The transcription factor ERG mediates multiple endothelial signalling pathways required for angiogenesis

ERG is a crucial regulator of endothelial gene expression and controls endothelial functions including cell survival and monolayer permeability. Previous studies indicate a role for ERG in angiogenesis and vascular development, however the pathways through which ERG controls angiogenesis are unclear. Transcriptome profiling comparing ERG-positive and ERG-deficient endothelial cells has previously shown that ERG controls a network of genes that are essential to angiogenesis. This analysis identified genes involved in the Wnt, Notch and Angiopoietin1/Tie2 signalling pathways as candidate ERG targets. ERG has been shown to drive expression of the junction molecule vascular endothelial (VE)–cadherin, which binds β-catenin, a crucial mediator of Wnt signalling, at the cell membrane. Here, I show that ERG controls β-catenin stability, by driving expression of both VE-cadherin and the Wnt receptor Frizzled-4- the balance of which regulates β-catenin localisation and activity. ERG promotes angiogenesis via Wnt/β-catenin signalling, since activation of Wnt signalling with lithium chloride, which stabilises β-catenin, corrects the angiogenic defect in ERG-deficient endothelial cells. The Notch signalling pathway is critical for promoting vascular quiescence and I demonstrate that ERG controls Notch signalling by regulating the levels of two Notch ligands, Delta like ligand (Dll)-4 and Jagged-1, with reported opposing roles in the vasculature. ERG simultaneously drives expression of pro-quiescent Dll4 and represses expression of pro-angiogenic Jagged-1, which has been shown to antagonize Dll4-mediated signalling. The Angiopoietin1/Tie2 pathway, also connected to the Wnt and Notch pathways, is a regulatory growth factor system essential for vessel maturation and quiescence. The results from this thesis suggest that ERG mediates growth factor Angiopoietin-1-dependent signals and ERG is required for Angiopoietin-1-induced Notch and Wnt signalling. Thus, ERG is able to integrate with three signalling pathways controlling vascular growth and stability - Wnt, Notch, Angiopoietin1/Tie2- which may function downstream of ERG to regulate blood vessel patterning during angiogenesis.Open Acces

Reduction of leukocyte microvascular adherence and preservation of blood-brain barrier function by superoxide-lowering therapies in a piglet model of neonatal asphyxia

Background: Asphyxia is the most common cause of brain damage in newborns. Substantial evidence indicates that leukocyte recruitment in the cerebral vasculature during asphyxia contributes to this damage. We tested the hypothesis that superoxide radical (O2⋅_) promotes an acute post-asphyxial inflammatory response and blood-brain barrier (BBB) breakdown. We investigated the effects of removing O2⋅_ by superoxide dismutase (SOD) or C3, the cell-permeable SOD mimetic, in protecting against asphyxia-related leukocyte recruitment. We also tested the hypothesis that xanthine oxidase activity is one source of this radical.Methods: Anesthetized piglets were tracheostomized, ventilated, and equipped with closed cranial windows for the assessment of post-asphyxial rhodamine 6G-labeled leukocyte-endothelial adherence and microvascular permeability to sodium fluorescein in cortical venules. Asphyxia was induced by discontinuing ventilation. SOD and C3 were administered by cortical superfusion. The xanthine oxidase inhibitor oxypurinol was administered intravenously.Results: Leukocyte-venular adherence significantly increased during the initial 2 h of post-asphyxial reperfusion. BBB permeability was also elevated relative to non-asphyxial controls. Inhibition of O2⋅_ production by oxypurinol, or elimination of O2⋅_ by SOD or C3, significantly reduced rhodamine 6G-labeled leukocyte-endothelial adherence and improved BBB integrity, as measured by sodium fluorescein leak from cerebral microvessels.Conclusion: Using three different strategies to either prevent formation or enhance elimination of O2⋅_ during the post-asphyxial period, we saw both reduced leukocyte adherence and preserved BBB function with treatment. These findings suggest that agents which lower O2⋅_ in brain may be attractive new therapeutic interventions for the protection of the neonatal brain following asphyxia

Catch Me if I Can: Detecting Strategic Behaviour in Peer Assessment

We consider the issue of strategic behaviour in various peer-assessment tasks, including peer grading of exams or homeworks and peer review in hiring or promotions. When a peer-assessment task is competitive (e.g., when students are graded on a curve), agents may be incentivized to misreport evaluations in order to improve their own final standing. Our focus is on designing methods for detection of such manipulations. Specifically, we consider a setting in which agents evaluate a subset of their peers and output rankings that are later aggregated to form a final ordering. In this paper, we investigate a statistical framework for this problem and design a principled test for detecting strategic behaviour. We prove that our test has strong false alarm guarantees and evaluate its detection ability in practical settings. For this, we design and execute an experiment that elicits strategic behaviour from subjects and release a dataset of patterns of strategic behaviour that may be of independent interest. We then use the collected data to conduct a series of real and semi-synthetic evaluations that demonstrate a strong detection power of our test

Measles, mumps and rubella vaccine as an intralesional immunotherapy in treatment of warts

Background: To observe the efficacy and safety of intralesional Measles Mumps and Rubella (MMR) vaccine in the treatment of warts.Methods: 50 patients with single or multiple warts more than 06 months duration in all age groups were included in the study. The patients received intralesional MMR vaccine 0.5ml into a single wart or the largest wart in case of multiple lesions at interval of two weeks for three treatments. The response was evaluated as 0-49% as no response, 50-99% as partial response and 100% as complete response. Follow up was made every 02 weeks for 06 weeks and then monthly for 06 months to detect any recurrence.Results: Complete response was seen in 36 (72%), partial response in 08 (16%) and no response in 06 (12%) patients. No recurrence was observed. Pain at the site of injection in 18 (36%) and flu like symptoms in 02 (04%) patients were observed.Conclusions: Intralesional immunotherapy with MMR vaccine was found to be a simple, effective, and safe treatment for warts. This study proved to be cost effective as patients can be treated with just 03 doses of MMR vaccine given at the interval of two weeks.

Successive-approximation-register based quantizer design for high-speed delta-sigma modulators

High-speed delta-sigma modulators are in high demand for applications such as wire-line and wireless communications, medical imaging, RF receivers and high-definition video processing. A high-speed delta-sigma modulator requires that all components of the delta-sigma loop operate at the desired high frequency. For this reason, it is essential that the quantizer used in the delta-sigma loop operate at a high sampling frequency. This thesis focuses on the design of high-speed time-interleaved multi-bit successive-approximation-register (SAR) quantizers. Design techniques for high-speed medium-resolution SAR analog-to-digital converters (ADCs) using synchronous SAR logic are proposed. Four-bit and 8-bit 5 GS/s SAR ADCs have been implemented in 65 nm CMOS using 8-channel and 16-channel time-interleaving respectively. The 4-bit SAR ADC achieves SNR of 24.3 dB, figure-of-merit (FoM) of 638 fJ/conversion-step and 42.6 mW power consumption, while the 8-bit SAR ADC achieves SNR of 41.5 dB, FoM of 191 fJ/conversion-step and 92.8 mW power consumption. High-speed operation is achieved by optimizing the critical path in the SAR ADC loop. A sampling network with a split-array with unit bridge capacitor topology is used to reduce the area of the sampling network and switch drivers