749 research outputs found
Mechanisms underlying activation of neural stem cells in the adult central nervous system
à la fin du 19e siÚcle, Dr. Ramón y Cajal, un pionnier scientifique, a découvert les
éléments cellulaires individuels, appelés neurones, composant le systÚme nerveux. Il a
Ă©galement remarquĂ© la complexitĂ© de ce systĂšme et a mentionnĂ© lâimpossibilitĂ© de ces nouveaux
neurones Ă ĂȘtre intĂ©grĂ©s dans le systĂšme nerveux adulte. Une de ses citations reconnues : âDans
les centres adultes, les chemins nerveux sont fixes, terminés, immuables. Tout doit mourir, rien
ne peut ĂȘtre rĂ©gĂ©nĂ©rerâ est reprĂ©sentative du dogme de lâĂ©poque (RamĂłn y Cajal 1928).
Dâimportantes Ă©tudes effectuĂ©es dans les annĂ©es 1960-1970 suggĂšrent un point de vue diffĂ©rent.
Il a Ă©tĂ© dĂ©montrĂ© que les nouveaux neurones peuvent ĂȘtre gĂ©nĂ©rĂ©s Ă lâĂąge adulte, mais cette
découverte a créé un scepticisme omniprésent au sein de la communauté scientifique. Il a fallu
30 ans pour que le concept de neurogenÚse adulte soit largement accepté. Cette découverte, en
plus de nombreuses avancées techniques, a ouvert la porte à de nouvelles cibles thérapeutiques
potentielles pour les maladies neurodégénératives. Les cellules souches neurales (CSNs) adultes
résident principalement dans deux niches du cerveau : la zone sous-ventriculaire des ventricules
latĂ©raux et le gyrus dentelĂ© de lâhippocampe. En condition physiologique, le niveau de
neurogenĂšse est relativement Ă©levĂ© dans la zone sous-ventriculaire contrairement Ă
lâhippocampe oĂč certaines Ă©tapes sont limitantes. En revanche, la moelle Ă©piniĂšre est plutĂŽt
définie comme un environnement en quiescence.
Une des principales questions qui a été soulevée suite à ces découvertes est : comment
peut-on activer les CSNs adultes afin dâaugmenter les niveaux de neurogenĂšse ? Dans
lâhippocampe, la capacitĂ© de lâenvironnement enrichi (incluant la stimulation cognitive,
lâexercice et les interactions sociales) Ă promouvoir la neurogenĂšse hippocampale a dĂ©jĂ Ă©tĂ©
démontrée. La plasticité de cette région est importante, car elle peut jouer un rÎle clé dans la
rĂ©cupĂ©ration de dĂ©ficits au niveau de la mĂ©moire et lâapprentissage. Dans la moelle Ă©piniĂšre, des
études effectuées in vitro ont démontré que les cellules épendymaires situées autour du canal
central ont des capacitĂ©s dâauto-renouvellement et de multipotence (neurones, astrocytes,
oligodendrocytes). Il est intĂ©ressant de noter quâin vivo, suite Ă une lĂ©sion de la moelle Ă©piniĂšre,
les cellules Ă©pendymaires sont activĂ©es, peuvent sâauto-renouveller, mais peuvent seulement
ii
donner naissance Ă des cellules de type gliale (astrocytes et oligodendrocytes). Cette nouvelle
fonction post-lésion démontre que la plasticité est encore possible dans un environnement en
quiescence et peut ĂȘtre exploitĂ© afin de dĂ©velopper des stratĂ©gies de rĂ©paration endogĂšnes dans
la moelle Ă©piniĂšre.
