Mechanisms underlying activation of neural stem cells in the adult central nervous system

À la fin du 19e siècle, Dr. Ramón y Cajal, un pionnier scientifique, a découvert les éléments cellulaires individuels, appelés neurones, composant le système nerveux. Il a également remarqué la complexité de ce système et a mentionné l’impossibilité de ces nouveaux neurones à être intégrés dans le système nerveux adulte. Une de ses citations reconnues : “Dans les centres adultes, les chemins nerveux sont fixes, terminés, immuables. Tout doit mourir, rien ne peut être régénérer” est représentative du dogme de l’époque (Ramón y Cajal 1928). D’importantes études effectuées dans les années 1960-1970 suggèrent un point de vue différent. Il a été démontré que les nouveaux neurones peuvent être générés à l’âge 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 neurogenèse 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 latéraux et le gyrus dentelé de l’hippocampe. En condition physiologique, le niveau de neurogenèse est relativement élevé dans la zone sous-ventriculaire contrairement à l’hippocampe où certaines étapes sont limitantes. En revanche, la moelle épinière est plutôt 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 d’augmenter les niveaux de neurogenèse ? Dans l’hippocampe, la capacité de l’environnement enrichi (incluant la stimulation cognitive, l’exercice et les interactions sociales) à promouvoir la neurogenèse hippocampale a déjà été démontrée. La plasticité de cette région est importante, car elle peut jouer un rôle clé dans la récupération de déficits au niveau de la mémoire et l’apprentissage. Dans la moelle épinière, des études effectuées in vitro ont démontré que les cellules épendymaires situées autour du canal central ont des capacités d’auto-renouvellement et de multipotence (neurones, astrocytes, oligodendrocytes). Il est intéressant de noter qu’in vivo, suite à une lésion de la moelle épinière, les cellules épendymaires sont activées, peuvent s’auto-renouveller, mais peuvent seulement ii donner naissance à 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 être exploité afin de développer des stratégies de réparation endogènes dans la moelle épinière. Les CSNs adultes jouent un rôle 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 général est d'élucider les mécanismes sous-jacents à l'activation des CSNs dans le système 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 épinière par la neuroinflammation suite à une lésion. De plus, 3) afin d’obtenir plus d’information sur les mécanismes moléculaires de ces modèles, nous utiliserons des approches transcriptomiques afin d’ouvrir de nouvelles perspectives. Le premier projet consiste à établir de nouveaux mécanismes cellulaires et moléculaires à travers lesquels l’environnement enrichi module la plasticité du cerveau adulte. Nous avons tout d’abord évalué la contribution de chacune des composantes de l’environnement enrichi à la neurogenèse hippocampale (Chapitre II). L’exercice volontaire promeut la neurogenèse, tandis que le contexte social augmente l’activation neuronale. Par la suite, nous avons déterminé l’effet de ces composantes sur les performances comportementales et sur le transcriptome à l’aide d’un labyrinthe radial à huit bras afin d’évaluer la mémoire spatiale et un test de reconnaissante d’objets nouveaux ainsi qu’un 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. Étonnamment, l’analyse du RNA-Seq a permis d’identifier des différences claires dans l’expression des transcripts entre les coureurs de courte et longue distance, en plus des souris sociales (dans l’environnement complexe). iii Le second projet consiste à découvrir comment les cellules épendymaires acquièrent les propriétés des CSNs in vitro ou la multipotence suite aux lésions in vivo (Chapitre IV). Une analyse du RNA-Seq a révélé que le transforming growth factor-β1 (TGF-β1) agit comme un régulateur, en amont des changements significatifs suite à une lésion de la moelle épinière. Nous avons alors confirmé la présence de cette cytokine suite à la lésion et caractérisé son rôle sur la prolifération, différentiation, et survie des cellules initiatrices de neurosphères de la moelle épinière. Nos résultats suggèrent que TGF-β1 régule l’acquisition et l’expression des propriétés de cellules souches sur les cellules épendymaires provenant de la moelle épinière.

