Farnesoid X receptor a (FXRa, NR1H4) is a bile acid- activated nuclear receptor that regulates the expression of glycolytic and lipogenic target genes by interacting with the 9-cis-retinoic acid receptor a (RXRa, NR2B1). Along with cofactors, the FXRa proteins reported thus far in humans and rodents have been observed to regulate both isoform (a1-4)- and tissue-specific gene expression profiles to integrate energy balance and metabolism. Here, we studied the biological functions of an FXRa naturally occurring spliced exon 5 isoform (FXRase5) lacking the second zinc-binding module of the DNA-binding domain. We demonstrate spliced exon 5 FXRa expression in all FXRa-expressing human and mouse tissues and cells, and that it is unable to bind to its response element or activate FXRa dependent transcription. In parallel, this spliced variant displays differential interaction capacities with its obligate heterodimer partner retinoid X receptor a that may account for silencing of this permissive dimer for signal transduction. Finally, deletion of exon 5 by gene edition in HepG2 cells leads to FXRa loss-of-function, increased expression of LRH1 metabolic sensor and CD36 fatty acid transporter in conjunction with changes in glucose and triglycerides homeostasis. Together, these fi ndings highlight a novel mechanism by which alternative splicing may regulate FXRa gene function to fi ne-tune adaptive and/or metabolic responses. This fi nding deepens our understanding on the role of splicing events in hindering FXRa activity to regulate specific transcriptional programs and their contribution in modifying energy metabolism in normal tissues and metabolic diseases.

During development, cell differentiation is associated to large-scale modifications in the methylome, which require the engagement of an active DNA demethylation machinery including Ten-Eleven-Translocation enzymes for oxidation of 5-methylcytosine and the T:G mismatch DNA glycosylase (TDG) for removal of the oxidized bases. Despite this well-defined molecular function, the biological output of TDG activity remains elusive. Here we combined transcriptomic and epigenomic approaches in TDG knock-out embryonal carcinoma cells, an epiblast stem-like cell model, to decipher TDG function in pluripotent cells and their retinoic acid-induced differentiated progeny. We determined that TDG activity is balancing differentiation in favor of a neural fate at the expense of a cardiac mesoderm fate. This process is associated with a sustained activity of a large set of ATF4-dependent genes in relation with a TDG-mediated nucleosome positioning at promoters and in conjunction with a TDG- dependent regulation of the mammalian target of rapamycin complex 1. These observations highlight the central role of TDG in cell differentiation and support a model linking metabolic reprogramming to cell fate acquisition. ### Competing Interest Statement The authors have declared no competing interest.

The rise of single-cell data highlights the need for a nondeterministic view of gene expression, while offering new opportunities regarding gene regulatory network inference. We recently introduced two strategies that specifically exploit time-course data, where single-cell profiling is performed after a stimulus: HARISSA, a mechanistic network model with a highly efficient simulation procedure, and CARDAMOM, a scalable inference method seen as model calibration. Here, we combine the two approaches and show that the same model driven by transcriptional bursting can be used simultaneously as an inference tool, to reconstruct biologically relevant networks, and as a simulation tool, to generate realistic transcriptional profiles emerging from gene interactions. We verify that CARDAMOM quantitatively reconstructs causal links when the data is simulated from HARISSA, and demonstrate its performance on experimental data collected on in vitro differentiating mouse embryonic stem cells. Overall, this integrated strategy largely overcomes the limitations of disconnected inference and simulation.

Sovereignty, for Derrida (2005, 2009), is defined by an exception-to-the rule attitude: the sovereign is the one who decides on an exception. A sovereign can thus "go rogue" and behave as an outlaw, transgressing the rules of his own community. This article applies this conception of sovereignty to analysis of the Kerviel-Société Générale (SocGen) rogue trading affair. It examines the exception-to-the-rule attitude found in the actors of the financial sphere (the trader, the bank, the State) and the underlying control dynamics. Our results show that the trader acts as a rogue when he takes the exceptional right to place himself above his bank's rules on position-taking. The bank is equally rogue when it reserves the exceptional right to place itself above the prudential regulations governing its sector. The State goes rogue too, granting the banking supervisory body the exceptional right to administer criminal justice. Following Boltanski (2011), our analysis explains these exception-to-the-rule behaviors by the contradictory logics that drive them. Two logics are identified in the financial sphere: the market logic, and the prudence logic. We highlight that fraud, and more generally the exception-to-the-rule attitude, result from the ambivalence generated by the coexistence of these contradictory logics of action, which are notably conveyed through control mechanisms. The study concludes that the State has a major role to play in this respect. More specifically, we raise the point that the neoliberal style of the penal State contributes to the occurrence of fraud.

This article examines how financialization affects the way public health missions are conceived and implemented. In particular, it deals with the role played by control technologies in this process. In order to conduct our investigation, we analyze the Orpea scandal using the notion of governmentality (Foucault, 1994, 2008) and, more specifically, the concepts of rationalities, programs, and technologies developed by Rose and Miller (1992, 2010). An analysis of control technologies at Orpea and the public authorities shows that the rationality corresponding to providing good care for dependent older adults was financialized and problematized by the pursuit of efficiency. This article contributes to the literature in two ways. First, it shows that the financialization of an organization does not hinge solely on financial technologies but can also be based on nonfinancial technologies. Second, it argues that public policies not only contribute to financialization but are themselves financialized, since the rationalities underpinning them are financialized. Hence, this article reports not only on financialization by public policies but also on the financialization of public policies.

The formation of a diploid zygote is a highly complex cellular process that is entirely controlled by maternal gene products stored in the egg cytoplasm. This highly specialized transcriptional program is tightly controlled at the chromatin level in the female germline. As an extreme case in point, the massive and specific ovarian expression of the essential thioredoxin Deadhead (DHD) is critically regulated in Drosophila by the histone demethylase Lid and its partner, the histone deacetylase complex Sin3A/Rpd3, via yet unknown mechanisms. Here, we identified Snr1 and Mod(mdg4) as essential for dhd expression and investigated how these epigenomic effectors act with Lid and Sin3A to hyperactivate dhd . Using Cut&Run chromatin profiling with a dedicated data analysis procedure, we found that dhd is intriguingly embedded in an H3K27me3/H3K9me3-enriched mini-domain flanked by DNA regulatory elements, including a dhd promoter-proximal element essential for its expression. Surprisingly, Lid, Sin3a, Snr1 and Mod(mdg4) impact H3K27me3 and this regulatory element in distinct manners. However, we show that these effectors activate dhd independently of H3K27me3/H3K9me3, and that dhd remains silent in the absence of these marks. Together, our study demonstrates an atypical and critical role for chromatin regulators Lid, Sin3A, Snr1 and Mod(mdg4) to trigger tissue-specific hyperactivation within a unique heterochromatin mini-domain.

This research studies the political and identity dynamics involved in the formation of a dominant mode of business ethics control. Through analysis of the ethical tool design process at five French multinationals, this empirical study reveals how business ethics is becoming legalized. This legalization is explained by a structure of domination that favours a legalistic approach, the diffusion of tools prepared by the legalistic designers, and a socio-cognitive identity strategy applied by the dominated group, the moralist designers. The individualization of responsibility is identified as a major risk associated with excessive legalization in business ethics.

Cet article explore le rôle des relations affinitaires dans les stratégies de valorisation de l’image des contrôleurs de gestion. Pour répondre à cet objectif, une étude de cas est menée au sein d’une université française. Les résultats mettent en évidence une stratégie de séduction visant à donner l’image de professionnels sympathiques avec qui il est agréable de travailler. Les relations affinitaires sont également mobilisées par les contrôleurs de gestion afin de diffuser au sein de l’organisation des narrations mélioratives de leur métier. L’article souligne enfin, que la mobilisation des affinités dans les stratégies des contrôleurs de gestion participe localement à faire accepter, à légitimer et à diffuser la financiarisation au sein des universités.

