, Jim; Nowak, Jessica

    2011-10-01

    In order to understand the structure-activity profile observed for a series of substituted dibenz[b,f]azepine antifolates, the crystal structure of the binary complex of human dihydrofolate reductase (hDHFR) with the potent and selective inhibitor 2,4-diamino-6-{2'-O-(3-carboxypropyl)oxydibenz[b,f]-azepin-5-yl}methylpteridine (PT684) was determined to 1.8 Å resolution. These data revealed that the carboxylate side chain of PT684 occupies two alternate positions, neither of which interacts with the conserved Arg70 in the active-site pocket, which in turn hydrogen bonds to water. These observations are in contrast to those reported for the ternary complex of mouse DHFR (mDHFR) with NADPH [Cody et al. (2008), Acta Cryst. D64, 977-984], in which the 3-carboxypropyl side chain of PT684 was hydrolyzed to its hydroxyl derivative, PT684a. The crystallization conditions differed for the human and mouse DHFR crystals (100 mM K2HPO4 pH 6.9, 30% ammonium sulfate for hDHFR; 15 mM Tris pH 8.3, 75 mM sodium cacodylate, PEG 4K for mDHFR). Additionally, the side chains of Phe31 and Gln35 in the hDHFR complex have a single conformation, whereas in the mDHFR complex they occupied two alternative conformations. These data show that the hDHFR complex has a decreased active-site volume compared with the mDHFR complex, as reflected in a relative shift of helix C (residues 59-64) of 1.2 Å, and a shift of 1.5 Å compared with the ternary complex of Pneumocystis carinii DHFR (pcDHFR) with the parent dibenz[b,f]azepine PT653. These data suggest that the greater inhibitory potency of PT684 against pcDHFR is consistent with the larger active-site volume of pcDHFR and the predicted interactions of the carboxylate side chain with Arg75.

  1. 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.

  2. Password-Only Authenticated Three-Party Key Exchange Proven Secure against Insider Dictionary Attacks

    Science.gov (United States)

    Nam, Junghyun; Choo, Kim-Kwang Raymond

    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. PMID:25309956

  3. Password-Only Authenticated Three-Party Key Exchange Proven Secure against Insider Dictionary Attacks

    Directory of Open Access Journals (Sweden)

    Junghyun Nam

    2014-01-01

    Full Text Available 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.

  4. Modeling substrate- and inhibitor-bound forms of liver alcohol dehydrogenase: chemistry of mononuclear nitrogen/sulfur-ligated zinc alcohol, formamide, and sulfoxide complexes.

    Science.gov (United States)

    Makowska-Grzyska, Magdalena M; Jeppson, Peter C; Allred, Russell A; Arif, Atta M; Berreau, Lisa M

    2002-09-23

    Using a mixed nitrogen/sulfur ligand possessing a single internal hydrogen bond donor (N,N-bis-2-(methylthio)ethyl-N-(6-amino-2-pyridylmethyl)amine (bmapa)), we prepared and structurally and spectroscopically characterized a series of zinc complexes possessing a single alcohol ([(bmapa)Zn(MeOH)](ClO(4))(2) (1)), formamide ([(bmapa)Zn(DMF)](ClO(4))(2) (3), [(bmapa)Zn(NMF)](ClO(4))(2) (4)), or sulfoxide ([(bmapa)Zn(DMSO)](ClO(4))(2) (7), [(bmapa)Zn(TMSO)](ClO(4))(2) (8)) ligand. X-ray crystallographic characterization was obtained for 1.MeOH, 3, 4, 7.DMSO, and 8. To enable studies of the influence of the single hydrogen bond donor amino group of the bmapa ligand on the chemistry of zinc/neutral oxygen donor binding interactions, analogous alcohol ([(bmpa)Zn(MeOH)](ClO(4))(2) (2)), formamide ([(bmpa)Zn(DMF)](ClO(4))(2) (5), [(bmpa)Zn(NMF)](ClO(4))(2) (6)), and sulfoxide ([(bmpa)Zn(DMSO)](ClO(4))(2) (9), [(bmpa)Zn(TMSO)](ClO(4))(2) (10)) complexes of the bmpa (N,N-bis-2-(methylthio)ethyl-N-(2-pyridylmethyl)amine) ligand system were generated and characterized. Of these, 2, 5, 6, and 9.2DMSO were characterized by X-ray crystallography. Solution spectroscopic methods ((1)H and (13)C NMR, FTIR) were utilized to examine the formamide binding properties of 3-6 in CH(3)CN and CH(3)NO(2) solutions. Conclusions derived from this work include the following: (1) the increased donicity of formamide and sulfoxide donors (versus alcohols) makes these competitive ligands for a cationic N/S-ligated zinc center, even in alcohol solution, (2) the inclusion of a single internal hydrogen bond donor, characterized by a heteroatom distance of approximately 2.80-2.95 A, produces subtle structural perturbations in N/S-ligated zinc alcohol, formamide, or sulfoxide complexes, (3) the heteroatom distance of a secondary hydrogen-bonding interaction involving the oxygen atom of a zinc-coordinated alcohol, formamide, and sulfoxide ligand is reduced with increasing donicity of the exogenous ligand

  5. 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...

  6. Outdoor Air Pollution, Heart Attack and Stroke

    Science.gov (United States)

    Elevated outdoor ambient air particle pollution triggers heart attacks, strokes, and abnormal heart rhythms and worsens heart failure in individuals at high risk due to underlying medical conditions. Emergency Medical Services in communities are the first responders to these eme...

  7. 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.

  8. How Is a Heart Attack Treated?

    Science.gov (United States)

    ... heart attack at age 36, it stopped her "dead in her tracks." Jennifer reminds us how heart disease takes too many of our moms, sisters, and friends from us every day. The more we share our stories, the faster ...

  9. How Is a Heart Attack Diagnosed?

    Science.gov (United States)

    ... heart attack at age 36, it stopped her "dead in her tracks." Jennifer reminds us how heart disease takes too many of our moms, sisters, and friends from us every day. The more we share our stories, the faster ...

  10. Transient ischemic attack: definition and natural history.

    Science.gov (United States)

    Caplan, Louis R

    2006-07-01

    The standard definition of a transient ischemic attack--"a cerebral dysfunction of an ischemic nature lasting no longer than 24 hours with a tendency to recur"--was arrived at arbitrarily and is no longer tenable. Experience shows that attacks are much briefer, usually less than an hour, and many are associated with brain infarction. A newer definition, more consonant with the data, is preferred--"transient ischemic attack is a brief episode of neurological dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than an hour, and without evidence of acute infarction." Patients with transient ischemic attacks require urgent evaluation that includes brain and vascular imaging, blood tests, and often cardiac investigations. Treatment will depend on the nature of the causative cervico-cranial vascular, cardiac, and hematologic abnormalities found on investigation.

