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

Assessment of the environmental impacts of ASR schemes.

This report describes the results of modelling studies undertaken to assess the impacts of ASR on the local environment. Understanding and quantifying these impacts, in relation to other existing or proposed schemes, will be vital in the development, and subsequent licensing of any ASR scheme. As each individual scheme has its own hydrogeological and environmental setting, as well as operational requirements, an all-encompassing model cannot be prescribed. Rather, a set of models, of increasing complexity, have been run for ‘typical’ scenarios to illustrate their use and limitations. They are designed to act as screening tools to assist practitioners, at all stages of an investigation, to decide on the suitability of a site and to identify what additional data are required in order to proceed to the next stage. The models are appended to the report so practitioners can apply them to their specific site, as appropriate

Spectral Reconstruction and Noise Model Estimation Based on a Masking Model for Noise Robust Speech Recognition

An effective way to increase noise robustness in automatic speech recognition (ASR) systems is feature enhancement based on an analytical distortion model that describes the effects of noise on the speech features. One of such distortion models that has been reported to achieve a good trade-off between accuracy and simplicity is the masking model. Under this model, speech distortion caused by environmental noise is seen as a spectral mask and, as a result, noisy speech features can be either reliable (speech is not masked by noise) or unreliable (speech is masked). In this paper, we present a detailed overview of this model and its applications to noise robust ASR. Firstly, using the masking model, we derive a spectral reconstruction technique aimed at enhancing the noisy speech features. Two problems must be solved in order to perform spectral reconstruction using the masking model: (1) mask estimation, i.e. determining the reliability of the noisy features, and (2) feature imputation, i.e. estimating speech for the unreliable features. Unlike missing data imputation techniques where the two problems are considered as independent, our technique jointly addresses them by exploiting a priori knowledge of the speech and noise sources in the form of a statistical model. Secondly, we propose an algorithm for estimating the noise model required by the feature enhancement technique. The proposed algorithm fits a Gaussian mixture model to the noise by iteratively maximising the likelihood of the noisy speech signal so that noise can be estimated even during speech-dominating frames. A comprehensive set of experiments carried out on the Aurora-2 and Aurora-4 databases shows that the proposed method achieves significant improvements over the baseline system and other similar missing data imputation techniques

Exact two-particle eigenstates in partially reduced QED

We consider a reformulation of QED in which covariant Green functions are used to solve for the electromagnetic field in terms of the fermion fields. It is shown that exact few-fermion eigenstates of the resulting Hamiltonian can be obtained in the canonical equal-time formalism for the case where there are no free photons. These eigenstates lead to two- and three-body Dirac-like equations with electromagnetic interactions. Perturbative and some numerical solutions of the two-body equations are presented for positronium and muonium-like systems, for various strengths of the coupling.Comment: 33 pages, LaTex 2.09, 4 figures in EPS forma

RESPOND – A patient-centred programme to prevent secondary falls in older people presenting to the emergency department with a fall: Protocol for a mixed methods programme evaluation.

Background Programme evaluations conducted alongside randomised controlled trials (RCTs) have potential to enhance understanding of trial outcomes. This paper describes a multi-level programme evaluation to be conducted alongside an RCT of a falls prevention programme (RESPOND). Objectives 1) To conduct a process evaluation in order to identify the degree of implementation fidelity and associated barriers and facilitators. 2) To evaluate the primary intended impact of the programme: participation in fall prevention strategies, and the factors influencing participation. 3) To identify the factors influencing RESPOND RCT outcomes: falls, fall injuries and ED re-presentations. Methods/ Design Five hundred and twenty eight community-dwelling adults aged 60–90 years presenting to two EDs with a fall will be recruited and randomly assigned to the intervention or standard care group. All RESPOND participants and RESPOND clinicians will be included in the evaluation. A mixed methods design will be used and a programme logic model will frame the evaluation. Data will be sourced from interviews, focus groups, questionnaires, clinician case notes, recruitment records, participant-completed calendars, hospital administrative datasets, and audio-recordings of intervention contacts. Quantitative data will be analysed via descriptive and inferential statistics and qualitative data will be interpreted using thematic analysis. Discussion The RESPOND programme evaluation will provide information about contextual and influencing factors related to the RCT outcomes. The results will assist researchers, clinicians, and policy makers to make decisions about future falls prevention interventions. Insights gained are likely to be transferable to preventive health programmes for a range of chronic conditions

Use of novel sensors combining local positioning and acceleration to measure feeding behavior differences associated with lameness in dairy cattle

