The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions

Nepsilon-(Carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined nonenzymatic glycation and oxidation (glycoxidation) reactions. We now report that CML is also formed during metal-catalyzed oxidation of polyunsaturated fatty acids in the presence of protein. During copper-catalyzed oxidation in vitro, the CML content of low density lipoprotein increased in concert with conjugated dienes but was independent of the presence of the Amadori compound, fructoselysine, on the protein. CML was also formed in a time-dependent manner in RNase incubated under aerobic conditions in phosphate buffer containing arachidonate or linoleate; only trace amounts of CML were formed from oleate. After 6 days of incubation the yield of CML in RNase from arachidonate was approximately 0.7 mmol/mol lysine compared with only 0.03 mmol/mol lysine for protein incubated under the same conditions with glucose. Glyoxal, a known precursor of CML, was also formed during incubation of RNase with arachidonate. These results suggest that lipid peroxidation, as well as glycoxidation, may be an important source of CML in tissue proteins in vivo and that CML may be a general marker of oxidative stress and long term damage to protein in aging, atherosclerosis, and diabetes.

Advanced glycation end products and diabetic retinopathy

Diabetic retinopathy (DR) has a complex pathogenesis which is impacted by a raft of systemic abnormalities and tissue-specific alterations occurring in response to the diabetes milieu. Many pathogenic processes play key roles in retinal damage in diabetic patients. One such pathway is the formation and accumulation of advanced glycation endproducts (AGEs) and advanced lipoxidation end products (ALEs) which are relevant modifications with roles in the initiation and progression of pathology. In this review, AGE/ALE formation in the diabetic retina is discussed alongside their impact on retinal cell function. In addition, various inhibitors of the AGE-RAGE system and their therapeutic utility for DR will also be evaluated.

Advanced glycation endproduct modified basement membrane attenuates endothelin-1 induced [Ca2+]i signalling and contraction in retinal microvascular pericytes

PURPOSE: To assess the effects of advanced glycation endproduct (AGE) modification of vascular basement membrane (BM) on endothelin-1 (Et-1) induced intracellular [Ca2+] ([Ca2+]i) homeostasis and contraction in retinal microvascular pericytes (RMP). METHODS: RMPs were isolated from bovine retinal capillaries and propagated on AGE modified BM extract (AGE-BM) or non-modified native BM. Cytosolic Ca2+ was estimated using fura-2 microfluorimetry and cellular contraction determined by measurement of planimetric cell surface area. ETA receptor mRNA and protein expression was assessed by real time RT-PCR and western blotting, respectively. RESULTS: Exogenous endothelin-1 (Et-1) evoked rises in [Ca2+]i and contraction in RMPs were found to be mediated entirely through ETA receptor (ETAR) activation. Both peak and plateau phases of the Et-1 induced [Ca2+]i response and contraction were impaired in RMPs propagated on AGE modified BM. ETAR mRNA expression remained unchanged in RMPs exposed to native or AGE-BM, but protein expression for ETAR (66 kDa) was lower in the AGE exposed cells. CONCLUSIONS: These results suggest that substrate derived AGE crosslinks can influence RMP physiology by mechanisms which include disruption of ETA receptor signalling. AGE modification of vascular BMs may contribute to the retinal hemodynamic abnormalities observed during diabetes.

Substrates modified by advanced glycation end-products cause dysfunction and death in retinal pericytes by reducing survival signals mediated by platelet-derived growth factor

AIMS/HYPOTHESIS: Premature death of retinal pericytes is a pathophysiological hallmark of diabetic retinopathy. Among the mechanisms proposed for pericyte death is exposure to AGE, which accumulate during diabetes. The current study used an in vitro model, whereby retinal pericytes were exposed to AGE-modified substrate and the mechanisms underlying pericyte death explored. METHODS: Pericytes were isolated from bovine retinal capillaries and propagated on AGE-modified basement membrane (BM) extract or non-modified native BM. The extent of AGE modification was analysed. Proliferative responses of retinal pericytes propagated on AGE-modified BM were investigated using a 5-bromo-2-deoxy-uridine-based assay. The effect of extrinsically added platelet-derived growth factor (PDGF) isoforms on these proliferative responses was also analysed alongside mRNA expression of the PDGF receptors. Apoptotic death of retinal pericytes grown on AGE-modified BM was investigated using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling labelling, mitochondrial membrane depolarisation and by morphological assessment. We also measured both the ability of PDGF to reverse Akt dephosphorylation that was mediated by AGE-modified BM, and increased pericyte apoptosis. RESULTS: Retinal pericytes exposed to AGE-modified BM showed reduced proliferative responses in comparison to controls (p

Why do people present late with advanced glaucoma?:A qualitative interview study

To explore the presentation behaviours and pathways to detection of adults who first presented to UK hospital eye services with severe glaucoma.

