Chronic denervation and chronic axotomy present independent barriers for axonal regeneration. Chronic denervation occurs when nerves are no longer connected to their neuronal cell bodies; chronic axotomy occurs when neurons are not connected to their targets for prolonged periods of time. The harmful effects of chronic denervation can be addressed by the side-to-side bridge surgical technique. Additionally, the negative effects of chronic axotomy can be reversed by GDNF delivery to the nerve. The experiments in this thesis were designed to evaluate nerve regeneration in a rat model of chronic injury after treatment with local GDNF delivery, side to-side bridge protection, or both. The GDNF delivery system consisted of poly(lactic-co-glycolic acid) microspheres embedded in fibrin for controlled delivery of GDNF. Overall, the side-to-side bridges technique was effective in protecting against the negative effects of chronic denervation regardless of treatment with or without GDNF. Local delivery of GDNF did not increase axonal regeneration or functional recovery.

No description available.

The evolution, development and function of the embryonic and larval peripheral nervous system (PNS) were investigated in a number of dipteran species, including Aedes aegypti, Hermetia pallescens, Lucilia cuprina, Bactrocera tryoni and Drosophila melanogaster. Comparative immuno-cytochemical data was generated for developmental proteins in the embryonic PNS and degenerative PCR was employed to identify homologous proneural genes amongst the species. Immunocytochemistry revealed aspects of sense-organ evolution amongst the Diptera, particularly an increase in sense-cell number and number of sensilla comprising proprioceptive organs in the crawling versus swimming larvae. The function of putative proprioceptive cells was investigated via mutant analysis and laser ablation. Results indicate that the multiple-dendrite (md) and bipolar-dendrite (bd) neurons contribute in a cumulative and roughly equal fashion to maintain peristaltic waves in crawling larvae. This work highlights the usefulness of the dipteran PNS as a model of adaptive evolution that can be investigated via developmental mechanisms.

