Browsing by Issue Date, starting with "2014-10"
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- Tissue damage control in disease tolerancePublication . Soares, Miguel P; Gozzelino, Raffaella; Weis, SebastianImmune-driven resistance mechanisms are the prevailing host defense strategy against infection. By contrast, disease tolerance mechanisms limit disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load. We propose here that tissue damage control underlies many of the protective effects of disease tolerance. We explore the mechanisms of cellular adaptation that underlie tissue damage control in response to infection as well as sterile inflammation, integrating both stress and damage responses. Finally, we discuss the potential impact of targeting these mechanisms in the treatment of disease.
- Centromere-Independent Accumulation of Cohesin at Ectopic Heterochromatin Sites Induces Chromosome Stretching during AnaphasePublication . Oliveira, Raquel A.; Kotadia, Shaila; Tavares, Alexandra; Mirkovic, Mihailo; Bowlin, Katherine; Eichinger, Christian S.; Nasmyth, Kim; Sullivan, WilliamPericentric heterochromatin, while often considered as "junk" DNA, plays important functions in chromosome biology. It contributes to sister chromatid cohesion, a process mediated by the cohesin complex that ensures proper genome segregation during nuclear division. Long stretches of heterochromatin are almost exclusively placed at centromere-proximal regions but it remains unclear if there is functional (or mechanistic) importance in linking the sites of sister chromatid cohesion to the chromosomal regions that mediate spindle attachment (the centromere). Using engineered chromosomes in Drosophila melanogaster, we demonstrate that cohesin enrichment is dictated by the presence of heterochromatin rather than centromere proximity. This preferential accumulation is caused by an enrichment of the cohesin-loading factor (Nipped-B/NIPBL/Scc2) at dense heterochromatic regions. As a result, chromosome translocations containing ectopic pericentric heterochromatin embedded in euchromatin display additional cohesin-dependent constrictions. These ectopic cohesion sites, placed away from the centromere, disjoin abnormally during anaphase and chromosomes exhibit a significant increase in length during anaphase (termed chromatin stretching). These results provide evidence that long stretches of heterochromatin distant from the centromere, as often found in many cancers, are sufficient to induce abnormal accumulation of cohesin at these sites and thereby compromise the fidelity of chromosome segregation.
- Extensive survey of the Endangered Coquerel’s sifaka Propithecus coquereliPublication . Salmona, J; Jan, F; Rasolondraibe, E; Besolo, A; Ousseni, DS; Beck, A; Zaranaina, R; Rakotoarisoa, H; Rabarivola, CJ; Chikhi, LCoquerel’s sifaka Propithecus coquereli has a large but highly fragmented distribution. Despite its Endangered (EN) IUCN conservation status, uncertainties persist regarding its actual distribution and its presence in forests that are thought to be part of its distribution range. We provide here the first extensive population surveys of Coquerel’s sifaka across a large number of forest fragments neighboring 27 sites of its known and expected distribution range in northwestern Madagascar, including 12 previously visited sites. During our diurnal surveys carried out in the dry seasons from 2009 to 2011 we observed the species in 26 of the 27 visited sites. Combining our results with previously published data, we propose a refined update of the species’ distribution range and identify areas to be surveyed. We also recorded the support tree species on which sifakas were observed, and note that, surprisingly, P. coquereli was frequently seen around villages and in areas dominated by introduced tree species. Although the species was present at almost all the visited sites of its highly fragmented distribution range, it remains unclear how viable the populations of a significant proportion of these sites actually are. Due to political instability and high rates of deforestation, large-scale conservation actions are urgently needed. We thus (1) discuss the outline of a possible metapopulation conservation action plan for P. coquereli and (2) identify priority sites and actions.
- Compartment-dependent activities of Wnt3a/β-catenin signaling during vertebrate axial extensionPublication . Jurberg, Arnon Dias; Aires, Rita; Nóvoa, Ana; Rowland, Jennifer Elizabeth; Mallo, MoisésExtension of the vertebrate body results from the concerted activity of many signals in the posterior embryonic end. Among them, Wnt3a has been shown to play relevant roles in the regulation of axial progenitor activity, mesoderm formation and somitogenesis. However, its impact on axial growth remains to be fully understood. Using a transgenic approach in the mouse, we found that the effect of Wnt3a signaling varies depending on the target tissue. High levels of Wnt3a in the epiblast prevented formation of neural tissues, but did not impair axial progenitors from producing different mesodermal lineages. These mesodermal tissues maintained a remarkable degree of organization, even within a severely malformed embryo. However, from the cells that failed to take a neural fate, only those that left the epithelial layer of the epiblast activated a mesodermal program. The remaining tissue accumulated as a folded epithelium that kept some epiblast-like characteristics. Together with previously published observations, our results suggest a dose-dependent role for Wnt3a in regulating the balance between renewal and selection of differentiation fates of axial progenitors in the epiblast. In the paraxial mesoderm, appropriate regulation of Wnt/β-catenin signaling was required not only for somitogenesis, but also for providing proper anterior-posterior polarity to the somites. Both processes seem to rely on mechanisms with different requirements for feedback modulation of Wnt/β-catenin signaling, once segmentation occurred in the presence of high levels of Wnt3a in the presomitic mesoderm, but not after permanent expression of a constitutively active form of β-catenin. Together, our findings suggest that Wnt3a/β-catenin signaling plays sequential roles during posterior extension, which are strongly dependent on the target tissue. This provides an additional example of how much the functional output of signaling systems depends on the competence of the responding cells.
