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Abstract Tumor-associated macrophages/microglia (TAMs) are highly plastic and heterogeneous immune cells that can be immune-supportive or tumor-supportive depending of the microenvironment. TAMs are the most abundant immune cells in glioblastoma (GB), and play a key role in immunosuppression. Therefore, TAMs reprogramming toward immune-supportive cells is a promising strategy to overcome immunosuppression. By leveraging scRNAseq human GB databases, we identified that Inhibitor of Apoptosis Proteins (IAP) were expressed by TAMs. To investigate their role in TAMs-related immunosuppression, we antagonized IAP using the central nervous system permeant SMAC mimetic GDC-0152 (SMg). On explants and cultured immune cells isolated from human GB samples, SMg modified TAMs activity. We showed that SMg treatment promoted microglia pro-apoptotic and anti-tumoral function via caspase-3 pro-inflammatory cleavage and the inhibition of tumoroids growth. Then we designed a relevant immunogenic mouse GB model to decipher the spatio-temporal densities, distribution, phenotypes and function of TAMs with or without SMg treatment. We used 3D imaging techniques, a transgenic mouse with fluorescent TAM subsets and mass cytometry. We confirmed that SMg promoted microglia activation, antigen-presenting function and tumor infiltration. In addition, we observed a remodeling of blood vessels, a decrease in anti-inflammatory macrophages and an increased level of monocytes and their mo-DC progeny. This remodeling of the TAM landscape is associated with an increase in CD8 T cell density and activation. Altogether, these results demonstrated that SMg drives the immunosuppressive basal microglia toward an active phenotype with pro-apoptotic and anti-tumoral function and modifies the GB immune landscape. This identifies IAP as targets of choice for a potential mechanism-based therapeutic strategy and SMg as a promising molecule for this application.

Cet article propose une analyse de l’élaboration guillaumienne de la distinction saussurienne entre langue et parole, en termes de distinction double : entre langue et parole et entre langue et discours. Nous montrons que la singularité de cette élaboration consiste en l’adjonction d’une construction spéculative à la démarche structuraliste d’analyse du donné idiomologique et de la parole. Apparaît ainsi en pleine lumière l’empirisme de la problématique guillaumienne. La distinction entre langue et discours constitue le cadre de construction du système linguistique, qui doit permettre de rendre compte de la multiplicité des effets de discours. La distinction entre langue et parole constitue la langue comme principe d’analyse. La construction guillaumienne vise cependant également à rendre compte du mécanisme de la parole. En tant que telle, elle est néanmoins nécessairement spéculative, dans la mesure où elle s’inscrit dans la double problématique structuraliste et des rapports son/sens : la définition de la langue intervient sur le fond de l’acceptation préalable du donné du langage. À la définition saussurienne de la langue comme fonctionnement, ainsi distinguée du langage, répond une dynamisation de la distinction entre langue et parole, dont le langage fournit le cadre : l’objectalité de la langue n’est pas remise en cause, mais construite comme le produit d’un processus langagier.

Cette communication, qui s’attache à la comparaison des histoires jakobsonienne et saussurienne de la linguistique, s’efforce de montrer que ces deux horizons de rétrospection, que tout oppose (l’histoire jakobsonienne est continuiste et met en valeur l’ancienneté de la science du langage tandis que l’histoire saussurienne, outre qu’elle situe la naissance de la linguistique au dix-neuvième siècle, est au contraire faite de ruptures), impliquent deux constructions distinctes de l’objet de la linguistique, et s’opposent ainsi avant tout comme deux problématiques radicalement différentes. L’histoire jakobsonienne de la linguistique est une synthèse dialectique dont la possibilité se fonde sur un objet donné et totalisant, le langage, dont la définition n’est pas interrogée, et qui fédère également la diversité des linguistiques et des différentes disciplines ayant trait au langage. Saussure nous donne en revanche à lire la constitution progressive d’un objet, en rupture avec la connaissance commune : la langue, objet distinct du langage et objet propre de la linguistique, dont le postulat permet la théorisation du son et du sens comme objets linguistiques et l’étiologie des idiomes. Il apparaît ainsi que l’opposition jakobsonienne à Saussure témoigne avant tout de la résistance d'une problématique présaussurienne. Néanmoins, s’il s’agit là d’épistémologie, il s’agit par ailleurs, corrélativement, et quoi qu’il faille penser de l’histoire saussurienne de la linguistique, de deux mises en œuvre distinctes de l’histoire des sciences : l’une, empirique, celle de Jakobson, l’autre, épistémologique, celle de Saussure.

