The formation of neural connections in the mammalian nervous system is a complex process. During development, axons are initially overproduced and compete for limited quantities of target-derived growth factors. Axons which participate in functional circuits and secure appropriate amounts of growth factors are stabilized, while those axons that are either inappropriately connected or do not obtain sufficient concentrations of growth factors are eliminated in a process termed ‘axon pruning’. In this thesis, I examined the mechanisms that regulate pruning of peripheral, NGF-dependent sympathetic neurons that project to the eye. I determined that pruning of these projections in vivo requires the p75 neurotrophin receptor (p75NTR) and synthesis of brain-derived neurotrophic factor (BDNF) from the activity-dependent exon IV promoter. Furthermore, analysis of an in vitro model of axon competition, which is regulated by the interplay between nerve growth factor (NGF) and neuronal activity, revealed that p75NTR and BDNF are also essential for axon competition in culture. In this model, in the presence of NGF, neural activity confers a competitive growth advantage to stimulated, active axons by enhancing downstream TrkA (NGF receptor) signaling locally in axons. More interestingly, the unstimulated, inactive axons deriving from the same and neighboring neurons acquire a "growth disadvantage" due to secreted BDNF acting through p75NTR, which induces axon degeneration by suppressing TrkA signaling that is essential for axonal integrity. These data support a model where, during developmental axon competition, successful axons secrete BDNF in an activity-dependent fashion which activates p75NTR on unsuccessful neighboring axons, suppressing TrkA signaling, and ultimately promoting pruning by a degenerative mechanism.

In contrast to cardiac rehabilitation (CR) programs, traditional stroke rehabilitation aims to maximize functional independence and does not have a strong focus on exercise training and risk factor modification. Given the parallels between stroke and heart disease in cardiovascular etiology and risk factors, CR may be suited to supplement stroke rehabilitation by providing opportunities to enhance fitness and manage stroke risk factors. The aim of this work was to 1) examine the use of a non-adapted CR program of care with individuals with stroke and/or transient ischemic attack (TIA) through a retrospective database review, 2) using a prospective trial, determine the feasibility and effects of an adapted CR program for people with mild to moderate impairment from stroke, and 3) explore characteristics related to degree of program response in aerobic and functional capacity through secondary data analysis. The results from Study 1 demonstrated that traditional CR is an underutilized service for individuals with stroke or TIA, yet improvements in aerobic fitness were comparable to their non-stroke counterparts. In Study 2, adapted CR was feasible for individuals with a range of stroke-related disability and effective in increasing aerobic capacity. The anticipated carry over to improved walking capacity was not observed. There were no changes in health-related quality of life or stroke risk factors. Study 3 identified subgroups of participants who improved or declined in aerobic and ambulatory capacity after the adapted CR program. There were no differences in baseline characteristics, indices of time, intensity or volume of exercise performed across the response subgroups. In summary, given the parallels between stroke and heart disease, the needs of the stroke population and dearth of community-based exercise programming available for them, the CR model of care may be applied for individuals with stroke to provide opportunities for exercise training and risk factor modification.

A complex network of transcription factors, which are regulated by signalling molecules, is responsible in coordinating the formation of differentiated skeletal and cardiac myocytes from undifferentiated stem cells. The present study aims to understand and compare the transcriptional regulation of skeletal and/or cardiac muscle development in the absence of Sox7 or in the presence of a collagen-based matrix in P19 embyonal carcinoma (EC) and mouse embryonic stem (ES) cells. First, knock-down of Sox7 , by shRNA, in muscle inducing conditions (+DMSO) and in the absence of RA (-RA), decreased muscle progenitor transcription factor and myogenic regulatory factor (MRF) levels, suggesting that Sox7 is necessary for myogenesis. However, knock-down of Sox7 in the presence of RA (+RA) and DMSO increased expression of muscle progenitor markers and MRFs, suggesting that Sox7 is inhibitory for myogenesis +RA. Furthermore, Sox7 overexpression enhanced myogenesis -RA, but inhibited myogenesis and enhanced neurogenesis +RA. These results suggest an important interplay between RA signalling and Sox7 function during P19 differentiation. Second, Q-PCR analysis showed that compared to the mouse ES cells differentiated on the regular TC plates, differentiation on the collagen matrices had a higher expression of skeletal and cardiac precursors, MRFs and terminal differentiation markers. Collagen alone enhanced myotube formation. The enhanced collagen matrix, containing the oligosaccharide sialyl LewisX (sLeX), specifically enhanced cardiomyogenesis. These studies have added to our understanding of the transcriptional regulation of premyogenic mesoderm factors and the role of Sox7 in this process. In addition these studies provide a vision for possible use of biomaterials in directed differentiation of stem cells for the purpose of cell therapy.

