Analysis of T cell receptor clonotypes in tumor microenvironment identifies shared cancer-type-specific signatures.

Despite the conventional view that a truly random V(D)J recombination process should generate a highly diverse immune repertoire, emerging reports suggest that there is a certain bias toward the generation of shared/public immune receptor chains. These studies were performed in viral diseases where public T cell receptors (TCR) appear to confer better protective responses. Selective pressures generating common TCR clonotypes are currently not well understood, but it is believed that they confer a growth advantage. As very little is known about public TCR clonotypes in cancer, here we set out to determine the extent of shared TCR clonotypes in the intra-tumor microenvironments of virus- and non-virus-driven head and neck cancers using TCR sequencing. We report that tumor-infiltrating T cell clonotypes were indeed shared across individuals with the same cancer type, where the majority of shared sequences were specific to the cancer type (i.e., viral versus non-viral). These shared clonotypes were not particularly enriched in EBV-associated nasopharynx cancer but, in both cancers, exhibited distinct characteristics, namely shorter CDR3 lengths, restricted V- and J-gene usages, and also demonstrated convergent V(D)J recombination. Many of these shared TCRs were expressed in patients with a shared HLA background. Pattern recognition of CDR3 amino acid sequences revealed strong convergence to specific pattern motifs, and these motifs were uniquely found to each cancer type. This suggests that they may be enriched for specificity to common antigens found in the tumor microenvironment of different cancers. The identification of shared TCRs in infiltrating tumor T cells not only adds to our understanding of the tumor-adaptive immune recognition but could also serve as disease-specific biomarkers and guide the development of future immunotherapies

'I'm sorry to hear that'-Empathy and Empathic Dissonance : the Perspectives of PA Students

Context: Our understanding of clinical empathy could be enhanced through qualitative research-research currently under-represented in the field. Physician associates within the UK undergo an intensive 2-year postgraduate medical education. As a new group of health professionals, they represent a fresh pair of eyes through which to examine clinical empathy, its nature and teaching. Methods: Working with a constructivist paradigm, utilising grounded theory methodology, researchers studied 19 purposively sampled physician associate students in two UK medical schools. One-to-one semi-structured interviews were transcribed verbatim. Data were analysed using a grounded theory approach. Results: The global themes were the pathways to empathy, empathy modifiers and empathic dissonance a novel term to describe the discomfort students experience when pressurised into making empathic statements they don't sincerely feel. Students preferred using non-verbal over verbal expressions of empathy. A conceptual model is proposed. The more substantial empathic pathway, affective empathy, involves input from the heart. An alternative empathy, more constrained, comes from the head: cognitive empathy was considered a solution to time pressure and emotional burden. Formal teaching establishes empathic dissonance, a problem which stems from over-reliance on the empathic statement as the means to deliver clinical empathy. Conclusions: This study furthers our understanding of the construct and teaching of empathy. It identifies empathic barriers, especially time pressure. It proposes a novel concept-empathic dissonance-a concept that challenges medical educationalists to reframe future empathy teaching

A Pilot Study with a Novel Setup for Collaborative Play of the Humanoid Robot KASPAR with children with autism

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.This article describes a pilot study in which a novel experimental setup, involving an autonomous humanoid robot, KASPAR, participating in a collaborative, dyadic video game, was implemented and tested with children with autism, all of whom had impairments in playing socially and communicating with others. The children alternated between playing the collaborative video game with a neurotypical adult and playing the same game with the humanoid robot, being exposed to each condition twice. The equipment and experimental setup were designed to observe whether the children would engage in more collaborative behaviours while playing the video game and interacting with the adult than performing the same activities with the humanoid robot. The article describes the development of the experimental setup and its first evaluation in a small-scale exploratory pilot study. The purpose of the study was to gain experience with the operational limits of the robot as well as the dyadic video game, to determine what changes should be made to the systems, and to gain experience with analyzing the data from this study in order to conduct a more extensive evaluation in the future. Based on our observations of the childrens’ experiences in playing the cooperative game, we determined that while the children enjoyed both playing the game and interacting with the robot, the game should be made simpler to play as well as more explicitly collaborative in its mechanics. Also, the robot should be more explicit in its speech as well as more structured in its interactions. Results show that the children found the activity to be more entertaining, appeared more engaged in playing, and displayed better collaborative behaviours with their partners (For the purposes of this article, ‘partner’ refers to the human/robotic agent which interacts with the children with autism. We are not using the term’s other meanings that refer to specific relationships or emotional involvement between two individuals.) in the second sessions of playing with human adults than during their first sessions. One way of explaining these findings is that the children’s intermediary play session with the humanoid robot impacted their subsequent play session with the human adult. However, another longer and more thorough study would have to be conducted in order to better re-interpret these findings. Furthermore, although the children with autism were more interested in and entertained by the robotic partner, the children showed more examples of collaborative play and cooperation while playing with the human adult.Peer reviewe

Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition

Philanthotoxin-433 (PhTX-433) is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 inhibits several excitatory ligand-gated ion channels, and to improve selectivity two synthetic analogues, PhTX-343 and PhTX-12, were developed. Previous work showed a 22-fold selectivity of PhTX-12 over PhTX-343 for embryonic muscle-type nicotinic acetylcholine receptors (nAChRs) in TE671 cells. We investigated their inhibition of different neuronal nAChR subunit combinations as well as of embryonic muscle receptors expressed in Xenopus oocytes. Whole-cell currents in response to application of acetylcholine alone or co-applied with PhTX analogue were studied by using two-electrode voltage-clamp. α3β4 nAChRs were most sensitive to PhTX-343 (IC50=12 nM at −80 mV) with α4β4, α4β2, α3β2, α7 and α1β1γδ being 5, 26, 114, 422 and 992 times less sensitive. In contrast α1β1γδ was most sensitive to PhTX-12 along with α3β4 (IC50values of 100 nM) with α4β4, α4β2, α3β2 and α7 being 3, 3, 26 and 49 times less sensitive. PhTX-343 inhibition was strongly voltage-dependent for all subunit combinations except α7, whereas this was not the case for PhTX-12 for which weak voltage dependence was observed. We conclude that PhTX-343 mainly acts as an open-channel blocker of nAChRs with strong subtype selectivity

On staying grounded and avoiding Quixotic dead ends

The 15 articles in this special issue on The Representation of Concepts illustrate the rich variety of theoretical positions and supporting research that characterize the area. Although much agreement exists among contributors, much disagreement exists as well, especially about the roles of grounding and abstraction in conceptual processing. I first review theoretical approaches raised in these articles that I believe are Quixotic dead ends, namely, approaches that are principled and inspired but likely to fail. In the process, I review various theories of amodal symbols, their distortions of grounded theories, and fallacies in the evidence used to support them. Incorporating further contributions across articles, I then sketch a theoretical approach that I believe is likely to be successful, which includes grounding, abstraction, flexibility, explaining classic conceptual phenomena, and making contact with real-world situations. This account further proposes that (1) a key element of grounding is neural reuse, (2) abstraction takes the forms of multimodal compression, distilled abstraction, and distributed linguistic representation (but not amodal symbols), and (3) flexible context-dependent representations are a hallmark of conceptual processing

Mechanistic insight into the pathology of polyalanine expansion disorders revealed by a mouse model for x linked hypopituitarism

Extent: 9 p.Polyalanine expansions in transcription factors have been associated with eight distinct congenital human diseases. It is thought that in each case the polyalanine expansion causes misfolding of the protein that abrogates protein function. Misfolded proteins form aggregates when expressed in vitro; however, it is less clear whether aggregation is of relevance to these diseases in vivo. To investigate this issue, we used targeted mutagenesis of embryonic stem (ES) cells to generate mice with a polyalanine expansion mutation in Sox3 (Sox3-26ala) that is associated with X-linked Hypopituitarism (XH) in humans. By investigating both ES cells and chimeric mice, we show that endogenous polyalanine expanded SOX3 does not form protein aggregates in vivo but rather is present at dramatically reduced levels within the nucleus of mutant cells. Importantly, the residual mutant protein of chimeric embryos is able to rescue a block in gastrulation but is not sufficient for normal development of the hypothalamus, a region that is functionally compromised in Sox3 null embryos and individuals with XH. Together, these data provide the first definitive example of a disease-relevant PA mutant protein that is both nuclear and functional, thereby manifesting as a partial loss-of-function allele.James Hughes Sandra Piltz, Nicholas Rogers, Dale McAninch, Lynn Rowley and Paul Thoma

Health Centre Surveys as a Potential Tool for Monitoring Malaria Epidemiology by Area and over Time

BACKGROUND: Presently, many malaria control programmes use health facility data to evaluate the impact of their interventions. Facility-based malaria data, although useful, have problems with completeness, validity and representativeness and reliance on routinely collected health facility data might undermine demonstration of the magnitude of the impact of the recent scaleups of malaria interventions. To determine whether carefully conducted health centre surveys can be reliable means of monitoring area specific malaria epidemiology, we have compared malaria specific indices obtained from surveys in health centres with indices obtained from cross-sectional surveys conducted in their catchment communities. METHODS: A series of age stratified, seasonal, cross-sectional surveys were conducted during the peak malaria transmission season in 2008 and during the following dry season in 2009 in six ecologically diverse areas in The Gambia. Participants were patients who attended the health centres plus a representative sample from the catchment villages of these health facilities. Parasitaemia, anaemia, attributable proportion of fever and anti-MSP1-(19) antibody seroprevalence were compared in the health facility attendees and community participants. RESULTS: A total of 16,230 subjects completed the study; approximately half participated in the health centre surveys and half in the wet season surveys. Data from both the health centre and community surveys showed that malaria endemicity in The Gambia is now low, heterogeneous and seasonal. In the wet season, parasitaemia, seroprevalence and fever prevalence were higher in subjects seen in the health centres than in the community surveys. Age patterns of parasitaemia, attributable proportions of fever and seroprevalence rates were similar in subjects who participated in the community and health centre surveys. CONCLUSION: Health centre surveys have potential as a surveillance tool for evaluating area specific malaria control activities and for monitoring changes in local malaria epidemiology over time

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation