Evolution of a Core Gene Network for Skeletogenesis in Chordates

The skeleton is one of the most important features for the reconstruction of vertebrate phylogeny but few data are available to understand its molecular origin. In mammals the Runt genes are central regulators of skeletogenesis. Runx2 was shown to be essential for osteoblast differentiation, tooth development, and bone formation. Both Runx2 and Runx3 are essential for chondrocyte maturation. Furthermore, Runx2 directly regulates Indian hedgehog expression, a master coordinator of skeletal development. To clarify the correlation of Runt gene evolution and the emergence of cartilage and bone in vertebrates, we cloned the Runt genes from hagfish as representative of jawless fish (MgRunxA, MgRunxB) and from dogfish as representative of jawed cartilaginous fish (ScRunx1–3). According to our phylogenetic reconstruction the stem species of chordates harboured a single Runt gene and thereafter Runt locus duplications occurred during early vertebrate evolution. All newly isolated Runt genes were expressed in cartilage according to quantitative PCR. In situ hybridisation confirmed high MgRunxA expression in hard cartilage of hagfish. In dogfish ScRunx2 and ScRunx3 were expressed in embryonal cartilage whereas all three Runt genes were detected in teeth and placoid scales. In cephalochordates (lancelets) Runt, Hedgehog and SoxE were strongly expressed in the gill bars and expression of Runt and Hedgehog was found in endo- as well as ectodermal cells. Furthermore we demonstrate that the lancelet Runt protein binds to Runt binding sites in the lancelet Hedgehog promoter and regulates its activity. Together, these results suggest that Runt and Hedgehog were part of a core gene network for cartilage formation, which was already active in the gill bars of the common ancestor of cephalochordates and vertebrates and diversified after Runt duplications had occurred during vertebrate evolution. The similarities in expression patterns of Runt genes support the view that teeth and placoid scales evolved from a homologous developmental module

Subjectivité, intersubjectivité et nostrité selon Ludwig Binswanger

La psychose oblige à repenser le "sujet" depuis Descartes jusqu'à la phénoménologie de Husserl et Heidegger. Les oeuvres de Binswanger révèlent à partir du "pathologique" le fond originaire intersubjectif et intercorporel, de toute "ipséité". Binswanger se réfère à Husserl dès 1922 puis prioritairement aux oeuvres de Heidegger, notamment "Sein und Zeit". Il "revient" enfin à Husserl dans ses derniers textes. L'inspiration heideggerienne permet de passer du sujet transcendantal à l'"être-au-monde" des psychotiques. Toutefois, contre Heidegger, Binswanger insiste sur l'intersubjectivité, la "nostrité" ("Wirheit") et oppose l'amour au souci. Le "retour" à Husserl questionne l'intentionnalité du sujet transcendantal, opère une distinction entre "ego" empirique, "ego" transcendantal et "ego" pur, et pense surtout à nouveau frais la dimension de l'"alter ego". Une phénoménologie de l'intimité ("Heimat") devient possible, qu'éclaire une référence privilégiée au concept de l'"Entre" de Bin Kimura.The occurence of psychosis causes one to rethink the subject concept, ranging in definition from the writing of Descartes to the phenomenology of Husserl and Heidegger. Binswanger's works on pathological cases shows the original intersubjective and intercorporal nature of all "ipseity". In 1922, Binswanger begins by refering to Husserl but later primarily focuses on the work of Heidegger, notably "Being and Time" ("Sein und Zeit"). He finally comes back to Husserl in his late texts. Heidegger's idea allow a transition from the transcendental subject to the "being-in-the-world" of psychotics. However, unlike Heidegger, Binswanger insists on intersubjectivity, "we-ness" ("Wirheit") and opposes love to anxiety. His return to Husserl questions the concept of the intentionality of the transcendental subject, establishes a distinction between empirical "ego", transcendental "ego" and pure "ego", gives a new light to the concept of the "alter ego". A new phenomenology of intimacy ("Heimat") becomes possible, clarified by a special reference to the concept of "in-between" as defined by Bin Kimura.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Evolution of a core gene network for skeletogenesis in chordates. PLoS Genet

