Evolutionary origin of synapses and neurons – Bridging the gap

The evolutionary origin of synapses and neurons is an enigmatic subject that inspires much debate. Non-bilaterian metazoans, both with and without neurons and their closest relatives already contain many components of the molecular toolkits for synapse functions. The origin of these components and their assembly into ancient synaptic signaling machineries are particularly important in light of recent findings on the phylogeny of non-bilaterian metazoans. The evolution of synapses and neurons are often discussed only from a metazoan perspective leaving a considerable gap in our understanding. By taking an integrative approach we highlight the need to consider different, but extremely relevant phyla and to include the closest unicellular relatives of metazoans, the ichthyosporeans, filastereans and choanoflagellates, to fully understand the evolutionary origin of synapses and neurons. This approach allows for a detailed understanding of when and how the first pre- and postsynaptic signaling machineries evolved

Evolutionary origin of synapses and neurons - Bridging the gap

The evolutionary origin of synapses and neurons is an enigmatic subject that inspires much debate. Non-bilaterian metazoans, both with and without neurons and their closest relatives already contain many components of the molecular toolkits for synapse functions. The origin of these components and their assembly into ancient synaptic signaling machineries are particularly important in light of recent findings on the phylogeny of non-bilaterian metazoans. The evolution of synapses and neurons are often discussed only from a metazoan perspective leaving a considerable gap in our understanding. By taking an integrative approach we highlight the need to consider different, but extremely relevant phyla and to include the closest unicellular relatives of metazoans, the ichthyosporeans, filastereans and choanoflagellates, to fully understand the evolutionary origin of synapses and neurons. This approach allows for a detailed understanding of when and how the first pre- and postsynaptic signaling machineries evolved

Phylogenetic Relationships within the Opisthokonta Based on Phylogenomic Analyses of Conserved Single-Copy Protein Domains

Many of the eukaryotic phylogenomic analyses published to date were based on alignments of hundreds to thousands of genes. Frequently, in such analyses, the most realistic evolutionary models currently available are often used to minimize the impact of systematic error. However, controversy remains over whether or not idiosyncratic gene family dynamics (i.e., gene duplications and losses) and incorrect orthology assignments are always appropriately taken into account. In this paper, we present an innovative strategy for overcoming orthology assignment problems. Rather than identifying and eliminating genes with paralogy problems, we have constructed a data set comprised exclusively of conserved single-copy protein domains that, unlike most of the commonly used phylogenomic data sets, should be less confounded by orthology miss-assignments. To evaluate the power of this approach, we performed maximum likelihood and Bayesian analyses to infer the evolutionary relationships within the opisthokonts (which includes Metazoa, Fungi, and related unicellular lineages). We used this approach to test 1) whether Filasterea and Ichthyosporea form a clade, 2) the interrelationships of early-branching metazoans, and 3) the relationships among early-branching fungi. We also assessed the impact of some methods that are known to minimize systematic error, including reducing the distance between the outgroup and ingroup taxa or using the CAT evolutionary model. Overall, our analyses support the Filozoa hypothesis in which Ichthyosporea are the first holozoan lineage to emerge followed by Filasterea, Choanoflagellata, and Metazoa. Blastocladiomycota appears as a lineage separate from Chytridiomycota, although this result is not strongly supported. These results represent independent tests of previous phylogenetic hypotheses, highlighting the importance of sophisticated approaches for orthology assignment in phylogenomic analyses. © The Author 2011. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved

Adverse Effects of Methylmercury: Environmental Health Research Implications

Background: The scientific discoveries of health risks resulting from methylmercury exposure began in 1865 describing ataxia, dysarthria, constriction of visual fields, impaired hearing, and sensory disturbance as symptoms of fatal methylmercury poisoning. Objective: Our aim was to examine how knowledge and consensus on methylmercury toxicity have developed in order to identify problems of wider concern in research. Data sources and extraction: We tracked key publications that reflected new insights into human methylmercury toxicity. From this evidence, we identified possible caveats of potential significance for environmental health research in general. Synthesis: At first, methylmercury research was impaired by inappropriate attention to narrow case definitions and uncertain chemical speciation. It also ignored the link between ecotoxicity and human toxicity. As a result, serious delays affected the recognition of methylmercury as a cause of serious human poisonings in Minamata, Japan. Developmental neurotoxicity was first reported in 1952, but despite accumulating evidence, the vulnerability of the developing nervous system was not taken into account in risk assessment internationally until approximately 50 years later. Imprecision in exposure assessment and other forms of uncertainty tended to cause an underestimation of methylmercury toxicity and repeatedly led to calls for more research rather than prevention. Conclusions: Coupled with legal and political rigidity that demanded convincing documentation before considering prevention and compensation, types of uncertainty that are common in environmental research delayed the scientific consensus and were used as an excuse for deferring corrective action. Symptoms of methylmercury toxicity, such as tunnel vision, forgetfulness, and lack of coordination, also seemed to affect environmental health research and its interpretation