Les gènes RUNX1 et CBFB codent pour les sous-unités du core binding factor (CBF), facteur de transcription hétérodimérique essentiel de l’hématopoïèse définitive. La dérégulation du CBF est l'une des anomalies les plus fréquemment rencontrées dans les hémopathies malignes. Puisque la perturbation seule du CBF est insuffisante au développement d’une leucémie aiguë myéloïde (LAM), les LAM impliquant le CBF sont considérées comme des modèles de leucémogénèse multi-étapes, nécessitant la coopération d’anomalies génétiques additionnelles.Dans ce travail, nous nous sommes intéressés aux LAM de type CBF, caractérisées soit par une t(8;21)/fusion RUNX1-RUNX1T1 soit par une inv(16)/fusion CBFB-MYH11, ainsi qu’aux LAM avec mutations germinales de RUNX1 (définissant la thrombopénie familiale avec prédisposition aux leucémies aiguës ou FPD/AML). Afin d’identifier des anomalies additionnelles, nous avons étudié les prélèvements de patients atteints de LAM CBF inclus dans les essais français ELAM02 (0-18 ans) et CBF2006 (18-60 ans) par séquençage à haut débit (n=215) et single nucleotide polymorphism-array (n=198). Les échantillons de 25 individus atteints de FPD/AML (issus de 15 familles), diagnostiqués entre 2005 et 2014, ont également été séquencés au stade thrombopénique et au moment de la transformation en leucémie aiguë.Dans les LAM CBF, les mutations activatrices des voies tyrosines kinases (TK) sont les événements les plus fré-quents quel que soit le sous-type de LAM CBF [t(8;21) ou inv(16)], comme cela a déjà été rapporté dans d’autres études. En revanche, les mutations affectant les gènes du remodelage chromatinien ou du complexe de la cohésine sont identifiées à des fréquences élevées (41% et 18% respectivement) dans les LAM avec t(8;21) tandis qu’elles sont pratiquement absentes dans les LAM avec inv(16). Dans les LAM avec t(8;21), la coexistence de ces mutations avec les mutations de type TK est associée à un pronostic défavorable suggérant une synergie entre ces événements. D'autres événements fréquemment retrouvés incluent les mutations de ZBTB7A et DHX15 dans les LAM avec t(8;21) (20% et 6% respectivement) et les délétions/mutations de FOXP1 dans les LAM avec inv(16) (7%). Enfin, nous avons décrit la perturbation de CCDC26 comme une possible lésion associée à une signalisation aberrante des TK dans les LAM CBF (4,5% des cas).Dans les FPD/AML, l'analyse mutationnelle a révélé l'acquisition d'un deuxième événement impliquant RUNX1 chez tous les patients ayant développé une LAM. Ce deuxième événement correspondait soit à une mutation somatique du second allèle de RUNX1 soit à la duplication de la mutation germinale de RUNX1 (par perte d'hétérozygotie sans anomalie du nombre de copies ou trisomie 21 acquise). En pratique clinique, cela suggère que la présence de deux mutations différentes de RUNX1 ou d'une seule mutation avec un ratio allélique supérieur à 50% chez un patient atteinte de LAM doit alerter sur la possibilité d’un syndrome FPD/AML sous-jacent. / RUNX1 and CBFB encode subunits of the core binding factor (CBF), a heterodimeric transcription factor required for the establishment of definitive hematopoiesis. Deregulation of the CBF is one of the most frequent aberrations in hematological malignancies. Since CBF disruption alone is insufficient to induce acute myeloid leukemia (AML) on its own, AML with CBF involvement is considered as a model of multistep leukemogenesis requiring additional genetic aberrations.Here, we focused on acute myeloid leukemia (AML) with t(8;21)/RUNX1-RUNX1T1 fusion and AML with inv(16)/CBFB-MYH11 fusion, reported together as CBF AML, as well as AML with germline RUNX1 mutation (defining the familial platelet disorder with propensity to develop leukemia or FPD/AML).In order to explore additional genomic aberrations, we performed comprehensive genetic profiling in CBF AML patients enrolled in the French trials ELAM02 (0-18 years) and CBF2006 (18-60 years) using both high-throughput sequencing (n=215) and single nucleotide polymorphism-array (n=198). In addition, we sequenced samples from 25 individuals with FPD/AML (15 pedigrees) diagnosed between 2005 and 2014 at thrombocyto-penic stage and during leukemic progression.In CBF AML, mutations in genes activating tyrosine kinase (TK) signaling were frequent in both subtypes as previously described by others. By contrast, we found mutations in genes encoding chromatin modifiers or members of the cohesin complex with high frequencies in t(8;21) AML (41% and 18% respectively) while they were nearly absent in inv(16) AML. Interestingly, such mutations were associated with a poor prognosis in patients with TK mutations suggesting synergic cooperation between these events. Other events included ZBTB7A and DHX15 mutations in t(8;21) AML (20% and 6% respectively) and FOXP1 deletions or truncating mutations in inv(16) AML (7%). Finally, we described CCDC26 disruption as a possible new lesion associated with aberrant TK signaling in this particular subtype of leukemia (4.5% of CBF AML).In FPD/AML, mutational analysis revealed the acquisition of a second event involving RUNX1 in all patients with AML including somatic mutation of the second allele or duplication of the germline RUNX1 mutation through copy-neutral loss of heterozygosity and trisomy 21. In clinical practice, we suggest that the occurrence of two different RUNX1 mutations or a single RUNX1 mutation with a variant allele frequency higher than 50% in a patient with AML should alert about the possibility of FPD/AML.