Abstract Background Radiotherapy is a major therapeutic approach in patients with brain tumors. However, it leads to cognitive impairments. To improve the management of radiation-induced brain sequalae, deformation-based morphometry (DBM) could be relevant. Here, we analyzed the significance of DBM using Jacobian determinants (JD) obtained by non-linear registration of MRI images to detect local vulnerability of healthy cerebral tissue in an animal model of brain irradiation. Methods Rats were exposed to fractionated whole-brain irradiation (WBI, 30 Gy). A multiparametric MRI (anatomical, diffusion and vascular) study was conducted longitudinally from 1 month up to 6 months after WBI. From the registration of MRI images, macroscopic changes were analyzed by DBM and microscopic changes at the cellular and vascular levels were evaluated by quantification of cerebral blood volume (CBV) and diffusion metrics including mean diffusivity (MD). Voxel-wise comparisons were performed on the entire brain and in specific brain areas identified by DBM. Immunohistology analyses were undertaken to visualize the vessels and astrocytes. Results DBM analysis evidenced time-course of local macrostructural changes; some of which were transient and some were long lasting after WBI. DBM revealed two vulnerable brain areas, namely the corpus callosum and the cortex. DBM changes were spatially associated to microstructural alterations as revealed by both diffusion metrics and CBV changes, and confirmed by immunohistology analyses. Finally, matrix correlations demonstrated correlations between JD/MD in the early phase after WBI and JD/CBV in the late phase both in the corpus callosum and the cortex. Conclusions Brain irradiation induces local macrostructural changes detected by DBM which could be relevant to identify brain structures prone to radiation-induced tissue changes. The translation of these data in patients could represent an added value in imaging studies on brain radiotoxicity.

IntroductionQuinidine (QND) sulfate is an effective treatment for atrial fibrillation (AF) in horses, and several dosage regimens have been proposed to address its wide variability in response and potential adverse effects. The purpose of this study was to analyze the variability in plasma quinidine concentrations using population pharmacokinetics to determine an effective and safe dosage regimen for Thoroughbred horses.MethodsSix healthy Thoroughbred horses were treated with 20 mg/kg quinidine sulfate dihydrate (16.58 mg/kg QND base) administered PO or 5 mg/kg quinidine hydrochloride monohydrate (4.28 mg/kg QND base) administered IV (single administration), and blood samples were taken regularly. Four healthy horses were treated with 20 mg/kg quinidine sulfate dihydrate administered twice (every 6 h) via PO route. For the other 19 Thoroughbred racehorses that developed AF, blood samples were taken during quinidine therapy. Quinidine concentrations were measured in all plasma samples using liquid chromatography with tandem mass spectrometry, and the data from 29 horses were modeled using a nonlinear mixed-effects model, followed by Monte Carlo simulations (MCS).ResultsThe median quinidine concentration for successful sinus rhythm conversion was 2.0 μg/mL (range: 0.5–2.7 μg/mL) in AF horses, while a median concentration of 3.8 μg/mL (range: 1.6–5.1 μg/mL) showed adverse effects. MCS predicted that plasma quinidine concentrations for quinidine sulfate dihydrate PO administration (loading dose: 30 mg/kg, maintenance dose: 6.5 mg/kg q 2 h) reached 1.4, 2.0 and 2.7 μg/mL in 90, 50 and 10% of the horse populations, respectively. Increasing the loading dose to 45 mg/kg and the maintenance dose to 9 mg/kg q 2 h, the plasma concentrations achieved were 1.9, 2.8, and 3.8 μg/mL in 90, 50, and 10% of horse populations, respectively.DiscussionUsing simulations, different empirical dosing regimens were proposed to achieve plasma quinidine concentrations immediately or progressively, representing a tradeoff between optimizing therapeutic effects and minimizing adverse effects. A combination of these dosing regimens is recommended to gradually increase the therapeutic concentration levels of quinidine for safe and effective treatment of AF in racehorses.

