Computer-aided discovery of biological activity spectra for anti-aging and anti-cancer olive oil oleuropeins

Aging is associated with common conditions, including cancer, diabetes, cardiovascular disease, and Alzheimer"s disease. The type of multi‐targeted pharmacological approach necessary to address a complex multifaceted disease such as aging might take advantage of pleiotropic natural polyphenols affecting a wide variety of biological processes. We have recently postulated that the secoiridoids oleuropein aglycone (OA) and decarboxymethyl oleuropein aglycone (DOA), two complex polyphenols present in health‐promoting extra virgin olive oil (EVOO), might constitute a new family of plant‐produced gerosuppressant agents. This paper describes an analysis of the biological activity spectra (BAS) of OA and DOA using PASS (Prediction of Activity Spectra for Substances) software. PASS can predict thousands of biological activities, as the BAS of a compound is an intrinsic property that is largely dependent on the compound"s structure and reflects pharmacological effects, physiological and biochemical mechanisms of action, and specific toxicities. Using Pharmaexpert, a tool that analyzes the PASS‐predicted BAS of substances based on thousands of"mechanism‐ effect" and"effect‐mechanism" relationships, we illuminate hypothesis‐generating pharmacological effects, mechanisms of action, and targets that might underlie the anti‐aging/anti‐cancer activities of the gerosuppressant EVOO oleuropeins.

Molecular Interactions of Prodiginines with the BH3 Domain of Anti-Apoptotic Bcl-2 Family Members.

Prodigiosin and obatoclax, members of the prodiginines family, are small molecules with anti-cancer properties that are currently under preclinical and clinical trials. The molecular target(s) of these agents, however, is an open question. Combining experimental and computational techniques we find that prodigiosin binds to the BH3 domain in some BCL-2 protein families, which play an important role in the apoptotic programmed cell death. In particular, our results indicate a large affinity of prodigiosin for MCL-1, an anti-apoptotic member of the BCL-2 family. In melanoma cells, we demonstrate that prodigiosin activates the mitochondrial apoptotic pathway by disrupting MCL-1/BAK complexes. Computer simulations with the PELE software allow the description of the induced fit process, obtaining a detailed atomic view of the molecular interactions. These results provide new data to understand the mechanism of action of these molecules, and assist in the development of more specific inhibitors of anti-apoptotic BCL-2 proteins.

Importância do metabolismo no planejamento de fármacos

It is widely recognized that pharmacokinetic optimization needs to be addressed early in drug discovery to reduce the high failure rate in bringing drugs to market. Poor absorption, too short duration of action due to high elimination rate, or the presence of active metabolites are examples of properties that can potentially lead to unsuccessful clinical programmes. Here I describe a brief overview of advantages and molecular strategies for improving metabolic and pharmacokinetic properties applied to the discovery of fluconazol, beta-blockers, ritonavir and ezetimibe and to the development of the prodrugs enalapril and bambuterol.

Development and validation of a method for the analysis of tetracyclines in chicken-muscle by liquid chromatography-electrospray-mass spectrometry in tandem (LC-ESI-MS/MS)

A LC-ESI-MS/MS method was developed and validated according to the European Union decision 2002/657/EC, for the determination of tetracyclines (TCs) in chicken-muscle since Europe is one of the main markets for Brazilian products. Linearity of r > 0.9979, limits of quantification in the range of 7.0-35.0 ng/g, average recoveries of 89.38 - 106.27%, within-day and between-day precision were adequate for all TCs. The decision limit and the detection capability were 93.00-106.46 ng/g and 95.84-114.38 ng/g, respectively. This method is suitable for application in surveillance programmes of residues of TCs in chicken-muscle samples.

