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Biology subjects

Salomon, R.

Publications and source records attributed to Salomon, R..

At least 19 recordsLinked to original sources

Domain-general computational integration in the Sense of Agency

The Sense of Agency (SoA), the experience of being in control of ones own actions, is thought to emerge from the comparison of internal sensorimotor predictions with afferent feedback. Classical comparator models treat SoA as arising from a prediction-feedback comparison. Volitional action likely engages multiple forward models that predict distinct features of an outcome, such as its timing and spatial trajectory. Whether prediction errors arising from these distinct forward models are integrated into a domain-general representation of agency, and if so by what computational logic, remains unresolved. We addressed this question using a Virtual Reality reaching task. Participants observed a virtual hand replicating their movements while we independently manipulated two sensorimotor domains: temporal delay and spatial angle deviation, in isolation and in factorial combinations. After each trial, participants made an SoA judgment. We examined whether SoA responses show computational hallmarks of integration between different features of sensorimotor prediction. Specifically, we pre-registered three computational models (Multiplicative, Minimum, and Mean) and compared their fit to per-trial responses. Across an exploratory sample (N = 16) and a pre-registered replication (N = 38), SoA declined monotonically with conflict magnitude in both domains. Critically, a Multiplicative integration rule consistently outperformed the Minimum and Mean rules. These results provide direct evidence for domain-general integration between prediction errors in SoA, governed by a multiplicative computational logic.

neuroscience↗

Preserved implicit metacognitive sensitivity distinguishes psychosis risk from first-episode psychosis: A cross-sectional virtual reality-based study

Relatively preserved insight distinguishes individuals at risk for psychosis from those with full-blown psychosis. Metacognitive processes thought to support insight and uncertainty monitoring may therefore serve as early markers of illness progression. Yet findings have been inconsistent, perhaps partly due to reliance on explicit confidence ratings that introduce reflection and response biases. To address these limitations, we used a novel implicit confidence measure derived from post-decision gaze in a virtual-reality probabilistic learning task. Gaze-based confidence quantifies the alignment between spatial predictions and gaze direction. We assessed first-order learning and gaze-based metacognition in four groups: clinical high-risk for psychosis (CHR-P), first episode psychosis (FEP), help-seeking controls (HSC), and healthy controls (HC). We tested whether implicit metacognition differentiates psychosis risk from psychosis. Learning accuracy was reduced in both CHR-P and FEP compared to control groups. At the metacognitive level, CHR-P confidence levels were approximately commensurate with their reduced first-order performance, indicating preserved confidence calibration, along with preserved metacognitive sensitivity--the ability to distinguish correct from incorrect decisions. In contrast, FEP showed impaired confidence calibration and reduced metacognitive sensitivity. Metacognitive calibration and sensitivity distinguished CHR-P from FEP and provided predictive value in distinguishing CHR-P from FEP, whereas learning accuracy did not. These findings reveal a dissociation between first-order cognitive processes and distinct aspects of implicit metacognition, including confidence calibration and metacognitive sensitivity, across the psychosis continuum. This dissociation may refine early clinical characterization and improve identification of preserved insight-related mechanisms in psychosis risk.

neuroscience↗

Single-cell RNA-sequencing of cerebral spinal fluid identifies circulating tumour cells in children with brain cancer

Paediatric central nervous system (CNS) tumours are the leading cause of cancer-related death in children, yet disease monitoring remains challenging. Conventional approaches, including imaging and cytology, lack sensitivity, delaying intervention. Liquid biopsy offers a minimally invasive alternative, but the utility of circulating tumour cells (CTCs) in paediatric CNS tumours as biomarkers is poorly defined. We developed a CTC detection and characterisation workflow from cerebrospinal fluid (CSF) utilising single-cell RNA-sequencing (scRNA-seq) and applied this to ten CNS tumour subtypes in 16 patients. CTCs were identified in all cases, with higher burdens in pineoblastoma, medulloblastoma and atypical teratoid rhabdoid tumours. Longitudinal profiling revealed CTC dynamics correlated with clinical disease course and anticipated relapse. Critically, scRNA-seq uncovered a sub-clonal canonical driver alteration at diagnosis that only became detectable by bulk RNA-seq at progression, underscoring its potential to resolve clonal dynamics. This workflow enables real-time molecular profiling, offering a transformative strategy for disease monitoring and personalised therapy in paediatric brain tumours.

cancer biology↗

CBL mutations in pediatric solid and CNS tumors are a marker of receptor tyrosine kinase activation and a potential therapeutic target

