Physiological effects of oxidized phospholipids and their cellular signaling mechanisms in inflammation

Oxidized phospholipids, such as the products of the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by nonenzymatic radical attack, are known to be formed in a number of inflammatory diseases. Interest in the bioactivity and signaling functions of these compounds has increased enormously, with many studies using cultured immortalized and primary cells, tissues, and animals to understand their roles in disease pathology. Initially, oxidized phospholipids were viewed largely as culprits, in line with observations that they have proinflammatory effects, enhancing inflammatory cytokine production, cell adhesion and migration, proliferation, apoptosis, and necrosis, especially in vascular endothelial cells, macrophages, and smooth muscle cells. However, evidence has emerged that these compounds also have protective effects in some situations and cell types; a notable example is their ability to interfere with signaling by certain Toll-like receptors (TLRs) induced by microbial products that normally leads to inflammation. They also have protective effects via the stimulation of small GTPases and induce up-regulation of antioxidant enzymes and cytoskeletal rearrangements that improve endothelial barrier function. Oxidized phospholipids interact with several cellular receptors, including scavenger receptors, platelet-activating factor receptors, peroxisome proliferator-activated receptors, and TLRs. The various and sometimes contradictory effects that have been observed for oxidized phospholipids depend on their concentration, their specific structure, and the cell type investigated. Nevertheless, the underlying molecular mechanisms by which oxidized phospholipids exert their effects in various pathologies are similar. Although our understanding of the actions and mechanisms of these mediators has advanced substantially, many questions do remain about their precise interactions with components of cell signaling pathways.

Overcoming network overload and redundancy in inter-organizational networks:the roles of potential and latent ties

This paper builds on Granovetter's distinction between strong and weak ties [Granovetter, M. S. 1973. The strength of weak ties. Amer. J. Sociol. 78(6) 1360–1380] in order to respond to recent calls for a more dynamic and processual understanding of networks. The concepts of potential and latent tie are deductively identified, and their implications for understanding how and why networks emerge, evolve, and change are explored. A longitudinal empirical study conducted with companies operating in the European motorsport industry reveals that firms take strategic actions to search for potential ties and reactivate latent ties in order to solve problems of network redundancy and overload. Examples are given, and their characteristics are examined to provide theoretical elaboration of the relationship between the types of tie and network evolution. These conceptual and empirical insights move understanding of the managerial challenge of building effective networks beyond static structural contingency models of optimal network forms to highlight the processes and capabilities of dynamic relationship building and network development. In so doing, this paper highlights the interrelationship between search and redundancy and the scope for strategic action alongside path dependence and structural influences on network processes.

The global audit profession and the international financial architecture:understanding regulatory relationships at a time of financial crisis

This paper explores how regulatory relationships in the global audit arena are being affected by the current financial crisis. Key policy initiatives and debates are analyzed, along with institutional interactions, in particular between the International Federation of Accountants (IFAC), international regulators and the large audit firms. The events are placed in the context of the new international financial architecture which has developed over the last decade. Using the illustrative lens of bank auditing, questions are asked of the nature and status of audit practice and the regulatory arrangements governing such practice. The paper shows the active nature of the regulatory responses to the crisis and the shifting and competing influences among key regulatory and professional participants in the global audit arena. Emphasis is placed on the need for audit researchers to be sensitive to the developing global financial architecture, and its potential implications for the study of audit practice in different national and international contexts.

A review of research and practice for the industrial networks of the future

Academic researchers have followed closely the interest of companies in establishing industrial networks by studying aspects such as social interaction and contractual relationships. But what patterns underlie the emergence of industrial networks and what support should research provide for practitioners? First, it appears that manufacturing is becoming a commodity rather than a unique capability, which accounts especially for low-technology approaches in downstream parts of the network, for example, in assembly operations. Second, the increased tendency towards specialisation has forced other, upstream, parts of industrial networks to introduce advanced manufacturing technologies for niche markets. Third, the capital market for investments in capacity, and the trade in manufacturing as a commodity, dominates resource allocation to a larger extent than was previously the case. Fourth, there is becoming a continuous move towards more loosely connected entities that comprise manufacturing networks. Finally, in these networks, concepts for supply chain management should address collaboration and information technology that supports decentralised decision-making, in particular to address sustainable and green supply chains. More traditional concepts, such as the keiretsu and chaibol networks of some Asian economies, do not sufficiently support the demands now being placed on networks. Research should address these five fundamental challenges to prepare for the industrial networks of 2020 and beyond. © 2010 Springer-Verlag London.

