”Base of the Pyramid” (BOP) beskriver de fyra miljarder människor som lever i extrem fattigdom. Även om de är fattiga har de tillsammans stark konsumentkraft, vilket gör BOP till en marknad som inte ska förbises. Företaget Emerging Cooking Solutions (ECS) tillverkar pellets av överbliven biomassa i Zambia som kan användas som bränsle i matlagningsspisar de säljer. Fallstudien på ECS avser att undersöka hur ett innovationsnätverk har möjlighet att påverka etablering av en innovation, i detta fall pellets, på en BOP-marknad. Från befintlig forskning kring BOP, innovationsprinciper samt de 4 A:na identifierades de fyra kategorierna: funktion, kostnad, distribution samt miljö som ett företag bör arbeta utifrån när de utvecklar och etablerar en produkt. Därefter analyseras kategorierna efter innovationsnätverkets nivåer. Studien visar att ifall en innovation är anpassad efter BOP-marknadens krav, samtidigt som den har tydligt koncept, är företaget mer benäget att attraherar rätt aktörer som kan påverka deras etablering. Ifall konceptet har andra värdefulla påföljder, såsom positiv miljöpåverkan, istället för bara ekonomiska kan företaget gynnas ytterligare av nätverket.

Primary human hepatocytes are a scarce resource with variable function, which diminishes with time in culture. As a consequence their use in tissue modelling and therapy is restricted. Human embryonic stem cells (hESCs) could provide a stable source of human tissue due to their properties of self-renewal and their ability to give rise to all three germ layers. hESCs have the potential to provide an unlimited supply of hepatic endoderm (HE) which could offer efficient tools for drug discovery, disease modelling and therapeutic applications. In order to create a suitable environment to enhance HE formation, hESC culture needed to be standardised. As such, a media trail was carried out to define serum free media capable of maintaining hESC in a pluripotent undifferentiated state. We also ensured hESC cultured in the various media could be directly differentiated to HE in a reproducible and efficient manner. The project then focused on the effect of post-translational modifications (PTMs), specifically SUMOylation, in hepatocyte differentiation and its subsequent manipulation to enhance HE viability. SUMOylation is a PTM known to modify a large number of proteins that play a role in various cellular processes including: cell cycle regulation, gene transcription, differentiation and cellular localisation. We hypothesised that SUMO modification may not only regulate hESC self renewal, but also maybe required for efficient hESC differentiation. We therefore interrogated the role of SUMOylation in hESC differentiation to hepatic endoderm (HE). hESC were differentiated and the cellular lysates were analysed by Western blotting for key proteins which modulate the conjugation and de conjugation of SUMO. We demonstrate that peak levels of SUMOylation were detectable in hESC populations and during cellular differentiation to definitive endoderm (DE), day 5. Following commitment to DE we observed a decrease in the level of SUMO modified proteins during cellular specialisation to a hepatic fate, corresponding with an increase in SENP 1, a SUMO deconjugation enzyme. We also detected reduced levels of hepatocyte nuclear factor 4 α (HNF4α), a critical regulator of hepatic status and metabolic function, as SUMOylation decreased. As a result, we investigated if HNF4α was SUMOylated and if this process was involved in modulating HNF4α’s critical role in HE. HNF4α is an important transcription factor involved in liver organogenesis during development and is a key regulator for efficient adult liver metabolic functions. We observed a decreasing pattern of HNF4α expression at day 17 of our differentiation protocol in conjunction with a decrease in SUMO modified proteins. In order to further investigate and validate a role of SUMOylation on HNF4α stability Immunoprecipitation (IP) was employed. HNF4α protein was pulled down and probed for SUMO 2. Results show an increase in the levels of SUMO2 modification as the levels of HNF4α decrease. Through deletion and mutation analysis we demonstrated that SUMO modification of HNF4α was restricted to the C-terminus on lysine 365. Protein degradation via the proteasome was responsible for the decrease in HNF4α, demonstrated by the use of a proteasome 26S inhibitor MG132. Additionally, a group at the University of Dundee has shown that polySUMOylation of promyelocytic leukaemia protein (PML) leads to its subsequent ubiquitination via RNF4, an ubiquitin E3 ligase, driving its degradation. Using an in vitro ubiquitination assay, we show that polySUMOylated HNF4α is preferentially ubiquitinated in the presence of RNF4. Overall polySUMOylation of HNF4α may reduce its stability by driving its degradation, hence regulating protein activity. In conclusion, polySUMOylation of HNF4α is associated with its stability. HNF4α is subsequently important for HE differentiation both driving the formation of the hepatocytes and in maintaining a mature phenotype, in agreement with a number of different laboratories. Creating the ideal environment for sustaining mature functional hepatocytes, primary and those derived from hESCs and iPSCs, is essential for further use in applications such as drug screening, disease modelling and extracorporeal devices.

