Virulence Determination for Rapid Extraintestinal Dissemination (Acute Infection) of Common Salmonella Serotypes in Swine

Salmonella enterica (Typhimurium and Choleraesuis) have been shown to rapidly disseminate extraintestinally (RED) within 3 hours of intranasal inoculation in pigs (1,2,5,6). Evaluation of RED serotypes may be an important indicator of Salmonella virulence. Experimentally, pigs were challenged with important lymph node, fecal, and vaccine isolates of Salmonella and evaluated for RED. These isolates include S. Heidelberg, S. Infantis, S. Derby, S. Worthington, S. 4, 12 imonophasic, S. untypable HL 10416, S. Typhimurium, S. Typhimurium variant Copenhagen, S. Bredeney, S. Muenchen, S. Brandenburg, S. Choleraesuis SC-38, S. Choleraesuis SC-54, and S. Choleraesuis strain Argus. Three hours after intranasal inoculation, the pigs were euthanized, necropsied, and the following tissues were collected for qualitative isolation: tonsil, thymus, blood, mandibular lymph node, lung, spleen, liver, ileocecal lymph node, colon contents, and cecum contents. Fewer tissues were positive for vaccine strains compared with wild type or parent strains

A Computational Approach for Deciphering the Organization of Glycosaminoglycans

BACKGROUND. Increasing evidence has revealed important roles for complex glycans as mediators of normal and pathological processes. Glycosaminoglycans are a class of glycans that bind and regulate the function of a wide array of proteins at the cell-extracellular matrix interface. The specific sequence and chemical organization of these polymers likely define function; however, identification of the structure-function relationships of glycosaminoglycans has been met with challenges associated with the unique level of complexity and the nontemplate-driven biosynthesis of these biopolymers. METHODOLOGY/PRINCIPAL FINDINGS. To address these challenges, we have devised a computational approach to predict fine structure and patterns of domain organization of the specific glycosaminoglycan, heparan sulfate (HS). Using chemical composition data obtained after complete and partial digestion of mixtures of HS chains with specific degradative enzymes, the computational analysis produces populations of theoretical HS chains with structures that meet both biosynthesis and enzyme degradation rules. The model performs these operations through a modular format consisting of input/output sections and three routines called chainmaker, chainbreaker, and chainsorter. We applied this methodology to analyze HS preparations isolated from pulmonary fibroblasts and epithelial cells. Significant differences in the general organization of these two HS preparations were observed, with HS from epithelial cells having a greater frequency of highly sulfated domains. Epithelial HS also showed a higher density of specific HS domains that have been associated with inhibition of neutrophil elastase. Experimental analysis of elastase inhibition was consistent with the model predictions and demonstrated that HS from epithelial cells had greater inhibitory activity than HS from fibroblasts. CONCLUSIONS/SIGNIFICANCE. This model establishes the conceptual framework for a new class of computational tools to use to assess patterns of domain organization within glycosaminoglycans. These tools will provide a means to consider high-level chain organization in deciphering the structure-function relationships of polysaccharides in biology.US National Institutes of Health (HL56200, HL088672); the Massachusetts Lions Eye Research Fund, Inc

Effects of receptor clustering on ligand dissociation: Theory and simulations

Receptor-ligand binding is a critical first step in signal transduction and the duration of the interaction can impact signal generation. In mammalian cells, clustering of receptors may be facilitated by heterogeneous zones of lipids, known as lipid rafts. In vitro experiments show that disruption of rafts significantly alters the dissociation of fibroblast growth factor-2 (FGF-2) from heparan sulfate proteoglycans, co-receptors for FGF-2. In this paper, we develop a continuum stochastic formalism in order to (i) study how rebinding affects the dissociation of ligands from a planar substrate, and (ii) address the question of how receptor clustering influences ligand rebinding. We find that clusters reduce the effective dissociation rate dramatically when the clusters are dense and the overall surface density of receptors is low. The effect is much less pronounced in the case of high receptor density and shows non-monotonic behavior with time. These predictions are verified via lattice Monte Carlo simulations. Comparison with experimental results suggests that the theory does not capture the complete biological system. We speculate that additional co-operative mechanisms might be present in order to increase ligand retention, and present one possible ``internal diffusion'' model.Comment: Expanded text and added figures, revised version to appear in Biophys.

