Search

International audience

This article studies, over the period 2006 to 2019, both the structure and the evolution of corporate networks built on shared board directors between the largest listed firms of three European countries: France, Germany, and the United Kingdom. It offers a longitudinal and up-to-date analysis of the state of links between companies through examining interlocking directorates. Contrary to previous studies which have emphasized a decline of interlocks when analyzed at the board director level, we observe relative stability of these networks at the corporate level with a number of connected firms remaining quite stable despite a decline of board ties. As a result, the most central companies remain mainly the same at the national and international level over the considered period. Our findings provide evidence for the resource perspective: access to key resources seemingly pushes firms to continue their network participation despite strengthened national regulations on directors with multiple board seats. This evolution echoes the concept of weak ties of Granovetter (Am J Sociol 78: 360–1380, 1973). Lastly, it is worth noting that it cannot be affirmed that there has been an emergence of a cross-national network which operates to substitute national board ties.

This study examines the influence of directors' and CEOs' networks in the appointment of female directors. Building on social identity theory and social network theory, we argue that since men and women are members of different networks, recruitment practices based on networks prevent women from accessing board positions. We also examine the role of board gender diversity regulation on the influence of networks, hypothesising that such regulations help in deinstitutionalising ‘old boys' networks’, based on institutional theory. Using a sample of 32,819 new board appointments in the largest listed firms of 17 European countries, the US, and Canada, we determine whether new directors are directly linked through employment, board, charities, or club memberships, to the incumbent directors or the CEO. We find that the probability that the new director appointed is a woman decreases by approximately 28% when the new director is associated with one of the incumbent directors. We also find that gender diversity regulation reduces the influence of networks in the appointment of female directors. Our results provide archival evidence that board networks hinder the recruitment of female directors and that gender diversity hard and soft laws deinstitutionalise old boys' networks.

Palliative care is still too often surrounded by prejudice and ignorance, even within the hospital. The mobile palliative care team at the Émile-Roux hospital in Puy-en-Velay (43) wanted to raise awareness among caregivers by enabling them to acquire and consolidate their knowledge of legislation in the field of palliative care. A serious game designed for this purpose aroused the interest of many participants.

International audience

Fanconi anemia (FA) is a rare human genetic disorder characterized by bone marrow failure, predisposition to cancer and developmental defects including hypogonadism. Reproductive defects leading to germ cell aplasia are the most consistent phenotypes seen in FA mouse models. We examined the role of the nuclear FA core complex gene Fancg in the development of primordial germ cells (PGCs), the embryonic precursors of adult gametes, during fetal development. PGC maintenance was severely impaired in Fancg−/− embryos. We observed a defect in the number of PGCs starting at E9.5 and a strong attrition at E11.5 and E13.5. Remarkably, we observed a mosaic pattern reflecting a portion of testicular cords devoid of PGCs in E13.5 fetal gonads. Our in vitro and in vivo data highlight a potential role of Fancg in the proliferation and in the intrinsic cell motility abilities of PGCs. The random migratory process is abnormally activated in Fancg−/− PGCs, altering the migration of cells. Increased cell death and PGC attrition observed in E11.5 Fancg−/− embryos are features consistent with delayed migration of PGCs along the migratory pathway to the genital ridges. Moreover, we show that an inhibitor of RAC1 mitigates the abnormal migratory pattern observed in Fancg−/− PGCs.

Male infertility is responsible for approximately half of all cases of reproductive issues. Spermatogenesis originates in a small pool of spermatogonial stem cells (SSCs), which are of interest for therapy of infertility but remain not well defined in humans. Using multiparametric analysis of the side population (SP) phenotype and the α-6 integrin, THY1, and β-2 microglobulin cell markers, we identified a population of human primitive undifferentiated spermatogonia with the phenotype β-2 microglobulin (β-2M)

Firms with high innovation intensity hire directors with specific skills, and different forms of innovation require different profiles of directors. Board members may bring human and social capital that support the innovative strategies of firms. In a sample of 735 French companies, firms with high innovation intensity hire directors with specific skills, while the profiles of directors required on boards are different according to the forms of innovation implemented. Board human capital is important for innovative firms and gives them benchmarks concerning board appointment criteria.