Mutations in CBL, an E3 ubiquitin ligase that negatively regulates receptor tyrosine kinases (RTKs) and potentiates intracellular signaling, have been extensively characterized in hematological malignancies. However, the impacts are unknown in other cancer types. We have identified established and novel aberrations in CBL in molecularly diverse pediatric CNS and solid tumors. Additionally, we present novel CBL splice mutations, including in the germline of a high-grade glioma patient, and alternative CBL splicing without corresponding genomic alterations. Functionally, we demonstrate that CBL exon 8/9{Delta}, typically associated with acute myeloid leukemia, is RTK activating in neuroblastoma and that novel CBL variants, CBL E366_E373del and CBL C384G, can cooperate with overexpression of EGFR to transform Ba/F3 cells. Collectively, these data represent a novel form of RTK activation in pediatric patients with solid and CNS tumors who might benefit from RTK-targeted therapies. Statement of significanceMolecularly targeted therapies improve childhood cancer outcomes. Therapies targeting genes called receptor tyrosine kinases are particularly effective. We have identified new genetic alterations that may be a marker for receptor tyrosine kinase activation and drug sensitivity, enabling more patients to benefit from targeted treatments.

cancer biology↗

Unreal? A Behavioral, Physiological, and Computational Model of the Sense of Reality

Our awareness of dreams, hallucinations, and illusions reflects an intriguing human capacity to recognize potentially false perceptions, known as the Sense of Reality (SoR). Though central to mental health, the study of SoR has been hindered by the subjective nature of hallucinatory experiences. Here we employed a novel virtual reality paradigm simulating virtual hallucinations, mirroring the phenomenology of clinical hallucinations. Combining psychophysics, physiological recordings, and computational modeling in one exploratory (n = 31) and one preregistered experiment (n = 32), we found that SoR varied with virtual hallucination magnitude and domain. SoR judgments were associated with distinct motor, pupillary, and cardiac responses, allowing classification of virtual hallucination exposure. We present a computational model in which SoR judgments arise from comparing current sensory input to an internal model of the world. Our results shed light on the age-old question how do we know what is real?

neuroscience↗

Neural Correlates of the Embodied Sense of Agency

The Sense of Agency (SoA) is the subjective experience that I am in control of my actions. Recent accounts have distinguished two levels in the formation of SoA - early implicit sensorimotor processes (feeling of agency) and later explicit higher-level processes, incorporating ones thoughts and beliefs (judgment of agency). Even though SoA is fundamental to our interactions with the external world and the construct of the self, its underlying neural mechanism remains elusive. In the current pre-registered electroencephalography (EEG) study, we used time-frequency analysis and Multivariate Pattern Analysis (MVPA) to investigate the electrophysiological characteristics associated with SoA. We used an established embodied virtual reality paradigm in which visual feedback of a movement is modulated to examine the effect of conflicts between the predicted and perceived sensory feedback. Participants moved their finger and were shown a virtual hand that either mimicked their movement or differed anatomically (different finger) or spatially (angular shift), then judged their SoA over the observed movement while their brain activity was recorded. In accordance with our pre-registered hypothesis, we found that a reduction of SoA is associated with decreased attenuation in the alpha frequency band. Increased power in the theta frequency band was also associated with SoA reduction. Importantly, we show that trials containing a sensorimotor alteration vs. trials containing no alteration can reliably be decoded with up to 68% accuracy starting around 200ms after the movement onset. Finally, cross-decoding analyses revealed similar neural patterns for reduced SoA in the anatomical and spatial conditions, starting around 500ms after the movement onset. Together, our results reveal a cortical signature of loss of SoA and provide neural evidence supporting the hypothesis of a two-level formation of SoA - an early domain-specific component, possibly the equivalent of the implicit feeling of agency, and a late domain-general component, possibly the equivalent of the explicit judgment of agency.

neuroscience↗

'Eye Know': Gaze reflects confidence in explicit predictions while relying on a distinct computational mechanism