Objectives: Depression is often unrecognised or sub-optimally treated in primary care. This has led to research exploring the barriers and enablers to effective recognition but little is known about health care professionals’ (HCPs) beliefs or personal illness models about depression in patients with long term conditions (LTCs), the presence of which may affect recognition and management. Using Leventhal’s Common Sense or Self-regulatory Model this thesis aimed to: explore HCPs’ illness representations and management in people with LTCs and depression; to understand the role of personal models and perceived barriers to depression recognition and management; and to address them in a theory-based online training intervention. Methods: This thesis was undertaken in three stages; a scoping review with narrative synthesis was conducted to explore the role of HCPs’ personal illness models of depression, a qualitative study using semi-structured interviews with 16 HCPs to investigate their illness beliefs about depression in patients with LTCs and finally, the development and feasibility assessment of a theory-based online training intervention to target HCPs’ attitudes, beliefs and self-efficacy. During this stage a new measure of HCPs’ beliefs and attitudes towards depression in patients with LTCs was developed as no appropriate measures were currently available to capture HCPs’ personal illness models of depression as a comorbid condition. Results: Twenty-seven papers were included in a mixed method scoping review. The review concluded that HCPs mainly normalised depression but lacked a complete conceptualisation of depression in primary care. HCPs reported time constraints and lack of skills as important barriers to recognising of depression in primary care. Negative attitudes towards depression and lack of confidence to recognise and manage depression were also commonly reported. In the qualitative study, the main themes were; 1) Recognition of depression in people with LTCs is complex (unclear illness identity) 2) Attitudes towards recognition and management of depression in people with LTCs act as either barriers and enablers to depression management 3) The necessary level of condition-related knowledge and understanding of depression in the context of a LTC 4) Controllability of depression in people with LTCs. The findings suggested that HCPs’ illness beliefs about depression in people with LTC varied in crucial ways with some participants prioritising the management of the LTC or expecting patients with diabetes or CHD to diagnose depression themselves due to time constraints. Some HCPs also reported simplistic views of causation which appeared to impact on their decisions whether or not to detect depression in people with LTCs. The findings of the qualitative study were used to inform the content of a novel online training intervention using illustrations to facilitate engagement. Thirty one HCPs were recruited and 15 completed the evaluation. The results of the feasibility study suggested that the method, context and mode of intervention was feasible but the lack of validated measures and the small sample size hinder conclusions about changes in participants’ illness beliefs, intentions, self-efficacy and perceived barriers towards depression. Comments: The scoping review study provided new insights into why HCPs may not engage with detection of depression but only a limited amount of research has explored HCPs’ beliefs about depression in patients with LTCs. The qualitative study addressed this and contributes new knowledge about the way HCPs conceptualise depression in patients with LTC and was used to design an online intervention to improve the management and recognition of depression in these patients. Further research to develop this intervention and evaluate it on a larger scale is needed.

Les cellules gliales qui forment les segments de myéline du système nerveux périphérique (SNP) sont appelées cellules de Schwann. Elles assurent aux nerfs un soutien fonctionnel et permettent une conduction rapide et efficace de l'influx nerveux. Cette fonction requiert une communication réciproque entre les neurones et les cellules gliales qui les entourent. Une perturbation de cette interaction entraine le plus souvent une situation pathologique comme les neuropathies périphériques dont la plus connue est la maladie de Charcot-Marie-Tooth. Cependant, les mécanismes qui conduisent à ces pathologies sont encore peu connus et leur compréhension demande au préalable l'élucidation des mécanismes physiologiques qui contrôlent le développement du SNP. Ce travail a consisté en l'analyse de nouvelles fonctions des gènes ndrg4 et elmo1, dans le développement du système nerveux périphérique, chez le poisson zèbre. Nous avons montré que ndrg4 (n-myc downstream regulated gene) est un facteur neuronal qui régule le développement de la myéline périphérique en contrôlant le regroupement des canaux sodiques aux nœuds de Ranvier et l'expression de la mbp. Ndrg4 semble moduler l'échange vésiculaire entre les axones et les cellules de Schwann, en contrôlant l'expression de certaines protéines de relargage vésiculaire comme SNAP25, membre du complexe SNARE.Ce travail décrit par ailleurs une nouvelle fonction de elmo1 (engulfment and cell motility 1) dans le développement du SNP du poisson zèbre, où il favorise la survie des neurones dans lesquels il est exprimé. Nous avons montré qu'elmo1 protège les neurones de l'apoptose et que cette fonction est contrôlée par la voie nétrine1/unc5b en amont de Rac1. De ce fait, elmo1 est requis pour le développement du ganglion de la ligne latérale postérieure et des axones qui en émergent pour donner un système nerveux fonctionnel. Ainsi, ces travaux contribuent à une meilleure connaissance du développement du SNP et élucident pour la première fois une nouvelle voie de signalisation requise pour la survie des neurones dans le SNP. / The glial cells that form myelin segments in the peripheral nervous system (PNS) are called Schwann cells (SCs). They provide functional support for nerves and allow a fast and efficient conduction of the action potentials. This requires a bilateral communication between axons and the associated glial cells. Disruption of this interaction often leads to peripheral neuropathies e.g. Charcot-Marie-Tooth disease. However, the mechanisms underlying these diseases remain poorly known and their understanding requires, at first, the elucidation of the physiological mechanisms responsible for PNS development. This work consists of a functional analysis of two genes, ndrg4 and elmo1, in the PNS development, using the zebrafish model. We showed that the neuronal factor ndrg4 (n-myc downstream regulated gene 4) regulates nodes of Ranvier organization and mbp expression along the Posterior Lateral Line nerve (PLLn). This is achieved, most likely, by the ability of ndrg4 to modulate vesicular exchange between axons and SCs. Indeed, the expression of some key proteins involved in vesicle docking and release such as SNAP25, a member of the SNARE complex, are significantly dependent on ndrg4.Moreover, this work describes a novel role for neuronal elmo1 (engulfment and cell motility 1) in PNS development by promoting neuronal survival within the PLL ganglion. We showed that elmo1 has protective role against apoptosis and that its function is controlled by the netrin1/unc5b signalling upstream of Rac1 and independently of macrophages role in apoptotic clearance. Therefore, elmo1 is required for the proper development of the PLL ganglion and the axonal development of the PLLn. Thus, this study further contributes to our understanding of PNS development and unravels a novel molecular pathway required for neuronal survival in the PNS.