// Sebastien Corbineau 1, 2, 3, 4 , Bruno Lassalle 1, 2, 3, 4 , Maelle Givelet 1, 2, 3, 4, 7, 8, 9 , Ines Souissi-Sarahoui 2, 3, 4, 6 , Virginie Firlej 1, 2, 3, 4 , Paul Henri Romeo 1, 2, 3, 4 , Isabelle Allemand 5 , Lydia Riou 1, 2, 3, 4 , Pierre Fouchet 1, 2, 3, 4 1 CEA DRF iRCM SCSR, Laboratoire de Recherche sur la reparation et la Transcription dans les cellules Souches, UMR 967, F-92265 Fontenay-aux-Roses, France 2 INSERM, UMR967, F-92265 Fontenay-aux-Roses, France 3 Universite Paris Diderot, Sorbonne Paris Cite, UMR 967, F-92265 Fontenay-aux-Roses, France 4 Universite Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France 5 CEA DRF iRCM SCSR, Laboratoire de Gametogenese, Apoptose et Genotoxicite, UMR 967, F-92265 Fontenay-aux-Roses, France 6 CEA DRF iRCM SCSR, Laboratoire de Radiopathologie, UMR 967, F-92265 Fontenay-aux-Roses, France 7 INSERM U1016, Institut Cochin, Paris 75014, France 8 CNRS UMR8104, Paris 75014, France 9 Universite Paris Descartes, Sorbonne Paris Cite, Faculte de Medecine, Paris 75014, France Correspondence to: Pierre Fouchet, email: pierre.fouchet@cea.fr Keywords: stem cell, germinal, reprogramming, pluripotency, testis Received: May 03, 2016 Accepted: November 30, 2016 Published: December 28, 2016 ABSTRACT The male germinal lineage, which is defined as unipotent, produces sperm through spermatogenesis. However, embryonic primordial germ cells and postnatal spermatogonial stem cells (SSCs) can change their fate and convert to pluripotency in culture when they are not controlled by the testicular microenvironment. The mechanisms underlying these reprogramming processes are poorly understood. Testicular germ cell tumors, including teratoma, share some molecular characteristics with pluripotent cells, suggesting that cancer could result from an abnormal differentiation of primordial germ cells or from an abnormal conversion of SCCs to pluripotency in the testis. Here, we investigated whether the somatic reprogramming factors Oct3/4, Sox2, Klf4 and c-Myc (OSKM) could play a role in SSCs reprogramming and induce pluripotency using a doxycycline-inducible transgenic Col1a1-4F2A-OSKM mouse model. We showed that, in contrast to somatic cells, SSCs from adult mice are resistant to this reprogramming strategy, even in combination with small molecules, hypoxia, or p53 deficiency, which were previously described to favour the conversion of somatic cells to pluripotency. This finding suggests that adult SSCs have developed specific mechanisms to repress reprogramming by OSKM factors, contributing to circumvent testicular cancer initiation events.

DNA damage response in adult spermatogenic cells should limit the propagation of mutations to the offspring, without being detrimental to fertility. In differentiating spermatogenic cells, the genomic instability is limited in time, whereas in spermatogonial stem cells it can be maintained all along life. Spermatogonial stem cells are long-lived cells that support normal germ cell differentiation and must be preserved throughout life. However after irradiation spermatogenesis recovery can be impaired as a consequence of the radiation-induced decline in spermatogonial stem cell. In this review, we summarize the differential sensitivities to DNA damage of spermatogenic cell populations, and the DNA repair mechanisms activated in these cells that paradoxically might favour the maintenance of cells with impaired genomic integrity. We describe how the testis tissue collapses in response to irradiation and we discuss the molecular pathways involved in the control of DNA damage response and homeostasis in spermatogonial stem cells.

Dans plusieurs pays europeens, la representation des femmes dans les conseils a augmente de facon significative au cours des dernieres annees. Notre etude analyse comment la theorie institutionnelle contribue a expliquer la place des femmes dans les conseils d’administration europeens. Nous confirmons que les pressions coercitives expliquent la croissance de la representation des femmes directrices dans les pays europeens au cours des 8 dernieres annees. Nous apportons la preuve de la relation entre les pressions normatives et la diversite des genres dans un pays donne. Cette etude a des implications pour les decideurs politiques qui souhaitent augmenter une mixite efficace dans les conseils. Elle montre que les lois sur les quotas de vote necessitent le developpement simultane ou prealable de contingents de femmes de talent.

Pour favoriser la féminisation des conseils d'administration, certains pays, comme la Norvège ou la France, ont voté une loi contraignante imposant un quota ; d'autres pays comme le Canada ont adopté une loi souple de type comply or explain. L'article propose une comparaison de l'efficacité des lois contraignantes et des lois souples dans le cas de la promotion de la diversité dans les conseils d'administration. L'étude France – Canada de 445 sociétés cotées sur la période 2011-2014 confirme la féminisation plus grande et plus rapide des conseils d'administration en France, sans s'écarter davantage qu'au Canada des normes de recrutement en vigueur. To improve gender diversity on boards, some countries, such as Norway and France, have passed a hard law with quotas while other countries like Canada use a soft approach. The aim of the article is to compare the effectiveness of soft and hard laws to promote board diversity. The study of 445 listed companies in France and Canada on the period 2011–2014 confirms that board diversity is higher and faster in France than in Canada, without higher deviation from directors’ appointment standards.

