Evolution of Axis Specification Mechanisms in Jawed Vertebrates: Insights from a Chondrichthyan

The genetic mechanisms that control the establishment of early polarities and their link with embryonic axis specification and patterning seem to substantially diverge across vertebrates. In amphibians and teleosts, the establishment of an early dorso-ventral polarity determines both the site of axis formation and its rostro-caudal orientation. In contrast, amniotes retain a considerable plasticity for their site of axis formation until blastula stages and rely on signals secreted by extraembryonic tissues, which have no clear equivalents in the former, for the establishment of their rostro-caudal pattern. The rationale for these differences remains unknown. Through detailed expression analyses of key development genes in a chondrichthyan, the dogfish Scyliorhinus canicula, we have reconstructed the ancestral pattern of axis specification in jawed vertebrates. We show that the dogfish displays compelling similarities with amniotes at blastula and early gastrula stages, including the presence of clear homologs of the hypoblast and extraembryonic ectoderm. In the ancestral state, these territories are specified at opposite poles of an early axis of bilateral symmetry, homologous to the dorso-ventral axis of amphibians or teleosts, and aligned with the later forming embryonic axis, from head to tail. Comparisons with amniotes suggest that a dorsal expansion of extraembryonic ectoderm, resulting in an apparently radial symmetry at late blastula stages, has taken place in their lineage. The synthesis of these results with those of functional analyses in model organisms supports an evolutionary link between the dorso-ventral polarity of amphibians and teleosts and the embryonic-extraembryonic organisation of amniotes. It leads to a general model of axis specification in gnathostomes, which provides a comparative framework for a reassessment of conservations both among vertebrates and with more distant metazoans

Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88

Toll-like receptors (TLRs) such as TLR2 and TLR4 have been implicated in host response to mycobacterial infection. Here, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88) were infected with Mycobacterium tuberculosis (MTB). While primary MyD88–/– macrophages and DCs are defective in TNF, IL-12, and NO production in response to mycobacterial stimulation, the upregulation of costimulatory molecules CD40 and CD86 is unaffected. Aerogenic infection of MyD88–/– mice with MTB is lethal within 4 weeks with 2 log10 higher CFU in the lung; high pulmonary levels of cytokines and chemokines; and acute, necrotic pneumonia, despite a normal T cell response with IFN-γ production to mycobacterial antigens upon ex vivo restimulation. Vaccination with Mycobacterium bovis bacillus Calmette-Guérin conferred a substantial protection in MyD88–/– mice from acute MTB infection. These data demonstrate that MyD88 signaling is dispensable to raise an acquired immune response to MTB. Nonetheless, this acquired immune response is not sufficient to compensate for the profound innate immune defect and the inability of MyD88–/– mice to control MTB infection

Molecular Characterization of the Gastrula in the Turtle Emys orbicularis: An Evolutionary Perspective on Gastrulation

Due to the presence of a blastopore as in amphibians, the turtle has been suggested to exemplify a transition form from an amphibian- to an avian-type gastrulation pattern. In order to test this hypothesis and gain insight into the emergence of the unique characteristics of amniotes during gastrulation, we have performed the first molecular characterization of the gastrula in a reptile, the turtle Emys orbicularis. The study of Brachyury, Lim1, Otx2 and Otx5 expression patterns points to a highly conserved dynamic of expression with amniote model organisms and makes it possible to identify the site of mesoderm internalization, which is a long-standing issue in reptiles. Analysis of Brachyury expression also highlights the presence of two distinct phases, less easily recognizable in model organisms and respectively characterized by an early ring-shaped and a later bilateral symmetrical territory. Systematic comparisons with tetrapod model organisms lead to new insights into the relationships of the blastopore/blastoporal plate system shared by all reptiles, with the blastopore of amphibians and the primitive streak of birds and mammals. The biphasic Brachyury expression pattern is also consistent with recent models of emergence of bilateral symmetry, which raises the question of its evolutionary significance

Molecular Characterization of the Gastrula in the Turtle Emys orbicularis: An Evolutionary Perspective on Gastrulation

Due to the presence of a blastopore as in amphibians, the turtle has been suggested to exemplify a transition form from an amphibian- to an avian-type gastrulation pattern. In order to test this hypothesis and gain insight into the emergence of the unique characteristics of amniotes during gastrulation, we have performed the first molecular characterization of the gastrula in a reptile, the turtle Emys orbicularis. The study of Brachyury, Lim1, Otx2 and Otx5 expression patterns points to a highly conserved dynamic of expression with amniote model organisms and makes it possible to identify the site of mesoderm internalization, which is a long-standing issue in reptiles. Analysis of Brachyury expression also highlights the presence of two distinct phases, less easily recognizable in model organisms and respectively characterized by an early ring-shaped and a later bilateral symmetrical territory. Systematic comparisons with tetrapod model organisms lead to new insights into the relationships of the blastopore/blastoporal plate system shared by all reptiles, with the blastopore of amphibians and the primitive streak of birds and mammals. The biphasic Brachyury expression pattern is also consistent with recent models of emergence of bilateral symmetry, which raises the question of its evolutionary significance

