Telomere length in circulating leukocytes is associated with lung function and disease

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (β= −0.0452, p=0.024) as well as COPD (β= −0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10−7), FVC (p=2.07×10−5), and FEV1/FVC (p=5.27×10−3). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

Genetic variants underlying risk of endometriosis: Insights from meta-analysis of eight genome-wide association and replication datasets

BACKGROUND Endometriosis is a heritable common gynaecological condition influenced by multiple genetic and environmental factors. Genome-wide association studies (GWASs) have proved successful in identifying common genetic variants of moderate effects for various complex diseases. To date, eight GWAS and replication studies from multiple populations have been published on endometriosis. In this review, we investigate the consistency and heterogeneity of the results across all the studies and their implications for an improved understanding of the aetiology of the condition. METHODS Meta-analyses were conducted on four GWASs and four replication studies including a total of 11 506 cases and 32 678 controls, and on the subset of studies that investigated associations for revised American Fertility Society (rAFS) Stage III/IV including 2859 cases. The datasets included 9039 cases and 27 343 controls of European (Australia, Belgium, Italy, UK, USA) and 2467 cases and 5335 controls of Japanese ancestry. Fixed and Han and Elkin random-effects models, and heterogeneity statistics (Cochran's Q test), were used to investigate the evidence of the nine reported genome-wide significant loci across datasets and populations. RESULTS Meta-analysis showed that seven out of nine loci had consistent directions of effect across studies and populations, and six out of nine remained genome-wide significant (P < 5 × 10(-8)), including rs12700667 on 7p15.2 (P = 1.6 × 10(-9)), rs7521902 near WNT4 (P = 1.8 × 10(-15)), rs10859871 near VEZT (P = 4.7 × 10(-15)), rs1537377 near CDKN2B-AS1 (P = 1.5 × 10(-8)), rs7739264 near ID4 (P = 6.2 × 10(-10)) and rs13394619 in GREB1 (P = 4.5 × 10(-8)). In addition to the six loci, two showed borderline genome-wide significant associations with Stage III/IV endometriosis, including rs1250248 in FN1 (P = 8 × 10(-8)) and rs4141819 on 2p14 (P = 9.2 × 10(-8)). Two independent inter-genic loci, rs4141819 and rs6734792 on chromosome 2, showed significant evidence of heterogeneity across datasets (P < 0.005). Eight of the nine loci had stronger effect sizes among Stage III/IV cases, implying that they are likely to be implicated in the development of moderate to severe, or ovarian, disease. While three out of nine loci were inter-genic, the remaining were in or near genes with known functions of biological relevance to endometriosis, varying from roles in developmental pathways to cellular growth/carcinogenesis. CONCLUSIONS Our meta-analysis shows remarkable consistency in endometriosis GWAS results across studies, with little evidence of population-based heterogeneity. They also show that the phenotypic classifications used in GWAS to date have been limited. Stronger associations with Stage III/IV disease observed for most loci emphasize the importance for future studies to include detailed sub-phenotype information. Functional studies in relevant tissues are needed to understand the effect of the variants on downstream biological pathways.

Size-resolved particle distribution and gaseous concentrations by real-world road tunnel measurement

Measurements of aerosol particle number size distributions (15-700 nm), CO and NOx were performed in a bus tunnel, Australia. Daily mean particle size distributions of mixed diesel/CNG (Compressed Natural Gas) buses traffic flow were determined in 4 consecutive measurement days. EFs (Emission Factors) of Particle size distribution of diesel buses and CNG buses were obtained by MLR (Multiple Linear Regression) methods, particle distributions of diesel buses and CNG buses were observed as single accumulation mode and nuclei-mode separately. Particle size distributions of mixed traffic flow were decomposed by two log-normal fitting curves for each 30 minutes interval mean scans, all the mix fleet PSD emission can be well fitted by the summation of two log-normal distribution curves, and these were composed of nuclei mode curve and accumulation curve, which were affirmed as the CNG buses and diesel buses PN emission curves respectively. Finally, particle size distributions of diesel buses and CNG buses were quantified by statistical whisker-box charts. For log-normal particle size distribution of diesel buses, accumulation mode diameters were 74.5～87.5nm, geometric standard deviations were 1.89～1.98. As to log-normal particle size distribution of CNG buses, nuclei-mode diameters were 21～24 nm, geometric standard deviations were 1.27～1.31.

