Electrochemical sensing of angiogenin induced endothelial nitric oxide synthase activity

This paper was presented at the 2nd Micro and Nano Flows Conference (MNF2009), which was held at Brunel University, West London, UK. The conference was organised by Brunel University and supported by the Institution of Mechanical Engineers, IPEM, the Italian Union of Thermofluid dynamics, the Process Intensification Network, HEXAG - the Heat Exchange Action Group and the Institute of Mathematics and its Applications.Angiogenesis, formation of new blood vessels, is a complex but critical phenomenon. In particular, it is regulated by different angiogenic factors. Nitric oxide (NO) is also a very well known biological mediator involved in vascular physiology. This study focuses on relationships between the effect of angiogenin, a major angiogenic factor, and extracellular NO release. NO concentration was sensed electrochemically using a fibronectin coated multiple microelectrode array. Angiogenin was shown to increase NO levels, thus triggering nitric oxide synthase (NOS) activity. Angiogenin reactive pathway being very complex, we have used various selective inhibitors of angiogenin to investigate the mechanism leading to NO production. Neomycin, an antibiotic blocking nuclear translocation, inhibited angiogenin effect on NOS. This result demonstrates that angiogenin activates NOS by interacting with the cell nucleus.This study is funded by Medermica Ltd; the DIUS; KICOS (K20602000681-08B0100-02210); the Korea Science and Engineering Foundation (M10749000231-08N4900-23110); and the Korea Biotech R&D Group of Next-Generation Growth Engine Project (F104AB010004-08A0201-00410)

Physiological Functions of the COPI Complex in Higher Plants

COPI vesicles are essential to the retrograde transport of proteins in the early secretory pathway. The COPI coatomer complex consists of seven subunits, termed alpha-, beta-, beta'-, gamma-, delta-, epsilon-, and zeta-COP, in yeast and mammals. Plant genomes have homologs of these subunits, but the essentiality of their cellular functions has hampered the functional characterization of the subunit genes in plants. Here we have employed virus-induced gene silencing (VIGS) and dexamethasone (DEX)-inducible RNAI of the COPI subunit genes to study the in vivo functions of the COPI coatomer complex in plants. The beta'-, gamma-, and delta-COP subunits localized to the Golgi as GFP-fusion proteins and interacted with each other in the Golgi. Silencing of beta'-, gamma-, and delta-COP by VIGS resulted in growth arrest and acute plant death in Nicotiana benthamiana, with the affected leaf cells exhibiting morphological markers of programmed cell death. Depletion of the COPI subunits resulted in disruption of the Golgi structure and accumulation of autolysosome-like structures in earlier stages of gene silencing. In tobacco BY-2 cells, DEX-inducible RNAi of beta'-COP caused aberrant cell plate formation during cytokinesis. Collectively, these results suggest that COPI vesicles are essential to plant growth and survival by maintaining the Golgi apparatus and modulating cell plate formation.1196Ysciescopu

Occupational noise exposure is associated with hypertension in China: Results from project ELEFANT

OBJECTIVES: We investigated the association between occupational noise exposure and the risk of elevated blood pressure and hypertension by stage in young adults. METHODS: We utilized 124,286 young adults (18-40 years) from the Project ELEFANT study. We categorized occupational noise exposure as high (75 dBA noise exposure for more than 4 hours per day) or low, and measured blood pressure (mmHg) and categorized participants by hypertension stage (normal, elevated, Stage 1, Stage 2). We applied adjusted logistic regression models to identify associations with hypertension risk, and we further examined the noise-BMI, noise-gender, and noise-residence interactions on hypertension risk in separate models. RESULTS: High occupational noise exposure was associated with increases in blood pressure among participants with elevated blood pressure (Estimate = 0.23, 95% CI: 1.09, 1.46, p = 0.0009), in Stage 1 hypertension (Estimate = 0.15, 95% CI: 1.06, 1.25, p = 0.0008), and in Stage 2 hypertension (Estimate = 0.41 95% CI: 1.31, 1.73, p<0.0001). Likewise, noise exposure-BMI interaction was consistently positively associated with increases in blood pressure in participants with elevated blood pressure (Estimate = 0.71, 95% CI: 1.55, 2.69, p<0.0001), in Stage 1 hypertension (Estimate = 0.78, 95% CI: 1.82, 2.61, p<0.0001), and in Stage 2 hypertension (Estimate = 2.06, 95% CI: 5.64, 10.81, p<0.0001). The noise exposure-male interaction showed higher risk for hypertension compared to the noise exposure-female interaction in participants with elevated blood pressure (Estimate = 1.24, 95% CI: 2.56, 4.71, p<0.0001), Stage 1 (Estimate = 1.67, 95% CI: 4.34, 6.42, p<0.0001) and Stage 2 hypertension (Estimate = 1.70, 95% CI: 3.86, 7.77, p<0.0001). Finally, we found that noise exposure-urban interaction was consistently associated with an increase in blood pressure in elevated blood pressure (Estimate = 0.32, 95% CI: 1.19, 1.62, p<0.0001) and in Stage 2 hypertension (Estimate = 0.44, 95% CI: 1.31, 1.80, p<0.0001)

Joint modelling of confounding factors and prominent genetic regulators provides increased accuracy in genetical genomics studies.

