Control of the innate immune response by the mevalonate pathway.

Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1ß that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

The neural coding of face and body orientation in occipitotemporal cortex.

Face and body orientation convey important information for us to understand other people's actions, intentions and social interactions. It has been shown that several occipitotemporal areas respond differently to faces or bodies of different orientations. However, whether face and body orientation are processed by partially overlapping or completely separate brain networks remains unclear, as the neural coding of face and body orientation is often investigated separately. Here, we recorded participants' brain activity using fMRI while they viewed faces and bodies shown from three different orientations, while attending to either orientation or identity information. Using multivoxel pattern analysis we investigated which brain regions process face and body orientation respectively, and which regions encode both face and body orientation in a stimulus-independent manner. We found that patterns of neural responses evoked by different stimulus orientations in the occipital face area, extrastriate body area, lateral occipital complex and right early visual cortex could generalise across faces and bodies, suggesting a stimulus-independent encoding of person orientation in occipitotemporal cortex. This finding was consistent across functionally defined regions of interest and a whole-brain searchlight approach. The fusiform face area responded to face but not body orientation, suggesting that orientation responses in this area are face-specific. Moreover, neural responses to orientation were remarkably consistent regardless of whether participants attended to the orientation of faces and bodies or not. Together, these results demonstrate that face and body orientation are processed in a partially overlapping brain network, with a stimulus-independent neural code for face and body orientation in occipitotemporal cortex.

Investigating holistic face processing within and outside of face-responsive brain regions.

It has been shown that human faces are processed holistically (i.e. as indecomposable wholes, rather than by their component parts) and this holistic face processing is linked to brain activity in face-responsive brain regions. Although several brain regions outside of the face-responsive network are also sensitive to relational processing and perceptual grouping, whether these non-face-responsive regions contribute to holistic processing remains unclear. Here, we investigated holistic face processing in the composite face paradigm both within and outside of face-responsive brain regions. We recorded participants' brain activity using fMRI while they performed a composite face task. Behavioural results indicate that participants tend to judge the same top face halves as different when they are aligned with different bottom face halves but not when they are misaligned, demonstrating a composite face effect. Neuroimaging results revealed significant differences in responses to aligned and misaligned faces in the lateral occipital complex (LOC), and trends in the anterior part of the fusiform face area (FFA2) and transverse occipital sulcus (TOS), suggesting that these regions are sensitive to holistic versus part-based face processing. Furthermore, the retrosplenial cortex (RSC) and the parahippocampal place area (PPA) showed a pattern of neural activity consistent with a holistic representation of face identity, which also correlated with the strength of the behavioural composite face effect. These results suggest that neural activity in brain regions both within and outside of the face-responsive network contributes to the composite-face effect.

Separated and overlapping neural coding of face and body identity.

Recognising a person's identity often relies on face and body information, and is tolerant to changes in low-level visual input (e.g., viewpoint changes). Previous studies have suggested that face identity is disentangled from low-level visual input in the anterior face-responsive regions. It remains unclear which regions disentangle body identity from variations in viewpoint, and whether face and body identity are encoded separately or combined into a coherent person identity representation. We trained participants to recognise three identities, and then recorded their brain activity using fMRI while they viewed face and body images of these three identities from different viewpoints. Participants' task was to respond to either the stimulus identity or viewpoint. We found consistent decoding of body identity across viewpoint in the fusiform body area, right anterior temporal cortex, middle frontal gyrus and right insula. This finding demonstrates a similar function of fusiform and anterior temporal cortex for bodies as has previously been shown for faces, suggesting these regions may play a general role in extracting high-level identity information. Moreover, we could decode identity across fMRI activity evoked by faces and bodies in the early visual cortex, right inferior occipital cortex, right parahippocampal cortex and right superior parietal cortex, revealing a distributed network that encodes person identity abstractly. Lastly, identity decoding was consistently better when participants attended to identity, indicating that attention to identity enhances its neural representation. These results offer new insights into how the brain develops an abstract neural coding of person identity, shared by faces and bodies.

Decoding subcategories of human bodies from both body- and face-responsive cortical regions.

Our visual system can easily categorize objects (e.g. faces vs. bodies) and further differentiate them into subcategories (e.g. male vs. female). This ability is particularly important for objects of social significance, such as human faces and bodies. While many studies have demonstrated category selectivity to faces and bodies in the brain, how subcategories of faces and bodies are represented remains unclear. Here, we investigated how the brain encodes two prominent subcategories shared by both faces and bodies, sex and weight, and whether neural responses to these subcategories rely on low-level visual, high-level visual or semantic similarity. We recorded brain activity with fMRI while participants viewed faces and bodies that varied in sex, weight, and image size. The results showed that the sex of bodies can be decoded from both body- and face-responsive brain areas, with the former exhibiting more consistent size-invariant decoding than the latter. Body weight could also be decoded in face-responsive areas and in distributed body-responsive areas, and this decoding was also invariant to image size. The weight of faces could be decoded from the fusiform body area (FBA), and weight could be decoded across face and body stimuli in the extrastriate body area (EBA) and a distributed body-responsive area. The sex of well-controlled faces (e.g. excluding hairstyles) could not be decoded from face- or body-responsive regions. These results demonstrate that both face- and body-responsive brain regions encode information that can distinguish the sex and weight of bodies. Moreover, the neural patterns corresponding to sex and weight were invariant to image size and could sometimes generalize across face and body stimuli, suggesting that such subcategorical information is encoded with a high-level visual or semantic code.

