The mean dehn functions of Abelian groups

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Differentiability of functions of contractions

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Post-translational modifications regulate distinct functions of CARMA1 and BCL10.

Activation of the transcription factor nuclear factor (NF)-kappaB is essential for the normal functioning of the immune system. Deregulated NF-kappaB signalling in lymphocytes can lead to immunodeficiency, but also to autoimmunity or lymphomas. Many of the signalling components controlling NF-kappaB activation in lymphocytes are now known, but it is less clear how distinct molecular components of this pathway are regulated. Here, we summarize recent findings on post-translational modifications of intracellular components of this pathway. Phosphorylation of the CARMA1 and BCL10 proteins and ubiquitylation of BCL10 affect the formation and stability of the CARMA1-BCL10-MALT1 (CBM) complex, and also control negative feedback regulation of the NF-kappaB signalling pathway. Moreover, the study of BCL10 phosphorylation isoforms has revealed a new mechanism controlling BCL10 nuclear translocation and an unexpected role for BCL10 in the regulation of the actin cytoskeleton.

Effector functions of eosinophils in schistosomiasis

The dual function of eosinophils is clearly illustred in schistosomiasis. Well equipped in membrane receptors for immunoglobulins and complement, and due to the presence of granule basic proteins, eosinophils can become cytotoxic for parasite larvae and thus participate to protective immunity. However mediators can also exert their cytolytic effect on normal cells or tissues, inducing therefore pathology. Through ADCC mechanisms against schistosome larvae in vitro involving different antibody isotypes (IgG, IgE and IgA) and also in experiments performed in vivo, eosinophils have been clearly involved in protective immunity. Although no direct evidence of the protective role of eosinophils were brought in humans, the striking association of eosinophil-dependent cytotoxic antibody isotypes with resistance to reinfection (for instance IgE and IgA antibodies), whereas in vitro blocking antibody isotypes (IgG4, IgM) were detected in susceptible subjects, strongly, suggested the participation of eosinophils in antibody-dependent protective immune response. However eosinophils could also participate to granuloma formation around S. mansoni eggs and consequently to the pathological reactions induced by schistosomiasis.

Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae.

One of the mediators of pleiotropic drug resistance in Saccharomyces cerevisiae is the ABC-transporter gene PDR5. This gene is regulated by at least two transcription factors with Zn(2)-Cys(6) finger DNA-binding motifs, Pdr1p and Pdr3p. In this work, we searched for functional homologues of these transcription factors in Candida albicans. A C. albicans gene library was screened in a S. cerevisiae mutant lacking PDR1 and PDR3 and clones resistant to azole antifungals were isolated. From these clones, three genes responsible for azole resistance were identified. These genes (CTA4, ASG1 and CTF1) encode proteins with Zn(2)-Cys(6)-type zinc finger motifs in their N-terminal domains. The C. albicans genes expressed in S. cerevisiae could activate the transcription of a PDR5-lacZ reporter system and this reporter activity was PDRE-dependent. They could also confer resistance to azoles in a S. cerevisiae strain lacking PDR1, PDR3 and PDR5, suggesting that CTA4-, ASG1- and CTF1-dependent azole resistance can be caused by genes other than PDR5 in S. cerevisiae. Deletion of CTA4, ASG1 and CTF1 in C. albicans had no effect on fluconazole susceptibility and did not alter the expression of the ABC-transporter genes CDR1 and CDR2 or the major facilitator gene MDR1, which encode multidrug transporters known as mediators of azole resistance in C. albicans. However, additional phenotypic screening tests on the C. albicans mutants revealed that the presence of ASG1 was necessary to sustain growth on non-fermentative carbon sources (sodium acetate, acetic acid, ethanol). In conclusion, C. albicans possesses functional homologues of the S. cerevisiae Pdr1p and Pdr3p transcription factors; however, their properties in C. albicans have been rewired to other functions.

Core Functions of the Health Service Report

The Government Decision1 on the Structural, Organisational, Financial Management and Systems Reform of the Health Sector of June, 2003 acknowledged that in order to increase the effectiveness of the health service generally, and its capacity to deliver the reform agenda, it was important that the service was fully concentrated on addressing its core health objectives. The Minister for Health and Children and Minister for Finance felt that there could be scope to transfer certain functions out of the health service and locate them more appropriately within other functional areas of Government. As part of the overall decision, it was agreed that a working group would be established, to include the Departments of Health and Children, Finance and An Taoiseach, to examine the scope for transfer of certain activities to other, more appropriate, Departments and agencies and that on completion of this review, the Minister for Health and Children would bring proposals to Government. Read the Report (PDF, 70kb)  

Anti-leishmania effector functions of CD4+ Th1 cells and early events instructing Th2 cell development and susceptibility to Leishmania major in BALB/c mice.