Decisions are naturally accompanied by a feeling of confidence in their correctness. Typically measured via self-reported judgments, decision confidence is also expressed implicitly through sensorimotor behavior. In one exploratory and two preregistered experiments (total N = 115), we combined VR-based probabilistic-learning and spatial-cueing paradigms with computational modeling to examine whether post-decision gaze can serve as an implicit behavioral measure of decision confidence. Gaze direction generally aligned with predictive decisions about a targets upcoming location, while the degree of alignment tracked the model-based probability underlying the decision. Gaze-decision alignment also exhibited previously established statistical hallmarks of confidence. Under increased uncertainty, gaze and decisions tended to diverge, reflecting strategic "hedging" behavior. Gaze-decision alignment and explicit confidence judgments were modestly correlated, and remained correlated after controlling for the decisions probability, suggesting that the two are partially overlapping manifestations of internal confidence. Notably, reported confidence showed higher metacognitive sensitivity and increased serial dependence across trials, while gaze-based confidence expressed a more trial-specific readout of internal confidence. These findings suggest that post-decision gaze in visual-spatial learning tasks is an implicit, embodied manifestation of confidence. The complementary functional characteristics of implicit and explicit expressions of confidence may support adaptive behavior during learning.

neuroscience↗

Trauma Under Psychedelics: MDMA Shows Protective Effects During the Peritraumatic Period

Traumatic events play a causal role in the etiology of stress-related psychopathologies such as depression and posttraumatic stress disorder (PTSD). Recent research highlighted the therapeutic potential of psychoactive substances in alleviating trauma symptoms among chronic stress-related patients. This study is the first to investigate the impact of psychoactive substances consumed during actual trauma exposure. Our cohort includes 772 adult survivors (487 males, Mean{+/-}SD Age: 26.96{+/-}6.55) of the high-casualty attack that occurred at the Supernova festival in Israel on October 7th, 2023. Survivors completed the study during the peritraumatic period of one to four months following the attack. Primary outcomes include the PTSD Checklist for DSM-5 (PCL-5), the Kessler Psychological Distress Scale (K6), and a self-reported rating of feeling overwhelmed. Secondary outcomes include subjective experiences during the attack and reports on social interactions and sleep quality. All survivors reported being in direct danger of death during the attack. Approximately two-thirds of the sampled survivors were under the influence of psychoactive substances at the time of the attack, including LSD, MDMA, Ketamine, Cannabis, and Alcohol, creating a tragic and unique natural experiment to study the impact of psychoactive compounds on trauma processing. Analysis revealed that participants that were under the influence of MDMA during the attack (n=99) reported feeling less overwhelmed, having more social interactions, improved sleep quality, and reduced psychological distress compared to those not under the influence of any substance during the attack (n=216). In contrast, those consuming Cannabis and/or Alcohol during the attack (n=68) showed higher psychological distress, more PTSD symptoms, and worse sleep quality compared to those not under the influence of any substance during the attack. Together, these novel findings suggest that trauma exposure under the influence of MDMA is associated with reduced psychological distress and higher sociality, possibly mediated through MDMAs known effects of reducing negative emotions and elevating prosociality, while Cannabis and/or Alcohol consumption produces deleterious effects. Further research is needed to explore the cognitive and physiological mechanisms linking psychoactive substances to trauma recovery and establish the putative protective role of MDMA.

neuroscience↗

The Body Knows Better: Sensorimotor signals reveal "Suboptimal" inference of the Sense of Agency in the human mind

Sense of Agency (SoA) is the feeling of control over our actions. SoA has been suggested to arise from both implicit sensorimotor integration as well as higher-level decision processes. SoA is typically measured by collecting participants subjective judgments, conflating both implicit and explicit processing. Consequently, the interplay between implicit sensorimotor processing and explicit agency judgments is not well understood. Here, we evaluated in one exploratory and one preregistered experiment (N=60), using a machine learning approach, the relation between a well-known mechanism of implicit sensorimotor adaptation and explicit SoA judgments. Specifically, we examined whether subjective judgments of SoA and sensorimotor conflicts could be inferred from hand kinematics in a sensorimotor task using a virtual hand (VH). In both experiments participants performed a hand movement and viewed a virtual hand making a movement that could either be synchronous with their action or include a parametric temporal delay. After each movement, participants judged whether their actual movement was congruent with the movement they observed. Our results demonstrated that sensorimotor conflicts could be inferred from implicit motor kinematics on a trial by trial basis. Moreover, detection of sensorimotor conflicts from machine learning models of kinematic data provided more accurate classification of sensorimotor congruence than participants explicit judgments. These results were replicated in a second, preregistered, experiment. These findings show evidence of diverging implicit and explicit processing for SoA and suggest that the brain holds high-quality information on sensorimotor conflicts that is not fully utilized in the inference of conscious agency.

neuroscience↗

Systematic comparison of high throughput Single-Cell RNA-Seq platforms in complex tissues

