Product Platform Development from the Product Lines' Perspective: Case of Switching Platform

In the era of fast product development and customized product requirements, the concept of product platform has proven its power in practice. The product platform approach has enabledcompanies to increase the speed of product introductions while simultaneously benefit from efficiency and effectiveness in the development and production activities. The product platforms are technological bases, which can be used to develop several derivative products, and hence, the differentiation can be pushed closer to the product introduction. The product platform development has some specific features, which differ somewhat from the product development of single products. The time horizon is longer, since the product platform¿slife cycle is longer than individual product's. The long time-horizon also proposes higher market risks and the use of new technologies increases the technological risks involved. The end-customer interface might be far away, but there is not a lack of needs aimed at the product platforms ¿ in fact, the product platform development is very much balancing between the varying needs set to it by thederivative products. This dissertation concentrated on product platform development from the internal product lines' perspective of a singlecase. Altogether six product platform development factors were identified: 'Strategic and business fit of product platform', 'Project communication and deliverables', 'Cooperation with product platform development', 'Innovativeness of product platform architecture and features', 'Reliability and quality of product platform', and 'Promised schedules and final product platform meeting the needs'. From the six factors, three were found to influence quite strongly the overall satisfaction, namely 'Strategic and business fit of product platform', 'Reliability and quality of product platform', and 'Promised schedules and final product platform meeting the needs'. Hence, these three factors might be the ones a new product platform development unit should concentrate first in order to satisfy their closest customers, the product lines. The 'Project communication and deliverables' and 'Innovativeness of product platform architecture and features' were weaker contributors to the overall satisfaction. Overall, the factors explained quite well the satisfaction of the product lines with product platform development. Along the research, several interesting aspects about the very basic nature of the product platform development were found. The long time horizon of the product platform development caused challenges in the area of strategic fIT - a conflict between the short-term requirements and long term needs. The fact that a product platform was used as basis of several derivative products resulted into varying needs, and hence the match with the needs and the strategies. The opinions, that the releases of the larger product lines were given higher priorities, give an interesting contribution to the strategy theory of powerand politics. The varying needs of the product lines, the strengths of them as well as large number of concurrent releases set requirements to prioritization. Hence, the research showed the complicated nature of the product platform development in the case unIT - the very basic nature of the product platform development might be its strength (gaining efficiency and effectiveness in product development and product launches) but also the biggest challenge (developing products to meet several needs). As a single case study, the results of this research are not directly generalizable to all the product platform development activities. Instead, the research serves best as a starting point for additional research as well as gives some insights about the factors and challengesof one product development unit.

Control and Simulation of Batch Crystallization

Concerning process control of batch cooling crystallization the present work focused on the cooling profile and seeding technique. Secondly, the influence of additives on batch-wise precipitation process was investigated. Moreover, a Computational Fluid Dynamics (CFD) model for simulation of controlled batch cooling crystallization was developed. A novel cooling model to control supersaturation level during batch-wise cooling crystallization was introduced. The crystallization kinetics together with operating conditions, i.e. seed loading, cooling rate and batch time, were taken into account in the model. Especially, the supersaturation- and suspension density- dependent secondary nucleation was included in the model. The interaction between the operating conditions and their influence on the control target, i.e. the constant level of supersaturation, were studied with the aid of a numerical solution for the cooling model. Further, the batch cooling crystallization was simulated with the ideal mixing model and CFD model. The moment transformation of the population balance, together with the mass and heat balances, were solved numerically in the simulation. In order to clarify a relationship betweenthe operating conditions and product sizes, a system chart was developed for anideal mixing condition. The utilization of the system chart to determine the appropriate operating condition to meet a required product size was introduced. With CFD simulation, batch crystallization, operated following a specified coolingmode, was studied in the crystallizers having different geometries and scales. The introduced cooling model and simulation results were verified experimentallyfor potassium dihydrogen phosphate (KDP) and the novelties of the proposed control policies were demonstrated using potassium sulfate by comparing with the published results in the literature. The study on the batch-wise precipitation showed that immiscible additives could promote the agglomeration of a derivative of benzoic acid, which facilitated the filterability of the crystal product.

