Integrin α2β1 Expression Regulates Matrix Metalloproteinase-1-Dependent Bronchial Epithelial Repair in Pulmonary Tuberculosis.

Pulmonary tuberculosis (TB) is caused by inhalation of Mycobacterium tuberculosis, which damages the bronchial epithelial barrier to establish local infection. Matrix metalloproteinase-1 plays a crucial role in the immunopathology of TB, causing breakdown of type I collagen and cavitation, but this collagenase is also potentially involved in bronchial epithelial repair. We hypothesized that the extracellular matrix (ECM) modulates M. tuberculosis-driven matrix metalloproteinase-1 expression by human bronchial epithelial cells (HBECs), regulating respiratory epithelial cell migration and repair. Medium from monocytes stimulated with M. tuberculosis induced collagenase activity in bronchial epithelial cells, which was reduced by ~87% when cells were cultured on a type I collagen matrix. Matrix metalloproteinase-1 had a focal localization, which is consistent with cell migration, and overall secretion decreased by 32% on type I collagen. There were no associated changes in the specific tissue inhibitors of metalloproteinases. Decreased matrix metalloproteinase-1 secretion was due to ligand-binding to the α2β1 integrin and was dependent on the actin cytoskeleton. In lung biopsies, samples from patients with pulmonary TB, integrin α2β1 is highly expressed on the bronchial epithelium. Areas of lung with disrupted collagen matrix showed an increase in matrix metalloproteinases-1 expression compared with areas where collagen was comparable to control lung. Type I collagen matrix increased respiratory epithelial cell migration in a wound-healing assay, and this too was matrix metalloproteinase-dependent, since it was blocked by the matrix metalloproteinase inhibitor GM6001. In summary, we report a novel mechanism by which α2β1-mediated signals from the ECM modulate matrix metalloproteinase-1 secretion by HBECs, regulating their migration and epithelial repair in TB

Battling on the Home Front: Posttraumatic Stress Disorder and Conflict Behavior Among Military Couples

This study evaluated interpersonal behavior differences among male military service members with and without PTSD and their female partners. Couples (N = 64) completed a 17-minute videotaped conflict discussion, and their interaction behavior was coded using the circumplex-based Structural Analysis of Social Behavior model (SASB; Benjamin, 1979, 1987, 2000). Within couples, the behavior of partners was very similar. Compared to military couples without PTSD, couples with PTSD displayed more interpersonal hostility and control. Couples with PTSD also exhibited more sulking, blaming, and controlling behavior, and less affirming and connecting behavior, than couples without PTSD. Results advance our understanding of the relational impacts of PTSD on military service members and their partners, and underscore the value of couple-based interventions for PTSD in the context of relationship distress

Chiral Spin Textures of Strongly Interacting Particles in Quantum Dots

We probe for statistical and Coulomb induced spin textures among the low-lying states of repulsively-interacting particles confined to potentials that are both rotationally and time-reversal invariant. In particular, we focus on two-dimensional quantum dots and employ configuration-interaction techniques to directly compute the correlated many-body eigenstates of the system. We produce spatial maps of the single-particle charge and spin density and verify the annular structure of the charge density and the rotational invariance of the spin field. We further compute two-point spin correlations to determine the correlated structure of a single component of the spin vector field. In addition, we compute three-point spin correlation functions to uncover chiral structures. We present evidence for both chiral and quasi-topological spin textures within energetically degenerate subspaces in the three- and four-particle system.Comment: 13 pages, 17 figures, 1 tabl

Effect of Preventive Home Visits by a Nurse on the Outcomes of Frail Elderly People in the Community: a randomized controlled trial

Background: Timely recognition and prevention of health problems among elderly people have been shown to improve their health. In this randomized controlled trial the authors examined the impact of preventive home visits by a nurse compared with usual care on the outcomes of frail elderly people living in the community. Methods: A screening questionnaire identified eligible participants (those aged 70 years or more at risk of sudden deterioration in health). Those randomly assigned to the visiting nurse group were assessed and followed up in their homes for 14 months. The primary outcome measure was the combined rate of deaths and admissions to an institution, and the secondary outcome measure the rate of health services utilization, during the 14 months; these rates were determined through a medical chart audit by a research nurse who was blind to group allocation. Results: The questionnaire was mailed to 415 elderly people, of whom 369 (88.9%) responded. Of these, 198 (53.7%) were eligible, and 142 consented to participate and were randomly assigned to either the visiting nurse group (73) or the usual care group (69). The combined rate of deaths and admissions to an institution was 10.0% in the visiting nurse group and 5.8% in the usual care group (p = 0.52). The rate of health services utilization did not differ significantly between the 2 groups. Influenza and pneumonia vaccination rates were significantly higher in the visiting nurse group (90.1% and 81.9%) than in the usual care group (53.0% and 0%) (p \u3c 0.001). Interpretation: The trial failed to show any effect of a visiting nurse other than vastly improved vaccination coverage

