DNA-guided transcription factor cooperativity shapes face and limb mesenchyme.

Transcription factors (TFs) can define distinct cellular identities despite nearly identical DNA-binding specificities. One mechanism for achieving regulatory specificity is DNA-guided TF cooperativity. Although in vitro studies suggest that it may be common, examples of such cooperativity remain scarce in cellular contexts. Here, we demonstrate how "Coordinator," a long DNA motif composed of common motifs bound by many basic helix-loop-helix (bHLH) and homeodomain (HD) TFs, uniquely defines the regulatory regions of embryonic face and limb mesenchyme. Coordinator guides cooperative and selective binding between the bHLH family mesenchymal regulator TWIST1 and a collective of HD factors associated with regional identities in the face and limb. TWIST1 is required for HD binding and open chromatin at Coordinator sites, whereas HD factors stabilize TWIST1 occupancy at Coordinator and titrate it away from HD-independent sites. This cooperativity results in the shared regulation of genes involved in cell-type and positional identities and ultimately shapes facial morphology and evolution.

Mechanopathology of biofilm-like Mycobacterium tuberculosis cords.

Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. The absence of these mechanopathological mechanisms explains the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation of cords that maintain structural integrity despite mechanical perturbation. Bacteria in cords remain translationally active despite antibiotic exposure and regrow rapidly upon cessation of treatment. This study provides a conceptual framework for the biophysics and function in tuberculosis infection and therapy of cord architectures independent of mechanisms ascribed to single bacteria.

Representational geometry of perceptual decisions in the monkey parietal cortex.

Lateral intraparietal (LIP) neurons represent formation of perceptual decisions involving eye movements. In circuit models for these decisions, neural ensembles that encode actions compete to form decisions. Consequently, representation and readout of the decision variables (DVs) are implemented similarly for decisions with identical competing actions, irrespective of input and task context differences. Further, DVs are encoded as partially potentiated action plans through balance of activity of action-selective ensembles. Here, we test those core principles. We show that in a novel face-discrimination task, LIP firing rates decrease with supporting evidence, contrary to conventional motion-discrimination tasks. These opposite response patterns arise from similar mechanisms in which decisions form along curved population-response manifolds misaligned with action representations. These manifolds rotate in state space based on context, indicating distinct optimal readouts for different tasks. We show similar manifolds in lateral and medial prefrontal cortices, suggesting similar representational geometry across decision-making circuits.

The Code for Facial Identity in the Primate Brain.

Primates recognize complex objects such as faces with remarkable speed and reliability. Here, we reveal the brain's code for facial identity. Experiments in macaques demonstrate an extraordinarily simple transformation between faces and responses of cells in face patches. By formatting faces as points in a high-dimensional linear space, we discovered that each face cell's firing rate is proportional to the projection of an incoming face stimulus onto a single axis in this space, allowing a face cell ensemble to encode the location of any face in the space. Using this code, we could precisely decode faces from neural population responses and predict neural firing rates to faces. Furthermore, this code disavows the long-standing assumption that face cells encode specific facial identities, confirmed by engineering faces with drastically different appearance that elicited identical responses in single face cells. Our work suggests that other objects could be encoded by analogous metric coordinate systems. PAPERCLIP.

Specialized Networks for Social Cognition in the Primate Brain.

Primates have evolved diverse cognitive capabilities to navigate their complex social world. To understand how the brain implements critical social cognitive abilities, we describe functional specialization in the domains of face processing, social interaction understanding, and mental state attribution. Systems for face processing are specialized from the level of single cells to populations of neurons within brain regions to hierarchically organized networks that extract and represent abstract social information. Such functional specialization is not confined to the sensorimotor periphery but appears to be a pervasive theme of primate brain organization all the way to the apex regions of cortical hierarchies. Circuits processing social information are juxtaposed with parallel systems involved in processing nonsocial information, suggesting common computations applied to different domains. The emerging picture of the neural basis of social cognition is a set of distinct but interacting subnetworks involved in component processes such as face perception and social reasoning, traversing large parts of the primate brain.

Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope.

Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448gp120 glycan. Effective bNAbs can therefore be raised against HIV-1 Env's silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.

A Neutralizing Antibody Recognizing Primarily N-Linked Glycan Targets the Silent Face of the HIV Envelope.

