A screen for modifiers of epigenetic reprogramming

Epigenetic modifiers are the proteins involved in establishing and maintaining the epigenome of an organism. They are particularly important for development. Changes in epigenetic modifiers have been shown be lethal, or cause diseases. Our laboratory has developed an ENU mutagenesis screen to produce mouse mutants displaying altered epigenetic gene silencing. The screen relies on a GFP transgene that is expressed in red blood cells in a variegated manner. In the orginal transgenic FVB mice expression occurs in approximately 55% of red blood cells. During the course of my Masters, I characterised four different Mommes (Modifiers of murine metastable epiallele), MommeD32, MommeD33, MommeD35 and MommeD36. For each Momme, I identified the underlying mutation, and observed the corresponding phenotype. In MommeD32 the causative mutation is in Dnmt1, (DNA methyltransferase 1). This gene was previously identified in the screen, as MommeD2, and the new allele, MommeD32 has a change in the BAH domain of the protein. MommeD33 is the result of a change at the transgene itself. MommeD35 carries a mutation in Suv39h1 (suppressor of variegation 3-9 homolog 1). This gene has not previously been identified in the screen, but it is a known epigenetic modifier. MommeD36 had the same ENU treated sire as MommeD32, and I found that it has the same mutation as MommeD32. These mutant strains provide valuable tools that can be used to further our knowledge of epigenetic reprogramming. An example being the cancer study done with MommeD9 which has a mutation in Trim28. By crossing MommeD9+/- mutant mice with Trp53+/- mice, it can be seen if Trim28 has an effect on the rate of tumour genesis. However no clear effect of Trim28 haploinsufficiency can be observed in Trp53+/- mice.

Chaos and creativity of play : designing emotional engagement in public spaces

How do we create strong urban narratives? How do we create affection for our cities? Play, an essential part of any species' biological existence and development, can often be perceived as chaotic and derogatory to social and spatial order. Play is also often perceived as a creative force which generates social and spatial value. This paper looks at the design approaches to both chaotic and creative perceptions of publics at play in urban space. Commonly, Urban and Architectural Design constitutes reactive management of perceived chaos, which derogatorily effects our sensory and emotional engagement with space. Alternatively, Urban and Architectural Design can appeal to the creativity of play, by encouraging unsolicited novelty that is vital to strong experiential narratives in the city and iterating environments that encourage the emergence of physical, emotional and cultural invention. These perceptions of chaos and creativity affect the design methodology of professional practice. Tested through the exciting vehicle of Parkour as urban narrative, the constraints and opportunities of both approaches are presented.

Design and rationale of a Prospective, Observational European Multicenter study on the efficacy of acute surgical decompression after traumatic Spinal Cord Injury: the SCI-POEM study

Objectives:Despite many years of research, there is currently no treatment available that results in major neurological or functional recovery after traumatic spinal cord injury (tSCI). In particular, no conclusive data related to the role of the timing of decompressive surgery, and the impact of injury severity on its benefit, have been published to date. This paper presents a protocol that was designed to examine the hypothesized association between the timing of surgical decompression and the extent of neurological recovery in tSCI patients.Study design: The SCI-POEM study is a Prospective, Observational European Multicenter comparative cohort study. This study compares acute (<12 h) versus non-acute (>12 h, <2 weeks) decompressive surgery in patients with a traumatic spinal column injury and concomitant spinal cord injury. The sample size calculation was based on a representative European patient cohort of 492 tSCI patients. During a 4-year period, 300 patients will need to be enrolled from 10 trauma centers across Europe. The primary endpoint is lower-extremity motor score as assessed according to the 'International standards for neurological classification of SCI' at 12 months after injury. Secondary endpoints include motor, sensory, imaging and functional outcomes at 3, 6 and 12 months after injury.Conclusion:In order to minimize bias and reduce the impact of confounders, special attention is paid to key methodological principles in this study protocol. A significant difference in safety and/or efficacy endpoints will provide meaningful information to clinicians, as this would confirm the hypothesis that rapid referral to and treatment in specialized centers result in important improvements in tSCI patients.Spinal Cord advance online publication, 17 April 2012; doi:10.1038/sc.2012.34.

