Taxonomy Visualization in Support of the Semi-Automatic Validation and Optimization of Organizational Schemas

Never before in history, mankind had access to and produced so much data, information, knowledge, and expertise as today. To organize, access, and manage these highly valuable assets effectively, we use taxonomies, classification hierarchies, ontologies, and controlled vocabularies among others. We create directory structures for our files. We use organizational hierarchies to structure our work environment. However, the design and continuous update of these organizational schemas that potentially have thousands of class nodes to organize millions of entities is challenging for any human being. The Taxonomy Visualization and Validation (TV) tool introduced in this paper supports the semi-automatic validation and optimization of organizational schemas such as file directories, classification hierarchies, taxonomies, or any other structure imposed on a data set as a means of organization, structuring, and naming. By showing the “goodness of fit” of a schema and the potentially millions of entities it organizes, the TV eases the identification and reclassification of misclassified information entities, the identification of classes that grew over-proportionally, the evaluation of the size and homogeneity of existing classes, the examination of the “well-formedness” of an organizational schema, etc. The TV is exemplarily applied to display the United States Patent and Trademark Office patent classification, which organizes more than three million patents into about 160,000 distinct patent classes. The paper concludes with a discussion and an outlook to future work

Interleukin-1 receptor 1 knockout has no effect on amyloid deposition in Tg2576 mice and does not alter efficacy following Aβ immunotherapy

BACKGROUND: Microglial activation has been proposed to facilitate clearance of amyloid β protein (Aβ) from the brain following Aβ immunotherapy in amyloid precursor protein (APP) transgenic mice. Interleukin-1 receptor 1 knockout (IL-1 R1-/-) mice are reported to exhibit blunted inflammatory responses to injury. To further define the role of IL-1-mediated inflammatory responses and microglial activation in this paradigm, we examined the efficacy of passive Aβ immunotherapy in Tg2576 mice crossed into the IL-1 R1-/- background. In addition, we examined if loss of IL-1 R1-/- modifies Aβ deposition in the absence of additional manipulations. METHODS: We passively immunized Tg2576 mice crossed into the IL-1 R1-/- background (APP/IL-1 R1-/- mice) with an anti-Aβ1-16 mAb (mAb9, IgG2a) that we previously showed could attenuate Aβ deposition in Tg2576 mice. We also examined whether the IL-1 R1 knockout background modifies Aβ deposition in untreated mice. Biochemical and immunohistochemical Aβ loads and microglial activation was assessed. RESULTS: Passive immunization with anti-Aβ mAb was effective in reducing plaque load in APP/IL-1 R1-/- mice when the immunization was started prior to significant plaque deposition. Similar to previous studies, immunization was not effective in older APP/IL-1 R1-/- mice or IL-1 R1 sufficient wild type Tg2576 mice. Our analysis of Aβ deposition in the untreated APP/IL-1 R1-/- mice did not show differences on biochemical Aβ loads during normal aging of these mice compared to IL-1 R1 sufficient wild type Tg2576 mice. CONCLUSION: We find no evidence that the lack of the IL-1 R1 receptor influences either Aβ deposition or the efficacy of passive immunotherapy. Such results are consistent with other studies in Tg2576 mice that suggest microglial activation may not be required for efficacy in passive immunization approaches

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

<p>Abstract</p> <p>Background</p> <p>Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified <it>R</it>-flurbiprofen (tarenflurbil) as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic <it>R</it>-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice.</p> <p>Results</p> <p>A four-month preventative treatment regimen with <it>R</it>-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of <it>R</it>-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning.</p> <p>Conclusion</p> <p>We have found that chronic administration of <it>R</it>-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its ability to selectively target Aβ42 production and improve cognitive impairments in transgenic APP mice, as well as promising data from a phase 2 human clinical trial, future studies are needed to investigate the utility of <it>R</it>-flurbiprofen as an AD therapeutic and its possible mechanisms of action.</p