Managing radical ICT implementation and politics: A case study of cost-efficient wireless networks

This paper analyzes a case study of wireless network implementation in a politically sensitive environment and seeks to gain practical insights for IT managers in today’s networked economy. The case evolved around an urgent decision to implement wireless networks that were a radical replacement for the existing wired network infrastructure. Although the wireless network infrastructure was well calculated as being considerably cost-efficient, inexperienced administrators and IT department failed to consult various involved stakeholders. Consequently, unintended results of wireless network implementation entangled with the cost efficiency of technology outcome and in turn undermined the objectives and achievement of the initial project plan. Drawing from social perspectives, this case study challenges traditionally dominant perspectives of technology efficiency and summarizes several lessons that could help IT managers and policy makers to better strategize ICT in general, and wireless networks in particular.

Hypoxia-inducible factor (HIF) network:insights from mathematical models

Oxygen is a crucial molecule for cellular function. When oxygen demand exceeds supply, the oxygen sensing pathway centred on the hypoxia inducible factor (HIF) is switched on and promotes adaptation to hypoxia by up-regulating genes involved in angiogenesis, erythropoiesis and glycolysis. The regulation of HIF is tightly modulated through intricate regulatory mechanisms. Notably, its protein stability is controlled by the oxygen sensing prolyl hydroxylase domain (PHD) enzymes and its transcriptional activity is controlled by the asparaginyl hydroxylase FIH (factor inhibiting HIF-1).To probe the complexity of hypoxia-induced HIF signalling, efforts in mathematical modelling of the pathway have been underway for around a decade. In this paper, we review the existing mathematical models developed to describe and explain specific behaviours of the HIF pathway and how they have contributed new insights into our understanding of the network. Topics for modelling included the switch-like response to decreased oxygen gradient, the role of micro environmental factors, the regulation by FIH and the temporal dynamics of the HIF response. We will also discuss the technical aspects, extent and limitations of these models. Recently, HIF pathway has been implicated in other disease contexts such as hypoxic inflammation and cancer through crosstalking with pathways like NF?B and mTOR. We will examine how future mathematical modelling and simulation of interlinked networks can aid in understanding HIF behaviour in complex pathophysiological situations. Ultimately this would allow the identification of new pharmacological targets in different disease settings.

Industrial networks of the future:a critical commentary on research and practice

Academia has followed the interest by companies in establishing industrial networks by studying aspects such as social interaction and contractual relationships. But what patterns underlie the emergence of industrial networks and what support should research provide for practitioners? Firstly, it seems that manufacturing is becoming a commodity rather than a unique capability, which accounts especially for low-technology approaches in downstream parts of the network, for example in assembly operations. Secondly, the increased tendency to specialize forces other parts of industrial networks to introduce advanced manufacturing technologies for niche markets. Thirdly, the capital market for investments in capacity and the trade in manufacturing as a commodity dominates resource allocation to a larger extent. Fourthly, there will be a continuous move toward more loosely connected entities forming manufacturing networks. More traditional concepts, like keiretsu and chaibol networks, do not sufficiently support this transition. Research should address these fundamental challenges to prepare for the industrial networks of 2020 and beyond.

Conditional osmotic stress in yeast:a system to study transport through aquaglyceroporins and osmostress signaling

The accumulation and transport of solutes are hallmarks of osmoadaptation. In this study we have employed the inability of the Saccharomyces cerevisiae gpd1Δ gpd2Δ mutant both to produce glycerol and to adapt to high osmolarity to study solute transport through aquaglyceroporins and the control of osmostress-induced signaling. High levels of different polyols, including glycerol, inhibited growth of the gpd1Δ gpd2Δ mutant. This growth inhibition was suppressed by expression of the hyperactive allele Fps1-AΔ of the osmogated yeast aquaglyceroporin, Fps1. The degree of suppression correlated with the relative rate of transport of the different polyols tested. Transport studies in secretory vesicles confirmed that Fps1-Δ1 transports polyols at increased rates compared with wild type Fps1. Importantly, wild type Fps1 and Fps1-Δ1 showed similarly low permeability for water. The growth defect on polyols in the gpd1Δ gpd2Δ mutant was also suppressed by expression of a heterologous aquaglyceroporin, rat AQP9. We surmised that this suppression was due to polyol influx, causing the cells to passively adapt to the stress. Indeed, when aquaglyceroporin-expressing gpd1Δ gpd2Δ mutants were treated with glycerol, xylitol, or sorbitol, the osmosensing HOG pathway was activated, and the period of activation correlated with the apparent rate of polyol uptake. This observation supports the notion that deactivation of the HOG pathway is closely coupled to osmotic adaptation. Taken together, our "conditional" osmotic stress system facilitates studies on aquaglyceroporin function and reveals features of the osmosensing and signaling system. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

On-line learning in multilayer neural networks

We present an analytic solution to the problem of on-line gradient-descent learning for two-layer neural networks with an arbitrary number of hidden units in both teacher and student networks. The technique, demonstrated here for the case of adaptive input-to-hidden weights, becomes exact as the dimensionality of the input space increases.

