102 research outputs found
Genetic Modifiers of CAG.CTG Repeat Instability in Huntington\u27s Disease Mouse Models
Huntington\u27s disease (HD) is a dominantly inherited neurodegenerative disorder whose characterstics were first described by George Huntington in 1872. Several decades later, in 1993, the mutation behind this disease was found to be an unstable expanded CAG repeat within exon 1 of the HTT gene localized on the short arm of chromosome 4. The majority of HD patients carry more than 40 CAG repeats, which become unstable and usually increase in size in successive generations and in tissues. In order to dissect the molecular mechanisms underlying CAG repeat instability, several HD mouse models have been created in the 1990s. Significant data have revealed that the absence of proteins from the mismatch repair (MMR) or the base and nucleotide excision repair decreased the pathogenic expansionâbiased somatic mosaicism and/or intergenerational expansions. Some polymorphic variants of MMR genes have also been associated with reduced somatic expansions. Since expansionâbiased somatic mosaicism likely contributes to disease manifestations, these results suggest that genetic modifiers of instability may also affect disease severity. In this chapter, we provide an overview of the data recently published about DNA instability; the roles of genetic modifiers of trinucleotide repeat dynamics in mouse models; and the possible therapeutic interventions
La structure de la rĂ©alitĂ© sociale abstraite inhĂ©rente aux sociĂ©tĂ©s prescrites : La quidditĂ© des liens et des structures de coopĂ©rations intra-organisationnels issus de lâactivitĂ© rĂ©elle, dans le cas du processus de co-construction de sens dĂ©coulant des dĂ©cisions stratĂ©giques
Based on the idea that the subsidiaries of a company are able to call into question the decisions of senior management (the parent company), the holistic approach developed in this study assumes that an organization can be a âbeingâ, implying thereby that the information in its possession is external to the individuals who compose it. This raises the question of whether it is conceivable to ignore the individual in such a relationship of domination. This thesis proposes a model based on the results which show the difficult exclusion of the individual in a meta-organizational context (in which members would be organizations and not individuals). Along these same lines, the organizationâs human dynamics are at the heart of this research: there exists by and through the individual a dynamic resulting from actual activity that allows the organization to live by itself, while also allowing prescribe to evolve. Although the results show that the organization is not a dead and strengthless object, and it has the opportunity to live by itself, it is the individuals who âthrough their conditional commitmentsâ allow the separate existence of an organizational structureâs intra-consciousness, which imposes rights and obligations. In this perspective, the proposed model aims to draw the structures of abstract social reality (referred as Entity X in this study) by showing the strengths and organizational constraints that weigh on individual members, while raising the human capacity to emerge from the structures prescribed by the sensemaking of links and transversal structures for cooperation that originate from the actual activity.Partant de lâidĂ©e que des filiales dâune entreprise sont en mesure de remettre en cause les dĂ©cisions de la direction gĂ©nĂ©rale (maison-mĂšre), lâapproche holistique dĂ©veloppĂ©e dans ce travail part du principe quâune organisation peut ĂȘtre un « ĂȘtre », laissant entendre ainsi que les informations dont elle dispose seraient extĂ©rieures aux individus qui la composent. Ce qui conduit Ă s'interroger sâil est concevable dâignorer lâindividu dans une telle relation de domination. Cette thĂšse propose justement un modĂšle autour de rĂ©sultats qui montrent la difficile exclusion de lâindividu dans un contexte mĂ©ta-organisationnel (dans lequel les membres seraient des organisations et non des individus). Dans cette veine, ce sont les dynamiques humaines de lâorganisation qui sont au cĆur de ce travail : il existe par et au travers de lâindividu une dynamique issue de lâactivitĂ© rĂ©elle qui permet de faire vivre lâorganisation par elle-mĂȘme, mais Ă©galement qui permet au prescrit de cette derniĂšre dâĂ©voluer. Bien que les rĂ©sultats obtenus montrent que lâorganisation nâest pas un objet mort et sans force et quâelle a bien la possibilitĂ© de vivre par elle-mĂȘme, ce sont les individus qui â par leurs engagements conditionnels â permettent cette existence propre de lâorganisation comme structure intra-consciente qui impose des droits et des obligations. Dans cette perspective, le modĂšle proposĂ© vise Ă dessiner les structures de la rĂ©alitĂ© sociale abstraite (dĂ©nommĂ© dans la recherche menĂ©e, lâEntitĂ© X) en montrant les forces et les contraintes organisationnelles qui pĂšsent sur les individus-membres, tout en relevant les capacitĂ©s humaines Ă sortir des structures prescrites par la co-construction de liens et de structures transversales de coopĂ©rations issus de lâactivitĂ© rĂ©elle
New approach of Ludwigia, an invasive macrophyte in Low Durance
La Ludwigia, communĂ©ment appelĂ©e Jussie, est une hydrophyte, Ă caractĂšre envahissant, introduite en France au xixe siĂšcle. Dâorigine amĂ©ricaine, elle pose, de par les nuisances quâelle engendre, de sĂ©rieux problĂšmes Ă©cologiques et Ă©conomiques dans de nombreux rĂ©seaux hydrographiques. La morphologie trĂšs proche et la grande plasticitĂ© phĂ©notypique des diffĂ©rentes espĂšces appartenant au genre Ludwigia engendrent de nombreuses confusions en ce qui concerne lâidentification des espĂšces prĂ©sentes sur le territoire et rendent, de ce fait, difficiles les analyses concernant leur autoĂ©cologie. La prĂ©sente Ă©tude a Ă©tĂ© menĂ©e sur trois sites mĂ©diterranĂ©ens, localisĂ©s en Basse-Durance (Bouches-du-RhĂŽne) qui se diffĂ©rencient de par leur origine et leur fonctionnement hydrologique. Elle a pris en compte lâidentification spĂ©cifique des Jussies prĂ©sentes sur ces sites Ă partir de leur caryologie et dâautre part, leur dĂ©veloppement et les paramĂštres abiotiques et biotiques caractĂ©ristiques de leur environnement aquatique. Les rĂ©sultats montrent quâen dĂ©pit de diffĂ©rences morphologiques marquĂ©es, une seule espĂšce se dĂ©veloppe dans ces sites, Ludwigia peploides. La qualitĂ© des eaux des diffĂ©rentes stations tĂ©moigne dâune certaine richesse en Ă©lĂ©ments nutritifs. Le dĂ©veloppement des herbiers est fortement corrĂ©lĂ© avec la concentration en orthophosphates des eaux, qui influencerait positivement la quantitĂ© de feuilles produites par la plante. La prĂ©sence dâautres espĂšces vĂ©gĂ©tales ainsi que celle dâune communautĂ© de macroinvertĂ©brĂ©s vivant au sein des herbiers met en Ă©vidence, pour la premiĂšre fois, la tolĂ©rance de la Jussie vis-Ă -vis dâautres organismes vĂ©gĂ©taux et lâhabitat favorable quâelle peut constituer pour la macrofaune.Ludwigia is an invasive hydrophyte, introduced in France in the nineteenth century. Native of America, it involves nowadays many ecological and economical troubles in many aquatic ecosystems. The likeness morphology and the big phenotypical plasticity of its different componing species engender many confusions concerning their ecological status. The study has investigated three mediterranean sites localized on Low-Durance river (Bouches-du-RhĂŽne) mainly distinguished by their physical properties and their hydrological functioning. The work consisted, in one hand, in the determination of present species from caryology, and, on the other hand, in the study of abiotic and biotic site characteristics. Caryological analysis reveal the single presence of Ludwigia peploides in this Low-Durance area. The water quality traduces an obvious eutrophication. The plant development shows a strong correlation with inorganic phosphorus (PO43-) concentration in the water column that could positively influence Ludwigia leaf number. Presence of some other macrophyte species and of a varied macroinvertebrate community inside Ludwigia communities, shows, for the first time, a relative tolerance of this hydrophyte in regard to the other plants and the favourable habitat it may constitute for the macrofauna
