Mike Barnes

The Collagen-binding A-domains of Integrins α1β1 and α2β1Recognize the Same Specific Amino Acid Sequence, GFOGER, in Native (Triple-helical) Collagens

We have previously assigned an integrin α2β1-recognition site in collagen I to the sequence, GFOGERGVEGPOGPA (O = Hyp), corresponding to residues 502–516 of the α1(I) chain and located in the fragment α1(I)CB3 (Knight, C. G., Morton, L. F., Onley, D. J., Peachey, A. R., Messent, A. J., Smethurst, P. A., Tuckwell, D. S., Farndale, R. W., and Barnes, M. J. (1998) J. Biol. Chem. 273, 33287–33294). In this study, we show that recognition is entirely contained within the six-residue sequence GFOGER. This sequence, when in triple-helical conformation, readily supports α2β1-dependent cell adhesion and exhibits divalent cation-dependent binding of isolated α2β1 and recombinant α2A-domain, being at least as active as the parent collagen. Replacement of E by D causes loss of recognition. The same sequence binds integrin α1 A-domain and supports integrin α1β1-mediated cell adhesion. Triple-helical GFOGER completely inhibits α2 A-domain binding to collagens I and IV and α2β1-dependent adhesion of platelets and HT 1080 cells to these collagens. It also fully inhibits α1 A-domain binding to collagen I and strongly inhibits α1β1-mediated adhesion of Rugli cells to this collagen but has little effect on either α1 A-domain binding or adhesion of Rugli cells to collagen IV. We conclude that the sequence GFOGER represents a high-affinity binding site in collagens I and IV for α2β1 and in collagen I for α1β1. Other high-affinity sites in collagen IV mediate its recognition of α1β1.

Glycoprotein VI is the collagen receptor in platelets which underlies tyrosine phosphorylation of the Fc receptor γ‐chain

We have recently shown that collagen activates platelets through a pathway dependent on the Fc receptor γ‐chain and the tyrosine kinase Syk. We report here that the Fc receptor γ‐chain and the candidate collagen receptor glycoprotein VI (GPVI) co‐associate. Furthermore, cross‐linking GPVI stimulates a similar pattern of tyrosine phosphorylation to that stimulated by collagen, including tyrosine phosphorylation of Fc receptor γ‐chain. These results support a model where GPVI couples collagen‐stimulation of platelets to phosphorylation of the Fc receptor γ‐chain leading to activation of Syk and phospholipase Cγ2.

Real-World MicroGrids-An Overview

Microgrids are networks of small, distributed electrical power generators operated as a collective unit - a system of energy systems. The range of hardware and control options for Microgrid operation are reviewed. The paper summarizes and highlights the operating principles and key conclusions of research and field trials to-date. An overview is given on demonstration projects for Microgrids which have been, and are being, constructed.