Adverse Effects of Methylmercury: Environmental Health Research Implications

Background: The scientific discoveries of health risks resulting from methylmercury exposure began in 1865 describing ataxia, dysarthria, constriction of visual fields, impaired hearing, and sensory disturbance as symptoms of fatal methylmercury poisoning. Objective: Our aim was to examine how knowledge and consensus on methylmercury toxicity have developed in order to identify problems of wider concern in research. Data sources and extraction: We tracked key publications that reflected new insights into human methylmercury toxicity. From this evidence, we identified possible caveats of potential significance for environmental health research in general. Synthesis: At first, methylmercury research was impaired by inappropriate attention to narrow case definitions and uncertain chemical speciation. It also ignored the link between ecotoxicity and human toxicity. As a result, serious delays affected the recognition of methylmercury as a cause of serious human poisonings in Minamata, Japan. Developmental neurotoxicity was first reported in 1952, but despite accumulating evidence, the vulnerability of the developing nervous system was not taken into account in risk assessment internationally until approximately 50 years later. Imprecision in exposure assessment and other forms of uncertainty tended to cause an underestimation of methylmercury toxicity and repeatedly led to calls for more research rather than prevention. Conclusions: Coupled with legal and political rigidity that demanded convincing documentation before considering prevention and compensation, types of uncertainty that are common in environmental research delayed the scientific consensus and were used as an excuse for deferring corrective action. Symptoms of methylmercury toxicity, such as tunnel vision, forgetfulness, and lack of coordination, also seemed to affect environmental health research and its interpretation

The impact of transposable element activity on therapeutically relevant human stem cells

Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016- 21395 and SAF2015–71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015–71589- P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the Federal Republic of Germany (FKZ2518FSB403)

Cystectomie avec conservation prostatique dans le traitement des tumeurs de vessie (bases anatomiques, techniques chirurgicales, étude clinique)

PARIS6-Bibl. St Antoine CHU (751122104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Modification de la structure chimique du bois par des alcoxysilanes diversement substitués

Une étude fondamentale des phénomènes au niveau moléculaire lors de la modification chimique du pin maritime (Pinus pinaster) par des trialcoxysilanes modèles diversement substitués a été entreprise au cours de ce travail de thèse. Dans un premier chapitre, la modification chimique du bois à partir du 3-isocyanatopropyltriéthoxysilane (IPTES) et son couplage ultérieur avec le méthyltriméthoxysilane (MTMS) ont été étudiés. La réaction avec IPTES a été réalisée en présence de dilaurate de dibutylétain (DBTDL) et a conduit au greffage de fonctions triethoxysilanes réactives à l'intérieur des parois cellulaires. Des polymères de MTMS ont ensuite été fixés durablement à l'intérieur du bois, par l'intermédiaire de ces fonctions . Dans un deuxième chapitre, les interactions entre les polymères lignocellulosiques et la fonction trialcoxysilane ont été plus particulièrement étudiées, grâce à des méthodes d'investigation moléculaires comme l'IRTF ou la RMN du solide. La condensation de la fonction triméthoxysilane avec les groupements hydroxyles du bois a été confirmée en milieu anhydre (en présence d'éthylamine) mais les liaisons formées se sont avérées hydrolysables. En présence d'eau (et de DBTDL), la fonction triméthoxysilane a été hydrolysée et condensée à l'intérieur du bois, sous forme de polysiloxanes stables. Un greffage durable et significatif a alors été obtenu pour une teneur en eau contrôlée de 8% à l'intérieur du bois.BORDEAUX1-BU Sciences-Talence (335222101) / SudocSudocFranceF

The striated urethral sphincter in female rats

International audienceThe aim of this study was to give a microscopic description of the organization, the innervation and the slow or fast type of the striated fibers of the external urethral sphincter in the female rat. Conventional methods for photonic microscopy and immunochemistry were applied to cross and longitudinal sections of snap-frozen urethra. With hematoxylin-eosin stained cross sections, striated fibers are of small diameter and attached directly to the surrounding connective tissue. They are innervated by cholinergic endplates as shown by acetylcholinesterase techniques and alpha-bungarotoxin binding. The histological aspects of the cross sections as well as the distribution of endplates along the length of the sphincter suggest an organization of the fibers in four bundles, possibly acting as a photographic diaphragm does. Like striated skeletal muscle fibers, the fibers bind monoclonal antibodies against dystrophin with subsarcolemmal distribution and against desmin which visualizes striations. All the fibers express fast myosin heavy chains and very few co-express slow myosin heavy chains as determined by immunocytochemistry. We are taking advantage of the diaphragmatic organization of the striated sphincter to develop a longitudinal section as a model of chronic incontinence to test the efficiency of grafted myoblasts provided by fast striated skeletal muscle

Improvement of Urethral Sphincter Deficiency in Female Rats following Autologous Skeletal Muscle Myoblasts Grafting

International audienceSphincteric deficiency is the most common cause of urinary incontinence in humans. Various treatments have lead to disappointing results due to a temporary benefit. Recent studies raised the possibility that sphincteric deficiency could be treated by implanting skeletal myoblasts. In the present study, we developed in the female rat a model of chronic sphincteric defect to assess the benefit of myoblast injection. Sphincter deficiency was induced by freezing, longitudinal sphincterotomy, and notexin injection, respectively, to obtain a reproducible and irreversible incontinence. Autologous tibialis anteriors were cultured to be injected in the best model. Functional results were evaluated by measuring the urethral pressure with an open catheter. Histology was performed in the excised urethras. Of the three techniques, only longitudinal sphincterotomy caused definitive incontinence by irreversibly destroying the striated sphincter muscle fibers: a 45% decrease of the closure pressure was observed 21 days after the sphincterotomy. At this time, we injected myoblasts at the sphincterotomy site. In the sham-injected group (n = 18), the closure pressure decrease was not significantly modified 21 days after injection. By comparison, a return to near normal value was observed after cell grafting (n = 21). These results and those obtained by others strongly suggest that the use of myoblasts could be a potential innovative therapy for urethral deficiencies leading to incontinence