New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: extended benefit after intracerebroventricular injection and efficacy of intravenous administration.

BACKGROUND: Lactate protects mice against the ischaemic damage resulting from transient middle cerebral artery occlusion (MCAO) when administered intracerebroventricularly at reperfusion, yielding smaller lesion sizes and a better neurological outcome 48 h after ischaemia. We have now tested whether the beneficial effect of lactate is long-lasting and if lactate can be administered intravenously. METHODS: Male ICR-CD1 mice were subjected to 15-min suture MCAO under xylazine + ketamine anaesthesia. Na L-lactate (2 ��l of 100 mmol/l) or vehicle was administered intracerebroventricularly at reperfusion. The neurological deficit was evaluated using a composite deficit score based on the neurological score, the rotarod test and the beam walking test. Mice were sacrificed at 14 days. In a second set of experiments, Na L-lactate (1 ��mol/g body weight) was administered intravenously into the tail vein at reperfusion. The neurological deficit and the lesion volume were measured at 48 h. RESULTS: Intracerebroventricularly injected lactate induced sustained neuroprotection shown by smaller neurological deficits at 7 days (median = 0, min = 0, max = 3, n = 7 vs. median = 2, min = 1, max = 4.5, n = 5, p < 0.05) and 14 days after ischaemia (median = 0, min = 0, max = 3, n = 7 vs. median = 3, min = 0.5, max = 3, n = 7, p = 0.05). Reduced tissue damage was demonstrated by attenuated hemispheric atrophy at 14 days (1.3 �� 4.0 mm(3), n = 7 vs. 12.1 �� 3.8 mm(3), n = 5, p < 0.05) in lactate-treated animals. Systemic intravenous lactate administration was also neuroprotective and attenuated the deficit (median = 1, min = 0, max = 2.5, n = 12) compared to vehicle treatment (median = 1.5, min = 1, max = 8, n = 12, p < 0.05) as well as the lesion volume at 48 h (13.7 �� 12.2 mm(3), n = 12 vs. 29.6 �� 25.4 mm(3), n = 12, p < 0.05). CONCLUSIONS: The beneficial effect of lactate is long-lasting: lactate protects the mouse brain against ischaemic damage when supplied intracerebroventricularly during reperfusion with behavioural and histological benefits persisting 2 weeks after ischaemia. Importantly, lactate also protects after systemic intravenous administration, a more suitable route of administration in a clinical emergency setting. These findings provide further steps to bring this physiological, commonly available and inexpensive neuroprotectant closer to clinical translation for stroke.

Modeling information in software languages

Ohjelmiston kehitysty��kalut k��ytt��v��t infromaatiota kehitt��j��n tuottamasta l��hdekoodista. Informaatiota hy��dynnet����n ohjelmistoprojektin eri vaiheissa ja eri tarkoituksissa. Moderneissa ohjelmistoprojekteissa k��ytetyn informaation m����r�� voi kasvaa eritt��in suureksi. Ohjelmistoty��kaluilla on omat informaatiomallinsa ja k��ytt��mekanisminsa. Informaation m����r�� sek�� erilliset ty��kaluinformaatiomallit tekev��t eritt��in hankalaksi rakentaa joustavaa ty��kaluymp��rist����, erityisesti ongelma-aluekohtaiseen ohjelmiston kehitysprosessiin. T��ss�� ty��ss�� on analysoitu perusinformaatiometamalleja Unified Modeling language kielest��, Python ohjelmointikielest�� ja C++ ohjelmointikielest��. Metainformaation taso on rajoitettu rakenteelliselle tasolle. Ajettavat rakenteet on j��tetty pois. ModelBase metamalli on yhdistetty olemassa olevista analysoiduista metamalleista. T��t�� metamallia voidaan k��ytt���� tulevaisuudessa ohjelmistoty��kalujen kehitykseen.

Study and modeling of the desintegration kinetics of coated paper

The disintegration of recovered paper is the first operation in the preparation of recycled pulp. It is known that the defibering process follows a first order kinetics from which it is possible to obtain the disintegration kinetic constant (KD) by means of different ways. The disintegration constant can be obtained from the Somerville index results (%lsv and from the dissipated energy per volume unit (Ss). The %slv is related to the quantity of non-defibrated paper, as a measure of the non-disintegrated fiber residual (percentage of flakes), which is expressed in disintegration time units. In this work, disintegration kinetics from recycled coated paper has been evaluated, working at 20 revise rotor speed and for different fiber consistency (6, 8, 10, 12 and 14%). The results showed that the values of experimental disintegration kinetic constant, Ko, through the analysis of Somerville index, as function of time. Increased, the disintegration time was drastically reduced. The calculation of the disintegration kinetic constant (modelled Ko), extracted from the Rayleigh���s dissipation function, showed a good correlation with the experimental values using the evolution of the Somerville index or with the dissipated energy

Characterization and functional identification of a novel plant extradiol 4,5-dioxygenase involved in betalain pigment biosynthesis in Portulaca Grandiflora

