357 research outputs found
Neurotrophins and their p75 receptor
No full textCarter BD, Dechant G, Frade JM, Kaltschmidt C, Barde Y-A. Neurotrophins and their p75 receptor. Cold Spring Harbor Symp. Quant. Biol. 1996;1996(61):407-415
General EM Algorithm for Fitting Non-Monotone Hazard Functions from Truncated and Censored Observations
No full textRecently, many researchers focused on modeling non-monotonic hazard functions such as bath-tube and hump shapes. However, most of their estimation methods are focused on complete observations. Since reliability data are typically censored and truncated, a general EM algorithm is proposed, which can fit any of those complex hazard functions. The proposed EM algorithm is analyzed by fitting well-known 4-parameter hazard functions, where its performance is compared by their specific direct methods through extensive Monte Carlo simulations. (c) 2022 Elsevier B.V. All rights reserved.11Nsciescopu
Mouse embryonic stem cells as a discovery tool in neurobiology
No full textMouse ES cells can recapitulate, under suitable tissue culture conditions, early events in neurogenesis. As wildtype or genetically modified ES cells can be grown in unlimited quantities, their differentiation into neurons represents an attractive model for studying the function of genes involved in early development, such as those controlling neuronal specification and survival. A few years ago, our laboratory established a robust differentiation protocol leading to the generation of well-defined and virtually pure populations of Pax6-positive radial glial (RG) cells with a profile and developmental potential characteristic of Pax6-positive RG cells of the cortex. Like their in vivo counterparts, these progenitors generate homogeneous populations of glutamatergic neurons. In my thesis work, I first addressed the role of Pax6 in the generation, specification and developmental potential of RG cells, by analyzing the progeny of ES cells isolated from homozygote Pax6-mutant embryos. I found that while Pax6 is not required for the generation of neurogenic RG, it is both sufficient and necessary for specifying them into a glutamatergic lineage. RG cells lacking Pax6 express genes specifying an interneuron fate, like Mash1, and generate GABAergic inhibitory neurons. These cells die prematurely due to an aberrant over-expression of the neurotrophin receptor p75. I could verify these findings in the cortex of mutant embryos lacking Pax6. This work led to new insights as to the regulation of neuronal specification and survival during neurogenesis.
In the second part of my thesis, I used this ES cell-based differentiation system to test any potential instructive roles of the 3 neurotrophin tyrosine kinase receptors TrkA, TrkB and TrkC, after recombining them into the neuron-specific mapt locus. This approach led to the surprising observations that TrkA and TrkC cause neuronal death when not activated by their neurotrophin ligands, whereas TrkB does not. Both the death inducing activity of TrkA and TrkC and the lack of death-inducing activity of TrkB were explained by differential distribution of these receptors with p75. The TrkA and TrkC-induced death involves their segregation together with p75 in lipid rafts, and the subsequent proteolysis of the latter signals to the apoptotic machinery. By contrast, TrkB is not recruited to lipid rafts and it does not result in p75 proteolysis. Subsequent analyses of TrkA and ngf mutants, as well as of embryos lacking both TrkA and p75 receptors confirmed the relevance of this novel death triggering mechanism during the development of the peripheral nervous system. These findings also point to a major, and so far un-described, difference in the way growth factors regulate the survival of neurons in the developing peripheral versus central nervous system. It is the receptors themselves that cause neurons to become growth factor dependent in the peripheral, but not in the central nervous system.