Various stakeholders, such as modelers, policy makers, farmers, and environmental regulators need reliable soil bulk density and coarse fragment content data. These two soil parameters are necessary to calculate soil carbon and nutrients stocks, to estimate water availability for plants, or to assess soil compaction. However, measuring these two parameters is labor intensive and time consuming. Therefore, many agricultural and environmental studies often miss these two soil parameters. Here, we provide four datasets, one with bulk density and coarse fragment contents of topsoil and subsoil, measured in two campaigns of the French Soil Quality Monitoring Network (RMQS for its acronym in French), a second one with the average values for bulk density and coarse fragments of the two campaigns at 0–30 cm and 30–50 cm. The third and the fourth ones are the raw data needed to calculate the two first datasets divided by campaign. In addition, the R script for calculating the depth-weighted values per soil layer is provided

Nous nous efforçons, dans cet article, de faire paraître le rôle joué par l’obstacle épistémologique de l’idiome dans la « grammaire nationale » de Damourette et Pichon. Nous montrons ainsi successivement la dépendance de la définition tout à la fois raciale et linguistique qu’ils donnent de la nation à l’égard d’une représentation de la langue en termes d’entité, et l’inscription de leur appréhension de la langue comme « pensée-langage » dans la problématique des rapports son/sens qui est corrélative de la définition traditionnelle du signe. Cette critique de l’élaboration linguistique de Damourette et Pichon est rendue possible par la comparaison avec l’élaboration saussurienne. Elle vise par ailleurs à faire paraître le caractère protéiforme de l’obstacle épistémologique de l’idiome, dont les enjeux sont cruciaux pour la linguistique et les sciences du langage contemporaines.

Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These alterations result in the dysfunction of proteasomes, which are multi-subunit protein complexes essential for maintaining cellular protein homeostasis. The clinical phenotype of these diseases manifests as a syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies and malformations of the cardiac outflow tract (OFT). These observations suggest that proteasome loss-of-function variants primarily affect specific embryonic cell types which serve as origins for both craniofacial structures and the conotruncal portion of the heart. In this hypothesis article, we propose that neural crest cells (NCCs), a highly multipotent cell population, which generates craniofacial skeleton, mesenchyme as well as the OFT of the heart, in addition to many other derivatives, would exhibit a distinctive vulnerability to protein homeostasis perturbations. Herein, we introduce the diverse cellular compensatory pathways activated in response to protein homeostasis disruption and explore their potential implications for NCC physiology. Altogether, the paper advocates for investigating proteasome biology within NCCs and their early cranial and cardiac derivatives, offering a rationale for future exploration and laying the initial groundwork for therapeutic considerations.

Abstract The field of dysmorphology has been changed by the use Artificial Intelligence (AI) and the development of Next Generation Phenotyping (NGP). The aim of this study was to propose a new NGP model for predicting KS (Kabuki Syndrome) on 2D facial photographs and distinguish KS1 (KS type 1, KMT2D-related) from KS2 (KS type 2, KDM6A-related). We included retrospectively and prospectively, from 1998 to 2023, all frontal and lateral pictures of patients with a molecular confirmation of KS. After automatic preprocessing, we extracted geometric and textural features. After incorporation of age, gender, and ethnicity, we used XGboost (eXtreme Gradient Boosting), a supervised machine learning classifier. The model was tested on an independent validation set. Finally, we compared the performances of our model with DeepGestalt (Face2Gene). The study included 1448 frontal and lateral facial photographs from 6 centers, corresponding to 634 patients (527 controls, 107 KS); 82 (78%) of KS patients had a variation in the KMT2D gene (KS1) and 23 (22%) in the KDM6A gene (KS2). We were able to distinguish KS from controls in the independent validation group with an accuracy of 95.8% (78.9–99.9%, p

Abstract The molecular mechanisms induced by hypoxia are misunderstood in non-small cell lung cancer (NSCLC), and above all the hypoxia and RASSF1A/Hippo signaling relationship. We confirmed that human NSCLC (n = 45) as their brain metastases (BM) counterpart are hypoxic since positive with CAIX-antibody (target gene of Hypoxia-inducible factor (HIF)). A severe and prolonged hypoxia (0.2% O2, 48 h) activated YAP (but not TAZ) in Human Bronchial Epithelial Cells (HBEC) lines by downregulating RASSF1A/kinases Hippo (except for NDR2) regardless their promoter methylation status. Subsequently, the NDR2-overactived HBEC cells exacerbated a HIF-1A, YAP and C-Jun-dependent-amoeboid migration, and mainly, support BM formation. Indeed, NDR2 is more expressed in human tumor of metastatic NSCLC than in human localized NSCLC while NDR2 silencing in HBEC lines (by shRNA) prevented the xenograft formation and growth in a lung cancer-derived BM model in mice. Collectively, our results indicated that NDR2 kinase is over-active in NSCLC by hypoxia and supports BM formation. NDR2 expression is thus a useful biomarker to predict the metastases risk in patients with NSCLC, easily measurable routinely by immunohistochemistry on tumor specimens.

Cet article s’attache à l’examen de la distinction martinettienne entre forme et substance, afin d’en faire apparaître la nature d’obstacle épistémologique. Après un rapide examen de la critique martinettienne de Hjelmslev sur cette question des rapports entre forme et substance, qui permet d’opposer problématiques saussurienne –théorique, définitoire de la langue comme un fonctionnement dont son et sens, en tant que linguistiques, sont les effets – et structuraliste – problématique empirique de construction de la langue comme un existant formel –, il s’efforce ainsi de montrer le caractère contradictoire du fonctionnement de cette distinction dans l’élaboration martinettienne. Cette distinction détermine la construction d’une structure tout à la fois formelle et substantielle, et en réalité doublement déterminée, par la problématique des rapports forme/substance et par celle des rapports son/sens. La problématique des rapports son/sens détermine pour sa part la construction d’une structure orientée du son vers le sens, dont l’examen révèle l’asymétrie, asymétrie qui nous reconduit à la dualité de détermination de la construction martinettienne de la langue comme structure, et qui témoigne de l’insistance du problème de la théorisation du rapport son/sens. A cet égard, l’élaboration martinettienne apparaît tout à la fois radicalement différente de celle de Saussure, et significativement différente de celle de Hjelmslev, dont elle met en valeur le caractère de pendant objectal de la théorisation saussurienne de la langue, ainsi que d’autres élaborations structuralistes. Elle est ainsi tout particulièrement propre à faire apparaître la nécessité d’une réflexion sur la problématique de la linguistique contemporaine.

IntroductionBenzylpenicillin (BP) is a first-line antibiotic in horses but there are discrepancies between manufacturers and literature recommendations regarding dosing regimen. Objectives of this study were to evaluate pharmacokinetics and local tolerance of four different formulations of BP in adult horses, and to suggest optimized dosing regimen according to the formulation.MethodsA cross-over design was used in 3 phases for the intramuscular injection of three different products: procaine BP alone, procaine BP/ benzathine BP combination or penethamate hydriodide were administered IM in the gluteal muscles of 6 horses for 3 days. Single IV administration of sodium BP was performed to the same horses with a dose of 22,000 IU BP/kg bwt 39 weeks after last IM injection. BP plasma concentrations were determined by UPLC assay coupled with mass spectrometry and a PK/PD analysis was conducted to predict the efficacy of various dosing regimens by estimating values of the fT>MIC index for different minimum inhibitory concentrations (MIC). Tolerance at the site of IM injection was monitored by creatine kinase activity quantified with a validated chemistry system and clinical scorings.Results and discussionExcept one neurological reaction following one administration of penethamate hydriodide, the tolerance was good. Procaine BP alone, procaine BP/benzathine BP combination or penethamate hydriodide intramuscular administrations at a dosage of 22,000 IU BP/kg bwt q24h for 5 days would yield plasma concentrations that should be effective against bacteria with MIC of ≤0.256, 0.125 or 0.064 mg/L respectively. Of all the tested treatments, the use of a sodium BP by IV Constant Rate Infusion (CRI) for 10 hours a day was deemed to be the most efficient. All the formulations tested in this study are adequate to treat infections with susceptible Streptococcus equi.