Les CSNs adultes jouent un rĂŽle important dans le maintien des fonctions physiologiques
du cerveau sain et dans la réparation neuronale suite à une lésion. Cependant, il y a peu de
données sur les mécanismes qui permettent l'activation des CSNs en quiescence permettant de
maintenir ces fonctions. L'objectif gĂ©nĂ©ral est d'Ă©lucider les mĂ©canismes sous-jacents Ă
l'activation des CSNs dans le systÚme nerveux central adulte. Pour répondre à cet objectif, nous
avons mis en place deux approches complémentaires chez les souris adultes : 1) L'activation des
CSNs hippocampales par l'environnement enrichi (EE) et 2) l'activation des CSNs de la moelle
Ă©piniĂšre par la neuroinflammation suite Ă une lĂ©sion. De plus, 3) afin dâobtenir plus
dâinformation sur les mĂ©canismes molĂ©culaires de ces modĂšles, nous utiliserons des approches
transcriptomiques afin dâouvrir de nouvelles perspectives.
Le premier projet consiste à établir de nouveaux mécanismes cellulaires et moléculaires
Ă travers lesquels lâenvironnement enrichi module la plasticitĂ© du cerveau adulte. Nous avons
tout dâabord Ă©valuĂ© la contribution de chacune des composantes de lâenvironnement enrichi Ă la
neurogenĂšse hippocampale (Chapitre II). Lâexercice volontaire promeut la neurogenĂšse, tandis
que le contexte social augmente lâactivation neuronale. Par la suite, nous avons dĂ©terminĂ© lâeffet
de ces composantes sur les performances comportementales et sur le transcriptome Ă lâaide dâun
labyrinthe radial Ă huit bras afin dâĂ©valuer la mĂ©moire spatiale et un test de reconnaissante
dâobjets nouveaux ainsi quâun RNA-Seq, respectivement (Chapitre III). Les coureurs ont
démontré une mémoire spatiale de rappel à court-terme plus forte, tandis que les souris exposées
aux interactions sociales ont eu une plus grande flexibilité cognitive à abandonner leurs anciens
souvenirs. Ătonnamment, lâanalyse du RNA-Seq a permis dâidentifier des diffĂ©rences claires
dans lâexpression des transcripts entre les coureurs de courte et longue distance, en plus des
souris sociales (dans lâenvironnement complexe).
iii
Le second projet consiste à découvrir comment les cellules épendymaires acquiÚrent les
propriétés des CSNs in vitro ou la multipotence suite aux lésions in vivo (Chapitre IV). Une
analyse du RNA-Seq a rĂ©vĂ©lĂ© que le transforming growth factor-ÎČ1 (TGF-ÎČ1) agit comme un
régulateur, en amont des changements significatifs suite à une lésion de la moelle épiniÚre. Nous
avons alors confirmé la présence de cette cytokine suite à la lésion et caractérisé son rÎle sur la
prolifération, différentiation, et survie des cellules initiatrices de neurosphÚres de la moelle
Ă©piniĂšre. Nos rĂ©sultats suggĂšrent que TGF-ÎČ1 rĂ©gule lâacquisition et lâexpression des propriĂ©tĂ©s
de cellules souches sur les cellules Ă©pendymaires provenant de la moelle Ă©piniĂšre.At the end of the 19th century, Dr. RamĂłn y Cajal, a scientific pioneer, discovered that
the nervous system was composed of individual cellular elements, later called neurons. He also
noticed the complexity of this system and mentioned the impossibility of new neurons to be
integrated into the adult nervous system. One of his famous quotes: âIn adult centers the nerve
paths are something fixed, ended, immutable. Everything may die, nothing may be regeneratedâ
is representative of the prevalent dogma at the time (RamĂłn y Cajal 1928). Key studies
conducted in the 1960-1970s suggested a different point of view. It was demonstrated that new
neurons could be born during adulthood, but this discovery created an omnipresent skepticism
in the scientific community. It took 30 years for the concept of adult neurogenesis to become
widely accepted. This discovery, along with more advanced techniques, opened doors to
potential therapeutic avenues for neurodegenerative diseases. Adult neural stem cells (NSCs)
reside mainly in two niches in the brain: the subventricular zone of the lateral ventricles and the
dentate gyrus of the hippocampus. Under normal conditions, neurogenesis level is relatively
high in the SVZ whereas some steps are rate-limiting in the hippocampus. In contrast, the spinal
cord is rather defined as a quiescent environment.