After Norway in 2003 and Spain and Iceland in 2007, France adopted gender quotas in boards. With the Cope Zimmermann law, voted on and implemented in January 2011, listed companies and non-listed companies with revenues or total of assets over 50 million euros or employing at least 500 persons for three consecutive years have to reach a minimum of 40% of each sex on boards within a six-year period, with an intermediary level of 20% in 2014. This example of hard law seems to have worked in the French context: after the General Assemblies of 2016, the 140 biggest listed companies (with a capitalisation of more than 1 billion euros) have an average of 36.7% of women on their board. Despite some criticisms about the legitimacy of quotas, and probably due to the existence of a compulsory regulation, no strong and structured hindering forces appeared as regards the increase of female representation on boards. In this chapter, we provide a general background of French companies’ corporate governance structure, and a discussion of the national policy. Along with figures on women representation, we also provide critical reflections on the case and a short reflection from Viviane Neiter, a French practitioner, director in several French listed companies.

We examine how the presence of women involved in the financial reporting process of public companies, and especially the interactions between them (i.e. the simultaneous presence of a woman CFO, women sitting on the audit committee, and women auditors), impacts financial reporting quality. For our sample of large French companies, we find that women do not affect financial reporting quality when interactions are not considered. However, the interactions between women involved in the financial reporting are associated with lower discretionary accruals and higher C-scores (our measure of conservatism), as expected because women are generally more risk averse and have greater ethical sensitivity. Furthermore, our result holds only for non-family firms, which is also expected because there is a greater demand for earnings quality in such firms. In addition, it appears that woman CFOs play a key role in these interactions. Overall, our results support the idea that women affect positively financial reporting quality only if several women are involved at various stages of the financial reporting process and only in specific contexts (i.e. non-family firms). These new results should be of great interest for researchers, investors and regulators.

L’article s’interesse aux antecedents de la succession des dirigeants et a pour objectif de verifier si la structure de propriete contribue a expliquer les caracteristiques des dirigeants recrutes. L’etude empirique menee sur 217 nominations de dirigeants a la tete d’une societe cotee francaise entre 1996 et 2005 confirme l’existence de profils de dirigeants differents selon le type de firmes. Dans les societes controlees, les dirigeants sont principalement d’origine externe, ont un niveau de formation plus eleve et une origine fonctionnelle plutot en finance, en production ou en management. Les dirigeants des firmes familiales ont plusieurs traits communs : ce sont des internes, avec plus d’anciennete dans la firme, moins d’annees d’etudes et une origine fonctionnelle plutot vente, marketing ou international. Dans les firmes manageriales, seule l’origine interne est expliquee par la structure de propriete. Ces resultats pourraient s’expliquer par l’existence d’un biais de proximite entre actionnaires et dirigeants.

L’objectif de l’article [1] est de decrire les mecanismes internes de gouvernance des banques francaises et de comparer leurs pratiques. L’appartenance au systeme cooperatif ou au groupe des banques SA ne suffit pas a expliquer les similitudes ou les ecarts releves. L’actionnariat semble plus pertinent pour identifier la proximite des comportements et conduit a definir trois categories de banques.

Several studies have shown that apoptotic pathways control fragmentation of unfertilized ovulated oocyte, induced by doxorubicin. But very few have investigated the basis of this process, from prophase I to later stages. Our results revealed the presence of caspase-2(L), caspase-9, and caspase-3 in their zymogen and cleaved forms in the oocyte before meiosis resumption. Caspase-2(L) and caspase-9 were detected in the nucleus of GV-oocytes in a distribution related to chromatin configuration. The inhibition of caspase activity by Z-VAD-fmk accelerated the transition from metaphase I to metaphase II, and caspase-9 and caspase-3 were detected along the meiotic spindle. Surprisingly, Western blot analysis revealed that the three cleaved caspases were present in similar amounts in healthy and fragmented oocytes and caspase inhibition did not prevent doxorubicin-induced apoptosis. Our results suggest that, if cleaved, caspases may be dispensable for final oocyte death and they could be involved in regulating the maturation process.

Fibrotest (FT) and Actitest (AT) are biochemical markers of fibrosis and activity for use as a non-invasive alternative to liver biopsy in patients with chronic hepatitis C virus (HCV). The aim of this study was to perform an external validation of FT and AT and to study the discordances between FT/AT and liver biopsy in patients with chronic hepatitis C.A total of 519 consecutive patients with chronic HCV were prospectively included in five centers, with liver biopsy and biochemical markers taken at the same day. Fifteen patients were excluded because their biopsies could not be interpreted. Diagnostic accuracies were assessed by receiver operating characteristic (ROC) curve analysis.Median biopsy size was 15 mm (range: 2-58), with 9 portal tracts (1-37) and 1 fragment (1-12). 46% (230/504) were classified F2-F4 in fibrosis and 39% A2-A3 in activity. FT area under ROC curve for diagnosis of activity (A2-A3), significant fibrosis (F2-F4), and severe fibrosis (F3-F4) were 0.73 [0.69-0.77], 0.79 [0.75-0.82], and 0.80 [0.76-0.83], respectively. Among the 92 patients (18%) with 2 fibrosis stages of discordance between FT and biopsy, the discordance was attributable to FT in 5% of cases, to biopsy in 4%, and undetermined in 9%.This prospective independent and multicenter study confirms the diagnostic value of FT and AT found in the princeps study and suggests that FT and AT can be an alternative to biopsy in most patients with chronic HCV.

Testis is one of the organs with the most telomerase activity in the adult. This activity protects chromosomes from telomere attrition and ensures the transmission of full-length chromosomes to progeny. Little is known about telomerase activity during adult germ cell differentiation, however. We demonstrate here that the telomerase activity of adult mouse testis resides in the α6-integrin-positive Side Population containing spermatogonia and enriched in spermatogonial stem cells. The telomerase activity of these cells fell upon entry into meiosis and during the subsequent spermiogenesis. In addition, the telomerase activity of cells in various stages of differentiation was unaffected by aging and, notably, remained high in the α6-integrin-positive Side Population.

We investigated the role of tumor suppressor p53 and Fas (CD95/APO-1), a member of the tumor necrosis factor receptor family, in neural progenitors response to gamma-irradiation exposure. Telencephalic cells were obtained from wild-type C57Bl/6, or p53-/- or fas-/-, 15-day-old mouse embryos. They were cultured in conditions allowing neural progenitors to form proliferating clusters (neurospheres). A 2 Gy gamma-irradiation induced a G1 cell cycle arrest and triggered apoptosis in wild-type neural progenitor cultures in correlation with an enhanced expression of p53 and of its downstream target p21(WAF1), both of them acquiring a nuclear localization. These effects did not occur in p53-/- neural progenitors demonstrating the central role played by p53 in their response to ionizing radiation. Furthermore, the monoclonal antibody Jo2 directed against Fas induced apoptosis of wild type but not of fas-/- neural progenitors, indicating the existence of a functional Fas signaling pathway in neural progenitors. Ionizing radiation induced an increase of Fas membrane expression related to a p53-dependent increase of fas mRNA expression in wild-type neural progenitors. Moreover, fas-/- neural progenitors exhibited delayed radiation-induced apoptosis compared to wild-type cells. Therefore, these findings establish a role for Fas/CD95 related to p53 in the response of neural progenitors to gamma-radiation exposure. Similar mechanisms could be triggered in neural progenitors in case of different stresses during brain development or in the course of various diseases affecting the adult brain.

Continuous or cyclic production of spermatozoa throughout life in adult male vertebrates depends on a subpopulation of undifferentiated germ cells acting as spermatogonial stem cells (SSCs). What makes these cells self-renew or differentiate is barely understood, in particular in nonmammalian species, including fish. In the highly seasonal rainbow trout, at the end of the annual spermatogenetic cycle, tubules of the spawning testis contain only spermatozoa, with the exception of scarce undifferentiated spermatogonia that remain on the tubular wall and that will support the next round of spermatogenesis. Taking advantage of this model, we identified putative SSCs in fish testis using morphological, molecular, and functional approaches. In all stages, large spermatogonia with ultrastructural characteristics of germinal stem cells were found, isolated or in doublet. Trout homologues of SSC and/or immature progenitor markers in mammals—nanos2 and nanos3, pou2, plzf, and piwil2—were preferentially expressed in the prepubertal testis and in the undifferentiated A spermatogonia populations purified by centrifugal elutriation. This expression profile strongly suggests that these genes are functionally conserved between fish and mammals. Moreover, transplantation into embryonic recipients of the undifferentiated spermatogonial cells demonstrated their high ‘‘stemness’’ efficiency in terms of migration into gonads and the ability to give functional gametes. Interestingly, we show that nanos2 expression was restricted to a subpopulation of undifferentiated spermatogonia (less than 20%) present as isolated cells or in doublet in the juvenile and in the maturing trout testis. In contrast, nanos2 transcript was detected in all the undifferentiated spermatogonia remaining in the spawning testis. Plzf was also immunodetected in A-Spg from spawning testis, reinforcing the idea that these cells are stem cells. From those results, we hypothesize that the subset of undifferentiated A spermatogonia expressing nanos2 transcript are putative SSC in trout.

Several reports suggested that steroidogenic hormones could be directly involved in the regulation of apoptosis in vitro, but whether this is due to blocking or promoting mechanism of these hormones remains controversial. However, it was shown that progesterone exhibited a protective effect against the apoptotic process during mouse mammary gland involution in vivo. In this study, we analyzed the effect of medroxyprogesterone acetate (MPA) treatment, an agonist of progesterone, on serum starvation induced apoptosis on breast cancer cell lines. Positive and negative progesterone receptor (PgR+ and PgR-) breast cancer cell lines were treated with MPA (10 nM), either in standard culture conditions or in serum-free medium to induce apoptosis. Cell survival, proliferation and apoptosis were simultaneously analyzed with the expression of apoptosis-related genes measured by a real time quantitative RT-PCR. At non cytotoxic doses, MPA protected PgR+ T47-D, MCF-7 and H466-B cell lines against serum depletion-induced apoptosis, while MPA did not protect PgR-MDA-MB-231 cells against serum depletion induced apoptosis. In PgR+ cell lines and in concordance with the protective effect, the pro-apoptotic HRK and BAK1 mRNAs were up-regulated after apoptosis induction, while they were no more induced in condition of protection against apoptosis after MPA treatment. We also observed, specifically in PgR+ cells, an up-regulation of BCLX-L and BCLX-S and a down-regulation of BCL2 mRNAs, which are specific to the MPA response and unrelated to apoptotic process. Involvement of these genes with regard to the MPA-mediated protection against apoptosis is discussed.

> La spermatogenese est l’ensemble des divisions et differenciations cellulaires conduisant, a partir des cellules souches germinales (CSG), a la formation des spermatozoides dans le testicule adulte. La preservation d’un stock de cellules souches fonctionnelles est indispensable pour le maintien de l’homeostasie et de la fonction tissulaire, mais egalement pour la regeneration du tissu apres une lesion. Ces CSG se multiplient soit pour s’autorenouveler soit pour entrer dans le processus de differenciation et donner naissance a des progeniteurs, qui seront a l’origine de la production des cellules specialisees. Le processus d’engagement d’une Les progeniteurs murins transplantes peuvent regenerer une spermatogenese a long terme Dans le testicule murin, les CSG ou spermatogonies As (single) debutent le processus de differenciation pour donner une premiere serie de progeniteurs, les spermatogonies Apr (paired) et Aal (aligned) dites indifferenciees. Les spermatogonies Aal se differencieront en une seconde serie de progeniteurs dits differencies, les spermatogonies A1, A2, A3, A4, Int et B dans lesquelles se produira par la suite le processus meiotique (Figure 1). Chez la souris, nous disposons d’un test fonctionnel identifiant les CSG : l’analyse cellule souche dans le processus de differenciation est considere comme irreversible. Ainsi, ces progeniteurs perdent la capacite de regenerer le tissu a long terme. Cependant des etudes recentes notamment dans le modele du tissu germinal chez la drosophile, soulignent la capacite qu’ont des progeniteurs deja engages a se reprogrammer et a acquerir a nouveau le potentiel de regeneration a long terme des cellules souches [1, 2]. Deux mecanismes pourraient ainsi coexister au sein de certains tissus afin de maintenir le pool de cellules souches : l’autorenouvellement des cellules souches et la reprogrammation des progeniteurs. Des progeniteurs transplantes peuvent generer des cellules souches germinales

While p53 is dispensable for development, an excess of p53 has dramatic consequences on the embryogenesis and on the cell differentiation. In an attempt to analyse in vivo the effects of p53 activity, we have generated transgenic mice expressing the wild-type p53 under the control of the metallothionein I promoter. In the three transgenic lines established, exogenous p53 is expressed constitutively in the postmeiotic cells of transgenic males and two lines are subfertile. Transgenic males expressing the upper level of p53 produce few spermatozoa since the majority of developing spermatids undergo apoptosis. In the subfertile males exhibiting an intermediate amount of p53, teratozoospermia is obvious suggesting an altered terminal differentiation of postmeiotic cells. In contrast lower level of p53 does not lead the third line to sterility. These results suggest that the activity of p53 is dependent in vivo on the amount of p53 present within cells, as it has been already demonstrated in vitro.

We report the isolation of the mouse Kin17 gene, located on chromosome 2, coding a nuclear Zn-finger protein that has a 39-residue region homologous to Escherichia coli RecA protein and that is recognized by anti-RecA antibodies. Kin17 protein preferentially binds to curved DNA in vitro and in vivo, suggesting a role in illegitimate recombination and in regulation of gene expression. We have shown that the Kin17 gene is about 8 kb in length and displays three exons and two introns. The 5' flanking region lacks a canonical TATAA box but presents several putative regulatory domains. A major transcription initiation site is located 322 nucleotides upstream of the translation start site. The 1.7-kb transcript of the Kin17 gene is weakly and ubiquitously expressed in murine tissues and cell lines as determined by Northern analysis. The cross-hybridization of Kin17 cDNA with the genomic DNA of other species in Southern analysis indicates the conservation of the gene among mammals and suggests that the Kin17 gene plays a conserved role in DNA metabolism.

Representation of women on boards is getting more and more attention these recent years (Hillman, Shropshire, & Cannella, 2007; Nielsen & Huse, 2010), all the more as recent influence by the legislator accelerates the pace of change. Indeed, in France, a new law adopted in January 2011 stated that the proportion of female directors should not be lower than 40% in all major companies. Most previous research focused on the impact of the presence of women in boards on performance, but there are few studies on female directors' networks. In order to help to better understand the ties at the origin of these networks, we study several characteristics and network ties of female directors of French companies belonging to the SBF 120 index and we compare them with male characteristics. We test the specificity of four types of board of directors' networks: attendance at the same elite educational institutions, use of business networks, civil servants' networks, and interlocking directorates. Our findings suggest that female directors' networks tend to find their origin in business networks more than men. Conversely, male directors have more board interlocking and are more often graduated from elite schools than women. These results show that female directors' networks have specific origins in comparison with men's ones. The exploration of this specificity could be an asset to better understand the role and influence of female directors' networks in governance.

Fanconi anemia (FA) is a human rare genetic disorder characterized by congenital defects, bone marrow (BM) failure and predisposition to leukemia. The progressive aplastic anemia suggests a defect in the ability of hematopoietic stem cells (HSC) to sustain hematopoieis. We have examined the role of the nuclear FA core complex gene Fancg in the functionality of HSC. In Fancg-/- mice, we observed a decay of long-term HSC and multipotent progenitors that account for the reduction in the LSK compartment containing primitive hematopoietic cells. Fancg-/- lymphoid and myeloid progenitor cells were also affected, and myeloid progenitors show compromised in vitro functionality. HSC from Fancg-/- mice failed to engraft and to reconstitute at short and long term the hematopoiesis in a competitive transplantation assay. Fancg-/- LSK cells showed a loss of quiescence, an impaired migration in vitro in response to the chemokine CXCL12 and a defective homing to the BM after transplantation. Finally, the expression of several key genes involved in self-renewal, quiescence and migration of HSC was dysregulated in Fancg-deficient LSK subset. Collectively, our data reveal that Fancg should play a role in the regulation of physiological functions of HSC.

Cet article s’intéresse à l’influence des caractéristiques des dirigeants de 135 sociétés françaises cotées sur la performance économique à long terme. Plus précisément, il cherche à vérifier si les élites, c’est-à-dire les dirigeants issus de grandes écoles d’ingénieur (notamment de l'Ecole Polytechnique) ou de commerce (notamment d'HEC), gèrent mieux les entreprises que les autres dirigeants. Nos résultats mettent en évidence que la performance, mesurée sur une période de 10 ans (1999-2008), ne diffère pas significativement pour les entreprises dirigées par les élites comparativement à celle enregistrée par les autres dirigeants, mais que des différences existent selon les profils des dirigeants issus des grandes écoles. En particulier, il semble que les rentabilités économiques moyennes soient plus faibles à long terme pour les entreprises dont les dirigeants sont issus de grandes écoles d’ingénieur. En revanche, le risque économique semble significativement moindre pour les entreprises ayant à leur tête des dirigeants issus de grandes écoles de commerce.

During testis development, proliferation and death of gonocytes are highly regulated to establish a standard population of adult stem spermatogonia that maintain normal spermatogenesis. As Transforming Growth Factor beta (TGFbeta) can regulate proliferation and apoptosis, we investigated its expression and functions during testis development. We show that TGFbeta2 is only expressed in quiescent gonocytes and decreases gonocyte proliferation in vitro. To study the functions of TGFbeta2, we developed conditional mice that invalidate the TGFbeta receptor type II in germ cells. Most of the knock-out animals die during fetal life, but the surviving adults show a reduced pool of spermatogonial stem/progenitor cells and become sterile with time. Using an organ culture system mimicking in vivo development, we show higher proportions of proliferating and apoptotic gonocytes from 13.5 dpc until 1 dpp, suggesting a reduction of germinal quiescence in these animals. Conversely, a 24-hour TGFbeta2-treatment of explanted wild-type testes, isolated every day from 13.5 dpc until 1 dpp, increased the duration of quiescence.These data show that the TGFbeta signaling pathway plays a physiological role during testis development by acting directly as a negative regulator of the fetal and neonatal germ cell proliferation, and indicate that the TGFbeta signaling pathway might regulate the duration of germ cell quiescence and is necessary to maintain adult spermatogenesis.

International audience; In adults, stem cells are responsible for the maintenance of many actively renewing tissues, such as haematopoietic, skin, gut and germinal tissues. These stem cells can self-renew or be committed to becoming progenitors. Stem-cell commitment is thought to be irreversible but in male and female Drosophila melanogaster, it was shown recently that differentiating germ cells can revert to functional stem cells that can restore germinal lineage. Whether progenitors are also able to generate stem cells in mammals remains unknown. Here we show that purified mouse spermatogonial progenitors committed to differentiation can generate functional germinal stem cells that can repopulate germ-cell-depleted testes when transplanted into adult mice. We found that GDNF, a key regulator of the stem-cell niche, and FGF2 are able to reprogram in vitro spermatogonial progenitors for reverse differentiation. This study supports the emerging concept that the stem-cell identity is not restricted in adults to a definite pool of cells that self-renew, but that stemness could be acquired by differentiating progenitors after tissue injury and throughout life.