INTRODUCTION:The aim of the present study was to describe autonomic urethral sphincter (US) innervation using specific muscular and neuronal antibody markers and 3D reconstruction.MATERIAL AND METHODS:We performed en-bloc removal of the entire pelvis of three male human fetuses between 18 and 40 weeks. Serial whole mount sections (5 μm intervals) were stained and investigated. The sections were stained with Masson's trichrome and Eosin Hematoxylin, and immunostained with: anti-SMA antibody for smooth muscle; anti-S100 antibody for all nerves; and anti-PMP22 antibody, anti-TH antibody, anti-CGRP antibody, anti-NOS antibody for somatic, adrenergic, sensory and nitrergic nerve fibers, respectively. The slides were digitized for 3D reconstruction to improve topographical understanding. An animated reconstruction of the autonomic innervation of the US was generated.RESULTS:The external and internal US are innervated by autonomic nerves of the inferior hypogastric plexus (IHP). These nerves are sympathetic (positive anti-TH antibody), sensory (positive anti-CGRP antibody), and nitrergic (positive anti-NOS antibody). Some autonomic fibers run within the neurovascular bundles, posterolaterally. Others run from the IHP to the posteromedial aspect of the prostate apex, above an through the rectourethral muscle. The external US is also innervated by somatic nerves (positive anti-PMP22 antibody) arising from the pudendal nerve, joining the midline but remaining below the rectourethral.CONCLUSIONS:This study provides anatomical evidence of an autonomic component in the innervation of the external US that travels in the neurovascular bundle. During radical prostatectomy, the rectourethral muscle and the neurovascular bundles are to be preserved, particularly during apical dissection.

Following fertilization of a mature oocyte, the formation of a diploid zygote involves a series of coordinated cellular events that ends with the first embryonic mitosis. In animals, this complex developmental transition is almost entirely controlled by maternal gene products. How such a crucial transcriptional program is established during oogenesis remains poorly understood. Here, we have performed an shRNA-based genetic screen in Drosophila to identify genes required to form a diploid zygote. We found that the Lid/KDM5 histone demethylase and its partner, the Sin3A-HDAC1 deacetylase complex, are necessary for sperm nuclear decompaction and karyogamy. Surprisingly, transcriptomic analyses revealed that these histone modifiers are required for the massive transcriptional activation of deadhead (dhd), which encodes a maternal thioredoxin involved in sperm chromatin remodeling. Unexpectedly, while lid knock-down tends to slightly favor the accumulation of its target, H3K4me3, on the genome, this mark was lost at the dhd locus. We propose that Lid/KDM5 and Sin3A cooperate to establish a local chromatin environment facilitating the unusually high expression of dhd, a key effector of the oocyte-to-zygote transition.

This paper explores the formalization of business ethics in corporations through an inductive analysis. Despite its incomplete and loose definition, business ethics is turned into formal ethical tools. Previous research on business ethics has focused on the efficacy of these tools. As a result, little is known about these tools' political nature, neither about how they embody a conception of business ethics. This paper addresses this gap. Our findings reveal a conflict between two ways of conceptualizing the regulation of business ethics: That of the non-legalists, who approach the topic of business ethics through values, and that of the legalists, who favor approaching business ethics through rules, procedures, and penalties. The latter approach dominates in the corporations studied and more broadly illustrates how corporations regard business ethics and the actors associated with it. On the whole, our results provide new insights into the limited efficacy of ethical tools and explains why the compliance approach to ethics has gained such power in the previous years.

La connaissance de l’anatomie du plancher pelvien musculaire masculin est importante pour la réalisation de la prostatectomie et de la protectomie. Décrire l’anatomie et l’innervation du plancher pelvien musculaire masculin. Nous avons réalisé une étude histologique et immunohistochimique chez trois fœtus humains masculins avec des coupes sériées de bassin. Les coupes étaient traitées par le trichrome de Masson puis immuno-marquées pour détecter les nerfs, les fibres somatiques, les fibres autonomes sympathiques et parasympathiques, les fibres nitriergiques, le muscle lisse et le muscle strié. Les coupes bidimensionnelles obtenues ont été scannées par un scanner de haute résolution optique. Au sein du plancher musculaire pelvien, nous avons individualisé un compartiment central médian (CCM) formé par des cellules musculaires lisses. Le CCM est limité par le rectum en arrière, l’urètre en avant et le muscle élévateur de l’anus latéralement. On distingue en son sein : – un contingent postérieur en arrière du rectum ; – un contingent antérieur en avant du rectum. Ces deux contingents sont en continuité. Ce compartiment s’insère sur le muscle élévateur de l’anus, le rectum, le sphincter lisse de l’urètre et le muscle bulbo-spongieux. Il est innervé par le système nerveux autonome via le plexus hypogastrique inférieur. Le plancher musculaire pelvien masculin contient une zone médiale faite de cellules musculaires lisses sous influence nerveuse autonome. Cette donnée est d’une importance majeure pour les chirurgiens dans le but d’éviter les lésions nerveuses, du rectum et de l’urètre au cours de la prostatectomie radicale et de la protectomie.