Variations temporelles des paramĂštres physicochimiques et microbiologiques de trois Ă©cosystĂšmes aquatiques (Sud-Est de la France) envahis par des <i>Ludwigia</i>
Internal transport of alien and native plants by geese and ducks: An experimental study
© 2015 John Wiley & Sons Ltd. Summary: Alien plant species are rapidly spreading in aquatic ecosystems around the world, causing major ecological effects. They are typically introduced by humans, after which natural vectors facilitate their further spread. Migratory waterbirds have long been recognised as important dispersal vectors for native and aquatic plants, yet little is known about their role in the spread of alien species. We determined experimentally the potential for long-distance dispersal of native and alien wetland plants in Europe by two abundant waterfowl: mallards Anas platyrhynchos and greylag geese Anser anser. We fed seeds from two plants alien to Europe and two native plants to 10 individuals of each bird species, testing for the effects of bird and plant species on the potential for dispersal. Intact seeds were retrieved from faeces for up to 4 days after ingestion. The proportion of seeds retrieved intact varied significantly between plant, but not bird, species. Retrieval was highest for the invasive water primrose Ludwigia grandiflora (>35% of ingested seeds), lowest for the invasive cordgrass Spartina densiflora (<3%) and intermediate for the native glasswort Arthrocnemum macrostachyum and seablite Suaeda vera (5-10%). Seed retrieval patterns over time varied between both plant and bird species. Contrary to expectations, seeds were retained in the gut for longer in the smaller mallards. No Spartina seeds germinated after retention for over 8 h, whereas some seeds of the other species germinated even after retention for 72 h. Germinability was reduced by gut passage for Ludwigia and Arthrocnemum seeds. Ludwigia seeds recovered from geese were more likely to germinate than those recovered from mallards. Time to germination was reduced by gut passage for Spartina and Ludwigia, but increased with retention time. Ducks and geese evidently have the potential for long-distance transport of alien and native plant seeds, with maximal dispersal distances of well over 1000 km. The much greater potential of Ludwigia than Spartina for dispersal by waterfowl is consistent with its faster expansion across Europe. Maximum retention times of wetland seeds have been underestimated in previous experimental studies that lasted only 1-2 days. Contrary to previous studies, wetland plants with large seeds, such as Ludwigia, can still show high potential for long-distance dispersal. More attention should be paid to the role of waterbirds as vectors of alien plants and to the role of migratory geese as vectors of plants in general.Peer Reviewe
Allelopathic Effects of Water Hyacinth [Eichhornia crassipes]
Eichhornia crassipes (Mart) Solms is an invasive weed known to out-compete native plants and negatively affect microbes including phytoplankton. The spread and population density of E. crassipes will be favored by global warming. The aim here was to identify compounds that underlie the effects on microbes. The entire plant of E. crassipes was collected from El Zomor canal, River Nile (Egypt), washed clean, then air dried. Plant tissue was extracted three times with methanol and fractionated by thin layer chromatography (TLC). The crude methanolic extract and five fractions from TLC (AâE) were tested for antimicrobial (bacteria and fungal) and anti-algal activities (green microalgae and cyanobacteria) using paper disc diffusion bioassay. The crude extract as well as all five TLC fractions exhibited antibacterial activities against both the Gram positive bacteria; Bacillus subtilis and Streptococcus faecalis; and the Gram negative bacteria; Escherichia coli and Staphylococcus aureus. Growth of Aspergillus flavus and Aspergillus niger were not inhibited by either E. crassipes crude extract nor its five fractions. In contrast, Candida albicans (yeast) was inhibited by all. Some antialgal activity of the crude extract and its fractions was manifest against the green microalgae; Chlorella vulgaris and Dictyochloropsis splendida as well as the cyanobacteria; Spirulina platensis and Nostoc piscinale. High antialgal activity was only recorded against Chlorella vulgaris. Identifications of the active antimicrobial and antialgal compounds of the crude extract as well as the five TLC fractions were carried out using gas chromatography combined with mass spectroscopy. The analyses showed the presence of an alkaloid (fraction A) and four phthalate derivatives (Fractions BâE) that exhibited the antimicrobial and antialgal activities