(VF)L'objectif de l'article est de tester sur une période récente si les changements de dirigeants suite à une mauvaise performance en France ont permis aux firmes un retour à de meilleurs résultats. L'étude empirique, menée sur un échantillon de 160 sociétés cotées à Paris ayant changé de dirigeant entre 1996 et 2004, confirme un effet positif sur la création de valeur des départs de dirigeants dans ce contexte si le successeur est un externe ou si la firme est contrôlée. La réflexion doit être prolongée pour mieux comprendre sous quelles conditions ces départs permettent un retour à de meilleurs résultats.(VA)The article studies the value creation of CEO departures in the context of poor performance in France. The empirical tests, on the basis of 160 firms listed in Paris whose CEOs were replaced between 1996 and 2004, bring evidence of the positive effect of these departures on firm performance when the successor is an outsider or when firms are controlled. Other factors should be analyzed to better understand in which cases CEO departures in the context of poor performance involve value creation.

(VF)L'objectif de l'article est de tester sur une période récente si les changements de dirigeants, suite à une mauvaise performance en France, ont permis aux firmes un retour à de meilleurs résultats. L'étude empirique, menée sur un échantillon de 160 sociétés cotées à Paris ayant changé de dirigeant entre 1996 et 2004, confirme un effet positif sur la création de valeur des départs de dirigeants dans ce contexte si le successeur est un externe, ou si la firme est contrôlée. La réflexion doit être prolongée pour mieux comprendre sous quelles conditions ces départs permettent un retour à de meilleurs résultats.(VA)This article examines the value creation related to CEO departures in the context of poor performing French corporations. The empirical tests conducted on a sample of 160 firms listed on the Paris stock exchange whose CEOs were replaced between 1996 and 2004 give evidence of the positive effect of these departures on firm performance when the successor is an outsider or when firms are controlled. Additional factors should ultimately be analyzed to better understand in which cases CEO departures in the context of poor performance involve value creation.

Spermatogenesis is a self-renewing process leading to production of spermatozoa in adult testis. The existence of male germinal stem cells was demonstrated by regeneration of spermatogenesis after transplantation of total testicular germ cells in testis [1], and we have previously shown that mouse testicular cells contain a side population (SP) of stem cells (Hoechst 33342 fluorescent dye efflux) that can repopulate germ celldepleted testis when transplanted into adult mice [2]. Several breakthroughs concerning the in vitro derivation of male and female germ cells from embryonic stem cells have challenged the field of reproductive biology and opened new perspectives for treatment of infertility [3–5]. Some reports have suggested that adult bone marrow-derived stem cells are able to regenerate various nonhematopoietic cell lineages in several organs, by

Background In patients with chronic hepatitis C virus, liver biopsy is the gold standard for assessing liver disease stage; nevertheless, it is prone to complications, some of them serious. Non-invasive methods have been proposed as surrogate markers for liver fibrosis. It was shown that serum hyaluronic acid (HA) level increases with the development for liver fibrosis. The aim of this study was to evaluate the diagnostic value of HA as well as to determine the HA level cut-off for predicting the presence or absence of fibrosis, severe fibrosis, and cirrhosis. Results 405 patients with chronic hepatitis C were prospectively included with biomarker measurement and liver biopsy done the same day: 151 in the training set (only biopsy lengths of 25 mm or more) and 254 in the validation set. For the discrimination of significant fibrosis, severe fibrosis, and cirrhosis in the training set, the areas under curve (AUCs) were 0.75 ± 0.03, 0.82 ± 0.02, and 0.89 ± 0.03, respectively. Absence of significant fibrosis, severe fibrosis, and cirrhosis can be predicted by HA levels of 16, 25, and 50 μg/l, respectively (with negative predictive values of 82%, 89%, and 100%, in the same order). Presence of significant fibrosis, severe fibrosis, and cirrhosis can be predicted by HA levels of 121, 160, and 237 μg/l, respectively (with positive predictive values of 94%, 100%, and 57%, in the same order). Conclusion In the validation set, HA was accurate in predicting significant fibrosis, severe fibrosis, and cirrhosis with AUCs of 0.73, 0.77, and 0.97, respectively. Moreover, accurate HA level cut-offs were defined for predicting significant fibrosis, severe fibrosis, and cirrhosis. Thus, the study supports that HA level may be clinically useful as a non-invasive marker for liver fibrosis and/or cirrhosis.