One of the main questions that arose from these discoveries is: how do you activate adult
NSCs in order to increase neurogenesis levels? In the hippocampus, environmental enrichment
(including cognitive stimulation, exercise and social interactions) has been shown to promote
hippocampal neurogenesis. The plasticity potential of this region is important as it could play a
crucial role in rescuing learning and memory deficits. In the spinal cord, studies conducted in
vitro demonstrated that ependymal cells found around the central canal have self-renewal and
multipotency capacities (neurons, astrocytes, oligodendrocytes). Interestingly, it turns out that
in vivo, following a spinal cord lesion, ependymal cells become activated, can self-replicate, but
can only give rise to glia cell fate (astrocytes and oligodendrocytes). This new post-injury
function shows that plasticity can still occur in a quiescent environment and could be exploited
to develop endogenous spinal cord repair strategies.
v
As mentioned above, NSCs play important roles in normal brain function and neural
repair following injury. However, little information is known about how a quiescent NSC
becomes activated in order to perform these functions. The general objective of this project was
to investigate the mechanisms underlying activation of neural stem cells in the adult central
nervous system. My specific aims were to address this question using adult mice in two
complementary models: 1) activation of hippocampal NSCs by environmental enrichment, and
2) activation of spinal cord NSCs by injury-induced neuroinflammation. Moreover, 3) to gain
new insights into the molecular mechanisms of these models, we will perform transcriptomics
studies to open new lines of investigation.
The first project is expected to provide us with new insights into the basic cellular and
molecular mechanisms through which environmental enrichment modulates adult brain
plasticity. We first evaluated the contribution of individual environmental enrichment
components to hippocampal neurogenesis (Chapter II). Voluntary exercise promotes
neurogenesis, whereas a social context increases neuronal activation. We then determined the
effect of these components on behavioural performances and transcriptome using an eight-arm
radial maze to assess spatial memory, novel object recognition, and RNA-Seq, respectively
(Chapter III). Runners show stronger spatial short-term memory recall, whereas mice exposed
to social interactions had a better cognitive flexibility to abandon old memory. Surprisingly,
RNA-Seq analysis indicated clear differences in the expression of modified transcripts between
low runners and high runners, as well as for social interacting mice (within the complex
environment).
The second project consists of discovering how ependymal cells acquire NSC properties
in vitro or multipotentiality following lesions in vivo. A RNA-Seq analysis revealed that the
transforming growth factor-ÎČ1 (TGF-ÎČ1) acts as an upstream regulator of significant changes
following spinal cord injury (Chapter IV). We therefore confirmed the presence of this cytokine
after lesion and investigated its role on proliferation, differentiation, and survival of
neurosphere-initiating cells from the spinal cord. Our results suggest that TGF-ÎČ1 regulates the
acquisition and expression of stem cell properties of spinal cord-derived ependymal cells
Sexual and relationship intimacy among women with provoked vestibulodynia and their partners : associations with sexual satisfaction, sexual function, and pain self-efficacy
Introduction
Provoked vestibulodynia (PVD) is the most frequent subtype of vulvodynia. Women report negative consequences of PVD on their sexual and romantic relationships. Researchers have recently highlighted the importance of examining interpersonal factors such as intimacy, and of including both women and their partners in study designs.
Aim
The aim of this study was to investigate sexual and relationship intimacy as defined by the Interpersonal Process Model of Intimacy and their associations with sexual satisfaction, sexual function, pain self-efficacy, and pain intensity among women with PVD and their partners.
Methods
Ninety-one heterosexual women (M ageâ=â27.38, SDâ=â6.04) diagnosed with PVD and their partners (M ageâ=â29.37, SDâ=â7.79) completed measures of sexual and relationship intimacy, sexual satisfaction, sexual function, pain self-efficacy, and pain intensity.
