The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors

Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumors. Using a primary human in vitro model for Merlin-deficient tumors, we report that the Ras/Raf/mitogen-activated protein, extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) scaffold, kinase suppressor of Ras 1 (KSR1), has a vital role in promoting schwannomas development. We show that KSR1 overexpression is involved in many pathological phenotypes caused by Merlin loss, namely multipolar morphology, enhanced cell-matrix adhesion, focal adhesion and, most importantly, increased proliferation and survival. Our data demonstrate that KSR1 has a wider role than MEK1/2 in the development of schwannomas because adhesion is more dependent on KSR1 than MEK1/2. Immunoprecipitation analysis reveals that KSR1 is a novel binding partner of Merlin, which suppresses KSR1's function by inhibiting the binding between KSR1 and c-Raf. Our proteomic analysis also demonstrates that KSR1 interacts with several Merlin downstream effectors, including E3 ubiquitin ligase CRL4DCAF1. Further functional studies suggests that KSR1 and DCAF1 may co-operate to regulate schwannomas formation. Taken together, these findings suggest that KSR1 serves as a potential therapeutic target for Merlin-deficient tumors.

Discrimination between strain and temperature effects using first and second-order diffraction from a long period grating

We study the effects of temperature and strain on the spectra of the first and second-order diffraction attenuation bands of a single long-period grating (LPG) in step-index fibre. The primary and second-order attenuation bands had comparable strength with the second-order bands appearing in the visible and near-infra red parts of the spectrum. Using first and second-order diffraction to the eighth cladding mode a sensitivity matrix was obtained with limiting accuracy given by cross-sensitivity of ~1.19% of the measurement. The sensing scheme presented as a limiting temperature and strain resolution of ±0.7 °C and ~±25 µ.

Analysis of organisational climate to improve the adequacy of primary health care in the State of Kuwait

This study covers two areas of contribution to the knowledge, firstly it tried to investigate rigourously the relationships of a number of factors believed that they may affect the climate perception, classified into three types to arrive to prove a hypothesis of the important role that qualification and personal factors play in shaping the climate perception, this is in contrast with situational factors. Secondly, the study tries to recluster the items of a wide-range applied scale for the measurement of climate named HAY in order to overcome the cross-cultural differences between the Kuwaiti and the American society, and to achieve a modified dimensions of climate for a civil service organisation in Kuwait. Furthermore, the study attempts to carry out a diagnostic test for the climate of the Ministry of Public Health in Kuwait, aiming to diagnose the perceived characteristics of the MoPH organisation, and suggests a number of areas to be given attention if an improvement is to be introduced. The study used extensively the statistical and the computer facilities to make the analysis more representing the field data, on the other hand this study is characterised by the very highly responsive rate of the main survey which would affect the findings reliability. Three main field studies are included, the first one was to conduct the main questionnaire where the second was to measure the "should be" climate by the experts of MoPH using the DELPHI technique, and the third was to conduct an extensive meeting with the very top management team in MoPH. Results of the first stage were subject to CLUSTER analysis for the reconstruction of the HAY tool, whereas comparative analysis was carried on between the results of the second and third stages on one side, the first from the other.

Discrimination between strain and temperature effects using first and second-order diffraction from a long-period grating

We study the effects of temperature and strain on the spectra of the first and second-order diffraction attenuation bands of a single long-period grating (LPG) in step-index fibre. The primary and second-order attenuation bands had comparable strength with the second-order bands appearing in the visible and near-infra red parts of the spectrum. Using first and second-order diffraction to the eighth cladding mode a sensitivity matrix was obtained with limiting accuracy given by cross-sensitivity of ∼ 1.19% of the measurement. The sensing scheme presented as a limiting temperature and strain resolution of ± 0.7 °C and ∼ ± 25 με. © 2002 Elsevier Science B.V. All rights reserved.

