In Silico Modeling of Shear-Stress-Induced Nitric Oxide Production in Endothelial Cells through Systems Biology

Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.National Institutes of Health (U.S.) (Grant R01HL090856)Singapore-MIT Alliance Computational and Systems Biology Progra

Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis.

BackgroundBudesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis.AimThe aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam.MethodsData from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam.ResultsA similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0%, respectively). Adverse events occurred in 41.4 and 36.3% of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic-pituitary-adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration.ConclusionsThis integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis

Capacity-building barriers to S3 implementation: an empirical framework for catch-up regions

In this paper, we investigate the implementation challenge of Smart Specialisation Strategies (S3) in catch-up regional environments, through the lens of capacity building. We analyse capacity building at two levels: micro-level (individual organisations) and meso-level (regional inter-organisational networks). We use empirical evidence from 50 interviews conducted in the period 2015–2017 from two Greek regions dramatically hit by the economic crisis (Crete and Central Macedonia). We argue that in the Cretan and Central Macedonian context, the difficulty of implementing S3 is directly linked with firms’ lack of adsorptive capability to exploit university-generated knowledge, university knowledge that is too abstract for firm’s to easily acquire, as well as to the capability of regional actors to build inter-organisational networking that fits their strategic needs

Gemini/GMOS Imaging of Globular Cluster Systems in Five Early-type Galaxies

This paper presents deep high quality photometry of globular cluster (GC) systems belonging to five early-type galaxies covering a range of mass and environment. Photometric data were obtained with the Gemini North and Gemini South telescopes in the filter passbands g', r', and i'. The combination of these filters with good seeing conditions allows an excellent separation between GC candidates and unresolved field objects. Bimodal GC colour distributions are found in all five galaxies. Most of the GC systems appear bimodal even in the (g' -r') vs (r' -i') plane. A population of resolved/marginally resolved GC and Ultra Compact Dwarf candidates was found in all the galaxies. A search for the so-called "blue tilt" in the colour-magnitude diagrams reveals that NGC 4649 clearly shows that phenomenon although no conclusive evidence was found for the other galaxies in the sample. This "blue tilt" translates into a mass-metallicity relation given by Z \propto M^0.28\pm0.03 . This dependence was found using a new empirical (g' -i') vs [Z/H] relation which relies on an homogeneous sample of GC colours and metallicities. This paper also explores the radial trends in both colour and surface density for the blue (metal-poor) and red (metal-rich) GC subpopulations. As usual, the red GCs show a steeper radial distribution than the blue ones. Evidence of galactocentric colour gradients is found in some of the GC systems, being more significant for the two S0 galaxies in the sample. Red GC subpopulations show similar colours and gradients to the galaxy halo stars in their inner region. A GC mean colour-galaxy luminosity relation, consistent with [Z/H] \propto L_B ^0.26\pm0.08, is present for the red GCs. An estimate of the total GC populations and specific frequency SN values is presented for NGC 3115, NGC 3379, NGC 3923 and NGC 4649.Comment: 23 pages, 13 figures and 9 tables. Tables A1 and A2 will be published in full online only. Accepted for publication in MNRA

Tuberculosis in Dr Granville's mummy: a molecular re-examination of the earliest known Egyptian mummy to be scientifically examined and given a medical diagnosis

‘Dr Granville's mummy’ was described to the Royal Society of London in 1825 and was the first ancient Egyptian mummy to be subjected to a scientific autopsy. The remains are those of a woman, Irtyersenu, aged about 50, from the necropolis of Thebes and dated to about 600 BC. Augustus Bozzi Granville (1783–1872), an eminent physician and obstetrician, described many organs still in situ and attributed the cause of death to a tumour of the ovary. However, subsequent histological investigations indicate that the tumour is a benign cystadenoma. Histology of the lungs demonstrated a potentially fatal pulmonary exudate and earlier studies attempted to associate this with particular disease conditions. Palaeopathology and ancient DNA analyses show that tuberculosis was widespread in ancient Egypt, so a systematic search for tuberculosis was made, using specific DNA and lipid biomarker analyses. Clear evidence for Mycobacterium tuberculosis complex DNA was obtained in lung tissue and gall bladder samples, based on nested PCR of the IS6110 locus. Lung and femurs were positive for specific M. tuberculosis complex cell-wall mycolic acids, demonstrated by high-performance liquid chromatography of pyrenebutyric acid–pentafluorobenzyl mycolates. Therefore, tuberculosis is likely to have been the major cause of death of Irtyersenu