Main Outcome Measures
Dependent measures were the (i) Global Measure of Sexual Satisfaction Scale; (ii) Female Sexual Function Index; (iii) Painful Intercourse Self-Efficacy Scale; and (iv) visual analog scale of pain intensity during intercourse.
Results
After controlling for women's age, women's greater sexual intimacy (ÎČâ=â0.49, Pâ<â0.001) was associated with women's greater sexual satisfaction and higher pain self-efficacy (ÎČâ=â0.39, Pâ=â0.001), beyond the effects of partnersâ sexual intimacy. Also, women's greater sexual intimacy (ÎČâ=â0.24, Pâ=â0.05) and women's greater relationship intimacy (ÎČâ=â0.54, Pâ=â0.003) were associated with greater women's sexual function, beyond the effects of partnersâ sexual and relationship intimacy.
Conclusions
Women's self-reported sexual and relationship intimacy in the couple relationship may promote higher sexual satisfaction, sexual function, and pain self-efficacy, as well as possibly foster greater sexual well-being among women with PVD. The authors discuss implications for the inclusion of emotional and interpersonal aspects of the couple's dynamic in clinical interventions and future research in PVD
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Tracers of physical and biogeochemical processes, past changes and ongoing anthropogenic impacts: the 43rd International Liege Colloquium on Ocean Dynamics, Liege, Belgium, May 2-6, 2011
The 43rd International Liege Colloquium on Ocean Dynamics (http://modb.oce.ulg.ac.be/colloquium/) gathered a hundred scientists from around the world to discuss new developments and insights related to tracers and proxies (from temperature and salinity to gases and isotopes) with a particular attention on the use of Trace Elements and Isotopes (TEI) as tracers. The colloquium was organized in connection with the Geotraces program (an ongoing international study of the global marine biogeochemical cycles of trace elements and their isotopes, http://www.geotraces.org/) and was the occasion to present the wealth of data collected during large oceanographic expeditions that occurred in connection with the International Polar year. In this framework, particular emphasis was given to the BONUS-GoodHope project, a multi-disciplinary oceanographic cruise that coupled full-depth ocean and atmosphere physical and biogeochemical observations, including trace metals and isotopes (Speich et al. 2013; Speich et al. 2008). The special issue presents a collection of papers dealing with these different thematics
Relations entre profils identitaires et profils motivationnels au lycée
International audienceLes annĂ©es lycĂ©es correspondent aux annĂ©es importantes en termes d'explorations et de choix dans des domaines qui comptent pour la construction identitaire (qui suis-je, qu'est-ce que je vaux, oĂč vais-je ? etc). La motivation intrinsĂšque ou l'autodĂ©termination (intĂ©gration d'une rĂ©gulation externe de la motivation) des Ă©lĂšves sont des facteurs de rĂ©ussite scolaire (Vallerand, Fortier & Guay (1997). De nombreux travaux menĂ©s auprĂšs de lycĂ©ens ou de collĂ©giens ont Ă©tudiĂ©s la prĂ©sence de profils d'Ă©lĂšves autodĂ©terminĂ©s ou non autodĂ©terminĂ©s (Ratelle, Guay, Vallerand, Larose et Senecal, 2007). Dans le cadre d'une Ă©tude exploratoire, notre objectif est de dĂ©finir chez les lycĂ©ens des profils motivationnels et d'Ă©tudier la façon dont ceux-ci se caractĂ©risent du point de vue des statuts identitaires et du niveau d'autodĂ©termination. L'Ă©chantillon de population est constituĂ© de 427 lycĂ©ens scolarisĂ©s en Terminale dans des Ă©tablissements des villes de Toulouse, Bordeaux et Grenoble (moyenne d'Ăąge =16.84, ET= .87 ; 62.3% filles). Les dimensions identitaires sont Ă©valuĂ©es Ă partir de la version française de la DIDS (Dimension of Identity Development Scale - Luyckx et al., 2008) validĂ©e par notre Ă©quipe (Zimmermann et al., EARA 2012) et les profils motivationnels Ă partir de l'Ă©chelle de motivation dans les Ă©tudes (EME-U28) de Vallerand et al. (1989). A partir d'une analyse en clusters nous identifions 4 profils allant de la motivation complĂšte Ă l'a-motivation. Le croisement entre les profils motivationnels et le genre et les profils identitaires (statuts et processus) montrent des associations significatives. Par exemple, les garçons et les identitĂ©s diffuses (en particulier les diffus insouciants) se retrouvent plutĂŽt dans la classe des amotivĂ©s. Le croisement des clusters motivationnels et identitaires, en nous permettant de disposer Ă la fois des caractĂ©ristiques de la motivation, de l'identitĂ© et du genre, nous amĂšne Ă identifier des profils d'Ă©lĂšves Ă risque de dĂ©crochage
