Finding neural correlates of intelligence and cognitive abilities in the developing brain during childhood may be important in many ways, such as predicting and understanding educational abilities or making clinical evaluations of patients. Even if substantial contemporary research has established relationships between brain structures and general intelligence, little is known about the lingual gyri and their links to IQ. In this thesis it is examined (1) whether cortical thickness in the right and left lingual gyri is associated with different levels of IQ in childrenand (2) if the rate of change in cortical thickness located in the lingual gyri is associated with change in Performance IQ (PIQ). Neuroimaging data originated from a study by Solé-Casals and colleagues (2019) as well as a dataset from a study by Suárez-Pellicioni and colleagues(2019). Both datasets were downloaded from the OpenNeuro library of brain imaging data. Neuroimaging metrics of twenty-nine boys of approximately twelve years of age were utilizedto test the hypothesis that higher IQ is related to thinner cortical thickness in lingual gyri. Neuroimaging metrics of twenty-one girls and fifteen boys under fourteen years of age utilized to examine if the rate of change in cortical thickness is related to a change in Performance IQ.Results revealed that high IQ was related to thinner cortical thickness at the age of twelve. Further results indicated that rate of thinning of the cortex in the lingual gyri is correlated to change in Performance IQ. The present thesis adds to the growing evidence that regional cortical thickness and change of cortical thickness are relevant biomarkers for intelligence. Future research with larger sample sizes and longitudinal design with additional points in timemight be needed to confirm the results of the present thesis.

Für die Beurteilung der Hirnentwicklung erfolgte eine postmortale MRT- Untersuchung von totgeborenen Kindern im Rahmen einer virtuellen Autopsie. Besondere Berücksichtigung innerhalb dieses Datenmaterials fand die Oberflächenveränderung im Sinne der Entstehung von Gyri und Sulci. Weiterhin wurde geprüft, wie sich die morphologische Entwicklung und damit die Germination und Migration der Nervenzellen in diesem Schwangerschaftszeitraum in der MRT darstellen und beurteilen lässt. Im Ergebnis der Untersuchung zur Germination und Migration war vor allem zwischen der 18. und 25. SSW die zonale Gliederung des Hirnmantels mit “ventricular zone“, “intermediate zone“, “subplate zone“ und “cortical plate“ durch wechselnde Hypo –bzw. Hyperintensitäten in der MRT gut zu beurteilen. Der zeitlich geordnete Ablauf in der Entstehung einzelner Sulci konnte in dieser Arbeit unter anderem auch mittels eines atlasartigen Teils abgebildet werden. Dabei zeigte sich eine häufig etwas frühere Darstellbarkeit einzelner Sulci im postmortalen MRT im Vergleich zu den Studien an pränatalen MRT´s bei Schwangeren. Eine Streubreite des Auftretens der einzelnen Sulci von 2-3 Wochen bei gesunden Feten ist dabei zu berücksichtigen.