Pterin-4a-carbinolamine dehydratase (PCD) is an essential component of the phenylalanine hydroxylase (PAH) system, catalyzing the regeneration of the essential cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin [6(R)BH4]. Mutations in PCD or its deactivation by hydrogen peroxide result in the generation of 7(R,S)BH4, which is a potent inhibitor of PAH that has been implicated in primapterinuria, a variant form of phenylketonuria, and in the skin depigmentation disorder vitiligo. We have synthesized and separated the 7(R) and 7(S) diastereomers confirming their structure by NMR. Both 7(R)- and 7(S)BH4 function as poor cofactors for PAH, whereas only 7(S)BH4 acts as a potent competitive inhibitor vs. 6(R)BH4 (Ki=2.3-4.9 µM). Kinetic and binding studies, as well as characterization of the pterin-enzyme complexes by fluorescence spectroscopy, revealed that the inhibitory effects of 7(R,S)BH4 on PAH are in fact specifically based on 7(S)BH4 binding. The molecular dynamics simulated structures of the pterin-PAH complexes indicate that 7(S)BH4 inhibition is due to its interaction with the polar region at the pterin binding site close to Ser-251, whereas its low efficiency as cofactor is related to a suboptimal positioning toward the catalytic iron. 7(S)BH4 is not an inhibitor for tyrosine hydroxylase (TH) in the physiological range, presumably due to the replacement of Ser-251 by the corresponding Ala297. Taken together, our results identified structural determinants for the specific regulation of PAH and TH by 7(S)BH4, which in turn aid in the understanding of primapterinuria and acute vitiligo.

Pterin-4a-carbinolamine dehydratase (PCD) is an essential component of the phenylalanine hydroxylase (PAH) system, catalyzing the regeneration of the essential cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin [6(R)BH4]. Mutations in PCD or its deactivation by hydrogen peroxide result in the generation of 7(R,S)BH4, which is a potent inhibitor of PAH that has been implicated in primapterinuria, a variant form of phenylketonuria, and in the skin depigmentation disorder vitiligo. We have synthesized and separated the 7(R) and 7(S) diastereomers confirming their structure by NMR. Both 7(R)- and 7(S)BH4 function as poor cofactors for PAH, whereas only 7(S)BH4 acts as a potent competitive inhibitor vs. 6(R)BH4 (Ki=2.3-4.9 µM). Kinetic and binding studies, as well as characterization of the pterin-enzyme complexes by fluorescence spectroscopy, revealed that the inhibitory effects of 7(R,S)BH4 on PAH are in fact specifically based on 7(S)BH4 binding. The molecular dynamics simulated structures of the pterin-PAH complexes indicate that 7(S)BH4 inhibition is due to its interaction with the polar region at the pterin binding site close to Ser-251, whereas its low efficiency as cofactor is related to a suboptimal positioning toward the catalytic iron. 7(S)BH4 is not an inhibitor for tyrosine hydroxylase (TH) in the physiological range, presumably due to the replacement of Ser-251 by the corresponding Ala297. Taken together, our results identified structural determinants for the specific regulation of PAH and TH by 7(S)BH4, which in turn aid in the understanding of primapterinuria and acute vitiligo. Pey, A. L., Martinez, A., Charubala, R., Maitland, D. J., Teigen, K., Calvo, A., Pfleiderer, W., Wood, J. M., Schallreuter, K. U. Specific interaction of the diastereomers 7(R)- and 7(S)-tetrahydrobiopterin with phenylalanine hydroxylase: implications for understanding primapterinuria and vitiligo Pterin-4a-carbinolamine dehydratase (PCD) is an essential component of the phenylalanine hydroxylase (PAH) system, catalyzing the regeneration of the essential cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin [6(R)BH4]. Mutations in PCD or its deactivation by hydrogen peroxide result in the generation of 7(R,S)BH4, which is a potent inhibitor of PAH that has been implicated in primapterinuria, a variant form of phenylketonuria, and in the skin depigmentation disorder vitiligo. We have synthesized and separated the 7(R) and 7(S) diastereomers confirming their structure by NMR. Both 7(R)- and 7(S)BH4 function as poor cofactors for PAH, whereas only 7(S)BH4 acts as a potent competitive inhibitor vs. 6(R)BH4 (Ki=2.3-4.9 µM). Kinetic and binding studies, as well as characterization of the pterin-enzyme complexes by fluorescence spectroscopy, revealed that the inhibitory effects of 7(R,S)BH4 on PAH are in fact specifically based on 7(S)BH4 binding. The molecular dynamics simulated structures of the pterin-PAH complexes indicate that 7(S)BH4 inhibition is due to its interaction with the polar region at the pterin binding site close to Ser-251, whereas its low efficiency as cofactor is related to a suboptimal positioning toward the catalytic iron. 7(S)BH4 is not an inhibitor for tyrosine hydroxylase (TH) in the physiological range, presumably due to the replacement of Ser-251 by the corresponding Ala297. Taken together, our results identified structural determinants for the specific regulation of PAH and TH by 7(S)BH4, which in turn aid in the understanding of primapterinuria and acute vitiligo. / ¿ ¿

