The role of myeloid receptors on murine plasmacytoid dendritic cells in induction of type I interferon

This study tested the hypothesis that a set of predominantly myeloid restricted receptors (F4/80, CD36, Dectin-1, CD200 receptor and mannan binding lectins) and the broadly expressed CD200 played a role in a key function of plasmacytoid DC (pDC), virally induced type I interferon (IFN) production. The Dectin-1 ligands zymosan, glucan phosphate and the anti-Dectin-1 monoclonal antibody (mAb) 2A11 had no effect on influenza virus induced IFNα/β production by murine splenic pDC. However, mannan, a broad blocking reagent against mannose specific receptors, inhibited IFNα/β production by pDC in response to inactivated influenza virus. Moreover, viral glycoproteins (influenza virus haemagglutinin and HIV-1 gp120) stimulated IFNα/β production by splenocytes in a mannan-inhibitable manner, implicating the function of a lectin in glycoprotein induced IFN production. Lastly, the effect of CD200 on IFN induction was investigated. CD200 knock-out macrophages produced more IFNα than wild-type macrophages in response to polyI:C, a MyD88-independent stimulus, consistent with CD200's known inhibitory effect on myeloid cells. In contrast, blocking CD200 with an anti-CD200 mAb resulted in reduced IFNα production by pDC-containing splenocytes in response to CpG and influenza virus (MyD88-dependent stimuli). This suggests there could be a differential effect of CD200 on MyD88 dependent and independent IFN induction pathways in pDC and macrophages. This study supports the hypothesis that a mannan-inhibitable lectin and CD200 are involved in virally induced type I IFN induction.

Changing standards revisited: children’s awareness and knowledge of features of written standard English at ages 10-11

This paper reports the findings of a small-scale research project which investigated the levels of awareness and knowledge of written standard English of 10 and 11 year old children in two English primary schools. The project involved repeating in 2010 a written questionnaire previously used with children in the same schools in three separate surveys in 1999, 2002 and 2005. Data from the latest survey are compared to those from the previous three. The analysis seeks to identify any changes over time in children’s ability to recognise non-standard forms and supply standard English alternatives, as well as their ability to use technical terms related to language variation. Differences between the performance of boys and girls and that of the two schools are also analysed. The paper concludes that the socio-economic context of the schools may be a more important factor than gender in variations over time identified in the data.

Features for detection of Parkinson's disease tremor from local field potentials of the subthalamic nucleus

Deep Brain Stimulation (DBS) is a treatment routinely used to alleviate the symptoms of Parkinson's disease (PD). In this type of treatment, electrical pulses are applied through electrodes implanted into the basal ganglia of the patient. As the symptoms are not permanent in most patients, it is desirable to develop an on-demand stimulator, applying pulses only when onset of the symptoms is detected. This study evaluates a feature set created for the detection of tremor - a cardinal symptom of PD. The designed feature set was based on standard signal features and researched properties of the electrical signals recorded from subthalamic nucleus (STN) within the basal ganglia, which together included temporal, spectral, statistical, autocorrelation and fractal properties. The most characterized tremor related features were selected using statistical testing and backward algorithms then used for classification on unseen patient signals. The spectral features were among the most efficient at detecting tremor, notably spectral bands 3.5-5.5 Hz and 0-1 Hz proved to be highly significant. The classification results for determination of tremor achieved 94% sensitivity with specificity equaling one.

Colloidal gas aphrons (CGA): dispersion and structural features

Colloidal gas aphrons (CGA) have previously been defined as surfactant stabilized gas microbubbles and characterized for a number of surfactants in terms of stability, gas holdup and bubble size even though there is no conclusive evidence of their structure (that is, orientation of surfactant molecules at the gas–liquid interface, thickness of gas–liquid interface, and/or number of surfactant layers). Knowledge of the structure would enable us to use these dispersions more efficiently for their diverse applications (such as for removal of dyes, recovery of proteins, and enhancement of mass transfer in bioreactors). This study investigates dispersion and structural features of CGA utilizing a range of novel predictive (for prediction of aphron size and drainage rate) and experimental (electron microscopy and X-ray diffraction) methods. Results indicate structural differences between foams and CGA, which may have been caused by a multilayer structure of the latter as suggested by the electron and X-ray diffraction analysis.

Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic micro-environment?

Objective: The objective of this study was to explore the relationship between low density lipoprotein (LDL) and dendritic cell (DC) activation, based upon the hypothesis that reactive oxygen species (ROS)-mediated modification of proteins that may be present in local DC microenvironments could be important as mediators of this activation. Although LDL are known to be oxidised in vivo, and taken up by macrophages during atherogenesis; their effect on DC has not been explored previously. Methods: Human DCs were prepared from peripheral blood monocytes using GM-CSF and IL-4. Plasma LDLs were isolated by sequential gradient centrifugation, oxidised in CuSO4, and oxidation arrested to yield mild, moderate and highly oxidised LDL forms. DCs exposed to these LDLs were investigated using combined phenotypic, functional (autologous T cell activation), morphological and viability assays. Results: Highly-oxidised LDL increased DC HLA-DR, CD40 and CD86 expression, corroborated by increased DC-induced T cell proliferation. Both native and oxidised LDL induced prominent DC clustering. However, high concentrations of highly-oxidised LDL inhibited DC function, due to increased DC apoptosis. Conclusions: This study supports the hypothesis that oxidised LDL are capable of triggering the transition from sentinel to messenger DC. Furthermore, the DC clustering–activation–apoptosis sequence in the presence of different LDL forms is consistent with a regulatory DC role in immunopathogenesis of atheroma. A sequence of initial accumulation of DC, increasing LDL oxidation, and DC-induced T cell activation, may explain why local breach of tolerance can occur. Above a threshold level, however, supervening DC apoptosis limits this, contributing instead to the central plaque core.

Participative modelling and big issues: defining features of system dynamics?

In this article the author discusses participative modelling in system dynamics and issues underlying it. It states that in the heart of system dynamics is the servo-mechanism theory. It argues that it is wrong to see an optimal solution being applied by the empowered parties just because it exhibits self-evident truth and an analysis is not enough to encourage people to do things in different way. It mentions other models including the simulation models used for developing strategy discussions.

What have dendritic cells ever done for adjuvant design? Cellular and molecular methods for the rational development of vaccine adjuvants

Our new molecular understanding of immune priming states that dendritic cell activation is absolutely pivotal for expansion and differentiation of naïve T lymphocytes, and it follows that understanding DC activation is essential to understand and design vaccine adjuvants. This chapter describes how dendritic cells can be used as a core tool to provide detailed quantitative and predictive immunomics information about how adjuvants function. The role of distinct antigen, costimulation, and differentiation signals from activated DC in priming is explained. Four categories of input signals which control DC activation – direct pathogen detection, sensing of injury or cell death, indirect activation via endogenous proinflammatory mediators, and feedback from activated T cells – are compared and contrasted. Practical methods for studying adjuvants using DC are summarised and the importance of DC subset choice, simulating T cell feedback, and use of knockout cells is highlighted. Finally, five case studies are examined that illustrate the benefit of DC activation analysis for understanding vaccine adjuvant function.

Ageing impairs the T cell response to dendritic cells

Dendritic cells (DCs) are critical in priming adaptive T-cell responses, but the effects of ageing on interactions between DCs and T cells are unclear. This study investigated the influence of ageing on the maturation of and cytokine production by human blood-enriched DCs, and the impact on T cell responses in an allogeneic mixed leucocyte reaction (MLR). DCs from old subjects (65-75y) produced significantly less TNF-α and IFN-γ than young subjects (20-30y) in response to lipopolysaccharide (LPS), but expression of maturation markers and co-stimulatory molecules was preserved. In the MLR, DCs from older subjects induced significantly restricted proliferation of young T cells, activation of CD8+ T cells and expression of IL-12 and IFN-γ in T cells compared with young DCs. T cells from older subjects responded more weakly to DC stimulation compared with young T cells, regardless of whether the DCs were derived from young or older subjects. In conclusion, the capacity of DCs to induce T cell activation is significantly impaired by ageing.