Resistance and susceptibility to infection with the intracellular parasite, Leishmania major, are mediated by parasite-specific CD4+ Th1 and Th2 cells, respectively. It is well established that the protective effect of parasite-specific CD4+ Th1 cells is largely dependent upon the IFN-gamma produced. However, recent results indicate that the effect of Th1 cells on resolution of lesions induced by L. major in genetically resistant mice also requires a functional Fas-FasL pathway of cytotoxicity. In contrast to resistant mice, susceptible BALB/c mice develop aberrant Th2 responses following infection with L. major and consequently suffer progressive disease. These outcomes clearly depends upon the production of interleukin 4 (IL-4) early after infection. We have shown that a burst of IL-4 mRNA, peaking in draining lymph nodes of BALB/c mice 16 hrs after infection, occurs within CD4+ T cells that express V beta 4-V alpha 8 T cell receptors. In contrast to control and V beta 6-deficient mice, V beta 4-deficient BALB/c mice were resistant to infection, demonstrating the role of these cells in Th2 development. The early IL-4 response was absent in these mice, and Th1 responses occurred following infection. The LACK antigen of L. major induced comparable IL-4 production in V beta 4-V alpha 8 CD4+ T cells. Thus, the IL-4 required for Th2 development and susceptibility to L. major is produced by a restricted population of V beta 4-V alpha 8 CD4+ T cells after cognate interaction with a single antigen from this complex parasite. The IL-4 produced rapidly by these CD4+ T cells induces within 48 hours a state of unresponsiveness to IL-12 among parasite-specific CD4+ T cell precursors by downregulating the IL-12 receptor beta 2 chain expression.

Genetic investigation of the functions of c-Myc and N-Myc in Hematopoietic stem cells

