Post-transcriptional regulation in the nucleus and cytoplasm: study of mean time to threshold (MTT) and narrow escape problem

Messenger RNAs (mRNAs) can be repressed and degraded by small non-coding RNA molecules. In this paper, we formulate a coarsegrained Markov-chain description of the post-transcriptional regulation of mRNAs by either small interfering RNAs (siRNAs) or microRNAs (miRNAs). We calculate the probability of an mRNA escaping from its domain before it is repressed by siRNAs/miRNAs via cal- culation of the mean time to threshold: when the number of bound siRNAs/miRNAs exceeds a certain threshold value, the mRNA is irreversibly repressed. In some cases,the analysis can be reduced to counting certain paths in a reduced Markov model. We obtain explicit expressions when the small RNA bind irreversibly to the mRNA and we also discuss the reversible binding case. We apply our models to the study of RNA interference in the nucleus, examining the probability of mRNAs escaping via small nuclear pores before being degraded by siRNAs. Using the same modelling framework, we further investigate the effect of small, decoy RNAs (decoys) on the process of post-transcriptional regulation, by studying regulation of the tumor suppressor gene, PTEN : decoys are able to block binding sites on PTEN mRNAs, thereby educing the number of sites available to siRNAs/miRNAs and helping to protect it from repression. We calculate the probability of a cytoplasmic PTEN mRNA translocating to the endoplasmic reticulum before being repressed by miRNAs. We support our results with stochastic simulations

Spatially explicit structural equation modeling

Structural equation modeling (SEM) is a powerful statistical approach for the testing of networks of direct and indirect theoretical causal relationships in complex data sets with intercorrelated dependent and independent variables. SEM is commonly applied in ecology, but the spatial information commonly found in ecological data remains difficult to model in a SEM framework. Here we propose a simple method for spatially explicit SEM (SE-SEM) based on the analysis of variance/covariance matrices calculated across a range of lag distances. This method provides readily interpretable plots of the change in path coefficients across scale and can be implemented using any standard SEM software package. We demonstrate the application of this method using three studies examining the relationships between environmental factors, plant community structure, nitrogen fixation, and plant competition. By design, these data sets had a spatial component, but were previously analyzed using standard SEM models. Using these data sets, we demonstrate the application of SE-SEM to regularly spaced, irregularly spaced, and ad hoc spatial sampling designs and discuss the increased inferential capability of this approach compared with standard SEM. We provide an R package, sesem, to easily implement spatial structural equation modeling.

Secondary structure element alignment kernel method for prediction of protein structural classes

In this paper, we aim at predicting protein structural classes for low-homology data sets based on predicted secondary structures. We propose a new and simple kernel method, named as SSEAKSVM, to predict protein structural classes. The secondary structures of all protein sequences are obtained by using the tool PSIPRED and then a linear kernel on the basis of secondary structure element alignment scores is constructed for training a support vector machine classifier without parameter adjusting. Our method SSEAKSVM was evaluated on two low-homology datasets 25PDB and 1189 with sequence homology being 25% and 40%, respectively. The jackknife test is used to test and compare our method with other existing methods. The overall accuracies on these two data sets are 86.3% and 84.5%, respectively, which are higher than those obtained by other existing methods. Especially, our method achieves higher accuracies (88.1% and 88.5%) for differentiating the α + β class and the α/β class compared to other methods. This suggests that our method is valuable to predict protein structural classes particularly for low-homology protein sequences. The source code of the method in this paper can be downloaded at http://math.xtu.edu.cn/myphp/math/research/source/SSEAK_source_code.rar.

Dioxin risk reduction programme at the most severe dioxin hot spot in Vietnam: Residual knowledge, attitude and practices five years post intervention

Bien Hoa Airbase was one of the bulk storage and supply facilities for defoliants during the Vietnam War. Environmental and biological samples taken around the airbase have elevated levels of dioxin. In 2007, a pre-intervention knowledge, attitude and practice (KAP) survey of local residents living in Trung Dung and Tan Phong wards was undertaken regarding appropriate strategies to reduce dioxin exposure. A risk reduction programme was implemented in 2008 and post-intervention KAP surveys were undertaken in 2009 and 2013 to evaluate the longer term impacts. Quantitative assessment was undertaken via a KAP survey in 2013 among 600 local residents randomly selected from the two intervention wards and one control ward (Buu Long). Eight in-depth interviews and two focus group discussions were also undertaken for qualitative assessment. Most programme activities had ceased and dioxin risk communication activities had not been integrated into local routine health education programmes; however, main results generally remained and were better than that in Buu Long. In total, 48.2% of households undertook measures to prevent exposure, higher than those in pre- and post-intervention surveys (25.8% and 39.7%) and the control ward (7.7%). Migration and the sensitive nature of dioxin issues were the main challenges for the programme's sustainability