Efficacy and safety of second-generation antipsychotic long-acting injections (SGA LAIs) in maintenance treatment of bipolar disorder:protocol for a systematic review and meta-analysis

INTRODUCTION: Bipolar disorder requires long-term treatment but non-adherence is a common problem. Antipsychotic long-acting injections (LAIs) have been suggested to improve adherence but none are licensed in the UK for bipolar. However, the use of second-generation antipsychotics (SGA) LAIs in bipolar is not uncommon albeit there is a lack of systematic review in this area. This study aims to systematically review safety and efficacy of SGA LAIs in the maintenance treatment of bipolar disorder. METHODS AND ANALYSIS: The protocol is based on Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and will include only randomised controlled trials comparing SGA LAIs in bipolar. PubMed, EMBASE, CINAHL, Cochrane Library (CENTRAL), PsychINFO, LiLACS, http://www.clinicaltrials.gov will be searched, with no language restriction, from 2000 to January 2016 as first SGA LAIs came to the market after 2000. Manufacturers of SGA LAIs will also be contacted. Primary efficacy outcome is relapse rate or delayed time to relapse or reduction in hospitalisation and primary safety outcomes are drop-out rates, all-cause discontinuation and discontinuation due to adverse events. Qualitative reporting of evidence will be based on 21 items listed on standards for reporting qualitative research (SRQR) focusing on study quality (assessed using the Jadad score, allocation concealment and data analysis), risk of bias and effect size. Publication bias will be assessed using funnel plots. If sufficient data are available meta-analysis will be performed with primary effect size as relative risk presented with 95% CI. Sensitivity analysis, conditional on number of studies and sample size, will be carried out on manic versus depressive symptoms and monotherapy versus adjunctive therapy.

Estimation of transportation battery second life for use in electricity grid systems

This paper presents research from part of a larger project focusing on the potential development of commercial opportunities for the reuse of batteries on the electricity grid system, subsequent to their primary use in low and ultra-low carbon vehicles, and investigating the life cycle issues surrounding the batteries. The work has three main areas; examination of electric vehicle fleet data in detail to investigate usage in first life. Batteries that have passed through a battery recycler at the end of their first life have been tested within the laboratory to confirm the general assumption that remaining capacity of 80% after use in transportation is a reasonable assumption as a basis for second-life applications. The third aspect of the paper is an investigation of the equivalent usage for three different second-life applications based on connection to the electricity grid. Additionally, the paper estimates the time to cell failure of the batteries within their second-life application to estimate lifespan for use within commercial investigations. © 2014 IEEE.

Modular ESS with second life batteries operating in grid independent mode

This work is part of a bigger project which aims to research the potential development of commercial opportunities for the re-use of batteries after their use in low carbon vehicles on an electricity grid or microgrid system. There are three main revenue streams (peak load lopping on the distribution Network to allow for network re-enforcement deferral, National Grid primary/ secondary/ high frequency response, customer energy management optimization). These incomes streams are dependent on the grid system being present. However, there is additional opportunity to be gained from also using these batteries to provide UPS backup when the grid is no longer present. Most UPS or ESS on the market use new batteries in conjunction with a two level converter interface. This produces a reliable backup solution in the case of loss of mains power, but may be expensive to implement. This paper introduces a modular multilevel cascade converter (MMCC) based ESS using second-life batteries for use on a grid independent industrial plant without any additional onsite generator as a potentially cheaper alternative. The number of modules has been designed for a given reliability target and these modules could be used to minimize/eliminate the output filter. An appropriate strategy to provide voltage and frequency control in a grid independent system is described and simulated under different disturbance conditions such as load switching, fault conditions or a large motor starting. A comparison of the results from the modular topology against a traditional two level converter is provided to prove similar performance criteria. The proposed ESS and control strategy is an acceptable way of providing backup power in the event of loss of grid. Additional financial benefit to the customer may be obtained by using a second life battery in this way.

Reliability estimation of second life battery system power electronic topologies for grid frequency response applications

This paper is part of a project which aims to research the opportunities for the re-use of batteries after their primary use in low and ultra low carbon vehicles on the electricity grid system. One potential revenue stream is to provide primary/secondary/high frequency response to National Grid through market mechanisms via DNO's or Energy service providers. Some commercial battery energy storage systems (BESS) already exist on the grid system, but these tend to use costly new or high performance batteries. Second life batteries should be available at lower cost than new batteries but reliability becomes an important issue as individual batteries may suffer from degraded performance or failure. Therefore converter topology design could be used to influence the overall system reliability. A detailed reliability calculation of different single phase battery-to-grid converter interfacing schemes is presented. A suitable converter topology for robust and reliable BESS is recommended.