A mechanism of carbapenem resistance due to a new insertion element (ISPa133) in Pseudomonas aeruginosa

This study explored the evolutionary mechanism by which the clinical isolate PA110514 yields the imipenemresistant derivative PA116136. Both isolates were examined by PFGE and SDS-PAGE, which led to the identification of a new insertion sequence, ISPa133. This element was shown to have distinct chromosomal locations in each of the original isolates that appeared to explain the differences in imipenem susceptibilty. In strain PA110514, ISPa133 is located 56 nucleotides upstream of the translational start codon, which has no effect on expression of the porin OprD. However, in strain PA116136 ISPa133 it is located in front of nucleotide 696 and, by interrupting the coding region, causes a loss of OprD expression, thus conferring imipenem resistance. In vitro experiments mimicking the natural conditions of selective pressure yielded imipenem-resistant strains in which ISPa133 similarly interrupted oprD. A mechanism is proposed whereby ISPa133 acts as a mobile switch, with its position in oprD depending on the degree of selective pressure exerted by imipenem

A mechanism of carbapenem resistance due to a new insertion element (ISPa133) in Pseudomonas aeruginosa

This study explored the evolutionary mechanism by which the clinical isolate PA110514 yields the imipenemresistant derivative PA116136. Both isolates were examined by PFGE and SDS-PAGE, which led to the identification of a new insertion sequence, ISPa133. This element was shown to have distinct chromosomal locations in each of the original isolates that appeared to explain the differences in imipenem susceptibilty. In strain PA110514, ISPa133 is located 56 nucleotides upstream of the translational start codon, which has no effect on expression of the porin OprD. However, in strain PA116136 ISPa133 it is located in front of nucleotide 696 and, by interrupting the coding region, causes a loss of OprD expression, thus conferring imipenem resistance. In vitro experiments mimicking the natural conditions of selective pressure yielded imipenem-resistant strains in which ISPa133 similarly interrupted oprD. A mechanism is proposed whereby ISPa133 acts as a mobile switch, with its position in oprD depending on the degree of selective pressure exerted by imipenem

A mechanism of carbapenem resistance due to a new insertion element (ISPa133) in Pseudomonas aeruginosa

This study explored the evolutionary mechanism by which the clinical isolate PA110514 yields the imipenemresistant derivative PA116136. Both isolates were examined by PFGE and SDS-PAGE, which led to the identification of a new insertion sequence, ISPa133. This element was shown to have distinct chromosomal locations in each of the original isolates that appeared to explain the differences in imipenem susceptibilty. In strain PA110514, ISPa133 is located 56 nucleotides upstream of the translational start codon, which has no effect on expression of the porin OprD. However, in strain PA116136 ISPa133 it is located in front of nucleotide 696 and, by interrupting the coding region, causes a loss of OprD expression, thus conferring imipenem resistance. In vitro experiments mimicking the natural conditions of selective pressure yielded imipenem-resistant strains in which ISPa133 similarly interrupted oprD. A mechanism is proposed whereby ISPa133 acts as a mobile switch, with its position in oprD depending on the degree of selective pressure exerted by imipenem

Niños "vergonzantes" y "pequeños rojos". La población marginal infantil en la Cataluña interior del primer franquismo

En el imaginario colectivo de la sociedad de posguerra siempre están presentes las duras condiciones de la vida cotidiana. La población infantil fue especialmente sensible a esta situación debido al alto índice de enfermedades infecciosas, el racionamiento dietético y las angustias derivadas del conflicto bélico. En estas condiciones, el Auxilio Social de la Falange fue el encargado de administrar la beneficencia y, a su vez, resocializar la población, en este caso, la infantil, dentro de los valores nacionalsindicalistas y nacionalcatólicos. Ello le permitió no sólo controlar la política social sino también criminalizar a los vencidos en el momento de administrarla. En definitiva, fue uno de los pilares fundamentales en el proceso de construcción del edificio franquista.

Surface functionalization of alumina ceramic foams with organic ligands.

Different anchoring groups have been studied with the aim of covalently binding organic linkers to the surface of alumina ceramic foams. The results suggested that a higher degree of functionalization was achieved with a pyrogallol derivative - as compared to its catechol analogue - based on the XPS analysis of the ceramic surface. The conjugation of organic ligands to the surface of these alumina materials was corroborated by DNP-MAS NMR measurements.

Optimized synthesis of O-carboxymethyl-N,N,N-trimethyl chitosan.

We present here the synthesis of a highly O-carboxymethylated chitosan derivative. First, an improved protocol for the two-step synthesis of N-trimethyl chitosan (TMC) from chitosan was developed, yielding a maximum degree of quaternization (DQ) of up to 46.6%. Successively, the chitosan derivative O-carboxymethyl-N-trimethyl chitosan (CMTMC) was synthesized from the TMC obtained by applying an optimized synthesis pathway. In contrast to previous reports, the optimized protocol was shown to yield very high rates (>85%) of O-carboxymethylation of CMTMC, as shown by (1)H NMR and heteronuclear single quantum correlation ((1)H-(13)C HSQC). Finally, in vitro cytocompatibility (viability >80%) of the polymer was demonstrated using human fibroblasts.

Assessment of the chemosensitizing activity of TAT-RasGAP317-326 in childhood cancers.

Although current anti-cancer protocols are reasonably effective, treatment-associated long-term side effects, induced by lack of specificity of the anti-cancer procedures, remain a challenging problem in pediatric oncology. TAT-RasGAP317-326 is a RasGAP-derived cell-permeable peptide that acts as a sensitizer to various anti-cancer treatments in adult tumor cells. In the present study, we assessed the effect of TAT-RasGAP317-326 in several childhood cancer cell lines. The RasGAP-derived peptide-induced cell death was analyzed in several neuroblastoma, Ewing sarcoma and leukemia cell lines (as well as in normal lymphocytes). Cell death was evaluated using flow cytometry methods in the absence or in the presence of the peptide in combination with various genotoxins used in the clinics (4-hydroperoxycyclophosphamide, etoposide, vincristine and doxorubicin). All tested pediatric tumors, in response to at least one genotoxin, were sensitized by TAT-RasGAP317-326. The RasGAP-derived peptide did not increase cell death of normal lymphocytes, alone or in combination with the majority of the tested chemotherapies. Consequently, TAT-RasGAP317-326 may benefit children with tumors by increasing the efficacy of anti-cancer therapies notably by allowing reductions in anti-cancer drug dosage and the associated drug-induced side effects.

Easy introduction of maleimides at different positions of oligonucleotide chains for conjugation purposes

[2,5-Dimethylfuran]-protected maleimides were placed at both internal positions and the 3'-end of oligonucleotides making use of solid-phase synthesis procedures. A new phosphoramidite derivative and a new solid support incorporating the protected maleimide moiety were prepared for this purpose. In all cases maleimide deprotection (retro-Diels-Alder reaction) followed by reaction with thiol-containing compounds afforded the target conjugate.

Neutron skin thickness in the droplet model with surface width dependence: Indications of softness of the nuclear symmetry energy

We analyze the neutron skin thickness in finite nuclei with the droplet model and effective nuclear interactions. The ratio of the bulk symmetry energy J to the so-called surface stiffness coefficient Q has in the droplet model a prominent role in driving the size of neutron skins. We present a correlation between the density derivative of the nuclear symmetry energy at saturation and the J/Q ratio. We emphasize the role of the surface widths of the neutron and proton density profiles in the calculation of the neutron skin thickness when one uses realistic mean-field effective interactions. Next, taking as experimental baseline the neutron skin sizes measured in 26 antiprotonic atoms along the mass table, we explore constraints arising from neutron skins on the value of the J/Q ratio. The results favor a relatively soft symmetry energy at subsaturation densities. Our predictions are compared with the recent constraints derived from other experimental observables. Though the various extractions predict different ranges of values, one finds a narrow window L∼45-75 MeV for the coefficient L that characterizes the density derivative of the symmetry energy that is compatible with all the different empirical indications.