Disaster management in Nepal: Media engagement in the Post-2015 Framework for Disaster Risk Reduction

Nepal, as a consequence of its geographical location and changing climate, faces frequent threats of natural disasters. According to the World Bank’s 2005 Natural Disasters Hotspots Report, Nepal is ranked the 11th most vulnerable country to earthquake and 30th to flood risk. Geo-Hazards International (2011) has classified Kathmandu as one of the world’s most vulnerable cities to earthquakes. In the last four decades more than 32,000 people in Nepal have lost their lives and annual monetary loss is estimated at more than 15 million (US) dollars. This review identifies gaps in knowledge, and progress towards implementation of the Post Hyogo Framework of Action. Nepal has identified priority areas: community resilience, sustainable development and climate change induced disaster risk reduction. However, one gap between policy and action lies in the ability of Nepal to act effectively in accordance with an appropriate framework for media activities. Supporting media agencies include the Press Council, Federation of Nepalese Journalists, Nepal Television, Radio Nepal and Telecommunications Authority and community based organizations. The challenge lies in further strengthening traditional and new media to undertake systematic work supported by government bodies and the National Risk Reduction Consortium (NRRC). Within this context, the ideal role for media is one that is proactive where journalists pay attention to a range of appropriate angles or frames when preparing and disseminating information. It is important to develop policy for effective information collection, sharing and dissemination in collaboration with Telecommunication, Media and Journalists. The aim of this paper is to describe the developments in disaster management in Nepal and their implications for media management. This study provides lessons for government, community and the media to help improve the framing of disaster messages. Significantly, the research highlights the prominence that should be given to flood, landslides, lightning and earthquakes.

Structural, physiological and molecular characterisation of the Australian native resurrection grass Tripogon loliiformis (F.Meull) C.E.Hubb during dehydration and rehydration

There is an urgent need to develop crops that can withstand future climates. Results from this thesis demonstrated that a native Australian resurrection grass exhibits structural, physiological and metabolic strategies to tolerate drying. These strategies may be utilized for the generation of stress tolerant crops.

PW376 A pilot study of a post-discharge nurse-led, educational intervention on cardiac self-efficacy and anxiety in post-PCI patients

Introduction Hospitalisation for percutaneous coronary intervention (PCI) is often short, with limited nurse-teaching time and poor information absorption. Currently, patients are discharged home only to wait up to 4-8 weeks to commence a secondary prevention program and visit their cardiologist. This wait is an anxious time for patients and confidence or self-efficacy (SE) to self-manage may be low. Objectives To determine the effects of a nurse-led, educational intervention on participant SE and anxiety in the early post-discharge period. Methods A pilot study was undertaken as a randomised controlled clinical trial. Thirty-three participants were recruited, with n=13 randomised to the intervention group. A face-to-face, nurse-led, educational intervention was undertaken within the first 5-7 days post-discharge. Intervention group participants received standard post-discharge education, physical assessment, with a strong focus on the emotional impact of cardiovascular events and PCI. Early reiteration of post-discharge education was offered, along with health professional support with the aim to increase patients’ SE and to effectively manage their post-discharge health and well being, as well as anxieties. Self-efficacy to return to normal activities was measured to gauge participants’ abilities to manage post-PCI after attending the intervention using the cardiac self-efficacy (CSE) scale. State and trait anxiety was also measured using the State-Trait Anxiety Inventory (STAI) to determine if an increase in SE would influence participant anxiety. Results There were some increases in mean CSE scores in the intervention group participants over time. Areas of increase included return to normal social activities and confidence to change diet. Although reductions were observed in mean state and trait anxiety scores in both groups, an overall larger reduction in intervention group participants was observed over time. Conclusion It is essential that patients are given the education, support, and skills to self-manage in the early post-discharge period so that they have greater SE and are less anxious. This study provides some initial evidence that nurse-led support and education during this period, particularly the first week following PCI, is beneficial and could be trialled using alternate modes of communication to support remote and rural PCI patients and extend to other cardiovascular patients.