  11. 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 ...

  12. 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 ...

  13. Marine Attack on Towed Hydrophone Arrays

    National Research Council Canada - National Science Library

    Kalmijn, Ad

    2002-01-01

    The original objective of the SIO Marine Attack project was to identify the electric and magnetic fields causing sharks to inflict serious damage upon the towed hydrophone arrays of US Navy submarines...

  14. Using agility to combat cyber attacks.

    Science.gov (United States)

    Anderson, Kerry

    2017-06-01

    Some incident response practitioners feel that they have been locked in a battle with cyber criminals since the popular adoption of the internet. Initially, organisations made great inroads in preventing and containing cyber attacks. In the last few years, however, cyber criminals have become adept at eluding defence security technologies and rapidly modifying their exploit strategies for financial or political gains. Similar to changes in military combat tactics, cyber criminals utilise distributed attack cells, real-time communications, and rapidly mutating exploits to minimise the potential for detection. Cyber criminals have changed their attack paradigm. This paper describes a new incident response paradigm aimed at combating the new model of cyber attacks with an emphasis on agility to increase the organisation's ability to respond rapidly to these new challenges.

  15. Being active after your heart attack

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/patientinstructions/000093.htm Being active after your heart attack To use the sharing ... urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows ...

  16. 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.

  17. Neurosurgical sequelae of domestic dog attacks in children.

    Science.gov (United States)

    Kumar, Ramesh; Deleyiannis, Frederic W B; Wilkinson, Corbett; O'Neill, Brent R

    2017-01-01

    OBJECTIVE The authors' goals in this study were to describe a series of dog attacks on children that required neurosurgical consultation and to better understand the pattern of injuries inflicted, the circumstances that place children at risk for attack, and the dog breeds involved. In addition, the authors review the surgical and medical management of these patients. METHODS The authors performed a retrospective review of all children requiring neurosurgical consultation for dog bite at a regional Level 1 pediatric trauma center over a 15-year period. RESULTS A total of 124 children with dog bites to the head, face, and neck were evaluated in the emergency department. Of these, 17 children (13.7%) incurred injuries requiring neurosurgical consultation. Fifty-three percent of victims were female. The mean age at the time of attack was 30 months. Twelve (71%) of the attacks were perpetrated by the family pet, and 13 (76%) occurred at the patient's home. Breeds involved in the attacks included German Shepherd, Pit Bull, American Bulldog, large mixed breed, Labrador Retriever, and Akita, with German Shepherds and Akitas being the most frequently involved. Neurosurgical injuries included nondepressed skull fracture in 5, depressed skull fracture in 10, intracranial hemorrhage in 5, cerebral contusions in 4, dural laceration in 4, pneumocephalus in 5, clinically evident CSF leak in 3, spinal fracture with complete spinal cord injury in 1, stroke in 2, vascular injury in 2, and cranial nerve injury (hypoglossal and facial nerve) in 1. Prophylactic antibiotics were administered in 16 patients (94%). Only 1 patient had a confirmed infection involving the site of injury. Neurosurgical intervention was required in 10 patients (59%) and ranged in severity from debridement and closure of a complex scalp wound to decompressive craniectomy. Neurological deficits, all of which were considered catastrophic, developed in 3 patients (18%). CONCLUSIONS Dog attacks on children

  18. Aminopurvalanol A, a Potent, Selective, and Cell Permeable Inhibitor of Cyclins/Cdk Complexes, Causes the Reduction of in Vitro Fertilizing Ability of Boar Spermatozoa, by Negatively Affecting the Capacitation-Dependent Actin Polymerization

    Directory of Open Access Journals (Sweden)

    Nicola Bernabò

    2017-12-01

    Full Text Available The adoption of high-througput technologies demonstrated that in mature spermatozoa are present proteins that are thought to be not present or active in sperm cells, such as those involved in control of cell cycle. Here, by using an in silico approach based on the application of networks theory, we found that Cyclins/Cdk complexes could play a central role in signal transduction active during capacitation. Then, we tested this hypothesis in the vitro model. With this approach, spermatozoa were incubated under capacitating conditions in control conditions (CTRL or in the presence of Aminopurvalanol A a potent, selective and cell permeable inhibitor of Cyclins/Cdk complexes at different concentrations (2, 10, and 20 μM. We found that this treatment caused dose-dependent inhibition of sperm fertilizing ability. We attribute this event to the loss of acrosome integrity due to the inhibition of physiological capacitation-dependent actin polymerization, rather than to a detrimental effect on membrane lipid remodeling or on other signaling pathways such as tubulin reorganization or MAPKs activation. In our opinion, these data could revamp the knowledge on biochemistry of sperm capacitation and could suggest new perspectives in studying male infertility.

  19. Attack by Pyemotes johnmoseri (Acari: Pyemotidae)

    Science.gov (United States)

    Tulin Askit; Ibrahim Cakmak; John Moser

    2007-01-01

    The Aegean Region of Turkey is one of the largest dried fig producers in the world. A Turkish cultivar sarilop (Ficus carica cv. Calimyrna L.) possesses good qualities for drying process, and has been grown extensively for many years in Turkey. Hypoborus ficus is the most common xylophagous insect attacking fig trees in Aydin (Aks¸it et al. 2003). This pest attacks...

  20. Panic attack history and smoking topography.

    Science.gov (United States)

    Farris, Samantha G; Brown, Lily A; Goodwin, Renee D; Zvolensky, Michael J

    2017-02-01

    Little is known about panic attacks and puffing topography, a behavioral index of the value of smoking reinforcement. This study examined smoking style during the course of smoking of a single cigarette among adult daily smokers with and without a history of panic attacks. Participants (n=124, Mage=43.9, SD=9.7; 44.4% female) were non-treatment seeking daily smokers. Lifetime panic attack history was assessed via diagnostic assessment; 28.2% (n=35) of the sample had a panic attack history. Participants smoked one cigarette during an ad libitum smoking trial. Puff volume, duration, and inter-puff interval were measured using the Clinical Research Support System (CReSS) pocket device. Regression analyses revealed that panic attack status was not associated with significant differences in average puff volume, duration, or inter-puff interval. Multi-level modeling was used to examine puffing trajectories. Puff-level data revealed that there was a significant quadratic time x panic effect for puff volume and duration. Those with a panic attack history demonstrated relatively sustained levels of both puff volume and duration over time, whereas those without a history of panic attacks demonstrated an increase followed by a decrease in volume and duration over time. These effects were not accounted for by the presence of general psychopathology. Smokers with a panic attack history demonstrate more persistent efforts to self-regulate the delivery of nicotine, and thus may be at risk for continued smoking and dependence. Tailored treatment may be needed to address unique vulnerabilities among this group. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Panic Attack History and Smoking Topography

    Science.gov (United States)

    Farris, Samantha G.; Brown, Lily A.; Goodwin, Renee D.; Zvolensky, Michael J.