- The evolution of metazoan α-carbonic anhydrases and their roles in calcium carbonate biomineralizationPublication . Le Roy, Nathalie; Jackson, Daniel J; Marie, Benjamin; Ramos-Silva, Paula; Marin, FrédéricThe carbonic anhydrase (CA; EC 4.2.1.1) superfamily is a class of ubiquitous metallo-enzymes that catalyse the reversible hydration of carbon dioxide. The ?-CA family, present in all metazoan clades, is a key enzyme involved in a wide range of physiological functions including pH regulation, respiration, photosynthesis, and biocalcification. This paper reviews the evolution of the ?-CA family, with an emphasis on metazoan ?-CA members involved in biocalcification. Phylogenetic analyses reveal a complex evolutionary history of ?-CAs, and suggest ?-CA was independently co-opted into a variety of skeleton forming roles (e.g. as a provider of HCO3? ions, a structural protein, a nucleation activator, etc.) in multiple metazoan lineages. This evolutionary history is most likely the result of multiple gene duplications coupled with the insertion of repetitive or non-repetitive low-complexity domains (RLCDs/LCDs). These domains, of largely unknown function, appear to be lineage-specific, and provide further support for the hypothesis of independent recruitment of ?-CAs to diverse metazoan biocalcification processes. An analysis of ?-CA sequences associated with biocalcification processes indicates that the domains involved in the activity and conformation of the active site are extremely conserved among metazoans.
- Modelling the onset of senescence at the G1/S cell cycle checkpointPublication . Mombach, José CM; Bugs, Cristhian A; Chaouiya, ClaudineDNA damage (single or double-strand breaks) triggers adapted cellular responses. These responses are elicited through signalling pathways, which activate cell cycle checkpoints and basically lead to three cellular fates: cycle arrest promoting DNA repair, senescence (permanent arrest) or cell death. Cellular senescence is known for having a tumour-suppressive function and its regulation arouses a growing scientific interest. Here, we advance a qualitative model covering DNA damage response pathways, focusing on G1/S checkpoint enforcement, supposedly more sensitive to arrest than G2/M checkpoint.
- Identification of the Microsporidian Encephalitozoon cuniculi as a New Target of the IFNγ-Inducible IRG Resistance SystemPublication . da Fonseca Ferreira-da-Silva, Marialice; Springer-Frauenhoff, Helen Maria; Bohne, Wolfgang; Howard, Jonathan C.The IRG system of IFNγ-inducible GTPases constitutes a powerful resistance mechanism in mice against Toxoplasma gondii and two Chlamydia strains but not against many other bacteria and protozoa. Why only T. gondii and Chlamydia? We hypothesized that unusual features of the entry mechanisms and intracellular replicative niches of these two organisms, neither of which resembles a phagosome, might hint at a common principle. We examined another unicellular parasitic organism of mammals, member of an early-diverging group of Fungi, that bypasses the phagocytic mechanism when it enters the host cell: the microsporidian Encephalitozoon cuniculi. Consistent with the known susceptibility of IFNγ-deficient mice to E. cuniculi infection, we found that IFNγ treatment suppresses meront development and spore formation in mouse fibroblasts in vitro, and that this effect is mediated by IRG proteins. The process resembles that previously described in T. gondii and Chlamydia resistance. Effector (GKS subfamily) IRG proteins accumulate at the parasitophorous vacuole of E. cuniculi and the meronts are eliminated. The suppression of E. cuniculi growth by IFNγ is completely reversed in cells lacking regulatory (GMS subfamily) IRG proteins, cells that effectively lack all IRG function. In addition IFNγ-induced cells infected with E. cuniculi die by necrosis as previously shown for IFNγ-induced cells resisting T. gondii infection. Thus the IRG resistance system provides cell-autonomous immunity to specific parasites from three kingdoms of life: protozoa, bacteria and fungi. The phylogenetic divergence of the three organisms whose vacuoles are now known to be involved in IRG-mediated immunity and the non-phagosomal character of the vacuoles themselves strongly suggests that the IRG system is triggered not by the presence of specific parasite components but rather by absence of specific host components on the vacuolar membrane.
- The roles of juvenile hormone, insulin/target of rapamycin, and ecydsone signaling in regulating body size inDrosophilaPublication . Mirth, Christen Kerry; Shingleton, Alexander WilliamUnderstanding how organisms regulate their body size has interested biologists for decades. Recent work has shown that both insulin/target of rapamycin (TOR) signaling and the steroid hormone ecdysone act to regulate rates of growth and the duration of the growth period in the fruit fly, Drosophila melanogaster. Our recent work has uncovered a third level of interaction, whereby juvenile hormone (JH) regulates levels of both ecdysone and insulin/TOR signaling to control growth rates. These studies highlight a complex network of interactions involved in regulating body and organ size.