A Shared Neural Substrate for Mentalizing and the Affective Component of Sentence Comprehension

Using event-related fMRI in a sample of 42 healthy participants, we compared the cerebral activity maps obtained when classifying spoken sentences based on the mental content of the main character (belief, deception or empathy) or on the emotional tonality of the sentence (happiness, anger or sadness). To control for the effects of different syntactic constructions (such as embedded clauses in belief sentences), we subtracted from each map the BOLD activations obtained during plausibility judgments on structurally matching sentences, devoid of emotions or ToM. The obtained theory of mind (ToM) and emotional speech comprehension networks overlapped in the bilateral temporo-parietal junction, posterior cingulate cortex, right anterior temporal lobe, dorsomedial prefrontal cortex and in the left inferior frontal sulcus. These regions form a ToM network, which contributes to the emotional component of spoken sentence comprehension. Compared with the ToM task, in which the sentences were enounced on a neutral tone, the emotional sentence classification task, in which the sentences were play-acted, was associated with a greater activity in the bilateral superior temporal sulcus, in line with the presence of emotional prosody. Besides, the ventromedial prefrontal cortex was more active during emotional than ToM sentence processing. This region may link mental state representations with verbal and prosodic emotional cues. Compared with emotional sentence classification, ToM was associated with greater activity in the caudate nucleus, paracingulate cortex, and superior frontal and parietal regions, in line with behavioral data showing that ToM sentence comprehension was a more demanding task.     

Brain responses to violet, blue, and green monochromatic light exposures in humans: prominent role of blue light and the brainstem

Background

Relatively long duration retinal light exposure elicits nonvisual responses in humans, including modulation of alertness and cognition. These responses are thought to be mediated in part by melanopsin-expressing retinal ganglion cells which are more sensitive to blue light than violet or green light. The contribution of the melanopsin system and the brain mechanisms involved in the establishment of such responses to light remain to be established.

Methodology/Principal Findings

We exposed 15 participants to short duration (50 s) monochromatic violet (430 nm), blue (473 nm), and green (527 nm) light exposures of equal photon flux (10¹³ph/cm²/s) while they were performing a working memory task in fMRI. At light onset, blue light, as compared to green light, increased activity in the left hippocampus, left thalamus, and right amygdala. During the task, blue light, as compared to violet light, increased activity in the left middle frontal gyrus, left thalamus and a bilateral area of the brainstem consistent with activation of the locus coeruleus.

Conclusion/Significance

These results support a prominent contribution of melanopsin-expressing retinal ganglion cells to brain responses to light within the very first seconds of an exposure. The results also demonstrate the implication of the brainstem in mediating these responses in humans and speak for a broad involvement of light in the regulation of brain function.     

The tail of the Ordovician fish Sacabambaspis

The tail of the earliest known articulated fully skeletonized vertebrate, the arandaspid Sacabambaspis from the Ordovician of Bolivia, is redescribed on the basis of further preparation of the only specimen in which it is most extensively preserved. The first, but soon discarded, reconstruction, which assumed the presence of a long horizontal notochordal lobe separating equal sized dorsal and ventral fin webs, appears to have considerable merit. Although the ventral web is significantly smaller than the dorsal one, the presence of a very long notochordal lobe bearing a small terminal web is confirmed. The discrepancy in the size of the ventral and dorsal webs rather suggests that the tail was hypocercal, a condition that would better accord with the caudal morphology of the living agnathans and the other jawless stem gnathostomes.     

The perpetuation and epidemic recurrence of communicable diseases in human populations

Recurrence of communicable diseases is a looming threat for human populations. Factors explaining the recurrences are partially known, involving demographics, biology, and complex relationships with the environment, but no comprehensive theory exists today. Here, we review some recent results obtained in modelling studies with a view to understanding better the mechanisms of perpetuation. Factors intrinsic to the interaction of pathogen and host have regained interest in this respect, especially with multiple pathogen and multiple population interactions. Extrinsic factors, including pure demography and environmental forcing are also strong predictors. With increasingly detailed data available, large-scale integrated models will help sorting out the multiple influences on recurrence.     