    2016-01-01

    Background Little is known about panic attacks and puffing topography, a behavioral index of the value of smoking reinforcement. This study examined smoking style during the course of smoking of a single cigarette among adult daily smokers with and without a history of panic attacks. Method Participants (n = 124, Mage = 43.9, SD = 9.7; 44.4% female) were non-treatment seeking daily smokers. Lifetime panic attack history was assessed via diagnostic assessment; 28.2% (n = 35) of the sample had a panic attack history. Participants smoked one cigarette during an ad libitum smoking trial. Puff volume, duration, and inter-puff interval were measured using the Clinical Research Support System (CReSS) pocket device. Results Regression analyses revealed that panic attack status was not associated with significant differences in average puff volume, duration, or inter-puff interval. Multi-level modeling was used to examine puffing trajectories. Puff-level data revealed that there was a significant quadratic time x panic effect for puff volume and duration. Those with a panic attack history demonstrated relatively sustained levels of both puff volume and duration over time, whereas those without a history of panic attacks demonstrated an increase followed by a decrease in volume and duration over time. These effects were not accounted for by the presence of general psychopathology. Discussion Smokers with a panic attack history demonstrate more persistent efforts to self-regulate the delivery of nicotine, and thus may be at risk for continued smoking and dependence. Tailored treatment may be needed to address unique vulnerabilities among this group. PMID:28033542

  2. 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.

  3. 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...

  4. Hierarchy measurement for modeling network dynamics under directed attacks

    Science.gov (United States)

    Rubinson, M.; Levit-Binnun, N.; Peled, A.; Naim-Feil, J.; Freche, D.; Moses, E.

    2017-11-01

    A fundamental issue in the dynamics of complex systems is the resilience of the network in response to targeted attacks. This paper explores the local dynamics of the network attack process by investigating the order of removal of the nodes that have maximal degree, and shows that this dynamic network response can be predicted from the graph's initial connectivity. We demonstrate numerically that the maximal degree M(τ) of the network at time step τ decays exponentially with τ via a topology-dependent exponent. Moreover, the order in which sites are removed can be approximated by considering the network's "hierarchy" function h , which measures for each node Vi how many of its initial nearest neighbors have lower degree versus those that have a higher one. Finally, we show that the exponents we identified for the attack dynamics are related to the exponential behavior of spreading activation dynamics. The results suggest that the function h , which has both local and global properties, is a novel nodal measurement for network dynamics and structure.

  5. A decoy chain deployment method based on SDN and NFV against penetration attack.

    Science.gov (United States)

    Zhao, Qi; Zhang, Chuanhao; Zhao, Zheng

    2017-01-01

    Penetration attacks are one of the most serious network security threats. However, existing network defense technologies do not have the ability to entirely block the penetration behavior of intruders. Therefore, the network needs additional defenses. In this paper, a decoy chain deployment (DCD) method based on SDN+NFV is proposed to address this problem. This method considers about the security status of networks, and deploys decoy chains with the resource constraints. DCD changes the attack surface of the network and makes it difficult for intruders to discern the current state of the network. Simulation experiments and analyses show that DCD can effectively resist penetration attacks by increasing the time cost and complexity of a penetration attack.

  6. An oracle-based attack on CAPTCHAs protected against oracle attacks

    OpenAIRE

    Hernández-Castro, Carlos Javier; R-Moreno, María D.; David F. Barrero; Li, Shujun

    2017-01-01

    CAPTCHAs/HIPs are security mechanisms that try to prevent automatic abuse of services. They are susceptible to learning attacks in which attackers can use them as oracles. Kwon and Cha presented recently a novel algorithm that intends to avoid such learning attacks and "detect all bots". They add uncertainties to the grading of challenges, and also use trap images designed to detect bots. The authors suggest that a major IT corporation is studying their proposal for mainstream implementation....

  7. Expectation-Maximization Tensor Factorization for Practical Location Privacy Attacks

    Directory of Open Access Journals (Sweden)

    Murakami Takao

    2017-10-01

    Full Text Available Location privacy attacks based on a Markov chain model have been widely studied to de-anonymize or de-obfuscate mobility traces. An adversary can perform various kinds of location privacy attacks using a personalized transition matrix, which is trained for each target user. However, the amount of training data available to the adversary can be very small, since many users do not disclose much location information in their daily lives. In addition, many locations can be missing from the training traces, since many users do not disclose their locations continuously but rather sporadically. In this paper, we show that the Markov chain model can be a threat even in this realistic situation. Specifically, we focus on a training phase (i.e. mobility profile building phase and propose Expectation-Maximization Tensor Factorization (EMTF, which alternates between computing a distribution of missing locations (E-step and computing personalized transition matrices via tensor factorization (M-step. Since the time complexity of EMTF is exponential in the number of missing locations, we propose two approximate learning methods, one of which uses the Viterbi algorithm while the other uses the Forward Filtering Backward Sampling (FFBS algorithm. We apply our learning methods to a de-anonymization attack and a localization attack, and evaluate them using three real datasets. The results show that our learning methods significantly outperform a random guess, even when there is only one training trace composed of 10 locations per user, and each location is missing with probability 80% (i.e. even when users hardly disclose two temporally-continuous locations.

  8. 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.

  9. Putative predictors of efficacy for immune checkpoint inhibitors in non-small-cell lung cancer: facing the complexity of the immune system.