Virtually the entire surface of the HIV-1-envelope trimer is recognized by neutralizing antibodies, except for a highly glycosylated region at the center of the "silent face" on the gp120 subunit. From an HIV-1-infected donor, #74, we identified antibody VRC-PG05, which neutralized 27% of HIV-1 strains. The crystal structure of the antigen-binding fragment of VRC-PG05 in complex with gp120 revealed an epitope comprised primarily of N-linked glycans from N262, N295, and N448 at the silent face center. Somatic hypermutation occurred preferentially at antibody residues that interacted with these glycans, suggesting somatic development of glycan recognition. Resistance to VRC-PG05 in donor #74 involved shifting of glycan-N448 to N446 or mutation of glycan-proximal residue E293. HIV-1 neutralization can thus be achieved at the silent face center by glycan-recognizing antibody; along with other known epitopes, the VRC-PG05 epitope completes coverage by neutralizing antibody of all major exposed regions of the prefusion closed trimer.

A familiar face and person processing area in the human temporal pole.

How does the brain process the faces of familiar people? Neuropsychological studies have argued for an area of the temporal pole (TP) linking faces with person identities, but magnetic susceptibility artifacts in this region have hampered its study with fMRI. Using data acquisition and analysis methods optimized to overcome this artifact, we identify a familiar face response in TP, reliably observed in individual brains. This area responds strongly to visual images of familiar faces over unfamiliar faces, objects, and scenes. However, TP did not just respond to images of faces, but also to a variety of high-level social cognitive tasks, including semantic, episodic, and theory of mind tasks. The response profile of TP contrasted with a nearby region of the perirhinal cortex that responded specifically to faces, but not to social cognition tasks. TP was functionally connected with a distributed network in the association cortex associated with social cognition, while PR was functionally connected with face-preferring areas of the ventral visual cortex. This work identifies a missing link in the human face processing system that specifically processes familiar faces, and is well placed to integrate visual information about faces with higher-order conceptual information about other people. The results suggest that separate streams for person and face processing reach anterior temporal areas positioned at the top of the cortical hierarchy.

Inactivation of face-selective neurons alters eye movements when free viewing faces.

During free viewing, faces attract gaze and induce specific fixation patterns corresponding to the facial features. This suggests that neurons encoding the facial features are in the causal chain that steers the eyes. However, there is no physiological evidence to support a mechanistic link between face-encoding neurons in high-level visual areas and the oculomotor system. In this study, we targeted the middle face patches of the inferior temporal (IT) cortex in two macaque monkeys using an functional magnetic resonance imaging (fMRI) localizer. We then utilized muscimol microinjection to unilaterally suppress IT neural activity inside and outside the face patches and recorded eye movements while the animals free viewing natural scenes. Inactivation of the face-selective neurons altered the pattern of eye movements on faces: The monkeys found faces in the scene but neglected the eye contralateral to the inactivation hemisphere. These findings reveal the causal contribution of the high-level visual cortex in eye movements.

Individual differences in human gaze behavior generalize from faces to objects.

Individuals differ in where they fixate on a face, with some looking closer to the eyes while others prefer the mouth region. These individual biases are highly robust, generalize from the lab to the outside world, and have been associated with social cognition and associated disorders. However, it is unclear, whether these biases are specific to faces or influenced by domain-general mechanisms of vision. Here, we juxtaposed these hypotheses by testing whether individual face fixation biases generalize to inanimate objects. We analyzed >1.8 million fixations toward faces and objects in complex natural scenes from 405 participants tested in multiple labs. Consistent interindividual differences in fixation positions were highly inter-correlated across faces and objects in all samples. Observers who fixated closer to the eye region also fixated higher on inanimate objects and vice versa. Furthermore, the inter-individual spread of fixation positions scaled with target size in precisely the same, non-linear manner for faces and objects. These findings contradict a purely domain-specific account of individual face gaze. Instead, they suggest significant domain-general contributions to the individual way we look at faces, a finding with potential relevance for basic vision, face perception, social cognition, and associated clinical conditions.

Dynamic brain communication underwriting face pareidolia.

