A mathematical framework for active circuits based on port equivalence using limit variables

Published versio

A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in sorsby's fundus dystrophy

Sorsby’s fundus dystrophy (SFD) is a dominantly inherited degenerative disease of the retina that leads to loss of vision in middle age. It has been shown to be caused by mutations in the gene for tissue inhibitor of metalloproteinases-3 (TIMP-3). Five different mutations have previously been identified, all introducing an extra cysteine residue into exon 5 (which forms part of the C-terminal domain) of the TIMP-3 molecule; however, the significance of these mutations to the disease phenotype was unknown. In this report, we describe the expression of several of these mutated genes, together with a previously unreported novel TIMP-3 mutation from a family with SFD that results in truncation of most of the C-terminal domain of the molecule. Despite these differences, all of these molecules are expressed and exhibit characteristics of the normal protein, including inhibition of metalloproteinases and binding to the extracellular matrix. However, unlike wild-type TIMP-3, they all form dimers. These observations, together with the recent finding that expression of TIMP-3 is increased, rather than decreased, in eyes from patients with SFD, provides compelling evidence that dimerized TIMP-3 plays an active role in the disease process by accumulating in the eye. Increased expression of TIMP-3 is also observed in other degenerative retinal diseases, including the more severe forms of agerelated macular degeneration, the most common cause of blindness in the elderly in developed countries. We hypothesize that overexpression of TIMP-3 may prove to be a critical step in the progression of a variety of degenerative retinopathies

SNIFFER WFD119: Enhancement of the River Invertebrate Classification Tool (RICT)

EXECUTIVE SUMMARY Project funders/partners: Environment Agency (EA), Northern Ireland Environment Agency (NIEA), Scotland & Northern Ireland Forum for Environmental Research (SNIFFER), Scottish Environment Protection Agency (SEPA) Background to research The Regulatory Agencies in the UK (the Environment Agency; Scottish Environment Protection Agency; and the Northern Ireland Environment Agency) now use the River Invertebrate Classification Tool (RICT) to classify the ecological quality of rivers for Water Framework Directive compliance monitoring. RICT incorporates RIVPACS IV predictive models and is a highly capable tool written in a modern software programming language. While RICT classifies waters for general degradation and organic pollution stress, producing assessments of status class and uncertainty, WFD compliance monitoring also requires the UK Agencies to assess the impacts of a wide range of pressures including hydromorphological and acidification stresses. Some of these pressures alter the predictor variables that current RIVPACS models use to derive predicted biotic indices. This project has sought to broaden the scope of RICT by developing one or more RIVPACS model(s) that do not use predictor variables that are affected by these stressors, but instead use alternative GIS based variables that are wholly independent of these pressures. This project has also included a review of the wide range of biotic indices now available in RICT, identifying published sources, examining index performance, and where necessary making recommendations on further needs for index testing and development. Objectives of research •To remove and derive alternative predictive variables that are not affected by stressors, with particular emphasis on hydrological/acidification metric predictors. •To construct one or more new RIVPACS model(s) using stressor independent variables. •Review WFD reporting indices notably AWIC(species), LIFE (species), PSI & WHPT. Key findings and recommendations : Predictor variables and intellectual property rights : An extensive suite of new variables have been derived by GIS for the RIVPACS reference sites that have been shown to act as stressor-independent predictor variables. These include measures of stream order, solid and drift geology, and a range of upstream catchment characteristics (e.g. catchment area, mean altitude of upstream catchment, and catchment aspect). It is recommended that decisions are reached on which of the newly derived model(s) are implemented in RICT so that IPR issues for the relevant datasets can be quickly resolved and the datasets licensed. It is also recommended that licensing is sought for a point and click system (where the dataset cannot be reverse engineered) that is capable of calculating any of the time-invariant RIVPACS environmental predictor variables used by any of the newly derived (and existing) RIVPACS models, and for any potential users. New stressor-independent RIVPACS models : Using the existing predictor variables, together with new ones derived for their properties of stressor-independence, initial step-wise forward selection discriminant models suggested a range of 36 possible models that merited further testing. Following further testing, the following models are recommended for assessing watercourses affected by flow/hydromorphological and/or acidity stress: • For flow/hydromorphological stressors that may have modified width, depth and/or substrate in GB, it is suggested that a new ‘RIVPACS IV – Hydromorphology Independent’ model (Model 24) is used (this does not use the predictor variables width, depth and substratum, but includes a suite of new stressor-independent variables). • For acidity related stressors in GB, it is suggested that a new ‘RIVPACS IV – Alkalinity Independent’ model (Model 35) is used (this does not use the predictor variable alkalinity, but includes new stressor-independent variables). • For flow/hydromorphological stressors and acidity related stressors in GB, it is suggested that a new ‘RIVPACS IV – Hydromorphology & Alkalinity Independent’ model (Model 13) is used (this does not use the predictor variables width, depth, substratum and alkalinity, but includes a suite of new stressor-independent variables). • Reduced availability of appropriate GIS tools at this time has meant that no new models have been developed for Northern Ireland. Discriminant functions and end group means have now been calculated to enable any of these models to be easily implemented in the RICT software. Biotic indices : The RIVPACS models in RICT can now produce expected values for a wide range of biotic indices addressing a variety of stressors. These indices will support the use of RICT as a primary tool for WFD classification and reporting of the quality of UK streams and rivers. There are however a number of outstanding issues with indices that need to be addressed: • There is a need to develop a biotic index for assessing metal pollution. • WFD EQR banding schemes are required for many of the indices to report what is considered an acceptable degree of stress (High-Good) and what is not (Moderate, Poor or Bad). • A comprehensive objective testing process needs to be undertaken on the indices in RICT using UK-wide, large-scale, independent test datasets to quantify their index-stressor relationships and their associated uncertainty, for example following the approach to acidity index testing in Murphy et al., (in review) or organic/general degradation indices in Banks & McFarland (2010). • Following objective testing, the UK Agencies should make efforts to address any index under-performance issues that have been identified, and where necessary new work should be commissioned to modify existing indices, or develop new ones where required so that indices for all stress types meet certain minimum performance criteria. • Testing needs to be done to examine index-stressor relationships with both observed index scores and RIVPACS observed/expected ratios. Work should also be done to compare the existing RIVPACS IV and the new stressor-independent models (developed in this project) as alternative sources of the expected index values for these tests. • Consideration should be given to assessing the extent to which chemical and biological monitoring points co-occur. Site-matched (rather than reach-matched) chemical and biological monitoring points would i) generate the substantial training datasets needed to refine or develop new indices and ii) generate the independent datasets for testing

