Targeting C-reactive protein for the treatment of cardiovascular disease

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement(1), increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively(2,3). Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement(4). Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP2,3. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.

Posttraumatic stress symptoms in London school children following September 11, 2001: an exploratory investigation of peri-traumatic reactions and intrusive imagery

Threatening intrusive images are central to posttraumatic stress disorder. It has been suggested that intrusive imagery in the context of a sense of threat leads to the development and persistence of posttraumatic stress symptoms. This study investigates London school children's (N = 76; age 10-11 years) self-reported posttraumatic stress symptoms in response to viewing the attacks of September 11, 2001 on television. Assessments were made at two time points. A minority of participants reported moderate-severe symptoms with functional impairment at 2 months (14.5%) and 6 months (9.2%) after viewing the September 11events. After controlling for symptom stability, persistent symptoms were associated with peri-traumatic factors, notably perceiving that one's life was in danger. The combined effect of intrusive imagery and peri-traumatic life threat was associated with symptom persistence. Assessments of intrusive image content via checklist and free-report indicated that the images were directly related to September 11 and were fairly stable over time. Implications for treating children's intrusive images following stressful events are explored. (C) 2007 Elsevier Ltd. All rights reserved.

Unsupervised genetic algorithm deployed for intrusion detection

This paper represents the first step in an on-going work for designing an unsupervised method based on genetic algorithm for intrusion detection. Its main role in a broader system is to notify of an unusual traffic and in that way provide the possibility of detecting unknown attacks. Most of the machine-learning techniques deployed for intrusion detection are supervised as these techniques are generally more accurate, but this implies the need of labeling the data for training and testing which is time-consuming and error-prone. Hence, our goal is to devise an anomaly detector which would be unsupervised, but at the same time robust and accurate. Genetic algorithms are robust and able to avoid getting stuck in local optima, unlike the rest of clustering techniques. The model is verified on KDD99 benchmark dataset, generating a solution competitive with the solutions of the state-of-the-art which demonstrates high possibilities of the proposed method.

Real-time context-aware network security policy enforcement system (RC-NSPES)

The major technical objectives of the RC-NSPES are to provide a framework for the concurrent operation of reactive and pro-active security functions to deliver efficient and optimised intrusion detection schemes as well as enhanced and highly correlated rule sets for more effective alerts management and root-cause analysis. The design and implementation of the RC-NSPES solution includes a number of innovative features in terms of real-time programmable embedded hardware (FPGA) deployment as well as in the integrated management station. These have been devised so as to deliver enhanced detection of attacks and contextualised alerts against threats that can arise from both the network layer and the application layer protocols. The resulting architecture represents an efficient and effective framework for the future deployment of network security systems.

Design and evaluation of intelligent classifier based intrusion detection system

We have discovered a novel approach of intrusion detection system using an intelligent data classifier based on a self organizing map (SOM). We have surveyed all other unsupervised intrusion detection methods, different alternative SOM based techniques and KDD winner IDS methods. This paper provides a robust designed and implemented intelligent data classifier technique based on a single large size (30x30) self organizing map (SOM) having the capability to detect all types of attacks given in the DARPA Archive 1999 the lowest false positive rate being 0.04 % and higher detection rate being 99.73% tested using full KDD data sets and 89.54% comparable detection rate and 0.18% lowest false positive rate tested using corrected data sets.

Proposing a hybrid-intelligent framework to secure e-government web applications

One of the essential needs to implement a successful e-Government web application is security. Web application firewalls (WAF) are the most important tool to secure web applications against the increasing number of web application attacks nowadays. WAFs work in different modes depending on the web traffic filtering approach used, such as positive security mode, negative security mode, session-based mode, or mixed modes. The proposed WAF, which is called (HiWAF), is a web application firewall that works in three modes: positive, negative and session based security modes. The new approach that distinguishes this WAF among other WAFs is that it utilizes the concepts of Artificial Intelligence (AI) instead of regular expressions or other traditional pattern matching techniques as its filtering engine. Both artificial neural networks and fuzzy logic concepts will be used to implement a hybrid intelligent web application firewall that works in three security modes.