À l’exception du courant des « workplace friendships », la plupart des travaux sur les relations affinitaires en management étudient leurs conséquences sur le fonctionnement des organisations. Évoluant dans des champs de recherche séparés, ces travaux peinent à offrir une vision contextualisée des interactions entre relations affinitaires et relations fonctionnelles dans les organisations. À partir d’une étude de cas réalisée sur une équipe de recherche, cet article propose ainsi d’éclairer les influences réciproques entre relations affinitaires et relations fonctionnelles au travail.

La bronchopneumopathie chronique obstructive (BPCO) est une maladie respiratoire chronique très fréquente, conduisant à une insuffisance respiratoire chronique sévère. Souvent occultée face au tabagisme, la fraction de risque attribuable des étiologies professionnelles est d’environ 15 %, avec un lien avéré avec l’exposition notamment aux poussières. Parmi elles, figure le secteur du bâtiment et travaux publics (BTP), mais avec des données très parcellaires dans la littérature. Nous émettons l’hypothèse que la pratique dans un service de Santé au travail de spirométries dans le diagnostic précoce d’un trouble ventilatoire obstructif (TVO) chez des travailleurs du BTP serait réalisable avec une bonne qualité des EFR. L’objectif principal est donc de tester la pratique d’une courbe débit-volume systématique en médecine du travail pour diagnostiquer un TVO dans le secteur du BTP avec une confirmation diagnostique de la BPCO en milieu hospitalier et d’en analyser la courbe d’apprentissage. Cette étude prospective s’est déroulée de février 2016 à novembre 2017 dans un service de Santé au travail spécialisé dans le BTP. Tout sujet vu en visite médicale, âgé de plus de 40 ans (quel que soit son tabagisme et sa symptomatologie) et travaillant dans le secteur du BTP (excluant tous les sujets avec un emploi dans le tertiaire) a bénéficié d’un questionnaire médical et d’une spirométrie. Si un sujet avait un TVO (rapport VEMS/CVF < 70 %) et/ou un VEMS inférieur à 80 %, celui-ci a été adressé dans un centre de consultation de pathologie professionnelle hospitalo-universitaire pour confirmer le diagnostic de BPCO, à l’aide d’une EFR et d’un test de bronchodilatation. Chaque EFR a été réalisée selon les recommandations de réalisation et les critères de qualité retenus par l’American Thoracic Society (ATS) et l’European Respiratory Society (ERS). Le contrôle des courbes débit-volume réalisé par un physiologiste a montré que 77,1 % des 3657 EFR pratiquées étaient au moins acceptables. Il existait une nette progression significative de la courbe d’apprentissage avec un taux d’EFR au moins acceptables passant de 81,3 % (< 6 mois) à 87 % (> 6 mois) (p < 0,05). À ce jour, 131 patients ont bénéficié d’un diagnostic final de BPCO dont deux tiers sans symptômes. En médecine du travail, la pratique de spirométries systématiques, par des professionnels de santé formés et respectant les recommandations, contribue au dépistage précoce des BPCO. Couplés à une enquête professionnelle détaillée, ces examens vont permettre la mise en évidence de métiers, de tâches et de nuisances à risque de BPCO dans le secteur du BTP et de promouvoir des actions de prévention adaptées.

Cette recherche aide à comprendre comment les contrôles technocratiques et les contrôles socio-idéologiques cohabitent en cas de tensions entre eux. Elle s’appuie sur 62 entretiens semi-directifs menés dans les armées françaises. Dans un premier temps, elle montre que les contrôles socio-idéologiques sont à même de freiner l’insertion de nouveaux contrôles technocratiques. Dans un second temps, l’étude souligne que l’insertion de systèmes de contrôle de gestion, loin d’affaiblir les contrôles socio-idéologiques, donne l’occasion aux acteurs organisationnels de réaffirmer la puissance de leurs contrôles socio-idéologiques. Dès lors, nos résultats montrent que les contrôles technocratiques et socio-idéologiques peuvent entrer en compétition. Par ailleurs, cette étude met en valeur l’importance des phénomènes identitaires et politiques dans la cohabitation entre contrôles technocratiques et socio-idéologiques.

