Oriented Spanners

Given a point set P in the Euclidean plane and a parameter t, we define an oriented t-spanner as an oriented subgraph of the complete bi-directed graph such that for every pair of points, the shortest cycle in G through those points is at most a factor t longer than the shortest oriented cycle in the complete bi-directed graph. We investigate the problem of computing sparse graphs with small oriented dilation. As we can show that minimising oriented dilation for a given number of edges is NP-hard in the plane, we first consider one-dimensional point sets. While obtaining a 1-spanner in this setting is straightforward, already for five points such a spanner has no plane embedding with the leftmost and rightmost point on the outer face. This leads to restricting to oriented graphs with a one-page book embedding on the one-dimensional point set. For this case we present a dynamic program to compute the graph of minimum oriented dilation that runs in ?(n?) time for n points, and a greedy algorithm that computes a 5-spanner in ?(nlog n) time. Expanding these results finally gives us a result for two-dimensional point sets: we prove that for convex point sets the greedy triangulation results in an oriented ?(1)-spanner

Behavioral Response to a Novel “X” Shape Target Stimuli in a Harbor Seal

The objective of this study was to provide an environmental enrichment device (shape target) to determine if it improved the Harbor Seal’s visibility in the underwater viewing windows when housed at the Blank Park Zoo. One male harbor seal (Phoca vitulina) 3-years of age weighing 39 kg was used. Testing occurred Saturday through Tuesday over 6 consecutive weeks between 1300 and 1330 h. Live observations were collected continuously by one observer. Latency, frequency, and duration were measured. All data is presented descriptively. During baseline the Seal had no interest in the window. Upon presenting the “X” target, he approached quickly and interacted well. However by week 5, the seal’s interest to approach took longer but once the seal targeted he spent more time interacting with the device. Within the context of this study, the use of novel target enrichment for the seal showed promise in causing the seal to be more active towards the target and he was more visible in the underwater viewing windows

Oriented Spanners

Given a point set $P$ in the Euclidean plane and a parameter $t$, we define an \emph{oriented $t$-spanner} as an oriented subgraph of the complete bi-directed graph such that for every pair of points, the shortest cycle in $G$ through those points is at most a factor $t$ longer than the shortest oriented cycle in the complete bi-directed graph. We investigate the problem of computing sparse graphs with small oriented dilation. As we can show that minimising oriented dilation for a given number of edges is NP-hard in the plane, we first consider one-dimensional point sets. While obtaining a $1$-spanner in this setting is straightforward, already for five points such a spanner has no plane embedding with the leftmost and rightmost point on the outer face. This leads to restricting to oriented graphs with a one-page book embedding on the one-dimensional point set. For this case we present a dynamic program to compute the graph of minimum oriented dilation that runs in $O(n^8)$ time for $n$ points, and a greedy algorithm that computes a $5$-spanner in $O(n\log n)$ time. Expanding these results finally gives us a result for two-dimensional point sets: we prove that for convex point sets the greedy triangulation results in an oriented $O(1)$-spanner.Comment: conference version: ESA '2

Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures

Abstract Aims Sildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects. Methods A population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance. Results The analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9) −1.33 L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus <10 mmHg (median area under the curve=533 versus 792 µg*h/L). Discussion Elevated hepatic pressure delays clearance of the sildenafil metabolite – des-methyl-sildenafil – and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

