A Study of the Effects of Tornado Translation on Wind Loading Using a Potential Flow Model

This paper investigates the effects of tornado translation on pressure and overall force experienced by an airfoil subjected to tornado loading and presents a framework to reproduce the flow conditions and effects of a moving tornado. A thin symmetrical airfoil was used to explore the effects of tornado translation on a body. A panel method was used to compute the flow around an airfoil and an idealised tornado is represented using a moving vortex via unsteady potential flow. Analysis showed that the maximum overall pressure at a point was found to increase by up to 20% when the normalised translating velocity was 10% of the tangential velocity, but increases up to 60% when the normalised translating velocity is 30% of the tangential velocity. Investigation on the impact of varying airfoil thickness (Case 2) revealed that the location of the tornado has significant effect on the overall lift force. However, the overall lift force appeared to be largely insensitive to the tornado translation velocity due gross changes in pressure on either side of the airfoil cancelling each other out. Further comparison with varying airfoil sizes and distance to tornado translating path (Case 3) showed that the relative inflow and outflow angle is the primary factor affecting the lift on the airfoil. Additionally, the maximum forces on a body subjected to a moving tornado can be predicted using uniform flow providing that the appropriate range of inflow angles are known. Based on the analysis on the database of National Oceanic and Atmospheric Administration (NOAA), the normalised translation speed of the recorded tornadoes across the EF scales, appears to vary from 0.25 to 0.37, with an average of 0.32 (∼18.8 m/s). Finally, the framework using uniform flow to reproduce the flow conditions which are comparable to those generated by a translating vortex simulator is proposed and discussed in detail

Capturing phenotypic heterogeneity in MPS I: results of an international consensus procedure

<p>Abstract</p> <p>Background</p> <p>Mucopolysaccharidosis type I (MPS I) is traditionally divided into three phenotypes: the severe Hurler (MPS I-H) phenotype, the intermediate Hurler-Scheie (MPS I-H/S) phenotype and the attenuated Scheie (MPS I-S) phenotype. However, there are no clear criteria for delineating the different phenotypes. Because decisions about optimal treatment (enzyme replacement therapy or hematopoietic stem cell transplantation) need to be made quickly and depend on the presumed phenotype, an assessment of phenotypic severity should be performed soon after diagnosis. Therefore, a numerical severity scale for classifying different MPS I phenotypes at diagnosis based on clinical signs and symptoms was developed.</p> <p>Methods</p> <p>A consensus procedure based on a combined modified Delphi method and a nominal group technique was undertaken. It consisted of two written rounds and a face-to-face meeting. Sixteen MPS I experts participated in the process. The main goal was to identify the most important indicators of phenotypic severity and include these in a numerical severity scale. The correlation between the median subjective expert MPS I rating and the scores derived from this severity scale was used as an indicator of validity.</p> <p>Results</p> <p>Full consensus was reached on six key clinical items for assessing severity: age of onset of signs and symptoms, developmental delay, joint stiffness/arthropathy/contractures, kyphosis, cardiomyopathy and large head/frontal bossing. Due to the remarkably large variability in the expert MPS I assessments, however, a reliable numerical scale could not be constructed. Because of this variability, such a scale would always result in patients whose calculated severity score differed unacceptably from the median expert severity score, which was considered to be the 'gold standard'.</p> <p>Conclusions</p> <p>Although consensus was reached on the six key items for assessing phenotypic severity in MPS I, expert opinion on phenotypic severity at diagnosis proved to be highly variable. This subjectivity emphasizes the need for validated biomarkers and improved genotype-phenotype correlations that can be incorporated into phenotypic severity assessments at diagnosis.</p

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species. © 2012 Neely et al

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species

PI3Kγ acts in DRG neurons as a negative regulator of thermal and TRPV1 responses.

<p>(A) Representative temperature response ramps and Arrhenius plots for heat-activated currents measured in single DRG neurons isolated from wild type (WT) and <i>PI3Kγ</i> mutant (KO) mice. For temperature response ramps, red lines depict temperature ramps and black lines depict inward current. (B) Q10 as a measure of the rate of inward current changes in response to temperature. n = 37 for isolated WT; n = 9 for <i>PI3Kγ</i> KO DRG neurons. (C,D) Capsaicin sensitivity of DRG neurons isolated from WT and <i>PI3Kγ</i> KO mice. (C) Representative capsaicin responses from a single DRG neuron. (D) Dose-response curves to different concentrations of capsaicin. The capsaicin EC50 is indicated. Numbers indicate numbers of single neurons tested with the indicated capsaicin doses at the respective data points. Electrophysiology data was generated by single neuron patch clamping. Data are presented as mean +/− sem. ** p<0.01, *** p<0.001 (Mann-Whitney u-test).</p

A global network map of thermal nociception.

<p>The systems network includes data from significantly enriched <i>Drosophila</i> KEGG pathways and GO processes, mouse and human KEGG pathways and C2 gene sets. Pathways, processes and gene sets that share a role in a biological process were pooled into functional classes while the underlying genes that constitute them are depicted with a connection to their respective functional class. Functional classes (gold), genes representing direct hits with a thermal nociception phenotype (red), their first degree binding partners (green), and developmental lethal genes (blue) represent the nodes in the network. Only select KEGG pathways, biological processes and C2 gene sets were used to build systems map. For the entire list of individual pathways, gene sets, and processes see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003071#pgen.1003071.s010" target="_blank">Tables S5</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003071#pgen.1003071.s011" target="_blank">S6</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003071#pgen.1003071.s012" target="_blank">S7</a>.</p