The Influence of 1,25-Dihydroxyvitamin D3 on the Cross-Priming of Lymphocytic Choriomeningitis Virus Nucleoprotein

Biologically active 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) binds the vitamin D receptor (VDR) to exert its effect on target cells. VDR expression is found in a number of immune cells including professional antigen-presenting cells such as dendritic cells. It has been found that the actions of 1,25-(OH)2D3 on the immune system are mainly immunosuppressive. The cross-presentation pathway allows for exogenously derived antigens to be presented by pAPCs on MHC-I molecules to CD8+ T cells. CD8+ T cell activation results in the expansion of epitope-specific T cell populations that confer host protection. These epitopes can be organized into an immunodominance hierarchy. Previous work demonstrated that introducing LCMV-NP via the cross-priming pathway significantly alters the immunodominance hierarchy of a subsequent LCMV infection. Building upon these observations, our study assessed the effects of LCMV-NP cross priming in the presence of a single dose of 1,25-(OH)2D3. Treatment with 1,25-(OH)2D3 was found to have biological effects in our model system. In vitro pAPCs were demonstrated to up-regulate IL-10 and CYP24A1 mRNA, in addition to the transactivation of cellular VDR, as demonstrated by a relocalization to the nuclear region. Mice treated with 1,25-(OH)2D3 were found to produce up-regulated IL-10 and CYP24A1 transcripts. Expression of VDR was increased at both the transcript and protein level. Our results demonstrate that a single dose of 1,25-(OH)2D3 does not affect the cross-priming pathway in this system. Treatment with 1,25-(OH)2D3 did not influence the ability of differentiated pAPCs to phagocytose or cross-present exogenous antigen to epitope-specific CD8+ T cells. Furthermore, 1,25-(OH)2D3 did not alter cross-priming or the establishment of the LCMV immunodominance hierarchy in vivo. By confirming that 1,25-(OH)2D3 does not suppress cross-priming in our model, our study helps to expand the understanding of the immunomodulatory role of exogenous 1,25-(OH)2D3 on the outcome of virus infection. Collectively, our data supports the observation that the role of 1,25-(OH)2D3 in the immune system is not always associated with suppressive effects.

Priming of CD8+ and CD4+ T Cells in Experimental Leishmaniasis Is Initiated by Different Dendritic Cell Subtypes

The biological role of Langerin(+) dendritic cells (DCs) such as Langerhans cells and a subset of dermal DCs (dDCs) in adaptive immunity against cutaneous pathogens remains enigmatic. Thus, we analyzed the impact of Langerin(+) DCs in adaptive T cell-mediated immunity toward Leishmania major parasites in a Lang-DTR mouse model that allows conditional diphtheria toxin (DT)-induced ablation of The biological role of Langerin+ dendritic cells (DCs) such as Langerhans cells and a subset of dermal DCs (dDCs) in adaptive immunity against cutaneous pathogens remains enigmatic. Thus, we analyzed the impact of Langerin+ DCs in adaptive T cell-mediated immunity toward Leishmania major parasites in a Lang-DTR mouse model that allows conditional diphtheria toxin (DT)-induced ablation of Langerin+ DCs in vivo. For the first time, infection experiments with DT-treated Lang-DTR mice revealed that proliferation of L. major-specific CD8+ T cells is significantly reduced during the early phase of the immune response following depletion of Langerin+ DCs. Consequently, the total number of activated CD8+ T cells within the draining lymph node and at the site of infection is diminished. Furthermore, we show that the impaired CD8+ T cell response is due to the absence of Langerin+ dDCs and not Langerhans cells. Nevertheless, the CD4+ T cell response is not altered and the infection is cleared as effectively in DT-treated Lang-DTR mice as in control mice. This clearly demonstrates that Langerin+ DCs are, in general, dispensable for an efficient adaptive immune response against L. major parasites. Thus, we propose a novel concept that, in the experimental model of leishmaniasis, priming of CD4+ T cells is mediated by Langerin− dDCs, whereas Langerin+ dDCs are involved in early priming of CD8+ T cells.

Conceptual and Perceptual Priming and Dissociation in Chronic Posttraumatic Stress Disorder.

Cognitive models of posttraumatic stress disorder (PTSD) assert that memory processes play a significant role in PTSD (see e.g., Ehlers & Clark, 2000). Intrusive reexperiencing in PTSD has been linked to perceptual processing of trauma-related material with a corresponding hypothesized lack of conceptual processing. In an experimental study that included clinical participants with and without PTSD (N = 50), perceptual priming and conceptual priming for trauma-related, general threat, and neutral words were investigated in a population with chronic trauma-induced complaints as a result of the Troubles in Northern Ireland. The study used a new version of the word-stem completion task (Michael, Ehlers, & Halligan, 2005) and a word-cue association task. It also assessed the role of dissociation in threat processing. Further evidence of enhanced perceptual priming in PTSD for trauma stimuli was found, along with evidence of lack of conceptual priming for such stimuli. Furthermore, this pattern of priming for trauma-related words was associated with PTSD severity, and state dissociation and PTSD group made significant contributions to predicting perceptual priming for trauma words. The findings shed light on the importance of state dissociation in trauma-related information processing and posttraumatic symptoms.