A case study in successful management of a data-poor fishery using simple decision rules: the Queensland spanner crab fishery

The Queensland spanner crab Ranina ranina is the target of a relatively data-poor, low-value fishery that has been managed for the last decade by using total allowable catches (TACs) in an individual transferable quota system. Despite the fact that this management system is usually applied to data-rich fisheries, it has been successfully used on this data-poor fishery. The key factor has been the use of harvest strategies that consisted only of simple decision rules that were appropriate given the size of the fishery and knowledge of the resource. These strategies were tested in a management strategy evaluation framework; however, it was not traditional in that (1) the operating model (or “true” resource to be managed) was not conditioned to data but rather was set to parameter ranges seen as appropriate for the resource and (2) the TAC was not set by using a stock assessment model, so the magnitude of the stock biomass was unknown. The important test was whether one could develop harvest strategies that were robust to this large uncertainty in knowledge by using only commercial catch rates. The management system had to be adaptive over time as more was learned about the biology of the species and how the harvest strategies affected the management of the fishery. This meant that the TAC was almost always set using the harvest strategies, but modifications to the decision rules were made on several occasions as more was learned about the fishery. The transparency and simplicity of the rules mean that the industry was empowered to make significant contributions to fine tuning the harvest strategies. As a result, the process does not rely solely on scientific advances but on the pooled knowledge of scientists, industry, and managers in a cooperative environment

The impact of pneumolysin on the macrophage response to Streptococcus pneumoniae is strain-dependent

Streptococcus pneumoniae is the world's leading cause of pneumonia, bacteremia, meningitis and otitis media. A major pneumococcal virulence factor is the cholesterol-dependent cytolysin, which has the defining property of forming pores in cholesterol-containing membranes. In recent times a clinically significant and internationally successful serotype 1 ST306 clone has been found to express a non-cytolytic variant of Ply (Ply306). However, while the pneumococcus is a naturally transformable organism, strains of the ST306 clonal group have to date been virtually impossible to transform, severely restricting efforts to understand the role of non-cytolytic Ply in the success of this clone. In this study isogenic Ply mutants were constructed in the D39 background and for the first time in the ST306 background (A0229467) to enable direct comparisons between Ply variants for their impact on the immune response in a macrophage-like cell line. Strains that expressed cytolytic Ply were found to induce a significant increase in IL-1β release from macrophage-like cells compared to the non-cytolytic and Ply-deficient strains in a background-independent manner, confirming the requirement for pore formation in the Ply-dependent activation of the NLRP3 inflammasome. However, cytolytic activity in the D39 background was found to induce increased expression of the genes encoding GM-CSF (CSF2), p19 subunit of IL-23 (IL23A) and IFNβ (IFNB1) compared to non-cytolytic and Ply-deficient D39 mutants, but had no effect in the A0229467 background. The impact of Ply on the immune response to the pneumococcus is highly dependent on the strain background, thus emphasising the importance of the interaction between specific virulence factors and other components of the genetic background of this organism

Distances to the high galactic latitude molecular clouds G192-67 and MBM 23-24

We report on distance determinations for two high Galactic latitude cloud complexes, G192-67 and MBM 23-24. No distance determination exists in the literature for either cloud. Thirty-four early type stars were observed towards the two clouds, more than half of which have parallaxes measured by the Hipparcos satellite. For the remaining stars we have made spectroscopic distance estimates. The data consist of high resolution echelle spectra centered on the Na I D lines, and were obtained over six nights at the Coude Feed telescope at Kitt Peak National Observatory. Interstellar absorption lines were detected towards some of the stars, enabling estimates of the distances to the clouds of 109 +/- 14 pc for G192-67, and of 139 +/- 33 pc for MBM 23-24. We discuss the relationship of these clouds to other ISM features such as the Local Hot Bubble and the local cavity in neutral hydrogen.Comment: 15 pages, 6 embedded figures, to be published in the ApJ Vol. 516, No.