The Impact of Vehicle-to-Grid on Electric Power Systems: A Review

Environmental concerns and fossil fuel shortage put pressure on both power and transportation systems. Electric vehicles (EVs) are thought to be a good solution to these problems. With EV adoption, energy flow is two way: from grid to vehicle and from vehicle to grid, which is known as vehicle-to-grid (V2G) today. This paper considers electric power systems and provides a review of the impact of V2G on power system stability. The concept and basics of V2G technology are introduced at first, followed by a description of EV application in the world. Several technical issues are detailed in V2G modeling and capacity forecasting, steady-state analysis and stability analysis. Research trends of such topics are declared at last.

Man-in-the-Middle Attack Test-bed Investigating Cyber-security Vulnerabilities in Smart Grid SCADA Systems

The increased complexity and interconnectivity of Supervisory Control and Data Acquisition (SCADA) systems in the Smart Grid has exposed them to a wide range of cyber-security issues, and there are a multitude of potential access points for cyber attackers. This paper presents a SCADA-specific cyber-security test-bed which contains SCADA software and communication infrastructure. This test-bed is used to investigate an Address Resolution Protocol (ARP) spoofing based man-in-the-middle attack. Finally, the paper proposes a future work plan which focuses on applying intrusion detection and prevention technology to address cyber-security issues in SCADA systems.

Impact of Cyber-Security Issues on Smart Grid

Greater complexity and interconnectivity across systems embracing Smart Grid technologies has meant that cyber-security issues have attracted significant attention. This paper describes pertinent cyber-security requirements, in particular cyber attacks and countermeasures which are critical for reliable Smart Grid operation. Relevant published literature is presented for critical aspects of Smart Grid cyber-security, such as vulnerability, interdependency, simulation, and standards. Furthermore, a preliminary study case is given which demonstrates the impact of a cyber attack which violates the integrity of data on the load management of real power system. Finally, the paper proposes future work plan which focuses on applying intrusion detection and prevention technology to address cyber-security issues. This paper also provides an overview of Smart Grid cyber-security with reference to related cross-disciplinary research topics.

Optimization of FRT Active Power Performance of a DFIG during Transient Grid Faults

Optimal fault ride-through (FRT) conditions for a doubly-fed induction generator (DFIG) during a transient grid fault are analyzed with special emphasis on improving the active power generation profile. The transition states due to crowbar activation during transient faults are investigated to exploit the maximum power during the fault and post-fault period. It has been identified that operating slip, severity of fault and crowbar resistance have a direct impact on the power capability of a DFIG, and crowbar resistance can be chosen to optimize the power capability. It has been further shown that an extended crowbar period can deliver enhanced inertial response following the transient fault. The converter protection and drive train dynamics have also been analyzed while choosing the optimum crowbar resistance and delivering enhanced inertial support for an extended crowbar period.

Active use of DFIG based Wind Farms for Transient Stability Improvement during Grid Disturbances

The doubly-fed induction generator (DFIG) now represents the dominant technology in wind turbine design. One consequence of this is limited damping and inertial response during transient grid disturbances. A dasiadecoupledpsila strategy is therefore proposed to operate the DFIG grid-side converter (GSC) as a static synchronous compensator (STATCOM) during a fault, supporting the local voltage, while the DFIG operates as a fixed-speed induction generator (FSIG) providing an inertial response. The modeling aspects of the decoupled control strategy, the selection of protection control settings, the significance of the fault location and operation at sub- and super-synchronous speeds are analyzed in detail. In addition, a case study is developed to validate the proposed strategy under different wind penetrations levels. The simulations show that suitable configuration of the decoupled strategy can be deployed to improve system voltage stability and inertial response for a range of scenarios, especially at high wind penetration. The conclusions are placed in context of the practical limitations of the technology employed and the system conditions.