Globular Cluster and Galaxy Formation: M31, the Milky Way and Implications for Globular Cluster Systems of Spiral Galaxies

The globular cluster (GC) systems of the Milky Way and of our neighboring spiral galaxy, M31, comprise 2 distinct entities, differing in 3 respects. 1. M31 has young GCs, ages from ~100 Myr to 5 Gyr old, as well as old globular clusters. No such young GCs are known in the Milky Way. 2. We confirm that the oldest M31 GCs have much higher nitrogen abundances than do Galactic GCs at equivalent metallicities. 3. Morrison et al. found M31 has a subcomponent of GCs that follow closely the disk rotation curve of M31. Such a GC system in our own Galaxy has yet to be found. These data are interpreted in terms of the hierarchical-clustering-merging (HCM) paradigm for galaxy formation. We infer that M31 has absorbed more of its dwarf systems than has the Milky Way. This inference has 3 implications: 1. All spiral galaxies likely differ in their GC properties, depending on how many companions each galaxy has, and when the parent galaxy absorbs them. The the Milky Way ties down one end of this spectrum, as almost all of its GCs were absorbed 10-12 Gyr ago. 2. It suggests that young GCs are preferentially formed in the dwarf companions of parent galaxies, and then absorbed by the parent galaxy during mergers. 3. Young GCs seen in tidally-interacting galaxies might come from dwarf companions of these galaxies, rather than be made a-new in the tidal interaction. There is no ready explanation for the marked difference in nitrogen abundance for old M31 GCs relative to the oldest Galactic GCs. The predictions made by Li & Burstein regarding the origin of nitrogen abundance in globular clusters are consistent with what is found for the old M31 GCs compared to that for the two 5 Gyr-old M31 GCs.Comment: to be published in ApJ, Oct 2004; 13 pages of text, 2 tables, 7 postscript figure

Integration of a 3D Variational data assimilation scheme with a coastal area morphodynamic model of Morecambe Bay

This paper describes the implementation of a 3D variational (3D-Var) data assimilation scheme for a morphodynamic model applied to Morecambe Bay, UK. A simple decoupled hydrodynamic and sediment transport model is combined with a data assimilation scheme to investigate the ability of such methods to improve the accuracy of the predicted bathymetry. The inverse forecast error covariance matrix is modelled using a Laplacian approximation which is calibrated for the length scale parameter required. Calibration is also performed for the Soulsby-van Rijn sediment transport equations. The data used for assimilation purposes comprises waterlines derived from SAR imagery covering the entire period of the model run, and swath bathymetry data collected by a ship-borne survey for one date towards the end of the model run. A LiDAR survey of the entire bay carried out in November 2005 is used for validation purposes. The comparison of the predictive ability of the model alone with the model-forecast-assimilation system demonstrates that using data assimilation significantly improves the forecast skill. An investigation of the assimilation of the swath bathymetry as well as the waterlines demonstrates that the overall improvement is initially large, but decreases over time as the bathymetry evolves away from that observed by the survey. The result of combining the calibration runs into a pseudo-ensemble provides a higher skill score than for a single optimized model run. A brief comparison of the Optimal Interpolation assimilation method with the 3D-Var method shows that the two schemes give similar results