Dynamic spatial coding in parietal cortex mediates tactile-motor transformation.

Movements towards touch on the body require integrating tactile location and body posture information. Tactile processing and movement planning both rely on posterior parietal cortex (PPC) but their interplay is not understood. Here, human participants received tactile stimuli on their crossed and uncrossed feet, dissociating stimulus location relative to anatomy versus external space. Participants pointed to the touch or the equivalent location on the other foot, which dissociates sensory and motor locations. Multi-voxel pattern analysis of concurrently recorded fMRI signals revealed that tactile location was coded anatomically in anterior PPC but spatially in posterior PPC during sensory processing. After movement instructions were specified, PPC exclusively represented the movement goal in space, in regions associated with visuo-motor planning and with regional overlap for sensory, rule-related, and movement coding. Thus, PPC flexibly updates its spatial codes to accommodate rule-based transformation of sensory input to generate movement to environment and own body alike.

A Distributed Model of Face and Body Integration.

Separated face- and body-responsive brain networks have been identified that show strong responses when observers view faces and bodies. It has been proposed that face and body processing may be initially separated in the lateral occipitotemporal cortex and then combined into a whole person representation in the anterior temporal cortex, or elsewhere in the brain. However, in contrast to this proposal, our recent study identified a common coding of face and body orientation (ie, facing direction) in the lateral occipitotemporal cortex, demonstrating an integration of face and body information at an early stage of face and body processing. These results, in combination with findings that show integration of face and body identity in the lateral occipitotemporal, parahippocampal and superior parietal cortex, and face and body emotional expression in the posterior superior temporal sulcus and medial prefrontal cortex, suggest that face and body integration may be more distributed than previously considered. I propose a new model of face and body integration, where areas at the intersection of face- and body-responsive regions play a role in integrating specific properties of faces and bodies, and distributed regions across the brain contribute to high-level, abstract integration of shared face and body properties.

The macaque ventral intraparietal area has expanded into three homologue human parietal areas.

The macaque ventral intraparietal area (VIP) in the fundus of the intraparietal sulcus has been implicated in a diverse range of sensorimotor and cognitive functions such as motion processing, multisensory integration, processing of head peripersonal space, defensive behavior, and numerosity coding. Here, we exhaustively review macaque VIP function, cytoarchitectonics, and anatomical connectivity and integrate it with human studies that have attempted to identify a potential human VIP homologue. We show that human VIP research has consistently identified three, rather than one, bilateral parietal areas that each appear to subsume some, but not all, of the macaque area's functionality. Available evidence suggests that this human "VIP complex" has evolved as an expansion of the macaque area, but that some precursory specialization within macaque VIP has been previously overlooked. The three human areas are dominated, roughly, by coding the head or self in the environment, visual heading direction, and the peripersonal environment around the head, respectively. A unifying functional principle may be best described as prediction in space and time, linking VIP to state estimation as a key parietal sensorimotor function. VIP's expansive differentiation of head and self-related processing may have been key in the emergence of human bodily self-consciousness.

Male or Female? - Influence of Gender Role and Sexual Attraction on Sex Categorization of Faces.

The categorization of dominant facial features, such as sex, is a highly relevant function for social interaction. It has been found that attributes of the perceiver, such as their biological sex, influence the perception of sexually dimorphic facial features with women showing higher recognition performance for female faces than men. However, evidence on how aspects closely related to biological sex influence face sex categorization are scarce. Using a previously validated set of sex-morphed facial images (morphed from male to female and vice versa), we aimed to investigate the influence of the participant's gender role identification and sexual orientation on face sex categorization, besides their biological sex. Image ratings, questionnaire data on gender role identification and sexual orientation were collected from 67 adults (34 females). Contrary to previous literature, biological sex per se was not significantly associated with image ratings. However, an influence of participant sexual attraction and gender role identity became apparent: participants identifying with male gender attributes and showing attraction toward females perceived masculinized female faces as more male and femininized male faces as more female when compared to participants identifying with female gender attributes and attraction toward males. Considering that we found these effects in a predominantly cisgender and heterosexual sample, investigation of face sex perception in individuals identifying with a gender different from their assigned sex (i.e., transgender people) might provide further insights into how assigned sex and gender identity are related.

Challenges in the evaluation of thiol-reactive inhibitors of human protein disulfide Isomerase.