La recherche des variations anatomiques du cortex, complémentaire des investigations fonctionnelles, a été fortement stimulée ces dernières années par le développement des méthodes d'analyse des images cérébrales. Ces nouvelles possibilités ont conduit à la création de vastes projets de cartographie anatomo-fonctionnelle du cerveau humain, comparables par l'ampleur qu'ils pourraient prendre aux projets de cartographie du génome. Durant les années 90, la communauté de la neuroimagerie a choisi d'appréhender ce problème en développant une technique appelée la normalisation spatiale. Il s'agit de doter chaque cerveau d'un système de coordonnées (surfaciques ou volumiques) qui indiquent une localisation dans un cerveau de référence. Ce système s'obtient en déformant chaque nouveau cerveau de manière à l'ajuster autant que possible au cerveau de référence. Cependant, cette morphométrie fond ée sur la technique de normalisation spatiale a des limites. En effet, il est largement admis qu'elle ne permet pas de gérer précisément la très grande variabilité des plissements corticaux et ne donne accès qu'aux différences anatomiques les plus marquées. Ces considérations ont motivé le développement de nouveaux outils de morphométrie, permettant l'analyse ne des structures corticales. Jusqu'à ces dernières années, une telle morphométrie structurelle, prenant en compte les particularités anatomiques individuelles de chaque cortex, était limitée par la difculté et la lourdeur du travail «manuel» à réaliser. Le développement récent de nouveaux outils d'analyse d'images, permettant d'extraire et de reconnaître automatiquement les sillons corticaux des images IRM anatomiques, a modié cet état de fait et a ouvert la voie aux études à grandes échelles de morphométrie structurelle. Cependant, d'un point de vue anatomo-fonctionnel, la structure de base du cortex est le gyrus et non pas le sillon. Or, si la littérature propose maintenant de nombreuses méthodes dédiées aux sillons corticaux, il n'en existe aucune spécifique aux gyri, essentiellement à cause de leur très grande variabilité morphologique. Le premier axe de travail de cette thèse est le développement d'une méthode entièrement automatique pour les segmenter, prenant en compte leur anatomie individuelle. Cette méthode propose un formalisme générique pour définir chaque gyrus à partir d'un ensemble de sillons-frontières le délimitant; un critère de distance, sous-jacent au diagramme de Voronoï utilisé pour parcelliser la surface corticale, permet d'extrapoler cette définition dans les zones où les sillons sont interrompus. L'étude des mécanismes mis en jeu lors du plissement du cortex durant son développement, ante- et post-natal, est un point clé pour analyser et comprendre les variations de l'anatomie corticale, normale ou non, et caractériser ses liens avec le fonctionnement du cerveau. Des travaux récents suggèrent qu'il existerait une proto-organisation sulcale stable, visible sur le cerveau du foeœtus, et qui laisserait une empreinte dans le relief cortical adulte. Pour le deuxième axe de travail de cette thèse, nous avons essayé de recouvrer les traces de ces structures enfouies, les racines sulcales, inscrites dans les plissements corticaux. Nous avons pour cela développé un modèle original du cortex, le primal sketch des courbures, permettant une description multi-échelles et structurelle de la courbure corticale. Cette description est issue d'un lissage surfacique de la carte (2D) de la courbure, obtenu par l'implantation de l'équation de la chaleur, calculée géodésiquement au maillage de la surface corticale. Cette description nous a permis de recouvrer les deux racines sulcales putatives enfouies dans le sillon central, et les quatre racines du sillon temporal supérieur. En parallèle, nous avons initié une étude directe des premiers plis sulcaux à travers la reconstruction tridimensionnel du cerveau foeœtal in utero.

Für die Beurteilung der Hirnentwicklung erfolgte eine postmortale MRT- Untersuchung von totgeborenen Kindern im Rahmen einer virtuellen Autopsie. Besondere Berücksichtigung innerhalb dieses Datenmaterials fand die Oberflächenveränderung im Sinne der Entstehung von Gyri und Sulci. Weiterhin wurde geprüft, wie sich die morphologische Entwicklung und damit die Germination und Migration der Nervenzellen in diesem Schwangerschaftszeitraum in der MRT darstellen und beurteilen lässt. Im Ergebnis der Untersuchung zur Germination und Migration war vor allem zwischen der 18. und 25. SSW die zonale Gliederung des Hirnmantels mit “ventricular zone“, “intermediate zone“, “subplate zone“ und “cortical plate“ durch wechselnde Hypo –bzw. Hyperintensitäten in der MRT gut zu beurteilen. Der zeitlich geordnete Ablauf in der Entstehung einzelner Sulci konnte in dieser Arbeit unter anderem auch mittels eines atlasartigen Teils abgebildet werden. Dabei zeigte sich eine häufig etwas frühere Darstellbarkeit einzelner Sulci im postmortalen MRT im Vergleich zu den Studien an pränatalen MRT´s bei Schwangeren. Eine Streubreite des Auftretens der einzelnen Sulci von 2-3 Wochen bei gesunden Feten ist dabei zu berücksichtigen.:Inhaltsverzeichnis 1. Einleitung............................................................................ 