Guanylate cyclase C limits systemic dissemination of a murine enteric pathogen

BACKGROUND: Guanylate Cyclase C (GC-C) is an apically-oriented transmembrane receptor that is expressed on epithelial cells of the intestine. Activation of GC-C by the endogenous ligands guanylin or uroguanylin elevates intracellular cGMP and is implicated in intestinal ion secretion, cell proliferation, apoptosis, intestinal barrier function, as well as the susceptibility of the intestine to inflammation. Our aim was to determine if GC-C is required for host defense during infection by the murine enteric pathogen Citrobacter rodentium of the family Enterobacteriacea. METHODS: GC-C(+/+) control mice or those having GC-C genetically ablated (GC-C(−/−)) were administered C. rodentium by orogastric gavage and analyzed at multiple time points up to post-infection day 20. Commensal bacteria were characterized in uninfected GC-C(+/+) and GC-C(−/−) mice using 16S rRNA PCR analysis. RESULTS: GC-C(−/−) mice had an increase in C. rodentium bacterial load in stool relative to GC-C(+/+). C. rodentium infection strongly decreased guanylin expression in GC-C(+/+) mice and, to an even greater degree, in GC-C(−/−) animals. Fluorescent tracer studies indicated that mice lacking GC-C, unlike GC-C(+/+) animals, had a substantial loss of intestinal barrier function early in the course of infection. Epithelial cell apoptosis was significantly increased in GC-C(−/−) mice following 10 days of infection and this was associated with increased frequency and numbers of C. rodentium translocation out of the intestine. Infection led to significant liver histopathology in GC-C(−/−) mice as well as lymphocyte infiltration and elevated cytokine and chemokine expression. Relative to naïve GC-C(+/+) mice, the commensal microflora load in uninfected GC-C(−/−) mice was decreased and bacterial composition was imbalanced and included outgrowth of the Enterobacteriacea family. CONCLUSIONS: This work demonstrates the novel finding that GC-C signaling is an essential component of host defense during murine enteric infection by reducing bacterial load and preventing systemic dissemination of attaching/effacing-lesion forming bacterial pathogens such as C. rodentium

Categorification of persistent homology

We redevelop persistent homology (topological persistence) from a categorical point of view. The main objects of study are diagrams, indexed by the poset of real numbers, in some target category. The set of such diagrams has an interleaving distance, which we show generalizes the previously-studied bottleneck distance. To illustrate the utility of this approach, we greatly generalize previous stability results for persistence, extended persistence, and kernel, image and cokernel persistence. We give a natural construction of a category of interleavings of these diagrams, and show that if the target category is abelian, so is this category of interleavings.Comment: 27 pages, v3: minor changes, to appear in Discrete & Computational Geometr

Focused Local Search for Random 3-Satisfiability

A local search algorithm solving an NP-complete optimisation problem can be viewed as a stochastic process moving in an 'energy landscape' towards eventually finding an optimal solution. For the random 3-satisfiability problem, the heuristic of focusing the local moves on the presently unsatisfiedclauses is known to be very effective: the time to solution has been observed to grow only linearly in the number of variables, for a given clauses-to-variables ratio $\alpha$ sufficiently far below the critical satisfiability threshold $\alpha_c \approx 4.27$. We present numerical results on the behaviour of three focused local search algorithms for this problem, considering in particular the characteristics of a focused variant of the simple Metropolis dynamics. We estimate the optimal value for the ``temperature'' parameter $\eta$ for this algorithm, such that its linear-time regime extends as close to $\alpha_c$ as possible. Similar parameter optimisation is performed also for the well-known WalkSAT algorithm and for the less studied, but very well performing Focused Record-to-Record Travel method. We observe that with an appropriate choice of parameters, the linear time regime for each of these algorithms seems to extend well into ratios $\alpha > 4.2$ -- much further than has so far been generally assumed. We discuss the statistics of solution times for the algorithms, relate their performance to the process of ``whitening'', and present some conjectures on the shape of their computational phase diagrams.Comment: 20 pages, lots of figure