Abstract The skeleton is one of the most important features for the reconstruction of vertebrate phylogeny but few data are available to understand its molecular origin. In mammals the Runt genes are central regulators of skeletogenesis. Runx2 was shown to be essential for osteoblast differentiation, tooth development, and bone formation. Both Runx2 and Runx3 are essential for chondrocyte maturation. Furthermore, Runx2 directly regulates Indian hedgehog expression, a master coordinator of skeletal development. To clarify the correlation of Runt gene evolution and the emergence of cartilage and bone in vertebrates, we cloned the Runt genes from hagfish as representative of jawless fish (MgRunxA, MgRunxB) and from dogfish as representative of jawed cartilaginous fish (ScRunx1-3). According to our phylogenetic reconstruction the stem species of chordates harboured a single Runt gene and thereafter Runt locus duplications occurred during early vertebrate evolution. All newly isolated Runt genes were expressed in cartilage according to quantitative PCR. In situ hybridisation confirmed high MgRunxA expression in hard cartilage of hagfish. In dogfish ScRunx2 and ScRunx3 were expressed in embryonal cartilage whereas all three Runt genes were detected in teeth and placoid scales. In cephalochordates (lancelets) Runt, Hedgehog and SoxE were strongly expressed in the gill bars and expression of Runt and Hedgehog was found in endo-as well as ectodermal cells. Furthermore we demonstrate that the lancelet Runt protein binds to Runt binding sites in the lancelet Hedgehog promoter and regulates its activity. Together, these results suggest that Runt and Hedgehog were part of a core gene network for cartilage formation, which was already active in the gill bars of the common ancestor of cephalochordates and vertebrates and diversified after Runt duplications had occurred during vertebrate evolution. The similarities in expression patterns of Runt genes support the view that teeth and placoid scales evolved from a homologous developmental module

A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation.

Synpolydactyly (SPD) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and an additional digit in the syndactylous web. In most cases SPD is caused by heterozygous mutations in HOXD13 resulting in the expansion of a N-terminal polyalanine tract. If homozygous, the mutation results in severe shortening of all metacarpals and phalanges with a morphological transformation of metacarpals to carpals. Here, we describe a novel homozygous missense mutation in a family with unaffected consanguineous parents and severe brachydactyly and metacarpal-to-carpal transformation in the affected child. We performed whole exome sequencing on the index patient, followed by Sanger sequencing of parents and patient to investigate cosegregation. The DNA-binding ability of the mutant protein was tested with electrophoretic mobility shift assays. We demonstrate that the c.938C>G (p.313T>R) mutation in the DNA-binding domain of HOXD13 prevents binding to DNA in vitro. Our results show to our knowledge for the first time that a missense mutation in HOXD13 underlies severe brachydactyly with metacarpal-to-carpal transformation. The mutation is non-penetrant in heterozygous carriers. In conjunction with the literature we propose the possibility that the metacarpal-to-carpal transformation results from a homozygous loss of functional HOXD13 protein in humans in combination with an accumulation of non-functional HOXD13 that might be able to interact with other transcription factors in the developing limb

Le rapport entre les femmes séropositives et la maltraitance sexuelle pendant l'enfance