Beneficial effects of reconstituted high-density lipoprotein (rHDL) on circulating CD34+ cells in patients after an acute coronary syndrome
Background:
High-density lipoproteins (HDL) favorably affect endothelial progenitor cells (EPC). Circulating progenitor cell level and function are impaired in patients with acute coronary syndrome (ACS). This study investigates the short-term effects of reconstituted HDL (rHDL) on circulating progenitor cells in patients with ACS.
Methods and Findings:
The study population consisted of 33 patients with recent ACS: 20 patients from the ERASE trial (randomized to receive 4 weekly intravenous infusions of CSL-111 40 mg/kg or placebo) and 13 additional patients recruited as controls using the same enrolment criteria. Blood was collected from 16 rHDL (CSL-111)-treated patients and 17 controls at baseline and at 6â7 weeks (i.e. 2â3 weeks after the fourth infusion of CSL-111 in ERASE). CD34+ and CD34+/kinase insert domain receptor (KDR+) progenitor cell counts were analyzed by flow cytometry. We found preserved CD34+ cell counts in CSL-111-treated subjects at follow-up (change of 1.6%), while the number of CD34+ cells was reduced (-32.9%) in controls (p = 0.017 between groups). The level of circulating SDF-1 (stromal cell-derived factor-1), a chemokine involved in progenitor cell recruitment, increased significantly (change of 21.5%) in controls, while it remained unchanged in CSL-111-treated patients (p = 0.031 between groups). In vitro exposure to CSL-111 of early EPC isolated from healthy volunteers significantly increased CD34+ cells, reduced early EPC apoptosis and enhanced their migration capacity towards SDF-1.
Conclusions:
The relative increase in circulating CD34+ cells and the low SDF-1 levels observed following rHDL infusions in ACS patients point towards a role of rHDL in cardiovascular repair mechanisms
Erythrocyte phospholipid and polyunsaturated fatty acid composition in diabetic retinopathy
Background: Long chain polyunsaturated fatty acids (LCPUFAs) including docosahexaenoic acid and arachidonic acid are suspected to play a key role in the pathogenesis of diabetes. LCPUFAs are known to be preferentially concentrated in specific phospholipids termed as plasmalogens. This study was aimed to highlight potential changes in the metabolism of phospholipids, and particularly plasmalogens, and LCPUFAs at various stages of diabetic retinopathy in humans. Methodology and Principal Findings: We performed lipidomic analyses on red blood cell membranes from controls and mainly type 2 diabetes mellitus patients with or without retinopathy. The fatty acid composition of erythrocytes was determined by gas chromatography and the phospholipid structure was determined by liquid chromatography equipped with an electrospray ionisation source and coupled with a tandem mass spectrometer (LC-ESI-MS/MS). A significant decrease in levels of docosahexaenoic acid and arachidonic acid in erythrocytes of diabetic patients with or without retinopathy was observed. The origin of this decrease was a loss of phosphatidyl-ethanolamine phospholipids esterified with these LCPUFAs. In diabetic patients without retinopathy, this change was balanced by an increase in the levels of several phosphatidyl-choline species. No influence of diabetes nor of diabetic retinopathy was observed on the concentrations of plasmalogen-type phospholipids. Conclusions and Significance: Diabetes and diabetic retinopathy were associated with a reduction of erythrocyte LCPUFAs in phosphatidyl-ethanolamines. The increase of the amounts of phosphatidyl-choline species in erythrocytes of diabetic patients without diabetic retinopathy might be a compensatory mechanism for the loss of LC-PUFA-rich phosphatidyl-ethanolamines