2012 ANNUAL REPORT JOINT CITIZENS AND LEGISLATIVE COMMITTEE ON CHILDREN EXECUTIVE SUMMARY

The South Carolina Joint Citizens and Legislative Committee on Children publishes an annual report for the governor and the General Assembly with information on topics of concern about the well-being of children in the state and policy recommendations. The Annual Report contains selected data which present a compelling overview of those children in need and more specifically focuses on the children who have been placed in the custody of the State. Central to this theme are services for child protection and welfare, juvenile justice, and mental health.

Corporate governance in european transition economies: Emerging models

The purpose of this paper is to contribute to the debate on corporate governance models in European transition economies. The paper consists of four parts. After a historic overview of the evolution of corporate governance, the introduction presents various understandings of the corporate governance function and describes current issues in corporate governance. Part two deals with governance systems in the (mainly domestically) privatized former state-owned companies in Central European transition countries, with the main types of company ownership structures, relationships between governing and management functions, and deficiencies in existing governance systems. Part three is dedicated to the analysis of factors that determine the efficiency of the relationship between the corporate governance and management functions in Central European transition economies. It deals with the issue of why the German (continental European) governance model is usually the preferred choice and why the chosen models underperform. In the conclusion the author offers his suggestions on how the Central European transition countries should improve their corporate governance in the future.

"The post-antibiotic apocalypse" and the "war on superbugs": catastrophe discourse in microbiology, its rhetorical form and political function

Discourses evoking an antibiotic apocalypse and a war on superbugs are emerging just at a time when so-called "catastrophe discourses" are undergoing critical and reflexive scrutiny in the context of global warming and climate change. This article combines insights from social science research into climate change discourses with applied metaphor research based on recent advances in cognitive linguistics, especially with relation to "discourse metaphors." It traces the emergence of a new apocalyptic discourse in microbiology and health care, examines its rhetorical and political function and discusses its advantages and disadvantages. It contains a reply by the author of the central discourse metaphor, "the post-antibiotic apocalypse," examined in the article.

RATE OF CONVERGENCE OF MAXIMUM LIKELIHOOD ESTIMATORS UNDER RELAXED SMOOTHNESS CONDITIONS ON THE LIKELIHOOD FUNCTION

This report reviews literature on the rate of convergence of maximum likelihood estimators and establishes a Central Limit Theorem, which yields an O(1/sqrt(n)) rate of convergence of the maximum likelihood estimator under somewhat relaxed smoothness conditions. These conditions include the existence of a one-sided derivative in θ of the pdf, compared to up to three that are classically required. A verification through simulation is included in the end of the report.

Effects of radiation therapy on the structure and function of the pelvic floor muscles of patients with cancer in the pelvic area : a systematic review

Purpose Radiation therapy (RT) is often recommended in the treatment of pelvic cancers. Following RT, a high prevalence of pelvic floor dysfunctions (urinary incontinence, dyspareunia, and fecal incontinence) is reported. However, changes in pelvic floor muscles (PFMs) after RT remain unclear. The purpose of this review was to systematically document the effects of RT on the PFM structure and function in patients with cancer in the pelvic area. Methods An electronic literature search using Pubmed Central, CINAHL, Embase, and SCOPUS was performed from date of inception up to June 2014. The following keywords were used: radiotherapy, muscle tissue, and pelvic floor. Two reviewers selected the studies in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA). Out of the 369 articles screened, 13 met all eligibility criteria. The methodological quality was assessed using the QualSyst scoring system, and standardized mean differences were calculated. Results Thirteen studies fulfilled all inclusion criteria, from which four were of good methodological quality. One presented strong evidence that RT affects PFM structure in men treated for prostate cancer. Four presented high-level evidence that RT affects PFM function in patients treated for rectal cancer. Meta-analysis was not possible due to heterogeneity and lack of descriptive statistics. Conclusion There is some evidence that RT has detrimental impacts on both PFMs’ structure and function. Implications for cancer survivors A better understanding of muscle damage and dysfunction following RT treatment will improve pelvic floor rehabilitation and, potentially, prevention of its detrimental impacts.