Early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion

IntroductionHigh mobility group box nuclear protein 1 (HMGB1) is a DNA nuclear binding protein that has recently been shown to be an early trigger of sterile inflammation in animal models of trauma-hemorrhage via the activation of the Toll-like-receptor 4 (TLR4) and the receptor for the advanced glycation endproducts (RAGE). However, whether HMGB1 is released early after trauma hemorrhage in humans and is associated with the development of an inflammatory response and coagulopathy is not known and therefore constitutes the aim of the present study.MethodsOne hundred sixty eight patients were studied as part of a prospective cohort study of severe trauma patients admitted to a single Level 1 Trauma center. Blood was drawn within 10 minutes of arrival to the emergency room before the administration of any fluid resuscitation. HMGB1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, von Willebrand Factor (vWF), angiopoietin-2 (Ang-2), Prothrombin time (PT), prothrombin fragments 1+2 (PF1+2), soluble thrombomodulin (sTM), protein C (PC), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and D-Dimers were measured using standard techniques. Base deficit was used as a measure of tissue hypoperfusion. Measurements were compared to outcome measures obtained from the electronic medical record and trauma registry.ResultsPlasma levels of HMGB1 were increased within 30 minutes after severe trauma in humans and correlated with the severity of injury, tissue hypoperfusion, early posttraumatic coagulopathy and hyperfibrinolysis as well with a systemic inflammatory response and activation of complement. Non-survivors had significantly higher plasma levels of HMGB1 than survivors. Finally, patients who later developed organ injury, (acute lung injury and acute renal failure) had also significantly higher plasma levels of HMGB1 early after trauma.ConclusionsThe results of this study demonstrate for the first time that HMGB1 is released into the bloodstream early after severe trauma in humans. The release of HMGB1 requires severe injury and tissue hypoperfusion, and is associated with posttraumatic coagulation abnormalities, activation of complement and severe systemic inflammatory response

Carbon monoxide in the solar atmosphere I. Numerical method and two-dimensional models

The radiation hydrodynamic code CO5BOLD has been supplemented with the time-dependent treatment of chemical reaction networks. Advection of particle densities due to the hydrodynamic flow field is also included. The radiative transfer is treated frequency-independently, i.e. grey, so far. The upgraded code has been applied to two-dimensional simulations of carbon monoxide (CO) in the non-magnetic solar photosphere and low chromosphere. For this purpose a reaction network has been constructed, taking into account the reactions which are most important for the formation and dissociation of CO under the physical conditions of the solar atmosphere. The network has been strongly reduced to 27 reactions, involving the chemical species H, H2, C, O, CO, CH, OH, and a representative metal. The resulting CO number density is highest in the cool regions of the reversed granulation pattern at mid-photospheric heights and decreases strongly above. There, the CO abundance stays close to a value of 8.3 on the usual logarithmic abundance scale with [H]=12 but is reduced in hot shock waves which are a ubiquitous phenomenon of the model atmosphere. For comparison, the corresponding equilibrium densities have been calculated, based on the reaction network but also under assumption of instantaneous chemical equilibrium by applying the Rybicki & Hummer (RH) code by Uitenbroek (2001). Owing to the short chemical timescales, the assumption holds for a large fraction of the atmosphere, in particular the photosphere. In contrast, the CO number density deviates strongly from the corresponding equilibrium value in the vicinity of chromospheric shock waves. Simulations with altered reaction network clearly show that the formation channel via hydroxide (OH) is the most important one under the conditions of the solar atmosphere.Comment: 15 pages, 6 figures, final version will contain online materia

Do motor control genes contribute to interindividual variability in decreased movement in patients with pain?

<p>Abstract</p> <p>Background</p> <p>Because excessive reduction in activities after back injury may impair recovery, it is important to understand and address the factors contributing to the variability in motor responses to pain. The current dominant theory is the "fear-avoidance model", in which the some patients' heightened fears of further injury cause them to avoid movement. We propose that in addition to psychological factors, neurochemical variants in the circuits controlling movement and their modification by pain may contribute to this variability. A systematic search of the motor research literature and genetic databases yielded a prioritized list of polymorphic motor control candidate genes. We demonstrate an analytic method that we applied to 14 of these genes in 290 patients with acute sciatica, whose reduction in movement was estimated by items from the Roland-Morris Disability Questionnaire.</p> <p>Results</p> <p>We genotyped a total of 121 single nucleotide polymorphisms (SNPs) in 14 of these genes, which code for the dopamine D2 receptor, GTP cyclohydrolase I, glycine receptor α1 subunit, GABA-A receptor α2 subunit, GABA-A receptor β1 subunit, α-adrenergic 1C, 2A, and 2C receptors, serotonin 1A and 2A receptors, cannabinoid CB-1 receptor, M1 muscarinic receptor, and the tyrosine hydroxylase, and tachykinin precursor-1 molecules. No SNP showed a significant association with the movement score after a Bonferroni correction for the 14 genes tested. Haplotype analysis of one of the blocks in the GABA-A receptor β1 subunit showed that a haplotype of 11% frequency was associated with less limitation of movement at a nominal significance level value (p = 0.0025) almost strong enough to correct for testing 22 haplotype blocks.</p> <p>Conclusion</p> <p>If confirmed, the current results may suggest that a common haplotype in the GABA-A β1 subunit acts like an "endogenous muscle relaxant" in an individual with subacute sciatica. Similar methods might be applied a larger set of genes in animal models and human laboratory and clinical studies to understand the causes and prevention of pain-related reduction in movement.</p