Treatment patterns in older patients with locally advanced head and neck squamous cell carcinoma:Results from an EORTC led survey
OBJECTIVES: We aimed to assess patterns of care delivered to older patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC), and to analyze the use of geriatric assessment (GA) and assessment of quality of life (QoL).MATERIALS AND METHODS: Members of the head and neck cancer group and the older task force of the European Organisation for Research and Treatment of Cancer (EORTC), members the European Head and Neck Society and members of national groups in Europe were asked to complete a questionnaire about treatment delivered, use of GA, and QoL assessment in older patients with LA-HNSCC.RESULTS: Investigators from 111 centers replied, including 90 (81.1%) academic centers, 16 (14.4%) community hospitals, and 5 (4.5%) private clinics. Large differences in treatment patterns were found. For instance, for oropharyngeal carcinoma, one third of the centers indicated that they treat <5% of older patients with chemoradiation, while 18 centers (16.2%) treat >40% of older patients with chemoradiation. Fourteen centers (12.6%) routinely perform GA, while 43 centers (38.7%) never do, and 39 centers (35.1%) sometimes do. QoL is assessed on a routine basis in one fifth of the centers.CONCLUSIONS: Large differences exist across institutions in the patterns of care delivered to older patients with LA-HNSCC. Prospective studies are required to learn how GA can guide treatment decisions, and how QoL and treatment outcome can be improved. For that, consensus on standard of care is essential.</p
Germline mutation in the RAD51B gene confers predisposition to breast cancer.
International audienceBACKGROUND: Most currently known breast cancer predisposition genes play a role in DNA repair by homologous recombination. Recent studies conducted on RAD51 paralogs, involved in the same DNA repair pathway, have identified rare germline mutations conferring breast and/or ovarian cancer predisposition in the RAD51C, RAD51D and XRCC2 genes. The present study analysed the five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3) to estimate their contribution to breast and ovarian cancer predisposition. METHODS: The study was conducted on 142 unrelated patients with breast and/or ovarian cancer either with early onset or with a breast/ovarian cancer family history. Patients were referred to a French family cancer clinic and had been previously tested negative for a BRCA1/2 mutation. Coding sequences of the five genes were analysed by EMMA (Enhanced Mismatch Mutation Analysis). Detected variants were characterized by Sanger sequencing analysis. RESULTS: Three splicing mutations and two likely deleterious missense variants were identified: RAD51B c.452 + 3A > G, RAD51C c.706-2A > G, RAD51C c.1026 + 5_1026 + 7del, RAD51B c.475C > T/p.Arg159Cys and XRCC3 c.448C > T/p.Arg150Cys. No RAD51D and XRCC2 gene mutations were detected. These mutations and variants were detected in families with both breast and ovarian cancers, except for the RAD51B c.475C > T/p.Arg159Cys variant that occurred in a family with 3 breast cancer cases. CONCLUSIONS: This study identified the first RAD51B mutation in a breast and ovarian cancer family and is the first report of XRCC3 mutation analysis in breast and ovarian cancer. It confirms that RAD51 paralog mutations confer breast and ovarian cancer predisposition and are rare events. In view of the low frequency of RAD51 paralog mutations, international collaboration of family cancer clinics will be required to more accurately estimate their penetrance and establish clinical guidelines in carrier individuals
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