    Science.gov (United States)

    Grizzi, Giulia; Caccese, Mario; Gkountakos, Anastasios; Carbognin, Luisa; Tortora, Giampaolo; Bria, Emilio; Pilotto, Sara

    2017-10-23

    In non-small-cell lung cancer (NSCLC) the recent introduction of immunotherapy in daily clinical practice produced a wave of enthusiasm, however, this was rapidly moderated by the evidence that only some patients could experience a relevant clinical benefit. Therefore, a great effort from the scientific community has been dedicated to the identification and validation of reliable biomarkers able to drive the activity of immunotherapeutic agents. Areas covered: This analysis aims to review the main findings about predictive biomarkers for immunotherapy in lung cancer, retracing the history of PD-L1 and focusing on a series of innovative candidates, such as mutational load, immune cell populations and microbiome. Expert commentary: Considering the complexity of the immune system-cancer interactions, the idea of identifying a single biomarker able to drive the activity of different immunotherapeutic agents alone, borrowing the idea of targeted therapy, is likely to represent an unrealistic objective. Nevertheless, the identification of those factors either positively or negatively affecting the response is mandatory in order to recruit the appropriate patients, but also to deeply understand the mechanisms of immune response and improve the clinical benefit deriving from these agents in monotherapy or in a biologically-rationale combination.

  10. 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...

  11. Exploiting Hardware Vulnerabilities to Attack Embedded System Devices: a Survey of Potent Microarchitectural Attacks

    Directory of Open Access Journals (Sweden)

    Apostolos P. Fournaris

    2017-07-01

    Full Text Available Cyber-Physical system devices nowadays constitute a mixture of Information Technology (IT and Operational Technology (OT systems that are meant to operate harmonically under a security critical framework. As security IT countermeasures are gradually been installed in many embedded system nodes, thus securing them from many well-know cyber attacks there is a lurking danger that is still overlooked. Apart from the software vulnerabilities that typical malicious programs use, there are some very interesting hardware vulnerabilities that can be exploited in order to mount devastating software or hardware attacks (typically undetected by software countermeasures capable of fully compromising any embedded system device. Real-time microarchitecture attacks such as the cache side-channel attacks are such case but also the newly discovered Rowhammer fault injection attack that can be mounted even remotely to gain full access to a device DRAM (Dynamic Random Access Memory. Under the light of the above dangers that are focused on the device hardware structure, in this paper, an overview of this attack field is provided including attacks, threat directives and countermeasures. The goal of this paper is not to exhaustively overview attacks and countermeasures but rather to survey the various, possible, existing attack directions and highlight the security risks that they can pose to security critical embedded systems as well as indicate their strength on compromising the Quality of Service (QoS such systems are designed to provide.

  12. Matrix metalloproteinase 9/neutrophil gelatinase associated lipocalin/tissue inhibitor of metalloproteinasess type 1 complexes are localized within cardiomyocytes and serve as a reservoir of active metalloproteinase in porcine female myocardium.

    Science.gov (United States)

    Kiczak, L; Tomaszek, A; Bania, J; Paslawska, U; Zacharski, M; Janiszewski, A; Rybinska, I; Dziegiel, P; von Haehling, S; Ardehali, H; Jankowska, E A; Ponikowski, P

    2014-06-01

    Matrix metalloproteinase 9 (MMP-9) is crucial for physiological tissue repair and pathophysiological myocardial remodeling. The regulation of its functioning has been shown to be mediated by formation of complexes with tissue inhibitor of metalloproteinases 1 (TIMP-1) and neutrophil gelatinase associated lipocalin (NGAL). We investigated the mRNA and protein expression of MMP-9, TIMP-1 and NGAL, the formation of complexes, their gelatinolytic activity and cellular localization in left ventricle (LV) from 10 female pigs with induced systolic heart failure (HF), 5 control pigs, and a woman with severe HF. The MMP-9, TIMP-1 and NGAL mRNA in LV did not differ between diseased and healthy pigs. In all pigs MMP-9, TIMP-1 and NGAL proteins were present in LV as high molecular weight (HMW) complexes (115, 130, 170 and 220 kDa), and no monomers were found. A 80 and 115 kDa gelatinolytically active bands were present in all LV homogenates. A 130-kDa active band was seen only in LV from pigs with severe HF. Similar results were found in the explanted heart of a female patient with severe HF. The incubation of the homogenates of porcine LV at 37°C resulted in appearance of 88 kDa active band, which was accompanied by a decreased intensity of HMW bands. The incubation of the homogenates of porcine LV (depleted of active MMP-9) with trypsin generated 80 and 115 kDa active bands. Immunohistochemistry revealed the presence of MMP-9 in the cytoplasm of porcine cardiomyocytes, but not in cardiofibroblasts. Our data suggest that MMP-9 originates from cardiomyocytes, forms the gelatinolytically inactive complexes with TIMP-1 and NGAL, present in normal and failing myocardium, likely serving as a reservoir of active MMP-9. Further studies are needed to elucidate the role of these HMW complexes in the extracellular matrix remodeling during the progression of HF, which presence should be considered when developing efficient strategies inhibiting myocardial matrix metalloproteinases.

  13. Histone deacetylase inhibitors in cancer therapy.

    Science.gov (United States)

    Lane, Andrew A; Chabner, Bruce A

    2009-11-10

    Epigenetic processes are implicated in cancer causation and progression. The acetylation status of histones regulates access of transcription factors to DNA and influences levels of gene expression. Histone deacetylase (HDAC) activity diminishes acetylation of histones, causing compaction of the DNA/histone complex. This compaction blocks gene transcription and inhibits differentiation, providing a rationale for developing HDAC inhibitors. In this review, we explore the biology of the HDAC enzymes, summarize the pharmacologic properties of HDAC inhibitors, and examine results of selected clinical trials. We consider the potential of these inhibitors in combination therapy with targeted drugs and with cytotoxic chemotherapy. HDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC inhibition also affects acetylation status and function of nonhistone proteins. HDAC inhibitors have demonstrated antitumor activity in clinical trials, and one drug of this class, vorinostat, is US Food and Drug Administration approved for the treatment of cutaneous T-cell lymphoma. Other inhibitors in advanced stages of clinical development, including depsipeptide and MGCD0103, differ from vorinostat in structure and isoenzyme specificity, and have shown activity against lymphoma, leukemia, and solid tumors. Promising preclinical activity in combination with cytotoxics, inhibitors of heat shock protein 90, and inhibitors of proteasome function have led to combination therapy trials. HDAC inhibitors are an important emerging therapy with single-agent activity against multiple cancers, and have significant potential in combination use.

  14. 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.

