Abstract The Dlx genes play an important role in the differentiation and migration of gamma-aminobutyric acid (GABA) interneurons of mice. GABAergic interneurons are born in the proliferative zones of the ventral telencephalon and migrate to the cortex early during mouse development. Single Dlx mutant mice show only subtle phenotypes. However, the migration of immature interneurons is blocked in the ventral telencephalon of Dlx1/Dlx2 double mutant mice leading to reduction of GABAergic interneurons in the cortex. Also, Dlx5/Dlx6 expression is almost entirely absent in the forebrain, most probably due to cross-regulatory mechanisms. In zebrafish, the role of dlx genes in GABAergic interneuron development is unknown. By injecting Morpholino, we double knocked down dlx1 and dlx2 genes in wildtype zebrafish to investigate the function of the two genes in zebrafish GABAergic interneuron development. By comparing different subsets of GABAergic interneuron development in wildtype and dlx1/2 morphant zebrafish forebrain, we found out that at 3dpf, 4dpf and 7dpf, double knockdown of dlx1 and dlx2 genes in zebrafish remarkably reduced the number of Calbindin-, Somatostatin- and Parvalbumin-positive GABAergic neurons, whereas the development of Calretinin-positive neurons is slightly affected. These results suggest that in zebrafish, dlx1a and dlx2a genes are important for the development of certain subtypes of GABAergic interneurons (Calbindin-, Somatostatin- and Parvalbumin-positive neurons) and may have minor influence on Calretinin-positive neuron development. This also suggests that different regulatory mechanisms are involved in the development of the different subtypes of GABAergic interneurons.

During storage of grain, there may have significant damage to its quality due to unfavorable physical and biological interactions and thus requires continuous monitoring. Therefore, an easy, cost-effective and environmentally friendly method is necessary for efficient monitoring of stored-grain. Arrays of sensors are being used for classifying liquors, perfumes, quality of food products mimicking mammalian olfactory systems. Monitoring of stored grain is a new application of sensor arrays. The main objective was to fabricate a carbon black polymer sensor array which can easily monitor incipient grain spoilage by detecting spoiling stored grain volatiles (benzene derivatives and aliphatic hydrocarbon derivatives) with minimum interference from relative humidity. Various aspects of a good sensor were analyzed using statistical analysis (RSD, LDA, PCA, t-test). The developed sensor array can identify red flour beetle-infected and uninfected wheat and fungal volatiles at ambient conditions as well as some stored grain conditions (MC 16%, RH 52%).

The Roman period is well represented in Kent’s long history of excavation and discovery and it has some prominent sites. Nevertheless, there has been relatively little in the way of up-to-date synthesis or the application of current theoretical approaches. In common with many other areas of the country, rural settlement, especially ‘non-villa’ settlement, has received scant attention, whilst even its villas are mostly poorly understood. Since the advent of PPG 16 many more such rural sites have been excavated and there has been a corresponding rise, both qualitative and quantitative, in associated data, much of which remains unpublished. This thesis aims to reassess the Roman period of Kent from a rural standpoint, using a wide range of materials to construct a more nuanced and theoretically informed narrative. The basis of the study is the Kent HER. The archaeological data are combined with a number of landscape resources in order to reveal the influence of Kent’s highly varied terrain and the ways in which it was understood and exploited. Aspects of building and settlement morphology are examined and the potential of artefactual and ecofactual data for adding refinement to our understanding is explored. In its use of unpublished (‘grey’) literature, it is in line with current research priorities at national level. Results indicate that strongly patterned distributions of evidence were influenced both by Kent’s physical landscape and by human landscapes of tradition and culture. The county’s archaeological record has features that distinguish it from other southern counties and from the received trajectory of Roman Britain as a whole. This thesis places Romano-British Kent within its wider chronological and geographical context, noting its particular characteristics and finding that it is an eastern, rather than a southern county, following a trajectory very similar to that of northern Gaul.