The Zwicky Transient Facility: Surveys and Scheduler

We present a novel algorithm for scheduling the observations of time-domain imaging surveys. Our Integer Linear Programming approach optimizes an observing plan for an entire night by assigning targets to temporal blocks, enabling strict control of the number of exposures obtained per field and minimizing filter changes. A subsequent optimization step minimizes slew times between each observation. Our optimization metric self-consistently weights contributions from time-varying airmass, seeing, and sky brightness to maximize the transient discovery rate. We describe the implementation of this algorithm on the surveys of the Zwicky Transient Facility and present its on-sky performance.Comment: Published in PASP Focus Issue on the Zwicky Transient Facility (https://dx.doi.org/10.1088/1538-3873/ab0c2a). 13 Pages, 11 Figure

New Frontiers in Food Production Beyond LEO

New technologies will be needed as mankind moves towards exploration of cislunar space, the Moon and Mars. Although many advances in our understanding of the effects of spaceflight on plant growth have been achieved in the last 40 years, spaceflight plant growth systems have been primarily designed to support space biology studies. Recently, the need for a sustainable and robust food system for future missions beyond Low Earth Orbit (LEO) has identified gaps in current technologies for food production. The goal is to develop safe and sustainable food production systems with reduced resupply mass and crew time compared to current systems

Docking Server for the Identification of Heparin Binding Sites on Proteins

Many proteins of widely differing functionality and structure are capable of binding heparin and heparan sulfate. Since crystallizing protein–heparin complexes for structure determination is generally difficult, computational docking can be a useful approach for understanding specific interactions. Previous studies used programs originally developed for docking small molecules to well-defined pockets, rather than for docking polysaccharides to highly charged shallow crevices that usually bind heparin. We have extended the program PIPER and the automated protein–protein docking server ClusPro to heparin docking. Using a molecular mechanics energy function for scoring and the fast Fourier transform correlation approach, the method generates and evaluates close to a billion poses of a heparin tetrasaccharide probe. The docked structures are clustered using pairwise root-mean-square deviations as the distance measure. It was shown that clustering of heparin molecules close to each other but having different orientations and selecting the clusters with the highest protein–ligand contacts reliably predicts the heparin binding site. In addition, the centers of the five most populated clusters include structures close to the native orientation of the heparin. These structures can provide starting points for further refinement by methods that account for flexibility such as molecular dynamics. The heparin docking method is available as an advanced option of the ClusPro server at http://cluspro.bu.edu/

Forty-Year Analysis of Colonoscopic Surveillance Program for Neoplasia in Ulcerative Colitis: An Updated Overview

C.R.C. was funded by the Derek Willoughby Fund for Inflammatory Research. A.L.H. and T.A.G. were funded by Higher Education Funding Council of England

Bose–Einstein condensation in large time-averaged optical ring potentials

Interferometric measurements with matter waves are established techniques for sensitive gravimetry, rotation sensing, and measurement of surface interactions, but compact interferometers will require techniques based on trapped geometries. In a step towards the realisation of matter wave interferometers in toroidal geometries, we produce a large, smooth ring trap for Bose–Einstein condensates using rapidly scanned time-averaged dipole potentials. The trap potential is smoothed by using the atom distribution as input to an optical intensity correction algorithm. Smooth rings with a diameter up to 300 μm are demonstrated. We experimentally observe and simulate the dispersion of condensed atoms in the resulting potential, with good agreement serving as an indication of trap smoothness. Under time of flight expansion we observe low energy excitations in the ring, which serves to constrain the lower frequency limit of the scanned potential technique. The resulting ring potential will have applications as a waveguide for atom interferometry and studies of superfluidity