  15. Power analysis attacks revealing the secrets of smart cards

    CERN Document Server

    Mangard, Stefan; Popp, Thomas

    2008-01-01

    A comprehensive treatment of power analysis attacks and countermeasures. Based on the principle that the only way to defend against power analysis attacks is to understand them, this book explains how power analysis attacks work. It discusses simple and differential power analysis as well as advanced techniques like template attacks.

  16. Transforming Graphical System Models to Graphical Attack Models

    DEFF Research Database (Denmark)

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

    2016-01-01

    approach to transforming graphical system models to graphical attack models in the form of attack trees. Based on an asset in the model, our transformations result in an attack tree that represents attacks by all possible actors in the model, after which the actor in question has obtained the asset....

  17. Fault Analysis Attacks and Its Countermeasure using Elliptic Curve Cryptography

    OpenAIRE

    M. Prabu; R. Shanmugalakshmi

    2010-01-01

    In the last decade, many researchers had published the overall analysis attacks of cryptographic devices against implementation on elliptic curve attacks. Usually such type of information is not sufficient to learn about the individual attacks. Now in this article, we indisputably concentrated on fault analysis attack and its countermeasure.

  18. Modelling Social-Technical Attacks with Timed Automata

    NARCIS (Netherlands)

    David, Nicolas; David, Alexandre; Hansen, René Rydhof; Larsen, K.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

  19. Noncombatants and liability to be attacked in wars

    DEFF Research Database (Denmark)

    Lippert-Rasmussen, Kasper

    2013-01-01

    attack," I mean that S has forfeited his or her right not to be attacked by armed forces. Here, "liable" is used in a normative-cum-legal sense, not descriptively as it is when one says "some colors are liable to darken in perpetual shade," and "attack" is used passively, as an equivalent of be attacked...

  20. Modeling attacking of high skills volleyball players

    Directory of Open Access Journals (Sweden)

    Vladimir Gamaliy

    2014-12-01

    Full Text Available Purpose: to determine the model indicators of technical and tactical actions in the attack highly skilled volleyball players. Material and Methods: the study used statistical data of major international competitions: Olympic Games – 2012 World Championships – 2010, World League – 2010–2014 European Championship – 2010–2014. A total of 130 analyzed games. Methods were used: analysis and generalization of scientific and methodological literature, analysis of competitive activity highly skilled volleyball players, teacher observation, modeling technical and tactical actions in attacking highly skilled volleyball players. Results: it was found that the largest volume application of technical and tactical actions in the attack belongs to the group tactics «supple movement», whose indicator is 21,3%. The smallest amount of application belongs to the group tactics «flight level» model whose indicators is 5,4%, the efficiency of 3,4%, respectively. It is found that the power service in the jump from model parameters used in 51,6% of cases, the planning targets – 21,7% and 4,4% planning to reduce. Attacks performed with the back line, on model parameters used in the amount of 20,8% efficiency –13,7%. Conclusions: we prove that the performance of technical and tactical actions in the attack can be used as model in the control system of training and competitive process highly skilled volleyball players

  1. 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.

  2. 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.

  3. On the anatomy of social engineering attacks : A literature-based dissection of successful attacks

    NARCIS (Netherlands)

    Bullee, Jan-Willem; Montoya, L.; Pieters, Wolter; Junger, Marianne; Hartel, Pieter H.

    2017-01-01

    The aim of this studywas to explore the extent towhich persuasion principles are used in successful social engineering attacks. Seventy-four scenarioswere extracted from 4 books on social engineering (written by social engineers) and analysed. Each scenariowas split into attack steps, containing

  4. 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.

  5. A taxonomy and discussion of software attack technologies

    Science.gov (United States)

    Banks, Sheila B.; Stytz, Martin R.

    2005-03-01

    Software is a complex thing. It is not an engineering artifact that springs forth from a design by simply following software coding rules; creativity and the human element are at the heart of the process. Software development is part science, part art, and part craft. Design, architecture, and coding are equally important activities and in each of these activities, errors may be introduced that lead to security vulnerabilities. Therefore, inevitably, errors enter into the code. Some of these errors are discovered during testing; however, some are not. The best way to find security errors, whether they are introduced as part of the architecture development effort or coding effort, is to automate the security testing process to the maximum extent possible and add this class of tools to the tools available, which aids in the compilation process, testing, test analysis, and software distribution. Recent technological advances, improvements in computer-generated forces (CGFs), and results in research in information assurance and software protection indicate that we can build a semi-intelligent software security testing tool. However, before we can undertake the security testing automation effort, we must understand the scope of the required testing, the security failures that need to be uncovered during testing, and the characteristics of the failures. Therefore, we undertook the research reported in the paper, which is the development of a taxonomy and a discussion of software attacks generated from the point of view of the security tester with the goal of using the taxonomy to guide the development of the knowledge base for the automated security testing tool. The representation for attacks and threat cases yielded by this research captures the strategies, tactics, and other considerations that come into play during the planning and execution of attacks upon application software. The paper is organized as follows. Section one contains an introduction to our research

  6. Rotational Rebound Attacks on Reduced Skein

    DEFF Research Database (Denmark)

    Khovratovich, Dmitry; Nikolić, Ivica; Rechberger, Christian

    2014-01-01

    number of rounds. We also use neutral bits and message modification methods from the practice of collision search in MD5 and SHA-1 hash functions. These methods push the rotational property through more rounds than previous analysis suggested, and eventually establish a distinguishing property......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...... 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...

  7. Limb-shaking transient ischemic attack

    Directory of Open Access Journals (Sweden)

    Abhijit Das

    2013-01-01

    Full Text Available Limb shaking Transient Ischemic Attack is a rare manifestation of carotid-occlusive disease. The symptoms usually present with seizure like activity and often misdiagnosed as focal seizures. Only on careful history the important clinical clues-which may help in differentiating from seizure-are revealed: Lack of Jacksonian march or aura; precipitation by maneuvers that lead to carotid compression. We present the case of an elderly gentleman with recurrent limb shaking transient ischemic attacks that was initially diagnosed as a case of epilepsy. His symptoms responded to optimization of blood pressure. The case report highlights the importance of accurate diagnosis as the treatment of the associated carotid artery occlusion may not only abolish the attacks but also reduce the risk of future stroke.

  8. 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...... twisted polynomials from Ore rings as forgery polynomials. We show how to construct sparse forgery polynomials with full control over the sets of roots. We also achieve complete and explicit disjoint coverage of the key space by these polynomials. We furthermore leverage this new construction...

