Le NAD+ apparaît comme un régulateur majeur du fonctionnement mitochondrial. En effet, ce cofacteur régule non seulement l’activité de nombreuses enzymes impliqués dans le métabolisme énergétique (enzymes de la β-oxydation des acides gras, du cycle de Krebs) mais joue également un rôle dans la production d’espèces réactives de l’oxygène (ROS). Le NAD+ est aussi le cofacteur des sirtuines, des enzymes déacétylases régulatrices notamment du métabolisme mitochondrial. De plus, la mitochondrie est l’organite au sein duquel la concentration en NAD+ est la plus élevée (jusqu’à 70% du NAD cellulaire). Le complexe I, qui possède une activité NADH déshydrogénase, pourrait être l’un des régulateurs majeurs du rapport NADH/NAD+ mitochondrial. L’objectif de ce travail de thèse a été d’étudier le rôle du rapport NADH/NAD+ mitochondrial dans le métabolisme énergétique et l’implication du complexe I dans les pathologies mitochondriales. Nous avons mis en évidence qu’une modulation du rapport NADH/NAD+ mitochondrial (augmentation par un activateur pharmacologique ou diminution consécutive à une mutation touchant une sous-unité du complexe I, modifie de manière drastique le métabolisme énergétique notamment en activant ou inhibant la protéine SIRT3, isoforme mitochondriale des sirtuines. Le complexe I semble jouer un rôle majeur dans cette modulation. Le resveratrol, ciblant le complexe I, ainsi que le NMN, un précurseur du NAD+, permettent de restaurer ce rapport et d’améliorer ainsi le métabolisme mitochondrial. Nos résultats suggèrent donc que le rapport NADH/NAD+ pourrait être une cible thérapeutique particulièrement intéressante dans les déficits du complexe I. / NAD+ appears as a main regulator of the mitochondrial function. Indeed, this compound not only regulates the enzymatic activity of enzymes involved in energetic metabolism (fatty acid oxidation, tricarboxylic acid cycle) but is also involved in ROS production. NAD+ is also the cofactor of sirtuins, deacetylase enzymes, in particular regulating the mitochondrial function. Moreover, mitochondria sequester most of the cellular NAD+ (up to 70 %). The complex I, which possesses an NADH dehydrogenase activity, is thought to be the most important regualtor of the mitochondrial NADH/NAD+ ratio. The work presented here aimed at studying the role of the mitochondrial NADH/NAD+ ratio in mitochondrial metabolism and to test the involvement of the complex I in mitochondrial disorders. We show that a modulation of the mitochondrial NADH/NAD+ ratio (increase by a pharmacological agent or decrease in complex-I mutated fibroplasts) severely affects the mitochondrial energetic function especially by interacting with SIRT3 a mitochondrial sirtuin isoform. The NADH/NAD+ ratio is highly regulated by complex I activity. Resveratrol, which targets the complex I, as well as NMN, a NAD+ precursor, improves the mitochondrial NADH/NAD+ ratio and consequently increases the mitochondrial metabolism. Our results strongly suggest that the mitochondrial NADH/NAD+ ratio could be an interesting therapeutic target especially in complex I- deficient patients.

The content of this thesis is the analysis of the Integrated Urban Development Plans in the Czech Republic, which is then particulary demonstrated on the example of Ustí nad Labem. The regional capital has now initiated the creation of three Integrated Urban Development Plans, two of them have a zone character -- IUDP Center and IUDP Nestemice -- Mojzir settlement, and one with a thematic orientation on the transportation -- IUDP Mobility. In the theoretical part is the urban dimension of Cohesion Policy discussed, followed by its form and metodology in the Czech Republic. The specific IUDPs of Usti nad Labem are subsequently summarized in the practical part which is focused on the application of the documents, the evaluation of the actual interconnection of projects and find new starting points for the next programming period