Volatile organic compounds: Characteristics, distribution and sources in urban schools

Long term exposure to organic pollutants, both inside and outside school buildings may affect children’s health and influence their learning performance. Since children spend significant amount of time in school, air quality, especially in classrooms plays a key role in determining the health risks associated with exposure at schools. Within this context, the present study investigated the ambient concentrations of Volatile Organic Compounds (VOCs) in 25 primary schools in Brisbane with the aim to quantify the indoor and outdoor VOCs concentrations, identify VOCs sources and their contribution, and based on these; propose mitigation measures to reduce VOCs exposure in schools. One of the most important findings is the occurrence of indoor sources, indicated by the I/O ratio >1 in 19 schools. Principal Component Analysis with Varimax rotation was used to identify common sources of VOCs and source contribution was calculated using an Absolute Principal Component Scores technique. The result showed that outdoor 47% of VOCs were contributed by petrol vehicle exhaust but the overall cleaning products had the highest contribution of 41% indoors followed by air fresheners and art and craft activities. These findings point to the need for a range of basic precautions during the selection, use and storage of cleaning products and materials to reduce the risk from these sources.

A normal-distribution based rating aggregation method for generating product reputations

With the extensive use of rating systems in the web, and their significance in decision making process by users, the need for more accurate aggregation methods has emerged. The Naïve aggregation method, using the simple mean, is not adequate anymore in providing accurate reputation scores for items [6 ], hence, several researches where conducted in order to provide more accurate alternative aggregation methods. Most of the current reputation models do not consider the distribution of ratings across the different possible ratings values. In this paper, we propose a novel reputation model, which generates more accurate reputation scores for items by deploying the normal distribution over ratings. Experiments show promising results for our proposed model over state-of-the-art ones on sparse and dense datasets.

Mechanisms of cisplatin resistance: DNA repair and cellular implications

Cisplatin (cis-diamminedichloroplatinum (II)), is a platinum based chemotherapeutic employed in the clinic to treat patients with lung, ovarian, colorectal or head and neck cancers. Cisplatin acts to induce tumor cell death via multiple mechanisms. The best characterized mode of action is through irreversible DNA cross-links which activate DNA damage signals leading to cell death via the intrinsic mitochondrial apoptosis pathway. However, the primary issue with cisplatin is that while patients initially respond favorably, sustained cisplatin therapy often yields chemoresistance resulting in therapeutic failure. In this chapter, we review the DNA damage and repair pathways that contribute to cisplatin resistance. We also examine the cellular implications of cisplatin resistance that may lead to selection of subpopulations of cells within a tumor. In better understanding the mechanisms conferring cisplatin resistance, novel targets may be identified to restore drug sensitivity.

The time taken for the regional distribution of ventilation to stabilise: An investigation using electrical impedance tomography

Electrical impedance tomography is a novel technology capable of quantifying ventilation distribution in the lung in real time during various therapeutic manoeuvres. The technique requires changes to the patient’s position to place the electrical impedance tomography electrodes circumferentially around the thorax. The impact of these position changes on the time taken to stabilise the regional distribution of ventilation determined by electrical impedance tomography is unknown. This study aimed to determine the time taken for the regional distribution of ventilation determined by electrical impedance tomography to stabilise after changing position. Eight healthy, male volunteers were connected to electrical impedance tomography and a pneumotachometer. After 30 minutes stabilisation supine, participants were moved into 60 degrees Fowler’s position and then returned to supine. Thirty minutes was spent in each position. Concurrent readings of ventilation distribution and tidal volumes were taken every five minutes. A mixed regression model with a random intercept was used to compare the positions and changes over time. The anterior-posterior distribution stabilised after ten minutes in Fowler’s position and ten minutes after returning to supine. Left-right stabilisation was achieved after 15 minutes in Fowler’s position and supine. A minimum of 15 minutes of stabilisation should be allowed for spontaneously breathing individuals when assessing ventilation distribution. This time allows stabilisation to occur in the anterior-posterior direction as well as the left-right direction.