Strategic innovation networks

This thesis draws on two key areas of the innovation literature, the strategic management of technology (SMOT) and innovation networks. The aim is to integrate these two areas of the management of innovation literature to develop a framework which I describe as the Strategic Innovation Network (SIN). The key proposition that the revised framework (SIN) aims to address is based on the work of Chandler (1962). Chandler's (1962) conclusion that 'structure follows strategy' is examined in relation to the interaction between corporate/technology strategy and network structure. The SIN is intended to address weaknesses in both the SMOT and network literature. The research data is based on five detailed longitudinal case studies. The organisations are defined as mid-corporate firms operating in traditional manufacturing sectors. Each organisation was chosen on the basis that it was aiming to develop its innovative capacity through product or process innovation projects. The research was carried out over an 18 month period with interviews being held regularly to develop the longitudinal aspect of the study analysis. The data for each individual case study is examined using the SIN framework. The longitudinal approach addresses the objective to provide a dynamic model of the innovation processes by mapping the changes in network structure during the course of individual projects. The network structural changes are examined in relation to each organisation's strategy and five key dynamic network stages are identified in relation to the innovation process. These network stages show the influence strategy has on the structures adopted by the five case studies.

Foreign direct investment and corruption

In the last few decades, the world has witnessed an enormous growth in the volume of foreign direct investment (FDI). The global stock of FDI reached US$ 7.5 trillion in 2003 and accounted for 11% of world Gross Domestic Product, up from 7% in 1990. The sales of multinational enterprises at around US$ 19 trillion were more than double the level of world exports. Substantial FDI inflows went into transition countries. Inflows into one of the region's largest recipient, the Russian Federation, almost doubled, enabling Russia to become one of the five top FDI destinations in 2005-2006. FDI inflows in Russia have increased almost threefold from 13.6% in 2003 to 35% in 2007. In 2003, these flows were twice greater than those into China; whilst in 2007 they were six times larger. Russia's FDI inflows were also about 2.5 times greater than those of Brazil. Efficient government institutions are argued by many economists to foster FDI and growth as a result. However, the magnitude of this effect has yet to be measured. This thesis takes a Political Economy approach to explore, empirically, the potential impact of malfunctioning governmental institutions, proxied by three indices of perceived corruption, on FDI stocks accumulation/distribution within Russia over the period of 2002-2004. Using a regional data-set it concentrates on three areas relating to FDI. Firstly, it considers the significance, the size and the sign of the impact of perceived corruption on accumulation of FDI stocks within Russia. Secondly, it quantifies the impact of perceived corruption on the volume of FDI stocks simultaneously estimating the impact of the investment in public capital such as telecommunications and transportation networks on FDI in the presence of corruption. In particular, it addresses the question whether more corrupt regions in Russia are also those that could have accumulated more of FDI stocks, and investigates whether those 'more corrupt' regions would have had lower level of public capital investment. Finally, it examines whether decentralisation increases or decreases corruption and whether a larger extent of decentralisation has a positive or negative impact on FDI (stocks). The results of three studies are as follows. Firstly, along with market potential, corruption is found to be one of the key factors in explaining FDI distribution within Russia between 2002 and 2004. Secondly, corruption on average is found to be related to FDI positively suggesting that it may act as speed money: to save their time foreign direct investors might be willing to bribe the regional authorities so to move in front of the bureaucratic lines. Thirdly, although when corruption is controlled for, the impact of the latter on unobservable FDI is found to be on average positive, no association between FDI and public investment is observed with the only exception of transportation infrastructure (i.e., railway). The results might suggest therefore that it is possible that not only regions with high levels of perceived corruption attract more FDI but also that expansions in public capital investments are not accompanied by an increase of the volume of FDI (stocks) in regions with high levels of corruption. This casts some doubt on the productivity of the investment in public capital in these regions as it might be that bureaucrats may prefer to use these infrastructural projects for rent extraction. Finally, we find decentralisation to have a significant and positive impact on both FDI stock accumulation and corruption, suggesting that local governments may spend more on public goods to make the area more attractive to foreign investors but at the same time they may be interested into extracting rents from foreign investors. These results support the idea that the regulation of FDI is associated with and facilitated by a larger public sector, which distorts competition and introduces opportunities for rent-seeking by particular economic and political factors.

Static energy analysis of MHC class I and class II peptide-binding affinity

Antigenic peptide is presented to a T-cell receptor (TCR) through the formation of a stable complex with a major histocompatibility complex (MHC) molecule. Various predictive algorithms have been developed to estimate a peptide's capacity to form a stable complex with a given MHC class II allele, a technique integral to the strategy of vaccine design. These have previously incorporated such computational techniques as quantitative matrices and neural networks. A novel predictive technique is described, which uses molecular modeling of predetermined crystal structures to estimate the stability of an MHC class II-peptide complex. The structures are remodeled, energy minimized, and annealed before the energetic interaction is calculated.

