Creating possibilities for collective creativity : Brokerage Functions in Practice-Based Innovation

In the network era, creative achievements like innovations are more and more often created in interaction among different actors. The complexity of today‘s problems transcends the individual human mind, requiring not only individual but also collective creativity. In collective creativity, it is impossible to trace the source of new ideas to an individual. Instead, creative activity emerges from the collaboration and contribution of many individuals, thereby blurring the contribution of specific individuals in creating ideas. Collective creativity is often associated with diversity of knowledge, skills, experiences and perspectives. Collaboration between diverse actors thus triggers creativity and gives possibilities for collective creativity. This dissertation investigates collective creativity in the context of practice-based innovation. Practice-based innovation processes are triggered by problem setting in a practical context and conducted in non-linear processes utilising scientific and practical knowledge production and creation in cross-disciplinary innovation networks. In these networks diversity or distances between innovation actors are essential. Innovation potential may be found in exploiting different kinds of distances. This dissertation presents different kinds of distances, such as cognitive, functional and organisational which could be considered as sources of creativity and thus innovation. However, formation and functioning of these kinds of innovation networks can be problematic. Distances between innovating actors may be so great that a special interpretation function is needed – that is, brokerage. This dissertation defines factors that enhance collective creativity in practice-based innovation and especially in the fuzzy front end phase of innovation processes. The first objective of this dissertation is to study individual and collective creativity at the employee level and identify those factors that support individual and collective creativity in the organisation. The second objective is to study how organisations use external knowledge to support collective creativity in their innovation processes in open multi-actor innovation. The third objective is to define how brokerage functions create possibilities for collective creativity especially in the context of practice-based innovation. The research objectives have been studied through five substudies using a case-study strategy. Each substudy highlights various aspects of creativity and collective creativity. The empirical data consist of materials from innovation projects arranged in the Lahti region, Finland, or materials from the development of innovation methods in the Lahti region. The Lahti region has been chosen as the research context because the innovation policy of the region emphasises especially the promotion of practice-based innovations. The results of this dissertation indicate that all possibilities of collective creativity are not utilised in internal operations of organisations. The dissertation introduces several factors that could support collective creativity in organisations. However, creativity as a social construct is understood and experienced differently in different organisations, and these differences should be taken into account when supporting creativity in organisations. The increasing complexity of most potential innovations requires collaborative creative efforts that often exceed the boundaries of the organisation and call for the involvement of external expertise. In practice-based innovation different distances are considered as sources of creativity. This dissertation gives practical implications on how it is possible to exploit different kinds of distances knowingly. It underlines especially the importance of brokerage functions in open, practice-based innovation in order to create possibilities for collective creativity. As a contribution of this dissertation, a model of brokerage functions in practice-based innovation is formulated. According to the model, the results and success of brokerage functions are based on the context of brokerage as well as the roles, tasks, skills and capabilities of brokers. The brokerage functions in practice-based innovation are also possible to divide into social and cognitive brokerage.

Influence of distal ileum exclusion on hepatic and renal functions in presence of extrahepatic cholestasis

OBJECTIVE: To verify whether the ileal exclusion interferes with liver and kidney functional changes secondary to extrahepatic cholestasis.METHODS: We studied 24 rats, divided into three groups with eight individuals each: Group 1 (control), Group 2 (ligation of the hepatic duct combined with internal biliary drainage), and Group 3 (bile duct ligation combined with internal biliary drainage and exclusion of the terminal ileum). Animals in Group 1 (control) underwent sham laparotomy. The animals of groups 2 and 3 underwent ligation and section of the hepatic duct and were kept in cholestasis for four weeks. Next, they underwent an internal biliary bypass. In Group 3, besides the biliary-enteric bypass, we associated the exclusion of the last ten centimeters of the terminal ileum and carried out an ileocolic anastomosis. After four weeks of monitoring, blood was collected from all animals of the three groups for liver and kidney biochemical evaluation (albumin, ALT, AST, direct and indirect bilirubin, alkaline phosphatase, cGT, creatinine and urea).RESULTS: there were increased values of ALT, AST, direct bilirubin, cGT, creatinine and urea in rats from Group 3 (p < 0.05).CONCLUSION: ileal exclusion worsened liver and kidney functions in the murine model of extrahepatic cholestasis, being disadvantageous as therapeutic procedure for cholestatic disorders.