RESUME Les b��tala��nes sont des pigments chromo-alcalo��des violets et jaunes pr��sents dans les plantes appartenant �� l'ordre des Caryophyllales et dans les champignons des genres Amanita et Hygrocybe. Leur courte voie de biosynth��se est ��lucid��e chimiquement depuis de nombreuses ann��es, mais les enzymes impliqu��es dans cette biosynth��se chez les plantes ne sont toujours pas caract��ris��es. L'enzyme de la DOPA-dioxyg��nase d' Amanita muscaria a ��t�� identifi��e (Girod et Zryd, 1991a), mais de nombreuses tentatives d'isolation d'un homologue chez les plantes ont ��chou��. Afin d'isoler les g��nes sp��cifiques des b��tala��nes chez les plantes, nous avons construit des banques soustraites d'ADNc �� partir d'ARN total de p��tales immatures de Portulaca grandiflora (Pg) de g��notypes jaunes et blancs, respectivement violets et blancs. Les clones couleur- sp��cifiques ont ��t�� d��tect��s en premier par analyse Northem du RNA de p��tales blancs et color��s. Les candidats positifs ont alors ��t�� soumis �� une analyse de transcription au niveau des tiges color��es, vertes et des feuilles, afin d'��tablir leur expression sp��cifique. Deux ARNs messagers complets ont une expression corr��l��e avec l'accumulation des b��tala��nes dans les tissus. Le premier de ces clones, A.16, code pour une oxydase de l'acyl-Coenzyme A (ACX) putative, mais le domaine de liaison du FAD essentiel pour l'activit�� d'ACX est absent. Toutes nos tentatives pour d��montrer sa fonction ont ��chou��. Le r��le de cette prot��ine dans la voie de synth��se des b��tala��nes reste inconnu. Le deuxi��me de ces clones sp��cifique aux b��tala��nes, L.6 (isol�� par Zaiko, 2000), a ��t�� renomm�� DODA en raison de son homologie avec le domaine LigB (pfam02900) d'une 4,5-dioxyg��nase extradiol bact��rienne. DODA a ��t�� identifi�� in silico comme une dioxyg��nase extradiol en raison de la conservation stricte, au niveau de sa s��quence peptidique, des r��sidus catalytiques de LigB et de ceux liant le cofacteur fer. Une analyse de transfert Southem a montr�� que ce g��ne est unique dans Pg. L'expression transitoire de DODA par transformation biolistique dans des p��tales blancs de Pg a produit des taches violettes ou jaunes dans des cellules transform��es. Une analyse HPLC de ces taches a d��montr�� leur identit�� avec les b��tala��nes pr��sentes naturellement dans les p��tales violets et jaunes de Pg, confirmant ainsi la compl��mentation par le g��ne Pg DODA de l'all��le r��cessif cc pr��sent dans les p��tales blancs de Pg. Des homologues de DODA (DOPA-dioxyg��nase) ont ��t�� identifi��s dans de nombreuses esp��ces de plantes, y compris dans celles sans b��tala��ne. L'alignement de ces homologues a permis l'identification d'un motif sp��cifique aux b��tala��nes �� c��t�� d'une histidine catalytique conserv��e. Ce motif [H-P-(S,A)-(N,D)-x-T-P] remplace le motif [H-N-L-R] conserv�� dans les plantes sans b��tala��ne et le motif [H-N-L-x] pr��sent dans tous les homologues bact��riens et archaebact��riens. Une mod��lisation tridimensionnelle pr��liminaire du site actif de Pg DODA et de son homologue dans la mousse Physcomitrella patens a montr�� l'importance de ce motif sp��cifique aux b��tala��nes pour l'accessibilit�� du substrat au site actif. L'analyse phylog��n��tique de DODA a confirm�� l'��volution s��par��e de cette prot��ine chez les plantes �� b��tala��nes par comparaison avec celle des plantes sans b��tala��ne. Nous avons donc conclu que les b��tala��nes sont apparues par modification de l'affinit�� pour un substrat d'enzymes similaires �� DODA, chez un anc��tre unique des Caryophyllales qui a perdu toute capacit�� de biosynth��se des anthocyanes. Finalement, Pg DODA n'a aucune similarit�� avec la prot��ine DODA d' Amanita muscaria, bien que celle-ci compl��mente aussi la pigmentation des p��tales blancs de Pg. La biosynth��se des b��tala��nes est un exemple remarquable de convergence ��volutive biochimique ind��pendante entre esp��ces de r��gnes diff��rents. ABSTRACT Betalains are violet and yellow chromo-alkaloid pigments present in plants belonging to the order Caryophyllales and also in the fungal genera Amanita and Hygrocybe. Their short biosynthetic pathway is chemically well understood since many years, but enzymes involved in the plant pathway are still uncharacterized. The DOPA-dioxygenase from Amanita muscaria was identified (Girod and Zryd, 1991a), but numerous attempts to identify a plant homologue to the corresponding gene, failed. In order to isolate betalain-specific genes in plants, subtractive cDNA libraries were built with total RNA from white and yellow and respectively, violet immature petals from Portulaca grandiflora (Pg) genotypes. Colour-specific clones were first detected by Northern blot analysis using RNA from white and coloured petals. Positive candidates were submitted to further transcription analysis in coloured, green stems and leaves in order to assess their specific expression. Two full-length mRNAs showed a correlated expression with betalain accumulation in tissues. One of them, A.16, encodes a putative acyl-Coenzyme A oxidase (ACX), but missing the FAD binding domain essential for the ACX activity. Thus, all attempts to demonstrate its function failed. The role of this protein in the betalain biosynthesis pathway, if any, is still unknown. The second betalain-specific mRNA, L.6 (isolated by Zaiko, 2000) shows a homology with a LigB domain (pfam02900) from a bacterial extradiol 4,5-dioxygenase. It was then renamed DODA (DOPA-dioxygenase). DODA was identified in silico as a highly conserved extradiol dioxygenase due to the strict conservation of its peptidic sequence with LigB catalytic residues and iron-binding cofactor residues. Southern blot analysis showed that this gene is a single copy-gene in Pg. Transient expression of DODA protein through biolistic transformation of Pg white petals produced violet or yellow spots in individual cells. HPLC analysis of these spots showed an identity with betalain pigments present naturally in yellow and violet Pg petals, thus confirming the complementation of the recessive cc allele present in Pg white petals by Pg DODA gene. DODA homologues were identified in numerous plant species including those without betalain. Alignment of these homologues allowed the identification of a betalain-specific pattern beside a highly conserved catalytic histidine. This [H-P-(S,A)-(N,D)-x-T-P] pattern replaces a [H-N-L-R] pattern strictly conserved in non-betalain plants and a [H-N-L-x] pattern present in all bacterial and archaebacterial homologues. Preliminary three-dimensional modeling of the active site of Pg DODA and its Physcomitrella patens moss homologue revealed the importance of this betalain-specific pattern for the substrate accessibility to the DODA active site. DODA phylogenetic analysis confirmed the separate evolution of this protein in betalain-producing plants. We conclude that betalain pigments appeared in a unique ancestor of the Caryophyllales order in which anthocyanin biosynthetic pathway was impaired, by a modification of enzymes of the DODA family for substrate affinity. The Pg DODA protein has no sequence similarity with Amanita muscaria DODA, despite the fact that they both complement Pg white petals for their pigmentation. Betalain biosynthesis is an interesting example of independent biochemical evolutionary convergence between species from different kingdoms.