Single-cell transcriptomics has emerged as the preferred tool to define cell identity through the analysis of gene expression signatures. However, there are limited studies that have comprehensively compared the performance of different scRNAseq systems in complex tissues. Here, we present a systematic comparison of two well-established high throughput 3-scRNAseq platforms: 10x Chromium and BD Rhapsody, using tumours that present high cell diversity. Our experimental design includes both fresh and artificially damaged samples from the same tumours, which also provides a comparable dataset to examine their performance under challenging conditions. The performance metrics used in this study consist of gene sensitivity, mitochondrial content, reproducibility, clustering capabilities, cell type representation and ambient RNA contamination. These analyses showed that BD Rhapsody and 10x Chromium have similar gene sensitivity, while BD Rhapsody has the highest mitochondrial content. Interestingly, we found cell type detection biases between platforms, including a lower proportion of endothelial and myofibroblast cells in BD Rhapsody and lower gene sensitivity in granulocytes for 10x Chromium. Moreover, the source of the ambient noise was different between plate-based and droplet-based platforms. In conclusion, our reported platform differential performance should be considered for the selection of the scRNAseq method during the study experimental designs.

genomics↗

Attachment Stimuli Trigger Widespread Synchrony across Multiple Brains

Infant stimuli elicit widespread neural and behavioral response in human adults and such massive allocation of resources attests to the evolutionary significance of the primary attachment. Here, we examined whether attachment-related cues also trigger cross-brain concordance, generating greater neural uniformity among individuals. Post-partum mothers were imaged twice in oxytocin/placebo administration design and stimuli included four ecological videos; two of infant/mother alone (Alone) and two mother-infant dyadic contexts (Social). Theory-driven analysis measured cross-brain synchrony in preregistered nodes of the parental caregiving network (PCN), which integrates subcortical structures underpinning mammalian mothering with cortical areas implicated in simulation, mentalization, and emotion regulation, and data--driven analysis assessed brain-wide concordance using whole brain parcellation. Results demonstrated widespread cross-brain synchrony in both the PCN and across the neuroaxis, from primary sensory and somatosensory areas, through insular-cingulate regions, to temporal and prefrontal cortices. The Social context yielded significantly more cross-brain concordance, with PCNs striatum, parahipporcampal gyrus, superior temporal sulcus, anterior cingulate cortex (ACC), and prefrontal cortex displaying cross-brain synchrony only to mother-infant social cues. Moment-by-moment fluctuations in mother-infant social synchrony, ranging from episodes of gaze aversion to rhythmically-coordinated positive bouts, were tracked online by cross-brain concordance in the pre-registered ACC. Findings indicate that social attachment stimuli, representing evolutionary-salient universal cues that require no verbal narrative for immediate comprehension, trigger substantial inter-brain concordance and suggest that the mother-infant bond, an icon standing at the heart of human civilization, may function to glue brains into a unified experience and bind humans into social groups. Significance StatementInfant stimuli elicit widespread neural response in human adults, attesting to their evolutionary significance, but do they also trigger cross-brain concordance and induce neural uniformity among perceivers? We measured cross-brain synchrony to ecological mother-infant videos. We employed theory-driven analysis, measuring cross-brain concordance in the parenting network, and data-driven analysis, assessing brain-wide concordance using whole-brain parcellation. Attachment cues triggered widespread cross-brain concordance in both the parenting network and across the neuroaxis. Moment-by-moment fluctuations in behavioral synchrony were tracked online by cross-brain variability in ACC. Attachment reminders bind humans brains into a unitary experience and stimuli characterized by social synchrony enhance neural similarity among participants, describing one mechanism by which attachment bonds provide the neural template for the consolidation of social groups.

neuroscience↗

Disentangling the Neural Correlates of Agency, Ownership and Multisensory Processing

The experience of the self as an embodied agent in the world is an essential aspect of human consciousness. This experience arises from the feeling of control over ones bodily actions, termed the Sense of Agency (SoA), and the feeling that the body belongs to the self, Body Ownership (BO). Despite long-standing philosophical and scientific interest in the relationship between the body and brain, the neural systems involved in SoA and BO and especially their interactions, are not yet understood. In this preregistered study using the Moving Rubber Hand Illusion inside an MR-scanner, we aimed to uncover the relationship between BO & SoA in the human brain. Importantly, by using both visuomotor and visuotactile stimulations and measuring online trial-by-trial fluctuations in the illusion magnitude, we were able to disentangle brain systems related to objective sensory stimulation and subjective judgments of the bodily-self. Our results indicate that at both the behavioral and neural levels, BO and SoA are strongly interrelated. Multisensory regions in the occipital and fronto-parietal regions encoded convergence of sensory stimulation conditions. However, the subjective judgments of bodily-self were also related to BOLD fluctuations in regions not activated by the sensory conditions such as the insular cortex and precuneus. Our results highlight the convergence of multisensory processing in specific neural systems for both BO and SoA with partially dissociable regions for subjective judgments in regions of the default mode network.

