Solid phase synthesis of Smac/DIABLO-derived peptides using a 'Safety-Catch' resin:Identification of potent XIAP BIR3 antagonists

The N-terminal sequence of the Smac/DIABLO protein is known to be involved in binding to the BIR3 domain of the anti-apoptotic proteins IAPs, antagonizing their action. Short peptides and peptide mimetics based on the first 4-residues of Smac/DIABLO have been demonstrated to re-sensitize resistant cancer cells, over-expressing IAPs, to apoptosis. Based on the well-defined structural basis for this interaction, a small focused library of C-terminal capped Smac/DIABLO-derived peptides was designed in silico using docking to the XIAP BIR3 domain. The top-ranked computational hits were conveniently synthesized employing Solid Phase Synthesis (SPS) on an alkane sulfonamide 'Safety-Catch' resin. This novel approach afforded the rapid synthesis of the target peptide library with high flexibility for the introduction of various C-terminal amide-capping groups. The library members were obtained in high yield (>65%) and purity (>85%), upon nucleophilic release from the activated resin by treatment with various amine nucleophiles. In vitro caspase-9 activity reconstitution assays of the peptides in the presence of the recombinant BIR3-domain of human XIAP (500nM) revealed N-methylalanyl-tertiarybutylglycinyl-4-(R)-phenoxyprolyl-N-biphenylmethyl carboxamide (11a) to be the most potent XIAP BIR3 antagonist of the series synthesized inducing 93% recovery of caspase-9 activity, when used at 1µM concentration. Compound (11a) also demonstrated moderate cytotoxicity against the breast cancer cell lines MDA-MB-231 and MCF-7, compared to the Smac/DIABLO-derived wild-type peptide sequences that were totally inactive in the same cell lines.

A Tunable Encryption Scheme and Analysis of Fast Selective Encryption for CAVLC and CABAC in H.264/AVC

Recently, two fast selective encryption methods for context-adaptive variable length coding and context-adaptive binary arithmetic coding in H.264/AVC were proposed by Shahid et al. In this paper, it was demonstrated that these two methods are not as efficient as only encrypting the sign bits of nonzero coefficients. Experimental results showed that without encrypting the sign bits of nonzero coefficients, these two methods can not provide a perceptual scrambling effect. If a much stronger scrambling effect is required, intra prediction modes, and the sign bits of motion vectors can be encrypted together with the sign bits of nonzero coefficients. For practical applications, the required encryption scheme should be customized according to a user's specified requirement on the perceptual scrambling effect and the computational cost. Thus, a tunable encryption scheme combining these three methods is proposed for H.264/AVC. To simplify its implementation and reduce the computational cost, a simple control mechanism is proposed to adjust the control factors. Experimental results show that this scheme can provide different scrambling levels by adjusting three control factors with no or very little impact on the compression performance. The proposed scheme can run in real-time and its computational cost is minimal. The security of the proposed scheme is also discussed. It is secure against the replacement attack when all three control factors are set to one.

GHMP Kinases - Structures, Mechanisms and Potential for Therapeutically Relevant Inhibition

The GHMP kinases are a structurally related family of small molecule kinases named after four of its members - galactokinase, homoserine kinase, mevalonate kinase and phosphomevalonate kinase. The group also includes the enzymes N-acetylgalactosamine kinase, arabinose kinase, mevalonate 5-diphosphate decarboxylase, archeal shikimate kinase and 4-(cytidine 5'-diphospho)-2-c-methyl-D-erythritol kinase. In addition the group includes two members not known to be catalytically active, the Caenorhabditis elegans sex-fate determining protein XOL-1 and the Saccharomyces cerevisiae transcriptional activator Gal3p. Two catalytic mechanisms have been proposed for GHMP kinases. The structure of mevalonate kinase suggests that an aspartate residue acts as an active site base, removing a proton from the substrate to facilitate attack on the ? phosphate of MgATP. In contrast, in homoserine kinase there is no potential catalytic base and it is proposed that catalysis is driven by transition state stabilisation. Potential chemotherapeutic interventions against GHMP kinases fall into three main categories: inhibition of galactokinase to assist suffers of galactosemia, inhibition of mevalonate kinase or mevalonate 5-diphosphate decarboxylase to reduce flux through the cholesterol biosynthesis pathway and inhibition of bacterial GHMP kinases for novel anti-microbial therapies. These are in the early stages of development, but the accumulation of structural and mechanistic data will assist future progress.