A single phenylalanine residue in β-arrestin2 critically regulates its binding to G protein–coupled receptors

Arrestins and their yeast homologs, arrestin-related trafficking adaptors (ARTs), share a stretch of 29 amino acids called the ART motif. However, the functionality of that motif is unknown. We now report that deleting this motif prevents agonist-induced ubiquitination of β-arrestin2 (β-arr2) and blocks its association with activated G protein–coupled receptors (GPCRs). Within the ART motif, we have identified a conserved phenylalanine residue, Phe116, that is critical for the formation of β-arr2–GPCR complexes. β-arr2 Phe116Ala mutant has negligible effect on blunting β₂-adrenergic receptor–induced cAMP generation unlike β-arr2, which promotes rapid desensitization. Furthermore, available structures for inactive and inositol hexakisphosphate 6–activated forms of bovine β-arr2 revealed that Phe116 is ensconced in a hydrophobic pocket, whereas the adjacent Phe117 and Phe118 residues are not. Mutagenesis of Phe117 and Phe118, but not Phe116, preserves GPCR interaction of β-arr2. Surprisingly, Phe116 is dispensable for the association of β-arr2 with its non-GPCR partners. β-arr2 Phe116Ala mutant presents a significantly reduced protein half-life compared with β-arr2 and undergoes constitutive Lys-48-linked polyubiquitination, which tags proteins for proteasomal degradation. We also found that Phe116 is critical for agonist-dependent β-arr2 ubiquitination with Lys-63-polyubiquitin linkages that are known mediators of protein scaffolding and signal transduction. Finally, we have shown that β-arr2 Phe116Ala interaction with activated β₂-adrenergic receptor can be rescued with an in-frame fusion of ubiquitin. Taken together, we conclude that Phe116 preserves structural stability of β-arr2, regulates the formation of β-arr2–GPCR complexes that inhibit G protein signaling, and promotes subsequent ubiquitin-dependent β-arr2 localization and trafficking.     

Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain

The number and localization of effector cells to the tumor site are crucial elements for immune rejection of solid tumors. However, for cerebral malignancies, antitumor responses need to be finely tuned to avoid neuropathologic consequences. In this study, we determine factors that regulate CTL localization and tumoricidal function after intracerebral implantation of tumors expressing model Ag. H-2(bxd) mice implanted with a CW3(+) murine glioma lacking H-2K(d) molecules necessary to present the CW3(170-179) epitope demonstrate cross-priming of H-2K(d)-restricted CTL, and moreover, Ag-dependent accumulation of functional H-2K(d)/CW3(170-179)-specific CTL within the tumor bed. This implicates a role for cross-presentation not only in priming, but also in retention of fully differentiated CTL in the tumor stroma at the effector stage of the response. Modulating cross-presentation of Ag may be the key in regulating specific immune responses in the brain: either by augmenting protective responses or by down-modulating destructive autoimmune reactions.     

Vaccination with a Melan-A peptide selects an oligoclonal T cell population with increased functional avidity and tumor reactivity

Both the underlying molecular mechanisms and the kinetics of TCR repertoire selection following vaccination against tumor Ags in humans have remained largely unexplored. To gain insight into these questions, we performed a functional and structural longitudinal analysis of the TCR of circulating CD8(+) T cells specific for the HLA-A2-restricted immunodominant epitope from the melanocyte differentiation Ag Melan-A in a melanoma patient who developed a vigorous and sustained Ag-specific T cell response following vaccination with the corresponding synthetic peptide. We observed an increase in functional avidity of Ag recognition and in tumor reactivity in the postimmune Melan-A-specific populations as compared with the preimmune blood sample. Improved Ag recognition correlated with an increase in the t(1/2) of peptide/MHC interaction with the TCR as assessed by kinetic analysis of A2/Melan-A peptide multimer staining decay. Ex vivo analysis of the clonal composition of Melan-A-specific CD8(+) T cells at different time points during vaccination revealed that the response was the result of asynchronous expansion of several distinct T cell clones. Some of these T cell clones were also identified at a metastatic tumor site. Collectively, these data show that tumor peptide-driven immune stimulation leads to the selection of high-avidity T cell clones of increased tumor reactivity that independently evolve within oligoclonal populations.     

Analysis of the collapsibility of the upper airway in a spectrum of sleep-disordered breathing: a modelling approach

Using a simplified model of the upper airways with two independent collapsible elements (nostrils and hypo-pharynx), we calculated the cross-sectional area of these two elements, taking into account pressure drops. We experimentally measured flow and pressure in the fossa and hypo-pharynx in various syndromes. This allowed us to compare the behaviour of the area supplied by our model with the aerodynamic resistance that is often used to analyse upper airway flow limitation events. We showed that nostril and hypo-pharyngeal areas are better correlated than the resistance values and thus concluded that the pressure divided by the square of the flow is a better parameter for analysing flow limitation in upper airways than resistance. Owing to its simplicity, our model is able to supply the area of the collapsible element in real time, which is impossible with more sophisticated models.