L'agudització de la malaltia pulmonar obstructiva crònica (MPOC) és important en termes de salut i econòmics. Malgrat això, no es coneix quins són els factors de risc o protectors de l'agudització de la MPOC, ni fins a quin punt els pacients amb MPOC són tractats de forma satisfactòria en referència a aquests factors. L'Estudi dels Factors de Risc d'Agudització de la MPOC, anomenat EFRAM, va sorgir amb els objectius de respondre aquestes qüestions. Es va reclutar una mostra sistemàtica d'1 de cada 2 pacients ingressats per agudització de la seva MPOC en quatre hospitals terciaris de l'àrea de Barcelona entre maig del 1997 i abril del 1998, i un grup de pacients amb MPOC clínicament estable que havien patit algun ingrés previ. Es van obtenir dades sobre els potencials factors de risc (variables sociodemogràfiques i clíniques, atenció mèdica, adequació terapèutica, compliment, estil de vida, i altres) a partir de: qüestionari extens, mostra d'esput i mesures antropomètriques a l'ingrés; i espirometria forçada i gasometria arterial basal en estabilitat clínica. A partir del Conjunt Mínim Bàsic de Dades d'Altes Hospitalàries (CMBDAH), es van obtenir dades sobre els ingressos hospitalaris fins maig del 1999. Es van creuar les bases de dades amb el Registre de Mortalitat de la Generalitat de Catalunya per obtenir l'estat vital dels individus seguits i les causes de mort.Es van reclutar 346 individus (29 dones) amb un total de 404 ingressos; edat (mitjana±de) 69±9, mediana FEV1 31% del valor de referència i mitjana PO2 63±13 mmHg; i 86 controls estables, de mitjana d'edat 69 anys i mitjana FEV1 43% del valor de referència. Vam trobar prevalences de factors de risc d'agudització de la MPOC potencialment modificables de moderades a altes, entre les quals cal remarcar l'elevada proporció d'individus (86%) que no assistia a programes de rehabilitació respiratòria i el 43% del total que fallava en alguna de les maniobres essencials de l'inhalador. L'estudi de l'associació entre un ampli ventall de potencials factors de risc d'agudització i l'ingrés per aquesta causa, tant en un disseny cas-control com en el seguiment durant 1.1 anys, va mostrar com a principals troballes que el major nivell d'activitat física habitual s'associa amb una reducció del risc d'ingrés per agudització de la MPOC, que la infraprescripció d'oxigenoteràpia crònica domiciliària s'associa a un augment d'aquest risc i que existeix un grup de factors clínics que es relacionen amb un augment del risc d'ingrés (els ingressos previs, el baix nivell de FEV1 i el baix nivell de PO2). D'altra banda, no vam trobar associació entre l'ingrés per agudització de la MPOC i la majoria de factors relacionats amb l'atenció mèdica (vacuna contra la grip i el neumococ, rehabilitació respiratòria, la majoria de fàrmacs, i compliment amb la medicació). El percentatge de FEV1 predit es va mostrar relacionat amb el risc d'infecció bacteriana, i el baix nivell socioeconòmic amb un major risc d'infecció per pseudomones.Durant la realització de l'estudi, s'ha posat de manifest l'escassa recerca existent sobre l'agudització de la MPOC. Aquesta manca d'evidència científica dificulta el fer recomanacions i fa palesa la necessitat d'investigar més sobre aquest tema. La informació proporcionada per aquest estudi pot ser útil pels plans de salut i guies específiques de la MPOC. / Exacerbation of chronic obstructive pulmonary disease (COPD) is important in terms of health and costs. However, there is little information about which are the risk or protective factors of COPD exacerbation and to which extent COPD patients are satisfactorily managed regarding to such factors. The Study of Risk Factors of COPD Exacerbation (EFRAM Study) has the aim of answer these questions. A systematic sampling of 1 out of 2 patients admitted for a COPD exacerbation in four tertiary hospitals in the Barcelona area, Spain, between May 1997 and April 1998, and a control group of COPD patients with a history of previous admissions, was recruited. All patients completed a questionnaire and performed spirometry, sputum sample, blood gases and physical examination. Information about potential risk factors was collected, including variables related to clinical status, characteristics of medical care, medical prescriptions, adherence to medication, lifestyle, quality of life, and other. Information on re-hospitalizations until May 1999 was obtained from the Minimum Basic Dataset (CMBD). Vital status and causes of death were ascertained through a record linkage with the Catalonia Mortality Registry.Three hundred and forty-six patients (29 women) with a total of 404 admissions were recruited; age (mean±sd) 69±9, median FEV1 31% and mean PO2 63±13 mmHg; and 86 stable controls, of mean age 69 years and mean FEV1 43%. We found a moderate to high prevalence of potentially modifiable