Fine Grained Component Engineering of Adaptive Overlays: Experiences and Perspectives

Recent years have seen significant research being carried out into peer-to-peer (P2P) systems. This work has focused on the styles and applications of P2P computing, from grid computation to content distribution; however, little investigation has been performed into how these systems are built. Component based engineering is an approach that has seen successful deployment in the field of middleware development; functionality is encapsulated in ‘building blocks’ that can be dynamically plugged together to form complete systems. This allows efficient, flexible and adaptable systems to be built with lower overhead and development complexity. This paper presents an investigation into the potential of using component based engineering in the design and construction of peer-to-peer overlays. It is highlighted that the quality of these properties is dictated by the component architecture used to implement the system. Three reusable decomposition architectures are designed and evaluated using Chord and Pastry case studies. These demonstrate that significant improvements can be made over traditional design approaches resulting in much more reusable, (re)configurable and extensible systems

Digest it all:the lysosomal turnover of cytoplasmic aggregates

Aggrephagy describes the selective lysosomal transport and turnover of cytoplasmic protein aggregates by macro-autophagy. In this process, protein aggregates and conglomerates are polyubiquitinated and then sequestered by autophagosomes. Soluble selective autophagy receptors (SARs) are central to aggrephagy and physically bind to both ubiquitin and the autophagy machinery, thus linking the cargo to the forming autophagosomal membrane. Because the accumulation of protein aggregates is associated with cytotoxicity in several diseases, a better molecular understanding of aggrephagy might provide a conceptual framework to develop therapeutic strategies aimed at delaying the onset of these pathologies by preventing the buildup of potentially toxic aggregates. We review recent advances in our knowledge about the mechanism of aggrephagy

Assessing the impact of intra-cloud live migration on anomaly detection

Virtualized cloud environments have emerged as a necessity within modern unified ICT infrastructures and have established themselves as a reliable backbone for numerous always-on services. `Live' intra-cloud virtual-machine (VM) migration is a widely used technique for efficient resource management employed within modern cloud infrastructures. Despite the benefits of such functionality, there are still several security issues which have not yet been thoroughly assessed and quantified. We investigate the impact of live virtual-machine migration on state-of-the-art anomaly detection (AD) techniques (namely PCA and K-means), by evaluating live migration under various attack types and intensities. We find that the performance for both detectors degrades as shown by their Receiver Operating Characteristics (ROC) curves when intra-cloud live migration is initiated while VMs are under a netscan (NS) or a denial-of-service (DoS) attack

WDR45, one gene associated with multiple neurodevelopmental disorders

The WDR45 gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ss-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat beta-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in WDR45 can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders

Multi-level Network Resilience: Traffic Analysis, Anomaly Detection and Simulation

Traffic analysis and anomaly detection have been extensively used to characterize network utilization as well as to identify abnormal network traffic such as malicious attacks. However, so far, techniques for traffic analysis and anomaly detection have been carried out independently, relying on mechanisms and algorithms either in edge or in core networks alone. In this paper we propose the notion of multi-level network resilience, in order to provide a more robust traffic analysis and anomaly detection architecture, combining mechanisms and algorithms operating in a coordinated fashion both in the edge and in the core networks. This work is motivated by the potential complementarities between the research being developed at IIT Madras and Lancaster University. In this paper we describe the current work being developed at IIT Madras and Lancaster on traffic analysis and anomaly detection, and outline the principles of a multi-level resilience architecture

Dupilumab-induced eosinophilia in patients with diffuse type 2 chronic rhinosinusitis.

BACKGROUND Dupilumab, a monoclonal anti-IL-4Rα antibody, is approved for several type 2 mediated inflammatory diseases like asthma, atopic dermatitis, and diffuse type 2 chronic rhinosinusitis (CRS). Clinical studies had reported a transient increase in blood eosinophils during dupilumab therapy. This study aimed to assess the impact of elevated blood eosinophils on clinical outcome and to investigate the cause of high blood eosinophil levels under dupilumab therapy. METHODS Patients suffering from diffuse type 2 CRS treated with dupilumab were examined on days 0, 28, 90, and 180 after therapy start. Sino-Nasal-Outcome-Test Score (SNOT-22), Total Nasal Polyp Score (TNPS), and blood samples were collected. Cytokine measurements and proteomics analysis were conducted. Flow cytometry analysis measured receptor expression on eosinophils. RESULTS Sixty-eighty patients were included. Baseline eosinophilia ≥0.3G/L was observed in 63.2% of patients, and in 30.9% of patients, eosinophils increased by ≥0.5G/L under dupilumab. Subjects with eosinophilia ≥0.3G/L at baseline had the best SNOT-22 mean change compared to no eosinophilia. Eosinophil elevation during dupilumab therapy had no impact on clinical scores. The eosinophil adhesion molecule VCAM-1 decreased significantly during therapy in all patients. The chemokine receptor CXCR4 was significantly down- and IL-4 upregulated in subjects with eosinophil increase. CONCLUSION Our findings suggest that increased eosinophils in type 2 CRS are associated with a good clinical response to dupilumab. Patients with elevated IL-4 at baseline developed dupilumab-induced transient eosinophilia. We identified the downregulation of VCAM-1 and surface markers CD49d and CXCR4 on eosinophils as possible explanations of dupilumab-induced eosinophilia