Giardia Cyst Wall Protein 1 Is a Lectin That Binds to Curled Fibrils of the GalNAc Homopolymer

The infectious and diagnostic stage of Giardia lamblia (also known as G. intestinalis or G. duodenalis) is the cyst. The Giardia cyst wall contains fibrils of a unique β-1,3-linked N-acetylgalactosamine (GalNAc) homopolymer and at least three cyst wall proteins (CWPs) composed of Leu-rich repeats (CWPLRR) and a C-terminal conserved Cys-rich region (CWPCRR). Our goals were to dissect the structure of the cyst wall and determine how it is disrupted during excystation. The intact Giardia cyst wall is thin (~400 nm), easily fractured by sonication, and impermeable to small molecules. Curled fibrils of the GalNAc homopolymer are restricted to a narrow plane and are coated with linear arrays of oval-shaped protein complex. In contrast, cyst walls of Giardia treated with hot alkali to deproteinate fibrils of the GalNAc homopolymer are thick (~1.2 µm), resistant to sonication, and permeable. The deproteinated GalNAc homopolymer, which forms a loose lattice of curled fibrils, is bound by native CWP1 and CWP2, as well as by maltose-binding protein (MBP)-fusions containing the full-length CWP1 or CWP1LRR. In contrast, neither MBP alone nor MBP fused to CWP1CRR bind to the GalNAc homopolymer. Recombinant CWP1 binds to the GalNAc homopolymer within secretory vesicles of Giardia encysting in vitro. Fibrils of the GalNAc homopolymer are exposed during excystation or by treatment of heat-killed cysts with chymotrypsin, while deproteinated fibrils of the GalNAc homopolymer are degraded by extracts of Giardia cysts but not trophozoites. These results show the Leu-rich repeat domain of CWP1 is a lectin that binds to curled fibrils of the GalNAc homopolymer. During excystation, host and Giardia proteases appear to degrade bound CWPs, exposing fibrils of the GalNAc homopolymer that are digested by a stage-specific glycohydrolase. Author SummaryWhile the walls of plants and fungi contain numerous sugar homopolymers (cellulose, chitin, and β-1,3-glucans) and dozens of proteins, the cyst wall of Giardia is relatively simple. The Giardia wall contains a unique homopolymer of β-1,3-linked N-acetylgalactosamine (GalNAc) and at least three cyst wall proteins (CWPs), each of which is composed of Leu-rich repeats and a C-terminal Cys-rich region. The three major discoveries here are: 1) Fibrils of the GalNAc homopolymer are curled and form a lattice that is compressed into a narrow plane by bound protein in intact cyst walls. 2) Leu-rich repeats of CWP1 form a novel lectin domain that is specific for fibrils of the GalNAc homopolymer, which can be isolated by methods used to deproteinate fungal walls. 3) A cyst-specific glycohydrolase is able to degrade deproteinated fibrils of the GalNAc homopolymer. We incorporate these findings into a new curled fiber and lectin model of the intact Giardia cyst wall and a protease and glycohydrolase model of excystation.National Institutes of Health (AI048082, AI44070, GM31318, RR1088

Isolation site influences virulence phenotype of serotype 14 Streptococcus pneumoniae strains belonging to multilocus sequence type 15

Streptococcus pneumoniae is a diverse species causing invasive as well as localized infections that result in massive global morbidity and mortality. Strains vary markedly in pathogenic potential, but the molecular basis is obscured by the diversity and plasticity of the pneumococcal genome. We have previously reported that S. pneumoniae serotype 3 isolates belonging to the same multilocus sequence type (MLST) differed markedly in in vitro and in vivo phenotypes, in accordance with the clinical site of isolation, suggesting stable niche adaptation within a clonal lineage. In the present study, we have extended our analysis to serotype 14 clinical isolates from cases of sepsis or otitis media that belong to the same MLST (ST15). In a murine intranasal challenge model, five ST15 isolates (three from blood and two from ears) colonized the nasopharynx to similar extents. However, blood and ear isolates exhibited significant differences in bacterial loads in other host niches (lungs, ear, and brain) at both 24 and 72 h postchallenge. In spite of these differences, blood and ear isolates were present in the lungs at similar levels at 6 h postchallenge, suggesting that early immune responses may underpin the distinct virulence phenotypes. Transcriptional analysis of lung tissue from mice infected for 6 h with blood isolates versus ear isolates revealed 8 differentially expressed genes. Two of these were exclusively expressed in response to infection with the ear isolate. These results suggest a link between the differential capacities to elicit early innate immune responses and the distinct virulence phenotypes of clonally related S. pneumoniae strains