A novel approach to detect hot-spots in large-scale multivariate data

Background: Progressive advances in the measurement of complex multifactorial components of biological processes involving both spatial and temporal domains have made it difficult to identify the variables (genes, proteins, neurons etc.) significantly changed activities in response to a stimulus within large data sets using conventional statistical approaches. The set of all changed variables is termed hot-spots. The detection of such hot spots is considered to be an NP hard problem, but by first establishing its theoretical foundation we have been able to develop an algorithm that provides a solution. Results: Our results show that a first-order phase transition is observable whose critical point separates the hot-spot set from the remaining variables. Its application is also found to be more successful than existing approaches in identifying statistically significant hot-spots both with simulated data sets and in real large-scale multivariate data sets from gene arrays, electrophysiological recording and functional magnetic resonance imaging experiments. Conclusion: In summary, this new statistical algorithm should provide a powerful new analytical tool to extract the maximum information from complex biological multivariate data

Detection of the optical counterpart of the proposed double degenerate polar RX J1914+24

We have detected the optical counterpart of the proposed double degenerate polar RX J1914+24. The I band light curve is modulated on the 9.5 min period seen in X-rays. There is no evidence for any other periods. No significant modulation is seen in J. The infrared colours of RX J1914+24 are not consistent with a main sequence dwarf secondary star. Our ASCA spectrum of RX J1914+24 is typical of a heavily absorbed polar and our ASCA light curve also shows only the 9.5 min period. We find that the folded I band and X-ray light curves are out of phase. We attribute the I band flux to the irradiated face of the donor star. The long term X-ray light curve shows a variation in the observed flux of up to an order of magnitude. These observations strengthen the view that RX J1914+24 is indeed the first double degenerate polar to be detected. In this light, we discuss the synchronising mechanisms in such a close binary and other system parameters.Comment: 11 pages, accepted for publication in MNRA

Network layer access control for context-aware IPv6 applications

As part of the Lancaster GUIDE II project, we have developed a novel wireless access point protocol designed to support the development of next generation mobile context-aware applications in our local environs. Once deployed, this architecture will allow ordinary citizens secure, accountable and convenient access to a set of tailored applications including location, multimedia and context based services, and the public Internet. Our architecture utilises packet marking and network level packet filtering techniques within a modified Mobile IPv6 protocol stack to perform access control over a range of wireless network technologies. In this paper, we describe the rationale for, and components of, our architecture and contrast our approach with other state-of-the- art systems. The paper also contains details of our current implementation work, including preliminary performance measurements

Investigating the role of epigenetics in the regulation of inflammatory skin disease

PhD ThesisPsoriasis represents a complex interplay between genetic predisposition, the environment and inflammatory responses, and increasing evidence suggests alterations in the epigenome, including histone acetylation, plays a role. Bromodomain-containing proteins regulate gene expression by binding to acetyl-lysine residues on histones and recruiting transcription factors to gene regulatory regions. The development of small molecule inhibitors of bromodomain extraterminal (BET) proteins has enabled interrogation of this pathway. Interestingly BET inhibitors demonstrate anti-proliferative and anti-inflammatory effects in in vitro and in vivo models of cancer and inflammation. An established in-vitro keratinocyte model of cutaneous inflammation was further developed to characterise IL-6 and IL-8 (mRNA and protein) responses to TNF+ IL-17 stimulation. Chromatin immunoprecipitation (ChIP) studies showed psoriasis-relevant stimuli induced dynamic, gene-specific alterations of the epigenome, including histone hyperacetylation, with co-ordinated recruitment of BET proteins (Brd2, Brd3 and Brd4) and RNA polymerase II, to the promoter region of IL-6 and IL-8. The effects of TNF+ IL-17 stimulation in keratinocytes were validated through global gene expression array studies which showed stimulation modulated expression of keratinocyte genes known to be differentially expressed in psoriasis and involved in its pathogenesis. The hypothesis that BET proteins are involved in regulating inflammatory responses in keratinocytes was tested using a specific BET inhibitor, I-BET151; this blocked pathogenic inflammatory responses. In particular, IL-6 and IL-8 responses to TNF + IL-17 stimulation demonstrated potent sensitivity to I-BET151 treatment; this could be accounted for by the decreased binding of BET proteins and RNA polymerase II to IL-6 and IL-8 gene promoter regions in the presence of the BET inhibitor. Global gene expression array studies showed genes sensitive to BET inhibition were primarily involved in the cell cycle and inflammation, with many relevant to the pathogenesis of psoriasis. In addition, ~20% of genes identified in a previously published meta-analysis of five psoriasis transcriptomic studies were differentially modulated by I-BET151 treatment in TNF + IL-17 stimulated NHEKs. Furthermore, acetate, a principle metabolite of ethanol, a factor implicated in the development and exacerbation of psoriasis, enhanced IL-6, but not IL-8, responses to TNF + IL-17 stimulation through gene-specific epigenetic modifications at the promoter region. IFN also enhanced IL-6, but not IL-8, response to TNF + IL-17 stimulation, suggesting i) IL-6 is more sensitive to enhancement by additional disease relevant stimuli and ii) IL-6 and IL-8 are differentially regulated at the transcriptional level; ChIP studies showed increased enrichment of Brd4/p65 at the IL-6 promoter compared to the IL-8 promoter.The Wellcome Trus