The relationship between changes in cardiovascular function and changes in VO2peak following SIT

Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2016-09-27 19:34:16.86

A Grammar of Tajio. A Language Spoken in Central Sulawesi

This work is a description of Tajio, a Western Malayo-Polynesian language spoken in Central Sulawesi, Indonesia. It covers the essential aspects of Tajio grammar without being exhaustive. Tajio has a medium sized phoneme inventory consisting of twenty consonants and five vowels. The language does not have lexical (word) stress; rather, it has a phrasal accent. This phrasal accent regularly occurs on the penultimate syllable of an intonational phrase, rendering this syllable auditorily prominent through a pitch rise. Possible syllable structures in Tajio are (C)V(C). CVN structures are allowed as closed syllables, but CVN syllables in word-medial position are not frequent. As in other languages in the area, the only sequence of consonants allowed in native Tajio words are sequences of nasals followed by a homorganic obstruent. The homorganic nasal-obstruent sequences found in Tajio can occur word-initially and word-medially but never in word-final position. As in many Austronesian languages, word class classification in Tajio is not straightforward. The classification of words in Tajio must be carried out on two levels: the morphosyntactic level and the lexical level. The open word classes in Tajio consist of nouns and verbs. Verbs are further divided into intransitive verbs (dynamic intransitive verbs and statives) and dynamic transitive verbs. Based on their morphological potential, lexical roots in Tajio fall into three classes: single-class roots, dual-class roots and multi-class roots. There are two basic transitive constructions in Tajio: Actor Voice and Undergoer Voice, where the actor or undergoer argument respectively serves as subjects. It shares many characteristics with symmetrical voice languages, yet it is not fully symmetric, as arguments in AV and UV are not equally marked. Neither subjects nor objects are marked in AV constructions. In UV constructions, however, subjects are unmarked while objects are marked either by prefixation or clitization. Evidence from relativization, control and raising constructions supports the analysis that AV and UV are in fact transitive, with subject arguments and object arguments behaving alike in both voices. Only the subject can be relativized, controlled, raised or function as the implicit subject of subjectless adverbial clauses. In contrast, the objects of AV and UV constructions do not exhibit these features. Tajio is a predominantly head-marking language with basic A-V-O constituent order. V and O form a constituent, and the subject can either precede or follow this complex. Thus, basic word order is S-V-O or V-O-S. Subject, as well as non-subject arguments, may be omitted when contextually specified. Verbs are marked for voice and mood, the latter of which is is obligatory. The two values distinguished are realis and non-realis. Depending on the type of predicate involved in clause formation, three clause types can be distinguished: verbal clauses, existential clauses and non-verbal clauses. Tajio has a small number of multi-verbal structures that appear to qualify as serial verb constructions. SVCs in Tajio always include a motion verb or a directional.

Effects of radiation therapy on the structure and function of the pelvic floor muscles of patients with cancer in the pelvic area : a systematic review

Purpose Radiation therapy (RT) is often recommended in the treatment of pelvic cancers. Following RT, a high prevalence of pelvic floor dysfunctions (urinary incontinence, dyspareunia, and fecal incontinence) is reported. However, changes in pelvic floor muscles (PFMs) after RT remain unclear. The purpose of this review was to systematically document the effects of RT on the PFM structure and function in patients with cancer in the pelvic area. Methods An electronic literature search using Pubmed Central, CINAHL, Embase, and SCOPUS was performed from date of inception up to June 2014. The following keywords were used: radiotherapy, muscle tissue, and pelvic floor. Two reviewers selected the studies in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA). Out of the 369 articles screened, 13 met all eligibility criteria. The methodological quality was assessed using the QualSyst scoring system, and standardized mean differences were calculated. Results Thirteen studies fulfilled all inclusion criteria, from which four were of good methodological quality. One presented strong evidence that RT affects PFM structure in men treated for prostate cancer. Four presented high-level evidence that RT affects PFM function in patients treated for rectal cancer. Meta-analysis was not possible due to heterogeneity and lack of descriptive statistics. Conclusion There is some evidence that RT has detrimental impacts on both PFMs’ structure and function. Implications for cancer survivors A better understanding of muscle damage and dysfunction following RT treatment will improve pelvic floor rehabilitation and, potentially, prevention of its detrimental impacts.

On polynomials with given Hilbert function and applications

Using Macaulay's correspondence we study the family of Artinian Gorenstein local algebras with fixed symmetric Hilbert function decomposition. As an application we give a new lower bound for the dimension of cactus varieties of the third Veronese embedding. We discuss the case of cubic surfaces, where interesting phenomena occur.