A multi-modular second life hybrid battery energy storage system for utility grid applications

The modern grid system or the smart grid is likely to be populated with multiple distributed energy sources, e.g. wind power, PV power, Plug-in Electric Vehicle (PEV). It will also include a variety of linear and nonlinear loads. The intermittent nature of renewable energies like PV, wind turbine and increased penetration of Electric Vehicle (EV) makes the stable operation of utility grid system challenging. In order to ensure a stable operation of the utility grid system and to support smart grid functionalities such as, fault ride-through, frequency response, reactive power support, and mitigation of power quality issues, an energy storage system (ESS) could play an important role. A fast acting bidirectional energy storage system which can rapidly provide and absorb power and/or VARs for a sufficient time is a potentially valuable tool to support this functionality. Battery energy storage systems (BESS) are one of a range suitable energy storage system because it can provide and absorb power for sufficient time as well as able to respond reasonably fast. Conventional BESS already exist on the grid system are made up primarily of new batteries. The cost of these batteries can be high which makes most BESS an expensive solution. In order to assist moving towards a low carbon economy and to reduce battery cost this work aims to research the opportunities for the re-use of batteries after their primary use in low and ultra-low carbon vehicles (EV/HEV) on the electricity grid system. This research aims to develop a new generation of second life battery energy storage systems (SLBESS) which could interface to the low/medium voltage network to provide necessary grid support in a reliable and in cost-effective manner. The reliability/performance of these batteries is not clear, but is almost certainly worse than a new battery. Manufacturers indicate that a mixture of gradual degradation and sudden failure are both possible and failure mechanisms are likely to be related to how hard the batteries were driven inside the vehicle. There are several figures from a number of sources including the DECC (Department of Energy and Climate Control) and Arup and Cenex reports indicate anything from 70,000 to 2.6 million electric and hybrid vehicles on the road by 2020. Once the vehicle battery has degraded to around 70-80% of its capacity it is considered to be at the end of its first life application. This leaves capacity available for a second life at a much cheaper cost than a new BESS Assuming a battery capability of around 5-18kWhr (MHEV 5kWh - BEV 18kWh battery) and approximate 10 year life span, this equates to a projection of battery storage capability available for second life of >1GWhrs by 2025. Moreover, each vehicle manufacturer has different specifications for battery chemistry, number and arrangement of battery cells, capacity, voltage, size etc. To enable research and investment in this area and to maximize the remaining life of these batteries, one of the design challenges is to combine these hybrid batteries into a grid-tie converter where their different performance characteristics, and parameter variation can be catered for and a hot swapping mechanism is available so that as a battery ends it second life, it can be replaced without affecting the overall system operation. This integration of either single types of batteries with vastly different performance capability or a hybrid battery system to a grid-tie 3 energy storage system is different to currently existing work on battery energy storage systems (BESS) which deals with a single type of battery with common characteristics. This thesis addresses and solves the power electronic design challenges in integrating second life hybrid batteries into a grid-tie energy storage unit for the first time. This study details a suitable multi-modular power electronic converter and its various switching strategies which can integrate widely different batteries to a grid-tie inverter irrespective of their characteristics, voltage levels and reliability. The proposed converter provides a high efficiency, enhanced control flexibility and has the capability to operate in different operational modes from the input to output. Designing an appropriate control system for this kind of hybrid battery storage system is also important because of the variation of battery types, differences in characteristics and different levels of degradations. This thesis proposes a generalised distributed power sharing strategy based on weighting function aims to optimally use a set of hybrid batteries according to their relative characteristics while providing the necessary grid support by distributing the power between the batteries. The strategy is adaptive in nature and varies as the individual battery characteristics change in real time as a result of degradation for example. A suitable bidirectional distributed control strategy or a module independent control technique has been developed corresponding to each mode of operation of the proposed modular converter. Stability is an important consideration in control of all power converters and as such this thesis investigates the control stability of the multi-modular converter in detailed. Many controllers use PI/PID based techniques with fixed control parameters. However, this is not found to be suitable from a stability point-of-view. Issues of control stability using this controller type under one of the operating modes has led to the development of an alternative adaptive and nonlinear Lyapunov based control for the modular power converter. Finally, a detailed simulation and experimental validation of the proposed power converter operation, power sharing strategy, proposed control structures and control stability issue have been undertaken using a grid connected laboratory based multi-modular hybrid battery energy storage system prototype. The experimental validation has demonstrated the feasibility of this new energy storage system operation for use in future grid applications.