Novel Functions of ErbB4 and NRG-1 in Development and Cancer

Cells communicate, or signal, with each other constantly to ensure proper functioning of tissues and organs. Cell signaling is often performed by interplay of receptors and ligands that bind these receptors. ErbB receptors (epidermal growth factor receptors, EGFR, HER) bind extracellular growth factors and transduce these signals inside of cells. ErbB dysfunction promotes carcinogenesis, and also results in numerous defects during normal development. This study focused on the functions of one member of the ErbB receptor family, ErbB4, and growth factor, neuregulin-1 (NRG-1), that can bind and activate ErbB4. This study aimed to find novel functions of ErbB4 and NRG-1. Hypoxia, or deficiency of oxygen, is common in cancer and ischemic conditions. One of the key findings of the work was the identification and characterization of a cross-talk between ErbB4 and Hypoxia-inducible factor 1α (HIF-1α), the central mediator of hypoxia signaling. ErbB4 activation by NRG-1 was found to increase HIF-1α activity. Interestingly, this regulation occurred in reciprocal manner as HIF-1α was also able to increase protein levels of NRG-1 and ErbB4. Moreover, expression of NRG-1 and ErbB4 was associated with HIF activity in vivo in human clinical samples and in mice. Reduction of functional ErbB4 in developing zebrafish embryos resulted in defects in development of the skeletal muscles. To study ErbB4 functions in pathological situation in humans, clinical samples of serous ovarian carcinoma were analyzed using tissue microarrays and real-time RT-PCR. A specific isoform of ErbB4, CYT-1, was associated with poor survival in serous ovarian cancer and increased anchorage independent growth of ovarian cancer cells in vitro. These observations demonstrate that ErbB4 and NRG-1 are essential regulators of cellular response to hypoxia, of development, and of ovarian carcinogenesis.

Training executive functions in the laboratory and in real life : cognitive consequences of computer-based exercises and bilingualism

The question of the trainability of executive functions and the impact of such training on related cognitive skills has stirred considerable research interest. Despite a number of studies investigating this, the question has not yet been solved. The general aim of this thesis was to investigate two very different types of training of executive functions: laboratory-based computerized training (Studies I-III) and realworld training through bilingualism (Studies IV-V). Bilingualism as a kind of training of executive functions is based on the idea that managing two languages requires executive resources, and previous studies have suggested a bilingual advantage in executive functions. Three executive functions were studied in the present thesis: updating of working memory (WM) contents, inhibition of irrelevant information, and shifting between tasks and mental sets. Studies I-III investigated the effects of computer-based training of WM updating (Study I), inhibition (Study II), and set shifting (Study III) in healthy young adults. All studies showed increased performance on the trained task. More importantly, improvement on an untrained task tapping the trained executive function (near transfer) was seen in Study I and II. None of the three studies showed improvement on untrained tasks tapping some other cognitive function (far transfer) as a result of training. Study I also used PET to investigate the effects of WM updating training on a neurotransmitter closely linked to WM, namely dopamine. The PET results revealed increased striatal dopamine release during WM updating performance as a result of training. Study IV investigated the ability to inhibit task-irrelevant stimuli in bilinguals and monolinguals by using a dichotic listening task. The results showed that the bilinguals exceeded the monolinguals in inhibiting task-irrelevant information. Study V introduced a new, complementary research approach to study the bilingual executive advantage and its underlying mechanisms. To circumvent the methodological problems related to natural groups design, this approach focuses only on bilinguals and examines whether individual differences in bilingual behavior correlate with executive task performances. Using measures that tap the three above-entioned executive functions, the results suggested that more frequent language switching was associated with better set shifting skills, and earlier acquisition of the second language was related to better inhibition skills. In conclusion, the present behavioral results showed that computer-based training of executive functions can improve performance on the trained task and on closely related tasks, but does not yield a more general improvement of cognitive skills. Moreover, the functional neuroimaging results reveal that WM training modulates striatal dopaminergic function, speaking for training-induced neural plasticity in this important neurotransmitter system. With regard to bilingualism, the results provide further support to the idea that bilingualism can enhance executive functions. In addition, the new complementary research approach proposed here provides some clues as to which aspects of everyday bilingual behavior may be related to the advantage in executive functions in bilingual individuals.