The aim of this study is to explore the issue, whether or not Matthew in 8.16- 17 quotes Isaiah 53.4a as a proof-text without considering its context. This issue of the quotation has a great significance for two areas: hermeneutics and theology. First, the hermeneutical significance of the quotation is concerned with the issue, whether the intention and method of Matthew’s quotations of the Old Testament is a contextual approach or a non-contextual approach. Second, the theological significance of the quotation is connected to theoretical (dogmatic) and practical theology. Firstly, the significance for theoretical theology is concerned with the discussion of Matthean Christology: the identity of Jesus, the nature of his healing ministry; the provenance of his understanding of atonement. Particularly, the last one is crucial, for the whole Christian doctrine of Atonement depends on the answer to this problem. Secondly, the significance for practical theology is related to the discussion of “healing in the atonement” in Charismatic circles. This discussion can be progressed, only when it is shown that Matthew quotes Isaiah 53.4a in Matthew 8.16-17 with regard to its context, because this at least provides the basis for such a discussion. This study has attempted to treat the issue of the quotation by applying narrative analysis to Matthew 8.16-17 and the necessary part of Isaiah 52.13-53.12. This analysis includes semantic, linguistic philosophical, literary and theological explorations. With this analysis, this study has discovered an answer to the issue and some important findings, which are significant in terms of methodology, hermeneutics and theology. The answer provided by this study is that Matthew does not quote Isaiah 53.4a as a proof-text without considering the context. Rather, he, familiar with the context, quotes it in Matthew 8.16-17 in order to strategically affect the implied reader’s recognition of Jesus as, firstly, the suffering servant who is finally to offer himself as a guilt offering or a ransom, and secondly, as the Messiah. The findings are the significance of “prolepsis” in Matthew; the relationship between “ransom” lu,trον and “guilt offering” םשָ אָ ; complementary parallelism (the relationship between structure and meaning); the complementary structure of the “we” and “they” in the unfolding narrative of Isaiah 52.13-53.12; the death of the servant; and the relationship of “diseases” and “sufferings/sorrows” in 53.4a. All of these findings have enabled this study to trace the events of Jesus’ ministry and their underlying causes as far as possible to the depiction of the servant in Isaiah 52.13-53.12.