The Hydrophobic interaction: modeling hydrophobic interactions and aggregation of non-polar particles in aqueous solutions

Malgr�� son importance dans notre vie de tous les jours, certaines propri��t��s de l?eau restent inexpliqu��es. L'��tude des interactions entre l'eau et les particules organiques occupe des groupes de recherche dans le monde entier et est loin d'��tre finie. Dans mon travail j'ai essay�� de comprendre, au niveau mol��culaire, ces interactions importantes pour la vie. J'ai utilis�� pour cela un mod��le simple de l'eau pour d��crire des solutions aqueuses de diff��rentes particules. R��cemment, l?eau liquide a ��t�� d��crite comme une structure form��e d?un r��seau al��atoire de liaisons hydrog��nes. En introduisant une particule hydrophobe dans cette structure �� basse temp��rature, certaines liaisons hydrog��nes sont d��truites ce qui est ��nerg��tiquement d��favorable. Les mol��cules d?eau s?arrangent alors autour de cette particule en formant une cage qui permet de r��cup��rer des liaisons hydrog��nes (entre mol��cules d?eau) encore plus fortes : les particules sont alors solubles dans l?eau. A des temp��ratures plus ��lev��es, l?agitation thermique des mol��cules devient importante et brise les liaisons hydrog��nes. Maintenant, la dissolution des particules devient ��nerg��tiquement d��favorable, et les particules se s��parent de l?eau en formant des agr��gats qui minimisent leur surface expos��e �� l?eau. Pourtant, �� tr��s haute temp��rature, les effets entropiques deviennent tellement forts que les particules se m��langent de nouveau avec les mol��cules d?eau. En utilisant un mod��le bas�� sur ces changements de structure form��e par des liaisons hydrog��nes j?ai pu reproduire les ph��nom��nes principaux li��s �� l?hydrophobicit��. J?ai trouv�� une r��gion de coexistence de deux phases entre les temp��ratures critiques inf��rieure et sup��rieure de solubilit��, dans laquelle les particules hydrophobes s?agr��gent. En dehors de cette r��gion, les particules sont dissoutes dans l?eau. J?ai d��montr�� que l?interaction hydrophobe est d��crite par un mod��le qui prend uniquement en compte les changements de structure de l?eau liquide en pr��sence d?une particule hydrophobe, plut��t que les interactions directes entre les particules. Encourag��e par ces r��sultats prometteurs, j?ai ��tudi�� des solutions aqueuses de particules hydrophobes en pr��sence de co-solvants cosmotropiques et chaotropiques. Ce sont des substances qui stabilisent ou d��stabilisent les agr��gats de particules hydrophobes. La pr��sence de ces substances peut ��tre incluse dans le mod��le en d��crivant leur effet sur la structure de l?eau. J?ai pu reproduire la concentration ��lev��e de co-solvants chaotropiques dans le voisinage imm��diat de la particule, et l?effet inverse dans le cas de co-solvants cosmotropiques. Ce changement de concentration du co-solvant �� proximit�� de particules hydrophobes est la cause principale de son effet sur la solubilit�� des particules hydrophobes. J?ai d��montr�� que le mod��le adapt�� pr��dit correctement les effets implicites des co-solvants sur les interactions de plusieurs corps entre les particules hydrophobes. En outre, j?ai ��tendu le mod��le �� la description de particules amphiphiles comme des lipides. J?ai trouv�� la formation de diff��rents types de micelles en fonction de la distribution des regions hydrophobes �� la surface des particules. L?hydrophobicit�� reste ��galement un sujet controvers�� en science des prot��ines. J?ai d��fini une nouvelle ��chelle d?hydrophobicit�� pour les acides amin��s qui forment des prot��ines, bas��e sur leurs surfaces expos��es �� l?eau dans des prot��ines natives. Cette ��chelle permet une comparaison meilleure entre les exp��riences et les r��sultats th��oriques. Ainsi, le mod��le d��velopp�� dans mon travail contribue �� mieux comprendre les solutions aqueuses de particules hydrophobes. Je pense que les r��sultats analytiques et num��riques obtenus ��claircissent en partie les processus physiques qui sont �� la base de l?interaction hydrophobe.<br/><br/>Despite the importance of water in our daily lives, some of its properties remain unexplained. Indeed, the interactions of water with organic particles are investigated in research groups all over the world, but controversy still surrounds many aspects of their description. In my work I have tried to understand these interactions on a molecular level using both analytical and numerical methods. Recent investigations describe liquid water as random network formed by hydrogen bonds. The insertion of a hydrophobic particle at low temperature breaks some of the hydrogen bonds, which is energetically unfavorable. The water molecules, however, rearrange in a cage-like structure around the solute particle. Even stronger hydrogen bonds are formed between water molecules, and thus the solute particles are soluble. At higher temperatures, this strict ordering is disrupted by thermal movements, and the solution of particles becomes unfavorable. They minimize their exposed surface to water by aggregating. At even higher temperatures, entropy effects become dominant and water and solute particles mix again. Using a model based on these changes in water structure I have reproduced the essential phenomena connected to hydrophobicity. These include an upper and a lower critical solution temperature, which define temperature and density ranges in which aggregation occurs. Outside of this region the solute particles are soluble in water. Because I was able to demonstrate that the simple mixture model contains implicitly many-body interactions between the solute molecules, I feel that the study contributes to an important advance in the qualitative understanding