Summary: Liver tumors account for approximately 2% of all pediatric malignancies. Children with advanced stages of hepatoblastoma (HB) are cured only 50–70% of the time while children with advanced hepatocellular carcinoma (HCC) have a

Abstract Background Brain metastases (BM) are the most frequent malignant brain tumors. The aim of this study was to characterize the tumor microenvironment (TME) of BM and particularly hypoxia and redox state, known to play a role in tumor growth and treatment resistance with multimodal PET and MRI imaging, immunohistochemical and proteomic approaches in a human lung cancer (H2030-BrM3)-derived BM model in rats. Results First, in vitro studies confirmed that H2030-BrM3 cells respond to hypoxia with increasing expression of HIF-1, HIF-2 and their target genes. Proteomic analyses revealed, among expression changes, proteins associated with metabolism, oxidative stress, metal response and hypoxia signaling in particular in cortical BM. [64Cu][Cu(ATSM)] PET revealed a significant uptake by cortical BM (p

In higher education, students with disabilities play an active role in securing and utilizing academic accommodations. Numerous studies have explored different aspects of the accommodations provision process and have addressed various barriers found to prevent the full implementation of these accommodations for students with disabilities. The present review explored these studies, in an attempt to discern common themes within this area of the literature. The review identified several themes that emerged across 23 empirical research studies. Barriers to accommodations were found in the lack of student knowledge or awareness of campus resources, the inability to provide appropriate documentation of a disability or receive accommodations students found useful, and the negative reactions of peers and faculty members that students experienced upon their disclosure of a disability or their request to implement accommodations. The review concludes by addressing the limitations of the study, offering recommendations for future research, and identifying ways in which disability resource offices may work to remove or reduce the impact of the barriers identified. Upon consideration of the breadth and depth of barriers to accommodations found in the literature, a shift towards "Universal Design for Learning" is presented as one potential way to mitigate these barriers.

Abstract The dosage of colistin for the treatment of enteric E. coli in animals necessitates considering the heteroresistant (HR) nature of the targeted inoculum, described by the presence of a major susceptible population (S1, representing 99.95% of total population) mixed with an initial minor subpopulation of less susceptible bacteria (S2). Herein, we report the 1-compartment population pharmacokinetics (PK) of colistin in chicken intestine (jejunum and ileum) and combined it with a previously established pharmacodynamic (PD) model of HR in E. coli. We then computed probabilities of target attainment (PTA) with a pharmacodynamic target (AUC24h/MIC) that achieves 50% of the maximal kill of bacterial populations (considering inoculums of pure S1, S2 or HR mixture of S1 + S2). For an MIC of 1 mg/L, PTA > 95% was achieved with the registered dose (75,000 IU/kg BW/day in drinking water) for the HR mixture of S1 + S2 E. coli, whether they harboured mcr or not. For an MIC of 2 mg/L (ECOFF), we predicted PTA > 90% against the dominant susceptible sub-population (S1) with this clinical dose given (i) over 24 h for mcr-negative isolates or (ii) over 6 h for mcr-positive isolates (pulse dosing). Colistin clinical breakpoint S ≤ 2 mg/L (EUCAST rules) should be confirmed clinically.

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

Abstract The medical literature is replete with articles in which there is confusion between “free concentration” and “unbound fraction” (fu), which is the ratio of free to total plasma concentration. The lack of clarity in distinguishing between these two terms has led to biased computations, erroneous interpretations, and misleading recommendations. The problems are highlighted in this paper, taking the example of calculation of Probability of Target Attainment (PTA). This metric is used to propose pharmacokinetic/pharmacodynamic (PK/PD) breakpoints required for the interpretation of Antimicrobial Susceptibility Testing. Based on Monte Carlo simulations of the PK/PD index, area under the unbound concentration time curve/minimum inhibitory concentration (fAUC/MIC), computation of PTA from total plasma concentrations scaled by fu ineluctably leads to biased estimates. The bias is greater if the variability associated with fu is added, instead of removing it during this scaling. The explanation for the bias is that total plasma drug concentrations are intrinsically more variable than the corresponding free concentrations. This is due to the variability of antimicrobial binding for total, but not for free plasma concentrations. In consequence, the greater variability always leads to underestimation of the PK/PD cutoff (i.e., the critical MIC that is guaranteed for a given percentile of the population). A further consequence is an increase in calculated dosage required to attain the targeted quantile. This erroneous approach, of using free antimicrobial drug fraction, is not limited to the derivation of PK/PD cutoff, but may also have consequences for antimicrobials drug safety in clinical patients.