Numerical study of film cooling scheme on a blunt-nosed body in hypersonic flow

In hypersonic flights, the prediction of aerodynamic heating and the construction of a proper thermal protection system (TPS) are significantly important. In this study, the method of a film cooling technique, which is already the state of the art in cooling gas turbine engine, is proposed for a fully reusable and active TPS. Effectiveness of the film cooling scheme to reduce convective heating rates for a blunt nosed spacecraft flying at Mach number 6.56 and 40 degree angle of attack is investigated numerically. The inflow boundary conditions used the standard values at an altitude of 30 km. Computational domain consists of infinite rows of film cooling holes on the bottom of a blunt-nosed slab. Laminar and several turbulent calculations have been performed and compared each other. The influence of blowing ratios on the film cooling effectiveness is investigated. The results exhibit that the film cooling technique could be an effective method for an active cooling of blunt-nosed bodies in hypersonic flows.

‘Darkened surfaces’: camouflage and the nocturnal observation of Britain, 1941–45

Positioned in relation to an emerging geographical interest into the effects of different atmospheric and observational conditions in shaping sensory engagements with the Earth's surfaces, this paper considers how a critical examination of the practices of camouflage can open up new dialogues into how the Earth's surfaces become known, are interacted with, and transformed in the conditions of darkness. With an empirical focus on the cultural and historical geographies of nocturnal camouflage practised during the Second World War, the paper examines the systematic attempts of civil camoufleurs to understand how natural and artificial landforms were visibly 'present' in the nocturnal landscape, despite darkness often being conceived as producing an environment of 'visual absence' through diminished sensory engagement. Furthermore, the paper highlights how the tensions between visual presence/absence that shape both the nocturnal experience and the 'knowing' of landscape can often be exploited for social, cultural, and political ends, in this case, to enable protection against aerial attack. © 2013 Pion and its Licensors.

Reduction of environmentally induced cracking of laser-welded shape memory NiTi wires via post-weld heat-treatment

In this study, the environmentally induced cracking behaviour of the NiTi weldment with and without post-weld heat-treatment (PWHT) in Hanks’ solution at 37.5 °C at OCP were studied by tensile and cyclic slow-strain-rate tests (SSRT), and compared with those tested in oil (an inert environment). Our previous results in the tensile and cyclic SSRT showed that the weldment without PWHT showed high susceptibility to the hydrogen cracking, as evidenced by the degradation of tensile and super-elastic properties when testing in Hanks' solution. The weldment after PWHT was much less susceptible to hydrogen attack in Hanks' solution as no obvious degradation in the tensile and super-elastic properties was observed, and only a very small amount of micro-cracks were found in the fracture surface. The susceptibility to hydrogen cracking of the NiTi weldment could be alleviated by applying PWHT at the optimized temperature of 350 °C after laser welding.

Impact of Cyber-Security Issues on Smart Grid

Greater complexity and interconnectivity across systems embracing Smart Grid technologies has meant that cyber-security issues have attracted significant attention. This paper describes pertinent cyber-security requirements, in particular cyber attacks and countermeasures which are critical for reliable Smart Grid operation. Relevant published literature is presented for critical aspects of Smart Grid cyber-security, such as vulnerability, interdependency, simulation, and standards. Furthermore, a preliminary study case is given which demonstrates the impact of a cyber attack which violates the integrity of data on the load management of real power system. Finally, the paper proposes future work plan which focuses on applying intrusion detection and prevention technology to address cyber-security issues. This paper also provides an overview of Smart Grid cyber-security with reference to related cross-disciplinary research topics.