of the hydrophobic effect. I have also studied the aggregation of hydrophobic particles in aqueous solutions in the presence of cosolvents. Here I have demonstrated that the important features of the destabilizing effect of chaotropic cosolvents on hydrophobic aggregates may be described within the same two-state model, with adaptations to focus on the ability of such substances to alter the structure of water. The relevant phenomena include a significant enhancement of the solubility of non-polar solute particles and preferential binding of chaotropic substances to solute molecules. In a similar fashion, I have analyzed the stabilizing effect of kosmotropic cosolvents in these solutions. Including the ability of kosmotropic substances to enhance the structure of liquid water, leads to reduced solubility, larger aggregation regime and the preferential exclusion of the cosolvent from the hydration shell of hydrophobic solute particles. I have further adapted the MLG model to include the solvation of amphiphilic solute particles in water, by allowing different distributions of hydrophobic regions at the molecular surface, I have found aggregation of the amphiphiles, and formation of various types of micelle as a function of the hydrophobicity pattern. I have demonstrated that certain features of micelle formation may be reproduced by the adapted model to describe alterations of water structure near different surface regions of the dissolved amphiphiles. Hydrophobicity remains a controversial quantity also in protein science. Based on the surface exposure of the 20 amino-acids in native proteins I have defined the a new hydrophobicity scale, which may lead to an improvement in the comparison of experimental data with the results from theoretical HP models. Overall, I have shown that the primary features of the hydrophobic interaction in aqueous solutions may be captured within a model which focuses on alterations in water structure around non-polar solute particles. The results obtained within this model may illuminate the processes underlying the hydrophobic interaction.<br/><br/>La vie sur notre plan��te a commenc�� dans l'eau et ne pourrait pas exister en son absence : les cellules des animaux et des plantes contiennent jusqu'�� 95% d'eau. Malgr�� son importance dans notre vie de tous les jours, certaines propri��t��s de l?eau restent inexpliqu��es. En particulier, l'��tude des interactions entre l'eau et les particules organiques occupe des groupes de recherche dans le monde entier et est loin d'��tre finie. Dans mon travail j'ai essay�� de comprendre, au niveau mol��culaire, ces interactions importantes pour la vie. J'ai utilis�� pour cela un mod��le simple de l'eau pour d��crire des solutions aqueuses de diff��rentes particules. Bien que l?eau soit g��n��ralement un bon solvant, un grand groupe de mol��cules, appel��es mol��cules hydrophobes (du grecque "hydro"="eau" et "phobia"="peur"), n'est pas facilement soluble dans l'eau. Ces particules hydrophobes essayent d'��viter le contact avec l'eau, et forment donc un agr��gat pour minimiser leur surface expos��e �� l'eau. Cette force entre les particules est appel��e interaction hydrophobe, et les m��canismes physiques qui conduisent �� ces interactions ne sont pas bien compris �� l'heure actuelle. Dans mon ��tude j'ai d��crit l'effet des particules hydrophobes sur l'eau liquide. L'objectif ��tait d'��claircir le m��canisme de l'interaction hydrophobe qui est fondamentale pour la formation des membranes et le fonctionnement des processus biologiques dans notre corps. R��cemment, l'eau liquide a ��t�� d��crite comme un r��seau al��atoire form�� par des liaisons hydrog��nes. En introduisant une particule hydrophobe dans cette structure, certaines liaisons hydrog��nes sont d��truites tandis que les mol��cules d'eau s'arrangent autour de cette particule en formant une cage qui permet de r��cup��rer des liaisons hydrog��nes (entre mol��cules d?eau) encore plus fortes : les particules sont alors solubles dans l'eau. A des temp��ratures plus ��lev��es, l?agitation thermique des mol��cules devient importante et brise la structure de cage autour des particules hydrophobes. Maintenant, la dissolution des particules devient d��favorable, et les particules se s��parent de l'eau en formant deux phases. A tr��s haute temp��rature, les mouvements thermiques dans le syst��me deviennent tellement forts que les particules se m��langent de nouveau avec les mol��cules d'eau. A l'aide d'un mod��le qui d��crit le syst��me en termes de restructuration dans l'eau liquide, j'ai r��ussi �� reproduire les ph��nom��nes physiques li��s �� l?hydrophobicit��. J'ai d��montr�� que les interactions hydrophobes entre plusieurs particules peuvent ��tre exprim��es dans un mod��le qui prend uniquement en compte les liaisons hydrog��nes entre les mol��cules d'eau. Encourag��e par ces r��sultats prometteurs, j'ai inclus dans mon mod��le des substances fr��quemment utilis��es pour stabiliser ou d��stabiliser des solutions aqueuses de particules hydrophobes. J'ai r��ussi �� reproduire les effets d��s �� la pr��sence de ces substances. De plus, j'ai pu d��crire la formation de micelles par des particules amphiphiles comme des lipides dont la surface est partiellement hydrophobe et partiellement hydrophile ("hydro-phile"="aime l'eau"), ainsi que le repliement des prot��ines d�� �� l'hydrophobicit��, qui garantit le fonctionnement correct des processus biologiques de notre corps. Dans mes ��tudes futures je poursuivrai l'��tude des solutions aqueuses de diff��rentes particules en utilisant les techniques acquises pendant mon travail de th��se, et en essayant de comprendre les propri��t��s physiques du liquide le plus important pour notre vie : l'eau.