Abstract Autism is a multifaceted neurodevelopmental condition whose accurate diagnosis may be challenging because the associated symptoms and severity vary considerably. The wrong diagnosis can affect families and the educational system, raising the risk of depression, eating disorders, and self-harm. Recently, many works have proposed new methods for the diagnosis of autism based on machine learning and brain data. However, these works focus on only one pairwise statistical metric, ignoring the brain network organization. In this paper, we propose a method for the automatic diagnosis of autism based on functional brain imaging data recorded from 500 subjects, where 242 present autism spectrum disorder considering the regions of interest throughout Bootstrap Analysis of Stable Cluster map. Our method can distinguish the control group from autism spectrum disorder patients with high accuracy. Indeed the best performance provides an AUC near 1.0, which is higher than that found in the literature. We verify that the left ventral posterior cingulate cortex region is less connected to an area in the cerebellum of patients with this neurodevelopment disorder, which agrees with previous studies. The functional brain networks of autism spectrum disorder patients show more segregation, less distribution of information across the network, and less connectivity compared to the control cases. Our workflow provides medical interpretability and can be used on other fMRI and EEG data, including small data sets.

IntroductionThe aim of this international project was to establish a species-specific Clinical Breakpoint for interpretation of Antimicrobial Susceptibility Testing of benzylpenicillin (BP) in horses.MethodsA population pharmacokinetic model of BP disposition was developed to compute PK/PD cutoff values of BP for different formulations that are commonly used in equine medicine around the world (France, Sweden, USA and Japan). Investigated substances were potassium BP, sodium BP, procaine BP, a combination of procaine BP and benzathine BP and penethamate, a prodrug of BP. Data were collected from 40 horses that provided 63 rich profiles of BP corresponding to a total of 1022 individual BP plasma concentrations.ResultsA 3-compartment disposition model was selected. For each of these formulations, the PK/PD cutoff was estimated for different dosage regimens using Monte Carlo simulations. The fAUC/MIC or fT>MIC were calculated with a free BP fraction set at 0.4. For fAUC/MIC, a target value of 72 h (for a 72h treatment) was considered. For fT>MIC, efficacy was assumed when free plasma concentrations were above the explored MIC (0.0625-2 mg/L) for 30 or 40 % of the dosing interval. For continuous infusion, a fT>MIC of 90 % was considered. It was shown that a PK/PD cutoff of 0.25 mg/L can be achieved in 90 % of horses with routine regimen (typically 22,000 IU/kg or 12.4 mg/kg per day) with IM procaine BP once a day (France, Japan, Sweden but not USA1) and with IM sodium BP at 14.07 mg/kg, twice a day or IV sodium BP infusion of 12.4 mg/kg per day. In contrast, penethamate and the combination of procaine BP and benzathine BP were unable to achieve this PK/PD cutoff not even an MIC of 0.125 mg/L.DiscussionThe PK/PD cutoff of 0.25 mg/L is one dilution lower than the clinical breakpoint released by the CLSI (0.5 mg/ L). From our simulations, the CLSI clinical breakpoint can be achieved with IM procaine BP twice a day at 22,000 IU i.e. 12.4 mg/kg.

Autism spectrum disorder (ASD) is characterized by interaction and communication differences, entailing visual attention skill specificities. Interactions with animals, such as in animal-assisted interventions or with service dogs, have been shown to be beneficial for individuals with ASD. While interacting with humans poses challenges for them, engaging with animals appears to be different. One hypothesis suggests that differences between individuals with ASD’s visual attention to humans and to animals may contribute to these interaction differences. We propose a scoping review of the research on the visual attention to animals of youths with ASD. The objective is to review the methodologies and tools used to explore such questions, to summarize the main results, to explore which factors may contribute to the differences reported in the studies, and to deduce how youth with ASD observe animals. Utilizing strict inclusion criteria, we examined databases between 1942 and 2023, identifying 21 studies in international peer-reviewed journals. Three main themes were identified: attentional engagement and detection, visual exploration, and behavior. Collectively, our findings suggest that the visual attention of youths with ASD towards animals appears comparable to that of neurotypical peers, at least in 2D pictures (i.e., eye gaze patterns). Future studies should explore whether these results extend to real-life interactions.