Molecular profiling of human endometrium and endometriosis

Endometriosis is a common hormone-dependent gynecological disease leading to severe menstrual and/or chronic pelvic pain with or without subfertility. The disease is defined by the presence of endometrium-like tissue outside the uterine cavity, primarily on the pelvic peritoneum, ovaries and infiltrating organs of the peritoneal cavity. The current tools for diagnosis and treatment of endometriosis need to be improved to ensure reliable diagnosis and effective treatment. In addition, endometriosis is associated with increased risk of ovarian cancer and, therefore, the differential diagnosis between the benign and malignant ovarian cysts is of importance. The long-term objective of the present study was to support the discovery of novel tools for diagnosis and treatment of endometriosis. This was approached by exploiting genome-wide expression analysis of endometriosis specimens. A novel expression profiling -based classification of endometriosis indicated specific subgroups of lesions partially consistent with the clinical appearance, but partially according to unknown factors. The peritoneum of women with endometriosis appeared to be altered in comparison to that of healthy control subjects, suggesting a novel aspect on the pathogenesis of the disease. The evaluation of action and metabolism of sex hormones in endometrium and endometriosis tissue indicated a novel role of androgens in regulation of the tissues. In addition, an enzyme involved in androgen and neurosteroid metabolism, hydroxysteroid (17beta) dehydrogenase 6, was found to be highly up-regulated in endometriosis tissue as compared to healthy endometrium. The enzyme may have a role in the pathogenesis of endometriosis or in the endometriosis associated pain generation. Finally, a new diagnostic biomarker, HE4, was discovered distinguishing patients with ovarian endometriotic cysts from those with malignant ovarian cancer. The information acquired in this study enables deeper understanding of endometriosis and facilitates the development of improved diagnostic tools and more specific treatments of the disease

Suorituskyvyn analysointijärjestelmän implementointi ammattikorkeakoulussa

Ammattikorkeakoulu on asiantuntijaorganisaatio, joka tietointensiivisenä organisaationa muodostaa haastavan mittausympäristön. Tämän tutkimuksen tavoitteena oli rakentaa ammattikorkeakoulun koulutusohjelmille suorituskyvyn analysointijärjestelmä. Tutkimuksen toissijaisena tavoitteena oli suorituskyvyn mittaamisen avulla luoda perusta oikeudenmukaiselle ja tasapuoliselle palkitsemisjärjestelmälle. Tutkimuksessa käytettiin pääasiassa konstruktiivista tutkimusotetta, mutta tutkimusote voidaan nähdä vahvasti myös toiminta-analyyttisenä. Tutkimuksen teoriaosassa käsitellään suorituskyvyn analysointijärjestelmän suunnittelua ja käyttöönottoa asiantuntijaorganisaatiossa. Lisäksi perehdytään suorituskyvyn mittaamisen teoriaan ja asiantuntijaorganisaatioita käsittelevään kirjallisuuteen. Tutkimuksen käytännön osassa suorituskyvyn analysointijärjestelmä rakennettiin ja implementoitiin kolmeen case-organisaation koulutusohjelmaan. Kehitetty suorituskyvyn analysointijärjestelmä koostuu kuudesta mittausnäkökulmasta: uudistuminen ja työkyky, opetus, kansainvälisyys, T&K ja maksullinen palvelutoiminta, talous ja vaikuttavuus. Suorituskyvyn analysointijärjestelmän mittausnäkökulmiin määritettiin 16 kriittistä menestystekijää ja niitä mittaamaan valittiin 25 mittaria. Lisäksi tutkimuksessa löydettiin koulutusohjelman ja henkilöstön oikeudenmukaiseen ja tasapuoliseen palkitsemiseen soveltuvia mittareita.

Photoinhibition of Photosystem II. Kinetics, Photoprotection and Mechanism

Photosystem II (PSII) is susceptible to light-induced damage defined as photoinhibition. In natural conditions, plants are capable of repairing the photoinhibited PSII by on-going degradation and re-synthesis of the D1 reaction centre protein of PSII. Photoinhibition is induced by both visible and ultraviolet light and photoinhibition occurs under all light intensities with the same efficiency per photon. In my thesis work, I studied the reaction kinetics and mechanism of photoinhibition of PSII, as well as photoprotection in leaves of higher plants. Action spectroscopy was used to identify photoreceptors of photoinhibition. I found that the action spectrum of photoinhibition in vivo shows resemblance to the absorption spectra of manganese model compounds of the oxygen evolving complex (OEC) suggesting a role for manganese as a photoreceptor of photoinhibition under UV and visible light. In order to study the protective effect of non-photochemical quenching, the action spectrum was measured from leaves of wild type Arabidopsis thaliana and two mutants impaired in nonphotochemical quenching of chlorophyll a excitations. The findings of action spectroscopy and simulations of chlorophyll-based photoinhibition mechanisms suggested that quenching of antenna excitations protects less efficiently than would be expected if antenna chlorophylls were the only photoreceptors of photoinhibition. The reaction kinetics of prolonged photoinhibition was studied in leaves of Cucurbita maxima and Capsicum annuum. The results indicated that photoinhibitory decrease in both the oxygen evolution activity and ratio of variable to maximum fluorescence follows firstorder kinetics in vivo. The persistence of first-order kinetics suggests that already photoinhibited reaction centres do not protect against photoinhibition and that the mechanism of photoinhibition does not have a reversible intermediate. When Cucurbita maxima leaves were photoinhibited with saturating single-turnover flashes and continuous light, the light response curve of photoinhibition was found to be essentially a straight line with both types of illumination, suggesting that similar photoinhibition mechanisms might function during illumination with continuous light and during illumination with short flashes.