Background Spermatogenesis in adult is a complex stepwise process leading to terminally differentiated spermatozoa. The cellular heterogeneity of testis renders complex the studies on molecular aspects of this differentiation process. Analysis of the regulation of adult spermatogenesis would undoubtedly benefit from the development of techniques to characterize each germinal differentiation step. Methods Hoechst 33342 staining of mouse testicular cells allows characterization of an enriched population in germinal stem cell and spermatogonia, called side population. In this study, we examined the definition of the various germinal populations stained by Hoechst 33342, notably meiotic and postmeiotic cells. Results Preleptotene spermatocytes, spermatocyte I, spermatocyte II, and round and elongated spermatids were discriminated by Hoechst 33342 staining. In addition, we associated differentiation of spermatocyte I through leptotene to diplotene with changes in Hoechst 33342 red fluorescence pattern. Conclusions Hoechst 33342 staining of viable germinal cells constitutes a valuable tool to study normal and impaired mouse adult spermatogenesis or to isolate viable cells from various differentiation stages for studies of molecular mechanisms regulating spermatogenesis. © 2005 Wiley-Liss, Inc.

Stem cells in various somatic tissues (bone marrow, skeletal muscle) can be identified by the `Side Population' marker based on Hoechst 33342 efflux. We show that mouse testicular cells also display a `Side Population' that express Bcrp1 mRNA, the ABC transporter responsible for Hoechst efflux in hematopoietic cells. Inhibition of Hoechst efflux by specific BCRP1 inhibitor Ko143 show that germinal `Side Population' phenotype is dependent on BCRP1 activity. Analysis of two well-defined models of altered spermatogenesis(W/Wv mutants and cryptorchid male mice) and RNA expression studies of differentiation markers demonstrate that germinal `Side Population' contains spermatogonial cells. In addition,α 6-integrin and Stra8 germinal stem cell markers, are expressed in the `Side Population'. In vivo repopulation assay clearly establishes that testis `Side Population' in adult mice is highly enriched in male germ stem cells.

We screened a mouse germinal cell expression library with a probe derived from Sob1, a human testis-specific cDNA, and identified 2P1, a new mouse cDNA. A database search revealed that 2P1 was 91% identical to ORF1 of E3-3, a rat gene probably involved in the regulation of alternative splicing. Sequencing showed that 2P1 has a destabilization motif in its 3'-untranslated region. Northern blotting showed strong gene expression in the testis and weak expression in the epididymis, with no signal detected in other tissues. RT-PCR analysis confirmed testis and epididymis expression. In situ hybridization revealed that 2P1 mRNA was absent in spermatogonia but expressed in spermatocytes. This last result was confirmed by RT-PCR of FACS isolated primary spermatocytes (pachytene stage). Using RT-PCR, purified spermatids were also shown to express 2P1.

Spermatogonia- stem cells and progenitors of adult spermatogenesis- are killed through a p53-regulated apoptotic process after gamma-irradiation but the death effectors are still poorly characterized. Our data demonstrate that both intrinsic and extrinsic apoptotic pathways are involved, and especially that spermatogonia can be split into two main populations, according to apoptotic effectors. Following irradiation both Dr5 and Puma genes are upregulated in the alpha6-integrin-positive Side Population (SP) fraction, which is highly enriched in spermatogonia. Flow cytometric analysis confirms an increased number of Dr5-expressing SP cells, and Puma-beta isoform accumulates in alpha6-integrin positive cellular extracts, enriched in spermatogonia. Trail-/- or Puma-/- spermatogonia display a reduced sensitivity to radiation-induced apoptosis. The TUNEL kinetics strongly suggest that the extrinsic and intrinsic pathways, via Trail/Dr5 and Puma respectively, could be engaged in distinct subpopulations of spermatogonia. Indeed flow cytometric studies show that Dr5 receptor is constitutively present on more than half of the undifferentiated progenitors (Kit- alpha6+ SP) and half of the differentiated ones (Kit+ alpha6+ SP). In addition after irradiation, Puma is not detected in the Dr5-positive cellular fraction isolated by immunomagnetic purification, while Puma is present in the Dr5-negative cell extracts. In conclusion, adult testicular progenitors are divided into distinct sub-populations by apoptotic effectors, independently of progenitor types (immature Kit-negative versus mature Kit-positive), underscoring differential radiosensitivities characterizing the stem cell/progenitors compartment.

Among their biological properties, several oxysterols display a stronger toxicity towards tumor cells than towards normal cells. Water-soluble phosphodiesters of 7 beta-hydroxycholesterol (JB69 and XA29), that were proved to retain a specific antitumoral activity in vitro, have been recently developed, allowing in vivo studies. They have been assayed on transgenic mice expressing the Large T antigen of SV40 in their liver and developing systematically hepatocarcinoma within 8 months. We show that JB69 and XA29 administered intraperitoneally into transgenic mice, before the onset of adenoma, may prevent or delay the tumor development. Consequently, oxysterol derivatives might constitute new efficient prodrugs against naturally occurring tumors.