Erythropoietin reduces pathogenic humoral immunity by inhibiting T Follicular Helper cell differentiation and function

A large fraction of organ transplant recipients develop anti-donor antibodies (DSA), with accelerated graft loss and increased mortality. We tested the hypothesis that erythropoietin (EPO) reduces DSA formation by inhibiting T follicular helper (TFH) cells. We measured DSA levels, splenic TFH, TFR cells, germinal center (GC), and class switched B cells, in murine models of allogeneic sensitization, allogeneic transplantation and in parent-to-F1 models of graft versus host disease (GVHD). We quantified the same cell subsets and specific antibodies, upon EPO or vehicle treatment, in wild type mice and animals lacking EPO receptor selectively on T or B cells, immunized with T-independent or T-dependent stimuli. In vitro, we tested the EPO effect on TFH induction. We isolated TFH and TFR cells to perform in vitro assay and clarify their role. EPO reduced DSA levels, GC, class switched B cells, and increased the TFR/TFH ratio in the heart transplanted mice and in two GVHD models. EPO did also reduce TFH and GC B cells in SRBC-immunized mice, while had no effect in TNP-AECM-FICOLL-immunized animals, indicating that EPO inhibits GC B cells by targeting TFH cells. EPO effects were absent in T cells EPOR conditional KO mice, confirming that EPO affects TFH in vivo through EPOR. In vitro, EPO affected TFH induction through an EPO-EPOR-STAT5-dependent pathway. Suppression assay demonstrated that the reduction of IgG antibodies was dependent on TFH cells, sustaining the central role of the subset in this EPO-mediated mechanism. In conclusion, EPO prevents DSA formation in mice through a direct suppression of TFH. Development of DSA is associated with high risk of graft rejection, giving our data a strong rationale for studies testing the hypothesis that EPO administration prevents their formation in organ transplant recipients. Our findings provide a foundation for testing EPO as a treatment of antibody mediated disease processes.

Analytic models of self-gravitating rotating gaseous tori with central black hole

In this thesis project, I present stationary models of rotating fluids with toroidal distributions that can be used to represent the active galactic nuclei (AGN) central obscurers, i.e. molecular tori (Combes et al., 2019), as well as geometrically thick accretion discs, like ADAF discs (Narayan and Yi, 1995) or Polish doughnuts (Abramowicz, 2005). In particular, I study stationary rotating systems with a more general baroclinic distribution (with a vertical gradient of the angular velocity), which are often more realistic and less studied, due to their complexity, than the barotropic ones (with cylindrical rotation), which are easier to construct. In the thesis, I compute analytically the main intrinsic and projected properties of the power-law tori based on the potential-density pairs of Ciotti and Bertin (2005). I study the density distribution and the resulting gravitational potential for different values of α, in the range 2 < α < 5. For the same models, I compute the surface density of the systems when seen face-on and edge-on. I then apply the stationary Euler equations to obtain rotational velocity and temperature distributions of the self-gravitating models in the absence of an external gravitational potential. In the thesis I also consider the power-law tori with the presence of a central black hole in addition to the gas self-gravity, and solving analytically the stationary Euler equations, I compute how the properties of the system are modified by the black hole and how they vary as a function of the black hole mass. Finally, applying the Solberg-Høiland criterion, I show that these baroclinic stationary models are linearly stable in the absence of the black hole. In the presence of the black hole I derive the analytical condition for stability, which depends on α and on the black hole mass. I also study the stability of the tori in the hypothesis that they are weakly magnetized, finding that they are always unstable to this instability.

Relationship Between Orofacial Function, Dentofacial Morphology, And Bite Force In Young Subjects.