Abstract The Dlx genes play an important role in the differentiation and migration of gamma-aminobutyric acid (GABA) interneurons of mice. GABAergic interneurons are born in the proliferative zones of the ventral telencephalon and migrate to the cortex early during mouse development. Single Dlx mutant mice show only subtle phenotypes. However, the migration of immature interneurons is blocked in the ventral telencephalon of Dlx1/Dlx2 double mutant mice leading to reduction of GABAergic interneurons in the cortex. Also, Dlx5/Dlx6 expression is almost entirely absent in the forebrain, most probably due to cross-regulatory mechanisms. In zebrafish, the role of dlx genes in GABAergic interneuron development is unknown. By injecting Morpholino, we double knocked down dlx1 and dlx2 genes in wildtype zebrafish to investigate the function of the two genes in zebrafish GABAergic interneuron development. By comparing different subsets of GABAergic interneuron development in wildtype and dlx1/2 morphant zebrafish forebrain, we found out that at 3dpf, 4dpf and 7dpf, double knockdown of dlx1 and dlx2 genes in zebrafish remarkably reduced the number of Calbindin-, Somatostatin- and Parvalbumin-positive GABAergic neurons, whereas the development of Calretinin-positive neurons is slightly affected. These results suggest that in zebrafish, dlx1a and dlx2a genes are important for the development of certain subtypes of GABAergic interneurons (Calbindin-, Somatostatin- and Parvalbumin-positive neurons) and may have minor influence on Calretinin-positive neuron development. This also suggests that different regulatory mechanisms are involved in the development of the different subtypes of GABAergic interneurons.

>Magister Scientiae - MSc / With the development of information and network technologies, Electronic Health Records (EHRs) management system has gained wide spread application in managing medical records. One of the major challenges of EHRs is the independent nature of medical institutions. This non-collaborative nature puts a significant barrier between patients, doctors, medical researchers and medical data. Moreover, unlike the unique and strong anti-tampering nature of traditional paper-based records, electronic health records stored in centralization database are vulnerable to risks from network attacks, forgery and tampering. In view of the data sharing difficulties and information security problems commonly found in existing EHRs, this dissertation designs and develops a credible Blockchain-based electronic health records (CB-EHRs) management system.

Masters of Science / With the development of information and network technologies, Electronic Health Records (EHRs) management system has gained wide spread application in managing medical records. One of the major challenges of EHRs is the independent nature of medical institutions. This non-collaborative nature puts a significant barrier between patients, doctors, medical researchers and medical data. Moreover, unlike the unique and strong anti-tampering nature of traditional paper-based records, electronic health records stored in centralization database are vulnerable to risks from network attacks, forgery and tampering. In view of the data sharing difficulties and information security problems commonly found in existing EHRs, this dissertation designs and develops a credible Blockchain-based electronic health records (CB-EHRs) management system. To improve security, the proposed system combines digital signature (using MD5 and RSA) with Role-Based Access Control (RBAC). The advantages of these are strong anti-tampering, high stability, high security, low cost, and easy implementation. To test the efficacy of the system, implementation was done using Java web programming technology. Tests were carried out to determine the efficiency of the Delegated Byzantine Fault Tolerance (dBFT) consensus algorithm, functionality of the RBAC mechanism and the various system modules. Results obtained show that the system can manage and share EHRs safely and effectively. The expectation of the author is that the output of this research would foster the development and adaptation of EHRs management system.

No description available.