Regulatory roles of microtubule-associated proteins in neuronal morphogenesis. Involvement of the extracellular matrix

As a result of recent investigations, the cytoskeleton can be viewed as a cytoplasmic system of interconnected filaments with three major integrative levels: self-assembling macromolecules, filamentous polymers, e.g., microtubules, intermediate filaments and actin filaments, and supramolecular structures formed by bundles of these filaments or networks resulting from cross-bridges between these major cytoskeletal polymers. The organization of this biological structure appears to be sensitive to fine spatially and temporally dependent regulatory signals. In differentiating neurons, regulation of cytoskeleton organization is particularly relevant, and the microtubule-associated protein (MAP) tau appears to play roles in the extension of large neuritic processes and axons as well as in the stabilization of microtubular polymers along these processes. Within this context, tau is directly involved in defining neuronal polarity as well as in the generation of neuronal growth cones. There is increasing evidence that elements of the extracellular matrix contribute to the control of cytoskeleton organization in differentiating neurons, and that these regulations could be mediated by changes in MAP activity. In this brief review, we discuss the possible roles of tau in mediating the effects of extracellular matrix components on the internal cytoskeletal arrays and its organization in growing neurons.

The pathogenesis of tropical spastic paraparesis/human T-cell leukemia type I-associated myelopathy

Tropical spastic paraparesis/human T-cell leukemia type I-associated myelopathy (TSP/HAM) is caused by a human T-cell leukemia virus type I (HTLV-I) after a long incubation period. TSP/HAM is characterized by a chronic progressive paraparesis with sphincter disturbances, no/mild sensory loss, the absence of spinal cord compression and seropositivity for HTLV-I antibodies. The pathogenesis of this entity is not completely known and involves a multivariable phenomenon of immune system activation against the presence of HTLV-I antigens, leading to an inflammatory process and demyelination, mainly in the thoracic spinal cord. The current hypothesis about the pathogenesis of TSP/HAM is: 1) presence of HTLV-I antigens in the lumbar spinal cord, noted by an increased DNA HTLV-I load; 2) CTL either with their lytic functions or release/production of soluble factors, such as CC-chemokines, cytokines, and adhesion molecules; 3) the presence of Tax gene expression that activates T-cell proliferation or induces an inflammatory process in the spinal cord; 4) the presence of B cells with neutralizing antibody production, or complement activation by an immune complex phenomenon, and 5) lower IL-2 and IFN-gamma production and increased IL-10, indicating drive to a cytokine type 2 pattern in the TSP/HAM subjects and the existence of a genetic background such as some HLA haplotypes. All of these factors should be implicated in TSP/HAM and further studies are necessary to investigate their role in the development of TSP/HAM.

Overexpression of Fc receptor-like 1 associated with B-cell activation during hepatitis B virus infection

The role of B cells in the pathogenesis of hepatitis B virus (HBV) infection has not been explored in depth. In the present study, the activation status of B cells from peripheral blood of healthy controls (N = 20) and patients with acute hepatitis B (AHB, N = 15) or chronic hepatitis B (CHB, N = 30) was evaluated by measuring the expression levels of B-cell activation markers CD69 and CD86, using quantitative real-time PCR and flow cytometry. Moreover, the potential mechanism underlying B-cell activation during HBV infection was further investigated by analyzing the expression profile of FCRL1, an intrinsic activation molecule of B cells. An elevation in the levels of B-cell activation markers including CD69 and CD86 was observed in the AHB patients (44.31 ± 9.27, 27.64 ± 9.26%) compared to CHB patients (30.35 ± 11.27, 18.41 ± 6.56%, P < 0.05), which was still higher than healthy controls (12.23 ± 7.84, 8.22 ± 3.43%, P < 0.05). Furthermore, the expression of FCRL1 was found to be similar to B-cell activation markers, which was highest in AHB patients (70.15 ± 17.11%), lowest in healthy donors (36.32 ± 9.98%, P < 0.05) and half-way between these levels in patients with CHB (55.17 ± 12.03%, P < 0.05). The results were positively associated with aberrant B-cell activation. These data suggest that B cells can play a role in HBV infection, and therefore more effort should be devoted to exploring their functions.

