Interference of the T cell and antigen-presenting cell costimulatory pathway using CTLA4-Ig (abatacept) prevents Staphylococcal enterotoxin B pathology

Abstract Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that binds the receptors in the APC/T cell synapse and causes increased proliferation of T cells and a cytokine storm syndrome in vivo. Exposure to the toxin can be lethal and cause significant pathology in humans. The lack of effective therapies for SEB exposure remains an area of concern, particularly in scenarios of acute mass casualties. We hypothesized that blockade of the T cell costimulatory signal by the CTLA4-Ig synthetic protein (abatacept) could prevent SEB-dependent pathology. In this article, we demonstrate mice treated with a single dose of abatacept 8 h post SEB exposure had reduced pathology compared with control SEB-exposed mice. SEB-exposed mice showed significant reductions in body weight between days 4 and 9, whereas mice exposed to SEB and also treated with abatacept showed no weight loss for the duration of the study, suggesting therapeutic mitigation of SEB-induced morbidity. Histopathology and magnetic resonance imaging demonstrated that SEB mediated lung damage and edema, which were absent after treatment with abatacept. Analysis of plasma and lung tissues from SEB-exposed mice treated with abatacept demonstrated significantly lower levels of IL-6 and IFN-γ (p &amp;lt; 0.0001), which is likely to have resulted in less pathology. In addition, exposure of human and mouse PBMCs to SEB in vitro showed a significant reduction in levels of IL-2 (p &amp;lt; 0.0001) after treatment with abatacept, indicating that T cell proliferation is the main target for intervention. Our findings demonstrate that abatacept is a robust and potentially credible drug to prevent toxic effects from SEB exposure.</jats:p

Sensitive response of the Greenland Ice Sheet to surface melt drainage over a soft bed

This is the accepted manuscript. The final version is available from Nature Communications at http://www.nature.com/ncomms/2014/140929/ncomms6052/full/ncomms6052.html.The dynamic response of the Greenland Ice Sheet (GrIS) depends on feedbacks between surface meltwater delivery to the subglacial environment and ice flow. Recent work has highlighted an important role of hydrological processes in regulating the ice flow, but models have so far overlooked the mechanical effect of soft basal sediment. Here we use a three-dimensional model to investigate hydrological controls on a GrIS soft-bedded region. Our results demonstrate that weakening and strengthening of subglacial sediment, associated with the seasonal delivery of surface meltwater to the bed, modulates ice flow consistent with observations. We propose that sedimentary control on ice flow is a viable alternative to existing models of evolving hydrological systems, and find a strong link between the annual flow stability, and the frequency of high meltwater discharge events. Consequently, the observed GrIS resilience to enhanced melt could be compromised if runoff variability increases further with future climate warming.RCU

Thin-layer effects in glaciological seismic amplitude-versus-angle (AVA) analysis: implications for characterising a subglacial till unit, Russell Glacier, West Greenland

Seismic amplitude-versus-angle (AVA) methods are a powerful means of quantifying the physical properties of subglacial material, but serious interpretative errors can arise when AVA is measured over a thinly-layered substrate. A substrate layer with a thickness less than 1/4 of the seismic wavelength, λ, is considered "thin", and reflections from its bounding interfaces superpose and appear in seismic data as a single reflection event. AVA interpretation of subglacial till can be vulnerable to such thin-layer effects, since a lodged (non-deforming) till can be overlain by a thin (metre-scale) cap of dilatant (deforming) till. We assess the potential for misinterpretation by simulating seismic data for a stratified subglacial till unit, with an upper dilatant layer between 0.1–5.0 m thick (λ / 120 to &gt; λ / 4, with &amp;lambda; = 12 m). For dilatant layers less than &amp;lambda; / 6 thick, conventional AVA analysis yields acoustic impedance and Poisson's ratio that indicate contradictory water saturation. A thin-layer interpretation strategy is proposed, that accurately characterises the model properties of the till unit. The method is applied to example seismic AVA data from Russell Glacier, West Greenland, in which characteristics of thin-layer responses are evident. A subglacial till deposit is interpreted, having lodged till (acoustic impedance = 4.26&amp;plusmn;0.59 &amp;times; 10&lt;sup&gt;6&lt;/sup&gt; kg m&lt;sup&gt;−2&lt;/sup&gt; s&lt;sup&gt;&amp;minus;1&lt;/sup&gt;) underlying a water-saturated dilatant till layer (thickness &lt; 2 m, Poisson's ratio ~ 0.5). Since thin-layer considerations offer a greater degree of complexity in an AVA interpretation, and potentially avoid misinterpretations, they are a valuable aspect of quantitative seismic analysis, particularly for characterising till units