There is a growing interest in the medical use of psychedelic substances, as preliminary studies using them for psychiatric disorders have shown positive results. In particular, one of these substances is N, N-dimethyltryptamine (DMT), an agonist serotonergic psychedelic that can induce profound alterations in the state of consciousness. In this work, we use an exploratory tool to reveal DMT-induced changes in brain activity using EEG data and provide new insights into the mechanisms of action of this psychedelic substance. We used a two-class classification based on (A) the connectivity matrix or (B) complex network measures derived from it as input to a support vector machine (SVM). We found that both approaches could detect changes in the brain’s automatic activity, with case (B) showing the highest AUC (89%), indicating that complex network measurements best capture the brain changes that occur due to DMT use. In the second step, we ranked the features that contributed the most to this result. For case (A), we found that differences in the high alpha, low beta, and delta frequency bands were most important in distinguishing between the state before and after DMT inhalation, which is consistent with the results described in the literature. Further, the connection between the temporal (TP8) and central cortex (C3) and between the precentral gyrus (FC5) and the lateral occipital cortex (P8) contributed most to the classification result. The connection between regions TP8 and C3 has been found in the literature associated with finger movements that might have occurred during DMT consumption. However, the connection between cortical areas FC5 and P8 has not been found in the literature and is presumably related to the volunteers’ emotional, visual, sensory, perceptual, and mystical experiences during DMT consumption. For case (B), closeness centrality was the most crucial complex network measure. Furthermore, we discovered larger communities and longer average path lengths when DMT was used and the converse when not, showing that the balance between functional segregation and integration had been disrupted. These findings support the idea that cortical brain activity becomes more entropic under psychedelics. Overall, a robust computational workflow has been developed here with interpretability of how DMT (or other psychedelics) modify brain networks and insights into their mechanism of action. Finally, the same methodology applied here may help interpret EEG time series from patients who consumed other psychedelic drugs.

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop’s classification (Witkop, J Oral Pathol, 1988, 17, 547–553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative.Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management.Methods: Individuals presenting with so called “isolated” or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/).Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance.Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI (CNNM4, WDR72, FAM20A … ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop’s AI classification.

IntroductionPrevious studies have demonstrated the effectiveness of therapeutic repetitive transcranial magnetic stimulation (rTMS) to treat pharmacoresistant depression. Nevertheless, these trials have primarily focused on the therapeutic and neurophysiological effects of rTMS following a long-term treatment course. Identifying brain-based biomarkers of early rTMS therapeutic response remains an important unanswered question. In this pilot study, we examined the effects of rTMS on individuals with pharmacoresistant depression using a graph-based method, called Functional Cortical Networks (FCN), and serial electroencephalography (EEG). We hypothesized that changes in brain activity would occur early in treatment course.MethodsA total of 15 patients with pharmacoresistant depression underwent five rTMS sessions (5Hz over the left dorsolateral prefrontal cortex, 120%MT, up to 4,000 pulses/session). Five participants received additional rTMS treatment, up to 40 sessions. Resting EEG activity was measured at baseline and following every five sessions, using 64-channel EEG, for 10 minutes with eyes closed. An FCN model was constructed using time-varying graphs and motif synchronization. The primary outcome was acute changes in weighted-node degree. Secondary outcomes included serial FFT-based power spectral analysis and changes in depressive symptoms measured by the 9-Item Patient Health Questionnaire (PHQ-9) and the 30-item Inventory of Depressive Symptoms-Self Report (IDS-SR).ResultsWe found a significant acute effect over the left posterior area after five sessions, as evidenced by an increase in weighted-node degree of 37,824.59 (95% CI, 468.20 to 75,180.98) and a marginal enhancement in the left frontal region (t (14) = 2.0820, p = 0.056). One-way repeated measures ANOVA indicated a significant decrease in absolute beta power over the left prefrontal cortex (F (7, 28) = 2.37, p = 0.048) following ten rTMS sessions. Furthermore, a significant clinical improvement was observed following five rTMS sessions on both PHQ-9 (t (14) = 2.7093, p = 0.017) and IDS-SR (t (14) = 2.5278, p = 0.024) and progressed along the treatment course.DiscussionOur findings suggest that FCN models and serial EEG may contribute to a deeper understanding of mechanisms underlying rTMS treatment. Additional research is required to investigate the acute and serial effects of rTMS in pharmacoresistant depression and assess whether early EEG changes could serve as predictors of therapeutic rTMS response.