Measuring voluntary dietary change in response to exercise : a focus on dietary fat

Traditional treatments for weight management have focussed on prescribed dietary restriction or regular exercise, or a combination of both. However recidivism for such prescribed treatments remains high, particularly among the overweight and obese. The aim of this thesis was to investigate voluntary dietary changes in the presence of prescribed mixed-mode exercise, conducted over 16 weeks. With the implementation of a single lifestyle change (exercise) it was postulated that the onerous burden of concomitant dietary and exercise compliance would be reduced, leading to voluntary lifestyle changes in such areas as diet. In addition, the failure of exercise as a single weight loss treatment has been reported to be due to compensatory energy intakes, although much of the evidence is from acute exercise studies, necessitating investigation of compensatory intakes during a long-term exercise intervention. Following 16 weeks of moderate intensity exercise, 30 overweight and obese (BMI≥25.00 kg.m-2) men and women showed small but statistically significant decreases in mean dietary fat intakes, without compensatory increases in other macronutrient or total energy intakes. Indeed total energy intakes were significantly lower for men and women following the exercise intervention, due to the decreases in dietary fat intakes. There was a risk that acceptance of the statistical validity of the small changes to dietary fat intakes may have constituted a Type 1 error, with false rejection of the Null hypothesis. Oro-sensory perceptions to changes in fat loads were therefore investigated to determine whether the measured dietary fat changes were detectable by the human palate. The ability to detect small changes in dietary fat provides sensory feedback for self-initiated dietary changes, but lean and overweight participants were unable to distinguish changes to fat loads of similar magnitudes to that measured in the exercise intervention study. Accuracy of the dietary measurement instrument was improved with the effects of random error (day-to-day variability) minimised with the use of a statistically validated 8-day, multiple-pass, 24 hour dietary recall instrument. However systematic error (underreporting) may have masked the magnitude of dietary change, particularly the reduction in dietary fat intakes. A purported biomarker (plasma Apolipoprotein A-IV) (apoA-IV) was subsequently investigated, to monitor systematic error in self-reported dietary intakes. Changes in plasma apoA-IV concentrations were directly correlated with increased and decreased changes to dietary fat intakes, suggesting that this objective marker may be a useful tool to improve the accuracy of dietary measurement in overweight and obese populations, who are susceptible to dietary underreporting.

Single-subject analysis reveals varied knee mechanics during step landing in response to isokinetic fatigue of the quadriceps

Introduction: The ability to regulate joint stiffness and coordinate movement during landing when impaired by muscle fatigue has important implications for knee function. Unfortunately, the literature examining fatigue effects on landing mechanics suffers from a lack of consensus. Inconsistent results can be attributed to variable fatigue models, as well as grouping variable responses between individuals when statistically detecting differences between conditions. There remains a need to examine fatigue effects on knee function during landing with attention to these methodological limitations. Aim: The purpose of this study therefore, was to examine the effects of isokinetic fatigue on pre-impact muscle activity and post-impact knee mechanics during landing using singlesubject analysis. Methodology: Sixteen male university students (22.6+3.2 yrs; 1.78+0.07 m; 75.7+6.3 kg) performed maximal concentric and eccentric knee extensions in a reciprocal manner on an isokinetic dynamometer and step-landing trials on 2 occasions. On the first occasion each participant performed 20 step-landing trials from a knee-high platform followed by 75 maximal contractions on the isokinetic dynamometer. The isokinetic data was used to calculate the operational definition of fatigue. On the second occasion, with a minimum rest of 14 days, participants performed 2 sets of 20 step landing trials, followed by isokinetic exercise until the operational definition of fatigue was met and a final post-fatigue set of 20 step-landing trials. Results: Single-subject analyses revealed that isokinetic fatigue of the quadriceps induced variable responses in pre impact activation of knee extensors and flexors (frequency, onset timing and amplitude) and post-impact knee mechanics(stiffness and coordination). In general however, isokinetic fatigue induced sig nificant (p<0.05) reductions in quadriceps activation frequency, delayed onset and increased amplitude. In addition, knee stiffness was significantly (p<0.05) increased in some individuals, as well as impaired sagittal coordination. Conclusions: Pre impact activation and post-impact mechanics were adjusted in patterns that were unique to the individual, which could not be identified using traditional group-based statistical analysis. The results suggested that individuals optimised knee function differently to satisfy competing demands, such as minimising energy expenditure, as well as maximising joint stability and sensory information.

