Exosomal cancer immunotherapy is independent of MHC molecules on exosomes

Peptide-loaded exosomes are promising cancer treatment vehicles; however, moderate T cell responses in human clinical trials indicate a need to further understand exosome-induced immunity. We previously demonstrated that antigen-loaded exosomes carry whole protein antigens and require B cells for inducing antigen-specific T cells. Therefore, we investigated the relative importance of exosomal major histocompatibility complex (MHC) class I for the induction of antigen-specific T cell responses and tumour protection. We show that ovalbumin-loaded dendritic cell-derived exosomes from MHCI-/- mice induce antigen-specific T cells at the same magnitude as wild type exosomes. Furthermore, exosomes lacking MHC class I, as well as exosomes with both MHC class I and II mismatch, induced tumour infiltrating T cells and increased overall survival to the same extent as syngeneic exosomes in B16 melanoma. In conclusion, T cell responses are independent of exosomal MHC/peptide complexes if whole antigen is present. This establishes the prospective of using impersonalised exosomes, and will greatly increase the feasibility of designing exosome-based vaccines or therapeutic approaches in humans

A ‘near‐life experience’: lived experiences of spirituality from the perspective of people who have been subject to inpatient psychiatric care

Aims: To describe lived experiences of spirituality from the perspective of people who have been subject to inpatient psychiatric care and to interpret these experiences from an understanding of health as dialectical. Methods: After approval from a regional ethical board,eleven participants were recruited from two organisations for people with mental health problems. Participants were asked to narrate about spiritual experiences and occasions where such experiences had come close. The transcribed interviews were analysed by means of a phenomenological hermeneutical approach. Findings: A structural analysis of the text resulted in three themes; perceiving the presence of something extra mundane, making sense of reality and struggling for acceptance. The comprehensive understanding highlights spiritual experiences as going beyond religion, even though religious experiences appear as part of it. These experiences can indeed be a resource contributing to experiences of hope, connectedness, meaning and coherence in life. However, they can also give rise to doubt, anxiety and feelings of loneliness and hopelessness. Rather than understanding spiritual experiences as being either ‘good’ or ‘bad’, we could approach spirituality as something that is always present in alternate and inter-related forms. Metaphorically, this could be understood as a ‘near-life experience’, summarising participants’experiences related to their struggle with issues related to suffering and health which are simultaneously present. Conclusions: If psychiatric nurses could approach this complexity and, without being judgemental, explore seemingly positive and negative experiences of spirituality as dialectically related to each other, rather than viewing them as either resources or problems, this could contribute to insiderness care and hopefully also support people who struggle with these experiences to seek help when needed

Temperament Systems Influence Emotion Induction but not Makam Recognition Performance in Turkish Makam Music

We tested how induced emotions and Turkish makam recognition are influenced by participation in an ear training classes, and if either is influenced by the temperament system employed. The ear training class was attended by 19 music students and was based on the Hicaz makam presented as a between-subjects factor in either unfamiliar Turkish Original Temperament (OT, pitches unequally divided into 24 intervals) or familiar Western Equal Temperament (ET, pitches equally divided into 12 intervals). Before the and after the class, participants listened to 20 music excerpts from five different Turkish makams (in both OT and ET versions). Emotion-induction was assessed via GEMS-25, and participants were also asked to identify the makam that was present in the excerpt. The unfamiliar original temperament was experienced as less vital and more uneasy before the ear training class, and recognition of the Hicaz makam increased after ear training classes (independent of the temperament system employed). Results suggest that unfamiliar temperament systems are experienced as less vital and more uneasy. Furthermore, being exposed to this temperament system for just one hour does not seem to be enough to change participants’ mental representations of it or their emotional responses to it

Ammonia formation over Pd/Al2O3 modified with cerium and barium

We report experimental results for ammonia formation from nitric oxide and either a direct source of hydrogen or from a mixture of carbon monoxide and water over palladium based catalysts. Specifically, the addition of barium or cerium into an alumina supported palladium sample was studied. Static and transient flow reactor experiments were performed in order to identify the effects of temperature and the presence of oxygen on the activity for ammonia formation. Modification of Pd/Al2O3 with cerium proved to be beneficial for the activity due mainly to its enhancement of the water-gas-shift reaction, thus providing a higher availability of hydrogen for ammonia formation, but also because it remains active in the presence of slightly oxidizing global conditions when hydrogen is provided directly to the feed. Although the modification of Pd/Al2O3 with barium did not affect the ammonia formation during static conditions, the activity during lean/rich cycling increased. This is important for applications of passive selective catalytic reduction

