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Prenatal processes are likely critical for the differences in cognitive ability and disease risk that unfold in postnatal life. Prenatally established cortical folding patterns are increasingly studied as an adult proxy for earlier development events - under the as yet untested assumption that an individual's folding pattern is developmentally fixed. Here, we provide the first empirical test of this stability assumption using 263 longitudinally-acquired structural MRI brain scans from 75 typically developing individuals spanning ages 7 to 32 years. We focus on the anterior cingulate cortex (ACC) - an intensely studied cortical region that presents two qualitatively distinct and reliably classifiable sulcal patterns with links to postnatal behavior. We show - without exception-that individual ACC sulcal patterns are fixed from childhood to adulthood, at the same time that quantitative anatomical ACC metrics are undergoing profound developmental change. Our findings buttress use of folding typology as a postnatally-stable marker for linking variations in early brain development to later neurocognitive outcomes in ex utero life.

Addresses the issue of policing the ethics of the British Members of Parliament. Debate surrounding the nature of parliamentary autonomy and self-regulation; Essential component of parliamentary privilege.

Motor activity is organized by neuronal networks composed of motor neurons and a wide variety of pre-motor interneuron populations located in the brainstem and spinal cord. Differential expression and single-cell RNA sequencing studies recently unveiled that these populations subdivide into multiple subsets. However, some interneuron subsets have not been described yet, and the mechanisms contributing to this neuronal diversification have only been partly deciphered. In this study, we aimed to identify additional markers to further describe the diversity of spinal V2 interneuron populations. Here, we compared the transcriptome of V2 interneurons with that of the other cells of the embryonic spinal cord and extracted a list of genes enriched in V2 interneurons, including Arid3c . Arid3c identifies an uncharacterized subset of V2 that partially overlaps with V2c interneurons. These two populations are characterized by the production of Onecut factors and Sox2, suggesting that they could represent a single functional V2 unit. Furthermore, we show that the overexpression or inactivation of Arid3c does not alter V2 production, but its absence results in minor defects in locomotor execution, suggesting a possible function in subtle aspects of spinal locomotor circuit formation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Renaux, Baudouin, Schakman, Gay, Martin, Marchese, Achouri, Rezsohazy, Gofflot and Clotman.)

Aim: Neuroimaging-based machine-learning predictions of psychosis onset rely on the hypothesis that structural brain anomalies may reflect the underlying pathophysiology. Yet, current predictors remain difficult to interpret in light of brain structure. Here, we combined an advanced interpretable supervised algorithm and a model of neuroanatomical age to identify the level of brain maturation of the regions most predictive of psychosis., Methods: We used the voxel-based morphometry of a healthy control dataset (N = 2024) and a prospective longitudinal UHR cohort (N = 82), of which 27 developed psychosis after one year. In UHR, psychosis was predicted at one year using Elastic-Net-Total-Variation (Enet-TV) penalties within a five-fold cross-validation, providing an interpretable map of distinct predictive regions. Using both the whole brain and each predictive region separately, a brain age predictor was then built and validated in 1605 controls, externally tested in 419 controls from an independent cohort, and applied in UHR. Brain age gaps were computed as the difference between chronological and predicted age, providing a proxy of whole-brain and regional brain maturation., Results: Psychosis prediction was performant with 80 ± 4% of area-under-curve and 69 ± 5% of balanced accuracy (P < 0.001), and mainly leveraged volumetric increases in the ventromedial prefrontal cortex and decreases in the left precentral gyrus and the right orbitofrontal cortex. These regions were predicted to have delayed and accelerated maturational patterns, respectively., Conclusion: By combining an interpretable supervised model of conversion to psychosis with a brain age predictor, we showed that inter-regional asynchronous brain maturation underlines the predictive signature of psychosis., (© 2023 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: Gender differences in symptomatology in chronic schizophrenia and first episode psychosis patients have often been reported. However, little is known about gender differences in those at risk of psychotic disorders. This study investigated gender differences in symptomatology, drug use, comorbidity (i.e. substance use, affective and anxiety disorders) and global functioning in patients with an at-risk mental state (ARMS) for psychosis., Methods: The sample consisted of 336 ARMS patients (159 women) from the prodromal work package of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI; 11 centers). Clinical symptoms, drug use, comorbidity and functioning were assessed at first presentation to an early detection center using structured interviews., Results: In unadjusted analyses, men were found to have significantly higher rates of negative symptoms and current cannabis use while women showed higher rates of general psychopathology and more often displayed comorbid affective and anxiety disorders. No gender differences were found for global functioning. The results generally did not change when corrected for possible cofounders (e.g. cannabis use). However, most differences did not withstand correction for multiple testing., Conclusions: Findings indicate that gender differences in symptomatology and comorbidity in ARMS are similar to those seen in overt psychosis and in healthy controls. However, observed differences are small and would only be reliably detected in studies with high statistical power. Moreover, such small effects would likely not be clinically meaningful., (Copyright © 2019. Published by Elsevier Masson SAS.)