Virtual reality Post Traumatic Stress Disorder (PTSD) exposure therapy results with active duty Iraq war combatants

Post Traumatic Stress Disorder (PTSD) is reported to be caused by traumatic events that are outside the range of usual human experience including (but not limited to) military combat, violent personal assault, being kidnapped or taken hostage and terrorist attacks. Initial data suggests that at least 1 out of 6 Iraq War veterans are exhibiting symptoms of depression, anxiety and PTSD. Virtual Reality (VR) delivered exposure therapy for PTSD has been used with reports of positive outcomes. The aim of the current paper is to present the rationale and brief description of a Virtual Iraq PTSD VR therapy application and present initial findings from its use with PTSD patients. Thus far, Virtual Iraq consists of a series of customizable virtual scenarios designed to represent relevant Middle Eastern VR contexts for exposure therapy, including a city and desert road convoy environment. User-centered design feedback needed to iteratively evolve the system was gathered from returning Iraq War veterans in the USA and from a system deployed in Iraq and tested by an Army Combat Stress Control Team. Results from an open clinical trial at San Diego Naval Medical Center of the first 18 treatment completers indicate that 14 no longer meet PTSD diagnostic criteria at post-treatment, with only one not maintaining treatment gains at 3 month follow-up. Clinical tests are also currently underway at Ft. Lewis, Emory University, Weill Cornell Medical College, Walter Reed Army Medical Center and 10 other sites. Other sites are preparing to use the application for a variety of PTSD and VR research purposes.

Multistep electrochemical reduction path of clusters [Os3(CO)10(α-diimine)]: comparison of electrochemical and photochemical Os-Os(α-diimine) bond cleavage

Electrochemical reduction of the triangular clusters [Os-3(CO)(10)(alpha-dimine)] (alpha-dimine = 2,2'-bipyridine (bpy), 2,2'-bipyrimidine (bpym)) and [Os-3(CO)(10)(mu-bpym) ReBr(CO)(3)] produces primarily the corresponding radical anions. Their stability is strongly determined by the pi acceptor ability of the reducible alpha-dimine ligand, which decreases in the order mu-bpym > bpym >> bpy. Along this series, increasing delocalisation of the odd electron density in the radical anion over the Os(alpha-dimine) chelate ring causes weakening of the axial (CO)(4)Os-Os(CO)(2)(alpha-dimine) bond and its facile cleavage for alpha-diimine = bpy. In contrast, the cluster radical anion is inherently stable for the bridging bpym ligand, the strongest pi-acceptor in the studied series. In the absence of the partial delocalisation of the unpaired electron over the Re( bpym) chelate bond, the Os-3-core of the radical anion remains intact only at low temperatures. Subsequent one-electron reduction of [Os-3(CO)(10)(bpym)](center dot-) at T = 223 K gives the open-triosmium core (= Os-3*) dianion, [Os-3*(CO)(10)(bpym)](2-). Its oxidation leads to the recovery of parent [Os-3(CO)(10)( bpym)]. At room temperature, [Os-3*( CO)(10)(bpym)](2-) is formed along a two-electron (ECE) reduction path. The chemical step (C) results in the formation of an open- core radical anion that is directly reducible at the cathodic potential of the parent cluster in the second electrochemical (E) step. In weakly coordinating tetrahydrofuran, [Os-3*(CO)(10)( bpym)](2-) rapidly attacks yet non- reduced parent cluster molecules, producing the relatively stable open- core dimer [Os-3*(CO)(10)(bpym)](2)(2-) featuring two open- triangle cluster moieties connected with an ( bpym) Os - Os( bpym) bond. In butyronitrile, [Os-3*( CO)(10)(bpym)](2-) is stabilised by the solvent and the dimer [Os-3*(CO)(10)(bpym)](2)(2-) is then mainly formed by reoxidation of the dianion on reverse potential scan. The more reactive cluster [Os-3(CO)(10)(bpy)] follows the same reduction path, as supported by spectroelectrochemical results and additional valuable evidence obtained from cyclic voltammetric scans. The ultimate process in the reduction mechanism is fragmentation of the cluster core triggered by the reduction of the dimer [Os-3*(CO)(10)(alpha- diimine)](2)(2-). The products formed are [Os-2(CO)(8)](2-) and {Os(CO)(2)(alpha- diimine)}(2). The latter dinuclear fragments constitute a linear polymeric chain [Os( CO)(2)(alpha-dimine)] n that is further reducible at the alpha-dimine ligands. For alpha-dimine = bpy, the charged polymer is capable of reducing carbon dioxide. The electrochemical opening of the triosmium core in the [Os-3( CO)(10)(alpha-dimine)] clusters exhibits several common features with their photochemistry. The same Os-alpha-dimine bond dissociates in both cases but the intimate mechanisms are different.