  9. European Airlines' TFP and the 2001 Attack: Towards Safety in a Risk Society

    Science.gov (United States)

    Michaelides, Panayotis; Theologou, Kostas; Vouldis, Angelos

    The purpose of this paper is to analyze in terms of security the complexity of European Air Transport after the 2001 terrorist attack, taking into account Total Factor Productivity (T.F.P.) change. Our approach regards European Air Transport as a complex system of airplanes, airports and control. The investigation is based on recent data from the Amadeus database for the largest European (EU-27) air transportation companies (1997-2005). The paper employs the Cobb-Douglas specification of the production function and, in this context, tests the hypothesis that the 2001 terrorist attack had a significant influence on the performance of the EU-27 air transportation companies. An interesting finding is that except for some companies that were negatively influenced, several others were positively influenced by the 2001 terrorist attack. The technological level of the companies included in our dataset remained almost unchanged. The empirical findings are discussed and some suggestions are made regarding policy issues.

  10. Crystal structures of cytochrome P450 2B4 in complex with the inhibitor 1-biphenyl-4-methyl-1H-imidazole: ligand-induced structural response through alpha-helical repositioning.

    Science.gov (United States)

    Gay, Sean C; Sun, Ling; Maekawa, Keiko; Halpert, James R; Stout, C David

    2009-06-09

    Two different ligand occupancy structures of cytochrome P450 2B4 (CYP2B4) in complex with 1-biphenyl-4-methyl-1H-imidazole (1-PBI) have been determined by X-ray crystallography. 1-PBI belongs to a series of tight binding, imidazole-based CYP2B4 inhibitors. 1-PBI binding to CYP2B4 yields a type II spectrum with a K(s) value of 0.23 microM and inhibits enzyme activity with an IC(50) value of 0.035 microM. Previous CYP2B4 structures have shown a large degree of structural movement in response to ligand size. With two phenyl rings, 1-PBI is larger than 1-(4-chlorophenyl)imidazole (1-CPI) and 4-(4-chlorophenyl)imidazole (4-CPI) but smaller than bifonazole, which is branched and contains three phenyl rings. The CYP2B4-1-PBI complex is a structural intermediate to the closed CPI and the open bifonazole structures. The B/C-loop reorganizes itself to include two short partial helices while closing one side of the active site. The F-G-helix cassette pivots over the I-helix in direct response to the size of the ligand in the active site. A cluster of Phe residues at the fulcrum of this pivot point allows for dramatic repositioning of the cassette with only a relatively small amount of secondary structure rearrangement. Comparisons of ligand-bound CYP2B4 structures reveal trends in plastic region mobility that could allow for predictions of their position in future structures based on ligand shape and size.

  11. Conditional beam splitting attack on quantum key distribution

    OpenAIRE

    Calsamiglia, John; Barnett, Stephen M.; Lütkenhaus, Norbert

    2001-01-01

    We present a novel attack on quantum key distribution based on the idea of adaptive absorption [calsam01]. The conditional beam splitting attack is shown to be much more efficient than the conventional beam spitting attack, achieving a performance similar to the, powerful but currently unfeasible, photon number splitting attack. The implementation of the conditional beam splitting attack, based solely on linear optical elements, is well within reach of current technology.

  12. Discovering Collaborative Cyber Attack Patterns Using Social Network Analysis

    Science.gov (United States)

    Du, Haitao; Yang, Shanchieh Jay

    This paper investigates collaborative cyber attacks based on social network analysis. An Attack Social Graph (ASG) is defined to represent cyber attacks on the Internet. Features are extracted from ASGs to analyze collaborative patterns. We use principle component analysis to reduce the feature space, and hierarchical clustering to group attack sources that exhibit similar behavior. Experiments with real world data illustrate that our framework can effectively reduce from large dataset to clusters of attack sources exhibiting critical collaborative patterns.

  13. Viden: Attacker Identification on In-Vehicle Networks

    OpenAIRE

    Cho, Kyong-Tak; Shin, Kang

    2017-01-01

    Various defense schemes --- which determine the presence of an attack on the in-vehicle network --- have recently been proposed. However, they fail to identify which Electronic Control Unit (ECU) actually mounted the attack. Clearly, pinpointing the attacker ECU is essential for fast/efficient forensic, isolation, security patch, etc. To meet this need, we propose a novel scheme, called Viden (Voltage-based attacker identification), which can identify the attacker ECU by measuring and utilizi...

  14. Security attack detection algorithm for electric power gis system based on mobile application

    Science.gov (United States)

    Zhou, Chao; Feng, Renjun; Wang, Liming; Huang, Wei; Guo, Yajuan

    2017-05-01

    Electric power GIS is one of the key information technologies to satisfy the power grid construction in China, and widely used in power grid construction planning, weather, and power distribution management. The introduction of electric power GIS based on mobile applications is an effective extension of the geographic information system that has been widely used in the electric power industry. It provides reliable, cheap and sustainable power service for the country. The accurate state estimation is the important conditions to maintain the normal operation of the electric power GIS. Recent research has shown that attackers can inject the complex false data into the power system. The injection attack of this new type of false data (load integrity attack LIA) can successfully bypass the routine detection to achieve the purpose of attack, so that the control center will make a series of wrong decision. Eventually, leading to uneven distribution of power in the grid. In order to ensure the safety of the electric power GIS system based on mobile application, it is very important to analyze the attack mechanism and propose a new type of attack, and to study the corresponding detection method and prevention strategy in the environment of electric power GIS system based on mobile application.

  15. Survival of child after lion attack

    OpenAIRE

    Carlos F Dabdoub; Dabdoub, Carlos B.; Chavez, Mario; Molina, Felipe

    2013-01-01

    Background: Injuries to humans caused by attacks from large predators are very rare, especially in the United States, Europe, or Latin America. A few cases were reported on accidents in zoos or animal farms, being very uncommon in children. The purposes of this report include describing the case of a child who sustained an attack by a lion named ?Bang-Bang?, which resulted in injuries to the head, chest, and abdomen, as well as the subsequent neurosurgical treatment and providing a review of ...