The stratigraphy of the Fishguard volcanic complex and associated sediments, SW Dyfed, Wales

This thesis describes the geology of a Lower Palaeozoic terrain, situated west of the town of Fishguard, SW Dyfed, Wales. The area is dominated by the Fishguard Volcanic Complex (Upper Llanvirn), and sediments that range in age from the Middle Cambrian to the Lower Llandeilo. The successions represent an insight into sedimentation and volcanism for c. 100 Ma. along the south-western margin of the Lower Palaeozoic Welsh Basin. The stratigraphy of the sedimentary sequence has been completely revised and the existing volcanostratigraphy modified. The observed complexity of the stratigraphy is primarily the consequence of Caldedonide deformation which resulted in large scale repetition. Fold-thrust tectonics dominates the structural style of the area. Caledonide trending (NE-SW) cross-faults complicate preexisting structures. Middle Cambrian (?) sedimentation is documented by shallow marine clastics and red shales deposited within tidal - subtidal environments. Upper Cambrian sedimentation was dominated by shallow marine `storm' and `fair weather' sedimentation within a muddy shelf environment. Shallow marine conglomerates and heterolithic intertidal siliciclastics mark the onset of Ordovician sedimentation during the lower Arenig transgression. Mid-Arenig sediments reflect deposits influenced by storm, fair-weather and wave related processes in various shallow marine environments, including; shoreface, inner shelf, shoaling bar, and deltaic. Graptolitic marine shales were deposited from the upper mid-Arenig through to the lower Llandeilo; during which time sediments accumulated by pelagic processes and fine grained turbidites. The varied nature of sedimentation reflects both localised change within the depositional system and the influence of larger regional eustatic events. Ordovician subaqueous volcanic activity produced thick accumulations of lavas, pyroclastics, hydroclastics, and hyaloclastics. The majority of volcanism was effusive in nature, erupted below the Pressure Compensation Level. Basaltic volcanism was characterised by pillowed lavas and tube networks, whilst sheet-flow lavas, pillow breccias and minor hyaloclastites developed locally. Silicic volcanism was dominated by rhyolitic clastics of various affinities, although coherent silicic obsidian lavas, sheet-flow lavas and pyroclastics developed. Hypabyssal intrusives of variable composition and habit occur throughout the volcanic successions. Low-grade regional metamorphism has variably affected the area, conditions of the prehnite-pumpellyite and greenschist facies having been attained. Numerous secondary phases developed in response to the conditions imposed, which collectively indicate that P-T conditions were of low-pressure facies series in the range P= 1.2-2.0 kbars and T= 230-350oC, under an elevated geothermal gradient of 40-45oC km-1. Polymineralic cataclastites associated with Caledonide deformation indicate that tectonism and metamorphism were in part contemporaneous.

Finding structures in information networks using the affinity network

This thesis proposes a novel graphical model for inference called the Affinity Network,which displays the closeness between pairs of variables and is an alternative to Bayesian Networks and Dependency Networks. The Affinity Network shares some similarities with Bayesian Networks and Dependency Networks but avoids their heuristic and stochastic graph construction algorithms by using a message passing scheme. A comparison with the above two instances of graphical models is given for sparse discrete and continuous medical data and data taken from the UCI machine learning repository. The experimental study reveals that the Affinity Network graphs tend to be more accurate on the basis of an exhaustive search with the small datasets. Moreover, the graph construction algorithm is faster than the other two methods with huge datasets. The Affinity Network is also applied to data produced by a synchronised system. A detailed analysis and numerical investigation into this dynamical system is provided and it is shown that the Affinity Network can be used to characterise its emergent behaviour even in the presence of noise.

A dynamic bandwidth reservation scheme for hybrid IEEE 802.16 wireless networks

A dynamic bandwidth reservation (DBR) scheme for hybrid IEEE 802.16 wireless networks is investigated, in which 802.16 networks serve as the backhaul for client networks, such as WiFi hotspots and cellular networks. The DBR scheme implemented in the subscription stations (SSs) (co-locating with access pointers) consists of two components: connection admission controller (CAC), and bandwidth controller (BC). The CAC processes the received connection set-up requests from the client networks connected to the SSs. The BC manages the request and release of bandwidth from the base station (BS). It dynamically changes the reserved bandwidth between a small number of values. Hysteresis is incorporated in bandwidth release to reduce bandwidth request signalling load and connection blocking probability. An analytical model is proposed to evaluate the performances of reserved bandwidth, connection blocking probability and signalling load. The impacts of hysteresis mechanism and probability of reservation request blocking are taken into account. Simulation verifies the analytical model. ©2008 IEEE.