The roles of ERK1/2 and PI3K in abnormal vascular functions in angiotensin II-infused hypertensive rats

Background: Ang II plays a major role in cardiovascular regulation. Recently, it has become apparent that vascular superoxide anion may play an important role in hypertension development. Treatment with antisense NAD(P)H oxidase or SOD decreased BP in Ang II-infused rats. Wang et al recently reported mice which lack one of the subunits of NAD(P)H oxidase developed hypertension at a much lower extent when compared to the wild type animals infused with Ang II, indicating that superoxide anion contributes to elevation in BP in the Ang II-infused hypertensive model. In the Ang II-infused hypertensive model, altered reactivity of blood vessels is often associated with the elevation of systolic blood pressure. We have observed abnormal tension development and impaired endothelium-dependent relaxation in the isolated aorta of Ang II-infused and DOCA-salt hypertensive rats. Recently, several other cellular signal molecules, including ERK1I2 and PI3K, have been determined to play important roles in the regulation of smooth muscle contraction and relaxation. ERKl/2 and PI3K pathways are also reported to contribute to Ang II induced cell growth, hypertrophy, remodeling and contraction. Moreover, these signaling pathways have shown ROS-sensitive properties. Therefore, the aim of the present study is to investigate the roles of ERKl12 and PI3K in vascular oxidative stress, spontaneous tone and impaired endothelium relaxation in Ang II-infused hypertensive model. Hypothesis: We hypothesize that the activation of ERKl12 and PI3K are elevated in response to an Ang II infusion for 6 days. The elevated activation of phospho-ERKl/2 and PI3K mediated the increased level of vascular superoxide anion, the abnormal vascular contraction and impaired endothelium-dependent vascular relaxation in Ang II-infused hypertensive rats. Methods: Vascular superoxide anion level is measured by lucigenin chemiluminescence. Spontaneous tone and ACh-induced endothelium-dependent relaxation was measured by isometric tension recording in organ chamber. The activity of ERK pathway will be measured by its Western blot of phosphorylation of ERK. PI3K activity was evaluated indirectly by Western blot of the phosphorylation of PDKl, a downstream protein of PI3K signaling pathway. The role of each pathway was also addressed via comparing the responses to the specific inhibitors. Results: Superoxide anion was markedly increased in the isolated thoracic aorta from Ang II-infused rats. There was spontaneous tone developed in rings from Ang II-induced hypertensive but not sham-operated normotensive rats. ACh-induced endothelium-dependent relaxation function is impaired in Ang II-infused hypertensive rats. Superoxide dismutase and NAD(P)H oxidase inhibitor, apocynin, inhibited the abnormal spontaneous tone and ameliorated impaired endothelium-dependent relaxation. The expression of phopho-ERKII2 was enhanced in Ang II-infused rats, indicating the activity of ERK1I2 could be increased. MEK1I2 inhibitors, PD98059 and U126, but not their inactive analogues, SB203580 and U124, significantly reduced the vascular superoxide anion in aortas from Ang II-infused rats. The MEK1I2 inhibitors reduced the spontaneous tone and improved the impaired endothelium-dependent relaxation in aorta of hypertension. These findings supported the role of ERKII2 signaling pathway in vascular oxidative stress, spontaneous tone and impaired endothelium-dependent relaxation in Ang II-infused hypertensive rats. The amount of phospho-PDK, a downstream protein of PI3K was increased in Ang II rats indicating the activity of PI3K activity was elevated. Strikingly, PI3K significantly inhibited the increase of superoxide anion level, abnormal spontaneous tone and restored endothelium-dependent relaxation in Ang II-infused hypertensive rats. These findings indicated the important role of PI3K in Ang II-infused hypertensive rats. Conclusion: ERKII2 and PI3K signaling pathways are sustained activated in Ang II-infused hypertensive rats. The activated ERKII2 and PI3K mediate the increase of vascular superoxide anion level, vascular abnormal spontaneous tone and impaired endothelium-dependent relaxation.