Time constraints for dairy farmers are an important factor contributing to the under-detection of lameness, resulting in delayed or missed treatment of lame cows within many commercial dairy herds. Hence, a need exists for flexible and affordable cow-based sensor systems capable of monitoring behaviors such as time spent feeding, which may be affected by the onset of lameness. In this study a novel neck-mounted mobile sensor system that combines local positioning and activity (acceleration) was tested and validated on a commercial UK dairy farm. Position and activity data were collected over 5 consecutive days for 19 high-yield dairy cows (10 lame, 9 non-lame) that formed a subset of a larger (120 cow) management group housed in a freestall barn. A decision tree algorithm that included sensor-recorded position and accelerometer data was developed to classify a cow as doing 1 of 3 categories of behavior: (1) feeding, (2) not feeding, and (3) out of pen for milking. For each classified behavior the mean number of bouts, the mean bout duration, and the mean total duration across all bouts was determined on a daily basis, and also separately for the time periods in between milking (morning = 0630–1300 h; afternoon = 1430–2100 h; night = 2230–0500 h). A comparative analysis of the classified cow behaviors was undertaken using a Welch -test with Benjamini-t Hochberg post-hoc correction under the null hypothesis of no differences in the number or duration of behavioral bouts between the 2 test groups of lame and nonlame cows. Analysis showed that mean total daily feeding duration was significantly lower for lame cows compared with non-lame cows. Behavior was also affected by time of day with significantly lower mean total duration of feeding and higher total duration of nonfeeding in the afternoons for lame cows compared with nonlame cows. The results demonstrate how sensors that measure both position and acceleration are capable of detecting differences in feeding behavior that may be associated with lameness. Such behavioral differences could be used in the development of predictive algorithms for the prompt detection of lameness as part of a commercially viable automated behavioral monitoring system

Thermodynamic Potential for Superfluid 3He in Aerogel

We present a free energy functional for superfluid 3He in the presence of homogeneously distributed impurity disorder which extends the Ginzburg-Landau free energy functional to all temperatures. We use the new free energy functional to calculate the thermodynamic potential, entropy, heat capacity and density of states for the B-phase of superfluid 3He in homogeneous, isotropic aerogel.Comment: 10 pages, 4 figure

Composition and evolution of the Ancestral South Sandwich Arc: implications for the flow of deep ocean water and mantle through the Drake Passage gateway

The Ancestral South Sandwich Arc (ASSA) has a short life-span of c.20 m.y. (Early Oligocene to Middle-Upper Miocene) before slab retreat and subsequent ‘resurrection’ as the active South Sandwich Island Arc (SSIA). The ASSA is, however, significant because it straddled the eastern margin of the Drake Passage Gateway where it formed a potential barrier to deep ocean water and mantle flow from the Pacific to Atlantic. The ASSA may be divided into three parts, from north to south: the Central Scotia Sea (CSS), the Discovery segment, and the Jane segment. Published age data coupled with new geochemical data (major elements, trace elements, Hf-Nd-Sr-Pb isotopes) from the three ASSA segments place constraints on models for the evolution of the arc and hence gateway development. The CSS segment has two known periods of activity. The older, Oligocene, period produced basic-acid, mostly calc-alkaline rocks, best explained in terms of subduction initiation volcanism of Andean-type (no slab rollback). The younger, Middle-Late Miocene period produced basic-acid, high-K calc-alkaline rocks (lavas and pyroclastic rocks with abundant volcanigenic sediments) which, despite being erupted on oceanic crust, have continental arc characteristics best explained in terms of a large, hot subduction flux most typical of a syn- or post-collision arc setting. Early-Middle Miocene volcanism in the Discovery and Jane arc segments is geochemically quite different, being typically tholeiitic and compositionally similar to many lavas from the active South Sandwich island arc front. There is indirect evidence for Western Pacific-type (slab rollback) subduction initiation in the southern part of the ASSA and for the back-arc basins (the Jane and Scan Basins) to have been active at the time of arc volcanism. Models for the death of the ASSA in the south following a series of ridge-trench collisions, are not positively supported by any geochemical evidence of hot subduction, but cessation of subduction by approach of progressively more buoyant oceanic lithosphere is consistent with both geochemistry and geodynamics. In terms of deep ocean water flow the early stages of spreading at the East Scotia Ridge (starting at 17-15 Ma) may have been important in breaking up the ASSA barrier while the subsequent establishment of a STEP (Subduction-Transform Edge Propagator) fault east of the South Georgia microcontinent (< 11 Ma) led to formation of the South Georgia Passage used by the Antarctic Circumpolar Current today. In terms of mantle flow, the subduction zone and arc root likely acted as a barrier to mantle flow in the CSS arc segment such that the ASSA itself became the Pacific-South Atlantic mantle domain boundary. This was not the case in the Discovery and Jane arc segments, however, because northwards flow of South Atlantic mantle behind the southern part of the ASSA gave an Atlantic provenance to the whole southern ASSA