Background-Heterozygous loss of function mutations in the KCNK3 gene cause hereditary pulmonary arterial hypertension (PAH). KCNK3 encodes an acid-sensitive potassium channel, which contributes to the resting potential of human pulmonary artery smooth muscle cells. KCNK3 is widely expressed in the body, and dimerizes with other KCNK3 subunits, or the closely related, acid-sensitive KCNK9 channel. Methods and Results-We engineered homomeric and heterodimeric mutant and nonmutant KCNK3 channels associated with PAH. Using whole-cell patch-clamp electrophysiology in human pulmonary artery smooth muscle and COS7 cell lines, we determined that homomeric and heterodimeric mutant channels in heterozygous KCNK3 conditions lead to mutation-specific severity of channel dysfunction. Both wildtype and mutant KCNK3 channels were activated by ONO-RS-082 (10 mu mol/L), causing cell hyperpolarization. We observed robust gene expression of KCNK3 in healthy and familial PAH patient lungs, but no quantifiable expression of KCNK9, and demonstrated in functional studies that KCNK9 minimizes the impact of select KCNK3 mutations when the 2 channel subunits co-assemble. Conclusions-Heterozygous KCNK3 mutations in PAH lead to variable loss of channel function via distinct mechanisms. Homomeric and heterodimeric mutant KCNK3 channels represent novel therapeutic substrates in PAH. Pharmacological and pH-dependent activation of wildtype and mutant KCNK3 channels in pulmonary artery smooth muscle cells leads to membrane hyperpolarization. Co-assembly of KCNK3 with KCNK9 subunits may provide protection against KCNK3 loss of function in tissues where both KCNK9 and KCNK3 are expressed, contributing to the lung-specific phenotype observed clinically in patients with PAH because of KCNK3 mutations.National Heart, Lung, and Blood Institute (NHLBI)Cardiovascular Medical Research and Education Fund (CMREF)Columbia Univ, Coll Phys & Surg, Dept Pharmacol, New York, NY USAColumbia Univ, Dept Pediat, Coll Phys & Surg, New York, NY 10027 USAUniv Fed São Paulo, Paulista Sch Med, Dept Biophys, São Paulo, BrazilNew York Stem Cell Fdn, Res Inst, New York, NY USAUniv Fed São Paulo, Paulista Sch Med, Dept Biophys, São Paulo, BrazilNHLBI: F30 HL129656NHLBI R24 grant: R24HL123767Web of Scienc

Miniaturized Environmental Scanning Electron Microscope for In Situ Planetary Studies

The exploration of remote planetary surfaces calls for the advancement of low power, highly-miniaturized instrumentation. Instruments of this nature that are capable of multiple types of analyses will prove to be particularly useful as we prepare for human return to the moon, and as we continue to explore increasingly remote locations in our Solar System. To this end, our group has been developing a miniaturized Environmental-Scanning Electron Microscope (mESEM) capable of remote investigations of mineralogical samples through in-situ topographical and chemical analysis on a fine scale. The functioning of an SEM is well known: an electron beam is focused to nanometer-scale onto a given sample where resulting emissions such as backscattered and secondary electrons, X-rays, and visible light are registered. Raster scanning the primary electron beam across the sample then gives a fine-scale image of the surface topography (texture), crystalline structure and orientation, with accompanying elemental composition. The flexibility in the types of measurements the mESEM is capable of, makes it ideally suited for a variety of applications. The mESEM is appropriate for use on multiple planetary surfaces, and for a variety of mission goals (from science to non-destructive analysis to ISRU). We will identify potential applications and range of potential uses related to planetary exploration. Over the past few of years we have initiated fabrication and testing of a proof-of-concept assembly, consisting of a cold-field-emission electron gun and custom high-voltage power supply, electrostatic electron-beam focusing column, and scanning-imaging electronics plus backscatter detector. Current project status will be discussed. This effort is funded through the NASA Research Opportunities in Space and Earth Sciences - Planetary Instrument Definition and Development Program

Improved Imputation of Common and Uncommon Single Nucleotide Polymorphisms (SNPs) with a New Reference Set

Statistical imputation of genotype data is an important technique for analysis of genome-wide association studies (GWAS). We have built a reference dataset to improve imputation accuracy for studies of individuals of primarily European descent using genotype data from the Hap1, Omni1, and Omni2.5 human SNP arrays (Illumina). Our dataset contains 2.5-3.1 million variants for 930 European, 157 Asian, and 162 African/African-American individuals. Imputation accuracy of European data from Hap660 or OmniExpress array content, measured by the proportion of variants imputed with R^2^>0.8, improved by 34%, 23% and 12% for variants with MAF of 3%, 5% and 10%, respectively, compared to imputation using publicly available data from 1,000 Genomes and International HapMap projects. The improved accuracy with the use of the new dataset could increase the power for GWAS by as much as 8% relative to genotyping all variants. This reference dataset is available to the scientific community through the NCBI dbGaP portal. Future versions will include additional genotype data as well as non-European populations