Age-related changes in ERPs associated with context-based and response-based interference

Age-related differences in information processing have often been explained through deficits in older adults' ability to ignore irrelevant stimuli and suppress inappropriate responses through inhibitory control processes. Functional imaging work on young adults by Nelson and colleagues (2003) has indicated that inferior frontal and anterior cingulate cortex playa key role in resolving interference effects during a delay-to-match memory task. Specifically, inferior frontal cortex appeared to be recruited under conditions of context interference while the anterior cingulate was associated with interference resolution at the stage of response selection. Related work has shown that specific neural activities related to interference resolution are not preserved in older adults, supporting the notion of age-related declines in inhibitory control (Jonides et aI., 2000, West et aI., 2004b). In this study the time course and nature of these inhibition-related processes were investigated in young and old adults using high-density ERPs collected during a modified Sternberg task. Participants were presented with four target letters followed by a probe that either did or did not match one of the target letters held in working memory. Inhibitory processes were evoked by manipulating the nature of cognitive conflict in a particular trial. Conflict in working memory was elicited through the presentation of a probe letter in immediately previous target sets. Response-based conflict was produced by presenting a negative probe that had just been viewed as a positive probe on the previous trial. Younger adults displayed a larger orienting response (P3a and P3b) to positive probes relative to a non-target baseline. Older adults produced the orienting P3a and 3 P3b waveforms but their responses did not differentiate between target and non-target stimuli. This age-related change in response to targetness is discussed in terms of "early selection/late correction" models of cognitive ageing. Younger adults also showed a sensitivity in their N450 response to different levels of interference. Source analysis of the N450 responses to the conflict trials of younger adults indicated an initial dipole in inferior frontal cortex and a subsequent dipole in anterior cingulate cortex, suggesting that inferior prefrontal regions may recruit the anterior cingulate to exert cognitive control functions. Individual older adults did show some evidence of an N450 response to conflict; however, this response was attenuated by a co-occurring positive deflection in the N450 time window. It is suggested that this positivity may reflect a form of compensatory activity in older adults to adapt to their decline in inhibitory control.

Role of the protein tyrosine phosphatase DEP-1 in Src activation and the mediation of biological cell functions of endothelial and breast cancer cells