Implication des voies de signalisation Toll (TLR) dans la réponse immunitaire aux mycobactéries

Dans le cadre de la recherche de nouvelles molécules permettant une meilleure vaccination des individus contre la tuberculose, mon étude consiste à mieux comprendre les voies de signalisation cellulaires dans la reconnaissance hôte-pathogène par l'analyse de la mise en place des réponses immunitaires innée et acquise dans des modèles murins déficients pour les récepteurs TLR impliqués dans la reconnaissance des mycobactéries (TLR2, TLR4, TLR6) ou la molécule adaptatrice MyD88 infectés par M.bovis BCG. Des études in vitro sur les cellules dérivées des souris déficientes ont mis en évidence les effets agonistes ou antagonistes de certains composants moléculaires de la paroi du BCG pour les différents TLR. Les études in vivo, d'autre part, ont montré que la déficience en TLR2 ou TLR6 n'entraîne pas de phénotype majeur de la réponse immunitaire à l'infection à M.bovis BCG. En revanche, l'absence de voie de signalisation MyD88 induit un défaut du contrôle de l'infection, avec une inflammation pulmonaire exacerbée.ORLEANS-BU Sciences (452342104) / SudocSudocFranceF

Geochemical and petrologic consequences of off-axis melt delivery: evidence from the Oman ophiolite

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Major and trace element and Sr and Nd isotopic results from mantle diapirs in the Oman ophiolite: Implications for off-axis magmatic processes

International audienceThe Oman ophiolite includes both a fossil fast spreading axis, defined by five mantle diapirs, and an off-axis mantle diapir emplaced 30 km from the axis, providing a natural laboratory for the study of off-axis magmatic processes. We compare field and petrological observations coupled with geochemical and isotopic analyses of samples from the off-axis diapir with those of the nearest on-axis diapir, with a particular focus on the Moho Transition Zone (MTZ). Both diapirs are defined by the presence of steeply plunging lineations, but in the on-axis case, these lineations rotate gradually into parallelism with the horizontal magmatic lineations of the overlying crust, while in the off-axis case, a shear zone separates the steeply plunging lineations from the horizontal lineations of the surrounding mantle. In the on-axis diapir, the MTZ is 50 to 500 m thick and composed of dunite with layered gabbro lenses whereas in the off-axis diapir, the MTZ is thicker and composed of dunite with massive (∼20% of MTZ) clinopyroxenite lenses and a notable absence of plagioclase. Moreover, the off-axis diapir is associated with amphibole-bearing intrusions, consisting of Mg-rich gabbroic sills in the mantle peripheral to the diapir, and microgabbroic lenses of broadly basaltic composition in the overlying crust. The ε Nd values of the pyroxenites in the MTZ of the off-axis diapir fully overlap with those of the intrusions in the surrounding mantle and crust, suggesting that they are genetically related. Calculated rare earth element (REE) abundances of liquids in equilibrium with clinopyroxene imply that the magmas that traversed the MTZ of the off-axis diapir were more depleted in highly incompatible elements than their counterparts in the MTZ of the on-axis diapir. On the other hand, Nd isotopic compositions of the off-axis samples (εNd=6.2–7.9εNd=6.2–7.9 in 18 of 19 samples) indicate derivation of their parental magmas from a less depleted source than that which produced the magma associated with the on-axis gabbro (εNd=7.8–9.2εNd=7.8–9.2, 10 analyses).To explain these observations, we suggest that the earliest magmas in the uprising off-axis diapir formed from the partial melting of pyroxenite veins with less radiogenic Nd isotopic compositions than those of the ambient peridotite. As the diapir traversed the cool, hydrated lithosphere these early melts interacted with depleted harzburgites, lowering the incompatible element contents of the melt products while having little effect on their Nd isotopic compositions. The great abundance of clinopyroxene in the off-axis MTZ might be explained by the high pyroxene component in the original melt but perhaps also by the presence of water in the lithosphere, which would favor the crystallization of clinopyroxene while inhibiting that of plagioclase. The intrusions in the overlying crust could represent, to first order, the secondary melts produced by the melt–harzburgite reaction, while the sills in the surrounding mantle may be cumulates from such secondary melts.These results shed light on processes occurring during interaction between rising off-axis material and depleted, hydrated lithospheric mantle. Furthermore, if our interpretation is correct, the low εNd values of the off-axis samples contribute to the growing body of evidence for the presence of pyroxenite veins in the MORB mantle source

Contrasting on- and off-axis melt delivery: a Sr and Nd isotopic study of the Moho transition zone of the Oman ophiolite