Le Nicotinamide Adénine Dinucléotide (NAD) est un cofacteur clé du métabolisme cellulaire. Synthétisé à partir d'acide quinolinique (QA) chez tous les organismes vivants, la biosynthèse du QA diffère entre les eucaryotes et les procaryotes. Chez les eucaryotes, il est produit à partir de L-tryptophane alors que chez les procaryotes et les plantes, il est synthétisé par l'action concertée de deux enzymes: la L-aspartate oxydase (NadB) qui permet la formation d'iminoaspartate (IA) à partir de L-aspartate et la quinolinate synthase (NadA) qui permet la condensation de deux molécules, la dihydroxyacétone-phosphate (DHAP) et l'iminoaspartate, pour former l'acide quinolinique. En plus de cette voie dite « de novo », la plupart des organismes possèdent une voie de secours qui produit le NAD à partir de niacine provenant de l'alimentation ou de la dégradation du NAD. Chez certains pathogènes tels que Mycobacterium leprae et Helicobacter pylori, cette voie de secours n'existe pas. Ceci fait de NadA une cible particulièrement attractive pour la conception d'antibactériens et ceci d'autant plus qu'elle est absente chez l'homme.NadA est la seule enzyme de la voie de biosynthèse de novo du NAD dont le mécanisme moléculaire et la structure tridimensionnelle sous forme active (avec son centre [4Fe-4S]2+) sont inconnus. Grâce à l'utilisation d'analogues de substrats ou d'intermédiaires réactionnels, nous avons pu non seulement avancer dans l'élucidation du mécanisme moléculaire de NadA et notamment dans la compréhension du rôle du centre [4Fe-4S]2+ dans la catalyse mais en plus, nous avons été en mesure de proposer un 1er inhibiteur in vitro et in vivo de NadA : l'acide 4,5 Dithiohydroxyphtalique (DTHPA). Le DTHPA nous a fourni de bonnes bases pour la conception d'inhibiteurs puissants et spécifiques de NadA grâce à une étude Structure-Activité. Par ailleurs, nous avons résolu la 1ère structure aux rayons X de NadA sous forme holoprotéine dont les données structurales nous ont grandement aidé dans la compréhension du mécanisme de NadA. / The Nicotinamide Adenine Dinucleotide (NAD) is a key cofactor essential for cellular metabolism. Synthesized from quinolinic acid (QA) in all living organisms, NAD biosynthesis is different between eucaryotes and procaryotes. Indeed, most of eukaryotes produce QA from L-tryptophan, whereas most of prokaryotes and plants synthesize QA by the concerted action of 2 enzymes: L-aspartate oxydase (NadB), an FAD enzyme, which catalyzes L-Aspartate oxidation to form iminoaspartate (IA) while quinolinate synthetase (NadA) allows condensation between IA and Dihydroxyacetone Phosphate (DHAP) to produce QA. Besides this « de novo » pathway, most eukaryotes and some bacteriae have a salvage pathway which allows NAD synthesis from nutrients and metabolites of NAD degradation in order to maintain a correct pool of NAD in the cell. However, some pathogens like Mycobacterium leprae, Helicobacter pylori do not possess this pathway. As a consequence, NadA represents a very attractive target for designing specific antibacterial agents since it does not exist in Human.NadA is the only metalloenzyme of NAD de novo biosynthesis whose molecular mechanism and tridimensional structure with its [4Fe-4S]2+ cluster are unknown. Using substrate and intermediate analogues, we have been able to understand better NadA mechanism, especially [4Fe-4S]2+ cluster role in catalysis. Moreover, we proposed the first in vitro and in vivo inhibitor of NadA : the 4,5 Dithiohydroxyphtalic Acid (DTHPA) which gave us basis to design powerful and specific NadA inhibitors thanks to a structure-activity relationship study. Besides, we resolved the first X-rays structure of NadA under its holoprotein form. Datas we extracted from it helped us greatly to understand NadA mechanism.

This thesis is focused on improving the organizational culture in the COOP Albrechtice Orlici. The current organizational culture is established on basis of own observation and consultation with the Head shop. Proposals to change the organizational structures emerge from the survey when they were surveyed customers' views and attitudes to the selected store. Based on this survey will be designed to improve to meet the requirements of all customers.

