Contrived Materials and a Data Set for the Evaluation of Liquid Biopsy Tests: A Blood Profiling Atlas in Cancer (BLOODPAC) Community Study.

The Blood Profiling Atlas in Cancer (BLOODPAC) Consortium is a collaborative effort involving stakeholders from the public, industry, academia, and regulatory agencies focused on developing shared best practices on liquid biopsy. This report describes the results from the JFDI (Just Freaking Do It) study, a BLOODPAC initiative to develop standards on the use of contrived materials mimicking cell-free circulating tumor DNA, to comparatively evaluate clinical laboratory testing procedures. Nine independent laboratories tested the concordance, sensitivity, and specificity of commercially available contrived materials with known variant-allele frequencies (VAFs) ranging from 0.1% to 5.0%. Each participating laboratory utilized its own proprietary evaluation procedures. The results demonstrated high levels of concordance and sensitivity at VAFs of >0.1%, but reduced concordance and sensitivity at a VAF of 0.1%; these findings were similar to those from previous studies, suggesting that commercially available contrived materials can support the evaluation of testing procedures across multiple technologies. Such materials may enable more objective comparisons of results on materials formulated in-house at each center in multicenter trials. A unique goal of the collaborative effort was to develop a data resource, the BLOODPAC Data Commons, now available to the liquid-biopsy community for further study. This resource can be used to support independent evaluations of results, data extension through data integration and new studies, and retrospective evaluation of data collection.

Single T Cell Sequencing Demonstrates the Functional Role of αß TCR Pairing in Cell Lineage and Antigen Specificity.

Although structural studies of individual T cell receptors (TCRs) have revealed important roles for both the α and ß chain in directing MHC and antigen recognition, repertoire-level immunogenomic analyses have historically examined the ß chain alone. To determine the amount of useful information about TCR repertoire function encoded within αß pairings, we analyzed paired TCR sequences from nearly 100,000 unique CD4+ and CD8+ T cells captured using two different high-throughput, single-cell sequencing approaches. Our results demonstrate little overlap in the healthy CD4+ and CD8+ repertoires, with shared TCR sequences possessing significantly shorter CDR3 sequences corresponding to higher generation probabilities. We further utilized tools from information theory and machine learning to show that while α and ß chains are only weakly associated with lineage, αß pairings appear to synergistically drive TCR-MHC interactions. Vαß gene pairings were found to be the TCR feature most informative of T cell lineage, supporting the existence of germline-encoded paired αß TCR-MHC interaction motifs. Finally, annotating our TCR pairs using a database of sequences with known antigen specificities, we demonstrate that approximately a third of the T cells possess α and ß chains that each recognize different known antigens, suggesting that αß pairing is critical for the accurate inference of repertoire functionality. Together, these findings provide biological insight into the functional implications of αß pairing and highlight the utility of single-cell sequencing in immunogenomics.

Increasing generosity by disrupting prefrontal cortex.

Recent research suggests that prosocial outcomes in sharing games arise from prefrontal control of self-maximizing impulses. We used continuous theta burst stimulation (cTBS) to disrupt the functioning of two prefrontal areas, the right dorsolateral prefrontal cortex (DLPFC) and the dorsomedial prefrontal cortex (DMPFC). We used cTBS in the right MT/V5, as a control area. We then tested subjects' prosocial inclinations with an unsupervised Dictator Game in which they allocated real money anonymously between themselves and low and high socioeconomic status (SES) players. cTBS over the two prefrontal sites made subjects more generous compared to MT/V5. More specifically, cTBS over DLPFC increased offers to high-SES players, while cTBS over DMPFC caused increased offers to low-SES players. These data, the first to demonstrate an effect of disruptive neuromodulation on costly sharing, suggest that DLPFC and MPFC exert inhibitory control over prosocial inclinations during costly sharing, though they may do so in different ways. DLPFC may implement contextual control, while DMPFC may implement a tonic form of control. This study demonstrates that humans' prepotent inclination is toward prosocial outcomes when cognitive control is reduced, even when prosocial decisions carry no strategic benefit and concerns for reputation are minimized.

The Brain Prize 2014: complex human functions.

Giacomo Rizzolatti, Stanislas Dehaene, and Trevor Robbins were recently awarded the 2014 Grete Lundbeck European Brain Research Prize for their 'pioneering research on higher brain mechanisms underpinning such complex human functions as literacy, numeracy, motivated behavior and social cognition, and for their effort to understand cognitive and behavioral disorders'. Why was their work highlighted? Is there anything that links together these seemingly disparate lines of research?

Empathy: gender effects in brain and behavior.

Evidence suggests that there are differences in the capacity for empathy between males and females. However, how deep do these differences go? Stereotypically, females are portrayed as more nurturing and empathetic, while males are portrayed as less emotional and more cognitive. Some authors suggest that observed gender differences might be largely due to cultural expectations about gender roles. However, empathy has both evolutionary and developmental precursors, and can be studied using implicit measures, aspects that can help elucidate the respective roles of culture and biology. This article reviews evidence from ethology, social psychology, economics, and neuroscience to show that there are fundamental differences in implicit measures of empathy, with parallels in development and evolution. Studies in nonhuman animals and younger human populations (infants/children) offer converging evidence that sex differences in empathy have phylogenetic and ontogenetic roots in biology and are not merely cultural byproducts driven by socialization. We review how these differences may have arisen in response to males' and females' different roles throughout evolution. Examinations of the neurobiological underpinnings of empathy reveal important quantitative gender differences in the basic networks involved in affective and cognitive forms of empathy, as well as a qualitative divergence between the sexes in how emotional information is integrated to support decision making processes. Finally, the study of gender differences in empathy can be improved by designing studies with greater statistical power and considering variables implicit in gender (e.g., sexual preference, prenatal hormone exposure). These improvements may also help uncover the nature of neurodevelopmental and psychiatric disorders in which one sex is more vulnerable to compromised social competence associated with impaired empathy.