A Physical Background Model for the Fermi Gamma-ray Burst Monitor

We present the first physically motivated background model for the Gamma-Ray Burst Monitor (GBM) onboard the Fermi satellite. Such a physically motivated background model has the potential to significantly improve the scientific output of Fermi/GBM, as it can be used to improve the background estimate for spectral analysis and localization of Gamma-Ray Bursts (GRBs) and other sources. Additionally, it can also lead to detections of new transient events, since long/weak or slowly rising ones do not activate one of the existing trigger algorithms. In this paper we show the derivation of such a physically motivated background model, which includes the modeling of the different background sources and the correct handling of the response of GBM. While the goal of the paper is to introduce the model rather than developing a transient search algorithm, we demonstrate the ability of the model to fit the background seen by GBM by showing four applications, namely (1) for a canonical GRB, (2) for the ultra-long GRB 091024, (3) for the V404 Cygni outburst in June 2015, and (4) the ultra-long GRB 130925A.Comment: Accepted for publication in A&A, 15 pages, 22 figure

Cytokine profiles of umbilical cord blood mononuclear cells upon in vitro stimulation with lipopolysaccharides of different vaginal gram-negative bacteria

Inflammatory immune responses induced by lipopolysaccharides (LPS) of gram-negative bacteria play an important role in the pathogenesis of preterm labor and delivery, and in neonatal disorders. To better characterize LPS-induced inflammatory response, we determined the cytokine profile of umbilical cord blood mononuclear cells (UBMC) stimulated with LPS of seven vaginal gram-negative bacteria commonly found in pregnant women with preterm labor and preterm rupture of membrane. UBMC from ten newborns of healthy volunteer mothers were stimulated with purified LPS of Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae, Proteus mirabilis, Acinetobacter calcoaceticus, Citrobacter freundii, and Pseudomonas aeruginosa. UBMC supernatants were tested for the presence of secreted pro-inflammatory cytokines (IL-6, IL-1β, TNF), anti-inflammatory cytokine (IL-10), TH1-type cytokines (IL-12, IFN-γ), and chemokines (IL-8, MIP-1α, MIP-1β, MCP-1) by Luminex technology. The ten cytokines were differentially induced by the LPS variants. LPS of E. coli and E. aerogenes showed the strongest stimulatory activity and P. aeruginosa the lowest. Interestingly, the ability of UBMC to respond to LPS varied greatly among donors, suggesting a strong individual heterogeneity in LPS-triggered inflammatory response

A Polymorphism of Bactericidal/Permeability-Increasing Protein Affects Its Neutralization Efficiency towards Lipopolysaccharide

Gram-negative sepsis driven by lipopolysaccharide (LPS) has detrimental outcomes, especially in neonates. The neutrophil-derived bactericidal/permeability-increasing protein (BPI) potently neutralizes LPS. Interestingly, polymorphism of the BPI gene at position 645 (rs4358188) corresponds to a favorable survival rate of these patients in the presence of at least one allele 645 A as opposed to 645 G. When we exploited the existing X-ray crystal structure, the corresponding amino acid at position 216 was revealed as surface exposed and proximal to the lipid-binding pocket in the N-terminal domain of BPI. Our further analysis predicted a shift in surface electrostatics by a positively charged lysine (BPI216K) exchanging a negatively charged glutamic acid (BPI216E). To investigate differences in interaction with LPS, we expressed both BPI variants recombinantly. The amino acid exchange neither affected affinity towards LPS nor altered bactericidal activity. However, when stimulating human peripheral blood mononuclear cells, BPI216K exhibited a superior LPS-neutralizing capacity (IC50 12.0 ± 2.5 pM) as compared to BPI216E (IC50 152.9 ± 113.4 pM, p = 0.0081) in respect to IL-6 secretion. In conclusion, we provide a functional correlate to a favorable outcome of sepsis in the presence of BPI216K

Bactericidal/Permeability-Increasing Protein Is an Enhancer of Bacterial Lipoprotein Recognition

Adequate perception of immunologically important pathogen-associated molecular patterns like lipopolysaccharide and bacterial lipoproteins is essential for efficient innate and adaptive immune responses. In the context of Gram-negative infection, bactericidal/permeability-increasing protein (BPI) neutralizes endotoxic activity of lipopolysaccharides, and thus prohibits hyperactivation. So far, no immunological function of BPI has been described in Gram-positive infections. Here, we show a significant elevation of BPI in Gram-positive meningitis and, surprisingly, a positive correlation between BPI and pro-inflammatory markers like TNF alpha. To clarify the underlying mechanisms, we identify BPI ligands of Gram-positive origin, specifically bacterial lipopeptides and lipoteichoic acids, and determine essential structural motifs for this interaction. Importantly, the interaction of BPI with these newly defined ligands significantly enhances the immune response in peripheral blood mononuclear cells (PBMCs) mediated by Gram-positive bacteria, and thereby ensures their sensitive perception. In conclusion, we define BPI as an immune enhancing pattern recognition molecule in Gram-positive infections

Scorpionfish BPI is highly active against multiple drug-resistant Pseudomonas aeruginosa isolates from people with cystic fibrosis