Anti-myeloma efficacy of CAR-iNKT is enhanced with a long-acting IL-7, rhIL-7-hyFc

Multiple myeloma (MM), a malignancy of mature plasma cells, remains incurable. B-cell maturation antigen (BCMA) is the lead protein target for chimeric antigen receptor (CAR) therapy because of its high expression in most MM, with limited expression in other cell types, resulting in favorable on-target, off tumor toxicity. The response rate to autologous BCMA CAR-T therapy is high; however, it is not curative and is associated with risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Outcomes in patients treated with BCMA CAR-T cells (CAR-Ts) may improve with allogeneic CAR T-cell therapy, which offer higher cell fitness and reduced time to treatment. However, to prevent the risk of graft-versus-host disease (GVHD), allogenic BCMA CAR-Ts require genetic deletion of the T-cell receptor (TCR), which has potential for unexpected functional or phenotype changes. Invariant natural killer T cells (iNKTs) have an invariant TCR that does not cause GVHD and, as a result, can be used in an allogeneic setting without the need for TCR gene editing. We demonstrate significant anti-myeloma activity of BCMA CAR-iNKTs in a xenograft mouse model of myeloma. We found that a long-acting interleukin-7 (IL-7), rhIL-7-hyFc, significantly prolonged survival and reduced tumor burden in BCMA CAR-iNKT-treated mice in both primary and re-challenge settings. Furthermore, in CRS in vitro assays, CAR-iNKTs induced less IL-6 than CAR-Ts, suggesting a reduced likelihood of CAR-iNKT therapy to induce CRS in patients. These data suggest that BCMA CAR-iNKTs are potentially a safer, effective alternative to BCMA CAR-Ts and that BCMA CAR-iNKT efficacy is further potentiated with rhIL-7-hyFc

Metabolic profiles of socio-economic position: a multi-cohort analysis

Background: Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear.Methods: We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in ∼30 000 adults and 4000 children across 10 UK and Finnish cohort studies.Results: In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents) and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids.Conclusions: Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities.Keywords: Socio-economic status; education; life course; lipoproteins; metabolomics; metabonomic; occupation.</p

An evaluation of the efficacy and safety of probiotic lactic acid bacteria

This project was undertaken as part of a commercial evaluation of two probiotic strains for subsequent use in the European market. Probiotic bacteria are thought to act as competitive exclusion agents against food home pathogens by several mechanisms. The aim of the study was to characterise the probiotic strains Lactobacillus salivarius 59 and Enterococcus faecium PXN-33, determine the safety of the probiotic strains and to evaluate the strains ability to competitively exclude Salmonella Enteritidis.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

An Evaluation of the Efficacy and Safety of Probiotic Lactic Acid Bacteria.

This project was undertaken as part of a commercial evaluation of two probiotic strains for subsequent use in the European market. Probiotic bacteria are thought to act as competitive exclusion agents against food borne pathogens by several mechanisms. The aim of the study was to characterise the probiotic strains Lactobacillus salivarius 59 and Enterococcus faecium PXN-33, determine the safety of the probiotic strains and to evaluate the strains ability to competitively exclude Salmonella Enteritidis. Analysis of the two novel probiotic strains in vitro confirmed their identity by biochemical and genetic analyses and demonstrated that neither probiotic strains possessed virulence or antibiotic resistance genes. When inoculated into specific pathogen free (SPF) White Leghorn Chicks to test for host tolerance, histological analysis of the gastro intestinal mucosa indicated that L. salivarius 59 and E. faecium PXN-33 were not detrimental towards the host. Inhibition of Salmonella Enteritidis by the probiotic strains was evaluated in vitro using cell free culture supernatant (CFCS) assays and plate diffusion assays. Inhibition was observed in both assays. Priming of macrophages with Enterococcus faecium and subsequent challenge with Salmonella Enteritidis increased TNF-a and IL-6 pro-inflammatory cytokines suggesting Salmonella inhibition was facilitated by immuno-modulation. Following in vitro analysis two in vivo trials were conducted. The first trial involved dosing of SPF chicks by oral gavage with the competitive exclusion (CE) product as individual or dual preparations followed by subsequent inoculation of the birds with Salmonella Enteritidis. A statistically significant reduction of Salmonella Enteritidis as determined by direct microbiological enumeration of samples from GI tissues and cloacal swabs was observed at day 43 in the dual treatment group compared to the control group. In a second study, SPF chicks were dosed with the probiotic preparation using four distinct dosing regimes and challenged by in contact sentinel birds dosed with S. Enteritidis. Significant reductions in Salmonella colonisation were observed in the chicken’s GI tract as compared to control groups