Résumé : c-Myc, le premier facteur de transcription de la famille Myc a été découvert il y a maintenant trente ans. Il reste à l'heure actuelle parmi les plus puissants proto-oncogènes connus. c-Myc est dérégulé dans plus de 50% des cancers, où il promeut la prolifération, la croissance cellulaire, et la néoangiogenèse. Myc peut aussi influencer de nombreuses autres fonctions de par sa capacité à activer ou à réprimer la transcription de nombreux gènes, et à agir globalement sur le génome à travers des modifications épigénétiques de la chromatine. La famille d'oncogènes Myc comprend, chez les mammifères, trois protéines structurellement proches: c-Myc, N-Myc et L-Myc. Ces protéines ont les mêmes proprietés biochimiques, exercent les mêmes fonctions mais sont le plus souvent exprimées de façon mutuellement exclusive. Myc a été récemment identifié comme un facteur clef dans la maintenance des cellules souches embryonnaires et adultes ainsi que dans la réacquisition des proprietés des cellules souches. Nous avons précédemment démontré que l'élimination de c-Myc provoque une accumulation de cellules souches hématopoïétiques (CSH) suite à un défaut de différenciation lié à la niche. Les CSH sont responsables de la production de tous les éléments cellulaires du sang pour toute la vie de l'individu et sont définies par leur capacité à s'auto-renouveler tout en produisant des précurseurs hématopoïétiques. Afin de mieux comprendre la fonction de Myc dans les CSH, nous avons choisi de combiner l'utilisation de modèles de souris génétiquement modifiées à une caractérisation systématique des schémas d'expression de c-Myc, N-Myc et L-Myc dans tout le système hématopoïétique. Nous avons ainsi découvert que les CSH les plus immatures expriment des quantités équivalentes de transcrits de c-myc et N-myc. Si les CSH déficientes en N-myc seulement ont une capacité d'auto-renouvellement à long-terme réduite, l'invalidation combinée des gènes c-myc et N-myc conduit à une pan-cytopénie suivie d'une mort rapide de l'animal, pour cause d'apoptose de tous les types cellulaires hématopoïétiques. En particulier, les CSH en cours d'auto-renouvelemment, mais pas les CSH quiescentes, accumulent du Granzyme B (GrB), une molécule fortement cytotoxique qui provoque une mort cellulaire rapide. Ces données ont ainsi mis au jour un nouveau mécanisme dont dépend la survie des CSH, à savoir la répression du GrB, une enzyme typiquement utilisée par le système immunitaire inné pour éliminer les tumeurs et les cellules infectées par des virus. Dans le but d'évaluer l'étendue de la redondance entre c-Myc et N-Myc dans les CSH, nous avons d'une part examiné des souris dans lesquelles les séquences codantes de c-myc sont remplacées par celles de N-myc (NCR) et d'autre part nous avons géneré une série allèlique de myc en éliminant de façon combinatoire un ou plusieurs allèles de c-myc et/ou de N-myc. Alors que l'analyse des souris NCR suggère que c-Myc et N-Myc sont qualitativement redondants, la série allélique indique que les efficiences avec lesquelles ces deux protéines influencent des procédés essentiels à la maintenance des CSH sont différentes. En conclusion, nos données génétiques montrent que l'activité générale de MYC, fournie par c-Myc et N-Myc, contrôle plusieurs aspects cruciaux de la fonction des CSH, notamment l'auto-renouvellement, la survie et la différenciation. Abstract : c-Myc, the first Myc transcription factor was discovered 30 years ago and is to date one of the most potent proto-oncogenes described. It is found to be misregulated in over 50% of all cancers, where it drives proliferation, cell growth and neo-angiogenesis. Myc can also influence a variety of other functions, owing to its ability to activate and repress transcription of many target genes and to globally regulate the genome via epigenetic modifications of the chromatin. The Myc family of oncogenes consists of three closely related proteins in mammals: c-Myc, N-Myc and L-Myc. These proteins share the same biochemical properties, exert mostly the same functions, but are most often expressed in mutually exclusive patterns. Myc is now emerging as a key factor in maintenance of embryonic and adult stem cells as well as in reacquisition of stem cell properties, including induced reprogramming. We previously showed that c-Myc deficiency can cause the accumulation of hematopoietic stem cells (HSCs) due to a niche dependent differentiation defect. HSCs are responsible for life-long replenishment of all blood cell types, and are defined by their ability to self-renew while concomitantly giving rise to more commited progenitors. To gain further insight into the function of Myc in HSCs, in this study we combine the use of genetically-modified mouse models with the systematic characterization of c-myc, N-myc and L-myc transcription patterns throughout the hematopoietic system. Interestingly, the most immature HSCs express not only c-myc, but also about equal amounts of N-myc transcripts. Although conditional deletion of N-myc alone in the bone marrow does not affect steady-state hematopoiesis, N-myc null HSCs show impaired long-term self-renewal capacity. Strikingly, combined deficiency of c-Myc and N-Myc results in pan-cytopenia and rapid lethality, due to the apoptosis of most hematopoietic cell types. In particular, self-renewing HSCs, but not quiescent HSCs or progenitor cell types rapidly up-regulate and accumulate the potent cytotoxic molecule GranzymeB (GrB), causing their rapid cell death. These data uncover a novel pathway on which HSC survival depends on, namely repression of GrB, a molecule typically used by the innate immune system to eliminate tumor and virus infected cells. To evaluate the extent of redundancy between c-Myc and N-Myc in HSCs, we examined mice in which c-myc coding sequences are replaced by that of N-myc (NCR) and also generated an allelic series of myc, by combinatorially deleting one or several c-myc and/or N-myc alleles. While the analysis of NCR mice suggests that c-Myc and N-Myc are qualitatively functionally redundant, our allelic series indicates that the efficiencies with which these two proteins affect crucial HSC maintenance processes are likely to be distinct. Collectively, our genetic data show that general "MYC" activity delivered by c-Myc and N-Myc controls crucial aspects of HSC function, including self-renewal, survival and niche dependent differentiation.

Novel functions of the polymeric Ig receptor: well beyond transport of immunoglobulins.

The polymeric Ig receptor (pIgR) ensures efficient secretion of polymeric IgA (pIgA) at mucosal surfaces. On basal to apical transport across epithelial cells, the pIgR extracellular domain is cleaved, releasing secretory component (SC) in association with pIgA. This finds its raison d'être in the recent observation that SC is directly involved in the protective function of secretory IgA. In addition, free SC exhibits scavenger properties with respect to enteric pathogens. However, although pIgR dedicates its life to mucosal protection, it also seems to permit pathogen entrance through the epithelial barrier. The multiple mechanisms that they are involved in make pIgR and SC instrumental to mucosal immunity.