Face pareidolia is a tendency to seeing faces in nonface images that reflects high tuning to a face scheme. Yet, studies of the brain networks underwriting face pareidolia are scarce. Here, we examined the time course and dynamic topography of gamma oscillatory neuromagnetic activity while administering a task with nonface images resembling a face. Images were presented either with canonical orientation or with display inversion that heavily impedes face pareidolia. At early processing stages, the peaks in gamma activity (40 to 45 Hz) to images either triggering or not face pareidolia originate mainly from the right medioventral and lateral occipital cortices, rostral and caudal cuneus gyri, and medial superior occipital gyrus. Yet, the difference occurred at later processing stages in the high-frequency range of 80 to 85 Hz over a set of the areas constituting the social brain. The findings speak rather for a relatively late neural network playing a key role in face pareidolia. Strikingly, a cutting-edge analysis of brain connectivity unfolding over time reveals mutual feedforward and feedback intra- and interhemispheric communication not only within the social brain but also within the extended large-scale network of down- and upstream regions. In particular, the superior temporal sulcus and insula strongly engage in communication with other brain regions either as signal transmitters or recipients throughout the whole processing of face-pareidolia images.

Improving forensic perpetrator identification with Super-Recognizers.

About a decade ago, Super-Recognizers (SRs) were first described as individuals with exceptional face identity processing abilities. Since then, various tests have been developed or adapted to assess individuals' abilities and identify SRs. The extant literature suggests that SRs may be beneficial in police tasks requiring individual identification. However, in reality, the performance of SRs has never been examined using authentic forensic material. This not only limits the external validity of test procedures used to identify SRs, but also claims concerning their deployment in policing. Here, we report the first-ever investigation of SRs' ability to identify perpetrators using authentic case material. We report the data of 73 SRs and 45 control participants. These include (a) performance on three challenging tests of face identity processing recommended by Ramon (2021) for SR identification; (b) performance for perpetrator identification using four CCTV sequences depicting five perpetrators and police line-ups created for criminal investigation purposes. Our findings demonstrate that the face identity processing tests used here are valid in measuring such abilities and identifying SRs. Moreover, SRs excel at perpetrator identification relative to control participants, with more correct perpetrator identifications, the better their performance across lab tests. These results provide external validity for the recently proposed diagnostic framework and its tests used for SR identification (Ramon, 2021). This study provides the first empirical evidence that SRs identified using these measures can be beneficial for forensic perpetrator identification. We discuss theoretical and practical implications for law enforcement, whose procedures can be improved via a human-centric approach centered around individuals with superior abilities.

Behavioral signatures of face perception emerge in deep neural networks optimized for face recognition.

Human face recognition is highly accurate and exhibits a number of distinctive and well-documented behavioral "signatures" such as the use of a characteristic representational space, the disproportionate performance cost when stimuli are presented upside down, and the drop in accuracy for faces from races the participant is less familiar with. These and other phenomena have long been taken as evidence that face recognition is "special". But why does human face perception exhibit these properties in the first place? Here, we use deep convolutional neural networks (CNNs) to test the hypothesis that all of these signatures of human face perception result from optimization for the task of face recognition. Indeed, as predicted by this hypothesis, these phenomena are all found in CNNs trained on face recognition, but not in CNNs trained on object recognition, even when additionally trained to detect faces while matching the amount of face experience. To test whether these signatures are in principle specific to faces, we optimized a CNN on car discrimination and tested it on upright and inverted car images. As we found for face perception, the car-trained network showed a drop in performance for inverted vs. upright cars. Similarly, CNNs trained on inverted faces produced an inverted face inversion effect. These findings show that the behavioral signatures of human face perception reflect and are well explained as the result of optimization for the task of face recognition, and that the nature of the computations underlying this task may not be so special after all.

Re-cognizing the new self: The neurocognitive plasticity of self-processing following facial transplantation.

The face is a defining feature of our individuality, crucial for our social interactions. But what happens when the face connected to the self is radically altered or replaced? We address the plasticity of self-face recognition in the context of facial transplantation. While the acquisition of a new face following facial transplantation is a medical fact, the experience of a new identity is an unexplored psychological outcome. We traced the changes in self-face recognition before and after facial transplantation to understand if and how the transplanted face gradually comes to be perceived and recognized as the recipient's own new face. Neurobehavioral evidence documents a strong representation of the pre-injury appearance pre-operatively, while following the transplantation, the recipient incorporates the new face into his self-identity. The acquisition of this new facial identity is supported by neural activity in medial frontal regions that are considered to integrate psychological and perceptual aspects of the self.

