Identification of Anchor Genes during Kidney Development Defines Ontological Relationships, Molecular Subcompartments and Regulatory Pathways

The development of the mammalian kidney is well conserved from mouse to man. Despite considerable temporal and spatial data on gene expression in mammalian kidney development, primarily in rodent species, there is a paucity of genes whose expression is absolutely specific to a given anatomical compartment and/or developmental stage, defined here as ‘anchor’ genes. We previously generated an atlas of gene expression in the developing mouse kidney using microarray analysis of anatomical compartments collected via laser capture microdissection. Here, this data is further analysed to identify anchor genes via stringent bioinformatic filtering followed by high resolution section in situ hybridisation performed on 200 transcripts selected as specific to one of 11 anatomical compartments within the midgestation mouse kidney. A total of 37 anchor genes were identified across 6 compartments with the early proximal tubule being the compartment richest in anchor genes. Analysis of minimal and evolutionarily conserved promoter regions of this set of 25 anchor genes identified enrichment of transcription factor binding sites for Hnf4a and Hnf1b, RbpJ (Notch signalling), PPARγ:RxRA and COUP-TF family transcription factors. This was reinforced by GO analyses which also identified these anchor genes as targets in processes including epithelial proliferation and proximal tubular function. As well as defining anchor genes, this large scale validation of gene expression identified a further 92 compartment-enriched genes able to subcompartmentalise key processes during murine renal organogenesis spatially or ontologically. This included a cohort of 13 ureteric epithelial genes revealing previously unappreciated compartmentalisation of the collecting duct system and a series of early tubule genes suggesting that segmentation into proximal tubule, loop of Henle and distal tubule does not occur until the onset of glomerular vascularisation. Overall, this study serves to illuminate previously ill-defined stages of patterning and will enable further refinement of the lineage relationships within mammalian kidney development

The blood vasculature instructs lymphatic patterning in a SOX7-dependent manner

Despite a growing catalog of secreted factors critical for lymphatic network assembly, little is known about the mechanisms that modulate the expression level of these molecular cues in blood vascular endothelial cells (BECs). Here, we show that a BEC-specific transcription factor, SOX7, plays a crucial role in a non-cell-autonomous manner by modulating the transcription of angiocrine signals to pattern lymphatic vessels. While SOX7 is not expressed in lymphatic endothelial cells (LECs), the conditional loss of SOX7 function in mouse embryos causes a dysmorphic dermal lymphatic phenotype. We identify novel distant regulatory regions in mice and humans that contribute to directly repressing the transcription of a major lymphangiogenic growth factor (Vegfc) in a SOX7-dependent manner. Further, we show that SOX7 directly binds HEY1, a canonical repressor of the Notch pathway, suggesting that transcriptional repression may also be modulated by the recruitment of this protein partner at Vegfc genomic regulatory regions. Our work unveils a role for SOX7 in modulating downstream signaling events crucial for lymphatic patterning, at least in part via the transcriptional repression of VEGFC levels in the blood vascular endothelium.Peer reviewe

Admission criteria and management of critical care patients in a pandemic context: position of the Ethics Commission of the French Intensive Care Society, update of April 2021.

Intensive care unit professionals have experience in critical care and its proportionality, collegial decision-making, withholding or withdrawal of treatment deemed futile, and communication with patients' relatives. These elements rely on ethical values from which we must not deviate in a pandemic situation. The recommendations made by the Ethics Commission of the French Intensive Care Society reflect an approach of responsibility and solidarity towards our citizens regarding the potential impact of a pandemic on critical care resources in France, with the fundamental requirement of respect for human dignity and equal access to health care for all

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development.

Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancers were able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SoxF binding sites established a clear requirement for members of this group of transcription factors (SOX7, SOX17 and SOX18) to drive the activity of these enhancers in vivo Endogenous deletion of the notch1b enhancer led to a significant loss of arterial connections to the dorsal aorta in Notch pathway-deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for NOTCH1 and notch1b enhancer activity and for correct endogenous transcription of these genes. These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (APP1107643); The Cancer Council Queensland (1107631) (M.Fran.); the Australian Research Council Discovery Project (DP140100485) and a Career Development Fellowship (APP1111169) (M.Fran.); the Ludwig Institute for Cancer Research (M.Frit., A.N., I.R., S.D.V.); the Medical Research Council (MR/J007765/1) (K.L., G.B.-G., S.D.V.); the Fondazione Cariplo (2011-0555) (M.B., B.H., M.Fran.); and the Biotechnology and Biological Sciences Research Council (BB/L020238/1) (A.N., K.L., G.B.-G., S.D.V.)

Migrant health in French Guiana: Are undocumented immigrants more vulnerable?

