Atherogenic, fibrotic and glucose utilising actions of glucokinase activators on vascular endothelium and smooth muscle

Abstract Backgroun

Cellular and molecular pathology of age-related macular degeneration: Potential role for proteoglycans

Age-related macular degeneration (AMD) is a retinal disease evident after the age of 50 that damages the macula in the centre of retina. It leads to a loss of central vision with retained peripheral vision but eventual blindness occurs in many cases. The initiation site of AMD development is Bruch's membrane (BM) where multiple changes occur including the deposition of plasma derived lipids, accumulation of extracellular debris, changes in cell morphology, and viability and the formation of drusen. AMD manifests as early and late stage; the latter involves cell proliferation and neovascularization in wet AMD. Current therapies target the later hyperproliferative and invasive wet stage whilst none target early developmental stages of AMD. In the lipid deposition disease atherosclerosis modified proteoglycans bind and retain apolipoproteins in the artery wall. Chemically modified trapped lipids are immunogenic and can initiate a chronic inflammatory process manifesting as atherosclerotic plaques and subsequent artery blockages, heart attacks, or strokes. As plasma derived lipoprotein deposits are found in BM in early AMD, it is possible that they arise by a similar process within the macula. In this review we consider aspects of the pathological processes underlying AMD with a focus on the potential role of modifications to secreted proteoglycans being a cause and therefore a target for the treatment of early AMD

Platelet-derived growth factor-stimulated versican synthesis but not glycosaminoglycan elongation in vascular smooth muscle is mediated via Akt phosphorylation

Proteoglycans are associated with the initiation of atherosclerosis due to their binding of apolipoproteins on lipid particles leading to retention in the vessel wall. The signaling pathways through which growth factors regulate the synthesis and structure of proteoglycans are potential therapeutic targets. Platelet-derived growth factor (PDGF) is present in atherosclerotic plaques and activates phosphorylation of the serine/threonine kinase Akt. We have investigated the role of Akt in the signaling pathways for proteoglycan core protein expression and elongation of glycosaminoglycan chains on proteoglycans secreted by human vascular smooth muscle cells. The pharmacological inhibitor of Akt phosphorylation, SN30978, blocked PDGF stimulated phosphorylation of Akt. SN30978 caused concentration dependent inhibition of PDGF stimulated radiosulfate incorporation into secreted proteoglycans and the response was blocked by the PDGF receptor antagonists Ki11502 and imatinib. Analysis of the size of the biglycan molecules by SDS-PAGE showed that PDGF increased the apparent size of biglycan but this effect on glycosaminoglycan chain elongation was blocked by Ki11502 but not by SN30978. PDGF also stimulated total protein core protein synthesis assessed as 35S-methionine/cysteine incorporation and specifically the expression of versican mRNA. Both of these responses were blocked by SN30978. This data shows that PDGF-stimulated proteoglycan core protein synthesis but not glycosaminoglycan chain elongation is mediated via Akt phosphorylation. These data identify potential pathways for the development of agents which can pharmacologically regulate individual components of the synthesis of proteoglycans

Improving neurophysiological biomarkers for functional myoclonic movements.

INTRODUCTION: Differentiating between functional jerks (FJ) and organic myoclonus can be challenging. At present, the only advanced diagnostic biomarker to support FJ is the Bereitschaftspotential (BP). However, its sensitivity is limited and its evaluation subjective. Recently, event related desynchronisation in the broad beta range (13-45 Hz) prior to functional generalised axial (propriospinal) myoclonus was reported as a possible complementary diagnostic marker for FJ. Here we study the value of ERD together with a quantified BP in clinical practice. METHODS: Twenty-nine patients with FJ and 16 patients with cortical myoclonus (CM) were included. Jerk-locked back-averaging for determination of the 'classical' and quantified BP, and time-frequency decomposition for the event related desynchronisation (ERD) were performed. Diagnostic gain, sensitivity and specificity were obtained for individual and combined techniques. RESULTS: We detected a classical BP in 14/29, a quantitative BP in 15/29 and an ERD in 18/29 patients. At group level we demonstrate that ERD in the broad beta band preceding a jerk has significantly higher amplitude in FJ compared to CM (respectively -0.14 ± 0.13 and +0.04 ± 0.09 (p < 0.001)). Adding ERD to the classical BP achieved an additional diagnostic gain of 53%. Furthermore, when combining ERD with quantified and classical BP, an additional diagnostic gain of 71% was achieved without loss of specificity. CONCLUSION: Based on the current findings we propose to the use of combined beta ERD assessment and quantitative BP analyses in patients with a clinical suspicion for all types of FJ with a negative classical BP