Architectural Fictions

Architectural Fictions was a curatorial project that brought together the work of eight artist that in different ways addressed principles of fictioning and narrative in relation to the built environment. The project brought critical focus to the narrative structures implicit in the production of space. Through dialogue with the participants, the project developed speculative critical exchange, examining questions such as the interplay between the real and the virtual and the role of design in relation to processes of habitation. Architectural Fictions formed a keynote exhibition in South Hill Park Arts Centre program. SHP is funded by the Arts Council England and is in partnership with ARC which delivers events by professionals from the field of art and culture. A public lecture about Architectural Fictions was delivered by Mary Maclean and Tim Renshaw who together make up the group Outside Architecture. Outside Architecture aims to open up speculative dialogues and images on the materials and signs that compose the texture of shared and lived in spaces.

Purification and functional characterisation of Rhinocerase, a novel serine protease from the venom of Bitis gabonica rhinoceros

Background: Serine proteases are a major component of viper venoms and are thought to disrupt several distinct elements of the blood coagulation system of envenomed victims. A detailed understanding of the functions of these enzymes is important both for acquiring a fuller understanding of the pathology of envenoming and because these venom proteins have shown potential in treating blood coagulation disorders. Methodology/Principal Findings: In this study a novel, highly abundant serine protease, which we have named rhinocerase, has been isolated and characterised from the venom of Bitis gabonica rhinoceros using liquid phase isoelectric focusing and gel filtration. Like many viper venom serine proteases, this enzyme is glycosylated; the estimated molecular mass of the native enzyme is approximately 36kDa, which reduces to 31kDa after deglycosylation. The partial amino acid sequence shows similarity to other viper venom serine proteases, but is clearly distinct from the sequence of the only other sequenced serine protease from Bitis gabonica. Other viper venom serine proteases have been shown to exert distinct biological effects, and our preliminary functional characterization of rhinocerase suggest it to be multifunctional. It is capable of degrading α and β chains of fibrinogen, dissolving plasma clots and of hydrolysing a kallikrein substrate. Conclusions/Significance: A novel multifunctional viper venom serine protease has been isolated and characterised. The activities of the enzyme are consistent with the known in vivo effects of Bitis gabonica envenoming, including bleeding disorders, clotting disorders and hypotension. This study will form the basis for future research to understand the mechanisms of serine protease action, and examine the potential for rhinocerase to be used clinically to reduce the risk of human haemostatic disorders such as heart attacks and strokes.

Flatpack revolution

The project consists of a trilogy of films and a live performance. The Future trilogy takes IKEA riot of 2005 as the starting point for a speculative history of a fictional future, culminating in a choreographed re-enactment of the original event. Shot on 16mm and 8mm film, the series explores the possibility of collective action emerging from the capitalist relations inherent in the consumer riot. The live performance No Haus Like Bau, staged at the HAU 1 theatre in Berlin for the 5th Berlin Biennale, continues this research into re-enactment and post-1989 politics by dramatizing the rise and fall of the soviet union as a neo-Constructivist mime using a stage set made of flatpack furniture. Using the aesthetics of Modernism and the avant garde, from Constructivist and Futurist constumes to biomechanics and Bauhaus theatre theory, the project transposes early twentieth century utopian ideology to a present day setting where mass uprisings are motivated by cheap commodities. These explorations of consumerism and revolution have been widely exhibited internationally and supported by Film London, Arts Council England, Collective Gallery and the Berlin Biennale. The Future Trilogy formed the basis of a solo exhibition at the Te Tuhi Art Centre in Auckland, New Zealand and was screened as part of the Signal and Noise media art festival in Vancouver, as well as other exhibitions and screenings including “Roll it to Me” at Collective Gallery, Edinburgh, and Apocatopia, Castlefield Gallery, Manchester.