neuroscience↗

Prostaglandin E1 as therapeutic molecule for Nephronophthisis and related ciliopathies

Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using an in cellulo medium-throughput drug-screen, we identified 51 FDA-approved compounds and selected 11 for their physicochemical properties, including prostaglandin E1 (PGE1). PGE1 was further validated to rescue ciliogenesis in immortalized patient NPHP1-/- urine-derived renal tubular cells and corroborated by the effects of its analog PGE2. The two molecules reduced pronephric cyst occurrence in vivo in nphp4 zebrafish model, and PGE1 treatment in Nphp1-/- mice led to a significant reduction of renal tubular dilatations, partially restoring cilia length within tubules. Finally, comparative transcriptomics allowed identification of key molecules downstream PGE1. Altogether, our drug-screen strategy led to the identification of PGE1 as the first potential therapeutic molecule for NPH-associated ciliopathies. Significant statementJuvenile nephronophthisis (NPH) is a renal ciliopathy due to a dysfunction of primary cilia and a common genetic cause of end-stage renal disease in children and young adults. No curative treatment is available. This paper describes the identification of Prostaglandin E1 (PGE1) as the first potential therapeutic molecule for NPH-associated ciliopathies. We demonstrated that PGE1 rescues defective ciliogenesis and ciliary composition in NPHP1-/- patient urine-derived renal tubular cells. Furthermore, PGE1 improves ciliary and kidney phenotypes in our NPH zebrafish and Nphp1-/- mouse models. Finally, in vitro experiments as well as transcriptomic analyses pointed out several pathways downstream PGE1 as cAMP, cell-cell/cell-matrix adhesion or actin cytoskeleton. Altogether, our findings provide a new alternative for treatment of NPH.

cell biology↗

Judgments of agency are affected by sensory noise without recruiting metacognitive processing

Judgments of agency, our sense of control over our actions and the environment, often occur in noisy conditions. We examined the computations underlying judgments of agency, in particular under the influence of sensory noise. Building on previous literature, we studied whether judgments of agency incorporate uncertainty in the same way that confidence judgments do, which would imply that the former share computational mechanisms with metacognitive judgments. In two tasks, participants rated agency, or confidence in a decision about their agency, over a virtual hand that tracked their movements, either synchronously or with a delay and either under high or low noise. We compared the predictions of two computational models to participants ratings and found that agency ratings, unlike confidence, were best explained by a model involving no estimates of sensory noise. We propose that agency judgments reflect first-order measures of the internal signal, without involving metacognitive computations, challenging the assumed link between the two cognitive processes.

neuroscience↗

Neural Representation of the Relational Self from Infancy to Adulthood

Investigations into the neural underpinnings of the "self" highlight its complexity and multi-dimensionality and emphasize that various aspects of the self are sustained by different neural systems. Here, we focused on the Relational Self, a dimension denoting the self-within-attachment-relationships that taps the continuity of attachment across individual development and affiliative bonds. Mothers and children were followed across two decades and videotaped in naturalistic interactions at three ages: infancy (3-6 months), childhood (9-12 years), and young adulthood (18-24 years). During fMRI scanning, young adults were exposed to videos of their own mother-child interactions from the three ages versus matched unfamiliar interactions. Relational Self-stimuli elicited greater activations across preregistered nodes of the human caregiving network, including thalamus-to-brainstem, amygdala, hippocampus, ACC, insula, and temporal cortex. Critically, Relational Self-stimuli were age-invariant in most regions of interest despite large variability of stimuli across multiple self-related features, such as similarity, temporal distance, affect, or mentalization, and Bayesian analysis indicated strong evidence for lack of age-related differences. PPI analysis demonstrated that Relational Self-stimuli elicited tighter connectivity between the ACC and insula. Greater child social engagement during interaction with mother correlated with higher ACC and insula response to Relational Self-stimuli. Findings highlight an important novel dimension in the neural representation of the self, suggest that the Relational Self may be sustained by a paralimbic interface integrating exteroceptive and interoceptive self-related signals, and demonstrate overlap in the attachment network of parents and children, lending support to perspectives on the continuity of attachment and self across the individuals developmental history. Significance StatementDescribing the neural underpinnings of the "self" is inherently complex due to the multi-dimensionality of the construct. Following mothers and children from infancy to adulthood, we focused on the Relational Self, a dimension denoting the self-within-attachment-relationships, and exposed young adults to own versus unfamiliar mother-child interactions across their relational history. Relational Self stimuli triggered greater activations in the human caregiving network, including thalamus-to-brainstem, amygdala, hippocampus, ACC, insula, and temporal cortex, were age-invariant, and elicited tighter connectivity between ACC and insula, creating a paralimbic interface of interoception-exteroception sustaining the Relational Self. Findings highlight a novel dimension in the neural representation of the self and lend support to perspectives emphasizing the cross-generational transmission of attachment and its continuity across the individuals developmental history.