Effects of simulated cataracts on speech intelligibility

Limited research is available on how well visual cues integrate with auditory cues to improve speech intelligibility in persons with visual impairments, such as cataracts. We investigated whether simulated cataracts interfered with participants’ ability to use visual cues to help disambiguate a spoken message in the presence of spoken background noise. We tested 21 young adults with normal visual acuity and hearing sensitivity. Speech intelligibility was tested under three conditions: auditory only with no visual input, auditory-visual with normal viewing, and auditory-visual with simulated cataracts. Central Institute for the Deaf (CID) Everyday Speech Sentences were spoken by a live talker, mimicking a pre-recorded audio track, in the presence of pre-recorded four-person background babble at a signal-to-noise ratio (SNR) of -13 dB. The talker was masked to the experimental conditions to control for experimenter bias. Relative to the normal vision condition, speech intelligibility was significantly poorer, [t (20) = 4.17, p < .01, Cohen’s d =1.0], in the simulated cataract condition. These results suggest that cataracts can interfere with speech perception, which may occur through a reduction in visual cues, less effective integration or a combination of the two effects. These novel findings contribute to our understanding of the association between two common sensory problems in adults: reduced contrast sensitivity associated with cataracts and reduced face-to-face communication in noise.

The silence of objects : forming the unsayable

The silence of objects phenomenologically explores the experience and memory of trauma through object-based artwork. It springs from a desire to map difficult psychological terrain and does so by tracking the process of a coming into 'expression' to communicate notions of loss, detachment and powerlessness. It maps a journey from silence to a forming 'voice' that gives shape to the unsayable. This practice-led research is multifaceted. Whilst the creative element uses transformed objects as material metaphors to tap into the sensory and affective operations of art, the written component blends reflection with theory and is informed by art theorists Jill Bennett and Mignon Nixon. By establishing a dialogue between theoretical constructs and creative works I consider how giving form to deep consciousness can counter the effects of trauma manifest as silence and invisibility.

Flight guardian: a common avionics architecture for collision avoidance and safe emergency landing for unmanned aerial systems

This paper presents an approach to derive requirements for an avionics architecture that provides onboard sense-and-avoid and autonomous emergency forced landing capabilities to a UAS. The approach is based on two design paradigms that (1) derive requirements analyzing the common functionality between these two functions to then derive requirements for sensors, computing capability, interfaces, etc. (2) consider the risk and safety mitigation associated with these functions to derive certification requirements for the system design. We propose to use the Aircraft Certification Matrix (ACM) approach to tailor the system Development Assurance Levels (DAL) and architecture requirements in accordance with acceptable risk criteria. This architecture is developed under the name “Flight Guardian”. Flight Guardian is an avionics architecture that integrates common sensory elements that are essential components of any UAS that is required to be dependable. The Flight Guardian concept is also applicable to conventionally piloted aircraft, where it will serve to reduce cockpit workload.