risk factors of COPD exacerbation, among which it is important to note the high proportion of subjects (86%) who did not attend respiratory rehabilitation programmes and the 43% that failed in some of the essential inhaler maneuvers. The study of the association between a wide range of potential risk factors and admission for a COPD exacerbation, both in the case-control design and in the 1.1 years of follow-up, showed as the main results that: higher levels of usual physical activity were associated with a reduction of the risk of admission for a COPD exacerbation, underprescription of long term oxygen therapy was related to an increase of this risk and that a group of clinical factors (previous admissions, lower FEV1 and lower PO2) was associated with a higher risk of admission for a COPD exacerbation. Moreover, there was no association between admission for a COPD exacerbation and most medical care factors (influenza and pneumococcal vaccination, respiratory rehabilitation, most drugs, and adherence to medication). FEV1 was also related to a higher risk of bacterial infection, and low socioeconomic status with a higher risk of pseudomonas infection.During the study, we have found that little research exists regarding COPD exacerbation. The lack of scientific evidence makes difficult to make recommendations and reveals that more research is needed about this issue. Information provided by the EFRAM study can be useful for health planning and COPD guidelines.

Justificació: encara que la pneumònia adquirida a la comunitat (PAC) és una malaltia clàssica i àmpliament estudiada, avui dia continua essent una important causa de morbimortalitat i es continua tenint un coneixement limitat dels factors que l'afavoreixen. La PAC es pot considerar una malaltia d'alta incidència, té un maneig clínic controvertit, una mortalitat important (especialment en els vells) i un cost elevat. Si a això s'hi afegeix l'aparició de resistències bacterianes als antibiòtics sembla lògic que en l'abordatge d'aquesta malaltia cada cop prengui més força la perspectiva de la prevenció.Objectius: conèixer els factors de risc d'adquirir una PAC, a la població major de 14 anys, relacionats amb els hàbits tòxics o estils de vida modificables, les condicions ambientals, laborals i de l'ahitatge, així com conèixer l'efecte de la vacuna antipneumocòccica en la prevenció de la PAC en la població major de 14 anys.Metodologia: per donar resposta a aquests objectius es va dissenyar un estudi observacional de tipus cas-control, de base poblacional, multicèntric i coordinat amb una base poblacional de 860.000 persones majors de 14 anys. Aquesta era la població necessària per, en un any, detectar 1.500 casos de PAC. Van participar 64 centres d'atenció primària de Catalunya, Andorra, València i les Illes Balears. Tots els casos de PAC diagnosticats a la població d'estudi durant el període novembre 1999 - novembre 2000 segons uns estrictes criteris clínics, radiològics i evolutius van ser inclosos. Per cada cas es va seleccionar un control aparellat per edat, sexe i centre d'atenció primària segons un procés de mostreig aleatori a partir del padró municipal. A tots ells, se'ls va administrar un extens qüestionari de factors de risc de PAC que feia referència al consum de tabac, alcohol, exposicions laborals, condicions de vida i de l'habitatge, vacunes, així com antecedents mèdics i comorbiditats.Resultats: Durant el període d'estudi es van identificar i reclutar 1.336 casos de PAC (participació 97 %) i 1.326 controls (participació 63 %), amb una edat mitjana de 57 anys i un lleuger predomini del sexe masculí (53 %). La incidència acumulada observada va ser de 1,6 casos/1.000 habitants any amb una clara relació estacional, de manera que la incidència el mes de gener era casi sis vegades superior a la dels mesos de juliol i agost. Pel que fa a la comorbiditat es va observar una associació estadísticament significativa entre la PAC i la infecció respiratòria de vies altes durant l'últim mes, la insuficiència cardíaca, la bronquitis crònica i el càncer, però no amb la diabetis, l'accident vascular cerebral ni la insuficiència renal crònica. Es va observar una associació estadísticament significativa entre el consum de tabac i la PAC independent de les esmentades comorbiditats, així com una relació dosi resposta entre la PAC i la intensitat de l'hàbit, la seva durada i la quantitat total de paquets fumats. Pel que fa al consum passiu de tabac es va observar una important interacció entre aquesta exposició i l'edat, de manera que en les persones de menys de 60 anys el consum passiu de tabac no tenia cap efecte (OR=1,0), mentre que en les de 60 anys o més s'observa un efecte significatiu (OR=1,52) amb una fracció atribuïble poblacional del 10%. En relació al consum d'alcohol es va observar un efecte significatiu només en