Omalizumab, an Anti-IgE mAb, Receives Approval for the Treatment of Chronic Idiopathic/Spontaneous Urticaria

Omalizumab, an anti-IgE mAb, has recently been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of chronic idiopathic urticaria. Saini et al. (2014) (this issue) report on ASTERIA I, a 40-week randomized, double-blinded, placebo-controlled phase III trial evaluating omalizumab for the treatment of this disease

Signal regulatory protein alpha initiates cachexia through muscle to adipose tissue crosstalk

BACKGROUND: Muscle wasting from chronic kidney disease (CKD) or from defective insulin signalling results in morbidity and, ultimately, mortality. We have identified an endogenous mediator of insulin resistance, signal regulatory protein alpha (SIRPα), which leads to cachexia in mice and is associated with cachexia in patients with CKD. METHODS: We assessed insulin signalling and mechanisms causing muscle atrophy plus white adipose tissue (WAT) metabolism in mouse models of CKD or acute diabetes (streptozotocin treatment). We then examined these factors in mice with global knockout (KO) of SIRPα and sought mediators of metabolic responses in muscle and adipose tissues of mice with either muscle-specific or adipose tissue-specific KO of SIRPα. Metabolic responses were confirmed in primary cultures of adipose cells. RESULTS: In mice with CKD, SIRPα expression was increased in WAT (three-fold, P \u3c 0.05), and this was associated with precursors of cachexia: \u27pathologic browning\u27, thermogenesis, and a two-fold activation of protein kinase A (P \u3c 0.05 vs. control mice) plus loss of adipose tissue mass. In contrast, mice with SIRPα global KO and CKD or acute diabetes experienced improved insulin signalling and activation of pAkt plus \u27physiologic browning\u27 of WAT. These mice avoided losses of muscle and adipose tissues and experienced a 31% improvement in survival (P \u3c 0.05) than did wild-type mice with CKD. In muscle-specific SIRPα KO mice with CKD, we uncovered that serum SIRPα levels (P \u3c 0.05) were suppressed and were associated with improved insulin signalling both in skeletal muscles and in WAT. These changes were accompanied by physiologic WAT browning. However, in adipose-specific SIRPα KO mice with CKD, levels of serum SIRPα were increased over two-fold (P \u3c 0.05), while muscle losses were minimally inhibited. Clinical implications of SIRPα signalling are suggested by our findings that include increased SIRPα expression in muscle and adipose tissues (P \u3c 0.05 vs. healthy controls) plus higher SIRPα levels in the serum of patients with CKD (2.4-fold, P=0.000017 vs. healthy controls). CONCLUSIONS: Our results show that SIRPα plays an important role as an anti-insulin mediator regulating pathways to cachexia. In muscle-specific SIRPα KO, changes in SIRPα serum levels seem to improve insulin signalling in muscle and WAT, suggesting crosstalk between muscle and adipose tissue. Therefore, targeting SIRPα may prevent cachexia in patients with CKD or acute diabetes

View-Upload Decoupling: A Redesign of Multi-Channel P2P Video Systems

Abstract—In current multi-channel live P2P video systems, there are several fundamental performance problems including exceedingly-large channel switching delays, long playback lags, and poor performance for less popular channels. These performance problems primarily stem from two intrinsic characteristics of multi-channel P2P video systems: channel churn and channelresource imbalance. In this paper, we propose a radically different cross-channel P2P streaming framework, called View-Upload Decoupling (VUD). VUD strictly decouples peer downloading from uploading, bringing stability to multichannel systems and enabling cross-channel resource sharing. We propose a set of peer assignment and bandwidth allocation algorithms to properly provision bandwidth among channels, and introduce substream swarming to reduce the bandwidth overhead. We evaluate the performance of VUD via extensive simulations as well with a PlanetLab implementation. Our simulation and PlanetLab results show that VUD is resilient to channel churn, and achieves lower switching delay and better streaming quality. In particular, the streaming quality of small channels is greatly improved. I