Maintaining a cognitive map in darkness : the need to fuse boundary knowledge with path integration

Spatial navigation requires the processing of complex, disparate and often ambiguous sensory data. The neurocomputations underpinning this vital ability remain poorly understood. Controversy remains as to whether multimodal sensory information must be combined into a unified representation, consistent with Tolman's "cognitive map", or whether differential activation of independent navigation modules suffice to explain observed navigation behaviour. Here we demonstrate that key neural correlates of spatial navigation in darkness cannot be explained if the path integration system acted independently of boundary (landmark) information. In vivo recordings demonstrate that the rodent head direction (HD) system becomes unstable within three minutes without vision. In contrast, rodents maintain stable place fields and grid fields for over half an hour without vision. Using a simple HD error model, we show analytically that idiothetic path integration (iPI) alone cannot be used to maintain any stable place representation beyond two to three minutes. We then use a measure of place stability based on information theoretic principles to prove that featureless boundaries alone cannot be used to improve localization above chance level. Having shown that neither iPI nor boundaries alone are sufficient, we then address the question of whether their combination is sufficient and - we conjecture - necessary to maintain place stability for prolonged periods without vision. We addressed this question in simulations and robot experiments using a navigation model comprising of a particle filter and boundary map. The model replicates published experimental results on place field and grid field stability without vision, and makes testable predictions including place field splitting and grid field rescaling if the true arena geometry differs from the acquired boundary map. We discuss our findings in light of current theories of animal navigation and neuronal computation, and elaborate on their implications and significance for the design, analysis and interpretation of experiments.

Utility of corneal confocal microscopy for assessing mild diabetic neuropathy: baseline findings of the LANDMark study

Background:  For those in the field of managing diabetic complications, the accurate diagnosis and monitoring of diabetic peripheral neuropathy (DPN) continues to be a challenge. Assessment of sub-basal corneal nerve morphology has recently shown promise as a novel ophthalmic marker for the detection of DPN. Methods:  Two hundred and thirty-one individuals with diabetes with predominantly mild or no neuropathy and 61 controls underwent evaluation of diabetic neuropathy symptom score, neuropathy disability score, testing with 10 g monofilament, quantitative sensory testing (warm, cold, vibration detection) and nerve conduction studies. Corneal nerve fibre length, branch density and tortuosity were measured using corneal confocal microscopy. Differences in corneal nerve morphology between individuals with and without DPN and controls were investigated using analysis of variance and correlations were determined between corneal morphology and established tests of, and risk factors for, DPN. Results:  Corneal nerve fibre length was significantly reduced in diabetic individuals with mild DPN compared with both controls (p < 0.001) and diabetic individuals without DPN (p = 0.012). Corneal nerve branch density was significantly reduced in individuals with mild DPN compared with controls (p = 0.032). Corneal nerve fibre tortuosity did not show significant differences. Corneal nerve fibre length and corneal nerve branch density showed modest correlations to most measures of neuropathy, with the strongest correlations to nerve conduction study parameters (r = 0.15 to 0.25). Corneal nerve fibre tortuosity showed only a weak correlation to the vibration detection threshold. Corneal nerve fibre length was inversely correlated to glycated haemoglobin (r = -0.24) and duration of diabetes (r = -0.20). Conclusion:  Assessment of corneal nerve morphology is a non-invasive, rapid test capable of showing differences between individuals with and without DPN. Corneal nerve fibre length shows the strongest associations with other diagnostic tests of neuropathy and with established risk factors for neuropathy.

Corneal sensitivity is related to established measures of diabetic peripheral neuropathy

Purpose:  The objective was to investigate the association between corneal sensitivity and established measures of diabetic peripheral neuropathy (DPN). Methods:  Corneal sensitivity was measured in 93 individuals with diabetes, 146 diabetic individuals without neuropathy and 61 control individuals without diabetes or neuropathy using a non-contact corneal aesthesiometer at the baseline visit of a five-year longitudinal natural history study of DPN. The correlation between corneal sensitivity and established measures of neuropathy was estimated and multi-dimensional scaling was used to represent similarities and dissimilarities between variables. Results:  The corneal sensitivity threshold was significantly correlated with a majority of established measures of DPN. Correlation coefficients ranged from -0.32 to 0.26. Using multi-dimensional scaling, non-contact corneal aesthesiometry was closer to the neuropathy disability score, diabetic neuropathy symptom score and Neuropad and most dissimilar to electrophysiological parameters and quantitative sensory testing. Conclusion:  Corneal sensitivity, although not strongly related, is associated with other functional measures of DPN and might provide a useful adjunct in identifying functional loss of small nerve fibre integrity.