Use of the dried blood spot sampling process coupled with fast gas chromatography and negative-ion chemical ionization tandem mass spectrometry: application to fluoxetine, norfluoxetine, reboxetine, and paroxetine analysis.

The objective of this work was to combine the advantages of the dried blood spot (DBS) sampling process with the highly sensitive and selective negative-ion chemical ionization tandem mass spectrometry (NICI-MS-MS) to analyze for recent antidepressants including fluoxetine, norfluoxetine, reboxetine, and paroxetine from micro whole blood samples (i.e., 10 microL). Before analysis, DBS samples were punched out, and antidepressants were simultaneously extracted and derivatized in a single step by use of pentafluoropropionic acid anhydride and 0.02% triethylamine in butyl chloride for 30 min at 60 degrees C under ultrasonication. Derivatives were then separated on a gas chromatograph coupled with a triple-quadrupole mass spectrometer operating in negative selected reaction monitoring mode for a total run time of 5 min. To establish the validity of the method, trueness, precision, and selectivity were determined on the basis of the guidelines of the "Société Française des Sciences et des Techniques Pharmaceutiques" (SFSTP). The assay was found to be linear in the concentration ranges 1 to 500 ng mL(-1) for fluoxetine and norfluoxetine and 20 to 500 ng mL(-1) for reboxetine and paroxetine. Despite the small sampling volume, the limit of detection was estimated at 20 pg mL(-1) for all the analytes. The stability of DBS was also evaluated at -20 degrees C, 4 degrees C, 25 degrees C, and 40 degrees C for up to 30 days. Furthermore, the method was successfully applied to a pharmacokinetic investigation performed on a healthy volunteer after oral administration of a single 40-mg dose of fluoxetine. Thus, this validated DBS method combines an extractive-derivative single step with a fast and sensitive GC-NICI-MS-MS technique. Using microliter blood samples, this procedure offers a patient-friendly tool in many biomedical fields such as checking treatment adherence, therapeutic drug monitoring, toxicological analyses, or pharmacokinetic studies.

Utilisation of Short Term Electricity Derivatives in Industrial Energy Management

Työn päätavoite on selvittää kuinka erityisesti sähkön markkinahinnan ennustamiseen ja johdannaismarkkinoiden tietämykseen perustuva lyhyen tähtäimen sähköjohdannaisten hyödyntäminen tapahtuu teollisessa energianhallinnassa. Tätä aihetta lähestytään luomalla prosessi lyhyen tähtäimen sähköjohdannaisten hyödyntämiselle. Prosessi esitellään ja selvitetään aina lähtökohdista todelliseen kaupankäyntiin asti erillisen esimerkkitehtaan avulla.Lyhyen tähtäimen sähköjohdannaisten hyödyntäminen teollisessa energianhallinnassa perustuu pääosin tulevaisuuden odotuksiin sähkön markkinahinnan kehittymisestä sekä tehtaiden operatiiviseen tilanteeseen. Operatiiviseen tilanteeseen perustuva lyhyen tähtäimen sähköjohdannaisten kaupankäynti on pääasiassa pitkän tähtäimen suojausten sopeuttamista lyhyelle tähtäimelle sopivaksi.Hinnan ennustamisella on suuri rooli lyhyen tähtäimen sähköjohdannaisten hyödyntämisprosessissa. Työssä esitelty hinnan ennustamismalli on sopiva päivä- ja viikkotason Nord Poolin Elspot -systeemihinnan ennustamiseen. Elspot -systeemihinnan ennustamismalli on suunniteltu käytännönläheiseksi ja sen perustana ovat todelliset fysikaaliset ja mitattavat suureet. Futuurimarkkinatietämys on tarpeen lyhyen tähtäimen johdannaisia käytettäessä. Työssä tutkitaan yleisiä markkinoiden odotuksia ja futuurimarkkinoiden tietoisuuden kehittymistä koskien tulevaa vallitsevaa tilannetta. Työssä luodaan myös työkalu, mikä auttaa kaupan laatijaa muodostamaan suuntaa-antavat todennäköisyydet eri hintanäkemyksille ja paikallistamaan mahdolliset markkinoiden epätodennäköiset hintaodotukset.Kokemukset Elspot -systeemihinnan ennustamismallin soveltamisesta ovat lupaavia. Lisäksi havainnot futuurimarkkinoiden käyttäytymisestä Nord Poolissa ja muodostettu työkalu suuntaa-antavien todennäköisyyksien selvittämiseksi auttavat kaupan laatijaa päätöksenteossa. Lyhyen tähtäimen sähköjohdannaisten hyödyntäminen teollisessa energianhallinnassa on periaatteessa mahdollista esitellyn prosessin avulla, vaikka täydellinen käyttöönotto vaatisi vielä joitakin järjestelyjä. Keskittymällä tilanteisiin jotka työssä kuvatulla prosessilla ovat hoidettavissa, työssä määritellyllä menettelyllä on mahdollisuudet saavuttaa epäedullisen hintakehityksen riskin väheneminen ja parempi taloudellinen tulos teollisen energianhallinnan sähkökaupankäynnissä.