This thesis deals with the design and implementation of the document modifications and another annotation editor improvements developed as the part of the Decipher project. Explains the nature of the Decipher project and the inclusion of annotation system 4A in this project. It examines the annotation editor and propose solutions to problems and adding new functionality which makes it easier to work with annotations and also with editor itself.

no / Pterin-4a-carbinolamine dehydratase (PCD) is an essential component of the phenylalanine hydroxylase (PAH) system, catalyzing the regeneration of the essential cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin [6(R)BH4]. Mutations in PCD or its deactivation by hydrogen peroxide result in the generation of 7(R,S)BH4, which is a potent inhibitor of PAH that has been implicated in primapterinuria, a variant form of phenylketonuria, and in the skin depigmentation disorder vitiligo. We have synthesized and separated the 7(R) and 7(S) diastereomers confirming their structure by NMR. Both 7(R)- and 7(S)BH4 function as poor cofactors for PAH, whereas only 7(S)BH4 acts as a potent competitive inhibitor vs. 6(R)BH4 (Ki=2.3–4.9 μM). Kinetic and binding studies, as well as characterization of the pterin-enzyme complexes by fluorescence spectroscopy, revealed that the inhibitory effects of 7(R,S)BH4 on PAH are in fact specifically based on 7(S)BH4 binding. The molecular dynamics simulated structures of the pterin-PAH complexes indicate that 7(S)BH4 inhibition is due to its interaction with the polar region at the pterin binding site close to Ser-251, whereas its low efficiency as cofactor is related to a suboptimal positioning toward the catalytic iron. 7(S)BH4 is not an inhibitor for tyrosine hydroxylase (TH) in the physiological range, presumably due to the replacement of Ser-251 by the corresponding Ala297. Taken together, our results identified structural determinants for the specific regulation of PAH and TH by 7(S)BH4, which in turn aid in the understanding of primapterinuria and acute vitiligo. —Pey, A. L., Martinez, A., Charubala, R., Maitland, D. J., Teigen, K., Calvo, A., Pfleiderer, W., Wood, J. M., Schallreuter, K. U. Specific interaction of the diastereomers 7(R)- and 7(S)-tetrahydrobiopterin with phenylalanine hydroxylase: implications for understanding primapterinuria and vitiligo

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Les exploitations d’argiles kaoliniques réfractaire d’Água Limpa/Brésil et de kaolins de couchage de Rio Capim/Brésil laissent des résidus d’exploitation en très grands tonnages. Dans la perspective d’une valorisation plus complète assurant un développement durable de l’industrie extractive, on a envisagé d’utiliser ces argiles résiduelles dans la fabrication de zéolites. On a obtenue dès une durée de synthèse de 24h, une zéolite 4A très proche de sa définition théorique. Le rendement de synthèse est meilleur avec les produits de Rio Capim. Le volume nanoporeux de la zéolite 4A est inaccessible à l’azote mais accessible à la molécule d’eau. Les zéolites synthétisées ont été testées comme adsorbants cationiques pour le cuivre, le plomb, le cadmium, le zinc, le magnésium, potassium et mercure. La rétention a voisine 60% du remplissage théorique pour toutes les espèces testées, sauf pour le cuivre où elle dépasse la capacité théorique et pour le mercure où elle est très faible. / Working Kaolinic refractory clays from Água Limpa (Minas Gerais) and paper coating kaolins from Rio Capim (Pará) - Brazil throw over very large amounts of mining residues. With the outlook of a more complete beneficiation, aiming at a sustainable development of mineral industry, the use of these residual clays has been considered for manufacturing zeolites. For a synthesis time of only 24h, a zeolite 4A very close to its theoretical definition is obtained.The nano-porous volume of the zeolite 4A is inaccessible to nitrogen molecules, but accessible to water molecules. Synthesised zeolites have been tested as cationic adsorbents of Cu, Pb, Cd, Zn, Mg, K and Hg. The retention is better for materials derived from Rio Capim Kaolins. The retention is close to 60% of the theoretical completion of the exchange capacity in all cases, except for copper for which the retention exceeds the capacity, and mercury for which the retention is very low.

This term paper is focused on theory and calculation of an induction motor with solid rotor. It is divided into six chapters, the first one being an introduction and the last being a conclusion. Second chapter is dedicated to magnetism. There is briefly description of a skin depth of a conductor and calculation method for impedance of a conductive solid. Third chapter is focused on theory of an induction machines, their construction, equivalent circuit and some of their properties. Fourth chapter is dedicated to calculation of an induction motor with solid rotor and its parameters. Fifth chapter is comparing results of calculation done in fourth chapter for an already existing motor with measured values.