Foveation time measure in Congenital Nystagmus through second order approximation of the slow phases

Congenital Nystagmus (CN) is an ocular-motor disorder characterised by involuntary, conjugated ocular oscillations, and its pathogenesis is still unknown. The pathology is de fined as "congenital" from the onset time of its arise which could be at birth or in the first months of life. Visual acuity in CN subjects is often diminished due to nystagmus continuous oscillations, mainly on the horizontal plane, which disturb image fixation on the retina. However, during short periods in which eye velocity slows down while the target image is placed onto the fovea (called foveation intervals) the image of a given target can still be stable, allowing a subject to reach a higher visual acuity. In CN subjects, visual acuity is usually assessed both using typical measurement techniques (e.g. Landolt C test) and with eye movement recording in different gaze positions. The offline study of eye movement recordings allows physicians to analyse nystagmus main features such as waveform shape, amplitude and frequency and to compute estimated visual acuity predictors. This analytical functions estimates the best corrected visual acuity using foveation time and foveation position variability, hence a reliable estimation of this two parameters is a fundamental factor in assessing visual acuity. This work aims to enhance the foveation time estimation in CN eye movement recording, computing a second order approximation of the slow phase components of nystag-mus oscillations. About 19 infraredoculographic eye-movement recordings from 10 CN subjects were acquired and the visual acuity assessed with an acuity predictor was compared to the one measured in primary position. Results suggest that visual acuity measurements based on foveation time estimation obtained from interpolated data are closer to value obtained during Landolt C tests. © 2010 IEEE.

Can neurodegenerative disease be defined by four 'primary determinants':anatomy, cells, molecules, and morphology?

Traditional methods of describing and classifying neurodegenerative disease are based on the clinico-pathological concept supported by molecular pathological studies and defined by 'consensus criteria'. Disease heterogeneity, overlap between disorders, and the presence of multiple co-pathologies, however, have questioned the validity and status of many traditional disorders. If cases of neurodegenerative disease are not easily classifiable into distinct entities, but more continuously distributed, then a new descriptive framework may be required. This review proposes that there are four key neuropathological features of neurodegenerative disease (the 'primary determinants') that could be used to provide such a framework, viz., the anatomical pathways affected by the disease ('anatomy'), the cell populations affected ('cells'), the molecular pathology of 'signature' pathological lesions ('molecules'), and the morphological types of neurodegeneration ('morphology'). This review first discusses the limitations of existing classificatory systems and second provides evidence that the four primary determinants could be used as axes to define all cases of neurodegenerative disease. To illustrate the methodology, the primary determinants were applied to the study of a group of closely related tauopathy cases and to heterogeneity within frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP).

Brillouin optical time-domain analysis assisted by second-order Raman amplification

We propose and experimentally demonstrate a new method to extend the range of Brillouin optical time domain analysis (BOTDA) systems. It exploits the virtual transparency created by second-order Raman pumping in optical fibers. The idea is theoretically analyzed and experimentally demonstrated in a 50 km fiber. By working close to transparency, we also show that the measurement length of the BOTDA can be increased up to 100 km with 2 meter resolution. We envisage extensions of this technique to measurement lengths well beyond this value, as long as the issue of relative intensity noise (RIN) of the primary Raman pump can be avoided. © 2010 Optical Society of America.