Ewing sarcoma cancer stem cells : from mechanisms to therapeutic targeting

Le sarcome d'Ewing (SE) est la 2ème tumeur des os la plus fréquente chez les enfants, et le pronostic est sombre au stade métastatique. La pathogenèse du SE repose sur une translocation, provocant la fusion du domaine activateur du facteur de transcription EWS, avec la partie liant l'ADN de la protéine FLI-1. Les cellules souches cancéreuses (CSC) sont supposées être les moteurs de la croissance tumorale, et représente de ce fait des cibles thérapeutiques préférentielles. Dans ce travail nous nous sommes efforcés de comprendre, ainsi que de cibler les mécanismes liés à l'émergence des CSC dans le sarcome d'Ewing. La formation des CSC du ES est liée à un défaut de maturation des miRNAs provoqué par une sous-expression d'un gène, TARBP2, dans les CSC. Ce défaut de maturation peut être corrigé par un traitement des cellules avec de l'enoxacine, une fluoroquinolone utilisée pour traiter les infections urinaires. L'enoxacine seule n'étant pas suffisante pour éradiquer les tumeurs in vivo, nous avons testé la combinaison d'une thérapie ciblée sur les CSC avec une chimiothérapie classique, la doxorubicine, ciblant les cellules différentiées. In vitro l'enoxacine induit l'apoptose dans les CCS sans affecter les cellules différentiées, alors que à l'inverse, la doxorubicine n'affecte que les cellules de la « masse » tumorale. In vivo la combinaison de ces deux drogues inhibe la croissance de tumeurs provenant de cellules primaires xenotranplantées et éradique les CSCs. Nos résultats mettent en lumière une nouvelle approche thérapeutique directement applicable pour le sarcome d'Ewing, et pourraient ainsi rapidement déboucher sur des essais cliniques. Dans la deuxième partie de ce travail nous avons essayé de comprendre comment EWS-FLI1, la protéine de fusion issue de la translocation chromosomique du sarcome d'Ewing conduit à la génération des CSC. Pour cela nous avons effectué des ChIPseq (immunoprecipitation de la chromatine suivi de séquençage) pour EWS-FLI1 ainsi que pour certaines modifications histoniques. -- Ewing sarcoma family tumors (ESFT) are the second most frequent bone tumors in children and have a high rate of recurrence when metastatic at presentation. The pathogenesis of Ewing sarcoma is underlayed by a translocation, leading to the fusion of the trans-activating domain of EWS with the FLU DNA binding domain. Cancer stem cells (CSCs) are thought to be the driving force of tumor growth. In this work we focused on understanding the mechanisms underlying ESFT CSC emergence as well as defining targeted therapeutic strategies. Emergence of CSCs in ESFT has been shown to arise from a defect in TARBP2-dependent microRNA maturation, which can be corrected by exposure to the fluoroquinolone enoxacin. As enoxacin alone is not sufficient to reverse tumor growth in vivo, we assessed the effect of combining a drug that abrogates CSC properties with doxorubicin, a standard-of-care therapy in ESFT. Primary ESFT CSCs and bulk tumor cells were treated with different concentration of drugs and displayed divergent responses to doxorubicin and enoxacin. Doxorubicin, which targets the tumor bulk, displayed toxicity toward primary adherent ESFT cells in culture but not to CSC-enriched ESFT spheres. Conversely, enoxacin induced apoptosis but only in ESFT spheres and specifically on the CD133+ population. In combination, the two drugs markedly depleted CSC and strongly reduced primary growth in xenograft assays of two primary ESFT. Our results identify a potentially attractive therapeutic strategy for ESFT that combines mechanism-based targeting of CSC using a low toxicity antibiotic with a standard-of-care cytotoxic drug, offering immediate applications for clinical evaluation. In the second part of this work we performed chromatin immunopercipitation on CSCs and bulk cells for EWS-FLI1 binding as well as some chromatin modifications, and concluded that EWS-FLI1 shows cell context dependent binding.