No description available.

The distribution of electricity is a natural monopoly. The infrastructure of the electricity grid is divided into areas and the distribution system operator (DSO) has concession for the distribution of the defined area. The concession is governed by laws and regulation.The Swedish Energy Markets Inspectorate (Ei) is the national regulatory authority. The continuity of supply of electricity is a part of the regulation. The incentive is given by a revenue cap regulation which may result in a reward or penalty.The performance indicators are a measure of the continuity of supply and used in the calculation of the revenue cap regulation.The Master thesis aims to specify the possible consequences for the electricity distribution system operators and their customers utilizing the electricity grid in case of a change of the current methods used to measure the continuity of supply in Sweden.With the current methods, the Ei regulation for year 2016-2019, is the continuity of supply in the local electrical grid estimated from a view where each disruption is treated equal and therefore is SAIFI and SAIDI used. In the regional electrical grid is another method used to measure the continuity of supply, estimated from a view where the loss of supplied energy is considered, therefore uses PNS and ENS. In the documentation is the term ILE used for ENS and ILEffekt for PNS.The Master thesis is constructed to analyze new performance indicators for the local and regional distribution grid. The new performance indicator is the mathematically instrument to measure the continuity of supply and is supported by analytically advantages and disadvantages.The result shows the choice of performance indicators cause a great impact in the revenue cap regulation. AIT, AIF corresponds to ENS and PNS, respectively, divided by power. The three most important results are given by:1. Mathematical and theoretical results show that ENS, PNS are not good indicators individually or in combination with SAIDI, SAIFI and CEMI4 as power consumption within each customer group varies in the local electrical grid.In the regional electrical grid, power consumption may also vary between the norm period and the supervisory period, which means that ENS, PNS can sometimes be misleading.2. The inclusion of power disruption over 12 hours generate stronger incentives in the regulation. Because it requires long term planning to avoid interruptions exceeding 12 hours. The difference is shown mainly in local electrical grid with the indicators SAIDI, SAIFI and CEMI4 and gives a slight increase in rewards in the regulation. This affects the DSO’s and their customers with a marginal difference.3. In the short term, the introduction of AIT, AIF as quality indicators means that customers who consume more power within their customer group get higher-value interruptions. An interruption of a high-consumption customer would then be prioritized compared to a customer with a lower consumption. One way to counteract this is to use CEMI4, in order to capture these customers' interruptions in the regulation.In the long term, the regulation does not become cyclically sensitive, meaning that reasonable rewards or penalties are made. This should benefit a long-term planning of the electrical grid, as the DSO’s do not have to compensate for this. / Det elektriska distributionsnätet är ett naturligt monopol. Infrastrukturen av nätet är uppdelat i områden och där nätägaren har nätkoncession för området som omfattas. Koncessionen är styrd av lagar och reglering.Energimarknadsinspektionen (Ei) är en tillsynsmyndighet som arbetar med uppdrag från regeringen. En del av tillsyn för energimarknaden, är reglering av leveranssäkerhet i det elektriska distributionsnätet. Incitamentet i regleringen ges av intäktsramens begränsning vilket kan resultera i en ökning eller minskning av intäktsramen.Kvalitetsindikatorer är ett matematiskt verktyg för att mäta leveranssäkerhet och används i regleringen av intäktsramen.Examensarbetet syftar till att synliggöra de möjliga konsekvenserna för nätföretagen respektive deras kunder av olika förändringar av de mätmetoder som används för att uppskatta leveranssäkerhet.De mätmetoder som används styrs av indikatorer. Indikatorer som mäter antal avbrott per totalt antal kunder kallas SAIFI. Indikatorer som mäter tid för dessa avbrott per totalt antal kunder kallas SAIDI. En annan metod är att de ingående indikatorerna ska mäta icke levererad energi eller effekt och då kallas de ILE respektive ILEffekt.Energimarknadsinspektionen har inför reglerperioden år 2016-2019 tillämpat SAIDI och SAIFI för kunder kopplade till lokalnät och ILE och ILEffekt för kunder och gränspunkter inom regionnätetExamensarbetet är utformat för att analysera nya typer av kvalitetsindikatorer i lokalnät och regionnät. De nya kvalitetsindikatorerna är olika matematiska verktyg för att mäta leveranssäkerheten och motiveras med analytiska för- och nackdelar.Resultatet visar att valet av indikator har stor betydelse i intäktsramens reglering. AIT, AIF motsvarar ILE respektive ILEffekt dividerat med effekt. De tre viktigaste resultaten ges av:1. Matematiska och teoretiska resultat visar att ILE, ILEffekt är inte bra indikatorer enskilt eller i kombination med SAIDI, SAIFI och CEMI4 då effektförbrukningen inom varje kundgrupp varierar för lokalnät.I regionnät så kan effektförbrukningen också variera mellan normperiod och tillsynsperiod vilket ger att ILE, ILEffekt ibland kan bli missvisande.2. Avbrott över 12 timmar genererar ett starkare incitament i regleringen. Eftersom det kräver långsiktig planering för att undvika avbrott som överstiger 12 timmar. Skillnaden visas främst i lokalnät med indikatorerna SAIDI, SAIFI och CEMI4 och ger en svag höjning av tillägg i regleringen sett på en systemnivå. Det påverkar nätföretagen och deras kunder med en marginell skillnad.3. På kort sikt innebär införandet av AIT, AIF som kvalitetsindikatorer att de kunder som förbrukar mer inom sin kundgrupp får högre värderade avbrott. Ett avbrott hos en kund med hög förbrukning skulle då prioriteras före en kund med lägre förbrukning. Ett sätt att motverka detta är att använda CEMI4 för att fånga upp dessa kunders avbrott i regleringen.På lång sikt innebär det att regleringen inte blir konjunkturkänslig, vilket innebär att rimliga tillägg eller avdrag görs. Det borde gynna en långsiktig planering av elnätet då elnätsföretagen inte behöver kompensera för detta inom regionnäten och lokalnäten.

