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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.

The residential experiences of students with disabilities in higher education play a pivotal role in their overall campus education. However, little is known about the ways that staff who manage and support these residential environments understand and work with issues and concepts of disability. Utilizing constructivist grounded theory, this study examines how resident directors think about and work with disability within their positions in residential management. The study also explores how resident directors think about and understand disability as a component of diversity, the steps that they take in working with students with disabilities, and the support they provide their student staff in fostering residential communities inclusive of students with disabilities. The findings suggest that resident directors' work related to disabilities and disability identity is marked by tensions between individual understandings of disability and institutional systems and job expectations. Suggestions are provided for ways to better support resident directors as they navigate a conflict between personal beliefs and positional responsibilities. [Discussion questions prepared by Abel Ramirez and Cornelia Forrester Slate.]

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.