Changing musical emotion: A computational rule system for modifying score and performance

CMERS system architecture has been implemented in the programming language scheme, and it uses the improvised music programming environment with the objective to provide researchers with a tool for testing the relationships between musical features and emotion. A music work represented in CMERS uses the music object hierarchy that is based on GTTM's grouping structure and is automatically generated from the phrase boundary markup and MIDI file. The Mode rule type of CMERS converts a note into those of the parallel mode and no change in pitch height occurs when converting to the parallel mode. It is reported that the odds of correctness with CMERS are approximately five times greater than that of DM. The repeated-measures analysis of variance for valence shows a significant difference between systems with F (1, 17) = 45.49, p < .0005 and the interaction between system and quadrant is significant with F (3, 51) = 4.23, p = .01, which indicates that CMERS is extensively more effective at correctly influencing valence than DM. c 2010 Massachusetts Institute of Technology

A Flexible Nonlinear Feedback System That Captures Diverse Patterns of Adaptation and Rebound

An important approach to modeling tolerance and adaptation employs feedback mechanisms in which the response to the drug generates a counter-regulating action which affects the response. In this paper we analyze a family of nonlinear feedback models which has recently proved effective in modeling tolerance phenomena such as have been observed with SSRI’s. We use dynamical systems methods to exhibit typical properties of the response-time course of these nonlinear models, such as overshoot and rebound, establish quantitive bounds and explore how these properties depend on the system and drug parameters. Our analysis is anchored in three specific in vivo data sets which involve different levels of pharmacokinetic complexity. Initial estimates for system (kin, kout, ktol ) and drug (EC50/IC50, Emax/Imax, n ) parameters are obtained on the basis of specific properties of the response-time course, identified in the context of exploratory (graphical) data analysis. Our analysis and the application of its results to the three concrete examples demonstrates the flexibility and potential of this family of feedback models

Awareness of social care needs in people with epilepsy and intellectual disability

Background: Nearly a quarter of people with intellectual disability (ID) have epilepsy with large numbers experiencing drug-resistant epilepsy, and premature mortality. To mitigate epilepsy risks the environment and social care needs, particularly in professional care settings, need to be met. Purpose: To compare professional care groups as regards their subjective confidence and perceived responsibility when managing the need of people with ID and epilepsy. Method: A multi-agency expert panel developed a questionnaire with embedded case vignettes with quantitative and qualitative elements to understand training and confidence in the health and social determinants of people with ID and epilepsy. The cross-sectional survey was disseminated amongst health and social care professionals working with people with ID in the UK using an exponential non-discriminative snow-balling methodology. Group comparisons were undertaken using suitable statistical tests including Fisher's exact, Kruskal-Wallis, and Mann-Whitney. Bonferroni correction was applied to significant (p < 0.05) results. Content analysis was conducted and relevant categories and themes were identified. Results: Social and health professionals (n = 54) rated their confidence to manage the needs of people with ID and epilepsy equally. Health professionals showed better awareness (p < 0.001) of the findings/recommendations of the latest evidence on premature deaths and identifying and managing epilepsy-related risks, including the relevance of nocturnal monitoring. The content analysis highlighted the need for clearer roles, improved care pathways, better epilepsy-specific knowledge, increased resources, and better multi-disciplinary work. Conclusions: A gap exists between health and social care professionals in awareness of epilepsy needs for people with ID, requiring essential training and national pathways

Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions

A feedback model was developed to describe the tolerance and oscillatory rebound seen in non-esterified fatty acid (NEFA) plasma concentrations following intravenous infusions of nicotinic acid (NiAc) to male Sprague-Dawley rats. NiAc was administered as an intravenous infusion over 30 min (0, 1, 5 or 20 μmol kg−1 of body weight) or over 300 min (0, 5, 10 or 51 μmol kg−1 of body weight), to healthy rats (n = 63), and serial arterial blood samples were taken for measurement of NiAc and NEFA plasma concentrations. Data were analyzed using nonlinear mixed effects modeling (NONMEM). The disposition of NiAc was described by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. The plasma concentration of NiAc was driving NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. The NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M1) inhibited the formation of R and the last compartment (MN) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC50, of NiAc was 45 nmol L−1, the fractional turnover rate kout was 0.41 L mmol−1 min−1 and the turnover rate of moderator ktol was 0.027 min−1. A lower physiological limit of NEFA was modeled as a NiAc-independent release (kcap) of NEFA into plasma and was estimated to 0.032 mmol L−1 min−1. This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc. The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats

The aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats