Development of primary invasive pneumococcal disease caused by serotype 1 pneumococci is driven by early increased type I interferon response in the lung

The pneumococcus is the world's foremost respiratory pathogen, but the mechanisms allowing this pathogen to proceed from initial asymptomatic colonization to invasive disease are poorly understood. We have examined the early stages of invasive pneumococcal disease (IPD) by comparing host transcriptional responses to an invasive strain and a noninvasive strain of serotype 1 Streptococcus pneumoniae in the mouse lung. While the two strains were present in equal numbers in the lung 6 h after intranasal challenge, only the invasive strain (strain 1861) had invaded the pleural cavity at that time point; this correlated with subsequent development of bacteremia in mice challenged with strain 1861 but not the noninvasive strain (strain 1). Progression beyond the lung was associated with stronger induction of the type I interferon (IFN-I) response in the lung at 6 h. Suppression of the IFN-I response through administration of neutralizing antibody to IFNAR1 (the receptor for type I interferons) led to significantly reduced invasion of the pleural cavity by strain 1861 at 6 h postchallenge. Our data suggest that strong induction of the IFN-I response is a key factor in early progression of invasive serotype 1 strain 1861 beyond the lung during development of IPD

Acoustic Performance of the GEAE UPS Research Fan in the NASA Glenn 9- by 15-Foot Low-Speed Wind Tunnel

A model advanced turbofan was acoustically tested in the NASA Glenn 9- by 15-Foot Low-Speed Wind Tunnel in 1994. The Universal Propulsion Simulator fan was designed and manufactured by General Electric Aircraft Engines, and included an active core, as well as bypass, flow paths. The fan was tested with several rotors featuring unswept, forward-swept and aft-swept designs of both metal and composite construction. Sideline acoustic data were taken with both hard and acoustically treated walls in the flow passages. The fan was tested within an airflow at a Mach number of 0.20, which is representative of aircraft takeoff/approach conditions. All rotors showed similar aerodynamic performance. However, the composite rotors typically showed higher noise levels than did corresponding metal rotors. Aft and forward rotor sweep showed at most modest reductions of transonic multiple pure tone levels. However, rotor sweep often introduced increased rotor-stator interaction tone levels. Broadband noise was typically higher for the composite rotors and also for the aft-swept metal rotor. Transonic MPT generation was reduced with increasing fan axis angle of attack (AOA); however, higher downstream noise levels did increase with AOA resulting in higher overall Effective Perceived Noise Level

Power of the Press: Studies of the Gospel Advocate, The Christian Standard, and the Christian-Evangelist

Based on the 1986 Reed Lectures, Power of the Press illustrates the important role that the Gospel Advocate, the Christian Standard, and the Christian-Evangelist played in shaping the identity of all three streams of the Stone-Campbell Movement in the nineteenth and early twentieth century. The essays also offer explanations as to why publishing offered such remarkable influence in this period.https://digitalcommons.acu.edu/acu_library_books/1020/thumbnail.jp

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

Dirac's Footsteps and Supersymmetry

One hundred years after its creator's birth, the Dirac equation stands as the cornerstone of XXth Century physics. But it is much more, as it carries the seeds of supersymmetry. Dirac also invented the light-cone, or "front form" dynamics, which plays a crucial role in string theory and in elucidating the finiteness of N=4 Yang-Mills theory. The light-cone structure of eleven-dimensional supergravity (N=8 supergravity in four dimensions) suggests a group-theoretical interpretation of its divergences. We speculate they could be compensated by an infinite number of triplets of massless higher spin fields, each obeying a Dirac-like equation associated with the coset $F_4/SO(9)$. The divergences are proportional to the trace over a non-compact structure containing the compact form of $F_4$. Its nature is still unknown, but it could show the way to $M$-theory.Comment: Invited Talk at Dirac's Centennial Symposium, Tallahasse, Florida, Dec 200

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

Overlapping functionality of the Pht proteins in zinc homeostasis of streptococcus pneumoniae

Streptococcus pneumoniae is a globally significant pathogen that causes a range of diseases, including pneumonia, sepsis, meningitis, and otitis media. Its ability to cause disease depends upon the acquisition of nutrients from its environment, including transition metal ions such as zinc. The pneumococcus employs a number of surface proteins to achieve this, among which are four highly similar polyhistidine triad (Pht) proteins. It has previously been established that these proteins collectively aid in the delivery of zinc to the ABC transporter substrate-binding protein AdcAII. Here we have investigated the contribution of each individual Pht protein to pneumococcal zinc homeostasis by analyzing mutant strains expressing only one of the four pht genes. Under conditions of low zinc availability, each of these mutants showed superior growth and zinc accumulation profiles relative to a mutant strain lacking all four genes, indicating that any of the four Pht proteins are able to facilitate delivery of zinc to AdcAII. However, optimal growth and zinc accumulation in vitro and pneumococcal survival and proliferation in vivo required production of all four Pht proteins, indicating that, despite their overlapping functionality, the proteins are not dispensable without incurring a fitness cost. We also show that surface-attached forms of the Pht proteins are required for zinc recruitment and that they do not contribute to defense against extracellular zinc stress