1 2. Zielstellung der Arbeit........................................................ 2 3. Material und Methode...................................................... ... 3 3.1. Patientengut.............................................................................. 3 3.1.1. Einschlusskriterien........................................................... 3 3.1.2 Ausschlusskriterien.......................................................... 4 3.2. Methodisches Vorgehen............................................................. 5 3.2.1. MRT- Technik.................................................................. 5 3.2.2. Auswertung...................................................................... 5 3.2.3. Statistische Methoden...................................................... 6 4. Ergebnisse............................................................................ 8 4.1. Beschreibung der periventrikulären Germination und Migration zwischen der 16. –und 30. Schwangerschaftswoche............ 8 4.1.1 Grundlagen....................................................................... 8 4.1.2 Germination und Migration in der 16. SSW...................... 10 4.1.3 Germination und Migration in der 17. –bis 20. SSW......... 12 4.1.4 Germination und Migration in der 21. –bis 23. SSW......... 14 4.1.5 Germination und Migration in der 24. –bis 26. SSW......... 16 4.1.6 Germination und Migration in der 27. –bis 30. SSW.......... 18 4.2 Statistische Kennwerte der Germination und Migration ........ 20 4.3 Auswertung der Cortexbreite..................................................... 22 4.3.1 Breitenentwicklung des Kortex im Frontallappen................ 22 4.3.2 Korrelation der frontalen Kortexbreite mit klinischen Daten.................................................................................. 23 4.3.2.1 Frontale Kortexbreite und Schwangerschaftswoche............................... 24 4.3.2.2 Frontale Kortexbreite und Geburtsgewicht.... 24 4.3.3 Breitenentwicklung des Kortex im Parietallappen............... 25 4.3.3 Korrelation der parietalen Kortexbreite mit klinischen Daten................................................................................... 27 4.3.4.1 Parietale Kortexbreite und Schwangerschaftswoche.............................. 27 4.3.4.2 Parietale Kortexbreite und Geburtsgewicht.. 27 4.3.5 Breitenentwicklung des Kortex im Temporallappen.......... 28 4.3.6 Korrelation der temporalen Kortexbreite mit klinischen Daten................................................................................. 29 4.3.6.1 Temporale Kortexbreite und Schwangerschaftswoche.............................. 29 4.3.6.2 Temporale Kortexbreite und Geburtsgewicht............................................. 30 4.3.7 Breitenentwicklung des Kortex im Occipitallappen............ 30 4.3.8 Korrelation der occipitalen Kortexbreite mit klinischen Daten.................................................................................. 32 4.3.8.1 Occipitale Kortexbreite und Schwangerschaftswoche.................................... 32 4.3.8.2 Occipitale Kortexbreite und Geburtsgewicht...... 32 4.3.9 Unterschiede der Breitenentwicklung in den einzelnen Hirnlappen.......................................................................... 33 4.4 Auftreten der Hirnsulci im Schwangerschaftsverlauf.............. 35 4.4.1 Mediale Hirnoberfläche....................................................... 35 4.4.2 Ventrale Hirnoberfläche....................................................... 37 4.4.3 Laterale Hirnoberfläche....................................................... 38 4.4.4 Sulci des Vertex................................................................... 42 4.5 Übersicht zur Entwicklung der Sulci........................................... 44 4.6 Corpus callosum........................................................................... 46 4.7 Varianz einzelner Parameter der Hirnentwicklung zwischen der 21. –und 24. Schwangerschaftswoche............................................. 47 4.7.1 Frontale Kortexbreite............................................................ 47 4.7.2 Parietale Kortexbreite........................................................... 48 4.7.3 Temporale Kortexbreite........................................................ 