The Post-Illumination Pupil Response (PIPR)

Purpose The post-illumination pupil response (PIPR) has been quantified using four metrics, but the spectral sensitivity of only one is known; here we determine the other three. To optimize the human PIPR measurement, we determine the protocol producing the largest PIPR, the duration of the PIPR, and the metric(s) with the lowest coefficient of variation. Methods The consensual pupil light reflex (PLR) was measured with a Maxwellian view pupillometer. - Experiment 1: Spectral sensitivity of four PIPR metrics [plateau, 6 s, area under curve (AUC) early and late recovery] was determined from a criterion PIPR to a 1s pulse and fitted with Vitamin A1 nomogram (λmax = 482nm). - Experiment 2: The PLR was measured as a function of three stimulus durations (1s, 10s, 30s), five irradiances spanning low to high melanopsin excitation levels (retinal irradiance: 9.8 to 14.8 log quanta.cm-2.s-1), and two wavelengths, one with high (465nm) and one with low (637nm) melanopsin excitation. Intra and inter-individual coefficients of variation (CV) were calculated. Results The melanopsin (opn4) photopigment nomogram adequately describes the spectral sensitivity of all four PIPR metrics. The PIPR amplitude was largest with 1s short wavelength pulses (≥ 12.8 log quanta.cm-2.s-1). The plateau and 6s PIPR showed the least intra and inter-individual CV (≤ 0.2). The maximum duration of the sustained PIPR was 83.0±48.0s (mean±SD) for 1s pulses and 180.1±106.2s for 30s pulses (465nm; 14.8 log quanta.cm-2.s-1). Conclusions All current PIPR metrics provide a direct measure of the intrinsic melanopsin photoresponse. To measure progressive changes in melanopsin function in disease, we recommend that the PIPR be measured using short duration pulses (e.g., ≤ 1s) with high melanopsin excitation and analyzed with plateau and/or 6s metrics. Our PIPR duration data provide a baseline for the selection of inter-stimulus intervals between consecutive pupil testing sequences.

Melanopsin mediated post-illumination pupil response in early age-related macular degeneration

Purpose To determine whether melanopsin expressing intrinsically photosensitive Retinal Ganglion Cell (ipRGC) inputs to the pupil light reflex (PLR) are affected in early age-related macular degeneration (AMD). Methods The PLR was measured in 40 participants (20 early AMD and 20 age-matched controls) using a custom-built Maxwellian-view pupillometer. Sinusoidal stimuli (0.5 Hz, 11.9 s duration, 35.6° diameter) were presented to the study eye and the consensual pupil response was measured for stimuli with high melanopsin excitation (464nm; blue) and with low melanopsin excitation (638 nm; red) that biased activation to the outer retina. Two melanopsin PLR metrics were quantified: the Phase Amplitude Percentage (PAP) during the sinusoidal stimulus presentation and the Post-Illumination Pupil Response (PIPR). The PLR during stimulus presentation was analyzed using latency to constriction, transient pupil response and maximum pupil constriction metrics. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curves. Results The blue PIPR was significantly less sustained in the early AMD group (p<0.001). The red PIPR was not significantly different between groups (p>0.05). The PAP and blue stimulus constriction amplitude were significantly lower in the early AMD group (p < 0.05). There was no significant difference between groups in the latency or transient amplitude for both stimuli (p>0.05). ROC analysis showed excellent diagnostic accuracy for the blue PIPR metrics (AUC>0.9). Conclusions This is the initial report that the melanopsin controlled PIPR is dysfunctional in early AMD. The non-invasive, objective measurement of the ipRGC controlled PIPR has excellent diagnostic accuracy for early AMD.

Effect of age and refractive error on the melanopsin mediated Post-Illumination Pupil Response (PIPR)

Melanopsin containing intrinsically photosensitive Retinal Ganglion cells (ipRGCs) mediate the pupil light reflex (PLR) during light onset and at light offset (the post-illumination pupil response, PIPR). Recent evidence shows that the PLR and PIPR can provide non-invasive, objective markers of age-related retinal and optic nerve disease, however there is no consensus on the effects of healthy ageing or refractive error on the ipRGC mediated pupil function. Here we isolated melanopsin contributions to the pupil control pathway in 59 human participants with no ocular pathology across a range of ages and refractive errors. We show that there is no effect of age or refractive error on ipRGC inputs to the human pupil control pathway. The stability of the ipRGC mediated pupil response across the human lifespan provides a functional correlate of their robustness observed during ageing in rodent models.