Composited structure of non-precipitating shallow cumulus clouds

The normalized distributions of thermodynamic and dynamical variables both within and outside shallow clouds are investigated through a composite algorithm using large eddy simulations of oceanic and continental cases. The normalized magnitude is maximum near cloud center and decreases outwards. While relative humidity (RH) and cloud liquid water ($q_l$) decrease smoothly to match the environment, the vertical velocity, virtual potential temperature ($\theta_v$) and potential temperature ($\theta$) perturbations have more complicated behaviour towards the cloud boundary. Below the inversion layer, $\theta_v^{'}$ becomes negative before the vertical velocity has turned from updraft to subsiding shell outside the cloud, indicating the presence of a transition zone where the updraft is negatively buoyant. Due to the downdraft outside the cloud and the enhanced horizontal turbulent mixing across the edge, the normalized turbulence kinetic energy (TKE) and horizontal turbulence kinetic energy (HTKE) decrease more slowly from the cloud center outwards than the thermodynamic variables. The distributions all present asymmetric structures in response to the vertical wind shear, with more negatively buoyant air, stronger downdrafts and larger TKE on the downshear side. We discuss several implications of the distributions for theoretical models and parameterizations. Positive buoyancy near cloud base is mostly due to the virtual effect of water vapor, emphasising the role of moisture in triggering. The mean vertical velocity is found to be approximately half the maximum vertical velocity within each cloud, providing a constraint to achieve possible power law distributions for some models. Finally, the normalized distributions for different variables are used to estimate the vertical heat and moisture fluxes within clouds. The results suggest the distributions near cloud edge and the variability of maximum perturbations need careful treatment. The fluxes are underestimated in the inversion layer because the cloud top downdrafts can not be well captured

Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Aβ levels

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is characterized by a decline in cognitive function and accumulation of amyloid-β peptide (Aβ) in extracellular plaques. Mutations in amyloid precursor protein (APP) and presenilins alter APP metabolism resulting in accumulation of Aβ42, a peptide essential for the formation of amyloid deposits and proposed to initiate the cascade leading to AD. However, the role of Aβ40, the more prevalent Aβ peptide secreted by cells and a major component of cerebral Aβ deposits, is less clear. In this study, virally-mediated gene transfer was used to selectively increase hippocampal levels of human Aβ42 and Aβ40 in adult Wistar rats, allowing examination of the contribution of each to the cognitive deficits and pathology seen in AD.</p> <p>Results</p> <p>Adeno-associated viral (AAV) vectors encoding BRI-Aβ cDNAs were generated resulting in high-level hippocampal expression and secretion of the specific encoded Aβ peptide. As a comparison the effect of AAV-mediated overexpression of APPsw was also examined. Animals were tested for development of learning and memory deficits (open field, Morris water maze, passive avoidance, novel object recognition) three months after infusion of AAV. A range of impairments was found, with the most pronounced deficits observed in animals co-injected with both AAV-BRI-Aβ40 and AAV-BRI-Aβ42. Brain tissue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble Aβ peptides. BRI-Aβ42 and the combination of BRI-Aβ40+42 overexpression resulted in elevated levels of detergent-insoluble Aβ. No significant increase in detergent-insoluble Aβ was seen in the rats expressing APPsw or BRI-Aβ40. No pathological features were noted in any rats, except the AAV-BRI-Aβ42 rats which showed focal, amorphous, Thioflavin-negative Aβ42 deposits.</p> <p>Conclusion</p> <p>The results show that AAV-mediated gene transfer is a valuable tool to model aspects of AD pathology <it>in vivo</it>, and demonstrate that whilst expression of Aβ42 alone is sufficient to initiate Aβ deposition, both Aβ40 and Aβ42 may contribute to cognitive deficits.</p