BSHI Guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation

A review of the British Society for Histocompatibility and Immunogenetics (BSHI) "Guideline for selection and HLA matching of related, adult unrelated donors and umbilical cord units for haematopoietic progenitor cell transplantation" was undertaken by a BSHI appointed writing committee. Literature searches were performed, and the data extracted were presented as recommendations according to the GRADE nomenclature

TGF-β stimulates biglycan core protein synthesis but not glycosaminoglycan chain elongation via Akt phosphorylation in vascular smooth muscle

Transforming growth factor-b (TGF-b) can mediate proteoglycan synthesis via Smad and non-Smad signalling pathways in vascular smooth muscle (VSM). We investigated whether TGF-b-mediated proteoglycan synthesis is via PI3K/Akt. TGF-b induced a rapid phosphorylation of Akt that continued upto 4 h. Akt phosphorylation was blocked by Akt1/2 inhibitor SN30978; however, it did not block Smad2 phosphorylation at either the carboxy or linker regions indicating that TGF-bmediated Akt phosphorylation is independent of Smad2 signalling. The role of Akt in TGF-b-mediated proteoglycan synthesis was investigated. Treatment with SN30978 showed a concentration-dependent decrease in TGF-b-mediated [35S]- sulphate and [35S]-Met/Cys incorporation into secreted proteoglycans; however, SDS-PAGE showed no change in biglycan size. In TGF-b-treated cells, biglycan mRNA levels increased by 40-100% in 24 h and was significantly blocked by SN30978. Our findings demonstrate that Akt is a downstream signalling component of TGF-b-mediated biglycan core protein synthesis but not glycosaminoglycan chain hyper-elongation in VSM

Electro-optically tunable microring resonators in lithium niobate

Optical microresonators have recently attracted a growing attention in the photonics community. Their applications range from quantum electro-dynamics to sensors and filtering devices for optical telecommunication systems, where they are likely to become an essential building block. The integration of nonlinear and electro-optical properties in the resonators represents a very stimulating challenge, as it would incorporate new and more advanced functionality. Lithium niobate is an excellent candidate material, being an established choice for electro-optic and nonlinear optical applications. Here we report on the first realization of optical microring resonators in submicrometric thin films of lithium niobate. The high index contrast films are produced by an improved crystal ion slicing and bonding technique using benzocyclobutene. The rings have radius R=100 um and their transmission spectrum has been tuned using the electro-optic effect. These results open new perspectives for the use of lithium niobate in chip-scale integrated optical devices and nonlinear optical microcavities.Comment: 15 pages, 8 figure

Coherent quantum phase slip

A hundred years after discovery of superconductivity, one fundamental prediction of the theory, the coherent quantum phase slip (CQPS), has not been observed. CQPS is a phenomenon exactly dual to the Josephson effect: whilst the latter is a coherent transfer of charges between superconducting contacts, the former is a coherent transfer of vortices or fluxes across a superconducting wire. In contrast to previously reported observations of incoherent phase slip, the CQPS has been only a subject of theoretical study. Its experimental demonstration is made difficult by quasiparticle dissipation due to gapless excitations in nanowires or in vortex cores. This difficulty might be overcome by using certain strongly disordered superconductors in the vicinity of the superconductor-insulator transition (SIT). Here we report the first direct observation of the CQPS in a strongly disordered indium-oxide (InOx) superconducting wire inserted in a loop, which is manifested by the superposition of the quantum states with different number of fluxes. Similarly to the Josephson effect, our observation is expected to lead to novel applications in superconducting electronics and quantum metrology.Comment: 14 pages, 3 figure

Patient-reported outcome measures for acne: a mixed-methods validation study (acne PROMs).