Internal transport of alien and native plants by geese and ducks: an experimental study
Familles atypiques et rÎle des interruptions sur l'instabilité des triplets CTG impliqués dans la Dystrophie Myotonique de type 1 (DM1)
The instability of microsatellite repeats is a key factor for 40 human diseases. Among these diseases, Myotonic Dystrophy Type 1 (DM1) is an autonomic dominant neuromuscular disease characterized by a strong phenomenon of anticipation: the symptoms worsen and appear earlier from one generation to the next. DM1 is caused by expanded CTG repeats in the 3 'UTR of the DMPK gene. In the general population, the CTG repeat is stable and ranges from 5 to 37 repetitions. Patients with DM1 have repeats that range from 50 to> 1000 CTG and are unstable from one generation to the next (intergenerational instability) and in the tissues (somatic instability), with a bias towards expansions. In general, there is a good correlation between the length of abnormal repeats and the symptoms severity. Instability of the CTG repeats involves various factors (DNA repair, transcription, replication, secondary structures etc...). However, the CTG repeats contraction mechanisms remain poorly understood. Repeat interruptions have been reported in patients with reduced CTG instability. It is suggested that interruptions could be a stabilization or contraction factor but so far, no direct demonstration of their impact has been presented. The aim of my thesis is to demonstrate whether and how interruptions impact the instability of CTG repeat expansions. We studied atypical DM1 families, with no anticipation and associated with contractions of the repeats on 2 to 4 successive transmissions. All patients in these families showed interruptions: a single CAG at 5 'of the CTG repeats (family A), or several CCG interruptions at 5' or 3 'of the repeat (in families B and E respectively). We demonstrated that the amplitude of somatic instability was reduced at least for families A and B. These interruptions are good candidates to learn more about the contraction / stabilization mechanisms of CTG repeats. I first demonstrated in vitro that the secondary structures were different between pure or interrupted CTG repeats. Then, I compared the binding of nuclear proteins to CTG repeats with or without interruption by EMSA (Electrophoretic Mobility Shift Assay). My results demonstrated different binding profiles depending on the nature of the repeats. To further study the impact of interruptions on CTG instability, I derived HEK293 cell models using Phi-Integrase technology and plasmids expressing the CTG repeats . These cells allow bidirectional transcription of the 3' UTR region of mutant DMPK carrying pure or interrupted CTG repeats, as observed in the family A. In these cells, I demonstrated via the newly optimized Flash-Small-Pool-PCR that the somatic mosaic of the interrupted CTG repeats was reduced compared to the pure repeat. I have also detected that the formation of DNA / RNA hybrids (R-loop) is reduced in cells with the single CAG interruption and follows the transcriptional pattern of mutant DMPK antisense transcripts. Thus, our cellular model demonstrates that the interruption of CAG has an impact on the instability of the CTG repeats, implying at least the metabolism of the R-loops. A better understanding of the mechanisms of contraction or stabilization of abnormal CTG repeats is crucial to being able to cure the molecular defect responsible for DM1. My project provides new insights into the mechanisms of instability of CTG repeats, which can provide new therapeutic targets and new clues to improve the prognosis of DM1.L'instabilitĂ© des rĂ©pĂ©titions de microsatellites