The reconstructed cranium of Pierolapithecus and the evolution of the great ape face.

Pierolapithecus catalaunicus (~12 million years ago, northeastern Spain) is key to understanding the mosaic nature of hominid (great ape and human) evolution. Notably, its skeleton indicates that an orthograde (upright) body plan preceded suspensory adaptations in hominid evolution. However, there is ongoing debate about this species, partly because the sole known cranium, preserving a nearly complete face, suffers from taphonomic damage. We 1) carried out a micro computerized tomography (CT) based virtual reconstruction of the Pierolapithecus cranium, 2) assessed its morphological affinities using a series of two-dimensional (2D) and three-dimensional (3D) morphometric analyses, and 3) modeled the evolution of key aspects of ape face form. The reconstruction clarifies many aspects of the facial morphology of Pierolapithecus. Our results indicate that it is most similar to great apes (fossil and extant) in overall face shape and size and is morphologically distinct from other Middle Miocene apes. Crown great apes can be distinguished from other taxa in several facial metrics (e.g., low midfacial prognathism, relatively tall faces) and only some of these features are found in Pierolapithecus, which is most consistent with a stem (basal) hominid position. The inferred morphology at all ancestral nodes within the hominoid (ape and human) tree is closer to great apes than to hylobatids (gibbons and siamangs), which are convergent with other smaller anthropoids. Our analyses support a hominid ancestor that was distinct from all extant and fossil hominids in overall facial shape and shared many features with Pierolapithecus. This reconstructed ancestral morphotype represents a testable hypothesis that can be reevaluated as new fossils are discovered.

Cleaner fish recognize self in a mirror via self-face recognition like humans.

Some animals have the remarkable capacity for mirror self-recognition (MSR), yet any implications for self-awareness remain uncertain and controversial. This is largely because explicit tests of the two potential mechanisms underlying MSR are still lacking: mental image of the self and kinesthetic visual matching. Here, we test the hypothesis that MSR ability in cleaner fish, Labroides dimidiatus, is associated with a mental image of the self, in particular the self-face, like in humans. Mirror-naive fish initially attacked photograph models of both themselves and unfamiliar strangers. In contrast, after all fish had passed the mirror mark test, fish did not attack their own (motionless) images, but still frequently attacked those of unfamiliar individuals. When fish were exposed to composite photographs, the self-face/unfamiliar body were not attacked, but photographs of unfamiliar face/self-body were attacked, demonstrating that cleaner fish with MSR capacity recognize their own facial characteristics in photographs. Additionally, when presented with self-photographs with a mark placed on the throat, unmarked mirror-experienced cleaner fish demonstrated throat-scraping behaviors. When combined, our results provide clear evidence that cleaner fish recognize themselves in photographs and that the likely mechanism for MSR is associated with a mental image of the self-face, not a kinesthetic visual-matching model. Humans are also capable of having a mental image of the self-face, which is considered an example of private self-awareness. We demonstrate that combining mirror test experiments with photographs has enormous potential to further our understanding of the evolution of cognitive processes and private self-awareness across nonhuman animals.

Encoding of dynamic facial information in the middle dorsal face area.

Faces in motion reveal a plethora of information through visual dynamics. Faces can move in complex patterns while transforming facial shape, e.g., during the generation of different emotional expressions. While motion and shape processing have been studied extensively in separate research enterprises, much less is known about their conjunction during biological motion. Here, we took advantage of the discovery in brain-imaging studies of an area in the dorsal portion of the macaque monkey superior temporal sulcus (STS), the middle dorsal face area (MD), with selectivity for naturalistic face motion. To gain mechanistic insights into the coding of facial motion, we recorded single-unit activity from MD, testing whether and how MD cells encode face motion. The MD population was highly sensitive to naturalistic facial motion and facial shape. Some MD cells responded only to the conjunction of facial shape and motion, others were selective for facial shape even without movement, and yet others were suppressed by facial motion. We found that this heterogeneous MD population transforms face motion into a higher dimensional activity space, a representation that would allow for high sensitivity to relevant small-scale movements. Indeed, we show that many MD cells carry such sensitivity for eye movements. We further found that MD cells encode motion of head, mouth, and eyes in a separable manner, requiring the use of multiple reference frames. Thus, MD is a bona fide face-motion area that uses highly heterogeneous cell populations to create codes capturing even complex facial motion trajectories.