The vertical motions of mono-abundance sub-populations in the Milky Way disk

We present the vertical kinematics of stars in the Milky Way's stellar disk inferred from SDSS/SEGUE G-dwarf data, deriving the vertical velocity dispersion, \sigma_z, as a function of vertical height |z| and Galactocentric radius R for a set of 'mono-abundance' sub-populations of stars with very similar elemental abundances [\alpha/Fe] and [Fe/H]. We find that all components exhibit nearly isothermal kinematics in |z|, and a slow outward decrease of the vertical velocity dispersion: \sigma_z (z,R|[\alpha/Fe],[Fe/H]) ~ \sigma_z ([\alpha/Fe],[Fe/H]) x \exp (-(R-R_0)/7 kpc}). The characteristic velocity dispersions of these components vary from ~ 15 km/s for chemically young, metal-rich stars, to >~ 50 km/s for metal poor stars. The mean \sigma_z gradient away from the mid plane is only 0.3 +/- 0.2 km/s/kpc. We find a continuum of vertical kinetic temperatures (~\sigma^2_z) as function of ([\alpha/Fe],[Fe/H]), which contribute to the stellar surface mass density as \Sigma_{R_0}(\sigma^2_z) ~ \exp(-\sigma^2_z). The existence of isothermal mono-abundance populations with intermediate dispersions reject the notion of a thin-thick disk dichotomy. This continuum of disks argues against models where the thicker disk portions arise from massive satellite infall or heating; scenarios where either the oldest disk portion was born hot, or where internal evolution plays a major role, seem the most viable. The wide range of \sigma_z ([\alpha/Fe],[Fe/H]) combined with a constant \sigma_z(z) for each abundance bin provides an independent check on the precision of the SEGUE abundances: \delta_[\alpha/Fe] ~ 0.07 dex and \delta_[Fe/H] ~ 0.15 dex. The radial decline of the vertical dispersion presumably reflects the decrease in disk surface-mass density. This measurement constitutes a first step toward a purely dynamical estimate of the mass profile the disk in our Galaxy. [abridged

Stellar Mass--Gas-phase Metallicity Relation at 0.5≤z≤0.70.5\leq z\leq0.7: A Power Law with Increasing Scatter toward the Low-mass Regime

We present the stellar mass ($M_{*}$)--gas-phase metallicity relation (MZR) and its scatter at intermediate redshifts ($0.5\leq z\leq0.7$) for 1381 field galaxies collected from deep spectroscopic surveys. The star formation rate (SFR) and color at a given $M_{*}$ of this magnitude-limited ($R\lesssim24$ AB) sample are representative of normal star-forming galaxies. For masses below $10^9 M_\odot$, our sample of 237 galaxies is $\sim$10 times larger than those in previous studies beyond the local universe. This huge gain in sample size enables superior constraints on the MZR and its scatter in the low-mass regime. We find a power-law MZR at $10^{8} M_\odot < M_{*} < 10^{11} M_\odot$: ${12+log(O/H) = (5.83\pm0.19) + (0.30\pm0.02)log(M_{*}/M_\odot)}$. Our MZR shows good agreement with others measured at similar redshifts in the literature in the intermediate and massive regimes, but is shallower than the extrapolation of the MZRs of others to masses below $10^{9} M_\odot$. The SFR dependence of the MZR in our sample is weaker than that found for local galaxies (known as the Fundamental Metallicity Relation). Compared to a variety of theoretical models, the slope of our MZR for low-mass galaxies agrees well with predictions incorporating supernova energy-driven winds. Being robust against currently uncertain metallicity calibrations, the scatter of the MZR serves as a powerful diagnostic of the stochastic history of gas accretion, gas recycling, and star formation of low-mass galaxies. Our major result is that the scatter of our MZR increases as $M_{*}$ decreases. Our result implies that either the scatter of the baryonic accretion rate or the scatter of the $M_{*}$--$M_{halo}$ relation increases as $M_{*}$ decreases. Moreover, our measures of scatter at $z=0.7$ appears consistent with that found for local galaxies.Comment: 18 pages, 10 figures. Accepted by ApJ. Typos correcte