Dendritic cells interact with CD4 T cells in intestinal mucosa

Absence of lymph nodes in nonmammalian species, expression of MHCII by APCs in the periphery, and the recent findings that T cells can change their polarization status after presentation in the lymph nodes imply a role for MHCII-mediated presentation outside the organized lymphoid tissue. This study shows that MHCII+ ECs and DCs from the intestinal mucosa of the pig can present antigen to T cells in vitro. In vivo, APCs colocalize with T cells in pig and mouse intestinal mucosa. In the pig, endothelium is involved in these interactions in neonates but not in adults, indicating different roles for stromal and professional APCs in the neonate compared with the adult. The ratio of expression of DQ and DR MHCII locus products was lower on ECs than on other mucosal APCs, indicating that the two types of cells present different peptide sets. Adult nonendothelial APCs expressed a higher ratio of DQ/DR than in neonates. These results suggest that mucosal DCs can present antigen locally to primed T cells and that stromal APCs are recruited to these interactions in some cases. This raises the possibility that local presentation may influence T cell responses at the effector stage after initial presentation in the lymph node.

Self-assembly of three bacterially-derived bioactive lipopeptides

The self-assembly in aqueous solution of three lipopeptides obtained from Bacillus subtilis has been investigated. The lipopeptides surfactin, plipastatin and mycosubtilin contain distinct cyclic peptide headgroups as well as differences in alkyl chain length, branching and chain length distribution. Cryogenic transmission electron microscopy and X-ray scattering reveal that surfactin and plipastatin aggregate into 2 nm-radius spherical micelles, whereas in complete contrast mycosubtilin self-assembles into extended nanotapes based on bilayer ordering of the lipopeptides. Circular dichroism and FTIR spectroscopy indicate the presence of turn structures in the cyclic peptide headgroup. The unexpected distinct mode of self-assembly of mycosubtilin compared to the other two lipopeptides is ascribed to differences in the surfactant packing parameter. This in turn is due to specific features of the conformation of the peptide headgroup and alkyl chain branching.

Probiotic modulation of dendritic cell function is influenced by ageing

Dendritic cells (DCs) are critical for the generation of T-cell responses. DC function may be modulated by probiotics, which confer health benefits in immunocompromised individuals, such as the elderly. This study investigated the effects of four probiotics, Bifidobacterium longum bv. infantis CCUG 52486, B. longum SP 07/3, L. rhamnosus GG (L.GG) and L. casei Shirota (LcS) on DC function in an allogeneic mixed leucocyte reaction (MLR) model, using DCs and T-cells from young and older donors in different combinations. All four probiotics enhanced expression of CD40, CD80 and CCR7 on both young and older DCs, but enhanced cytokine production (TGF-β, TNF-α) by old DCs only. LcS induced IL-12 and IFNγ production by DC to a greater degree than other strains, while Bifidobacterium longum bv. infantis CCUG 52486 favoured IL-10 production. Stimulation of young T cells in an allogeneic MLR with DC was enhanced by probiotic pretreatment of old DCs, which demonstrated greater activation (CD25) than untreated controls. However, pretreatment of young or old DCs with LPS or probiotics failed to enhance the proliferation of T-cells derived from older donors. In conclusion, this study demonstrates that ageing increases the responsiveness of DCs to probiotics, but this is not sufficient to overcome the impact of immunosenescence in the MLR.

Results of PMIP2 coupled simulations of the mid-Holocene and Last Glacial Maximum, Part 1: experiments and large-scale features

A set of coupled ocean-atmosphere simulations using state of the art climate models is now available for the Last Glacial Maximum and the Mid-Holocene through the second phase of the Paleoclimate Modeling Intercomparison Project (PMIP2). This study presents the large-scale features of the simulated climates and compares the new model results to those of the atmospheric models from the first phase of the PMIP, for which sea surface temperature was prescribed or computed using simple slab ocean formulations. We consider the large-scale features of the climate change, pointing out some of the major differences between the different sets of experiments. We show in particular that systematic differences between PMIP1 and PMIP2 simulations are due to the interactive ocean, such as the amplification of the African monsoon at the Mid-Holocene or the change in precipitation in mid-latitudes at the LGM. Also the PMIP2 simulations are in general in better agreement with data than PMIP1 simulations.