Datasets for generic relation extraction

A vast amount of usable electronic data is in the form of unstructured text. The relation extraction task aims to identify useful information in text (e.g. PersonW works for OrganisationX, GeneY encodes ProteinZ) and recode it in a format such as a relational database or RDF triplestore that can be more effectively used for querying and automated reasoning. A number of resources have been developed for training and evaluating automatic systems for relation extraction in different domains. However, comparative evaluation is impeded by the fact that these corpora use different markup formats and notions of what constitutes a relation. We describe the preparation of corpora for comparative evaluation of relation extraction across domains based on the publicly available ACE 2004, ACE 2005 and BioInfer data sets. We present a common document type using token standoff and including detailed linguistic markup, while maintaining all information in the original annotation. The subsequent reannotation process normalises the two data sets so that they comply with a notion of relation that is intuitive, simple and informed by the semantic web. For the ACE data, we describe an automatic process that automatically converts many relations involving nested, nominal entity mentions to relations involving non-nested, named or pronominal entity mentions. For example, the first entity is mapped from 'one' to 'Amidu Berry' in the membership relation described in 'Amidu Berry, one half of PBS'. Moreover, we describe a comparably reannotated version of the BioInfer corpus that flattens nested relations, maps part-whole to part-part relations and maps n-ary to binary relations. Finally, we summarise experiments that compare approaches to generic relation extraction, a knowledge discovery task that uses minimally supervised techniques to achieve maximally portable extractors. These experiments illustrate the utility of the corpora.39 page(s

Small, Low-energy, Dispersive Solar Energetic Particle Events Observed by Parker Solar Probe

The Energetic Particle Instrument–Low Energy (EPI-Lo) experiment has detected several weak, low-energy (~30–300 keV nucleon⁻¹) solar energetic particle (SEP) events during its first two closest approaches to the Sun, providing a unique opportunity to explore the sources of low-energy particle acceleration. As part of the Parker Solar Probe (PSP) Integrated Science Investigation of the Sun (IS⊙IS) suite, EPI-Lo was designed to investigate the physics of energetic particles; however, in the special lowest-energy "time-of-flight only" product used in this study, it also responds to solar photons in a subset of approximately sunward-looking apertures lacking special light-attenuating foils. During the first three perihelia, in a frame rotating with the Sun, PSP undergoes retrograde motion, covering a 17° heliographic longitudinal range three times during the course of the ~11-day perihelion passes, permitting a unique spatial and temporal study into the location, correlation, and persistence of previously unmeasurable SEPs. We examine the signatures of these SEPs (during the first PSP perihelion pass only) and the connection to possible solar sources using remote observations from the Solar Dynamics Observatory (SDO), the Solar TErrestrial RElations Observatory (STEREO), and the ground-based Global Oscillation Network Group (GONG). The orientation of the Sun relative to STEREO, SDO, and GONG makes such identifications challenging, but we do have several candidates, including an equatorial coronal hole at a Carrington longitude of ~335°. To analyze observations from EPI-Lo, which is a new type of particle instrument, we examine instrumental effects and provide a preliminary separation of the ion signal from the photon background

Isospin Breaking and ω\omega->ππ\pi\pi Decay

We study $\omega\to\pi^+\pi^-$ decay up to including all orders of the chiral expansion and one-loop level of mesons in formlism of chiral constituent quark model. This G-parity forbidden decay is caused by $m_u\neq m_d$ and electromagnetic interaction of mesons. We illustrate that in the formlism both nonresonant contact interaction and $\rho$ resonance exchange contribute to this process, and the contribution from $\rho$ resonance exchange is dominant. We obtain that transition matrix element is $=[-(3956\pm 280)-(1697\pm 130)i]$MeV$^2$, and isospin breaking parameter is $m_d-m_u=3.9\pm 0.22$MeV at energy scale $\mu\sim m_\omega$.Comment: Revtex file, 16 pages, four eps figur