Wet Oxidation of Concentrated Wastewaters: Process Combination and Reaction Kinetic Modeling

The accumulation of aqueous pollutants is becoming a global problem. The search for suitable methods and/or combinations of water treatment processes is a task that can slow down and stop the process of water pollution. In this work, the method of wet oxidation was considered as an appropriate technique for the elimination of the impurities present in paper mill process waters. It has been shown that, when combined with traditional wastewater treatment processes, wet oxidation offers many advantages. The combination of coagulation and wet oxidation offers a new opportunity for the improvement of the quality of wastewater designated for discharge or recycling. First of all, the utilization of coagulated sludge via wet oxidation provides a conditioning process for the sludge, i.e. dewatering, which is rather difficult to carry out with untreated waste. Secondly, Fe2(SO4)3, which is employed earlier as a coagulant, transforms the conventional wet oxidation process into a catalytic one. The use of coagulation as the post-treatment for wet oxidation can offer the possibility of the brown hue that usually accompanies the partial oxidation to be reduced. As a result, the supernatant is less colored and also contains a rather low amount of Fe ions to beconsidered for recycling inside mills. The thickened part that consists of metal ions is then recycled back to the wet oxidation system. It was also observed that wet oxidation is favorable for the degradation of pitch substances (LWEs) and lignin that are present in the process waters of paper mills. Rather low operating temperatures are needed for wet oxidation in order to destruct LWEs. The oxidation in the alkaline media provides not only the faster elimination of pitch and lignin but also significantly improves the biodegradable characteristics of wastewater that contains lignin and pitch substances. During the course of the kinetic studies, a model, which can predict the enhancements of the biodegradability of wastewater, was elaborated. The model includes lumped concentrations suchas the chemical oxygen demand and biochemical oxygen demand and reflects a generalized reaction network of oxidative transformations. Later developments incorporated a new lump, the immediately available biochemical oxygen demand, which increased the fidelity of the predictions made by the model. Since changes in biodegradability occur simultaneously with the destruction of LWEs, an attempt was made to combine these two facts for modeling purposes.

Modeling of non-isothermalvapor membrane separation with thermodynamic models and generalized mass transfer equations

A rigorous unit operation model is developed for vapor membrane separation. The new model is able to describe temperature, pressure, and concentration dependent permeation as wellreal fluid effects in vapor and gas separation with hydrocarbon selective rubbery polymeric membranes. The permeation through the membrane is described by a separate treatment of sorption and diffusion within the membrane. The chemical engineering thermodynamics is used to describe the equilibrium sorption of vapors and gases in rubbery membranes with equation of state models for polymeric systems. Also a new modification of the UNIFAC model is proposed for this purpose. Various thermodynamic models are extensively compared in order to verify the models' ability to predict and correlate experimental vapor-liquid equilibrium data. The penetrant transport through the selective layer of the membrane is described with the generalized Maxwell-Stefan equations, which are able to account for thebulk flux contribution as well as the diffusive coupling effect. A method is described to compute and correlate binary penetrant��membrane diffusion coefficients from the experimental permeability coefficients at different temperatures and pressures. A fluid flow model for spiral-wound modules is derived from the conservation equation of mass, momentum, and energy. The conservation equations are presented in a discretized form by using the control volume approach. A combination of the permeation model and the fluid flow model yields the desired rigorous model for vapor membrane separation. The model is implemented into an inhouse process simulator and so vapor membrane separation may be evaluated as an integralpart of a process flowsheet.

Applying the principles of life cycle assessment and costing in process modeling to examine profit-making capability

Static process simulation has traditionally been used to model complex processes for various purposes. However, the use of static processsimulators for the preparation of holistic examinations aiming at improving profit-making capability requires a lot of work because the production of results requires the assessment of the applicability of detailed data which may be irrelevant to the objective. The relevant data for the total assessment gets buried byirrelevant data. Furthermore, the models do not include an examination of the maintenance or risk management, and economic examination is often an extra property added to them which can be performed with a spreadsheet program. A process model applicable to holistic economic examinations has been developed in this work. The model is based on the life cycle profit philosophy developed by Hagberg and Henriksson in 1996. The construction of the model has utilized life cycle assessment and life cycle costing methodologies with a view to developing, above all, a model which would be applicable to the economic examinations of complete wholes and which would require the need for information focusing on aspects essential to the objectives. Life cycle assessment and costing differ from each other in terms of the modeling principles, but the features of bothmethodologies can be used in the development of economic process modeling. Methods applicable to the modeling of complex processes can be examined from the viewpoint of life cycle methodologies, because they involve the collection and management of large corpuses of information and the production of information for the needs of decision-makers as well. The results of the study shows that on the basis of the principles of life cycle modeling, a process model can be created which may be used to produce holistic efficiency examinations on the profit-making capability of the production line, with fewer resources thanwith traditional methods. The calculations of the model are based to the maximum extent on the information system of the factory, which means that the accuracyof the results can be improved by developing information systems so that they can provide the best information for this kind of examinations.