Expression quantitative trait loci (eQTL) studies are an integral tool to investigate the genetic component of gene expression variation. A major challenge in the analysis of such studies are hidden confounding factors, such as unobserved covariates or unknown subtle environmental perturbations. These factors can induce a pronounced artifactual correlation structure in the expression profiles, which may create spurious false associations or mask real genetic association signals. Here, we report PANAMA (Probabilistic ANAlysis of genoMic dAta), a novel probabilistic model to account for confounding factors within an eQTL analysis. In contrast to previous methods, PANAMA learns hidden factors jointly with the effect of prominent genetic regulators. As a result, this new model can more accurately distinguish true genetic association signals from confounding variation. We applied our model and compared it to existing methods on different datasets and biological systems. PANAMA consistently performs better than alternative methods, and finds in particular substantially more trans regulators. Importantly, our approach not only identifies a greater number of associations, but also yields hits that are biologically more plausible and can be better reproduced between independent studies. A software implementation of PANAMA is freely available online at http://ml.sheffield.ac.uk/qtl/

A Novel Genome-Wide Association Study Approach Using Genotyping by Exome Sequencing Leads to the Identification of a Primary Open Angle Glaucoma Associated Inversion Disrupting ADAMTS17

Closed breeding populations in the dog in conjunction with advances in gene mapping and sequencing techniques facilitate mapping of autosomal recessive diseases and identification of novel disease-causing variants, often using unorthodox experimental designs. In our investigation we demonstrate successful mapping of the locus for primary open angle glaucoma in the Petit Basset Griffon Vendéen dog breed with 12 cases and 12 controls, using a novel genotyping by exome sequencing approach. The resulting genome-wide association signal was followed up by genome sequencing of an individual case, leading to the identification of an inversion with a breakpoint disrupting the ADAMTS17 gene. Genotyping of additional controls and expression analysis provide strong evidence that the inversion is disease causing. Evidence of cryptic splicing resulting in novel exon transcription as a consequence of the inversion in ADAMTS17 is identified through RNAseq experiments. This investigation demonstrates how a novel genotyping by exome sequencing approach can be used to map an autosomal recessive disorder in the dog, with the use of genome sequencing to facilitate identification of a disease-associated variant

On the ability of spectroscopic SZ effect measurements to determine the temperature structure of galaxy clusters

(abridged) We explore in this paper the ability of spatially resolved spectroscopic measurements of the SZ effect (SZE) to determine the temperature profile of galaxy clusters. We derive a general formalism for the thermal SZE in galaxy clusters with a non-uniform temperature profile that can be applied to both cool-core clusters and non-cool core cluster with an isothermal or non-isothermal temperature structure. We derive an inversion technique through which the electron distribution function can be extracted from spectroscopic SZE observations over a wide frequency range. We study the fitting procedure to extract the cluster temperature from a set of simulated spatially resolved spectroscopic SZE observations in different bands of the spectrum, from 100 to 450 GHz. The results of our analysis for three different cluster prototypes (A2199 with a low-temperature cool core, Perseus with a relatively high-temperature cool core, Ophiuchus with an isothermal temperature distribution) provide both the required precision of the SZE observations and the optimal frequency bands for a determination of the cluster temperature similar or better than that obtainable from X-ray observations. The precision of SZE-derived temperature is also discussed for the outer regions of clusters. We also study the possibility to extract, from our method, the parameters characterizing the non-thermal SZE spectrum of the relativistic plasma contained in the lobes of radio galaxies as well as the spectrum of relativistic electrons co-spatially distributed with the thermal plasma in clusters with non-thermal phenomena. We find that the next generation SZE experiments with spectroscopic capabilities can provide precise temperature distribution measurements (...)Comment: Submitted to Astronomy & Astrophysic

Spread of Mutant Middle East Respiratory Syndrome Coronavirus with Reduced Affinity to Human CD26 during the South Korean Outbreak