Evolutionary origin and functions of retrogene introns.

Retroposed genes (retrogenes) originate via the reverse transcription of mature messenger RNAs from parental source genes and are therefore usually devoid of introns. Here, we characterize a particular set of mammalian retrogenes that acquired introns upon their emergence and thus represent rare cases of intron gain in mammals. We find that although a few retrogenes evolved introns in their coding or 3' untranslated regions (untranslated region, UTR), most introns originated together with untranslated exons in the 5' flanking regions of the retrogene insertion site. They emerged either de novo or through fusions with 5' UTR exons of host genes into which the retrogenes inserted. Generally, retrogenes with introns display high transcription levels and show broader spatial expression patterns than other retrogenes. Our experimental expression analyses of individual intron-containing retrogenes show that 5' UTR introns may indeed promote higher expression levels, at least in part through encoded regulatory elements. By contrast, 3' UTR introns may lead to downregulation of expression levels via nonsense-mediated decay mechanisms. Notably, the majority of retrogenes with introns in their 5' flanks depend on distant, sometimes bidirectional CpG dinucleotide-enriched promoters for their expression that may be recruited from other genes in the genomic vicinity. We thus propose a scenario where the acquisition of new 5' exon-intron structures was directly linked to the recruitment of distant promoters by these retrogenes, a process potentially facilitated by the presence of proto-splice sites in the genomic vicinity of retrogene insertion sites. Thus, the primary role and selective benefit of new 5' introns (and UTR exons) was probably initially to span the often substantial distances to potent CpG promoters driving retrogene transcription. Later in evolution, these introns then obtained additional regulatory roles in fine tuning retrogene expression levels. Our study provides novel insights regarding mechanisms underlying the origin of new introns, the evolutionary relevance of intron gain, and the origin of new gene promoters.

Dual functions of DP1 promote biphasic Wnt-on and Wnt-off states during anteroposterior neural patterning.

DP1, a dimerization partner protein of the transcription factor E2F, is known to inhibit Wnt/β-catenin signalling along with E2F, although the function of DP1 itself was not well characterized. Here, we present a novel dual regulatory mechanism of Wnt/β-catenin signalling by DP1 independent from E2F. DP1 negatively regulates Wnt/β-catenin signalling by inhibiting Dvl-Axin interaction and by enhancing poly-ubiquitination of β-catenin. In contrast, DP1 positively modulates the signalling upon Wnt stimulation, via increasing cytosolic β-catenin and antagonizing the kinase activity of NLK. In Xenopus embryos, DP1 exerts both positive and negative roles in Wnt/β-catenin signalling during anteroposterior neural patterning. From subcellular localization analyses, we suggest that the dual roles of DP1 in Wnt/β-catenin signalling are endowed by differential nucleocytoplasmic localizations. We propose that these dual functions of DP1 can promote and stabilize biphasic Wnt-on and Wnt-off states in response to a gradual gradient of Wnt/β-catenin signalling to determine differential cell fates.

Multi-faceted functions of secretory IgA at mucosal surfaces.

Secretory IgA (SIgA) plays an important role in the protection and homeostatic regulation of intestinal, respiratory, and urogenital mucosal epithelia separating the outside environment from the inside of the body. This primary function of SIgA is referred to as immune exclusion, a process that limits the access of numerous microorganisms and mucosal antigens to these thin and vulnerable mucosal barriers. SIgA has been shown to be involved in avoiding opportunistic pathogens to enter and disseminate in the systemic compartment, as well as tightly controlling the necessary symbiotic relationship existing between commensals and the host. Clearance by peristalsis appears thus as one of the numerous mechanisms whereby SIgA fulfills its function at mucosal surfaces. Sampling of antigen-SIgA complexes by microfold (M) cells, intimate contact occurring with Peyer's patch dendritic cells (DC), down-regulation of inflammatory processes, modulation of epithelial, and DC responsiveness are some of the recently identified processes to which the contribution of SIgA has been underscored. This review aims at presenting, with emphasis at the biochemical level, how the molecular complexity of SIgA can serve these multiple and non-redundant modes of action.