Uncertain species distribution: From interpolation to extrapolation

Species distribution models (SDMs) are considered to exemplify Pattern rather than Process based models of a species' response to its environment. Hence when used to map species distribution, the purpose of SDMs can be viewed as interpolation, since species response is measured at a few sites in the study region, and the aim is to interpolate species response at intermediate sites. Increasingly, however, SDMs are also being used to also extrapolate species-environment relationships beyond the limits of the study region as represented by the training data. Regardless of whether SDMs are to be used for interpolation or extrapolation, the debate over how to implement SDMs focusses on evaluating the quality of the SDM, both ecologically and mathematically. This paper proposes a framework that includes useful tools previously employed to address uncertainty in habitat modelling. Together with existing frameworks for addressing uncertainty more generally when modelling, we then outline how these existing tools help inform development of a broader framework for addressing uncertainty, specifically when building habitat models. As discussed earlier we focus on extrapolation rather than interpolation, where the emphasis on predictive performance is diluted by the concerns for robustness and ecological relevance. We are cognisant of the dangers of excessively propagating uncertainty. Thus, although the framework provides a smorgasbord of approaches, it is intended that the exact menu selected for a particular application, is small in size and targets the most important sources of uncertainty. We conclude with some guidance on a strategic approach to identifying these important sources of uncertainty. Whilst various aspects of uncertainty in SDMs have previously been addressed, either as the main aim of a study or as a necessary element of constructing SDMs, this is the first paper to provide a more holistic view.

Information-theoretic analysis of brain white matter fiber orientation distribution functions

We propose a new information-theoretic metric, the symmetric Kullback-Leibler divergence (sKL-divergence), to measure the difference between two water diffusivity profiles in high angular resolution diffusion imaging (HARDI). Water diffusivity profiles are modeled as probability density functions on the unit sphere, and the sKL-divergence is computed from a spherical harmonic series, which greatly reduces computational complexity. Adjustment of the orientation of diffusivity functions is essential when the image is being warped, so we propose a fast algorithm to determine the principal direction of diffusivity functions using principal component analysis (PCA). We compare sKL-divergence with other inner-product based cost functions using synthetic samples and real HARDI data, and show that the sKL-divergence is highly sensitive in detecting small differences between two diffusivity profiles and therefore shows promise for applications in the nonlinear registration and multisubject statistical analysis of HARDI data.

Probabilistic multi-tensor estimation using the tensor distribution function

Diffusion weighted magnetic resonance (MR) imaging is a powerful tool that can be employed to study white matter microstructure by examining the 3D displacement profile of water molecules in brain tissue. By applying diffusion-sensitized gradients along a minimum of 6 directions, second-order tensors can be computed to model dominant diffusion processes. However, conventional DTI is not sufficient to resolve crossing fiber tracts. Recently, a number of high-angular resolution schemes with greater than 6 gradient directions have been employed to address this issue. In this paper, we introduce the Tensor Distribution Function (TDF), a probability function defined on the space of symmetric positive definite matrices. Here, fiber crossing is modeled as an ensemble of Gaussian diffusion processes with weights specified by the TDF. Once this optimal TDF is determined, the diffusion orientation distribution function (ODF) can easily be computed by analytic integration of the resulting displacement probability function.

A novel measure of fractional anisotropy based on the tensor distribution function

Fractional anisotropy (FA), a very widely used measure of fiber integrity based on diffusion tensor imaging (DTI), is a problematic concept as it is influenced by several quantities including the number of dominant fiber directions within each voxel, each fiber's anisotropy, and partial volume effects from neighboring gray matter. With High-angular resolution diffusion imaging (HARDI) and the tensor distribution function (TDF), one can reconstruct multiple underlying fibers per voxel and their individual anisotropy measures by representing the diffusion profile as a probabilistic mixture of tensors. We found that FA, when compared with TDF-derived anisotropy measures, correlates poorly with individual fiber anisotropy, and may sub-optimally detect disease processes that affect myelination. By contrast, mean diffusivity (MD) as defined in standard DTI appears to be more accurate. Overall, we argue that novel measures derived from the TDF approach may yield more sensitive and accurate information than DTI-derived measures.