The post-illumination pupil response of melanopsin expressing retinal ganglion cells

Purpose The post-illumination pupil response (PIPR) has been quantified in the literature by four metrics. The spectral sensitivity of only one metric is known and this study quantifies the other three. To optimize the measurement of the PIPR in humans, we also determine the stimulus protocol producing the largest PIPR, the duration of the PIPR, and the metric(s) with the lowest coefficient of variation. Methods The consensual pupil light reflex (PLR) was measured with a Maxwellian view pupillometer (35.6° diameter stimulus). - Experiment 1: Spectral sensitivity of four PIPR metrics [plateau, 6 s, area under curve (AUC) early and late recovery] was determined from a criterion PIPR (n = 2 participants) to a 1 s pulse at five wavelengths (409-592nm) and fitted with Vitamin A nomogram (ƛmax = 482 nm). - Experiment 2: The PLR was measured in five healthy participants [29 to 42 years (mean = 32.6 years)] as a function of three stimulus durations (1 s, 10 s, 30 s), five irradiances spanning low to high melanopsin excitation levels (retinal irradiance: 9.8 to 14.8 log quanta.cm-2.s-1), and two wavelengths, one with high (465 nm) and one with low (637 nm) melanopsin excitation. Intra and inter-individual coefficients of variation (CV) were calculated. Results The melanopsin (opn4) photopigment nomogram adequately described the spectral sensitivity derived from all four PIPR metrics. The largest PIPR amplitude was observed with 1 s short wavelength pulses (retinal irradiance ≥ 12.8 log quanta.cm-2.s-1). Of the 4 PIPR metrics, the plateau and 6 s PIPR showed the least intra and inter-individual CV (≤ 0.2). The maximum duration of the sustained PIPR was 83.4 ± 48.0 s (mean ± SD) for 1 s pulses and 180.1 ± 106.2 s for 30 s pulses (465 nm; 14.8 log quanta.cm-2.s-1). Conclusions All current PIPR metrics provide a direct measure of intrinsic melanopsin retinal ganglion cell function. To measure progressive changes in melanopsin function in disease, we recommend that the intrinsic melanopsin response should be measured using a 1 s pulse with high melanopsin excitation and the PIPR should be analyzed with the plateau and/or 6 s metrics. That the PIPR can have a sustained constriction for as long as 3 minutes, our PIPR duration data provide a baseline for the selection of inter-stimulus intervals between consecutive pupil testing sequences.

Standardised antibacterial Manuka honey in the management of persistent post-operative corneal oedema: A case series

Background Corneal oedema is a common post-operative problem that delays or prevents visual recovery from ocular surgery. Honey is a supersaturated solution of sugars with an acidic pH, high osmolarity and low water content. These characteristics inhibit the growth of micro-organisms, reduce oedema and promote epithelialisation. This clinical case series describes the use of a regulatory approved Leptospermum species honey ophthalmic product, in the management of post-operative corneal oedema and bullous keratopathy. Methods A retrospective review of 18 consecutive cases (30 eyes) with corneal oedema persisting beyond one month after single or multiple ocular surgical procedures (phacoemulsification cataract surgery and additional procedures) treated with Optimel Antibacterial Manuka Eye Drops twice to three times daily as an adjunctive therapy to conventional topical management with corticosteroid, aqueous suppressants, hypertonic sodium chloride five per cent, eyelid hygiene and artificial tears. Visual acuity and central corneal thickness were measured before and at the conclusion of Optimel treatment. Results A temporary reduction in corneal epithelial oedema lasting up to several hours was observed after the initial Optimel instillation and was associated with a reduction in central corneal thickness, resolution of epithelial microcysts, collapse of epithelial bullae, improved corneal clarity, improved visualisation of the intraocular structures and improved visual acuity. Additionally, with chronic use, reduction in punctate epitheliopathy, reduction in central corneal thickness and improvement in visual acuity were achieved. Temporary stinging after Optimel instillation was experienced. No adverse infectious or inflammatory events occurred during treatment with Optimel. Conclusions Optimel was a safe and effective adjunctive therapeutic strategy in the management of persistent post-operative corneal oedema and warrants further investigation in clinical trials.