The aim was to evaluate the relationship between orofacial function, dentofacial morphology, and bite force in young subjects. Three hundred and sixteen subjects were divided according to dentition stage (early, intermediate, and late mixed and permanent dentition). Orofacial function was screened using the Nordic Orofacial Test-Screening (NOT-S). Orthodontic treatment need, bite force, lateral and frontal craniofacial dimensions and presence of sleep bruxism were also assessed. The results were submitted to descriptive statistics, normality and correlation tests, analysis of variance, and multiple linear regression to test the relationship between NOT-S scores and the studied independent variables. The variance of NOT-S scores between groups was not significant. The evaluation of the variables that significantly contributed to NOT-S scores variation showed that age and presence of bruxism related to higher NOT-S total scores, while the increase in overbite measurement and presence of closed lip posture related to lower scores. Bite force did not show a significant relationship with scores of orofacial dysfunction. No significant correlations between craniofacial dimensions and NOT-S scores were observed. Age and sleep bruxism were related to higher NOT-S scores, while the increase in overbite measurement and closed lip posture contributed to lower scores of orofacial dysfunction.

Impaired Compensatory Beta-cell Function And Growth In Response To High-fat Diet In Ldl Receptor Knockout Mice.

In this study, we investigated the effect of low density lipoprotein receptor (LDLr) deficiency on gap junctional connexin 36 (Cx36) islet content and on the functional and growth response of pancreatic beta-cells in C57BL/6 mice fed a high-fat (HF) diet. After 60 days on regular or HF diet, the metabolic state and morphometric islet parameters of wild-type (WT) and LDLr-/- mice were assessed. HF diet-fed WT animals became obese and hypercholesterolaemic as well as hyperglycaemic, hyperinsulinaemic, glucose intolerant and insulin resistant, characterizing them as prediabetic. Also they showed a significant decrease in beta-cell secretory response to glucose. Overall, LDLr-/- mice displayed greater susceptibility to HF diet as judged by their marked cholesterolaemia, intolerance to glucose and pronounced decrease in glucose-stimulated insulin secretion. HF diet induced similarly in WT and LDLr-/- mice, a significant decrease in Cx36 beta-cell content as revealed by immunoblotting. Prediabetic WT mice displayed marked increase in beta-cell mass mainly due to beta-cell hypertrophy/replication. Nevertheless, HF diet-fed LDLr-/- mice showed no significant changes in beta-cell mass, but lower islet-duct association (neogenesis) and higher beta-cell apoptosis index were seen as compared to controls. The higher metabolic susceptibility to HF diet of LDLr-/- mice may be explained by a deficiency in insulin secretory response to glucose associated with lack of compensatory beta-cell expansion.

Long-term Postoperative Atrophy Of Contralateral Hippocampus And Cognitive Function In Unilateral Refractory Mtle With Unilateral Hippocampal Sclerosis.

This study aimed to evaluate long-term atrophy in contralateral hippocampal volume after surgery for unilateral MTLE, as well as the cognitive outcome for patients submitted to either selective transsylvian amygdalohippocampectomy (SelAH) or anterior temporal lobe resection (ATL). We performed a longitudinal study of 47 patients with MRI signs of unilateral hippocampal sclerosis (23 patients with right-sided hippocampal sclerosis) who underwent surgical treatment for MTLE. They underwent preoperative/postoperative high-resolution MRI as well as neuropsychological assessment for memory and estimated IQ. To investigate possible changes in the contralateral hippocampus of patients, we included 28 controls who underwent two MRIs at long-term intervals. The volumetry using preoperative MRI showed significant hippocampal atrophy ipsilateral to the side of surgery when compared with controls (p<0.0001) but no differences in contralateral hippocampal volumes. The mean postoperative follow-up was 8.7 years (± 2.5 SD; median=8.0). Our patients were classified as Engel I (80%), Engel II (18.2%), and Engel III (1.8%). We observed a small but significant reduction in the contralateral hippocampus of patients but no volume changes in controls. Most of the patients presented small declines in both estimated IQ and memory, which were more pronounced in patients with left TLE and in those with persistent seizures. Different surgical approaches did not impose differences in seizure control or in cognitive outcome. We observed small declines in cognitive scores with most of these patients, which were worse in patients with left-sided resection and in those who continued to suffer from postoperative seizures. We also demonstrated that manual volumetry can reveal a reduction in volume in the contralateral hippocampus, although this change was mild and could not be detected by visual analysis. These new findings suggest that dynamic processes continue to act after the removal of the hippocampus, and further studies with larger groups may help in understanding the underlying mechanisms.