Le nombre de personnes contaminées dans le monde par le syndrome d'immunodéficience acquise (sida) augmente chaque année. Les femmes représentent la moitié des ces cas (UNAIDS, 2003). Cependant, il y a peu de recherches générales sur les femmes séropositives et pratiquement aucun écrit sur la plan psychologique. En attendant une cure, la prévention de la transmission et l'identification des facteurs à haut risque chez les femmes sont primordiales. Cette recherche introduit l'hypothèse que l'on trouvera un pourcentage élevé de maltraitance sexuelle de l'enfant chez ces femmes. Sachant que deux effets à long terme de la maltraitance sexuelle de l'enfant sont en même temps les deux modes de transmission les plus communs: l'usage des drogues intraveineuses et les rapports sexuels sans protection, la maltraitance sexuelle dans l'enfance est présentée comme un facteur à haut risque pour attraper le virus. En partant de cette hypothèse, un système d'analyse, appelé Les Femmes Affrontant le Sida (FAS), a été créé pour identifier et expliquer les facteurs clés dans le fonctionnement de ces femmes et dans l'adaptation à leur premier trauma, la maltraitance sexuelle, et à leur deuxième trauma, le diagnostic du virus ou du sida. Sur 60 femmes évaluées, ayant un statut séropositif ou un diagnostic du sida, 59 ont avoué avoir été victimes de maltraitance sexuelle durant leur enfance. D'autres résultats (statistiques simples, corrélations, analyses de la régression) mettent en évidence d'autres facteurs dans le système FAS et éclairent les processus de base et certains composants de l'adaptation ou de la "maladaptation" aux traumas chez les femmes séropositives ou vivant avec le sida. Les données soulignent le besoin d'une intervention psychologique auprès de ces femmes malades pour améliorer leur adaptation au virus, mais aussi l'urgence d'une intervention auprès des adolescentes et femmes non porteuses du virus mais abusées sexuellement dans leur enfance, car elles forment une nouvelle population à haut risque d'attraper le virus. De cette façon, on pourrait enrayer la propagation de ce virus dévastateur.The number of people infected worldwide with the Acquired Immune Deficiency Syndrome (AIDS) increases each year. Women account for half of these cases (UNAIDS, 2003). However, there are few studies about women and AIDS in general, and there is virtually nothing written from a psychological perspective. While we await a cure, the prevention of transmission and the identification of high-risk factors for women are paramount. This study introduces the hypothesis that one will find a high percentage of childhood sexual abuse among these women. Since we know that two long-term effects of childhood sexual abuse are at the same time the two most common modes of transmission: intravenous drug use and unprotected sexual intercourse, childhood sexual abuse is presented as a high-risk factor for contracting the virus. Using this hypothesis as a starting point, an analytical model, called Women Confronting AIDS (WCA), was designed to identify and explain the key factors involved in the overall functioning of these women and in their adaptation to their first trauma, childhood sexual abuse, and to their second trauma, a diagnosis of HIV or AIDS. Of the 60 women evaluated, each having either an HIV positive status or a diagnosis of AIDS, 59 disclosed having been a victim of sexual abuse during their childhood. Other results (simple statistics, correlations, analyses of regression) support other factors in the WCA model and clarify the fundamental processes and certain components of adaptation or maladapation to trauma in HIV positive women or women living with AIDS. The results highlight the need for a psychological intervention to ameliorate their adaptation to the virus, but also the urgent need for an intervention with teenage girls and women who are HIV negative but were sexually abused during their childhood, because they constitute a new population at risk for contracting the virus. In this way, it may be possible to slow the spread of this devastating virus.NANTERRE-BU PARIS10 (920502102) / SudocSudocFranceF

Embo J.

In tailed bacteriophages and herpes viruses, the viral DNA is packaged through the portal protein channel. Channel closure is essential to prevent DNA release after packaging. Here we present the connector structure from bacteriophage SPP1 using cryo-electron microscopy and single particle analysis. The multiprotein complex comprises the portal protein gp6 and the head completion proteins gp15 and gp16. Although we show that gp6 in the connector has a fold similar to that of the isolated portal protein, we observe conformational changes in the region of gp6 exposed to the DNA-packaging ATPase and to gp15. This reorganization does not cause closure of the channel. The connector channel traverses the full height of gp6 and gp15, but it is closed by gp16 at the bottom of the complex. Gp16 acts as a valve whose closure prevents DNA leakage, while its opening is required for DNA release upon interaction of the virus with its host

Gene Expr. Patterns

Runx2 is an essential factor for skeletogenesis and heterozygous loss causes cleidocranial dysplasia in humans and a corresponding phenotype in the mouse. Homozygous Runx2-deficient mice lack hypertrophic cartilage and bone. We compared the expression profiles of E14.5 wildtype and Runx2−/− murine embryonal humeri to identify new transcripts potentially involved in cartilage and bone development. Seventy-one differentially expressed genes were identified by two independent oligonucleotide-microarray hybridizations and quantitative RT-PCR experiments. Gene Ontology analysis demonstrated an enrichment of the differentially regulated genes in annotations to terms such as extracellular, skeletal development, and ossification. In situ hybridization on E15.5 limb sections was performed for all 71 differentially regulated genes. For 54 genes conclusive in situ hybridization results were obtained and all of them showed skeletal expression. Co-expression with Runx2 was demonstrated for 44 genes. While 41 of the 71 differentially expressed genes have a known role in bone and cartilage, we identified 21 known genes that have not yet been implicated in skeletal development and 9 entirely new transcripts. Expression in the developing skeleton was demonstrated for 21 of these genes

Immunoglobulin receptor evolution in follicular lymphoma and a review of literature.

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