Rhodobacter capsulatus is a versatile organism capable of growing on different growth conditions including photofermentation in the presence of carbon source, aerobic respiration, anaerobic respiration in the presence of an external electron acceptor such as DMSO. The photofermentative growth of R.capsulatus results in hydrogen production which stands out as an environmentally harmless method to produce hydrogen and accepted as one of the most promising process. Due to the serious problems such as as global climate change and environmental pollution caused by the fossil fuels, there is an increasing requirement for a clean and sustainable energy source. Furtherrmore, the ability of R.capsulatus to fix nitrogen, to use solar energy makes it a model to study various aspects of its metabolism. Thus the goal of this study is to increase the potential in biohydrogen production with the photofermentative bacteria and to investigate the proteins playing roles in different growth modes of the bacteria. In the present study, protein profiles of Rhodobacter capsulatus grown on respiratory, anaerobic respiratory and photofermentative growth modes were obtained. LC-MS/MS system is used to analyze the proteome as a high throughput technique. Physiological analysis such as HPLC for the analysis of the carbon source consumption, GC and analysis of pigments were carried out to state the environmental conditions. As a result, total of 460 proteins were identified with 17 proteins being unique to particular growth condition. Ratios of the proteins in different growth conditions were compared and important proteins were highlighted.

No description available.