Analyzing multi-fiber reconstruction in high angular resolution diffusion imaging using the tensor distribution function

High-angular resolution diffusion imaging (HARDI) can reconstruct fiber pathways in the brain with extraordinary detail, identifying anatomical features and connections not seen with conventional MRI. HARDI overcomes several limitations of standard diffusion tensor imaging, which fails to model diffusion correctly in regions where fibers cross or mix. As HARDI can accurately resolve sharp signal peaks in angular space where fibers cross, we studied how many gradients are required in practice to compute accurate orientation density functions, to better understand the tradeoff between longer scanning times and more angular precision. We computed orientation density functions analytically from tensor distribution functions (TDFs) which model the HARDI signal at each point as a unit-mass probability density on the 6D manifold of symmetric positive definite tensors. In simulated two-fiber systems with varying Rician noise, we assessed how many diffusionsensitized gradients were sufficient to (1) accurately resolve the diffusion profile, and (2) measure the exponential isotropy (EI), a TDF-derived measure of fiber integrity that exploits the full multidirectional HARDI signal. At lower SNR, the reconstruction accuracy, measured using the Kullback-Leibler divergence, rapidly increased with additional gradients, and EI estimation accuracy plateaued at around 70 gradients.

The rapid manufacture of uniform composite multicellular-biomaterial micropellets, their assembly into macroscopic organized tissues, and potential applications in cartilage tissue engineering

We and others have published on the rapid manufacture of micropellet tissues, typically formed from 100-500 cells each. The micropellet geometry enhances cellular biological properties, and in many cases the micropellets can subsequently be utilized as building blocks to assemble complex macrotissues. Generally, micropellets are formed from cells alone, however when replicating matrix-rich tissues such as cartilage it would be ideal if matrix or biomaterials supplements could be incorporated directly into the micropellet during the manufacturing process. Herein we describe a method to efficiently incorporate donor cartilage matrix into tissue engineered cartilage micropellets. We lyophilized bovine cartilage matrix, and then shattered it into microscopic pieces having average dimensions < 10 μm diameter; we termed this microscopic donor matrix "cartilage dust (CD)". Using a microwell platform, we show that ~0.83 μg CD can be rapidly and efficiently incorporated into single multicellular aggregates formed from 180 bone marrow mesenchymal stem/stromal cells (MSC) each. The microwell platform enabled the rapid manufacture of thousands of replica composite micropellets, with each micropellet having a material/CD core and a cellular surface. This micropellet organization enabled the rapid bulking up of the micropellet core matrix content, and left an adhesive cellular outer surface. This morphological organization enabled the ready assembly of the composite micropellets into macroscopic tissues. Generically, this is a versatile method that enables the rapid and uniform integration of biomaterials into multicellular micropellets that can then be used as tissue building blocks. In this study, the addition of CD resulted in an approximate 8-fold volume increase in the micropellets, with the donor matrix functioning to contribute to an increase in total cartilage matrix content. Composite micropellets were readily assembled into macroscopic cartilage tissues; the incorporation of CD enhanced tissue size and matrix content, but did not enhance chondrogenic gene expression.

Provisioning a 3.3 MW PhotoVoltaic generation system onto a distribution authority’s 11 kV rural feeder

This paper describes part of an engineering study that was undertaken to demonstrate that a multi-megawatt Photovoltaic (PV) generation system could be connected to a rural 11 kV feeder without creating power quality issues for other consumers. The paper concentrates solely on the voltage regulation aspect of the study as this was the most innovative part of the study. The study was carried out using the time-domain software package, PSCAD/EMTDC. The software model included real time data input of actual measured load and scaled PV generation data, along with real-time substation voltage regulator and PV inverter reactive power control. The outputs from the model plot real-time voltage, current and power variations throughout the daily load and PV generation variations. Other aspects of the study not described in the paper include the analysis of harmonics, voltage flicker, power factor, voltage unbalance and system losses.

Impact of electric energy storage scheduling on reliability of distribution system

The development of Electric Energy Storage (EES) integrated with Renewable Energy Resources (RER) has increased use of optimum scheduling strategy in distribution systems. Optimum scheduling of EES can reduce cost of purchased energy by retailers while improve the reliability of customers in distribution system. This paper proposes an optimum scheduling strategy for EES and the evaluation of its impact on reliability of distribution system. Case study shows the impact of the proposed strategy on reliability indices of a distribution system.