48 4.7.4 Occipitale Kortexbreite......................................................... 49 4.7.5 Länge des Corpus callosum zwischen 21. und 24.SSW...... 49 4.7.6 Entwicklungsvariabilität ausgewählter Sulci......................... 50 4.7.6.1 Sylvi´sche Furche………………………………….. 50 4.7.6.2 Sulcus parietooccipitalis………………………… 51 4.7.6.3 Sulcus calcarinus……………………………….... 52 4.7.6.4 Sulcus centralis…………………………………... 53 4.7.6.5 Sulcus lateralis ………………………………….. 54 4.7.6.6 Sulcus frontalis superior…………………………. 55 4.7.6.7 Sulcus praecentralis……………………………… 56 5. Diskussion.............................................................................. 57 6. Zusammenfassung................................................................ 73 7. Limitationen............................................................................ 75 8. Bildatlas als Zusammenfassung einer normalen zeitlichen Hirnentwicklung zwischen der 16. –und 30. SSW................................................................... 76 Quellenverzeichnis................................................................................. 98 Abbildungsverzeichnis.......................................................................... 101 Tabellenverzeichnis............................................................................... 105 Erklärung über die eigenständige Abfassung der Arbeit Lebenslauf Danksagung

A steady state level of negative supercoiling is essential for chromosome condensation, initiation of replication and subsequent elongation step. DNA gyrase, found in every eubacteria, serves the essential housekeeping function of maintenance of the negative supercoiling status of the genome. The functional holoenzyme is a heterotetramer, comprising of two GyrA and two GyrB subunits. DNA gyrase is an indispensable enzyme and serves as a readily susceptible target for natural antibacterial agents. The enzymatic steps of topoisomerisation by gyrase involve transient double strand break and rejoining of the strands after intact duplex transfer. Corruption of its catalytic cycle can lead to the generation of cytotoxic double-strand DNA breaks. Most of the anti-gyrase agents achieve their objective by targeting the vulnerable step of the reaction cycle i.e. DNA cleavage step. Bacteria on their part must have evolved and adopted strategies to counter the action of external agents and prevent the generation of double strand breaks thereby safeguarding their genome. In the present thesis, attempts have been made to understand the role of three endogenous gyrase interacting proteins in gyrase modulation and cellular defense against anti-gyrase agents. The thesis is divided into six chapters. Chapter 1 introduces the wonder enzymes “DNA topoisomerases” starting with a brief classification of these enzymes and their physiological functions. In the next section, DNA gyrase has been discussed in greater detail. The structural aspects as well as the mechanism of the topoisomerisation reaction catalyzed by gyrase have been discussed. Final section gives an overview of different gyrase modulators known till date focusing on their source, structure and mode of action. The scope and objectives of the present study is presented at the end of this chapter. In Chapter 2 is aimed at understanding the physiological role of GyrI. GyrI, originally identified in Escherichia coli as an inhibitor of DNA gyrase, has been previously shown in the laboratory to render protection against gyrase poisons and also various other DNA damaging agents (mitomycin C, MNNG). Abolishing GyrI expression renders the cell hypersensitive to these cytotoxic agents. Interestingly, GyrI exhibits contrasting behavior towards two plasmid encoded proteinaceous poisons of DNA gyrase. It reduces microcin B17-mediated double-strand breaks in vivo, imparting protection to the cells against the toxin. However, a positive cooperation between GyrI and F plasmid encoded toxin CcdB, results in enhanced DNA damage and cell death. These results suggest a more complex functional interplay and physiological role for GyrI. Search for other chromosomally encoded gyrase inhibitors led to YacG, a small zinc finger protein (7.3kDa) from E. coli, shown to be a member of DNA gyrase interactome, in a protein-protein interaction network described recently. Chapter 3 deals with the detailed characterization of YacG. It is shown that YacG inhibits DNA gyrase by binding to GyrB subunit and preventing DNA binding activity of the enzyme. More importantly, it protects against the cytotoxic effects of other gyrase inhibitors like ciprofloxacin, novobiocin, microcin B17 and CcdB. Further investigations revealed that YacG and its homologues are found only in proteobacteria. Hence, it appears to be a defense strategy developed by gram-negative bacteria