A multiscale study on the structural and mechanical properties of the luffa sponge from Luffa cylindrica plant

Cellular materials that are often observed in biological systems exhibit excellent mechanical properties at remarkably low densities. Luffa sponge is one of such materials with a complex interconnecting porous structure. In this paper, we studied the relationship between its structural and mechanical properties at different levels of its hierarchical organization from a single fiber to a segment of whole sponge. The tensile mechanical behaviors of three single fibers were examined by an Instron testing machine and the ultrastructure of a fractured single fiber was observed in a scanning electronic microscope. Moreover, the compressive mechanical behaviors of the foam-like blocks from different locations of the sponge were examined. The difference of the compressive stress-strain responses of four sets of segmental samples were also compared. The result shows that the single fiber is a porous composite material mainly consisting of cellulose fibrils and lignin/hemicellulose matrix, and its Young's modulus and strength are comparable to wood. The mechanical behavior of the block samples from the hoop wall is superior to that from the core part. Furthermore, it shows that the influence of the inner surface on the mechanical property of the segmental sample is stronger than that of the core part; in particular, the former's Young's modulus, strength and strain energy absorbed are about 1.6 times higher. The present work can improve our understanding of the structure-function relationship of the natural material, which may inspire fabrication of new biomimetic foams with desirable mechanical efficiency for further applications in anti-crushing devices and super-light sandwich panels.

Stress analysis of carotid atheroma in transient ischemic attack patients: Evidence for extreme stress-induced plaque rupture

Plaque rupture has been considered to be the result of its structural failure. The aim of this study is to suggest a possible link between higher stresses and rupture sites observed from in vivo magnetic resonance imaging (MRI) of transient ischemic attack (TIA) patients, by using stress analysis methods. Three patients, who had recently suffered a TIA, underwent in vivo multi-spectral MR imaging. Based on plaque geometries reconstructed from the post-rupture status, six pre-rupture plaque models were generated for each patient dataset with different reconstructions of rupture sites to bridge the gap of fibrous cap from original MRI images. Stress analysis by fluid structure interaction simulation was performed on the models, followed by analysis of local stress concentration distribution and plaque rupture sites. Furthermore, the sensitivity of stress analysis to the pre-rupture plaque geometry reconstruction was examined. Local stress concentrations were found to be located at the plaque rupture sites for the three subjects studied. In the total of 18 models created, the locations of the stress concentration regions were similar in 17 models in which rupture sites were always associated with high stresses. The local stress concentration region moved from circumferential center to the shoulder region (slightly away from the rupture site) for a case with a thick fibrous cap. Plaque wall stress level in the rupture locations was found to be much higher than the value in non-rupture locations. The good correlation between local stress concentrations and plaque rupture sites, and generally higher plaque wall stress level in rupture locations in the subjects studied could provide indirect evidence for the extreme stress-induced plaque rupture hypothesis. Local stress concentration in the plaque region could be one of the factors contributing to plaque rupture.

Association between biomechanical structural stresses of atherosclerotic carotid plaques and subsequent ischaemic cerebrovascular events - A longitudinal in vivo magnetic resonance imaging-based finite element study

Background: High-resolution magnetic resonance (MR) imaging has been used for MR imaging-based structural stress analysis of atherosclerotic plaques. The biomechanical stress profile of stable plaques has been observed to differ from that of unstable plaques; however, the role that structural stresses play in determining plaque vulnerability remains speculative. Methods: A total of 61 patients with previous history of symptomatic carotid artery disease underwent carotid plaque MR imaging. Plaque components of the index artery such as fibrous tissue, lipid content and plaque haemorrhage (PH) were delineated and used for finite element analysis-based maximum structural stress (M-C Stress) quantification. These patients were followed up for 2 years. The clinical end point was occurrence of an ischaemic cerebrovascular event. The association of the time to the clinical end point with plaque morphology and M-C Stress was analysed. Results: During a median follow-up duration of 514 days, 20% of patients (n=12) experienced an ischaemic event in the territory of the index carotid artery. Cox regression analysis indicated that M-C Stress (hazard ratio (HR): 12.98 (95% confidence interval (CI): 1.32-26.67, pZ0.02), fibrous cap (FC) disruption (HR: 7.39 (95% CI: 1.61e33.82), p Z 0.009) and PH (HR: 5.85 (95% CI: 1.27e26.77), p Z 0.02) are associated with the development of subsequent cerebrovascular events. Plaques associated with future events had higher M-C Stress than those which had remained asymptomatic (median (interquartile range, IQR): 330 kPa (229e494) vs. 254 kPa (166-290), p Z0.04). Conclusions: High biomechanical structural stresses, in addition to FC rupture and PH, are associated with subsequent cerebrovascular events.