The effect of priming on perceptions of dog breed traits

This study examined whether priming cues embedded in mediastyle presentations shaped people's perceptions of specific dog breeds, and in particular, the German shepherd dog (GSD). Two hundred and four adult females were exposed to one of two types of media-style presentation (stories or pictures). Half of the participants in each condition were exposed to versions designed to portray the GSD in a positive light; the remainder to stimuli developed to present the same breed in a negative light. Participants subsequently rated six individual breeds of dog, including the target breed, on a number of traits (e.g., “friendliness,“ “aggression“). Analysis revealed a significant effect of priming on people's perceptions of the GSD. Participants exposed to the negative stimuli perceived this breed as significantly less approachable, and more dangerous and aggressive, than those exposed to the positive stimuli. Priming did not influence the participants' perceptions of other breeds, even those often regarded in a negative light, although there was some evidence of breed-related category-based stereotyping. Overall, results suggest that people's perceptions of dog breeds can be influenced by verbal and visual representations. The results have implications for how dogs are portrayed in the media and other publically available sources of information.

Informational masking in young and elderly listeners for speech masked by simultaneous speech and noise

Three experiments measured the effects of age on informational masking of speech by competing speech. The experiments were designed to minimize the energetic contributions of the competing speech so that informational masking could be measured with no large corrections for energetic masking. Experiment 1 used a "speech-in-speech-in-noise" design, in which the competing speech was presented in noise at a signal-to-noise ratio (SNR) of -4 dB. This ensured that the noise primarily contributed the energetic masking but the competing speech contributed the informational masking. Equal amounts of informational masking (3 dB) were observed for young and elderly listeners, although less was found for hearing-impaired listeners. Experiment 2 tested a range of SNRs in this design and showed that informational masking increased with SNR up to about an SNR of -4 dB, but decreased thereafter. Experiment 3 further reduced the energetic contribution of the competing speech by filtering it into different frequency bands from the target speech. The elderly listeners again showed approximately the same amount of informational masking (4-5 dB), although some elderly listeners had particular difficulty understanding these stimuli in any condition. On the whole, these results suggest that young and elderly listeners were equally susceptible to informational masking. © 2009 Acoustical Society of America.

Dissolving Microneedle Delivery of Nanoparticle Encapsulated Antigen Elicits Efficient Cross-Priming and Th1 Immune Responses by Murine Langerhans Cells

Dendritic cells (DCs) of the skin play an important role in skin-mediated immunity capable of promoting potent immune responses. We availed of polymeric dissolving microneedle (MN) arrays laden with nano-encapsulated antigen to specifically target skin DC networks. This modality of immunization represents an economic, efficient and potent means of antigen delivery directly to skin DCs, which are inefficiently targeted by more conventional immunization routes. Following MN immunization, Langerhans cells (LCs) constituted the major skin DC subset capable of cross-priming antigen-specific CD8(+) T cells ex-vivo. While all DC subsets were equally efficient in priming CD4(+) T cells, LCs were largely responsible for orchestrating the differentiation of CD4(+) IFN-γ and IL-17 producing effectors. Importantly, depletion of LCs prior to immunization had a profound effect on CD8(+) CTL responses in vivo, and vaccinated animals displayed reduced protective anti-tumour and viral immunity. Interestingly, this cross-priming bias was lost following MN immunization with soluble antigen, suggesting that processing and cross-presentation of nano-particulate antigen is favoured by LCs. Therefore, these studies highlight the importance of LCs in skin immunization strategies and that targeting of nano-particulate immunogens through dissolvable polymeric MNs potentially provides a promising technological platform for improved vaccination strategies.Journal of Investigative Dermatology accepted article preview online, 22 September 2014. doi:10.1038/jid.2014.415.

Solventless synthesis of acyl phosphonamidates, precursors to masked bisphosphonates

A series of acyl phosphonamidates, the synthetic precursors to bisphosphonates, have been readily prepared from phosphoramidite type reagents and a range of acid chlorides. These reactions were performed using solventless conditions, where purification was easily achieved using column chromatography with yields ranging from 71-90%. Furthermore, we have demonstrated that these acyl phosphonamidates could be used for the preparation of unsymmetrical bisphosphonates, which do date are scarcely reported in the literature.

Autism in the air: using Point of View Video Priming and Natural Environment Teaching to help children with autism travel by plane

This paper describes a study that used video materials and visits to an airport to prepare children on the autism spectrum for travel by plane. Twenty parents and carers took part in the study with children aged from 3 to 16 years. The authors explain that the methods they used were based on Applied Behaviour Analysis (ABA) research; a video modeling technique called Point-Of-View Video-priming and during visits to an airport they used procedures known as Natural Environment Teaching. The findings suggest that using video and preparing children by taking them through what is likely to happen in the real environment when they travel by plane is effective and the authors suggest these strategies could be used to support children with autism with other experiences they need or would like to engage in such as visits to the dentist or hairdressers and access to leisure centres and other public spaces.