This paper addresses how to evaluate the efficacy of the growing inventory of thiol-reactive inhibitors of mammalian protein disulfide Isomerase (PDI) enzymes under realistic concentrations of potentially competing thiol-containing peptides and proteins. For this purpose, we introduce a variant of the widely-used reductase assay by using a commercially-available cysteine derivative (BODIPY FL L-Cystine; BD-SS) that yields a 55-fold increase in fluorescence (excitation/emission; 490/513nm) on scission of the disulfide bond. This plate reader-compatible method detects human PDI down to 5-10nM, can utilize a range of thiol substrates (including 5µM dithiothreitol, 10µM reduced RNase thiols, and 5mM glutathione; GSH), and can operate from pH 6-9.5 in a variety of buffers. PDI assays often employ low micromolar levels of substrates leading to ambiguities when thiol-directed inhibitors are evaluated. The present work utilizes 5mM GSH for both pre-incubation and assay phases to more realistically reflect the high concentration of thiols that an inhibitor would encounter intracellularly. Extracellular PDI faces a much lower concentration of potentially competing thiols; to assess reductase activity under these conditions, the pre-reduced PDI is treated with inhibitor and then fluorescence increase upon reduction of BD-SS is followed in the absence of additional competing thiols. Both assay modes were tested with four mechanistically diverse PDI inhibitors. Two reversible reagents, 3,4-methylenedioxy-ß-nitrostyrene (MNS) and the arsenical APAO, were found to be strong inhibitors of PDI in the absence of competing thiols, but were ineffective in the presence of 5mM GSH. A further examination of the nitrostyrene showed that MNS not only forms facile Michael adducts with GSH, but also with the thiols of unfolded proteins (Kd values of 7 and <0.1µM, respectively) suggesting the existence of multiple potential intracellular targets for this membrane-permeant reagent. The inhibition of PDI by the irreversible alkylating agent, the chloroacetamide 16F16, was found to be only modestly attenuated by 5mM GSH. Finally, the thiol-independent flavonoid inhibitor quercetin-3-O-rutinoside was found to show equal efficacy in reoxidation and turnover assay types. This work provides a framework to evaluate inhibitors that may target the CxxC motifs of PDI and addresses some of the complexities in the interpretation of the behavior of thiol-directed reagents in vivo.

How vision and self-motion combine or compete during path reproduction changes with age.

Human adults can optimally integrate visual and non-visual self-motion cues when navigating, while children up to 8 years old cannot. Whether older children can is unknown, limiting our understanding of how our internal multisensory representation of space develops. Eighteen adults and fifteen 10- to 11-year-old children were guided along a two-legged path in darkness (self-motion only), in a virtual room (visual + self-motion), or were shown a pre-recorded walk in the virtual room while standing still (visual only). Participants then reproduced the path in darkness. We obtained a measure of the dispersion of the end-points (variable error) and of their distances from the correct end point (constant error). Only children reduced their variable error when recalling the path in the visual + self-motion condition, indicating combination of these cues. Adults showed a constant error for the combined condition intermediate to those for single cues, indicative of cue competition, which may explain the lack of near-optimal integration in this group. This suggests that later in childhood humans can gain from optimally integrating spatial cues even when in the same situation these are kept separate in adulthood.

Social Stress Engages Neurochemically-Distinct Afferents to the Rat Locus Coeruleus Depending on Coping Strategy.

Stress increases vulnerability to psychiatric disorders, partly by affecting brain monoamine systems, such as the locus coeruleus (LC)-norepinephrine system. During stress, LC activity is coregulated by corticotropin-releasing factor (CRF) and endogenous opioids. This study identified neural circuitry that regulates LC activity of intruder rats during the resident-intruder model of social stress. LC afferents were retrogradely labeled with Fluorogold (FG) and rats were subjected to one or five daily exposures to an aggressive resident. Sections through the nucleus paragigantocellularis (PGi) and central amygdalar nucleus (CNA), major sources of enkephalin (ENK) and CRF LC afferents, respectively, were immunocytochemically processed to detect c-fos, FG, and CRF or ENK. In response to a single exposure, intruder rats assumed defeat with a relatively short latency (SL). LC neurons, PGI-ENK LC afferents, and CNA-CRF LC afferents were activated in these rats as indicated by increased c-fos expression. With repeated stress, rats exhibited either a SL or long latency (LL) to defeat and these strategies were associated with distinct patterns of neuronal activation. In SL rats, LC neurons were activated, as were CNA-CRF LC afferents but not PGI-ENK LC afferents. LL rats had an opposite pattern, maintaining activation of PGi-ENK LC afferents but not CNA-CRF LC afferents or LC neurons. Together, these results indicate that the establishment of different coping strategies to social stress is associated with changes in the circuitry that regulates activity of the brain norepinephrine system. This may underlie differential vulnerability to the consequences of social stress that characterize these different coping strategies.