Selective catalytic reduction of nitrogen oxides with ammonia in forced unsteady state reactors - Case based reasoning and mathematical model simulation reasoning

The application of forced unsteady-state reactors in case of selective catalytic reduction of nitrogen oxides (NOx) with ammonia (NH3) is sustained by the fact that favorable temperature and composition distributions which cannot be achieved in any steady-state regime can be obtained by means of unsteady-state operations. In a normal way of operation the low exothermicity of the selective catalytic reduction (SCR) reaction (usually carried out in the range of 280-350��C) is not enough to maintain by itself the chemical reaction. A normal mode of operation usually requires supply of supplementary heat increasing in this way the overall process operation cost. Through forced unsteady-state operation, the main advantage that can be obtained when exothermic reactions take place is the possibility of trapping, beside the ammonia, the moving heat wave inside the catalytic bed. The unsteady state-operation enables the exploitation of the thermal storage capacity of the catalyticbed. The catalytic bed acts as a regenerative heat exchanger allowing auto-thermal behaviour when the adiabatic temperature rise is low. Finding the optimum reactor configuration, employing the most suitable operation model and identifying the reactor behavior are highly important steps in order to configure a proper device for industrial applications. The Reverse Flow Reactor (RFR) - a forced unsteady state reactor - corresponds to the above mentioned characteristics and may be employed as an efficient device for the treatment of dilute pollutant mixtures. As a main disadvantage, beside its advantages, the RFR presents the 'wash out' phenomena. This phenomenon represents emissions of unconverted reactants at every switch of the flow direction. As a consequence our attention was focused on finding an alternative reactor configuration for RFR which is not affected by the incontrollable emissions of unconverted reactants. In this respect the Reactor Network (RN) was investigated. Its configuration consists of several reactors connected in a closed sequence, simulating a moving bed by changing the reactants feeding position. In the RN the flow direction is maintained in the same way ensuring uniformcatalyst exploitation and in the same time the 'wash out' phenomena is annulated. The simulated moving bed (SMB) can operate in transient mode giving practically constant exit concentration and high conversion levels. The main advantage of the reactor network operation is emphasizedby the possibility to obtain auto-thermal behavior with nearly uniformcatalyst utilization. However, the reactor network presents only a small range of switching times which allow to reach and to maintain an ignited state. Even so a proper study of the complex behavior of the RN may give the necessary information to overcome all the difficulties that can appear in the RN operation. The unsteady-state reactors complexity arises from the fact that these reactor types are characterized by short contact times and complex interaction between heat and mass transportphenomena. Such complex interactions can give rise to a remarkable complex dynamic behavior characterized by a set of spatial-temporal patterns, chaotic changes in concentration and traveling waves of heat or chemical reactivity. The main efforts of the current research studies concern the improvement of contact modalities between reactants, the possibility of thermal wave storage inside the reactor and the improvement of the kinetic activity of the catalyst used. Paying attention to the above mentioned aspects is important when higher activity even at low feeding temperatures and low emissions of unconverted reactants are the main operation concerns. Also, the prediction of the reactor pseudo or steady-state performance (regarding the conversion, selectivity and thermal behavior) and the dynamicreactor response during exploitation are important aspects in finding the optimal control strategy for the forced unsteady state catalytic tubular reactors. The design of an adapted reactor requires knowledge about the influence of its operating conditions on the overall process performance and a precise evaluation of the operating parameters rage for which a sustained dynamic behavior is obtained. An apriori estimation of the system parameters result in diminution of the computational efforts. Usually the convergence of unsteady state reactor systems requires integration over hundreds of cycles depending on the initial guess of the parameter values. The investigation of various operation models and thermal transfer strategies give reliable means to obtain recuperative and regenerative devices which are capable to maintain an auto-thermal behavior in case of low exothermic reactions. In the present research work a gradual analysis of the SCR of NOx with ammonia process in forced unsteady-state reactors was realized. The investigation covers the presentationof the general problematic related to the effect of noxious emissions in the environment, the analysis of the suitable catalysts types for the process, the mathematical analysis approach for modeling and finding the system solutions and the experimental investigation of the device found to be more suitable for the present process. In order to gain information about the forced unsteady state reactor design, operation, important system parameters and their values, mathematical description, mathematicalmethod for solving systems of partial differential equations and other specific aspects, in a fast and easy way, and a case based reasoning (CBR) approach has been used. This approach, using the experience of past similarproblems and their adapted solutions, may provide a method for gaining informations and solutions for new problems related to the forced unsteady state reactors technology. As a consequence a CBR system was implemented and a corresponding tool was developed. Further on, grooving up the hypothesis of isothermal operation, the investigation by means of numerical simulation of the feasibility of the SCR of NOx with ammonia in the RFRand in the RN with variable feeding position was realized. The hypothesis of non-isothermal operation was taken into account because in our opinion ifa commercial catalyst is considered, is not possible to modify the chemical activity and its adsorptive capacity to improve the operation butis possible to change the operation regime. In order to identify the most suitable device for the unsteady state reduction of NOx with ammonia, considering the perspective of recuperative and regenerative devices, a comparative analysis of the above mentioned two devices performance was realized. The assumption of isothermal conditions in the beginningof the forced unsteadystate investigation allowed the simplification of the analysis enabling to focus on the impact of the conditions and mode of operation on the dynamic features caused by the trapping of one reactant in the reactor, without considering the impact of thermal effect on overall reactor performance. The non-isothermal system approach has been investigated in order to point out the important influence of the thermal effect on overall reactor performance, studying the possibility of RFR and RN utilization as recuperative and regenerative devices and the possibility of achieving a sustained auto-thermal behavior in case of lowexothermic reaction of SCR of NOx with ammonia and low temperature gasfeeding. Beside the influence of the thermal effect, the influence of the principal operating parameters, as switching time, inlet flow rate and initial catalyst temperature have been stressed. This analysis is important not only because it allows a comparison between the two devices and optimisation of the operation, but also the switching time is the main operating parameter. An appropriate choice of this parameter enables the fulfilment of the process constraints. The level of the conversions achieved, the more uniform temperature profiles, the uniformity ofcatalyst exploitation and the much simpler mode of operation imposed the RN as a much more suitable device for SCR of NOx with ammonia, in usual operation and also in the perspective of control strategy implementation. Theoretical simplified models have also been proposed in order to describe the forced unsteady state reactors performance and to estimate their internal temperature and concentration profiles. The general idea was to extend the study of catalytic reactor dynamics taking into account the perspectives that haven't been analyzed yet. The experimental investigation ofRN revealed a good agreement between the data obtained by model simulation and the ones obtained experimentally.