Prolegomenon for an ethics of visibility in Hannah Arendt

This paper aims to discuss the Arendtian notions of appearance and perception in order to promote a displacement of those conceptions from the generally associated domain of passive apprehension of the faculty of knowledge towards the domain of a praxiology of action and language, based on an active perception. Arendt's appropriations on the Heideggerian "to take one's place" (sich hin-stellen) will be discussed, as well as the Augustinian "finding oneself in the world" (diligere). A twofold disposition of appearance will be distinguished: producing and position, whose transposed to the Arendtian notion of world correspond, respectively, to fabrication (poiesis) of the world, man's objective in-between space, and to action (praxis) in the world, man's subjective in-between space. Those conceptual replacements, in a broad sense, uphold a closer imbrication between the activities of the mind and acting, stricto sensu, and consequently, foment not only the valorization of the public space, but the visibility of our acts and deeds as well, calling out the dignity of appearance in ethics.

Induction of plant defense responses by Ocimum gratissimum L. (Lamiaceae) leaf extracts

Aqueous extracts of the leaves of Ocimum gratissimum at 10, 25, 40 and 50% (w/v) concentrations induced the production of phytoalexins in soybean cotyledons and sorghum mesocotyls. The aqueous extracts also induced systemic resistance in cucumber to Colletotrichum lagenarium, reflected by reduction in disease incidence and an increase in chitinase production. Modes of action and the existence of possible elicitors of defense response in O. gratissimum leaf extracts are discussed.

Innovations of ageing and societal transition : Dynamics of change of the socio-technical regime of ageing