Encoding of 3D physical dimensions by face-selective cortical neurons.

Neurons throughout the primate inferior temporal (IT) cortex respond selectively to visual images of faces and other complex objects. The response magnitude of neurons to a given image often depends on the size at which the image is presented, usually on a flat display at a fixed distance. While such size sensitivity might simply reflect the angular subtense of retinal image stimulation in degrees, one unexplored possibility is that it tracks the real-world geometry of physical objects, such as their size and distance to the observer in centimeters. This distinction bears fundamentally on the nature of object representation in IT and on the scope of visual operations supported by the ventral visual pathway. To address this question, we assessed the response dependency of neurons in the macaque anterior fundus (AF) face patch to the angular versus physical size of faces. We employed a macaque avatar to stereoscopically render three-dimensional (3D) photorealistic faces at multiple sizes and distances, including a subset of size/distance combinations designed to cast the same size retinal image projection. We found that most AF neurons were modulated principally by the 3D physical size of the face rather than its two-dimensional (2D) angular size on the retina. Further, most neurons responded strongest to extremely large and small faces, rather than to those of normal size. Together, these findings reveal a graded encoding of physical size among face patch neurons, providing evidence that category-selective regions of the primate ventral visual pathway participate in a geometric analysis of real-world objects.

Modeling naturalistic face processing in humans with deep convolutional neural networks.

Deep convolutional neural networks (DCNNs) trained for face identification can rival and even exceed human-level performance. The ways in which the internal face representations in DCNNs relate to human cognitive representations and brain activity are not well understood. Nearly all previous studies focused on static face image processing with rapid display times and ignored the processing of naturalistic, dynamic information. To address this gap, we developed the largest naturalistic dynamic face stimulus set in human neuroimaging research (700+ naturalistic video clips of unfamiliar faces). We used this naturalistic dataset to compare representational geometries estimated from DCNNs, behavioral responses, and brain responses. We found that DCNN representational geometries were consistent across architectures, cognitive representational geometries were consistent across raters in a behavioral arrangement task, and neural representational geometries in face areas were consistent across brains. Representational geometries in late, fully connected DCNN layers, which are optimized for individuation, were much more weakly correlated with cognitive and neural geometries than were geometries in late-intermediate layers. The late-intermediate face-DCNN layers successfully matched cognitive representational geometries, as measured with a behavioral arrangement task that primarily reflected categorical attributes, and correlated with neural representational geometries in known face-selective topographies. Our study suggests that current DCNNs successfully capture neural cognitive processes for categorical attributes of faces but less accurately capture individuation and dynamic features.

Neuronal Population Encoding of Identity in Primate Prefrontal Cortex.

The ventrolateral prefrontal cortex (VLPFC) shows robust activation during the perception of faces and voices. However, little is known about what categorical features of social stimuli drive neural activity in this region. Since perception of identity and expression are critical social functions, we examined whether neural responses to naturalistic stimuli were driven by these two categorical features in the prefrontal cortex. We recorded single neurons in the VLPFC, while two male rhesus macaques (Macaca mulatta) viewed short audiovisual videos of unfamiliar conspecifics making expressions of aggressive, affiliative, and neutral valence. Of the 285 neurons responsive to the audiovisual stimuli, 111 neurons had a main effect (two-way ANOVA) of identity, expression, or their interaction in their stimulus-related firing rates; however, decoding of expression and identity using single-unit firing rates rendered poor accuracy. Interestingly, when decoding from pseudo-populations of recorded neurons, the accuracy for both expression and identity increased with population size, suggesting that the population transmitted information relevant to both variables. Principal components analysis of mean population activity across time revealed that population responses to the same identity followed similar trajectories in the response space, facilitating segregation from other identities. Our results suggest that identity is a critical feature of social stimuli that dictates the structure of population activity in the VLPFC, during the perception of vocalizations and their corresponding facial expressions. These findings enhance our understanding of the role of the VLPFC in social behavior.