The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition

BackgroundGenetic effects on asthma of genes in the T-helper 2 (Th2) pathway may interact with epigenetic factors including DNA methylation. We hypothesized that interactions between genetic variants and methylation in genes in this pathway (IL4, IL4R, IL13, GATA3, and STAT6) influence asthma risk, that such influences are age-dependent, and that methylation of some CpG sites changes over time in accordance with asthma transition. We tested these hypotheses in subsamples of girls from a population-based birth cohort established on the Isle of Wight, UK, in 1989.ResultsLogistic regression models were applied to test the interaction effect of DNA methylation and SNP on asthma within each of the five genes. Bootstrapping was used to assess the models identified. From 1,361 models fitted at each age of 10 and 18 years, 8 models, including 4 CpGs and 8 SNPs, showed potential associations with asthma risk. Of the 4 CpGs, methylation of cg26937798 (IL4R) and cg23943829 (IL4) changes between ages 10 and 18 (both higher at 10; P?=?9.14?×?10?6 and 1.07?×?10?5, respectively).At age 10, the odds of asthma tended to decrease as cg12405139 (GATA3) methylation increased (log-OR?=??12.15; P?=?0.049); this effect disappeared by age 18. At age 18, methylation of cg09791102 (IL4R) was associated with higher risk of asthma among subjects with genotype GG compared to AG (P?=?0.003), increased cg26937798 methylation among subjects with rs3024685 (IL4R) genotype AA (P?=?0.003) or rs8832 (IL4R) genotype GG (P?=?0.01) was associated with a lower asthma risk; these CpGs had no effect at age 10. Increasing cg26937798 methylation over time possibly reduced the risk of positive asthma transition (asthma-free at age 10???asthma at age 18; log-OR?=??3.11; P?=?0.069) and increased the likelihood of negative transition (asthma at age 10???asthma-free at age 18; log-OR?=?3.97; P?=?0.074).ConclusionsThe interaction of DNA methylation and SNPs in Th2 pathway genes is likely to contribute to asthma risk. This effect may vary with age. Methylation of some CpGs changed over time, which may influence asthma transition

RELEVANCE OF VASCULAR STRUCTURAL AND SMOOTH MUSCLE SENSITIVITY CHANGES IN HYPERTENSION

This is a mini-review of the vascular changes that occur in experimental hypertension. Augmented vascular resistance and reactivity appear to be due to an increase both in wall thickness and in vascular smooth muscle sensitivity. The increase in wall thickness is an adaptive change that is secondary to the increase in arterial pressure; the altered smooth muscle sensitivity occurs in the absence of an increase in arterial pressure and hence may initiate the increase in vascular resistance and reactivity of experimental hypertension. Studies of subcellular function indicate that changes in smooth muscle sensitivity may be caused by an increase in cell membrane permeability and an altered handling of calcium by its subcellular sequestering system. This review was supported by U.S. Public Health Service grant HL-03756 from the National Heart and Lung Institute. K.H. Berecek is a predoctoral fellow supported by NIH grant PHS-4620.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72098/1/j.1445-5994.1976.tb03320.x.pd

NASA's Robotic Lunar Lander Development Program

NASA Marshall Space Flight Center and the Johns Hopkins University Applied Physics Laboratory have developed several mission concepts to place scientific and exploration payloads ranging from 10 kg to more than 200 kg on the surface of the moon. The mission concepts all use a small versatile lander that is capable of precision landing. The results to date of the lunar lander development risk reduction activities including high pressure propulsion system testing, structure and mechanism development and testing, and long cycle time battery testing will be addressed. The most visible elements of the risk reduction program are two fully autonomous lander flight test vehicles. The first utilized a high pressure cold gas system (Cold Gas Test Article) with limited flight durations while the subsequent test vehicle, known as the Warm Gas Test Article, utilizes hydrogen peroxide propellant resulting in significantly longer flight times and the ability to more fully exercise flight sensors and algorithms. The development of the Warm Gas Test Article is a system demonstration and was designed with similarity to an actual lunar lander including energy absorbing landing legs, pulsing thrusters, and flight-like software implementation. A set of outdoor flight tests to demonstrate the initial objectives of the WGTA program was completed in Nov. 2011, and will be discussed

Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes.

Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease

The 2006 NESCent Phyloinformatics Hackathon: A Field Report

In December, 2006, a group of 26 software developers from some of the most widely used life science programming toolkits and phylogenetic software projects converged on Durham, North Carolina, for a Phyloinformatics Hackathon, an intense five-day collaborative software coding event sponsored by the National Evolutionary Synthesis Center (NESCent). The goal was to help researchers to integrate multiple phylogenetic software tools into automated workflows. Participants addressed deficiencies in interoperability between programs by implementing “glue code” and improving support for phylogenetic data exchange standards (particularly NEXUS) across the toolkits. The work was guided by use-cases compiled in advance by both developers and users, and the code was documented as it was developed. The resulting software is freely available for both users and developers through incorporation into the distributions of several widely-used open-source toolkits. We explain the motivation for the hackathon, how it was organized, and discuss some of the outcomes and lessons learned. We conclude that hackathons are an effective mode of solving problems in software interoperability and usability, and are underutilized in scientific software development