The purpose of this dissertation is to examine the dynamics of the socio-technical system in the field of ageing. The study stems from the notion that the ageing of the population as a powerful megatrend has wide societal effects, and is not just a matter for the social and health sector. The central topic in the study is change: not only the age structures and structures of society are changing, but also at the same time there is constant development, for instance, in technologies, infrastructures and cultural perceptions. The changing concept of innovation has widened the understanding of innovations related to ageing from medical and assistive technological innovations to service and social innovations, as well as systemic innovations at different levels, which means the intertwined and co-evolutionary change in technologies, structures, services and thinking models. By the same token, the perceptions of older people and old age are becoming more multi-faceted: old age is no longer equated to illnesses and decline, but visions of active ageing and a third age have emerged, which are framed by choices, opportunities, resources and consumption in later life. The research task in this study is to open up the processes and mechanisms of change in the field of ageing, which are studied as a complex, multi-level and interrelated socio-technical system. The question is about co-effective elements consisting of macro-level landscape changes, the existing socio-technical regime (the rule system, practices and structures) and bottom-up niche-innovations. Societal transitions do not account for the things inside the regime alone, or for the long-term changes in the landscape, nor for the radical innovations, but for the interplay between all these levels. The research problem is studied through five research articles, which offer micro-level case studies to macro-level phenomenon. Each of the articles focus on different aspects related to ageing and change, and utilise various datasets. The framework of this study leans on the studies of socio-technical systems and multi-level perspective on transitions mainly developed by Frank Geels. Essential factors in transition from one socio-technological regime to another are the co-evolutionary processes between landscape changes, regime level and experimental niches. Landscape level changes, like the ageing of the population, destabilise the regime in the forms of coming pressures. This destabilization offers windows for opportunity to niche-innovations outside or at fringe of the regime, which, through their breakthrough, accelerate the transition process. However, the change is not easy because of various kinds of lock-ins and inertia, which tend to maintain the stability of the regime. In this dissertation, a constructionist approach of society is applied leaning mainly to the ideas of Anthony Giddens’ theory of structuration, with the dual nature of structures. The change is taking place in the interplay between actors and structures: structures shape people’s practices, but at the same time these practices constitute and reproduce social systems. Technology and other material aspects, as part of socio-technical systems, and the use of them, also take part in the structuration process. The findings of the study point out that co-evolutionary and co-effective relationships between economic, cultural, technological and institutional fields, as well as relationships between landscape changes, changes in the local and regime-level practices and rule systems, are a very complex and multi-level dynamic socio-technical phenomenon. At the landscape level of ageing, which creates the pressures and triggers to the regime change, there are three remarkable megatrends: demographic change, changes in the global economy and the development of technologies. These exert pressures to the socio-technical regime, which as a rule system is experiencing changes in the form of new markets and consumer habits, new ways of perceiving ageing, new models of organising the health care and other services and as new ways of considering innovation and innovativeness. There are also inner dynamics in the relationships between these aspects within the regime. These are interrelated and coconstructed: the prevailing perceptions of ageing and innovation, for instance, reflect the ageing policies, innovation policies, societal structures, organising models, technology and scientific discussion, and vice versa. Technology is part of the inner dynamics of the sociotechnological regime. Physical properties of the artefacts set limitations and opportunities with regard to their functions and uses. The use of and discussion about technology, contributes producing and reproducing the perceptions of old age. For societal transition, micro-level changes are also needed, in form of niche-innovations, for instance new services, organisational models or new technologies, Regimes, as stabilitystriven systems, tend to generate incremental innovations, but radically new innovations are generated in experimental niches protected from ‘normal’ market selection. The windows of opportunity for radical novelties may be opened if the circumstances are favourable for instance by tensions in the socio-technical regime affected by landscape level changes. This dissertation indicates that a change is taking place, firstly, in the dynamic interactionbetween levels, as a result of purposive action and governance to some extent. Breaking the inertia and using the window of opportunity for change and innovation offered by dynamics between levels, presupposes the actors’ special capabilities and actions such as dynamic capabilities and distance management. Secondly, the change is taking place the socio-technological negotiations inside the regime: interaction between technological and social, which is embodied in the use of technology. The use of technology includes small-level contextual scripts that also participate in forming broader societal scripts (for instance defining old age at the society level), which in their turn affect the formation of policies for innovation and ageing. Thirdly, the change is taking place by the means of active formation of the multi-actor innovation networks, where the role of distance management is crucial to facilitate the communication between actors coming from different backgrounds as well as to help the niches born outside the regime to utilise the window of opportunity offered by regime destabilisation. This dissertation has both theoretical and practical contributions. This study participates in the discussion of action-oriented view on transition by opening up of the socio-technological, coevolutionary processes of the multi-faceted phenomenon of ageing, which has lacked systematic analyses. The focus of this study, however, is not on the large-scale coordination and governance, but rather on opening up the incremental elements and structuration processes, which contribute to the transition little by little, and which can be affected to. This increases the practical importance of this dissertation, by highlighting the importance of very tiny, everyday elements in the change processes in the long run.

First-Line Chemotherapy with Anthracycline and Taxane Combination in Metastatic Breast Cancer. Detection of bone metastases with TRACP 5b