The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe respiratory infection with a high mortality rate (similar to 35%). MERS-CoV has been a global threat due to continuous outbreaks in the Arabian peninsula and international spread by infected travelers since 2012. From May to July 2015, a large outbreak initiated by an infected traveler from the Arabian peninsula swept South Korea and resulted in 186 confirmed cases with 38 deaths (case fatality rate, 20.4%). Here, we show the rapid emergence and spread of a mutant MERS-CoV with reduced affinity to the human CD26 receptor during the South Korean outbreak. We isolated 13 new viral genomes from 14 infected patients treated at a hospital and found that 12 of these genomes possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. Specifically, 11 of these genomes have an I529T mutation in RBD, and 1 has a D510G mutation. Strikingly, both mutations result in reduced affinity of RBD to human CD26 compared to wild-type RBD, as measured by surface plasmon resonance analysis and cellular binding assay. Additionally, pseudotyped virus bearing an I529T mutation in S protein showed reduced entry into host cells compared to virus with wild-type S protein. These unexpected findings suggest that MERS-CoV adaptation during human-to-human spread may be driven by host immunological pressure such as neutralizing antibodies, resulting in reduced affinity to host receptor, and thereby impairs viral fitness and virulence, rather than positive selection for a better affinity to CD26. IMPORTANCE Recently, a large outbreak initiated by an MERS-CoV-infected traveler from the Middle East swept South Korea and resulted in 186 confirmed cases with 38 deaths. This is the largest outbreak outside the Middle East, and it raised strong concerns about the possible emergence of MERS-CoV mutations. Here, we isolated 13 new viral genomes and found that 12 of them possess a point mutation in the receptor-binding domain of viral spike protein, resulting in reduced affinity to the human cognate receptor, CD26, compared to the wild-type virus. These unexpected findings suggest that MERS-CoV adaptation in humans may be driven by host immunological pressure.111819Ysciescopu

Dark matter direct detection from new interactions in models with spin-two mediators

We consider models where a massive spin-two resonance acts as the mediator between Dark Matter (DM) and the SM particles through the energy-momentum tensor. We examine the effective theory for fermion, vector and scalar DM generated in these models and find novel types of DM-SM interaction never considered before. We identify the effective interactions between DM and the SM quarks when the mediator is integrated out, and match them to the gravitational form factors relevant for spin-independent DM-nucleon scattering. We also discuss the interplay between DM relic density conditions, direct detection bounds and collider searches for the spin-two mediator

phenosim - A software to simulate phenotypes for testing in genome-wide association studies

<p>Abstract</p> <p>Background</p> <p>There is a great interest in understanding the genetic architecture of complex traits in natural populations. Genome-wide association studies (GWAS) are becoming routine in human, animal and plant genetics to understand the connection between naturally occurring genotypic and phenotypic variation. Coalescent simulations are commonly used in population genetics to simulate genotypes under different parameters and demographic models.</p> <p>Results</p> <p>Here, we present <monospace>phenosim</monospace>, a software to add a phenotype to genotypes generated in time-efficient coalescent simulations. Both qualitative and quantitative phenotypes can be generated and it is possible to partition phenotypic variation between additive effects and epistatic interactions between causal variants. The output formats of <monospace>phenosim</monospace> are directly usable as input for different GWAS tools. The applicability of <monospace>phenosim</monospace> is shown by simulating a genome-wide association study in <it>Arabidopsis thaliana</it>.</p> <p>Conclusions</p> <p>By using the coalescent approach to generate genotypes and <monospace>phenosim</monospace> to add phenotypes, the data sets can be used to assess the influence of various factors such as demography, genetic architecture or selection on the statistical power of association methods to detect causal genetic variants under a wide variety of population genetic scenarios. <monospace>phenosim</monospace> is freely available from the authors' website <url>http://evoplant.uni-hohenheim.de</url></p

ImageParser: a tool for finite element generation from three-dimensional medical images

BACKGROUND: The finite element method (FEM) is a powerful mathematical tool to simulate and visualize the mechanical deformation of tissues and organs during medical examinations or interventions. It is yet a challenge to build up an FEM mesh directly from a volumetric image partially because the regions (or structures) of interest (ROIs) may be irregular and fuzzy. METHODS: A software package, ImageParser, is developed to generate an FEM mesh from 3-D tomographic medical images. This software uses a semi-automatic method to detect ROIs from the context of image including neighboring tissues and organs, completes segmentation of different tissues, and meshes the organ into elements. RESULTS: The ImageParser is shown to build up an FEM model for simulating the mechanical responses of the breast based on 3-D CT images. The breast is compressed by two plate paddles under an overall displacement as large as 20% of the initial distance between the paddles. The strain and tangential Young's modulus distributions are specified for the biomechanical analysis of breast tissues. CONCLUSION: The ImageParser can successfully exact the geometry of ROIs from a complex medical image and generate the FEM mesh with customer-defined segmentation information