L’implication des protéines tyrosines phosphatases (PTPs) dans la régulation de la signalisation et la médiation des fonctions cellulaires a été bien établie dans les dernières années. Cependant, les mécanismes moléculaires par lesquels les PTPs régulent les processus fondamentaux tels que l’angiogenèse demeurent méconnus. Il a été rapporté que l’expression de la PTP DEP-1 (Density-enhanced phosphatase 1) augmente avec la densité cellulaire et corrèle avec la déphosphorylation du récepteur VEGFR2. Cette déphosphorylation contribue à l’inhibition de contact dans les cellules endothéliales à confluence et diminue l’activité du VEGFR2 en déphosphorylant spécifiquement ses résidus catalytiques Y1054/1059. De plus, la plupart des voies de signalisation en aval du VEGFR2 sont diminuées sauf la voie Src-Gab1-AKT. DEP-1 déphosphoryle la Y529 de Src et contribue à la promotion de la survie dans les cellules endothéliales. L’objectif de cette thèse est de mieux définir le rôle de DEP-1 dans la régulation de l’activité de Src et les réponses biologiques dans les cellules endothéliales. Nous avons identifié les résidus Y1311 et Y1320 dans la queue C-terminale de DEP-1 comme sites majeurs de phosphorylation en réponse au VEGF. La phosphorylation de ces résidus est requise pour l’activation de Src et médie le remodelage des jonctions cellules-cellules dépendantes de Src. Ce remodelage induit la perméabilité, l’invasion et la formation de capillaires en réponse au VEGF. Nos résultats démontrent que la phosphorylation de DEP-1 sur résidu tyrosine est requise pour diriger la spécificité de DEP-1 vers son substrat Src. Les travaux révèlent pour la première fois un rôle positif de DEP-1 sur l’induction du programme angiogénique des cellules endothéliales. En plus de la phosphorylation sur tyrosine, DEP-1 est constitutivement phosphorylé sur la thréonine 1318 situé à proximité de la Y1320 en C-terminal. Cette localisation de la T1318 suggère que ce résidu pourrait être impliqué dans la régulation de la Y1320. En effet, nous avons observé que la T1318 de DEP-1 est phosphorylée potentiellement par CK2, et que cette phosphorylation régule la phosphorylation de DEP-1 sur tyrosine et sa capacité de lier et d’activer Src. En accord avec ces résultats, nos travaux révèlent que la surexpression du mutant DEP-1 T1318A diminue le remodelage des jonctions cellules-cellules et par conséquent la perméabilité. Nos résultats suggèrent donc que la T1318 de DEP-1 constitue un nouveau mécanisme de contrôle de la phosphorylation sur tyrosine et que ceci résulte en l’activation de Src et l’induction des fonctions biologiques des cellules endothéliales en réponse au VEGF. Suite à ces travaux dans les cellules endothéliales qui démontrent un rôle positif de DEP-1 dans la médiation des réponses angiogéniques, nous avons voulu approfondir nos connaissances sur l’implication potentielle de DEP-1 dans les cellules cancéreuses où l’activité de Src est requise pour la progression tumorale. Malgré le rôle connu de DEP-1 comme suppresseur tumoral dans différents types de cancer, nous avons émis l’hypothèse que DEP-1 pourrait promouvoir les fonctions biologiques dépendantes de Src telles que la migration et l’invasion dans les cellules cancéreuses. Ainsi, nous avons observé que l’expression de DEP-1 est plus élevée dans les lignées basales de cancer du sein qui sont plus invasives comparativement aux lignées luminales peu invasives. Dans les lignées basales, DEP-1 active Src, médie la motilité cellulaire dépendante de Src et régule la localisation des protéines impliquées dans l’organisation du cytosquelette. L’analyse d’un micro-étalage de tissu a révélé que l’expression de DEP-1 est associée avec une réduction tendencielle de survie des patients. Nos résultats proposent donc, un rôle de promoteur tumoral pour DEP-1 dans la progression du cancer du sein. Les travaux présentés dans cette thèse démontrent pour la première fois que DEP-1 peut agir comme promoteur des réponses angiogéniques et du phénotype pro-invasif des lignées basales du cancer du sein probablement du à sa capacité d’activer Src. Nos résultats suggèrent ainsi que l’expression de DEP-1 pourrait contribuer à la progression tumorale et la formation de métastases. Ces découvertes laissent donc entrevoir que DEP-1 représente une nouvelle cible thérapeutique potentielle pour contrer l’angiogenèse et le développement du cancer.

Warfarin-induced vitamin K deficiency is associated with cognitive and behavioral perturbations, and alterations in brain sphingolipids in rats

La Vitamine K (VK) est largement reconnue pour son rôle dans la coagulation sanguine toutefois, de plus en plus de travaux indiquent son implication dans la fonction cérébrale. La VK est requise pour l'activation de différentes protéines, par exemple la protéine Gas6, et la ménaquinone-4 (MK-4), le principal vitamère K dans le cerveau, est impliquée dans le métabolisme des sphingolipides. Dans un rapport précédent, nous avons montré qu'un régime alimentaire faible en VK tout au long de la vie était associé à des déficits cognitifs chez des rats âgés. La warfarine sodique est un puissant antagoniste de la VK qui agit en bloquant le cycle de la VK, provoquant un «déficit relatif de VK » au niveau cellulaire. À la lumière du rôle émergent de la VK dans le cerveau, la warfarine pourrait représenter un facteur de risque pour la fonction cérébrale. Ce travail est donc pertinente en raison de la forte proportion d'adultes traîtés à la warfarine sodique. Dans la présente étude, 14 rats mâles Wistar ont été traités avec 14 mg de warfarine/kg /jour (dans l'eau potable) et des injections sous-cutanées de VK (85 mg/kg), 3x/sem, pendant 10 semaines. Quatorze rats témoins ont été traités avec de l'eau normale et injectés avec une solution saline. Les rats ont été soumis à différents tests comportementaux après quoi les niveaux de phylloquinone, MK-4, sphingolipides (cérébroside, sulfatide, sphingomyéline, céramide et gangliosides), et les sous-types de gangliosides (GT1b, GD1a, GM1, GD1b), ont été évalués dans différentes régions du cerveau. Comparativement aux rats du groupe contrôle, les rats traités à la warfarine présentaient des latences plus longues au test de la piscine de Morris (p <0,05) ainsi qu'une hypoactivité et un comportement exploratoire plus faible au test de « l’open field » (p <0,05). Le traitement par warfarine a également entraîné une diminution spectaculaire du niveau de MK-4 dans toutes les régions du cerveau (p <0,001), une altération des concentrations de sphingolipidiques, en particulier dans le cortex frontal et le mésencéphale (p <0,05), et une perte de différences régionales sphingolipidiques, notamment pour les gangliosides. Le traitement par warfarine a été associé à un niveau inférieur de GD1a dans l'hippocampe et un niveau supérieur de GT1b dans le cortex préfrontal et le striatum. En conclusion, la déficience en VK induite par warfarine altère les niveaux de VK et sphingolipides dans le cerveau, avec de potentiels effets néfastes sur les fonctions cérébrales.