  16. MACHINE LEARNING IMPLEMENTATION FOR THE CLASSIFICATION OF ATTACKS ON WEB SYSTEMS. PART 2

    Directory of Open Access Journals (Sweden)

    K. Smirnova

    2017-11-01

    Full Text Available The possibility of applying machine learning for the classification of malicious requests to aWeb application is considered. This approach excludes the use of deterministic analysis systems (for example, expert systems,and is based on the application of a cascade of neural networks or perceptrons on an approximate model to the real humanbrain. The main idea of the work is to enable to describe complex attack vectors consisting of feature sets, abstract terms forcompiling a training sample, controlling the quality of recognition and classifying each of the layers (networks participatingin the work, with the ability to adjust not the entire network, but only a small part of it, in the training of which a mistake orinaccuracy crept in. The design of the developed network can be described as a cascaded, scalable neural network.When using neural networks to detect attacks on web systems, the issue of vectorization and normalization of features isacute. The most commonly used methods for solving these problems are not designed for the case of deliberate distortion ofthe signs of an attack.The proposed approach makes it possible to obtain a neural network that has been studied in more detail by small features,and also to eliminate the normalization issues in order to avoid deliberately bypassing the intrusion detection system. Byisolating one more group of neurons in the network and teaching it to samples containing various variants of circumvention ofthe attack classification, the developed intrusion detection system remains able to classify any types of attacks as well as theiraggregates, putting forward more stringent measures to counteract attacks. This allows you to follow the life cycle of theattack in more detail: from the starting trial attack to deliberate sophisticated attempts to bypass the system and introducemore decisive measures to actively counteract the attack, eliminating the chances of a false alarm system.

  17. Proteasome inhibitor patents (2010 - present).

    Science.gov (United States)

    Metcalf, Rainer; Scott, Latanya M; Daniel, Kenyon G; Dou, Q Ping

    2014-04-01

    Over the past 3 years, numerous patents and patent applications have been submitted and published involving compounds designed to inhibit the proteasome. Proteasome inhibition has been of great interest in cancer research since disruption of proteolysis leads to a significant buildup of cytotoxic proteins and activation of apoptotic pathways, particularly in rapidly proliferating cells. The current standards in proteasome inhibition are the only FDA-approved inhibitors, bortezomib and carfilzomib. Although these drugs are quite effective in treating multiple myeloma and other blood tumors, there are shortcomings, including toxicities and resistance. Most of the current patents attempt to improve on existing compounds, by increasing bioavailability and selectivity, while attempting to reduce toxicity. A general categorization of similar compounds was employed to evaluate and compare drug design strategies. This review focuses on novel compounds and subsequent analogs developed for proteasome inhibition, used in preventing and treating human cancers. A comprehensive description and categorization of patents related to each type of compound and its derivatives, as well as their uses and efficacies as anticancer agents is included. A review of combination therapy patents has also been included. Although there are many diverse chemical scaffolds being published, there are few patented proteasome inhibitors whose method of inhibition is genuinely novel. Most patents utilize a destructive chemical warhead to attack the catalytic threonine residue of the proteasome active sites. Few patents try to depart from this, emphasizing the need for developing new mechanisms of action and specific targeting.

  18. Synthesis and enantiopreferential DNA-binding profile of late 3d transition metal R- and S-enantiomeric complexes derived from N,N-bis-(1-benzyl-2-ethoxyethane): Validation of R-enantiomer of copper(II) complex as a human topoisomerase II inhibitor.

    Science.gov (United States)

    Arjmand, Farukh; Sharma, Girish Chandra; Muddassir, Mohd; Tabassum, Sartaj

    2011-08-01

    To evaluate the biological preference of chiral drug candidates for molecular target DNA, new potential metal-based chemotherapeutic agents 1-3 (a and b) of late 3d transition metals Ni(II), Cu(II), and Zn(II), respectively, derived from (R)- and (S)-2-amino-2-phenylethanol with CH(2) CH(2)  linker were synthesized and thoroughly characterized. Interaction studies of 1-3 (a and b) with calf thymus DNA in Tris buffer were studied by electronic absorption titrations, luminescence titrations, cyclic voltammetry, and circular dichroism. The results reveal that the extent of DNA binding of R-enantiomer of copper 1a was highest in comparison to rest of the complexes via electrostatic interaction mode. The nuclease activity of 1(a and b) with supercoiled pBR322 DNA was further examined by gel electrophoresis, which reveals that complex 1a exhibits a remarkable DNA cleavage activity (concentration dependent) with pBR322DNA, and the cleavage activity of both enantiomers of complex 1 was significantly enhanced in the presence of activators. The activating efficiency follows the order Asc > H(2) O(2) > MPA for 1a, and reverse order was observed for 1b, because of the differences in enantioselectivity and conformation. Further, it was observed that cleavage reaction involves singlet oxygen species and superoxide radicals via oxidative cleavage mechanism. In addition, complex 1a exhibits significant inhibitory effects on the topoisomerase II (topo II) activity at a very low concentration ∼24 μM, which suggest that complex 1a is indeed catalytic inhibitor or (poison) of human topo II. Copyright © 2011 Wiley-Liss, Inc.

  19. 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…

  20. Durability of Steel Fibres Reinforcement Concrete Beams in Chloride Environment Combined with Inhibitor

    Directory of Open Access Journals (Sweden)

    AbdelMonem Masmoudi

    2016-01-01

    Full Text Available This paper presented the effect of the combination of an inhibitor and steel fibre reinforced concrete (SFRC for concrete structures in chloride environments. Twelve beams were cast and tested to study their flexural behavior. The morphology of steel surfaces using the inhibitor after observing the scanning electron microscope showed a low layer of corrosion products. The steel surface immersed in the inhibitor free solution was seen to have been subject to chloride ions attacks as shown in this study. The interest to the field of the present study is the relatively higher durability of the performance when using the inhibitor. Crack width and crack spacing for beams under the same load showed that the use of SFRC with the inhibitor for concrete structures in chloride environments must have transferred tension across cracks that led to reducing crack spacing without any chloride ions attack.

  1. A Study of Gaps in Attack Analysis

    Science.gov (United States)

    2016-10-12

    Kührer, Thomas Hupperich, Christian Rossow, and Thorsten Holz. Exit from Hell? Re- ducing the Impact of Amplification DDoS Attacks. In Proceedings of...Revisiting Network Protocols for DDoS Abuse. In 21st Annual Network and Distributed System Security Symposium, NDSS 2014, San Diego, California, USA

  2. Using an ontology for network attack planning

    CSIR Research Space (South Africa)

    Van Heerden, R

    2016-09-01

    Full Text Available -1 International Journal of Cyber Warfare and Terrorism, vol. 6(3), 65-78 Using an Ontology for Network Attack Planning Renier van Heerden1,2, Peter Chan2 , Louise Leenen2,3 Jacques Theron4 1 Nelson Mandela Metropolitan University, South Africa 2...