Energy Requirements and Nutritional Strategies for Male Soccer Players:A Review and Suggestions for Practice

Soccer is a high intensity intermittent sport, featuring critical events completed at high/maximal intensity which is superimposed onto an aerobic base of lower intensity activities and rest. Due to these varying energic demands and the duration of competition the need for optimal nutritional strategies to offset and delay fatigue are paramount. Over the last 50 years, several investigations have been reported on aspects of soccer be they nutrition-focused or those concerning the demands of the sport. Emanating from these scientific papers, observations have been made on the likely factors which result in the fatigue during match-play. Factors such as muscle glycogen depletion and hypoglycaemia are discussed. Studies on the energy demands of soccer have employed a variety of methodologies which are briefly reviewed and vary between the use of heart rate telemetry to the use of global positioning systems (GPS). Moving on from observations of the energy demands of the sport leads to the major focus of this review which highlights key nutritional strategies to support the preparation and recovery of male soccer players to enhance performance, or at least to enable players to perform adequately. This review examines relevant methodologies in assessing training and competitive energy costs as well as the concomitant energy intakes demanded for successful performance outcomes. In order to bring an applied aspect to the overall findings from areas discussed, some practical ideas of feeding strategies are presented

Direct health costs of inflammatory polyarthritis 10 years after disease onset:Results from the Norfolk Arthritis Register