Special functions of Weyl groups and their continuous and discrete orthogonality

Cette thèse s'intéresse à l'étude des propriétés et applications de quatre familles des fonctions spéciales associées aux groupes de Weyl et dénotées $C$, $S$, $S^s$ et $S^l$. Ces fonctions peuvent être vues comme des généralisations des polynômes de Tchebyshev. Elles sont en lien avec des polynômes orthogonaux à plusieurs variables associés aux algèbres de Lie simples, par exemple les polynômes de Jacobi et de Macdonald. Elles ont plusieurs propriétés remarquables, dont l'orthogonalité continue et discrète. En particulier, il est prouvé dans la présente thèse que les fonctions $S^s$ et $S^l$ caractérisées par certains paramètres sont mutuellement orthogonales par rapport à une mesure discrète. Leur orthogonalité discrète permet de déduire deux types de transformées discrètes analogues aux transformées de Fourier pour chaque algèbre de Lie simple avec racines des longueurs différentes. Comme les polynômes de Tchebyshev, ces quatre familles des fonctions ont des applications en analyse numérique. On obtient dans cette thèse quelques formules de <>, pour des fonctions de plusieurs variables, en liaison avec les fonctions $C$, $S^s$ et $S^l$. On fournit également une description complète des transformées en cosinus discrètes de types V--VIII à $n$ dimensions en employant les fonctions spéciales associées aux algèbres de Lie simples $B_n$ et $C_n$, appelées cosinus antisymétriques et symétriques. Enfin, on étudie quatre familles de polynômes orthogonaux à plusieurs variables, analogues aux polynômes de Tchebyshev, introduits en utilisant les cosinus (anti)symétriques.

Early-onset and late-onset Alzheimer’s disease are associated with distinct patterns of memory impairment

The goal of this study was to investigate the specific patterns of memory breakdown in patients suffering from early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD). Twenty EOAD patients, twenty LOAD patients, twenty matched younger controls, and twenty matched older controls participated in this study. All participants underwent a detailed neuropsychological assessment, an MRI scan, an FDG-PET scan, and AD patients had biomarkers as supporting evidence of both amyloïdopathy and neuronal injury. Results of the neuropsychological assessment showed that both EOAD and LOAD groups were impaired in the domains of memory, executive functions, language, praxis, and visuoconstructional abilities, when compared to their respective control groups. EOAD and LOAD groups, however, showed distinct patterns of memory impairment. Even though both groups were similarly affected on measures of episodic, short term and working memory, in contrast semantic memory was significantly more impaired in LOAD than in EOAD patients. The EOAD group was not more affected than the LOAD group in any memory domain. EOAD patients, however, showed significantly poorer performance in other cognitive domains including executive functions and visuoconstructional abilities. A more detailed analysis of the pattern of semantic memory performance among patient groups revealed that the LOAD was more profoundly impaired, in tasks of both spontaneous recall and semantic recognition. Voxel-Based Morphometry (VBM) analyses showed that impaired semantic performance in patients was associated with reduced gray matter volume in the anterior temporal lobe region, while PET-FDG analyses revealed that poorer semantic performance was associated with greater hypometabolism in the left temporoparietal region, both areas reflecting key regions of the semantic network. Results of this study indicate that EOAD and LOAD patients present with distinct patterns of memory impairment, and that a genuine semantic impairment may represent one of the clinical hallmarks of LOAD.