International audienceRecent tomographic images from the East Pacific Rise [1] indicate that nearly 50% of the melt is delivered off-axis instead of beneath the ridge axis. The consequences of this process can be studied on land in the Oman ophiolite, where structural mapping has shown the existence of both on- and off-axis melt delivery systems [2]. Off-axis diapirs impinge directly on hydrothermally-altered lithosphere and may be contaminated by this material. Petrologically, off-axis melt delivery results in the development of an unusually thick Moho Transition Zone (MTZ) composed largely of clinopyroxenite,whereas on-axis MTZ contains troctolite and gabbro lenses. We are analyzing the Sr and Nd isotopic compositions of pyroxenites, gabbros, diorites, and dunites, from an on-axis (Maqsad) and an off-axis (Mansah) diapir in the Semail massif of the Oman ophiolite to explore the geochemical consequences of these contrasting settings. Leached and unleached whole rocks, as well as clinopyroxene (cpx) separates are being studied, to allow us to investigate both magmatic and later hydrothermal processes. Initial Nd isotopic compositions from unleached whole rock powders are comparable for the two diapirs (HNd = 8.5-9.2 on-axis; HNd = 5.6-10.3 off-axis), although off-axis rocks display a larger range of variation. In contrast, whole rock Sr isotopic ratios differ markedly, with on-axis samples displaying a limited range of enriched MORB-like compositions (87Sr/86Sr =0.703010 - 0.703438) whereas off-axis samples have more radiogenic and highly heterogeneous compositions (87Sr/86Sr = 0.703277 - 0.706192). We attribute this difference to the presence of a magma chamber above the on-axis diapir, which protects the MTZ from the effects of hydrothermal circulation. Separated cpx and leached whole rocks from off-axis pyroxenites have less radiogenic compositions (87Sr/86Sr = 0.703218 - 0.703576) than the corresponding unleached whole rocks. Nevertheless, several of these samples have 87Sr/86Sr ratios that approach the upper limit of the Indian MORB field. In outcrop, a mixing zone is observed between pyroxenites and crustal gabbros in the MTZ overlying the off-axis diapir. Samples from this mixing zone have more radiogenic cpx compositions than samples collected further from the Moho, suggesting magmatic contamination of the pyroxenites by incorporation of hydrated material rich in seawater-derived Sr

Two in one: bifunctional derivatives of trolox acting as antimalarial and antioxidant agents

International audienceBackground: The aim of the present work was to set-up compounds that are able to act simultaneously as antimalarial and antioxidants. Trolox, a known antioxidant was chosen as a core structure to ensure the antioxidant activity and contribute to antiplasmodial effect. Results: Ten compounds were prepared in one step and evaluated on chloroquino-sensitive (3D7) and chloroquino-resistant (FcB1) strains of Plasmodium falciparum. The most active compound (3d) shows antiplasmodial activity in the range of chloroquine against chloroquino-sensitive and chloroquino-resistant P. falciparum strain. The antioxidant activity of (3d) was conducted through four tests and was found to be more potent than trolox itself and L-ascorbic acid. Conclusion: Compound (3d) can be considered as an excellent lead molecule for further in vivo studies. This study paves the way for building large chemical libraries to be investigated in the field of malaria

Control of Mycobacterium bovis BCG infection with increased inflammation in TLR4-deficient mice.

Live mycobacteria have been reported to signal through several pattern recognition receptors (PRR), among them toll-like receptor 4 (TLR4) and TLR2 in vitro. Here, we investigated the role of TLR4 in host resistance to Mycobacterium bovis (BCG) infection in vivo. In vitro, macrophages of TLR4 mutant C3H/HeJ mice infected with BCG expressed lower levels of TNF than controls, and TNF release was further decreased, although not completely absent, in the absence of TLR2. In vivo, TLR4 mutant C3H/HeJ and control C3H/HeOUJ mice were infected with BCG (2 x 10(6) CFU i.v.). Both TLR4 mutant and wild-type mice were able to control the infection and survived 8 months post-BCG infection. Macrophage activation with abundant acid-fast bacilli and expression of inducible nitric oxide synthase (iNOS) and MHC class II antigens was seen in both groups of mice. However, TLR4 mutant mice experienced an arrest of body weight gain and showed signs of increased inflammation, with persistent splenomegaly, increase in granuloma number and augmented neutrophil infiltration. Infection of TLR4-deficient mice with higher doses of BCG (1 and 3 x 10(7) CFU, i.v.) increased the inflammation in spleen and liver, associated with a transient, higher bacterial load in the liver. In summary, TLR4 mutant mice show normal macrophage recruitment and activation, granuloma formation and control of the BCG infection, but this is associated with persistent inflammation. Therefore, TLR4 signaling is not essential for early control of BCG infection, but it may have a critical function in fine tuning of inflammation during chronic mycobacterial infection.info:eu-repo/semantics/publishe