to fight against the gyrase targeting cytotoxic agents. Inhibition by YacG appears to be specific to E. coli gyrase as mycobacterial enzyme is refractile to YacG action. GyrB, only in gram-negative organisms, possesses extra stretch of 165 amino acids, indispensable for DNA binding. Biochemical experiments with the truncated GyrB lacking the extra stretch reveal the importance of this stretch for stable YacG-GyrB interaction. E. coli topoisomerase IV is also resistant to YacG mediated inhibition, probably due to the absence of the extra stretch in ParE subunit, which is otherwise highly similar to GyrB. Further, YacG homologues from other proteobacterial members (Sinorhizobium meliloti and Haemophilus influenzae homologues sharing 35% and 63 % identity with E. coli YacG respectively ) also inhibits E. coli DNA gyrase at comparable levels. YacG thus emerges as a proteobacteria specific inhibitor of DNA gyrase. The occurrence of both YacG and the gyrase extra stretch only in proteobacteria, suggest co-evolution of interacting partners in proteobacteria. In Chapter 4, the study of endogenous gyrase modulators is extended to Mycobacterium sp. glutamate racemase (MurI) from E. coli has been shown earlier to be an inhibitor of DNA gyrase. However, nothing much was known about its mode of action. MurI is an important enzyme in the cell wall biosynthesis pathway, which catalyses the conversion of L-glutamate to D-glutamate, an integral component of the bacterial cell wall. In this chapter, it is demonstrated that M. tuberculosis MurI inhibits DNA gyrase activity, in addition to its precursor independent racemization function. The inhibition is not species specific as E. coli gyrase is also inhibited. However, it is gyrase specific as topoisomerase I activity remains unaltered. The mechanism of inhibition by MurI has been elucidated for the first time and it is shown that MurI binds to GyrA subunit of the enzyme leading to a decrease in DNA binding of the holoenzyme. The sequestration of the gyrase by MurI results in inhibition of all reactions catalyzed by DNA gyrase. Chapter 5 is the extension of the studies on glutamate racemase into another species, i.e. Mycobacterium smegmatis. DNA gyrase inhibition seems to be an additional attribute of some of the glutamate racemases, but not all, as Glr isozyme from B. subtilis has no effect on gyrase activity in spite of sharing a high degree of similarity with the gyrase inhibitory glutamate racemases. It is shown that like the M. tuberculosis MurI, M. smegmatis enzyme is also a bifunctional enzyme. It inhibits DNA gyrase in addition to its racemization activity. Further, overexpression of the enzyme in M. smegmatis provides protection to the organism against fluoroquinolones. DNA gyrase inhibitory property thus appears to be a typical characteristic of these MurI and seems to have evolved to either modulate the function of the essential housekeeping enzyme or to provide protection to gyrase against gyrase inhibitors, which cause double strand breaks in the genome. In the above chapters, it is shown that besides its crucial role in cell wall biosynthesis, mycobacterial MurI moon lights as DNA gyrase inhibitor. That the two activities exhibited by M. tuberculosis MurI are unlinked and independent of each other is demonstrated in Chapter 6. Racemization function of MurI is not essential for its gyrase inhibitory property as mutants compromised in racemization activity retain gyrase inhibition property. MurI- DNA gyrase interaction influences gyrase activity but has no effect on racemization activity of MurI. MurI expression in mycobacterial cells provides protection against the action of ciprofloxacin, thereby suggesting a role of MurI in countering external agents targeting DNA gyrase. Further M. tuberculosis MurI overexpressed in near homologous expression system of M. smegmatis yields highly soluble enzyme which can be further used for structural and functional studies. In conclusion, the studies reveal that the endogenous inhibitors essentially influence the enzyme activity by sequestering the enzyme away from DNA. None of them cause cytotoxicity, which usually arises as a result of DNA damage caused by accumulation of gyrase-DNA covalent intermediate. On the contrary they provide protection against such gyrase poisons. Comparative analysis of these proteinaceous inhibitors, however, does not reveal a common motif or structural fold, required for their ability to inhibit DNA gyrase. Based on these studies, it can be proposed that these endogenous proteins exist to serve as cellular defense strategies against external abuse and also to modulate the intracellular activity of DNA gyrase as and when required, for accurate division, functioning and survival of the cells.