els homes i quan el consum era superior als 80 g/dia (OR=2,34) sense que s'observi un increment del risc en consums inferiors encara que es facin diàriament. Altres variables associades a la PAC van ser l'exposició laboral a pols (OR=1,65), animals, vísceres o excrements (OR=1,78) i canvis sobtats de temperatura (OR=3,27), conviure més de 10 persones a la llar (OR=2,20), conviure o treballar amb nens de menys de 15 anys (OR=1,48) o tenir animals domèstics (OR=1,37). Les anàlisis multivariades en les que s'ajusta l'efecte de les vacunes per la comorbiditat mostren un efecte protector i estadísticament significatiu tant de la vacuna de la grip (OR=0,76) com de la vacuna antipneumocòccica (OR=0,55).Conclusions: Aquest estudi identifica diversos factors de risc modificables de PAC, el que ha de permetre dissenyar mesures preventives encaminades a disminuir la seva incidència. A més, aporta nova evidència científica sobre l'efectivitat de la vacuna de la grip i la antipneumocòccica en la prevenció de la PAC. / Context: Although community-acquired pneumonia (CAP) is a well-known and widely studied disease, morbimortality is high and knowledge of the factors that favor CAP limited. CAP is a disease with high incidence, cost and mortality (especially among the elderly) and disputed clinical management. If to all this one adds antibiotic-resistant bacteria it is hardly surprising that the prevention perspective of the disease is gaining importance.Objectives: to determine the risk factors of acquiring CAP that are related to toxic habits or modifiable lifestyles, environmental, working and living conditions, as well as the effect of the antipneumococcal vaccine in preventing CAP, in a population of over 14 years of age.Methods: A population-based, multicenter, coordinated, observational, case-control study was designed with a population base of 860,000 people of over 14 years of age. This was the population needed to detect 1,500 cases of CAP in one year. Sixty-four primary health care clinics in Catalonia, Andorra, Valencia and the Balearic Islands participated in the study. All cases of CAP, diagnosed according to strict clinical, radiological and evolutional criteria between November 1999 and November 2000, were included in the study. A control matched by age, sex and primary health care clinic was selected for each case, following a random sampling process from the town census. All participants were given a detailed questionnaire on the risk factors of CAP which covered tobacco and alcohol use, occupational exposures, living and housing conditions, vaccines, and medical history and comorbidities. Results: During the study period, 1,336 cases of CAP were identified and enrolled (97% participation) and 1,326 controls were selected (63% participation) with an average age of 57 years and a slight predominance of men (53%). The accumulated incidence observed was of 1.6 cases/1,000 inhabitants/year with a marked seasonal relation reflected by the incidence in January being nearly 6 times greater than the incidence in July or August. With regard to comorbidity, a significant association was found between CAP and upper respiratory infections within the previous month, cardiac insufficiency, chronic bronchitis, and cancer, but not with diabetes, stroke, or chronic renal insufficiency. A significant association was found between smoking and CAP, independent of the above-mentioned comorbidities, and a dose-response relation between CAP and the intensity and duration of the smoking habit and the total number of packets smoked. With regard to passive smoking, a clear interaction between exposure and age was observed, there being no effect on people under 60 years of age (OR=1.0) but a significant effect was observed in people over 60 years (OR=1.52) with a population attributable fraction of 10%. Regarding alcohol consumption, a significant effect was observed for men only and when consumption was greater than 80 g/day (OR=2.34), no increased risk being observed for lower consumption even when daily. Other variables associated with CAP were occupational exposure to dust (OR=1.65), animals, offal, or excrements (OR=3.27) and sharp changes in temperature (OR=3.27), living with more than 10 people in the home (OR=2.20), living or working with children under 15 years of age (OR=1.48), or having pets (OR=1.37). Multivariate analysis where the effect of vaccines was adjusted for comorbidities showed a significant protector effect for both the influenza vaccine (OR=.76) and the antipneumococcal vaccine (OR=.55).Conclusions: This study identified several modifiable risk factors of CAP which should allow preventative measures to be designed to reduce incidence. New scientific evidence on the effectiveness of the influenza and antipneumococcal vaccines in the prevention of CAP has also been presented.