Spermatogenesis is the process by which spermatozoa are generated from spermatogonia. This cell population is heterogeneous, with self-renewing spermatogonial stem cells (SSCs) and progenitor spermatogonia that will continue on a path of differentiation. Only SSCs have the ability to regenerate and sustain spermatogenesis. This makes the testis a good model to investigate stem cell biology. The Farnesoid X Receptor alpha (FXRα) was recently shown to be expressed in the testis. However, its global impact on germ cell homeostasis has not yet been studied. Here, using a phenotyping approach in Fxrα-/- mice, we describe unexpected roles of FXRα on germ cell physiology independent of its effects on somatic cells. FXRα helps establish and maintain an undifferentiated germ cell pool and in turn influences male fertility. FXRα regulates the expression of several pluripotency factors. Among these, in vitro approaches show that FXRα controls the expression of the pluripotency marker Lin28 in the germ cells.

Introduction: The ultrastructure of a nerve has implications for surgical nerve repair. The aim of our study was to characterize the fascicular versus fibrillar anatomy and the autonomic versus somatic nature of the fetal sciatic nerve (SN). Methods: Immunohistochemistry for vesicular acetylcholine transporter, tyrosine hydroxylase, and peripheral myelin protein 22 was performed to identify cholinergic, adrenergic, and somatic axons, respectively, in the human fetal SN. Two-dimensional (2D) analysis and 3D reconstructions were performed. Results: The fetal SN is composed of one-third stromal tissue and two-thirds neural tissue. Autonomic fibers are predominant over somatic fibers within the neural tissue. The distribution of somatic fibers is initially random, but then become topographically organized after intra- and interfascicular rearrangements have occurred within the nerve. Conclusions: The fetal model presents limitations but enables illustration of the nature of the nerve fibers and the 3D fascicular anatomy of the SN.

Le présent article revient sur le conflit judiciaire qui oppose la Société Générale à son ex-trader, Jérôme Kerviel. Plus précisément, il part de la mutation juridique qui s’opère en 2014 au niveau de son volet civil pour mettre en lumière la décision judiciaire ultime qui en découle. Le 23 septembre 2016, tout en confirmant Kerviel comme le seul coupable pénalement, la cour d’appel de Versailles responsabilise civilement la Société Générale. Le conflit est ainsi une occasion pour étudier les normes juridiques en rapport avec les normes et la pratique managériales.

BACKGROUND:Injury to the levator ani muscle or pelvic nerves during pregnancy and vaginal delivery is responsible for pelvic floor dysfunction.OBJECTIVE:We sought to demonstrate the presence of smooth muscular cell areas within the levator ani muscle and describe their localization and innervation.STUDY DESIGN:Five female human fetuses were studied after approval from the French Biomedicine Agency. Specimens were serially sectioned and stained by Masson trichrome and immunostained for striated and smooth muscle, as well as for somatic, adrenergic, cholinergic, and nitriergic nerve fibers. Slides were digitized for 3-dimensional reconstruction. One fetus was reserved for electron microscopy. We explored the structure and innervation of the levator ani muscle.RESULTS:Smooth muscular cell beams were connected externally to the anococcygeal raphe and the levator ani muscle and with the longitudinal anal muscle sphincter. The caudalmost part of the pubovaginal muscle was found to bulge between the rectum and the vagina. This bulging was a smooth muscular interface between the levator ani muscle and the longitudinal anal muscle sphincter. The medial (visceral) part of the levator ani muscle contained smooth muscle cells, in relation to the autonomic nerve fibers of the inferior hypogastric plexus. The lateral (parietal) part of the levator ani muscle contained striated muscle cells only and was innervated by the somatic nerve fibers of levator ani and pudendal nerves. The presence of smooth muscle cells within the medial part of the levator ani muscle was confirmed under electron microscopy in 1 fetus.CONCLUSION:We characterized the muscular structure and neural control of the levator ani muscle. The muscle consists of a medial part containing smooth muscle cells under autonomic nerve influence and a lateral part containing striated muscle cells under somatic nerve control. These findings could result in new postpartum rehabilitation techniques.