OBJECTIVES: To examine the acceptability and validity of two patient-reported outcome measures (PROMs) for adult acne, comparing them to the validated Acne-specific Quality of Life (Acne-QoL) measure. DESIGN: Mixed-methods validation study. SETTING: Participants were recruited by (1) mail-out through primary care if they had ever consulted for acne and received a prescription for acne treatment within the last 6 months, (2) opportunistically in secondary care and (3) poster advertisement in community venues. PARTICIPANTS: 221 (204 quantitative and 17 qualitative) participants with acne, aged 18-50 years. OUTCOME MEASURES: Quantitative sub-study participants completed Acne-QoL, Skindex-16 and Comprehensive Acne Quality of Life Scale (CompAQ) at baseline, 24 hours and 6 weeks. Qualitative sub-study participants took part in cognitive think-aloud interviews, while completing the same measures. Transcribed audio recordings were analysed using inductive thematic analysis. RESULTS: Quantitative analyses suggested high internal consistency (Cronbach's alpha 0.74-0.96) and reliability (intraclass correlation coefficient values 0.88-0.97) for both questionnaires. Both scales showed floor effects on some subdomains. Skindex-16 and CompAQ showed good evidence of construct validity when compared with Acne-QoL with Spearman's correlation coefficients 0.54-0.81, and good repeatability over 24 hours.Qualitative data uncovered wide-ranging views regarding usability and acceptability. Interviewees held strong but differing views about layout, question/response wording, redundant/similar questions and guidance notes. Similarly, interviewees differed in perceptions of acceptability of the different scales, particularly on relatability of questions and emotive reactions to scales. CONCLUSIONS: All PROMs performed well in statistical analyses. No PROM showed superior usability and acceptability in the qualitative study. Any PROM should be acceptable for further research in adult acne but researchers should consider the different domains and whether they will measure only facial or facial and trunk acne before making a selection. A new PROM or further evaluation of novel PROMs may be beneficial

Atherogenic, fibrotic and glucose utilising actions of glucokinase activators on vascular endothelium and smooth muscle

Pharmaceutical interventions for diabetes aim to control glycaemia and to prevent the development of complications, such as cardiovascular diseases. Some anti-hyperglycaemic drugs have been found to have adverse cardiovascular effects in their own right, limiting their therapeutic role. Glucokinase activity in the pancreas is critical in enhancing insulin release in response to hyperglycaemia. Glucokinase activators (GKAs) are novel agents for diabetes which act by enhancing the formation of glucose-6-phosphate leading to increased insulin production and subsequent suppression of blood glucose. Little, however, is known about the direct effects of GKAs on cardiovascular cells.Methods: The effect of the GKAs RO28-1675 and Compound A on glucose utilisation in bovine aortic endothelial cells (BAEC) and rat MIN6 was observed by culturing the cells at high and low glucose concentration in the presence and absence of the GKAs and measuring glucose consumption. The effect of RO28-1675 at various concentrations on glucose-dependent signalling in BAEC was observed by measuring Smad2 phosphorylation by Western blotting. The effect of RO28-1675 on TGF-ß stimulated proteoglycan synthesis was measured by 35S-SO4 incorporation and assessment of proteoglycan size by SDS-PAGE. The effects of RO28-1675 on TGF-ß mediated Smad2C phosphorylation in BAEC was observed by measurement of pSmad2C levels. The direct actions of RO28-1675 on vascular reactivity were observed by measuring arteriole tone and lumen diameter