This thesis is the main product of a Masters degree in Health Science, written by a student at the Department of Social Work and Health Science at Norwegian University of Science and Technology. The thesis discusses sickness presenteeism in general and sickness presenteeism among nurses in particular. Nursing is one of the occupations that are more exposed to sickness presenteeism. Despite this, very little research has yet been done on this correlation – in Norway, almost none. The thesis consists of two articles. The first article presents the concept of sickness presenteeism along with existing theories and research in general and concerning nurses. This is a theoretical article, in which the purpose is to identify why sickness presenteeism is not an ideal situation for nurses and which work-related factors that influence sickness presenteeism among nurses. The research question for this article is “What work-environmental factors have an influence on nurses sickness presenteeisem?” The second article is an empirical article and is done in connection with a survey of nurses’ sickness presenteeism within a Norwegian hospital. The survey examines the connection between sickness presenteeism and the use of substitutes, different working time arrangements and the influence of teamwork. The purpose of this article is to assess how the three work-environmental factors influences nurses’ sickness presenteeism, conducted with the help of three hypotheses. These are: H1: Working-time arrangements have an influence on sickness presenteeism H2: Low extent of using substitutes is related to higher level of sickness presenteeism H3: Good working relationship between co-workers is related to higher level of sickness presenteeism The empirical work for this master’s thesis has been conducted using a quantitative method. This method was chosen based on a desire to investigate the extent, distribution and differences within sickness presenteeism among nurses. A quantitative method gives an opportunity to investigate a larger group of nurses, and obtain results that can also be valid for other nurses. If a qualitative method were to be used, it would not have been possible to collect information from the same number of nurses and the results would most likely not represent nurses in general because of assumed differences between nurses. By using a qualitative method I was also able to compare the results with results from similar studies done in other countries. Still, the quantitative method has little room for a flexible approach to theory, and does not provide information about what might cause the sickness presenteeism. I still found this method to be the most suitable for what I wanted to achieve in this master’s thesis. A survey based on questions used by other researchers with an interest in the same field, was used to collect data. Using questions that others had already used made the results easier to compare, and also acted as some kind of quality control to the questions I first developed. The choices made concerning the survey, items and analysis is further described in chapter 2.0 Method of my empirical article. The strength and limitations of the method is discussed in chapter 4.1 Strengths and limitations of that same article.