The exact modalities of switching between two antipsychotics are rarely studied despite the high frequency of this issue in clinical practice. In this context, description of clinical cases may be enlightening. We report on three new cases of agitation after replacing a dopaminergic antagonist with aripiprazole. A literature review indicated no other predictive clinical feature associated with a higher risk of agitation than therapeutic history. In fact, patients who previously received a greater dose of antipsychotic are more at risk to present paradoxical agitation when switching to aripiprazole. This has led to the hypothesis of dopaminergic hypersensitivity: dopaminergic antagonists could increase the number of receptors to be activated by a partial agonist-like aripiprazole. In one of the cases described here, the patient had received aripiprazole two years previously without any particular side effects. The reintroduction of aripiprazole after a treatment by risperidone was followed by agitation. Other pharmacological hypotheses to explain this agitation involve cholinergic and histaminergic rebounds as well. The frequency of these paradoxical reactions is probably underreported, and psychiatrists should be more attentive to them. During the replacement, aripiprazole should be prescribed at the maximal posology from the start, and the previous antipsychotic should be maintained and slowly decreased in no fewer than four weeks., (Copyright © 2017 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Background: Several clinical and radiological markers of early neurodevelopmental deviations have been independently associated with cognitive impairment in patients with schizophrenia. The aim of our study was to test the cumulative and/or interactive effects of these early neurodevelopmental factors on cognitive control (CC) deficit, a core feature of schizophrenia., Methods: We recruited patients with first-episode schizophrenia-spectrum disorders, who underwent structural MRI. We evaluated CC efficiency using the Trail Making Test (TMT). Several markers of early brain development were measured: neurological soft signs (NSS), handedness, sulcal pattern of the anterior cingulate cortex (ACC) and ventricle enlargement., Results: We included 41 patients with schizophrenia in our analysis, which revealed a main effect of ACC morphology ( p = 0.041) as well as interactions between NSS and ACC morphology ( p = 0.005), between NSS and handedness ( p = 0.044) and between ACC morphology and cerebrospinal fluid (CSF) volume ( p = 0.005) on CC measured using the TMT-B score - the TMT-A score., Limitations: No 3- or 4-way interactions were detected between the 4 neurodevelopmental factors. The sample size was clearly adapted to detect main effects and 2-way interactions, but may have limited the statistical power to investigate higher-order interactions. The effects of treatment and illness duration were limited as the study design involved only patients with first-episode psychosis., Conclusion: To our knowledge, our study provides the first evidence of cumulative and interactive effects of different neurodevelopmental markers on CC efficiency in patients with schizophrenia. Such findings, in line with the neurodevelopmental model of schizophrenia, support the notion that CC impairments in patients with schizophrenia may be the final common pathway of several early neurodevelopmental mechanisms.

Refilins (RefilinA and RefilinB) are members of a novel family of Filamin binding proteins that function as molecular switches to conformationally alter the Actin filament network into bundles. We show here that Refilins are extremely labile proteins. An N-terminal PEST/DSG(X) 2-4 S motif mediates ubiquitin-independent rapid degradation. A second degradation signal is localized within the C-terminus. Only RefilinB is protected from rapid degradation by an auto-inhibitory domain that masks the PEST/DSG(X) 2-4 S motif. Dual regulation of RefilinA and RefilinB stability was confirmed in rat brain NG2 precursor cells (polydendrocyte). Using loss- and gain-of-function approaches we show that in these cells, and in U373MG cells, Refilins contribute to the dynamics of lamellipodium protrusion by catalysing Actin bundle formation within the lamella Actin network. These studies extend the Actin bundling function of the Refilin-Filamin complex to dynamic regulation of cell membrane remodelling., Competing Interests: The authors declare no competing or financial interests., (© 2016. Published by The Company of Biologists Ltd.)

Background: Several clinical and radiological markers of early neurodevelopmental deviations have been independently associated with cognitive impairment in patients with schizophrenia. The aim of our study was to test the cumulative and/or interactive effects of these early neurodevelopmental factors on cognitive control (CC) deficit, a core feature of schizophrenia., Methods: We recruited patients with first-episode schizophrenia-spectrum disorders, who underwent structural MRI. We evaluated CC efficiency using the Trail Making Test (TMT). Several markers of early brain development were measured: neurological soft signs (NSS), handedness, sulcal pattern of the anterior cingulate cortex (ACC) and ventricle enlargement., Results: We included 41 patients with schizophrenia in our analysis, which revealed a main effect of ACC morphology ( p = 0.041) as well as interactions between NSS and ACC morphology ( p = 0.005), between NSS and handedness ( p = 0.044) and between ACC morphology and cerebrospinal fluid (CSF) volume ( p = 0.005) on CC measured using the TMT-B score - the TMT-A score., Limitations: No 3- or 4-way interactions were detected between the 4 neurodevelopmental factors. The sample size was clearly adapted to detect main effects and 2-way interactions, but may have limited the statistical power to investigate higher-order interactions. The effects of treatment and illness duration were limited as the study design involved only patients with first-episode psychosis., Conclusion: To our knowledge, our study provides the first evidence of cumulative and interactive effects of different neurodevelopmental markers on CC efficiency in patients with schizophrenia. Such findings, in line with the neurodevelopmental model of schizophrenia, support the notion that CC impairments in patients with schizophrenia may be the final common pathway of several early neurodevelopmental mechanisms.

Schizophrenia is a complex brain disorder associated with numerous etiological factors and pathophysiological pathways leading to multiple clinical outcomes. Compelling evidence suggests that deviations in neurodevelopmental processes are a major risk factor of schizophrenia. The identification of patients with high neurodevelopmental deviance is an important issue as it could help to identify homogeneous subgroups of patients with similar pathophysiological pathways, a key step to decipher the etiology of this complex condition. Several clinical arguments suggest that schizophrenia patients with Neurological Soft Signs (NSS)--ie, observable defects in motor coordination, motor integration, and sensory integration--would have high neurodevelopmental deviance. Based on the analysis of magnetic resonance imaging of 44 first-episode psychosis patients, we compared the cortex morphology, a marker of brain development, in patients with NSS vs patients with nonsignificant NSS. The cortex morphology was automatically assessed from three-dimensional global sulcal index (g-SI, the ratio between total sulcal area and outer cortex area) and regional sulcal indexes (r-SI, the ratio between the area of pooled labeled sulci and the total outer cortex area). Patients with NSS were found to have a lower g-SI in both hemispheres and a lower r-SI in left dorsolateral prefrontal and right lateral occipital cortices. Exploratory analyses revealed correlations between NSS dimensions and r-SI in distinct cortical areas, including dorsolateral and medial prefrontal cortices, lateral temporal, occipital, superior parietal, and medial parieto-occipital cortices. These findings provide evidence of distinct neurodevelopmental pathways in patients with NSS as compared with patients with nonsignificant NSS.

The Refilins (RefilinA and RefilinB) are a novel family of short-lived actin regulatory proteins that are expressed during changes in cellular phenotype such as epithelial to mesenchymal transition (EMT). The Refilins promote to the formation of actin- and myosin-rich perinuclear bundles that are characteristic of cellular phenotypic switches. In epithelial cells, RefilinB is up-regulated in response to TGF-β stimulation and function in organization of apical perinuclear actin fibers during early stage of the EMT process1. In fibroblasts, RefilinB stabilizes perinuclear parallel actin bundles which resemble actin cap 2. Refilins bind and modulate the function of Filamin A (FLNA). Upon binding to Refilins, FLNA is capable of assembling actin filaments into parallel bundles, possibly by undergoing conformational changes at the C-terminal. Perinuclear actin structures determine nuclear shape, cell morphology, cell adhesion and possibly cell proliferation and gene regulation. Identifying the role of Refilins in organizing perinuclear actin networks provides additional insight in the process of intracellular mechanotransduction that regulate changes in cellular phenotype such as those observed during EMT.

Actin cytoskeleton dynamics lie at the heart of cell mechanosensing signaling. In fibroblast cells, two perinuclear acto-myosin structures, the actin cap and the transmembrane actin-associated nuclear (TAN) line, are components of a physical pathway transducing extracellular physical signals to changes in nuclear shape and movements. We recently demonstrated the existence of a previously uncharacterized third apical perinuclear actin organization in epithelial cells that forms during epithelial-mesenchymal transition (EMT) mediated by TGFβ (TGFβ). A common regulatory mechanism for these different perinuclear actin architectures has emerged with the identification of a novel family of actin bundling proteins, the Refilins. Here we provide updates on some characteristics of Refilin proteins, and we discuss potential function of the Refilins in cell mechanosensing signaling.

The intracellular localization and shape of the nucleus plays a central role in cellular and developmental processes. In fibroblasts, nuclear movement and shape are controlled by a specific perinuclear actin network made of contractile actin filament bundles called transmembrane actin-associated nuclear (TAN) lines that form a structure called the actin cap. The identification of regulatory proteins associated with this specific actin cytoskeletal dynamic is a priority for understanding actin-based changes in nuclear shape and position in normal and pathological situations. Here, we first identify a unique family of actin regulators, the refilin proteins (RefilinA and RefilinB), that stabilize specifically perinuclear actin filament bundles. We next identify the actin-binding filamin A (FLNA) protein as the downstream effector of refilins. Refilins act as molecular switches to convert FLNA from an actin branching protein into one that bundles. In NIH 3T3 fibroblasts, the RefilinB/FLNA complex organizes the perinuclear actin filament bundles forming the actin cap. Finally, we demonstrate that in epithelial normal murine mammary gland (NmuMG) cells, the RefilinB/FLNA complex controls formation of a new perinuclear actin network that accompanies nuclear shape changes during the epithelial-mesenchymal transition (EMT). Our studies open perspectives for further functional analyses of this unique actin-based network and shed light on FLNA function during development and in human syndromes associated with FLNA mutations.

Dynamic interactions between components of the outer (OM) and inner (IM) membranes control a number of critical mitochondrial functions such as channeling of metabolites and coordinated fission and fusion. We identify here the mitochondrial AAA(+) ATPase protein ATAD3A specific to multicellular eukaryotes as a participant in these interactions. The N-terminal domain interacts with the OM. A central transmembrane segment (TMS) anchors the protein in the IM and positions the C-terminal AAA(+) ATPase domain in the matrix. Invalidation studies in Drosophila and in a human steroidogenic cell line showed that ATAD3A is required for normal cell growth and cholesterol channeling at contact sites. Using dominant-negative mutants, including a defective ATP-binding mutant and a truncated 50-amino-acid N-terminus mutant, we showed that ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery. The capacity of ATAD3A to impact essential mitochondrial functions and organization suggests that it possesses unique properties in regulating mitochondrial dynamics and cellular functions in multicellular organisms.

Quantum key distribution (QKD) is the first commercial quantum technology operating at the level of single quanta and is a leading light for quantum-enabled photonic technologies. However, controlling these quantum optical systems in real world environments presents significant challenges. For the first time, we have brought together three key concepts for future QKD systems: a simple high-speed protocol; high performance detection; and integration both, at the component level and for standard fibre network connectivity. The QKD system is capable of continuous and autonomous operation, generating secret keys in real time. Laboratory and field tests were performed and comparisons made with robust InGaAs avalanche photodiodes and superconducting detectors. We report the first real world implementation of a fully functional QKD system over a 43 dB-loss (150 km) transmission line in the Swisscom fibre optic network where we obtained average real-time distribution rates over 3 hours of 2.5 bps.

A large body of research documents the high prevalence and devastating consequences of substance abuse among individuals diagnosed with schizophrenia. One prominent theory of the high rate of comorbidity between these disorders is that substance abuse in schizophrenia is an attempt to self-medicate psychiatric symptoms including negative symptoms and depression as well as side effects including extrapyramidal reactions (EPR). Consistent with this notion, novel antipsychotic medications, which have been shown to reduce negative and depressive symptoms while exhibiting a lower propensity to cause EPR, have been associated with reduced substance abuse in patients with schizophrenia. To further explore the self-medication hypothesis as it relates to the mechanism by which atypical antipsychotics reduce substance abuse, we compared schizophrenia patients with a history of substance abuse medicated with either conventional (n = 35) or atypical (n = 35) antipsychotics. Patients with schizophrenia who did not have a history of substance abuse who were on conventional (n = 23) vs. atypical antipsychotics (n = 29) were also examined. Assessments included the Positive and Negative Symptom Scale, Hamilton Rating Scale for Depression, Simpson-Angus, and Abnormal Involuntary Movement Scale. Compared with conventional medications, atypical antipsychotic drugs were associated with reduced levels of substance use (primarily alcohol). Interestingly, however, in substance-abusing patients there were no significant differences between patients on conventional vs. atypical agents with respect to positive or negative symptoms, depression, or EPR. These data suggest that theories related to self-medication of symptoms and side effects do not appear to account for the difference in rates of substance use found in schizophrenia patients on atypical vs. conventional antipsychotic medications.