Reconciling Malicious and Accidental Risk in Cyber Security

Abstract Consider the question whether a cyber security investment is cost-effective. The result will depend on the expected frequency of attacks. Contrary to what is referred to as threat event frequencies or hazard rates in safety risk management, frequencies of targeted attacks are not independent from system design, due to the strategic behaviour of attackers. Although there are risk assessment methods that deal with strategic attackers, these do not provide expected frequencies as outputs, making it impossible to integrate those in existing (safety) risk management practices. To overcome this problem, we propose to extend the FAIR (Factor Analysis of Information Risk) framework to support malicious, targeted attacks. Our approach is based on (1) a clear separation of system vulnerability and environmental threat event frequencies, and (2) deriving threat event frequencies from attacker resources and attacker strategies rather than estimating them directly, drawing upon work in adversarial risk analysis. This approach constitutes an innovative way to quantify expected attack frequencies as a component of (information) security metrics for investment decisions

Ixonnexin from Tick Saliva Promotes Fibrinolysis by Interacting with Plasminogen and Tissue-Type Plasminogen Activator, and Prevents Arterial Thrombosis

Tick saliva is a rich source of modulators of vascular biology. We have characterized Ixonnexin, a member of the “Basic-tail” family of salivary proteins from the tick Ixodes scapularis. Ixonnexin is a 104 residues (11.8 KDa), non-enzymatic basic protein which contains 3 disulfide bonds and a C-terminal rich in lysine. It is homologous to SALP14, a tick salivary FXa anticoagulant. Ixonnexin was produced by ligation of synthesized fragments (51–104) and (1–50) followed by folding. Ixonnexin, like SALP14, interacts with FXa. Notably, Ixonnexin also modulates fibrinolysis in vitro by a unique salivary mechanism. Accordingly, it accelerates plasminogen activation by tissue-type plasminogen activator (t-PA) with Km 100 nM; however, it does not affect urokinase-mediated fibrinolysis. Additionally, lysine analogue ε-aminocaproic acid inhibits Ixonnexin-mediated plasmin generation implying that lysine-binding sites of Kringle domain(s) of plasminogen or t-PA are involved in this process. Moreover, surface plasmon resonance experiments shows that Ixonnexin binds t-PA, and plasminogen (KD 10 nM), but not urokinase. These results imply that Ixonnexin promotes fibrinolysis by supporting the interaction of plasminogen with t-PA through formation of an enzymatically productive ternary complex. Finally, in vivo experiments demonstrates that Ixonnexin inhibits FeCl3-induced thrombosis in mice. Ixonnexin emerges as novel modulator of fibrinolysis which may also affect parasite-vector-host interactions

Cyr61/CCN1 Displays High-Affinity Binding to the Somatomedin B 1–44 Domain of Vitronectin

OV) family of extracellular-associated (matricellular) proteins that present four distinct functional modules, namely insulin-like growth factor binding protein (IGFBP), von Willebrand factor type C (vWF), thrombospondin type 1 (TSP), and C-terminal growth factor cysteine knot (CT) domain. While heparin sulphate proteoglycans reportedly mediate the interaction of Cyr61 with the matrix and cell surface, the role of other extracellular associated proteins has not been revealed. at high concentrations attenuate Cyr61 binding to immobilized VTNC, while monomeric VTNC was ineffective. Therefore, immobilization of VTNC exposes cryptic epitopes that recognize Cyr61 with high affinity, as reported for a number of antibodies, β-endorphin, and other molecules. domain suggests that VTNC represent a point of anchorage for CCN family members to the matrix. Results are discussed in the context of the role of CCN and VTNC in matrix biology and angiogenesis

Cyr61 displays high-affinity binding to immobilized VTNC.

<p>(<b>A</b>) Sensorgrams for Cyr61 (in nM: <i>a</i>, 40; <i>b</i>, 20; <i>c</i>, 5; <i>d</i>, 2.5) binding to immobilized monomeric VTNC. (<b>B</b>) Sensorgrams show Cyr61 (in nM: <i>a</i>, 50; <i>b</i>, 25, <i>c</i>, 12.5; <i>d</i>, 6.25) binding to multimeric VTNC. Data were fitted using global two-state binding model. RU, resonance units. (<b>C</b>) and (<b>D</b>) solid-phase-binding assay for Cyr61 (0–1 µM) interaction with immobilized monomeric or multimeric VTNC, respectively. Binding was estimated with anti-Cyr61 monoclonal antibody followed by alkaline-phosphatase labeled anti-mouse secondary antibody and appropriate substrate as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009356#s4" target="_blank">Materials and Methods</a>. (<b>E</b>) and (<b>F</b>) Semi log-transformation of the data depicted in (<b>C</b>) and (<b>D</b>), respectively. The (apparent) <i>K_D</i> values for Cyr61/VTNC interactions were calculated by nonlinear regression analysis of the binding data according to the Langmuir isotherm equation. All treatments were performed in quadruplicate or quintuplicate (n = 3).</p

Molecular Analysis of CPRα, a MATα-Specific Pheromone Receptor Gene of Cryptococcus neoformans

The putative Cryptococcus neoformans pheromone receptor gene CPRα was isolated and studied for its role in mating and filamentation. CPRα is MATα specific and located adjacent to STE12α at the MATα locus. It encodes a protein which possesses high sequence similarity to the seven-transmembrane class of G-protein-coupled pheromone receptors reported for other basidiomycetous fungi. Strains containing a deletion of the CPRα gene exhibited drastic reductions in mating efficiency but were not completely sterile. Δcprα cells displayed wild-type mating efficiency when reconstituted with the wild-type CPRα gene. Hyphal production on filament agar was not affected in the Δcprα strain, indicating no significant role for CPRα in sensing environmental cues during haploid fruiting. The wild-type MATα CPRα strain produced abundant hyphae in response to synthetic MATa pheromone; however, the hyphal response to pheromone by Δcprα cells was significantly reduced. Exposure of wild-type cells to synthetic MATa pheromone for 2 h induced MFα pheromone expression, whereas unexposed cells showed only basal levels of the MFα transcript. The Δcprα cells, however, exhibited only basal levels of MFα message with or without pheromone exposure, suggesting that CPRα and MFα are components of the same signaling pathway

Cyr61 prevents U937 cell adhesion to vitronectin.

<p>uPAR-bearing U937 cells were incubated for 120 minutes with VTNC-coated wells previously incubated with buffer or Cyr61 or PAI-1 (1.5 µM) as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009356#s4" target="_blank">Materials and Methods</a>. As a control, wells were coated with gelatin only. One hundred % cell adhesion was estimated in the presence of buffer (vehicle) only, and 0% as adhesion to gelatin. Results from quintuplicate experiments are shown.</p

Cyr61 does not interact with SMTB ^1–44 domain in solution.

<p>(<b>A</b>) Isothermal titration calorimetry for stable mutant PAI-1 interaction with SMTB ^1–44. Base line-adjusted heats per injection of SMTB ^1–44 (10 µM) into PAI-1 (1.0 µM). (<b>B</b>) Molar enthalpies per injection for PAI-1 interaction with SMTB ^1–44. Filled circles, measured enthalpies; solid line, fit of experimental data to a single-site binding model. Thermodynamic parameters: Δ<i>H</i> = −24±1.34 kcal/mol. (<b>C</b>) Base line-adjusted heats per injection of SMTB ^1–44 (10 µM) into Cyr61 (1.0 µM). (<b>D</b>) Molar enthalpies per injection for SMTB ^1–44 interaction with Cyr61 where no heat exchange is observable. Filled circles, measured enthalpies.</p