Modeling and measuring organizational renewal capability

Globalization and new information technologies mean that organizations have to face world-wide competition in rapidly transforming, unpredictable environments, and thus the ability to constantly generate novel and improved products, services and processes has become quintessential for organizational success. Performance in turbulent environments is, above all, influenced by the organization's capability for renewal. Renewal capability consists of the ability of the organization to replicate, adapt, develop and change its assets, capabilities and strategies. An organization with a high renewal capability can sustain its current success factors while at the same time building new strengths for the future. This capability does not only mean that the organization is able to respond to today's challenges and to keep up with the changes in its environment, but also that it can actas a forerunner by creating innovations, both at the tactical and strategic levels of operation and thereby change the rules of the market. However, even though it is widely agreed that the dynamic capability for continuous learning, development and renewal is a major source of competitive advantage, there is no widely shared view on how organizational renewal capability should be defined, and the field is characterized by a plethora of concepts and definitions. Furthermore,there is a lack of methods for systematically assessing organizational renewal capability. The dissertation aims to bridge these gaps in the existing research by constructing an integrative theoretical framework for organizational renewal capability and by presenting a method for modeling and measuring this capability. The viability of the measurement tool is demonstrated in several contexts, andthe framework is also applied to assess renewal in inter-organizational networks. In this dissertation, organizational renewal capability is examined by drawing on three complimentary theoretical perspectives: knowledge management, strategic management and intellectual capital. The knowledge management perspective considers knowledge as inherently social and activity-based, and focuses on the organizational processes associated with its application and development. Within this framework, organizational renewal capability is understood as the capacity for flexible knowledge integration and creation. The strategic management perspective, on the other hand, approaches knowledge in organizations from the standpoint of its implications for the creation of competitive advantage. In this approach, organizational renewal is framed as the dynamic capability of firms. The intellectual capital perspective is focused on exploring how intangible assets can be measured, reported and communicated. From this vantage point, renewal capability is comprehended as the dynamic dimension of intellectual capital, which consists of the capability to maintain, modify and create knowledge assets. Each of the perspectives significantly contributes to the understanding of organizationalrenewal capability, and the integrative approach presented in this dissertationcontributes to the individual perspectives as well as to the understanding of organizational renewal capability as a whole.

Reliability of the density functional approximation to describe the charge transfer and electrostatic complexes involved in the modeling of organic conducting polymers

Both the intermolecular interaction energies and the geometries for M �� thiophene, M �� pyrrole, M n+ �� thiophene, and M n+ �� pyrrole ��with M = Li, Na, K, Ca, and Mg; and M n+ = Li+ , Na+ , K+ , Ca2+, and Mg2+�� have been estimated using four commonly used density functional theory ��DFT�� methods: B3LYP, B3PW91, PBE, and MPW1PW91. Results have been compared to those provided by HF, MP2, and MP4 conventional ab initio methods. The PBE and MPW1PW91 are the only DFT methods able to provide a reasonable description of the M �� complexes. Regarding M n+ �� ��� complexes, the four DFT methods have been proven to be adequate in the prediction of these electrostatically stabilized systems, even though they tend to overestimate the interaction energies.

Dynamic drag modeling of submerged aquatic vegetation canopy flows

Vegetation has a profound effect on flow and sediment transport processes in natural rivers, by increasing both skin friction and form drag. The increase in drag introduces a drag discontinuity between the in-canopy flow and the flow above, which leads to the development of an inflection point in the velocity profile, resembling a free shear layer. Therefore, drag acts as the primary driver for the entire canopy system. Most current numerical hydraulic models which incorporate vegetation rely either on simple, static plant forms, or canopy-scaled drag terms. However, it is suggested that these are insufficient as vegetation canopies represent complex, dynamic, porous blockages within the flow, which are subject to spatially and temporally dynamic drag forces. Here we present a dynamic drag methodology within a CFD framework. Preliminary results for a benchmark cylinder case highlight the accuracy of the method, and suggest its applicability to more complex cases.

Development and application of computational methodologies in qualitative modeling