Duplication coefficients via generating functions

In this paper, we solve the duplication problem P_n(ax) = sum_{m=0}^{n}C_m(n,a)P_m(x) where {P_n}_{n>=0} belongs to a wide class of polynomials, including the classical orthogonal polynomials (Hermite, Laguerre, Jacobi) as well as the classical discrete orthogonal polynomials (Charlier, Meixner, Krawtchouk) for the specific case a = −1. We give closed-form expressions as well as recurrence relations satisfied by the duplication coefficients.

Characterization of Lipid Droplets and Functional Analysis of Lipid Droplet-Associated Proteins in Dictyostelium discoideum

Lipid droplets (LDs) are the universal storage form of fat as a reservoir of metabolic energy in animals, plants, bacteria and single celled eukaryotes. Dictyostelium LD formation was investigated in response to the addition of different nutrients to the growth medium. LDs were induced by adding exogenous cholesterol, palmitic acid (PA) as well as growth in bacterial suspension, while glucose addition fails to form LDs. Among these nutrients, PA addition is most effective to stimulate LD formation, and depletion of PA from the medium caused LD degradation. The neutral lipids incorporated into the LD-core are composed of triacylglycerol (TAG), steryl esters, and an unknown neutral lipid (UKL) species when the cells were loaded simultaneously with cholesterol and PA. In order to avoid the contamination with other cellular organelles, the LD-purification method was modified. The isolated LD fraction was analysed by mass spectrometry and 100 proteins were identified. Nineteen of these appear to be directly involved in lipid metabolism or function in regulating LD morphology. Together with a previous study, a total of 13 proteins from the LD-proteome were confirmed to localize to LDs after the induction with PA. Among the identified LD-proteins, the localization of Ldp (lipid droplet membrane protein), GPAT3 (glycerol-3-phosphate acyltransferase 3) and AGPAT3 (1-acylglycerol-3-phosphate-acyltransferase 3) were further verified by GFP-tagging at the N-termini or C-termini of the respective proteins. Fluorescence microscopy demonstrated that PA-treatment stimulated the translocation of the three proteins from the ER to LDs. In order to clarify DGAT (diacylglycerol acyltransferase) function in Dictyostelium, the localization of DGAT1, that is not present in LD-proteome, was also investigated. GFP-tagged DGAT1 localized to the ER both, in the presence and absence of PA, which is different from the previously observed localization of GFP-tagged DGAT2, which almost exclusively binds to LDs. The investigation of the cellular neutral lipid level helps to elucidate the mechanism responsible for LD-formation in Dictyostelium cells. Ldp and two short-chain dehydrogenases, ADH (alcohol dehydrogenase) and Ali (ADH-like protein), are not involved in neutral lipid biosynthesis. GPAT, AGPAT and DGAT are three transferases responsible for the three acylation steps of de novo TAG synthesis. Knock-out (KO) of AGPAT3 and DGAT2 did not affect storage-fat formation significantly, whereas cells lacking GPAT3 or DGAT1 decreased TAG and LD accumulation dramatically. Furthermore, DGAT1 is responsible for the accumulation of the unknown lipid UKL. Overexpression of DGAT2 can rescue the reduced TAG content of the DGAT1-KO mutant, but fails to restore UKL content in these cells, indicating that of DGAT1 and DGAT2 have overlapping functions in TAG synthesis, but the role in UKL formation is unique to DGAT1. Both GPAT3 and DGAT1 affect phagocytic activity. Mutation of GPAT3 increases it but a DGAT1-KO decreases phagocytosis. The double knockout of DGAT1 and 2 also impairs the ability to grow on a bacterial lawn, which again can be rescued by overexpression of DGAT2. These and other results are incorporated into a new model, which proposes that up-regulation of phagocytosis serves to replenish precursor molecules of membrane lipid synthesis, whereas phagocytosis is down-regulated when excess fatty acids are used for storage-fat formation.