Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Mindfulness-based interventions in epilepsy: a systematic review

Mindfulness based interventions (MBIs) are increasingly used to help patients cope with physical and mental long-term conditions (LTCs). Epilepsy is associated with a range of mental and physical comorbidities that have a detrimental effect on quality of life (QOL), but it is not clear whether MBIs can help. We systematically reviewed the literature to determine the effectiveness of MBIs in people with epilepsy. Medline, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, Allied and Complimentary Medicine Database, and PsychInfo were searched in March 2016. These databases were searched using a combination of subject headings where available and keywords in the title and abstracts. We also searched the reference lists of related reviews. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Three randomised controlled trials (RCTs) with a total of 231 participants were included. The interventions were tested in the USA (n = 171) and China (Hong Kong) (n = 60). Significant improvements were reported in depression symptoms, quality of life, anxiety, and depression knowledge and skills. Two of the included studies were assessed as being at unclear/high risk of bias - with randomisation and allocation procedures, as well as adverse events and reasons for drop-outs poorly reported. There was no reporting on intervention costs/benefits or how they affected health service utilisation. This systematic review found limited evidence for the effectiveness of MBIs in epilepsy, however preliminary evidence suggests it may lead to some improvement in anxiety, depression and quality of life. Further trials with larger sample sizes, active control groups and longer follow-ups are needed before the evidence for MBIs in epilepsy can be conclusively determined

Gelotophobia and the challenges of implementing laughter into virtual agents interactions

This study investigated which features of AVATAR laughter are perceived threatening for individuals with a fear of being laughed at (gelotophobia), and individuals with no gelotophobia. Laughter samples were systematically varied (e.g., intensity, laughter pitch, and energy for the voice, intensity of facial actions of the face) in three modalities: animated facial expressions, synthesized auditory laughter vocalizations, and motion capture generated puppets displaying laughter body movements. In the online study 123 adults completed, the GELOPH (Ruch and Proyer, 2008a,b) and rated randomly presented videos of the three modalities for how malicious, how friendly, how real the laughter was (0 not at all to 8 extremely). Additionally, an open question asked which markers led to the perception of friendliness/maliciousness. The current study identified features in all modalities of laughter stimuli that were perceived as malicious in general, and some that were gelotophobia specific. For facial expressions of AVATARS, medium intensity laughs triggered highest maliciousness in the gelotophobes. In the auditory stimuli, the fundamental frequency modulations and the variation in intensity were indicative of maliciousness. In the body, backwards and forward movements and rocking vs. jerking movements distinguished the most malicious from the least malicious laugh. From the open answers, the shape and appearance of the lips curling induced feelings that the expression was malicious for non-gelotophobes and that the movement round the eyes, elicited the face to appear as friendly. This was opposite for gelotophobes. Gelotophobia savvy AVATARS should be of high intensity, containing lip and eye movements and be fast, non-repetitive voiced vocalization, variable and of short duration. It should not contain any features that indicate a down-regulation in the voice or body, or indicate voluntary/cognitive modulation.the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no. 270780 (ILHAIRE project)

Recycled gabbro signature in hotspot magmas unveiled by plume–ridge interactions

Lavas erupted within plate interiors above upwelling mantle plumes have chemical signatures that are distinct from midocean ridge lavas. When a plume interacts with a mid-ocean ridge, the compositions of both their lavas changes, but there is no consensus as to how this interaction occurs1–3. For the past 15 Myr, the Pacific–Antarctic mid-ocean ridge has been approaching the Foundation hotspot4 and erupted lavas have formed seamounts. Here we analyse the noble gas isotope and trace element signature of lava samples collected from the seamounts. We find that both intraplate and on-axis lavas have noble gas isotope signatures consistent with the contribution from a primitive plume source. In contrast, nearaxis lavas show no primitive noble gas isotope signatures, but are enriched in strontium and lead, indicative of subducted former oceanic lower crust melting within the plume source5–7. We propose that, in a near-ridge setting, primitive, plumesourced magmas formed deep in the plume are preferentially channelled to and erupted at the ridge-axis. The remaining residue continues to rise and melt, forming the near-axis seamounts. With the deep melts removed, the geochemical signature of subduction contained within the residue becomes apparent. Lavas with strontium and lead enrichments are found worldwide where plumes meet mid-ocean ridges6–8, suggesting that subducted lower crust is an important but previously unrecognised plume component

Subcellular localization and tissue specific expression of amidase 1 from Arabidopsis thaliana

Amidase 1 (AMI1) from Arabidopsis thaliana converts indole-3-acetamide (IAM), into indole-3-acetic acid (IAA). AMI1 is part of a small isogene family comprising seven members in A. thaliana encoding proteins which share a conserved glycine- and serine-rich amidase-signature. One member of this family has been characterized as an N-acylethanolamine-cleaving fatty acid amidohydrolase (FAAH) and two other members are part of the preprotein translocon of the outer envelope of chloroplasts (Toc complex) or mitochondria (Tom complex) and presumably lack enzymatic activity. Among the hitherto characterized proteins of this family, AMI1 is the only member with indole-3-acetamide hydrolase activity, and IAM is the preferred substrate while N-acylethanolamines and oleamide are not hydrolyzed significantly, thus suggesting a role of AMI1 in auxin biosynthesis. Whereas the enzymatic function of AMI1 has been determined in vitro, the subcellular localization of the enzyme remained unclear. By using different GFP-fusion constructs and an A. thaliana transient expression system, we show a cytoplasmic localization of AMI1. In addition, RT-PCR and anti-amidase antisera were used to examine tissue specific expression of AMI1 at the transcriptional and translational level, respectively. AMI1-expression is strongest in places of highest IAA content in the plant. Thus, it is concluded that AMI1 may be involved in de novo IAA synthesis in A. thaliana