Although the identification of numerous genes involved in neurodevelopmental disorders (NDDs) has reshaped our understanding of their etiology, there are still major obstacles in the way of developing therapeutic solutions for intellectual disability (ID) and other NDDs. These include extensive clinical and genetic heterogeneity, rarity of recurrent pathogenic variants, and comorbidity with other psychiatric traits. Moreover, a large intragenic mutational landscape is at play in some NDDs, leading to a broad range of clinical symptoms. Such diversity of symptoms is due to the different effects DNA variations have on protein functions and their impacts on downstream biological processes. The type of functional alterations, such as loss or gain of function, and interference with signaling pathways, has yet to be correlated with clinical symptoms for most genes. This review aims at discussing our current understanding of how the molecular changes of group I p21-activated kinases (PAK1, 2 and 3), which are essential actors of brain development and function; contribute to a broad clinical spectrum of NDDs. Identifying differences in PAK structure, regulation and spatio-temporal expression may help understanding the specific functions of each group I PAK. Deciphering how each variation type affects these parameters will help uncover the mechanisms underlying mutation pathogenicity. This is a prerequisite for the development of personalized therapeutic approaches.

Neurodevelopmental conditions, such as Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD), present unique challenges due to overlapping symptoms, making an accurate diagnosis and targeted intervention difficult. Our study employs advanced machine learning techniques to analyze functional magnetic resonance imaging (fMRI) data from individuals with ASD, ADHD, and typically developed (TD) controls, totaling 120 subjects in the study. Leveraging multiclass classification (ML) algorithms, we achieve superior accuracy in distinguishing between ASD, ADHD, and TD groups, surpassing existing benchmarks with an area under the ROC curve near 98%. Our analysis reveals distinct neural signatures associated with ASD and ADHD: individuals with ADHD exhibit altered connectivity patterns of regions involved in attention and impulse control, whereas those with ASD show disruptions in brain regions critical for social and cognitive functions. The observed connectivity patterns, on which the ML classification rests, agree with established diagnostic approaches based on clinical symptoms. Furthermore, complex network analyses highlight differences in brain network integration and segregation among the three groups. Our findings pave the way for refined, ML-enhanced diagnostics in accordance with established practices, offering a promising avenue for developing trustworthy clinical decision-support systems. [ABSTRACT FROM AUTHOR]

Time-kill curves (TKCs) are more informative compared with the use of minimum inhibitory concentration (MIC) as they allow the capture of bacterial growth and the development of drug killing rates over time, which allows to compute key pharmacodynamic (PD) parameters. Our study aimed, using a semi-mechanistic mathematical model, to estimate the best pharmacokinetic/pharmacodynamic (PK/PD) indices (ƒAUC/MIC or %ƒT > MIC) for the prediction of clinical efficacy of veterinary FQs in Staphylococcus pseudintermedius, Staphylococcus aureus, and Escherichia coli collected from canine pyoderma cases with a focus on the comparison between marbofloxacin and pradofloxacin. Eight TCKs for each bacterial species (4 susceptible and 4 resistant) were analysed in duplicate. The best PK/PD index was ƒAUC24h/MIC in both staphylococci and E. coli. For staphylococci, values of 25–40 h were necessary to achieve a bactericidal effect, whereas the calculated values (25–35 h) for E. coli were lower than those predicting a positive clinical outcome (100–120 h) in murine models. Pradofloxacin showed a higher potency (lower EC50) in comparison with marbofloxacin. However, no difference in terms of a maximal possible pharmacological killing rate (Emax) was observed. Taking into account in vivo exposure at the recommended dosage regimen (3 and 2 mg/kg for pradofloxacin and marbofloxacin, respectively), the overall killing rates (Kdrug) computed were also similar in most instances.