Sp1 i Sp3 pertanyen a la família de factors de transcripció Sp que controla la transcripció de gens implicats en gairebé tots els processos cel.lulars. Estudis previs al nostre grup van estudiar la regulació del promotor del gen Sp1 i van demostrar que la transcripció de Sp1 estava regulada principalment de forma positiva per Sp1 i NF-Y, i que Sp3 era capaç de contrarrestar l'activació produïda per Sp1 sobre el seu propi promotor. Donat que la relació Sp1/Sp3 a la cèl·lula és important per a la regulació dels gens diana, en aquest treball ens vam proposar estudiar la regulació del promotor de Sp3.Vam clonar una regió de 546 bp que corresponia al promotor de Sp3 i vam procedir a la seva caracterització. Sp3 presenta múltiples inicis de transcripció localitzats entre les posicions -132 i -70 respecte de l'inici de traducció i la seva màxima activitat promotora es localitza a la regió fins a -281bp respecte de l'inici de traducció. Mitjançant les tècniques de retardament de la movilitat electroforètica (EMSA) i Immunoprecipitació de la Cromatina (ChIP) hem demostrat la unió dels factors Sp1, Sp3, NF-Y, NF-1, c-Myb, B-Myb i c-Jun al promotor de Sp3. D'altra banda hem estudiat l'efecte de la sobreexpressió i la inhibició d'aquestes proteïnes sobre l'activitat d'aquest promotor utilitzant assajos d'activitat luciferasa, i sobre els nivells endògens de mRNA utilitzant RT-Real Time-PCR. Sp3 activa la transcripció del seu propi promotor. El promotor de Sp3 també és activat de forma més potent per Sp1, Sp3 i NF-Y; tot i que NF-1, c-Myb, B-Myb, c-Jun i c-Fos també poden activar aquest promotor. Un altre fet remarcable és que E2F1 es comporta com a repressor del promotor de Sp3. Tots els resultats observats a nivell de l'activitat del promotor es van confirmar amb la mesura dels nivells endogens de mRNA per Sp3.Addicionalment, s'ha estudiat la interacció de Sp1 amb diferents proteïnes implicades en la regulació del cicle cel·lular i s'ha caracteritzat l'efecte de la seva sobreexpressió sobre l'activitat del promotor de Sp1, ja que està regulat per Sp1. Utilitzant un array d'anticossos, es va fer un cribatge de proteïnes que poguessin interaccionar amb Sp1, i algunes d'elles es van confirmar per co-immunoprecipitació. Això ens va permetre demostrar que Sp1 és capaç d'interaccionar amb CDK4, p21, SKP2 i BRCA2. Posteriorment, vam analitzar l'efecte d'aquestes i altres proteïnes que interaccionen amb Sp1 sobre el promotor de Sp1, i vam observar que el promotor de Sp1 és regulat de forma positiva per la sobreexpressió de CDK4, SKP2, BRCA2, Ciclina D1, E2F1/DP1 i Stat3; mentre que és reprimit per la sobreexpressió de p53 i NFB. Per tal d'analitzar si hi havia una correlació entre els efectes sobre el promotor de Sp1 i una alteració dels nivells endogens de Sp1, vam confirmar tots els efectes observats a nivell de l'activitat del promotor tot emprant la tècnica de RT-Real Time-PCR. A més, els efectes sobre el promotor de Sp1 es produeixen mentre aquestes proteïnes estan unides, directa o indirectament, al promotor tal com van demostrar els assajos de ChIP. També vam estudiar l'efecte de la sobreexpressió d'aquestes proteïnes sobre un promotor que només contenia caixes Sp1 i, en general, vam observar efectes equivalents als observats per al promotor de Sp1. La interacció entre Sp1-p21 va ser objecte d'estudi en més detall i vam determinar que l'expressió de p21 en cèl·lules de fibrosarcoma indueix el promotor de Sp1 així com els nivells de mRNA, però, al mateix temps, indueix la degradació de Sp1.Com a conclusió final, hem vist que el procés de transcripció és un mecanisme molt complex que involucra un gran número de factors de transcripció, així com d'altres proteïnes que puguin interaccionar amb aquests factors. / Sp1 and Sp3 belong to the Sp family of transcription factors that controls transcription of genes involved in almost all processes in the cell. We performed a detailed analysis of the promoter region of the Sp3 transcription factor, including the identification of its transcriptional start sites and the putative binding sites for transcription factors. Multiple transcriptional starts sites were located at position sranging from -70 to -132 relative to the translational start of the gene. We defined the minimal promoter region cooresponding to 281 bp relative to the translational start. Along the promoter sequence we demonstrated the binding of Sp1, Sp3, NF-Y, NF-1, c-Myb, B-Myb and c-Jun. Moreover, we studied the effect of the overexpression or knocking down of these factors on the Sp3 promoter activity and the endogenous mRNA levels. Sp3 is positively autoregulated and it is also activated by Sp1, NF-Y, Myb, AP-1 and NF-1. On the contrary, Sp3 transcription is repressed by E2F/DP1 overexpression.Additionally, we studied the interaction of Sp1 with other proteins involved in the cell cycle regulation and we characterized the effect the overexpression of these proteins on the Sp1promoter activity, given that this promoter is regulated by Sp1. Sp1 is able to interact with CDK4, p21, SKP2 and BRCA2. The Sp1 promoter is positively regulated by the overexpression of CDK4, SKP2, BRCA2, Ciclina D1, E2F1/DP1 and Stat3 whereas the overepression of p53 and NFB represses the promoter. The effects of all these proteins were also analyzed at the Sp1 mRNA level and by using an artificial promoter containing only Sp1 binding sites. The interaction between Sp1 and p21 was further analyzed and we demonstrated that, in fibrosarcoma cells, p21 induces the Sp1 promoter and its mRNA expression but, at the same time, it induces the degradation of Sp1 protein.The process of transcription is a very complex mechanism that involves a great number of transcription factors and other proteins interacting with these factors.