  3. Cyber Attack! Crime or Act of War?

    Science.gov (United States)

    2011-04-13

    informational, or economic.54 Other legal scholars concur in this interpretation, one using the term ― agressive force‖ in lieu of ―armed force‖ but...distributed whiteboard to determine legal responses to online cyber attacks. Internet Research 16, no. 5, (October 20): 475-490. http

  4. Wrap-Attack Pack: Product Packaging Exercise

    Science.gov (United States)

    Lee, Seung Hwan; Hoffman, K. Douglas

    2016-01-01

    Although many marketing courses discuss traditional concepts pertaining to product strategy, concepts specifically relating to packaging are often glossed over. This exercise, "Wrap-Attack Pack," teaches students about the utilitarian and hedonic design elements of packaging. More specifically, the primary objective is to creatively…

  5. Management of an acute asthma attack.

    Science.gov (United States)

    Barnard, Amanda

    2005-07-01

    Despite a more proactive approach to asthma management, which includes an increased range of drugs, wide dissemination of guidelines, and the use of asthma action plans, an acute severe asthma attack is one of the most common emergencies a general practitioner will encounter. This article discusses the management of an acute asthma attack in the general practice setting. Assessment of severity is vital and can be ascertained quite quickly with a brief history and rapid physical examination. It is important to remember that wheeze is an unreliable indicator of the severity of attack and may be absent in severe asthma. The cornerstones of treatment are oxygen and inhaled beta 2 agonists. Beta 2 agonists can be given continuously in severe life threatening asthma. Early administration of systemic steroids is important. Patients discharged to home after treatment of an asthma attack require close follow up including beta 2 agonists for symptom control, review of medications including a consideration of a short course of oral steroids, a written asthma action plan and detailed advice about what to do in case of deterioration in the next 24 hours. They should be reviewed in 24-48 hours.

  6. Understand Your Risk of Heart Attack

    Science.gov (United States)

    ... other risk factors. Overweight and obese adults with risk factors for cardiovascular disease such as high blood pressure, high cholesterol, ... over 40, or if you have multiple risk factors, work especially closely with ... cardiovascular disease. Heart attack prevention should begin early in ...

  7. Afghanistan: Green-on-Blue Attacks

    Science.gov (United States)

    2013-05-02

    spike-insider-attacks- stress- ramadan - fasting , 24 August 2012 37 Yousafzai, Sami and Moreau, Ron, http://www.thedailybeast.com/newsweek/2012/08/26...Ramazan.” “And so the daily pressures that are on some of these [Afghan] troops, compounded by the sacrifice associated with fasting , the nature of

  8. 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)

  9. Attack Classification Schema for Smart City WSNs

    Directory of Open Access Journals (Sweden)

    Victor Garcia-Font

    2017-04-01

    Full Text Available 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.

  10. 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.

  11. 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...

  12. 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…

  13. 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…

  14. 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…

  15. 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.

  16. 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.

  17. Organoiridium Complexes: Anticancer Agents and Catalysts

    Science.gov (United States)

    2014-01-01

    Conspectus Iridium is a relatively rare precious heavy metal, only slightly less dense than osmium. Researchers have long recognized the catalytic properties of square-planar IrI complexes, such as Crabtree’s hydrogenation catalyst, an organometallic complex with cyclooctadiene, phosphane, and pyridine ligands. More recently, chemists have developed half-sandwich pseudo-octahedral pentamethylcyclopentadienyl IrIII complexes containing diamine ligands that efficiently catalyze transfer hydrogenation reactions of ketones and aldehydes in water using H2 or formate as the hydrogen source. Although sometimes assumed to be chemically inert, the reactivity of low-spin 5d6 IrIII centers is highly dependent on the set of ligands. Cp* complexes with strong σ-donor C∧C-chelating ligands can even stabilize IrIV and catalyze the oxidation of water. In comparison with well developed Ir catalysts, Ir-based pharmaceuticals are still in their infancy. In this Account, we review recent developments in organoiridium complexes as both catalysts and anticancer agents. Initial studies of anticancer activity with organoiridium complexes focused on square-planar IrI complexes because of their structural and electronic similarity to PtII anticancer complexes such as cisplatin. Recently, researchers have studied half-sandwich IrIII anticancer complexes. These complexes with the formula [(Cpx)Ir(L∧L′)Z]0/n+ (with Cp* or extended Cp* and L∧L′ = chelated C∧N or N∧N ligands) have a much greater potency (nanomolar) toward a range of cancer cells (especially leukemia, colon cancer, breast cancer, prostate cancer, and melanoma) than cisplatin. Their mechanism of action may involve both an attack on DNA and a perturbation of the redox status of cells. Some of these complexes can form IrIII-hydride complexes using coenzyme NAD(P)H as a source of hydride to catalyze the generation of H2 or the reduction of quinones to semiquinones. Intriguingly, relatively unreactive organoiridium

  18. Natural Inhibitors of Maillard Browning

    Science.gov (United States)

    2013-12-01

    incorporated into pre-selected candidate ration components for evaluation via storage, sensory and chemical analysis. The concentration of inhibitor was...inhibiting Maillard browning, also known as non-enzymatic browning, a complex reaction which can lead to darkening of color, off- odors , off-flavors...nutritional intake, and decrease waste due to non-consumption of sensory degraded ration components. 1.1 Maillard Browning Maillard browning, also

  19. Words Mean Things: The Case for Information System Attack and Control System Attack

    Science.gov (United States)

    2008-10-31

    FINAL 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Words Mean Things: The Case for Information System Attack and Control System...Standard Form 298 (Rev. 8-98) NAVAL WAR COLLEGE Newport, R.I. WORDS MEAN THINGS: THE CASE FOR INFORMATION SYSTEM ATTACK AND... words , the DepSecDef definition acknowledges the existence of a new domain, but strongly implies the accepted definition of CNO is sufficient to

  20. Chosen-name attacks: An overlooked class of type-flaw attacks

    OpenAIRE

    Ceelen, Pieter; Mauw, Sjouke; Radomirovic, Sasa

    2008-01-01

    In the context of Dolev-Yao style analysis of security protocols, we consider the capability of an intruder to dynamically choose and assign names to agents. This capability has been overlooked in all significant protocol verification frameworks based on formal methods. We identify and classify new type-flaw attacks arising from this capability. Several examples of protocols that are vulnerable to this type of attack are given, including Lowe’s modification of KSL. The consequences for automa...