Intrusion Detection System for Network Security in Synchrophasor Systems

Synchrophasor systems will play a crucial role in next generation Smart Grid monitoring, protection and control. However these systems also introduce a multitude of potential vulnerabilities from malicious and inadvertent attacks, which may render erroneous operation or severe damage. This paper proposes a Synchrophasor Specific Intrusion Detection System (SSIDS) for malicious cyber attack and unintended misuse. The SSIDS comprises a heterogeneous whitelist and behavior-based approach to detect known attack types and unknown and so-called ‘zero-day’ vulnerabilities and attacks. The paper describes reconnaissance, Man-in-the-Middle (MITM) and Denial-of-Service (DoS) attack types executed against a practical synchrophasor system which are used to validate the real-time effectiveness of the proposed SSIDS cyber detection method.

Multi-Attribute SCADA-Specific Intrusion Detection System for Power Networks

The increased interconnectivity and complexity of supervisory control and data acquisition (SCADA) systems in power system networks has exposed the systems to a multitude of potential vulnerabilities. In this paper, we present a novel approach for a next-generation SCADA-specific intrusion detection system (IDS). The proposed system analyzes multiple attributes in order to provide a comprehensive solution that is able to mitigate varied cyber-attack threats. The multiattribute IDS comprises a heterogeneous white list and behavior-based concept in order to make SCADA cybersystems more secure. This paper also proposes a multilayer cyber-security framework based on IDS for protecting SCADA cybersecurity in smart grids without compromising the availability of normal data. In addition, this paper presents a SCADA-specific cybersecurity testbed to investigate simulated attacks, which has been used in this paper to validate the proposed approach.

Xheal: A localized self-healing algorithm using expanders

We consider the problem of self-healing in reconfigurable networks e.g., peer-to-peer and wireless mesh networks. For such networks under repeated attack by an omniscient adversary, we propose a fully distributed algorithm, Xheal, that maintains good expansion and spectral properties of the network, while keeping the network connected. Moreover, Xheal does this while allowing only low stretch and degree increase per node. The algorithm heals global properties like expansion and stretch while only doing local changes and using only local information. We also provide bounds on the second smallest eigenvalue of the Laplacian which captures key properties such as mixing time, conductance, congestion in routing etc. Xheal has low amortized latency and bandwidth requirements. Our work improves over the self-healing algorithms Forgiving tree [PODC 2008] andForgiving graph [PODC 2009] in that we are able to give guarantees on degree and stretch, while at the same time preserving the expansion and spectral properties of the network.

The forgiving tree: a self-healing distributed data structure

We consider the problem of self-healing in peer-to-peer networks that are under repeated attack by an omniscient adversary. We assume that the following process continues for up to n rounds where n is the total number of nodes initially in the network: the adversary deletesan arbitrary node from the network, then the network responds by quickly adding a small number of new edges.

We present a distributed data structure that ensures two key properties. First, the diameter of the network is never more than O(log Delta) times its original diameter, where Delta is the maximum degree of the network initially. We note that for many peer-to-peer systems, Delta is polylogarithmic, so the diameter increase would be a O(loglog n) multiplicative factor. Second, the degree of any node never increases by more than 3 over its original degree. Our data structure is fully distributed, has O(1) latency per round and requires each node to send and receive O(1) messages per round. The data structure requires an initial setup phase that has latency equal to the diameter of the original network, and requires, with high probability, each node v to send O(log n) messages along every edge incident to v. Our approach is orthogonal and complementary to traditional topology-based approaches to defending against attack.

Picking up the Pieces: Self-Healing in reconfigurable networks

We consider the problem of self-healing in networks that are reconfigurable in the sense that they can change their topology during an attack. Our goal is to maintain connectivity in these networks, even in the presence of repeated adversarial node deletion, by carefully adding edges after each attack. We present a new algorithm, DASH, that provably ensures that: 1) the network stays connected even if an adversary deletes up to all nodes in the network; and 2) no node ever increases its degree by more than 2 log n, where n is the number of nodes initially in the network. DASH is fully distributed; adds new edges only among neighbors of deleted nodes; and has average latency and bandwidth costs that are at most logarithmic in n. DASH has these properties irrespective of the topology of the initial network, and is thus orthogonal and complementary to traditional topology- based approaches to defending against attack. We also prove lower-bounds showing that DASH is asymptotically optimal in terms of minimizing maximum degree increase over multiple attacks. Finally, we present empirical results on power-law graphs that show that DASH performs well in practice, and that it significantly outperforms naive algorithms in reducing maximum degree increase.