<p>Abstract</p> <p>Background</p> <p>Few data exist on the health status of the immigrant population in French Guiana. The main objective of this article was to identify differences in its health status in relation to that of the native-born population.</p> <p>Methods</p> <p>A representative, population-based, cross-sectional survey was conducted in 2009 among 1027 adults living in Cayenne and St-Laurent du Maroni. Health status was assessed in terms of self-perceived health, chronic diseases and functional limitations. The migration variables were immigration status, the duration of residence in French Guiana and the country of birth. Logistic regression models were conducted.</p> <p>Results</p> <p>Immigrants account for 40.5% and 57.8% of the adult population of Cayenne and St-Laurent du Maroni, respectively. Most of them (60.7% and 77.5%, respectively) had been living in French Guiana for more than 10 years. A large proportion were still undocumented or had a precarious legal status. The undocumented immigrants reported the worst health status (OR = 3.18 [1.21-7.84] for self-perceived health, OR = 2.79 [1.22-6.34] for a chronic disease, and OR = 2.17 [1.00-4.70] for a functional limitation). These differences are partially explained by socioeconomic status and psychosocial factors. The country of birth and the duration of residence also had an impact on health indicators.</p> <p>Conclusion</p> <p>Data on immigrant health are scarce in France, and more generally, immigrant health problems have been largely ignored in public health policies. Immigrant health status is of crucial interest to health policy planners, and it is especially relevant in French Guiana, considering the size of the foreign-born population in that region.</p

Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice.

Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Assessment of the normal and pathological fetal face

L’objectif de ce travail doctoral est d’exposer l’enjeu que représente l’étude de la face fœtale normale et pathologique en anthropologie biologique et en médecine périnatale. Dans le cadre spécifique des fentes du palais, nous avons posé l’hypothèse du rôle de facteurs pronostiques identifiés en période prénatale comme déterminants dans l’apparition de ce trouble du développement en période postnatale. Dans un premier temps, la croissance normale des os et des angles du massif facial fœtal a été décrite et modélisée par la réalisation d’un travail original reposant sur l’étude de 118 scanners de fœtus.Notre évaluation s’est portée dans un second temps sur la description des manifestations pathologiques de la face fœtale. Nous avons discuté des problématiques inhérentes à leur diagnostic en anténatal, ainsi que de leurs conséquences en période postnatale. Deux travaux originaux sont issus de cette évaluation. Par la suite, dans le cadre des fentes de la face, nous avons recherché les facteurs pronostiques prénataux pouvant avoir un impact dans l’apparition de troubles du développement en postnatal. Nous nous sommes appuyés pour cela sur les caractéristiques anatomiques des fentes. L’atteinte du palais secondaire au moins, était le principal facteur de risque retrouvé, suivi de la largeur et du décalage antéro-postérieur de la fente.Enfin, dans une dernière partie, à partir de la description des issues postnatales, nous avons évalué l’apparition de troubles du neurodéveloppement, ainsi que les résultats des explorations génétiques réalisées, la possibilité d’optimiser les diagnostics syndromiques en anténatal chez les enfants porteurs d’une fente du palais.The objective of this doctoral work was to expose the challenge of studying the normal and pathological fetal face n biological anthropology and perinatal medicine. In the specific context of cleft palates, we hypothesized the role of prognostic factors searched for prenatally, as determinant in the appearance of acquisition disorders in postnatal. In a first step, we described and modeled the normal growth of the bones and angles of the fetal face from 118 fetal scans.Our evaluation was then focused on the description of the pathological manifestations of the fetal face. We discussed the problems inherent to their diagnosis in the antenatal period as well as their consequences in the postnatal period. Two original works have resulted from this evaluation. Subsequently, in the context of facial clefts, the prognostic factors that may have an impact on the apparition of developmental disorders in the postnatal period were researched in the prenatal period, from the anatomical characteristics of the clefts. The involvement of secondary palate at least was the main risk factor found, followed by the width and the anteroposterior shift of the cleft.Finally, based on the description of postnatal outcomes, the apparition of neuro-developmental disorders, as well as the results of the genetic explorations carried out, the possibility of optimizing antenatal syndromic diagnoses in children with a cleft palate was evaluated in the last part

Teaching and performing audits on caesarean delivery reduce the caesarean delivery rate.

AIM:To assess the factors associated with lower rate of caesarean deliveries in the South of France, based on the characteristics and organisation of the region's 40 maternity facilities and the characteristics of the practitioners in these facilities. METHOD:A retrospective study from 1 January 2012 to 31 December 2015. Data were collected by the Mediterranean network and a declarative survey was completed by each maternity facility in the region to study factor which could be associated with lower caesarean rate by univariate and multivariate analysis. RESULTS:250 564 women gave birth during this period, of which 55 097 by caesarean section. The mean caesarean delivery rate over the four years was 22.0%. The rate was significantly higher in private maternity facilities [23.9% (21.9%- 25.8%), p<0.05] and type III (maximum care level) maternity facilities [24.2% (21.3%- 27.1%), p<0.05]. After a stepwise regression, the factors associated with a decrease in the caesarean delivery rate were audits concerning caesarean delivery (19.83%, β = - 2.48, p = 0.03 over the four years) and the provision of training to trainee doctors at the maternity facility (20.28%, β = - 1.08, p = 0.04 over the four years). CONCLUSION:Performing audits in relation to caesarean deliveries could affect the caesarean. Teaching trainee doctors could be an indicator of quality of caesarean practices. They should be encouraged in maternity facilities to reduce the rate of caesareans