Positive impacts of environmental characteristics on health and wellbeing in health-care facilities : a review

Well-designed indoor environments can support people’s health and welfare. In this literature review, we identify the environmental features that affect human health and wellbeing. Environmental characteristics found to influence health outcomes and/or wellbeing included: environmental safety; indoor air quality (e.g. odour and temperature); sound and noise; premises and interior design (e.g. construction materials, viewing nature and experiencing nature, windows versus no windows, light, colours, unit layout and placement of the furniture, the type of room, possibilities to control environmental elements, environmental complexity and sensory simulations, cleanliness, ergonomics and accessibility, ‛‛wayfinding’’); art, and music, among others. Indoor environments that incorporate healing elements can, for instance, reduce anxiety, lower blood pressure, lessen pain and shorten hospital stays.

Relationship among CFH and ARMS2 genotypes, macular pigment optical density, and neuroretinal function in persons without age-related macular degeneration

Purpose: To determine whether there is a difference in neuroretinal function and in macular pigment optical density between persons with high- and low-risk gene variants for age-related macular degeneration (AMD) and no ophthalmoscopic signs of AMD, and to compare the results on neuroretinal function to patients with manifest early AMD. Methods and Participants: Neuroretinal function was assessed with the multifocal electroretinogram (mfERG) for 32 participants (22 healthy persons with no AMD and 10 early AMD patients). The 22 healthy participants with no AMD had high- or low-risk genotypes for either CFH (rs380390) and/or ARMS2 (rs10490924). Trough-to-peak response densities and peak-implicit times were analyzed in 5 concentric rings. Macular pigment optical densitometry was assessed by customized heterochromatic flicker photometry. Results: Trough-to-peak response densities for concentric rings 1 to 3 were, on average, significantly greater in participants with high-risk genotypes than in participants with low-risk genotypes and in persons with early AMD after correction for age and smoking (p<0.05). The group peak- implicit times for ring 1 were, on average, delayed in the patients with early AMD compared with the participants with high- or low-risk genotypes, although these differences were not significant. There was no significant correlation between genotypes and macular pigment optical density. Conclusion: Increased neuroretinal activity in persons who carry high-risk AMD genotypes may be due to genetically determined subclinical inflammatory and/or histological changes in the retina. Neuroretinal function in healthy persons genetically susceptible to AMD may be a useful additional early biomarker (in combination with genetics) before there is clinical manifestation.

The 'variety effect' is anticipated in meal planning

The 'variety effect' describes the greater consumption that is observed when multiple foods with different sensory characteristics are presented either simultaneously or sequentially. Variety increases the amount of food consumed in test of ad libitum intake. However, outside the laboratory, meals are often planned in advance and then consumed in their entirety. We sought to explore the extent to which the variety effect is anticipated in this pre-meal planning. Participants were shown two food images, each representing a first or a second course of a hypothetical meal. The two courses were either, i) exactly the same food, ii) different foods from the same sensory category (sweet or savoury) or, iii) different foods from a different sensory category. In Study 1 (N = 30) these courses comprised typical ‘main meal’ foods and in Study 2 (N = 30) they comprised snack foods. For each pair of images, participants rated their expected liking of the second course and selected ideal portion sizes, both for the second course and the first and second course, combined. In both studies, as the difference between the courses (from (i) same to (ii) similar to (iii) different) increased, the second course was selected in a larger portion and it was rated as more pleasant. To our knowledge, these are the first studies to show that the variety effect is evident in the energy content of self-selected meals. This work shows that effects of variety are learned and anticipated. This extends our characterisation beyond a passive process that develops towards the end of a meal.