Can objects perform?: agency and thingliness in contemporary sculpture and installation

In his 1967 essay, “Art and Objecthood”, Michael Fried bemoaned the theatricality of minimalist sculpture, which replaced the presentness of compositional sculpture with the staging of an experience for the viewer as performer. His argument has since been inverted by artists and art writers invested in the idea of sculptures as props forming part of an artistic experience economy. This discourse has accompanied the rise of relational aesthetics as a dominant paradigm for contemporary art. More recently, however, there has been a turn away from relationality to ‘object-oriented’ art, where objects are seen to stage their own theatrical experiences, performing themselves without requiring the activation of a viewer’s body. We trace parallels between the philosophy of Bruno Latour and the “Speculative Materialism” group and this emerging trend in sculpture. In ascribing agency to objects, Latour proposes a radical shift from philosophy’s traditional investigation of the relationship between the mind and the world. Drawn to the idea that matter can be creative, artists have embraced his thinking. However, we argue that this has lead to a generalized, universalizing humanism that disables political action. Moreover, it undermines the potential for anti-humanist critique latent in object-oriented philosophy.

Should we be utopophobes about democracy in particular?

In his book Democratic Authority, David Estlund puts forward a case for democracy, which he labels epistemic proceduralism, that relies on democracy's ability to produce good – that is, substantively just – results. Alongside this case for democracy Estlund attacks what he labels ‘utopophobia’, an aversion to idealistic political theory. In this article I make two points. The first is a general point about what the correct level of ‘idealisation’ is in political theory. Various debates are emerging on this question and, to the extent that they are focused on ‘political theory’ as a whole, I argue, they are flawed. This is because there are different kinds of political concept, and they require different kinds of ideal. My second point is about democracy in particular. If we understand democracy as Estlund does, then we should see it as a problem-solving concept – the problem being that we need coercive institutions and rules, but we do not know what justice requires. As democracy is a response to a problem, we should not allow our theories of it, even at the ideal level, to be too idealised – they must be embedded in the nature of the problem they are to solve, and the beings that have it.

Virtual reality Post Traumatic Stress Disorder (PTSD) exposure therapy results with active duty OIF/OEF service members

Posttraumatic stress disorder (PTSD) is reported to be caused by exposure to traumatic events including (but not limited to) military combat, violent personal assault, being kidnapped or taken hostage and terrorist attacks. Initial data suggest that at least 1 out of 6 Iraq War veterans are exhibiting symptoms of depression, anxiety and PTSD. Virtual reality (VR) delivered exposure therapy for PTSD has been used with reports of positive outcomes. The aim of the current paper, is to present the rationale and brief description of a Virtual Iraq/Afghanistan PTSD VR therapy application and present initial findings from its use with PTSD patients. Thus far, Virtual Iraq/Afghanistan consists of a series of customizable virtual scenarios designed to represent relevant Middle Eastern VR contexts for exposure therapy, including a city and desert road convoy environment. User-centered design feedback, needed to iteratively evolve the system, was gathered from returning Iraq War veterans in the USA and from a system deployed in Iraq and tested by an Army Combat Stress Control Team. Results from an open clinical trial at San Diego Naval Medical Center of the first 20 treatment completers indicate that 16 no longer met PTSD screening criteria at post-treatment, with only one not maintaining treatment gains at 3 month follow-up.

Spatial patterns of office employment in the New York region

This study analyzes the regional spatial dynamics of the New York region for a period of roughly twenty years and places the effects of the 9/11 terrorist attacks in the context of longer-term regional dynamics. The analysis reveals that office-using industries are still heavily concentrated in Manhattan despite ongoing decentralization in many of these industries over the last twenty years. Financial services tend to be highly concentrated in Manhattan whereas administrative and support services are the least concentrated of the six major office-using industry groups. Although office employment has been by and large stagnant in Manhattan for at least two decades, growth of output per worker has outpaced the CMSA as well as the national average. This productivity differential is mainly attributable to competitive advantages of office-using industries in Manhattan and not to differences in industry composition. Finally, the zip-code level analysis of the Manhattan core area yielded further evidence of the existence of significant spillover effects at the small-scale level.