Role of structural dynamics at the receptor G protein interface for signal transduction

GPCRs catalyze GDP/GTP exchange in the α-subunit of heterotrimeric G proteins (Gαßγ) through displacement of the Gα C-terminal α5 helix, which directly connects the interface of the active receptor (R*) to the nucleotide binding pocket of G. Hydrogen-deuterium exchange mass spectrometry and kinetic analysis of R* catalysed G protein activation have suggested that displacement of α5 starts from an intermediate GDP bound complex (R*•GGDP). To elucidate the structural basis of receptor-catalysed displacement of α5, we modelled the structure of R*•GGDP. A flexible docking protocol yielded an intermediate R*•GGDP complex, with a similar overall arrangement as in the X-ray structure of the nucleotide free complex (R*•Gempty), however with the α5 C-terminus (GαCT) forming different polar contacts with R*. Starting molecular dynamics simulations of GαCT bound to R* in the intermediate position, we observe a screw-like motion, which restores the specific interactions of α5 with R* in R*•Gempty. The observed rotation of α5 by 60° is in line with experimental data. Reformation of hydrogen bonds, water expulsion and formation of hydrophobic interactions are driving forces of the α5 displacement. We conclude that the identified interactions between R* and G protein define a structural framework in which the α5 displacement promotes direct transmission of the signal from R* to the GDP binding pocket

Differential Effects of Attention-, Compassion-, and Socio-Cognitively Based Mental Practices on Self-Reports of Mindfulness and Compassion

Research on the effects of mindfulness- and compassion-based interventions is flourishing along with self-report scales to assess facets of these broad concepts. However, debates remain as to which mental practices are most appropriate to develop the attentional, cognitive, and socio-affective facets of mindfulness and compassion. One crucial question is whether present-moment, attention-focused mindfulness practices are sufficient to induce a cascade of changes across the different proposed facets of mindfulness, including nonjudgmental acceptance, as well as compassion or whether explicit socio-affective training is required. Here, we address these questions in the context of a 9-month longitudinal study (the ReSource Project) by examining the differential effects of three different 3-month mental training modules on subscales of mindfulness and compassion questionnaires. The “Presence” module, which aimed at cultivating present-moment-focused attention and body awareness, led to increases in the observing, nonreacting, and presence subscales, but not to increases in acceptance or nonjudging. These latter facets benefitted from specific cultivation through the socio-cognitive “Perspective” module and socio-affective, compassion-based “Affect” module, respectively. These modules also led to further increases in scores on the subscales affected by the Presence module. Moreover, scores on the compassion scales were uniquely influenced by the Affect module. Thus, whereas a present-moment attention-focused training, as implemented in many mindfulness-based programs, was indeed able to increase attentional facets of mindfulness, only socio-cognitive and compassion-based practices led to broad changes in ethical-motivational qualities like a nonjudgmental attitude, compassion, and self-compassion

Snout Shape in Extant Ruminants

Copyright: © 2014 Tennant, MacLeod. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. [4.0 license]. The attached file is the published version of the article

Primary carbonatite melt from deeply subducted oceanic crust

Partial melting in the Earth's mantle plays an important part in generating the geochemical and isotopic diversity observed in volcanic rocks at the surface. Identifying the composition of these primary melts in the mantle is crucial for establishing links between mantle geochemical 'reservoirs' and fundamental geodynamic processes. Mineral inclusions in natural diamonds have provided a unique window into such deep mantle processes. Here we provide experimental and geochemical evidence that silicate mineral inclusions in diamonds from Juina, Brazil, crystallized from primary and evolved carbonatite melts in the mantle transition zone and deep upper mantle. The incompatible trace element abundances calculated for a melt coexisting with a calcium-titanium-silicate perovskite inclusion indicate deep melting of carbonated oceanic crust, probably at transition-zone depths. Further to perovskite, calcic-majorite garnet inclusions record crystallization in the deep upper mantle from an evolved melt that closely resembles estimates of primitive carbonatite on the basis of volcanic rocks. Small-degree melts of subducted crust can be viewed as agents of chemical mass-transfer in the upper mantle and transition zone, leaving a chemical imprint of ocean crust that can possibly endure for billions of years.4 page(s

Integrating Positive and Clinical Psychology: Viewing Human Functioning as Continua from Positive to Negative Can Benefit Clinical Assessment, Interventions and Understandings of Resilience

In this review we argue in favour of further integration between the disciplines of positive and clinical psychology. We argue that most of the constructs studied by both positive and clinical psychology exist on continua ranging from positive to negative (e.g., gratitude to ingratitude, anxiety to calmness) and so it is meaningless to speak of one or other field studying the “positive” or the “negative”. However, we highlight historical and cultural factors which have led positive and clinical psychologies to focus on different constructs; thus the difference between the fields is more due to the constructs of study rather than their being inherently “positive” or “negative”. We argue that there is much benefit to clinical psychology of considering positive psychology constructs because; (a) constructs studied by positive psychology researchers can independently predict wellbeing when accounting for traditional clinical factors, both cross-sectionally and prospectively, (2) the constructs studied by positive psychologists can interact with risk factors to predict outcomes, thereby conferring resilience, (3) interventions that aim to increase movement towards the positive pole of well-being can be used encourage movement away from the negative pole, either in isolation or alongside traditional clinical interventions, and (4) research from positive psychology can support clinical psychology as it seeks to adapt therapies developed in Western nations to other cultures