The role of collagen in thrombosis and hemostasis

Collagens represent up to 40% of the total protein of the vessel wall, forming an insoluble scaffold which is essential for tissue integrity and which provides a surface for the attachment of other matrix constituents and for the adhesion of vascular cells. Thus collagens exercise important regulatory functions within the vasculature. At least 25 different types of collagen exist [1], a number of which, including major, widely distributed types I, III, IV, V and VI, occur in the vessel wall [2]. Three polypeptide chains (a-chains) form the fundamental structure of the collagen molecule, which is characterized by the presence of one or more triple-helical domains. Within these domains, the three a-chains, which are different gene products depending on collagen type, wind around one another in a characteristic lefthanded triple helix (Fig. 1). This conformation of collagen is of crucial importance, since the three-dimensional structure is needed for recognition of collagen by its ligands. The primary structure of the triple-helical regions of collagen chains is characterized by its repetitive Gly–X–Y sequence, with Gly– Pro–Hyp (GPO) as the most frequent, forming about 10% of the primary structure of collagen types I and III [3]. The presence of glycine as every third residue is essential for the close packing of the chains. The high content of the imino acids proline and hydroxyproline is responsible for hydrogen bonds which hold the three chains of the helix together, and which stabilize helix–helix interactions within the polymeric structure of collagen. Collagens can be divided into fibrous and non-fibrous types. Triple-helical monomers of the fibrous collagens, types I–III, V and XI, self-associate to form typical highly ordered tissue collagen fibers, cross-striated with a periodicity of 67 nm, as observed by electron microscopy (Fig. 1). In vivo, mixed fibers may be assembled from various types of collagens. In contrast, non-fibrous collagens form other higher order structures. For example, type IV collagen has a modular structure composed of triple-helical segments separated by globular domains. A two-dimensional network forms, stabilized via lateral interaction between the globular domains, and forming an important component of basement membranes. Collagens, located in the matrix underlying vascular endothelial cells, are not exposed to flowing blood. After injury, however, blood will flow directly over subendothelial structures including connective tissue that contains a high percentage of collagen. Thus collagen is ideally situated to initiate hemostasis. There is ample evidence that collagen is one of the major activators of the platelet response after injury. Collagen is the only matrix protein which supports both platelet adhesion and complete activation. When collagen becomes exposed to flowing blood, platelets rapidly adhere, spread, become activated and begin to form an aggregate. Figure 2 shows the intimate contact between aggregating platelets and collagen, and Fig. 3, the extent of platelet activation and aggregate formation on collagen, compared with the adhesion only that occurs on fibrinogen-coated surfaces. The early concept that collagen was also directly responsible for the activation of the intrinsic coagulation cascade [4] turned out to be incorrect [5]. However, collagen indirectly plays a crucial role in regulating thrombin formation because negatively charged phospholipids such as phosphatidylserine become exposed on the surface of platelets after interaction with collagen and form the catalytic surface for the assembly of active coagulation complexes and thrombin generation [6]. There is additional evidence (reviewed below) that collagen participates in other ways in the regulation of the coagulation cascade. Here we will review the role of collagen in the regulation of hemostasis, embracing both coagulation and platelet aggregation.

Tyrosine phosphorylation of the Fc receptor gamma-chain in collagen-stimulated platelets

Stimulation of platelets by the extracellular matrix protein collagen leads to activation of a tyrosine kinase-dependent mechanism resulting in secretion and aggregation. Tyrosine phosphorylation of the tyrosine kinase Syk and phospholipase Cγ2 are early events in collagen-induced activation. We recently proposed that collagen-signaling in platelets involves a receptor or a receptor-associated protein containing an immunoreceptor tyrosine-based activation motif (ITAM) enabling interaction with Syk. In this report we show that collagen stimulation of platelets causes rapid tyrosine phosphorylation of the ITAM containing Fc receptor γ-chain and that this is precipitated by the tandem Src homology 2 (SH2) domains of Syk expressed as a fusion protein. In addition we demonstrate an association between the Fc receptor γ-chain with endogenous Syk in collagen-stimulated platelets. The Fc receptor γ-chain undergoes tyrosine phosphorylation in platelets stimulated by a collagen-related peptide which does not bind the integrin α2β1 and by the lectin wheat germ agglutinin. In contrast, cross-linking of the platelet low affinity receptor for immune complexes, FcγRIIA, or stimulation by thrombin does not induce phosphorylation of the Fc receptor γ-chain. The present results provide a molecular basis for collagen activation of platelets which is independent of the integrin α2β1 and involves phosphorylation of the Fc receptor γ-chain, its association with Syk and subsequent phosphorylation of phospholipase Cγ2. Collagen is the first example of a nonimmune receptor stimulus to signal through a pathway closely related to signaling by immune receptors.

The Impact of Transport Electrification on Electrical Networks

In order to satisfy the growing expectation for energy-efficient ecofriendly transportation, a number of vehicle concepts have emerged, including the hybrid electric vehicle (HEV) and battery electric vehicle. Vehicle dynamics necessitate careful sizing of onboard energy storage systems. As the penetration of electric vehicles, in both the public and private sector increases, the requirement to facilitate and utilize them becomes paramount. A particular class of vehicle, the plug-in HEV also poses a greater challenge to existing terrestrial-based electrical supply systems. This paper establishes a series of well-defined electric vehicle loads that are subsequently used to analyze their electrical energy usage and storage in the context of more electrified road transportation. These requirements are then applied to a European Union residential load profile to evaluate the impact of increasing electrification of private road vehicles on local loads and the potential for vehicle and residential load integration in the U.K.

Power electronic converters for switched reluctance drives

A number of power electronic converter circuits exist for switched reluctance motor (SRM) drives which are generally applicable to most loads. A larger number of circuits exist which are suitable for particular niche applications, but which have the potential to be the most cost-effective within that niche. Due to the variable methods of operation of these circuits and the rapid progress in this field, comparisons of these circuits have so far been limited. This paper attempts to bring together the sum total of power converter topologies so far published for SRM drives. A novel classification methodology is presented. The power converters are compared using a straightforward total semiconductor VA per phase sum, and the relative cost of the drive system elements is considered.

Power Flow Algorithms for Multi-Terminal VSC-HVDC With Droop Control

This paper addresses the problem posed by complex, nonlinear controllers for power system load flows employing multi-terminal voltage source converter (VSC) HVDC systems. More realistic dc grid control strategies can thus be carefully considered in power flow analysis of ac/dc grids. Power flow methods for multi-terminal VSC-HVDC (MTDC) systems are analyzed for different types of dc voltage control techniques and the weaknesses of present methods are addressed. As distributed voltage control is likely to be adopted by practical dc grids, a new generalized algorithm is proposed to solve the power flow problems with various nonlinear voltage droops, and the method to incorporate this algorithm with ac power flow models is also developed. With five sets of voltage characteristics implemented, the proposed scheme is applied to a five-terminal test system and shows satisfactory performance. For a range of wind power variations and converter outages, post-contingency behaviors of the system under the five control scenarios are examined. The impact of these controls on the power flow solutions is assessed.

The collagen-platelet interaction.

Collagen-platelet interaction, occurring in hemostasis but also a cause of thrombosis, is a two-step process of adhesion and activation involving the sequential recognition of distinct receptors. Adhesion involves first the reversible recognition of collagen-bound von Willebrand factor by the platelet receptor complex Gp lb/IX/V, followed by direct interaction between collagen and the platelet integrin receptor α2β1, which binds to specific sequences in collagen in which the GER motif appears important. Platelet activation then follows from the recognition by the receptor Gp VI of GPP* sequences in collagen, culminating in signalling events unique to collagen as a platelet agonist: Gp VI leads via the novel platelet Fc receptor γ-chain to p72syk and phospholipase Cγ2.

Voltage sag detection technique for a dynamic voltage restorer

Dynamic voltage restorers (DVRs) are used to protect sensitive loads from the effects of voltage sags on the distribution feeder. This paper presents and verifies a novel voltage sag detection technique for the control system of a DVR. In some cases it may be necessary for the DVR control system to not only detect the start and end of a voltage sag but also to determine the sag depth and any associated phase shift. The DVR, which is placed in series with a sensitive load, must be able to respond quickly to a voltage sag if end users of sensitive equipment are to experience no voltage fluctuations. A problem arises when fast evaluation of these parameters is required, as standard information tracking or detection methods such as the Fourier transform or phase-locked-loop (PLL) are too slow. As a result of this the voltage sag detection method this paper proposes a new state-space matrix method, which is able to compute the phase shift and voltage reduction of the supply voltage much quicker than the Fourier transform or a PLL. The paper also illustrates that the state space matrix method returns results that can be directly interpreted whereas other methods such as the wavelet transform, which return results that can be difficult to interpret.