neuroscience↗

The renal inflammatory network of nephronophthisis.

STRUCTURED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSThe majority of genetic kidney disease leading to kidney failure is caused by mutations in ciliary genes. How cilia malfunction leads to progressive kidney damage is poorly understood, but recent evidence links ciliopathy genes to CCL2 dependent macrophage recruitment in autosomal dominant polycystic kidney disease (ADPKD), the most studied renal ciliopathy. Whether or not renal inflammation is involved in other renal ciliopathies is unclear. METHODSWe combined mice models with kidney biopsies and renal epithelial cells sampled from human urine to characterize the renal inflammatory network of nephronophthisis (NPH), the most frequent renal ciliopathy in children. RESULTSIn human, mutations in cilia genes involved in NPH enhance urine excretion of the chemokine CCL2, causing abnormal macrophage recruitment in kidney tissues from NPH patients. Differing from ADPKD, inactivating Ccl2 specifically in mouse tubular cells does not rescue the NPH phenotype, suggesting that other inflammatory mediators are involved. Using transcriptional data from 2 NPH models, we identify a set of pro-inflammatory cytokines upregulated in this disease, independently of CCL2. The majority of detectable transcripts from this set are specifically upregulated in kidney cells from NPH patients. In line with the function of these cytokines, NPH kidneys show disproportionate neutrophils and T cells infiltrates compared to healthy subject or hypertensive and diabetic chronic kidney disease patients. CONCLUSIONSThis study reveals that inflammation is a central aspect in human NPH and delineates a specific set of inflammatory mediators that regulates immune cell recruitment in human NPH. SIGNIFICANCE STATEMENTMutations in genes encoding primary cilia proteins are the leading cause of genetic kidney failure. In autosomal dominant polycystic kidney disease (ADPKD), deregulated cilia signaling leads to kidney infiltration by macrophages through the chemokine CCL2. Little is known about renal inflammation in nephronophthisis (NPH), the most frequent pediatric renal ciliopathy. Using NPH mice models, tissues and cells from NPH patients, we unveil renal inflammation as preeminent feature of NPH. Remarkably, the renal inflammatory evoked by ciliary gene mutations in NPH does not overlap with ADPKD: it is CCL2 independent, involves a prominent recruitment of neutrophils and T cells and a specific cytokine signature. This unforeseen findings strengthen the link between primary cilia and renal inflammation.

physiology↗

Mother Brain is Wired for Social Moments

Reorganization of the maternal brain, primed by oxytocin surge during childbirth, triggers the species-typical maternal social behavior. These brief social moments carry profound effects on the infants social brain and likely have a distinct signature in the maternal brain. Utilizing a double-blind, oxytocin/placebo administration crossover design, we imaged mothers twice while observing three naturalistic maternal-infant contexts in the home ecology; "unavailable", "unresponsive", and "social", when mothers engaged in synchronous pick-a-boo play. We found four processes by which mothers brain registers social moments. Salience - social moments increased activations throughout the maternal brain network; Brain-behavior coupling - caregiving behavior linked with socially-driven neural response; Oxytocin sensitivity - administration impacted neural response mainly to the social context; and Temporal engrams-consistent temporal patterns in insula and TP characterized response to social play. Findings describe how mothers brain compiles and amplifies these precious social moments to generate dyad-specific brain-behavior patterns that initiate the cross-generational transmission of human sociality.

neuroscience↗

Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes

Systemic Lupus Erythematosus (SLE) is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. To identify genetic factors associated with SLE we performed whole exome sequencing and identified two RELA heterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-{kappa}B consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFN-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets. SummaryHeterozygous RELA mutations are associated with Systemic Lupus Erythematosus, with increased expression of genes controlled by the IFN-consensus sequences.

immunology↗