est un facteur clĂ© pour plus de 40 maladies humaines. Parmi elles, la Dystrophie Myotonique de type 1 (DM1) est une maladie neuromusculaire autosomique dominante caractĂ©risĂ©e par un fort phĂ©nomĂšne d'anticipation : les symptĂŽmes s'aggravent et apparaissent plus tĂŽt d'une gĂ©nĂ©ration Ă l'autre. La DM1 est causĂ©e par une expansion de triplet CTG rĂ©pĂ©tĂ©s dans la rĂ©gion 3'UTR du gĂšne DMPK. Dans la population gĂ©nĂ©rale, la rĂ©pĂ©tition CTG est stable et varie de 5 Ă 37 rĂ©pĂ©titions. Les patients DM1 ont des rĂ©pĂ©titions instables variant de 50 Ă > 1 000 CTG d'une gĂ©nĂ©ration Ă l'autre (instabilitĂ© intergĂ©nĂ©rationnelle) et dans les tissus (instabilitĂ© somatique), avec un biais vers les expansions. En gĂ©nĂ©ral, il existe une bonne corrĂ©lation entre la longueur des rĂ©pĂ©titions anormales et la gravitĂ© des symptĂŽmes. L'instabilitĂ© des triplets CTG implique divers facteurs (rĂ©paration, transcription, structures secondaires...). Cependant, les mĂ©canismes de contractions des triplets CTG restent peu compris. Des interruptions dans les rĂ©pĂ©titions ont Ă©tĂ© rapportĂ©es chez des patients avec une instabilitĂ© des triplets CTG rĂ©duite. Il est suggĂ©rĂ© que les interruptions puissent ĂȘtre un facteur de stabilisation ou de contraction mais jusqu'Ă prĂ©sent, aucune dĂ©monstration directe de leur impact n'a Ă©tĂ© prĂ©sentĂ©e. L'objectif de ma thĂšse est de dĂ©montrer si les interruptions impactent l'instabilitĂ© des triplets CTG et par quels mĂ©canismes. Nous avons Ă©tudiĂ© des familles DM1 atypiques, exemptes de phĂ©nomĂšne d'anticipation et prĂ©sentant des contractions de triplets CTG sur 2 Ă 4 transmissions successives. Tous les patients de ces familles prĂ©sentent des interruptions : un seul CAG en 5' de la rĂ©pĂ©tition CTG (famille A), ou plusieurs interruptions de la CCG en 5' ou 3' de la rĂ©pĂ©tition (dans les familles B et E respectivement). Nous avons dĂ©montrĂ© que l'amplitude de l'instabilitĂ© somatique est rĂ©duite au moins pour les familles A et B. Ces d'interruptions sont de bons candidats pour Ă©tudier les mĂ©canismes de contraction/ stabilisation des rĂ©pĂ©titions CTG. J'ai d'abord dĂ©montrĂ© in vitro que les structures secondaires de l'ADN Ă©taient diffĂ©rentes entre les rĂ©pĂ©titions pures ou interrompues. J'ai ensuite comparĂ© la fixation des protĂ©ines nuclĂ©aires aux rĂ©pĂ©titions CTG, avec ou sans interruption, par EMSA. Mes rĂ©sultats ont dĂ©montrĂ© des profils de fixation diffĂ©rents selon la nature des rĂ©pĂ©titions. Afin d'Ă©tudier plus prĂ©cisĂ©ment l'impact des interruptions sur l'instabilitĂ© des rĂ©pĂ©titions, j'ai dĂ©rivĂ© des modĂšles de cellules HEK293 en utilisant la technologie Phi-Integrase permettant l'intĂ©gration de plasmides d'expression. Ces cellules permettent la transcription bidirectionnelle de la rĂ©gion 3 'UTR du gĂšne DMPK mutant portant des rĂ©pĂ©titions CTG pures ou interrompues avec une unique interruption CAG en 5' des rĂ©pĂ©titions CTG, reproduisant le motif identifiĂ© chez la famille A. GrĂące Ă ce modĂšle, j'ai dĂ©montrĂ© que la mosaĂŻque somatique des rĂ©pĂ©titions CTG interrompues Ă©tait rĂ©duite comparĂ©e Ă celle prĂ©sentĂ©e par les clones Ă rĂ©pĂ©titions pures reproduisant ainsi ce qui a Ă©tĂ© prĂ©cĂ©demment observĂ©e chez la famille A comparĂ©e Ă des contrĂŽles DM1 Ă rĂ©pĂ©titions pures. Avec ce modĂšle, j'ai montrĂ© que la formation d'hybrides ADN/ARN (R-loops) est rĂ©duite dans les cellules avec une seule interruption CAG et qu'il y a une bonne corrĂ©lation entre la formation d'R-loop et le niveau de transcription de DMPK mutant antisens. Ainsi, ce modĂšle cellulaire dĂ©montre que l'interruption de CAG a un impact sur l'instabilitĂ© des rĂ©pĂ©titions CTG, impliquant notamment le mĂ©tabolisme des R-loops. Une meilleure comprĂ©hension des mĂ©canismes de contraction ou de stabilisation des rĂ©pĂ©titions anormales de CTG est crucial pour pouvoir guĂ©rir la DM1. Mon projet fournit de nouvelles informations sur les mĂ©canismes de l'instabilitĂ© des triplets CTG, qui peuvent orienter vers de nouvelles cibles thĂ©rapeutiques
Distribution et ecologie de quelques mammiferes de l'est du Congo
Zoologica Africana 1(1): 167-17
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