Le développement et le fonctionnement harmonieux des plantes dépendent de cofacteurs comme le nicotinamide adénine dinucléotide (NAD). Outre ses rôles dans le recyclage redox, le NAD est également impliqué dans les processus de signalisation cellulaire, qui sont des acteurs centraux dans les conditions de stress. Ainsi, le NAD est l'un des principaux déterminants de l'homéostasie de l'énergie des plantes et a un impact important sur la productivité des plantes et la résistance au stress. La L-aspartate oxydase (LASPO) et l'acide nicotinique / nicotinamide mononucléotide adénylyltransférase (N(a)NMNAT) sont deux enzymes importantes dans la biosynthèse du NAD. Par surproduction de ces deux enzymes dans E. coli, nous avons identifié les propriétés biochimiques de ces enzymes. Il ressort que la surexpression de la N(a)MNAT stimule la croissance des plantes en activant les métabolismes photosynthétiques et respiratoires, sans pour autant augmenter les teneurs en NAD. La surproduction de la LASPO augmente la teneur en NAD des plantes, laquelle est corrélée à une augmentation significative de la production de biomasse foliaire et des rendements en graines, et l’inverse est observé lorsque les teneurs en NAD diminuent. La modification des teneurs en NAD affecte les fonctions photosynthétiques et respiratoires, et l’expression de quelques gènes qui pourraient participer au contrôle de la croissance des plantes semble régulée par les histones déacétylases NAD-dépendantes. / The development and smooth functioning of plants depends on co-factors such as nicotinamide adenine dinucleotide (NAD). In addition to its roles in redox recycling, NAD is also involved in cell signaling processes, which are central actors in stress conditions. Thus, NAD is one of the main determinants of plant energy homeostasis and has a significant impact on plant productivity and stress resistance. L-aspartate oxidase (LASPO) and nicotinic acid / nicotinamide mononucleotide adenylyltransferase (N (a) NMNAT) are two important enzymes in the biosynthesis of NAD. By overproducing these enzymes in E. coli, we have identified the biochemical properties of these enzymes. Overexpression of N(a)MNAT stimulates plant growth by activating photosynthetic and respiratory metabolisms, without increasing NAD levels. Overproduction of LASPO enhances NAD content in plants, which is correlated with a significant increase in foliar biomass production and seed yields, and the reverse is observed when NAD levels decrease. Changes in NAD levels affect photosynthetic and respiratory functions, and the expression of a few genes that may be involved in plant growth control appears to be regulated by NAD-dependent histones deacetylases.

Following text is focused on a revision processing of a burial place that is located on the acropolis of the early medieval settlement in Libice nad Cidlinou. There is one of the most important early medieval necropolises on the territory of the Czech Republic where evidences of elite's burials were found. The church was built during an existence of the cemetery. The necropolis was surveyed between years 1948-1957 and 1967-1973. An existing monograph doesn't fulfill criteria that are required for a modern evaluation in many ways. For this reason there were a complex revision of an extant documentation and archaeological material, consequently a new analysis and interpretation of established facts were made.

THE NORTH WEST SIDE OF THE LAND IS NOT LOADED BY TRAFFIC OPERATION, THEREFORE THAT SITUATION WAS PRIMARY IN THE PROPOSAL DESIGNED FOR THE LOCATION OF CROPS WHICH REQUIRE MAXIMUM SAFETY IN THE ENVIRONMENT. THE CONNECTION BETWEEN THE FACILITIES AND THE FAMILY BUILDING IS A MEETING IN THE BUILDING. THESE TWO PARAMETERS FOLLOW THE LOCATION OF THE CULTURAL CENTER IN THE MEDITERRANEAN THROUGH THE BUILDING, WHERE THE INSIDE IS FROM THE SOUTH SIDE. TO 2ND, ON THE CENTER OF MEDITERRANEAN MOTORCYCLE, MISSY CHILDREN CENTER WHICH HAS A RELATIONSHIP WITH THE CULTURAL CENTER. THESE TWO PROGRAMS TOGETHER TOGETHER TOGETHER, THEIR CONNECTION IS LOGICAL. THE EASTERNESS I HAVE LOOKED FOR THE LOCATION OF THE BUILDING PROGRAM OF THE CLUB IN THEIR 9TH REQUIREMENTS IS ALSO INCLUDED IN THE INTERNAL AND EXTERNAL AREAS THAT ARE THROUGH JESUS. THE ROOMS AROUND THE BUILDINGS ARE FILLED BY THE BUILDINGS, THEY WERE USED BY THE USERS THROUGH THAT BUILDING TO GO TO 2ND, WHERE THEY ARE PRESENTED FOR THE USE OF THE BUILDINGS. THE LARGE AREAS OF THE LAND ARE IN THE NORTH OF THE COUNTRY TREATED AS A PUBLIC AREA DESIGNED FOR REMOVAL OR RELAXATION. Yet, in the southern part, there is a pavilion for the public to various sports. THERAPEUTICAL ADJUSTMENTS OF THE SOUTH PART MAKES THE OPPORTUNITY OF CULTURAL PROJECTS FOR THE PUBLIC.

This thesis presents a safety inspection in selected places in the Vysocina region of the Czech Republic. Six intersections in rural and municipal areas, plus three rural road sections were selected for the inspection and an accident rate analysis. The places selected were compared in terms of the accident rate and one case of each group was then selected for a detailed safety inspection encompassing visual inspection and identification of possible hazards. By eliminating such safety hazards, it is possible to ensure a traffic fluency and to preclude traffic accidents or at least minimize the harm caused by it.