The competition and increasing customers‘ demands makes traditional manufacturing companies consider new ways of differentiate themselves. One way of doing this is to develop product service system (PSS) solutions. PSS solutions are a total offering, where the customer purchases the use of a solution instead of a physical product. This bachelor thesis within the School of Innovation Design and Engineering at Mälardalen University aims to determine the success factor of PSS development at ICT and AM, which are two traditional Swedish manufacturing companies. To do this, the main challenges of transforming ICT and AM into PSS providers will be identified. The thesis also aims to determine if there is a need for change of performance measurements and key performance indicators (KPIs) to enable this transformation. A theoretical review is presented to help the readers in the understanding of the thesis areas. Interviews at ICT and AM were made to get a view of the situations at the companies considering PSS development. The information gathered at the interviews stated the major challenges of transforming both companies into PSS developers. With the theoretical framework and the stated challenges, an analysis was made to determine the success factors of PSS development.The identified success factors of PSS development were Senior management clarification of strategic intent, Cultural change management, Teamwork culture, Internal communication mechanisms, External communication mechanism, Customer relationship, Motivating breakthrough ideas, Project core competency, Cross-functional collaboration, Cross-functional development, Allocation of resources, Training and education, Knowledge management, Customer satisfaction data, Risk management, Product positioning, Portfolio of product opportunities, Product functional content, Knowledge of market potential, Product service processes, Product environment, Development process, Responsibilities of team members, Concurrent development, Internal task coordination, Organizational readiness for sales, Internal marketing and External marketing.Based on the theoretical framework and interviews a statement was made; it is crucial to change the performance measurement and KPIs if implementing PSS, to support collaboration between departments and contribute to the overall success for the companies.

Individuals with functional blindness must often utilise assistive aids to enable them to complete tasks of daily living. One of these tasks, locomotion, poses considerable risk. The long white cane is often used to perform haptic exploration, but cannot detect obstacles that are not ground-based. Although devices have been developed to provide information above waist height, these do not provide auditory interfaces that are easy to learn. Development of such devices should adapt to the user, not require adaptation by the user. Can obstacle avoidance be achieved through direct perception? This research presents an auditory interface that has been designed with the user as the primary focus. An analysis of the tasks required has been taken into account resulting in an interface that audifies ultrasound. Audification provides intuitive information to the user to enable perceptive response to environmental obstacles. A device was developed that provides Doppler shift signals that are audible as a result of intentional aliasing. This system provides acoustic flow that is evident upon initiation of travel and has been shown to be effective in perceiving apertures and avoiding environmental obstacles. The orientation of receivers on this device was also examined, resulting in better distance perception and centreline accuracy when oriented outward as compared to forward. The design of this novel user interface for visually impaired individuals has also provided a tool that can be used to evaluate direct perception and acoustic flow in a manner that has never been studied before.

Individuals with functional blindness must often utilise assistive aids to enable them to complete tasks of daily living. One of these tasks, locomotion, poses considerable risk. The long white cane is often used to perform haptic exploration, but cannot detect obstacles that are not ground-based. Although devices have been developed to provide information above waist height, these do not provide auditory interfaces that are easy to learn. Development of such devices should adapt to the user, not require adaptation by the user. Can obstacle avoidance be achieved through direct perception? This research presents an auditory interface that has been designed with the user as the primary focus. An analysis of the tasks required has been taken into account resulting in an interface that audifies ultrasound. Audification provides intuitive information to the user to enable perceptive response to environmental obstacles. A device was developed that provides Doppler shift signals that are audible as a result of intentional aliasing. This system provides acoustic flow that is evident upon initiation of travel and has been shown to be effective in perceiving apertures and avoiding environmental obstacles. The orientation of receivers on this device was also examined, resulting in better distance perception and centreline accuracy when oriented outward as compared to forward. The design of this novel user interface for visually impaired individuals has also provided a tool that can be used to evaluate direct perception and acoustic flow in a manner that has never been studied before.