La pr��sente th��se s'intitule "D��veloppent et Application des M��thodologies Computationnelles pour la Mod��lisation Qualitative". Elle comprend tous les diff��rents projets que j'ai entrepris en tant que doctorante. Plut��t qu'une mise en oeuvre syst��matique d'un cadre d��fini a priori, cette th��se devrait ��tre consid��r��e comme une exploration des m��thodes qui peuvent nous aider �� d��duire le plan de processus regulatoires et de signalisation. Cette exploration a ��t�� mue par des questions biologiques concr��tes, plut��t que par des investigations th��oriques. Bien que tous les projets aient inclus des syst��mes divergents (r��seaux r��gulateurs de g��nes du cycle cellulaire, r��seaux de signalisation de cellules pulmonaires) ainsi que des organismes (levure �� fission, levure bourgeonnante, rat, humain), nos objectifs ��taient compl��mentaires et coh��rents. Le projet principal de la th��se est la mod��lisation du r��seau de l'initiation de septation (SIN) du S.pombe. La cytokin��se dans la levure �� fission est contr��l��e par le SIN, un r��seau signalant de prot��ines kinases qui utilise le corps �� p��le-fuseau comme ��chafaudage. Afin de d��crire le comportement qualitatif du syst��me et pr��dire des comportements mutants inconnus, nous avons d��cid�� d'adopter l'approche de la mod��lisation bool��enne. Dans cette th��se, nous pr��sentons la construction d'un mod��le bool��en ��tendu du SIN, comprenant la plupart des composantes et des r��gulateurs du SIN en tant que noeuds individuels et testable exp��rimentalement. Ce mod��le utilise des niveaux d'activit�� du CDK comme noeuds de contr��le pour la simulation d'��v��nements du SIN �� diff��rents stades du cycle cellulaire. Ce mod��le a ��t�� optimis�� en utilisant des exp��riences d'un seul "knock-out" avec des effets ph��notypiques connus comme set d'entra��nement. Il a permis de pr��dire correctement un set d'��valuation de "knock-out" doubles. De plus, le mod��le a fait des pr��dictions in silico qui ont ��t�� valid��es in vivo, permettant d'obtenir de nouvelles id��es de la r��gulation et l'organisation hi��rarchique du SIN. Un autre projet concernant le cycle cellulaire qui fait partie de cette th��se a ��t�� la construction d'un mod��le qualitatif et minimal de la r��ciprocit�� des cyclines dans la S.cerevisiae. Les prot��ines Clb dans la levure bourgeonnante pr��sentent une activation et une d��gradation caract��ristique et s��quentielle durant le cycle cellulaire, qu'on appelle commun��ment les vagues des Clbs. Cet ��v��nement est coordonn�� avec la courbe d'activation inverse du Sic1, qui a un r��le inhibitoire dans le syst��me. Pour l'identification des mod��les qualitatifs minimaux qui peuvent expliquer ce ph��nom��ne, nous avons s��lectionn�� des exp��riences bien d��finies et construit tous les mod��les minimaux possibles qui, une fois simul��s, reproduisent les r��sultats attendus. Les mod��les ont ��t�� filtr��s en utilisant des simulations ODE qualitatives et standardis��es; seules celles qui reproduisaient le ph��notype des vagues ont ��t�� gard��es. L'ensemble des mod��les minimaux peut ��tre utilis�� pour sugg��rer des relations regulatoires entre les mol��cules participant qui peuvent ensuite ��tre test��es exp��rimentalement. Enfin, durant mon doctorat, j'ai particip�� au SBV Improver Challenge. Le but ��tait de d��duire des r��seaux sp��cifiques �� des esp��ces (humain et rat) en utilisant des donn��es de phosphoprot��ines, d'expressions des g��nes et des cytokines, ainsi qu'un r��seau de r��f��rence, qui ��tait mis �� disposition comme donn��e pr��alable. Notre solution pour ce concours a pris la troisi��me place. L'approche utilis��e est expliqu��e en d��tail dans le dernier chapitre de la th��se. -- The present dissertation is entitled "Development and Application of Computational Methodologies in Qualitative Modeling". It encompasses the diverse projects that were undertaken during my time as a PhD student. Instead of a systematic implementation of a framework defined a priori, this thesis should be considered as an exploration of the methods that can help us infer the blueprint of regulatory and signaling processes. This exploration was driven by concrete biological questions, rather than theoretical investigation. Even though the projects involved divergent systems (gene regulatory networks of cell cycle, signaling networks in lung cells), as well as organisms (fission yeast, budding yeast, rat, human), our goals were complementary and coherent. The main project of the thesis is the modeling of the Septation Initiation Network (SIN) in S.pombe. Cytokinesis in fission yeast is controlled by the SIN, a protein kinase signaling network that uses the spindle pole body as scaffold. In order to describe the qualitative behavior of the system and predict unknown mutant behaviors we decided to adopt a Boolean modeling approach. In this thesis, we report the construction of an extended, Boolean model of the SIN, comprising most SIN components and regulators as individual, experimentally testable nodes. The model uses CDK activity levels as control nodes for the simulation of SIN related events in different stages of the cell cycle. The model was optimized using single knock-out experiments of known phenotypic effect as a training set, and was able to correctly predict a double knock-out test set. Moreover, the model has made in silico predictions that have been validated in vivo, providing new insights into the regulation and hierarchical organization of the SIN. Another cell cycle related project that is part of this thesis was to create a qualitative, minimal model of cyclin interplay in S.cerevisiae. CLB proteins in budding yeast present a characteristic, sequential activation and decay during the cell cycle, commonly referred to as Clb waves. This event is coordinated with the inverse activation curve of Sic1, which has an inhibitory role in the system. To generate minimal qualitative models that can explain this phenomenon, we selected well-defined experiments and constructed all possible minimal models that, when simulated, reproduce the expected results. The models were filtered using standardized qualitative ODE simulations; only the ones reproducing the wave-like phenotype were kept. The set of minimal models can be used to suggest regulatory relations among the participating molecules, which will subsequently be tested experimentally. Finally, during my PhD I participated in the SBV Improver Challenge. The goal was to infer species-specific (human and rat) networks, using phosphoprotein, gene expression and cytokine data and a reference network provided as prior knowledge. Our solution to the challenge was selected as in the final chapter of the thesis.

Functional error modeling for uncertainty quantification in hydrogeology

Approximate models (proxies) can be employed to reduce the computational costs of estimating uncertainty. The price to pay is that the approximations introduced by the proxy model can lead to a biased estimation. To avoid this problem and ensure a reliable uncertainty quantification, we propose to combine functional data analysis and machine learning to build error models that allow us to obtain an accurate prediction of the exact response without solving the exact model for all realizations. We build the relationship between proxy and exact model on a learning set of geostatistical realizations for which both exact and approximate solvers are run. Functional principal components analysis (FPCA) is used to investigate the variability in the two sets of curves and reduce the dimensionality of the problem while maximizing the retained information. Once obtained, the error model can be used to predict the exact response of any realization on the basis of the sole proxy response. This methodology is purpose-oriented as the error model is constructed directly for the quantity of interest, rather than for the state of the system. Also, the dimensionality reduction performed by FPCA allows a diagnostic of the quality of the error model to assess the informativeness of the learning set and the fidelity of the proxy to the exact model. The possibility of obtaining a prediction of the exact response for any newly generated realization suggests that the methodology can be effectively used beyond the context of uncertainty quantification, in particular for Bayesian inference and optimization.