Vakioidut optiot sähkökaupassa

Pohjoismaiset sähkömarkkinat ovat muuttuneet viime vuosina huomattavasti. Sähkömarkkinalakiuudistuksessa poistettiin muodollisesti kilpailun esteet, mutta uusien toimintamuotojen omaksuminen on Suomessa vasta alussa. Sähkömarkkinaosapuolet altistuvat riskriskeille, joita toimialalla ei ole aikaisemmin esiintynyt. Suurimpana riskitekijänä voidaan pitää epävarmuutta tulevasta sähkön hintatasosta, joka voi vaikuttaa merkittävästi yrityksen liiketoiminnan tulokseen. Tässä diplomityössä tarkastellaan, miten hinnanvaihtelua vastaan pystytään suojautumaan sähköjohdannaisten avulla. Kaupankäynti johdannaissopimuksilla edellyttää markkinoiden aktiivista seuraamista ja organisoitua sähkökaupan riskienhallintaa. Riskienhallinnan tehtävänä ei ole riskien eliminoiminen, vaan niiden sopeuttaminen yrityksen tuotto-odotuksien ja riskiensietokyvyn mukaisiksi. Ennen sähkömarkkinoiden avautumista suojauduttiin sähkön hintariskeiltä pitkillä toimitussopimuksilla. Uudessa markkinatilanteessa suojaus voidaan toteuttaa joustavasti ja kohtuullisin kustannuksin käyttämällä johdannaissopimuksia, joilla voidaan poistaa tulevaisuuteen kohdistuvaa epävarmuutta sähkönhinnasta. Pohjoismaisessa sähköpörssissä, Nord Pool ASA:ssa, noteerattavat johdannaiset ovat vakioituja. Lokakuun lopussa 1999 kaupankäynnin kohteeksi otetaan termiinien lisäksi myös vakioidut sähköoptiot. Option ostajalle avautuu mahdollisuus hintasuojaukseen instrumenteilla, joita käyttäen suojaustaso voidaan määrittää etukäteen. Vakioitujen sähköoptioiden mukaan ottaminen sähköpörssin tuotevalikoimaan monipuolistaa huomattavasti ostajien ja myyjien suojautumismahdollisuuksia. Suojaustasoa on tarpeen vaatiessa mahdollista muuttaa vastamaan uutta markkinatilannetta. Työn loppuosassa on tutkittu mahdollisia kaupankäyntistrategioita ja hinnoittelumalleja sähköoptioille. Koska tutkimus on tehty ennen pörssissä tapahtuvan optiokaupan alkamista, useisiin tässä työssä avoimiksi jääneisiin kysymyksiin tullaan saaman vastauksia käytännön kokemuksista.