Taken together, my results demonstrate that the differentiation of mouse embryonic stem cells into defined neuronal populations represents a useful tool allowing observations to be made that are relevant to the development of the nervous system
Voyages dans les Alpes : précédés d'un essai sur l'histoire naturelle des environs de Genève.Tome premier
No full textAntep.Las h. de lám. son grab. calc., algunos de ellos mapas, La 1ª, entre la port. y primera p. de texto: "Carte du Lac de Ggeneve et des montagnes adiacentes", la 2ªentre p. XXXI y p.1: " Vue de la côte Orientale du Lac de Genévre, M.T. Bourrit Delin, C G Geisjsler Sculps., la 3º entre p. 64 y 65 representan fósilesPastaa-b8, A-Z
Disease modelling of a human neurodevelopmental disorder using mouse embryonic stem cells
No full textAs cultured embryonic stem (ES) cells can be differentiated in neurons under well-defined conditions, they provide a unique opportunity to model and study diseases of the nervous system such as Rett syndrome. Most cases of this tragic neurodevelopmental disorder affecting about 1 young girl in 10’000 are caused by mutations in MECP2, a gene encoding the methyl-CpG-binding protein 2. Despite the generation of very useful mouse models recapitulating some important features of Rett syndrome, like the lack of normal brain growth, breathing arrhythmia and movement deficits, the function of MeCP2 in the brain remains unclear at this point. A few years ago, our laboratory established a differentiation procedure allowing the generation of virtually pure progenitors defined as Pax6-positive radial glial cells. As they do in vivo, these cells go on to generate glutamatergic neurons. One key characteristic of this system is that essentially all cells differentiate synchronously and I used it during the course of my PhD thesis to compare wild-type ES cells with ES cells lacking MeCP2. During the transition from progenitors to neurons, the size of nuclei increases by about 40% within a period of about 10 days, while nuclei of neurons lacking MeCP2 fail to grow at the same rate. Both the acute re-expression of MeCP2 in MeCP2 Stop-Floxed neurons following the excision of a stop cassette using Cre, as well as the viral delivery of MeCP2 to null neurons were found to rescue the small nuclear size phenotype. In an effort to correlate the size of the nuclei with their transcriptional activity, I compared the rate of total in vitro RNA transcription in pure nuclei isolated from wild-type vs. Mecp2 -/y (null) and Mecp2 Stop-Floxed ES cell-derived neurons. Regardless of the type of MeCP2 mutation, the neuronal nuclei lacking MeCP2 were found to be significantly less transcriptionally active compared to the wild-type nuclei. These results suggest that MeCP2 may have a general, genome-wide role in regulating the rate of RNA transcription, including ribosomal RNA that represents the major species investigated in such experiments. As BDNF levels have been reported to be reduced in the brain of Mecp2 -/y mice, I also examined if ES cell-derived neuron lacking MeCP2 would reflect this potentially important aspect of the disease, since decreased levels of BDNF could be hoped to be corrected and to improve the patients’ condition. At about 15 days in vitro, the levels of BDNF were found to be reduced by about 30% and the acute expression of MeCP2 was found to restore the expression of BDNF to levels similar to those seen in wild-type neurons.
In the second part of my work, I found that the sphingosine-1 phosphate analogue fingolimod (FTY720), recently introduced as the first oral treatment of multiple sclerosis, increases BDNF levels both in wild-type and Mecp2 -/y ES cell-derived neurons by mechanisms involving MAPK signaling and neuronal activity. In MeCP2 mutant mice, FTY720 increases BDNF levels in the striatum as well its volume, ameliorates locomotor activity and extends the lifespan by 50%.
As microcephaly is one of major symptoms of Rett syndrome, I also investigated in the third part of my PhD work the effects of the lack of MeCP2 on cell proliferation. While MeCP2-deficient ES cells do not have a proliferation defect, neuronal progenitors lacking MeCP2 generate fewer neurons compared with wild-type cells. This difference between ES cells and neuronal progenitors may result from the fact that the levels of MeCP2 expression are much higher in neurons and neuronal progenitors compared to ES cells.
Taken together, my results show that an ES cell based system represent a useful tool to understand molecular mechanisms underlying human neurological disorders
Steinbeck in Vietnam : il consenso e l'ombra lunga degli anni Trenta
No full textIntroduzione all'edizione italiana dei dispacci di John Steinbeck dal Vietnam, "Steinbeck in Vietnam" a cura di Thomas E. Barde
Fin-de-siècle: fin de l’art? Destins de l’art dans les discours de la fin des xixe et xxe siècles, C. Barde, S. Chassaing, H. Pernoud
No full textCosa c’è dietro all’idea che la fine di un secolo comporti decadenza, che un periodo cronologico corrisponda a un’epoca? Se l’immaginario della fin-de-siècle si fonda su fenomeni storici, culturali, estetici concreti, a quale punto la storia sfuma nel mito – un mito capace di rigenerarsi a ogni centenario, pur mantenendo intatta l’inquietudine greve, il senso di distruzione, la speranza incerta della rinascita? Tra queste domande si snoda il volume curato da Cyril Barde, Sylvia Chassaing e He..
Back to the Future: A Simple Solution to Schelling Segregation
No full textThe maximum entropy methodology is applied to the Schelling model of urban segregation in order to obtain a reliable prediction of the stable configuration of the system without resorting to numerical simulations. We show that this approach also provides an implicit equation describing the distribution of agents over a city which allows for directly assessing the effect of model parameters on the solution. Finally, we discuss the information theoretic motivation for applying this methodology to the Schelling model, and show that it effectively rests on the presence of a potential function, suggesting a broader applicability of the methodology.
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