La survie des cellules cancéreuses dépend d’une activité énergétique et biosynthétique accrue et la glutamine participe à de nombreux processus nécessaires à cette adaptation métabolique. Dans les leucémies aiguës myéloïdes (LAM), la croissance et la prolifération sont favorisées par l’activation anormale de plusieurs voies de signalisation, et notamment par la voie mTORC1. Les acides aminés essentiels, et en particulier la leucine, sont indispensables à l’activation de mTORC1. La glutamine est captée par la cellule via le transporteur SLC1A5 et permet ensuite l’entrée de la leucine via le transporteur bidirectionnel SLC7A5. La concentration en glutamine est donc une étape limitante dans l’activation de mTORC1 par la leucine. Nous avons étudié les effets de la privation en glutamine dans les LAM à l’aide de différents outils (milieu sans glutamine, shARN inhibant l’expression du transporteur de la glutamine SLC1A5 et la drogue L-asparaginase, qui a une activité de glutaminase extracellulaire), et observé une inhibition de mTORC1 et de la synthèse protéique. L’inhibition du transporteur SLC1A5 inhibe la pousse tumorale dans un modèle de xénotransplantation. La L-asparaginase inhibe mTORC1 et induit une apoptose de façon proportionnelle à son activité glutaminase et complètement indépendante de la concentration en asparagine. La privation en glutamine induit l’expression de la glutamine synthase et l’autophagie, et ces deux processus peuvent être des mécanismes de résistance intrinsèques ou acquis dans certaines lignées leucémiques. L’apoptose induite par la privation en glutamine n’est cependant pas liée à l’inhibition de mTORC1, puisqu’elle n’est pas diminuée par l’utilisation d’un mutant de mTOR non inhibé par la privation en glutamine. Nous nous sommes donc intéressés à une autre voie dépendante de la glutamine dans de nombreux cancers, la phosphorylation oxydative. L’étape initiale du catabolisme intracellulaire de la glutamine est la conversion de la glutamine en glutamate par des enzymes appelées glutaminases. Différentes isoformes des glutaminases existent qui sont codées chez l’homme par les gènes GLS1 et GLS2. Le glutamate est ensuite transformé en α-cétoglutarate, intermédiaire du cycle TCA. Dans les lignées de LAM, la privation en glutamine inhibe la phosphorylation oxydative mitochondriale. Nous avons observé que la protéine glutaminase C (GAC), une des isoformes de GLS1, est constamment exprimée dans les LAM mais aussi dans les progéniteurs hématopoïétiques CD34+ normaux. L’inhibition d’expression de la GLS1 par des shARN inductibles ou bien par le composé CB-839 réduit la phosphorylation oxydative, conduisant à une inhibition de prolifération et à une induction d’apoptose des cellules leucémiques. L’invalidation génétique de la GLS1 inhibe la formation de tumeur et améliore la survie des souris dans un modèle de xénotransplantation. A l’inverse, le ciblage de la GLS1 n’a pas d’effets cytotoxiques ni cytostatiques sur les progéniteurs hématopoïétiques normaux. Ces effets anti-leucémiques sont inhibés par l’adjonction d’α-cétoglutarate, et ceux induit par le CB-839 sont abrogés lorsqu’est exprimé de façon ectopique un mutant GACK320A hyperactif, attestant du rôle essentiel du maintien d’un cycle TCA actif dans les cellules de LAM. Enfin, nous montrons que l’inhibition de la glutaminolyse active la voie d’apoptose mitochondriale intrinsèque et agit en synergie avec l’inhibition spécifique de BCL-2 par l’ABT-199. Ces résultats démontrent que le ciblage spécifique de la glutaminolyse est une autre façon d’exploiter l’addiction à la glutamine des cellules leucémiques de LAM et que le maintien d’un cycle TCA actif est essentiel à la survie de ces cellules. / Cancer cells survival is dependent on high energetic and biosynthetic activity, and glutamine is involved in many metabolic processes necessary for this adaptation. In acute myeloid leukemia (AML), growth and proliferation are promoted by activation of several signaling pathways, including mTORC1. Essential amino acids, in particular leucine, are required for mTORC1 activation. Glutamine enters into the cell via the SLC1A5 transporter and then allows the input of leucine via the bidirectional SLC7A5 transporter. Therefore, the intracellular glutamine concentration is a limiting step in the activation of mTORC1 by leucine. We studied the effects of glutamine deprivation in AML using different tools (medium without glutamine, shRNA against the SLC1A5 glutamine transporter and the drug L-asparaginase, which has an extracellular glutaminase activity) and observed mTORC1 and protein synthesis inhibition. SLC1A5 transporter knockdown inhibits tumor growth in a xenotransplantation model. L-asparaginase inhibits mTORC1 and induces apoptosis in proportion to its glutaminase activity and independently of asparagine concentration. Glutamine privation induces the expression of glutamine synthase and autophagy, and these two processes are involved in the resistance to glutamine privation in some leukemic cell lines. However, apoptosis induced by glutamine privation is not related to the inhibition of mTORC1, since it is not modified in the presence of a constitutively active mutant of mTOR. We next focused on the oxidative phosphorylation, another glutamine dependent pathway in many cancers. The initial step of the intracellular catabolism of glutamine is the conversion of glutamine to glutamate by enzymes called glutaminases. Different glutaminases isoforms exist that are encoded by the GLS1 and GLS2 genes. Glutamate is then converted to α-ketoglutarate, an essential TCA cycle intermediate. In AML cell lines, we observed that glutamine privation inhibits mitochondrial oxidative phosphorylation. The protein glutaminase C (GAC), an isoform of GLS1, is constantly expressed in AML but also in normal CD34 + hematopoietic progenitors. The knockdown of GLS1 by inducible shRNA or by the CB-839 compound reduced oxidative phosphorylation, leading to proliferation inhibition and apoptosis induction in leukemia cells. Genetic invalidation of GLS1 inhibits tumor formation and improves survival of mice in a xenograft model. Conversely, the targeting of GLS1 has no cytotoxic or cytostatic effects on normal hematopoietic progenitors. These anti-leukemic effects are inhibited by the addition of α-ketoglutarate, and those induced by the CB-839 are suppressed in the presence of an ectopically expressed GACK320A hyperactive mutant, confirming the essential role of maintaining an active TCA cycle in AML cells. Finally, we showed that glutaminolysis inhibition induces the intrinsic mitochondrial pathway of apoptosis and acts synergistically with the specific inhibition of BCL-2 by ABT-199. These results demonstrate that specific targeting of glutaminolysis is another way to exploit glutamine addiction in AML and that an active TCA cycle in essential for AML cell survival.