Objectives: To explore the change in direct medical costs associated with inflammatory polyarthritis (IP) 10 to 15 years after its onset. Methods: Patients from the Norfolk Arthritis Register who had previously participated in a health economic study in 1999 were traced 10 years later and invited to participate in a further prospective questionnaire-based study. The study was designed to identify direct medical costs and changes in health status over a 6-month period using previously validated questionnaires as the primary source of data. Results: A representative sample of 101 patients with IP from the 1999 cohort provided complete data over the 6-month period. The mean disease duration was 14 years (SD 2.1, median 13.6, interquartile range 12.6–15.4). The mean direct medical cost per patient over the 6-month period was £1496 for IP (inflated for 2013 prices). This compared with £582 (95% CI £355–£964) inflated to 2013 prices per patient with IP 10 years earlier in their disease. The increased cost was largely associated with the use of biologics in the rheumatoid arthritis subgroup of patients (51% of total costs incurred). Other direct cost components included primary care costs (11%), hospital outpatient (19%), day care (12%), and inpatient stay (4%). Conclusion: The direct healthcare costs associated with IP have more than doubled with increasing disease duration, largely as a result of the use of biologics. The results showed a shift in the direct health costs from inpatient to outpatient service use

Optimized performance map of an EAM for pulse generation and demultiplexing via FROG characterization

We demonstrate the complete characterization of a sinusoidally driven electro-absorption modulator (EAM) over a range of RF drive voltages and reverse bias conditions. An accurate performance map for the EAM, to be employed as a pulse generator and demultiplexer in an optical time division multiplexed (OTDM) system, can be realized by employing the Frequency Resolved Optical Gating technique. The generated pulses were characterized for chirp, extinction ratio (ER) and pulse width (<4 ps). The optimization of the EAM’s drive conditions is important to ensure that the generated pulses have the required spectral and temporal characteristics to be used in high-speed systems. The ER and pulse width also influence the demultiplexing performance of an EAM in an OTDM system. This is confirmed by utilizing the EAM as a demultiplexer in an 80 Gb/s OTDM system and measuring the BER as a function of the received optical power for various values of the ER and pulse width. It is of paramount importance to accurately characterize the performance of each individual EAM as the modulators characteristics are device dependant, thus optimum performance can be achieved with slight variations to the device’s drive conditions. By employing FROG, an optimum performance map of each specific device can be deduced. Simulations carried out verified the experimental results achieved

Experimental investigation of the impact of optical injection on vital parameters of a gain-switched pulse source

An analysis of optical injection on a gain-switched distributed feedback (DFB) laser and its impact on pulse parameters that influence the performance of the pulse source in high-speed optical communication systems is presented in this paper. A range of 10 GHz in detuning and 5 dB in injected power has been experimentally identified to attain pulses, from an optically injected gain-switched DFB laser, with durations below 10 ps and pedestal suppression higher than 35 dB. These pulse features are associated with a side mode suppression ratio of about 30 dB and a timing jitter of less than 1 ps. This demonstrates the feasibility of using optical injection in conjunction with appropriate pulse compression schemes for developing an optimized and cost-efficient pulse source, based on a gain-switched DFB laser, for high-speed photonic systems

Backward Cherenkov radiation emitted by polariton solitons in a microcavity wire

Exciton-polaritons in semiconductor microcavities form a highly nonlinear platform to study a variety of effects interfacing optical, condensed matter, quantum and statistical physics. We show that the complex polariton patterns generated by picosecond pulses in microcavity wire waveguides can be understood as the Cherenkov radiation emitted by bright polariton solitons, which is enabled by the unique microcavity polariton dispersion, which has momentum intervals with positive and negative group velocities. Unlike in optical fibres and semiconductor waveguides, we observe that the microcavity wire Cherenkov radiation is predominantly emitted with negative group velocity and therefore propagates backwards relative to the propagation direction of the emitting soliton. We have developed a theory of the microcavity wire polariton solitons and of their Cherenkov radiation and conducted a series of experiments, where we have measured polariton-soliton pulse compression, pulse breaking and emission of the backward Cherenkov radiation

Polariton Pattern Formation and Photon Statistics of the Associated Emission

We report on the formation of a diverse family of transverse spatial polygon patterns in a microcavity polariton fluid under coherent driving by a blue-detuned pump. Patterns emerge spontaneously as a result of energy-degenerate polariton-polariton scattering from the pump state to interfering high order vortex and antivortex modes, breaking azimuthal symmetry. The interplay between a multimode parametric instability and intrinsic optical bistability leads to a sharp spike in the value of second order coherence g (2)(0) of the emitted light, which we attribute to the strongly superlinear kinetics of the underlying scattering processes driving the formation of patterns. We show numerically by means of a linear stability analysis how the growth of parametric instabilities in our system can lead to spontaneous symmetry breaking, predicting the formation and competition of different pattern states in good agreement with experimental observations