Multimedia delivery in the future internet

The term “Networked Media” implies that all kinds of media including text, image, 3D graphics, audio and video are produced, distributed, shared, managed and consumed on-line through various networks, like the Internet, Fiber, WiFi, WiMAX, GPRS, 3G and so on, in a convergent manner [1]. This white paper is the contribution of the Media Delivery Platform (MDP) cluster and aims to cover the Networked challenges of the Networked Media in the transition to the Future of the Internet. Internet has evolved and changed the way we work and live. End users of the Internet have been confronted with a bewildering range of media, services and applications and of technological innovations concerning media formats, wireless networks, terminal types and capabilities. And there is little evidence that the pace of this innovation is slowing. Today, over one billion of users access the Internet on regular basis, more than 100 million users have downloaded at least one (multi)media file and over 47 millions of them do so regularly, searching in more than 160 Exabytes1 of content. In the near future these numbers are expected to exponentially rise. It is expected that the Internet content will be increased by at least a factor of 6, rising to more than 990 Exabytes before 2012, fuelled mainly by the users themselves. Moreover, it is envisaged that in a near- to mid-term future, the Internet will provide the means to share and distribute (new) multimedia content and services with superior quality and striking flexibility, in a trusted and personalized way, improving citizens’ quality of life, working conditions, edutainment and safety. In this evolving environment, new transport protocols, new multimedia encoding schemes, cross-layer inthe network adaptation, machine-to-machine communication (including RFIDs), rich 3D content as well as community networks and the use of peer-to-peer (P2P) overlays are expected to generate new models of interaction and cooperation, and be able to support enhanced perceived quality-of-experience (PQoE) and innovative applications “on the move”, like virtual collaboration environments, personalised services/ media, virtual sport groups, on-line gaming, edutainment. In this context, the interaction with content combined with interactive/multimedia search capabilities across distributed repositories, opportunistic P2P networks and the dynamic adaptation to the characteristics of diverse mobile terminals are expected to contribute towards such a vision. Based on work that has taken place in a number of EC co-funded projects, in Framework Program 6 (FP6) and Framework Program 7 (FP7), a group of experts and technology visionaries have voluntarily contributed in this white paper aiming to describe the status, the state-of-the art, the challenges and the way ahead in the area of Content Aware media delivery platforms

Cell transformation assays for prediction of carcinogenic potential: State of the science and future research needs

Copyright @ 2011 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Cell transformation assays (CTAs) have long been proposed as in vitro methods for the identification of potential chemical carcinogens. Despite showing good correlation with rodent bioassay data, concerns over the subjective nature of using morphological criteria for identifying transformed cells and a lack of understanding of the mechanistic basis of the assays has limited their acceptance for regulatory purposes. However, recent drivers to find alternative carcinogenicity assessment methodologies, such as the Seventh Amendment to the EU Cosmetics Directive, have fuelled renewed interest in CTAs. Research is currently ongoing to improve the objectivity of the assays, reveal the underlying molecular changes leading to transformation and explore the use of novel cell types. The UK NC3Rs held an international workshop in November 2010 to review the current state of the art in this field and provide directions for future research. This paper outlines the key points highlighted at this meeting

Mitochondrial dysfunction mediates neuronal cell response to DMMB photodynamic therapy

Photodynamic therapy (PDT) is a process in which a photosensitizer (PS) is exposed to specific wavelengths and generates reactive oxygen species (ROS) which act within nanometers. The low invasive nature and directed cytotoxicity of this approach render it attractive to the treatment of different conditions, including the ones that affect the central nervous system (CNS). The effect of PDT on healthy neurons is one main concern over its use in the CNS, since neuronal-like cells were shown to be particularly sensitive to certain PSs. Among available PSs, 1,9-dimethyl-methylene blue (DMMB) stands out as being resistant to reduction to its inactive leuco form and by being able to produce high levels of singlet‑oxygen. In this study, we aimed to investigate DMMB photodamage mechanisms in the hippocampal cell line HT22. Our results demonstrate that DMMB-PDT decrease in cell viability was linked with an increase in cell death and overall ROS production. Besides, it resulted in a significant increase in mitochondrial ROS production and decreased mitochondria membrane potential. Furthermore, DMMB-PDT significantly increased the presence of acidic autolysosomes, which was accompanied by an increase in ATG1 and ATG8 homologue GaBarap1 expression, and decreased DRAM1 expression. Taken together our results indicated that mitochondrial and autophagic dysfunction underlie DMMB-PDT cytotoxicity in neuronal cells.</p