<p>Stalna promena postala je način života u svetu biznisa. U stvari, da bi se danas održala konkurentnost, potrebno je da se pored pa- žnje koja se posvećuje pobolj&scaron;anju posla koji se danas obavlja misli i na to &scaron;ta treba da se preduzme da bi se izdržala konkurencija i opstalo u budućnosti. Naime, uspe&scaron;ni poslovni subjekti u sve turbulentnijem okruženju moraju da uvažavaju činjenicu da je poslovna izvrsnost osnovna determinanta koja obezbeđuje njihov opstanak, razvoj i rast. Zbog toga ocena stanja poslovne izvrsnosti i postavljenih ciljeva mora da se meri kao i sve drugo putem tehnike benčmarkinga, kako u slučaju usavr&scaron;avanja proizvoda, usluga i procesa, tako i kod projektovanog razvoja. Poslovni subjekt treba, prema autoru Piteru Drakeru (Piter Drucker), da se u određenim intervalima kritički osvrne na rezultate postignute u poslovnoj izvrsnosti. Benčmarking omoguća- va poslovnim subjektima da sagledaju svoju trži&scaron;nu poziciju i na bazi učenja, prevashodno od trži&scaron;nih lidera, unaprede svoju konkurentsku prednost.<br />Nepostojanje modela za brzu ocenu poslovne izvrsnosti zasnovanog na kvantifikovanim atributima koji je determini&scaron;u otežava prethodno utvrđivanje stanja konkurentske prednosti. Kreirani model (CB MODEL) za ocenu atributa benčmarkinga koji determini&scaron;u poslovnu izvrsnost poslovnog subjekta u sada&scaron;njosti i u budućnosti i edukacija s provedena na bazi utvrđene ocene znače aktueli- zaciju novih znanja, koja neutrali&scaron;u uočene probleme i omogućuju top-menadžmentu poslovnog subjekta dono&scaron;enje brze i efikasne odluke koja povećava verovatnoću njegovog opstanka, razvoja i rasta.</p>

The purpose of my thesis is to study the lament in ancient Greek culture, and to show how its ritual meaning is interpreted by literature. The terms goos, oimoge, threnos and linos not only indicate the presence of different ritual attitudes to death but also the existence of different interpretations for each of them. The goos and the oimoge mirror an archaic religiosity and consist of sinister utterances aimed at summoning ghosts, requesting for divine revenge, etc. Aeschylus introduces them as aischrologic acts as he implies the presence of a god or a daimon. Sophocles and Euripides use them as dysphemic elements and censure an approach to death which implies that gods are vindictive, deceitful and unjust. However, they also introduce an euphemic goos consisting in an expression of feelings. The threnos only appears in funerary contexts in Homer while is often introduced as dysphemic in drama. The linos-song is mentioned as a vintage-song in Homer, it appears as a lament and then as a song for some hero’s apotheosis or return to life in drama. The poetic use of these terms serves to understand how the social and political meaning of the ritual was understood and codified by literature.