Le nicotinamide est une vitamine fournie par l'alimentation et utilisée en thérapie dans le traitement de certaines pathologies humaines. Chez Leishmania, un protozoaire parasite responsable des leishmanioses, cette vitamine présente une action toxique contre le parasite et une action synergique avec l'antimoine, la principale molécule utilisée dans le traitement des leishmanioses. En recherchant le mode d'action de cette vitamine, nous avons observé qu'elle était en réalité un précurseur essentiel à la synthèse du NAD+ chez le parasite, un cofacteur responsable de la plupart des réactions d'oxydoréduction chez tous les êtres vivants. Leishmania étant en effet dépourvu des voies de synthèse de novo du NAD+, il doit le générer à partir de précurseurs qu'il importe depuis son environnement (nicotinamide, nicotinamide riboside, acide nicotinique). Cette auxotrophie du parasite pour le NAD+ révèle donc un rôle ambivalent du nicotinamide, à la fois toxique à fortes concentrations et pourtant essentiel à sa survie en tant que précurseur majeur du NAD+. À partir des bases de données, nous avons reconstitué l'ensemble de la voie de synthèse du NAD+ chez Leishmania. Parmi les enzymes impliquées, nous avons identifié une nicotinamidase qui n'a pas d'homologue chez les mammifères, et qui assure la conversion du nicotinamide en acide nicotinique, première étape à la synthèse du NAD+. Cette enzyme étant un candidat intéressant pour le développement de molécules ciblant spécifiquement le parasite, nous avons réalisé la caractérisation fonctionnelle de ce gène. Son inactivation induit une diminution importante de la concentration en NAD+ chez le parasite et provoque un arrêt de la prolifération en culture, ainsi qu'une incapacité des mutants à établir une infection durable chez la souris. L'obtention de la structure de la nicotinamidase de L. infantum nous offre désormais la possibilité de développer des inhibiteurs spécifiques contre cette nouvelle cible thérapeutique. / Nicotinamide is a vitamin provided by food that is already used in human therapy. In Leishmania protozoan parasites, this molecule shows toxic activity against parasites and has synergistic activity with antimonials, the main drugs used to treat leishmaniasis. By investigating the mode of action of this cheap vitamin, we discovered that nicotinamide is in fact the main precursor of NAD+ synthesis in Leishmania, a redox cofactor essential for all living cells. Leishmania are indeed devoid of a de novo NAD+ pathway and must synthesize it by scavenging precursors from their environment (nicotinamide, nicotinic acid and nicotinamide riboside). This NAD+ auxotrophy reveals a mixed pattern of activity of nicotinamide in Leishmania, i.e. toxic at high concentrations but also essential for parasite survival through its role in NAD+ synthesis. All enzymes of the Leishmania NAD+ salvage pathway were then identified from genome databases. We focused on a putative nicotinamidase, which has no homolog in mammals and governs the conversion of nicotinamide to nicotinic acid, the first step in the NAD+ salvage pathway. Since this enzyme could be considered as an attractive therapeutic target to develop specific parasite inhibitors, we performed a functional analysis of the corresponding gene. Targeted deletion of the nicotinamidase encoding gene induced a marked drop in parasite NAD+ content and a phenotype with strongly delayed growth. Additionally, these mutants are unable to establish durable infections in mice. The crystal structure of the nicotinamidase from L. infantum will allow us to develop specific inhibitors against this new therapeutic target.

The thesis deals with specialized departments instituted in prisons for persons who are in jail execution. It picks up on the bachelor's thesis on compulsory treatment of persons while the imprisonment. Its sub-objective is to introduce the issue of prison system as a whole, apprise of the specific groups of convicted offenders who are currently put into specialized departments. The thesis is divided into two parts, theoretical and empirical. Theoretical part presents the development of the prison system, the philosophy of punishment and highlights the humanization of the Czech prison system. The section, which is dedicated to specialized departments, itemizes the different types of these departments. An example of concrete prison which establishes such department is also always presented. More attention is paid to the Světlá nad Sázavou Prison, to its conception and to its specialized department for mothers with children. The objective of the thesis was to find out what view of Světlá nad Sázavou Prison with its specialized department take the citizens of Světlá nad Sázavou and the neighbouring residents and how the media affects the overall insight into this concernment or what other factors assert.