Chronic pulmonary infection is a hallmark of cystic fibrosis (CF) and requires continuous antibiotic treatment. In this context, Pseudomonas aeruginosa (Pa) is of special concern since colonizing strains frequently acquire multiple drug resistance (MDR). Bactericidal/permeability-increasing protein (BPI) is a neutrophil-derived, endogenous protein with high bactericidal potency against Gram-negative bacteria. However, a significant range of people with CF (PwCF) produce anti-neutrophil cytoplasmic antibodies against BPI (BPI-ANCA), thereby neutralizing its bactericidal function. In accordance with literature, we describe that 51.0% of a total of 39 PwCF expressed BPI-ANCA. Importantly, an orthologous protein to human BPI (huBPI) derived from the scorpionfish Sebastes schlegelii (scoBPI) completely escaped recognition by these autoantibodies. Moreover, scoBPI exhibited high anti-inflammatory potency towards Pa LPS and was bactericidal against MDR Pa derived from PwCF at nanomolar concentrations. In conclusion, our results highlight the potential of highly active orthologous proteins of huBPI in treatment of MDR Pa infections, especially in the presence of BPI-ANCA

Bactericidal/permeability-increasing protein instructs dendritic cells to elicit Th22 cell response

Neutrophil-derived bactericidal/permeability-increasing protein (BPI) is known for its bactericidal activity against gram-negative bacteria and neutralization of lipopolysaccharide. Here, we define BPI as a potent activator of murine dendritic cells (DCs). As shown in GM-CSF-cultured, bone-marrow-derived cells (BMDCs), BPI induces a distinct stimulation profile including IL-2, IL-6, and tumor necrosis factor expression. Conventional DCs also respond to BPI, while M-CSF-cultivated or peritoneal lavage macrophages do not. Subsequent to BPI stimulation of BMDCs, CD4+ T cells predominantly secrete IL-22 and, when naive, preferentially differentiate into T helper 22 (Th22) cells. Congruent with the tissue-protective properties of IL-22 and along with impaired IL-22 induction, disease severity is significantly increased during dextran sodium sulfate-induced colitis in BPI-deficient mice. Importantly, physiological diversification of intestinal microbiota fosters BPI-dependent IL-22 induction in CD4+ T cells derived from mesenteric lymph nodes. In conclusion, BPI is a potent activator of DCs and consecutive Th22 cell differentiation with substantial relevance in intestinal homeostasis

High Na+ Environments Impair Phagocyte Oxidase-Dependent Antibacterial Activity of Neutrophils

Infection and inflammation can augment local Na+ abundance. These increases in local Na+ levels boost proinflammatory and antimicrobial macrophage activity and can favor polarization of T cells towards a proinflammatory Th17 phenotype. Although neutrophils play an important role in fighting intruding invaders, the impact of increased Na+ on the antimicrobial activity of neutrophils remains elusive. Here we show that, in neutrophils, increases in Na+ (high salt, HS) impair the ability of human and murine neutrophils to eliminate Escherichia coli and Staphylococcus aureus. High salt caused reduced spontaneous movement, degranulation and impaired production of reactive oxygen species (ROS) while leaving neutrophil viability unchanged. High salt enhanced the activity of the p38 mitogen-activated protein kinase (p38/MAPK) and increased the interleukin (IL)-8 release in a p38/MAPK-dependent manner. Whereas inhibition of p38/MAPK did not result in improved neutrophil defense, pharmacological blockade of the phagocyte oxidase (PHOX) or its genetic ablation mimicked the impaired antimicrobial activity detected under high salt conditions. Stimulation of neutrophils with phorbol-12-myristate-13-acetate (PMA) overcame high salt-induced impairment in ROS production and restored antimicrobial activity of neutrophils. Hence, we conclude that high salt-impaired PHOX activity results in diminished antimicrobial activity. Our findings suggest that increases in local Na+ represent an ionic checkpoint that prevents excessive ROS production of neutrophils, which decreases their antimicrobial potential and could potentially curtail ROS-mediated tissue damage

The 999th Swift gamma-ray burst: Some like it thermal: A multiwavelength study of GRB 151027A

We present a multiwavelength study of GRB 151027A. This is the 999th GRB detected by the Swift satellite and it has a densely sampled emission in the X-ray and optical band and has been observed and detected in the radio up to 140 days after the prompt. The multiwavelength light curve from 500 s to 140 days can be modelled through a standard forward shock afterglow but requires an additional component to reproduce the early X-ray and optical emission. We present TNG and LBT optical observations performed 19.6, 33.9 and 92.3 days after the trigger which show a bump with respect to a standard afterglow flux decay and are possibly interpreted as due to the underlying SN and host galaxy (of 0.4 uJy in the R band). Radio observations, performed with SRT, Medicina, EVN and VLBA between day 4 and 140, suggest that the burst exploded in an environment characterised by a density profile scaling with the distance from the source (wind profile). A remarkable feature of the prompt emission is the presence of a bright flare 100 s after the trigger, lasting 70 seconds in the soft X-ray band, which was simultaneously detected from the optical band up to the MeV energy range. By combining Swift-BAT/XRT and Fermi-GBM data, the broadband (0.3-1000 keV) time resolved spectral analysis of the flare reveals the coexistence of a non-thermal (power law) and thermal blackbody components. The BB component contributes up to 35% of the luminosity in the 0.3-1000 keV band. The gamma-ray emission observed in Swift-BAT and Fermi-GBM anticipates and lasts less than the soft X-ray emission as observed by Swift-XRT, arguing against a Comptonization origin. The BB component could either be produced by an outflow becoming transparent or by the collision of a fast shell with a slow, heavy and optically thick fireball ejected during the quiescent time interval between the initial and later flares of the burst

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands