De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay.

The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature

In a substantial share of patients suffering from multiple sclerosis (MS), neurological functions slowly deteriorate despite a lack of radiological activity. Such a silent progression, observed in either relapsing-remitting or progressive forms of MS, is driven by mechanisms that appear to be independent from plaque activity. In this context, we previously reported that, in the spinal cord of MS patients, periplaques cover large surfaces of partial demyelination characterized notably by a transforming growth factor beta (TGF-beta) molecular signature and a decreased expression of the oligodendrocyte gene NDRG1 (N-Myc downstream regulated 1). In the present work, we re-assessed a previously published RNA expression dataset in which brain periplaques were originally used as internal controls. When comparing the mRNA profiles obtained from brain periplaques with those derived from control normal white matter samples, we found that, irrespective of plaque activity, brain periplaques exhibited a TGF-beta molecular signature, an increased expression of TGFB2 (transforming growth factor beta 2) and a decreased expression of the oligodendrocyte genes NDRG1 (N-Myc downstream regulated 1) and MAG (myelin-associated glycoprotein). From these data obtained at the mRNA level, a survey of the human proteome allowed predicting a protein–protein interaction network linking TGFB2 to the down-regulation of both NDRG1 and MAG in brain periplaques. To further elucidate the role of NDRG1 in periplaque-associated partial demyelination, we then extracted the interaction network linking NDRG1 to proteins detected in human central myelin sheaths. We observed that such a network was highly significantly enriched in RNA-binding proteins that notably included several HNRNPs (heterogeneous nuclear ribonucleoproteins) involved in the post-transcriptional regulation of MAG. We conclude that both brain and spinal cord periplaques host a chronic process of tissue remodeling, during which oligodendrocyte myelinating functions are altered. Our findings further suggest that TGFB2 may fuel such a process. Overall, the present work provides additional evidence that periplaque-associated partial demyelination may drive the silent progression observed in a subset of MS patients

Characterization of a Topically Testable Model of Burn Injury on Human Skin Explants

International audienceSevere burn injuries remain a major health problem due to high rates of mortality, residual morbidity, and/or aesthetic damages. To find new therapies aimed at promoting a harmonious healing of skin burns, it is important to develop models which take into account the unique properties of the human skin. Based on previously described models of burn injury performed on human skin explants, we hypothesized that maintaining explants under constant tension forces would allow to more closely reproduce the pathophysiological processes of skin remodeling. We thus. Here, we set up and characterized an improved model of deep second-degree burn injury on ex vivo cultured human skin explants at air-liquid interface and maintained under conditions of constant tension forces. A spontaneous re-epithelialization of the lesion was observed 8 to 9 days post burn and was found to rely on the proliferation of basal keratinocytes at the wound edges. Collagen VII at the dermo-epidermal junction reformed along with the progression of re-epithelializatio and a synthesis of procollagen III was observed in the dermis at the wound site. These findings indicate that our model is suitable for the assessment of clinically-relevant therapies aimed at modulating the kinetics of re-epithelialization and/or the activation of fibroblasts following skin burn injuries. In this regard, we evaluated the use of a thermoreversible poloxamer hydrogel as a vehicle for topically-testable therapeutic molecules. Our data showed that, although useful for drug formulation, the p407/p188 poloxamer hydrogel induces a delay of skin re-epithelialization in humans skin explants submitted to experimental burn injury

Perceptive biases in major depressive episode

INTRODUCTION: Alterations in emotional processing occur during a major depressive episode (MDE), and olfaction and facial expressions have implications in emotional and social interactions. To gain a better understanding of these processes, we characterized the perceptive sensorial biases, potential links, and potential remission after antidepressant treatment of MDE. METHODS: We recruited 22 patients with acute MDE, both before and after three months of antidepressant treatment, and 41 healthy volunteers matched by age and smoking status. The participants underwent a clinical assessment (Mini International Neuropsychiatry Interview, Montgomery-Åsberg Depression Rating Scale, State-Trait Anxiety Inventory, Physical and Social Anhedonia scales, Pleasure-Displeasure Scale), an olfactory evaluation (hedonic aspect, familiarity and emotional impact of odors), and a computerized Facial Affect Recognition task. RESULTS: MDE was associated with an olfactory bias concerning hedonic and emotional aspects, including negative olfactory alliesthesia (unpleasant odorants perceived as more unpleasant), facial emotion expression recognition (happy facial expressions), and in part olfactory anhedonia (pleasant odorants perceived as less pleasant). In addition, the results revealed that these impairments represent state markers of MDE, suggesting that the patients recovered the same sensory processing as healthy subjects after antidepressant treatment. DISCUSSION: This study demonstrated that MDE is associated with negative biases toward olfactory perception and the recognition of facial emotional expressions. The link between these two sensory parameters suggests common underlying processes

Discrimination accuracy of each emotional face.

<p>Between-groups comparison of mean (SD) discrimination accuracy of emotional faces (presented for 500 ms and 2000 ms). Patients at V1 versus patients at V2 (Wilcoxon test; ^*≤0.05, ^***≤0.01, ^****≤0.001); patients at V1 versus controls (Mann- Whitney test; ^##≤0.025); patients at V2 versus controls (Mann-Whitney test; ^ttt≤0.01). The level of significance was set at p = 0.025 to avoid error due to multiple comparisons; a 0.05 level indicates a marginal effect.</p

Odor hedonic scores.

<p>Comparison of the mean of odor hedonic scores (SD) of pleasant, neutral, and unpleasant odorants among depressed patients (n = 22), clinically improved patients (n = 22), and controls (n = 41).</p><p><i>Patients at V1 versus patients at V2 (Wilcoxon test: ^***≤0.01).</i></p><p><i>Patients at V1 versus controls (Mann-Whitney test: ^#≤0.05, ^###≤0.01).</i></p><p><i>The level of significance was set at p = 0.025 to avoid error due to multiple comparisons; a 0.05 level indicates a marginal effect.</i></p

Emotional responses to odors.

<p>Between-groups comparison of the emotional responses to odors (z test). Patients at V1 versus patients at V2 (^***≤0.01, ^****≤0.001); patients at V1 versus controls (^#≤0.05, ^###≤0.01); patients at V2 versus controls (^ttt≤0.01). The level of significance was set at p = 0.025 to avoid error due to multiple comparisons; a 0.05 level indicates a marginal effect.</p

Clinical scale scores.

<p>Comparison of the mean (SD) of physical and social anhedonia scores and pleasure-displeasure scores among depressed patients (n = 22), clinically improved patients (n = 22), and controls (n = 41).</p><p><i>Patients at V1 versus patients at V2 (Wilcoxon test: ^*≤0.05, ^**≤0.025).</i></p><p><i>Patients at V1 versus controls (Mann-Whitney test: ^##≤0.025, ^####≤0.001).</i></p><p><i>Patients at V2 versus controls (Mann-Whitney test: ^tttt≤0.001).</i></p><p><i>The level of significance was set at p = 0.025 to avoid error due to multiple comparisons; a 0.05 level indicates a marginal effect.</i></p