Background: In Finland, breast cancer (BC) is the most common cancer among women, and prostate cancer (PC) that among men. At the metastatic stage both cancers remain essentially incurable. The goals of therapy include palliation of symptoms, improvement or maintenance of quality of life (QoL), delay of disease progression, and prolongation of survival. Balancing between efficacy and toxicity is the major challenge. With increasing costs of new treatments, appropriate use of resources is paramount. When new treatment regimes are introduced into clinical practice a comprehensive assessment of clinical benefit, adverse effects and cost is necessary. Both BC and PC show a predilection to metastasize to bone. Bone metastases cause significant morbidity impairing the patients´ QoL. Diagnosis of bone metastases relies mainly on radiological methods, which however lack optimal sensitivity and specificity. New tools are needed for detection and follow-up of bone metastases. Aims: Anthracyclines and taxanes are effective chemotherapeutic agents in the treatment of metastatic breast cancer (MBC) with different mechanisms of action. Therefore, evaluation of the combination of anthracyclines with taxanes was a justifiable approach in the treatment of MBC patients. We assessed the efficacy, toxicity, cost of treatment and QoL of BC patients treated with first-line chemotherapy for metastatic disease with the combination epirubicin and docetaxel. We also evaluated the diagnostic potential of tartrate-resistant acid phosphatase 5b (TRACP 5b) and carboxyterminal telopeptides of type I collagen (ICTP) in the diagnosis of bone metastases in BC and TRACP 5b in PC patients. Results: The combination of epirubicin and docetaxel was effective in this phase II study, but required individual dose adjustment to avoid neutropenic infections, and the use of growth factors to maintain a feasible dose level. The response rate was 54 % (95 % CI 37-71) and the median overall survival (OS) was 26 months. Of the patients, 87 % were treated for infections. The treatment of adverse events required additional use of health resources mainly due to neutropenic infections, thereby raising direct treatment costs by 20 %. Despite adverse events, the global QoL was not significantly compromised during the treatment. Clinically evident acute cardiac toxicity was not observed. The combination of serum TRACP 5b and ICTP was at least equally sensitive and specific in detection of of bone metastases as commonly used total alkaline phosphatise (tALP) in BC patients. In contrast, TRACP 5b was less specific and sensitive than tALP as a marker of skeletal changes in PC patients. Conclusions: Treatment with epirubicin and docetaxel showed high efficacy in first-line chemotherapy of MBC. The relatively high incidence of neutropenic infections requiring hospitalization increased the treatment costs. Despite adverse events, the global QoL of the patients was not significantly compromised. The combination of TRACP 5b and ICTP showed similar activity as tALP in detecting bone metastases in MBC. In contrast, TRACP 5b was less specific and sensitive than tALP as a marker of skeletal changes in PC.

Use of preclinical and early clinical data for dose selection of a selective estrogen receptor modulator toremifene in treatment of breast cancer

In development of human medicines, it is important to predict early and accurately enough the disease and patient population to be treated as well as the effective and safe dose range of the studied medicine. This is pursued by using preclinical research models, clinical pharmacology and early clinical studies with small sample sizes. When successful, this enables effective development of medicines and reduces unnecessary exposure of healthy subjects and patients to ineffectice or harmfull doses of experimental compounds. Toremifene is a selective estrogen receptor modulator (SERM) used for treatment of breast cancer. Its development was initiated in 1980s when selection of treatment indications and doses were based on research in cell and animal models and on noncomparative clinical studies including small number of patients. Since the early development phase, the treatment indication, the patient population and the dose range were confirmed in large comparative clinical studies in patients. Based on the currently available large and long term clinical study data the aim of this study was to investigate how the early phase studies were able to predict the treatment indication, patient population and the dose range of the SERM. As a conclusion and based on the estrogen receptor mediated mechanism of action early studies were able to predict the treatment indication, target patient population and a dose range to be studied in confirmatory clinical studies. However, comparative clinical studies are needed to optimize dose selection of the SERM in treatment of breast cancer.

Yliopiston reunalla. Tutkimus suomalaisen avoimen yliopiston muotoutumisesta

Avoin yliopisto on koulutusmuoto, johon kuka tahansa voi osallistua ja jossa voi suorittaa yliopistotasoisia opintoja. Avoimen yliopiston ideassa keskeistä on koulutuksellisen tasa-arvon edistämisen tavoite. Tämän tutkimuksen tehtävänä on kuvata ja analysoida suomalaisen avoimen yliopiston muotoutumista. Tutkimuksella etsitään vastauksia kolmeen kysymykseen: 1. Millaisten vaiheiden kautta avoin yliopisto on muotoutunut? Mitä avoimen yliopiston historiassa on tapahtunut ja millaista keskustelua näistä tapahtumista on käyty? 2. Millaisia diskursseja avointa yliopistoa koskeneessa keskustelussa voidaan tunnistaa ja miten eri toimijatahot ovat näihin puhetapoihin kiinnittyneet? 3. Millaisena koulutuksellisen tasa-arvon toteuttajana avoin yliopisto näyttäytyy tutkimusaineiston valossa? Tutkimuksen aineisto koostuu erilaisista julkisista teksteistä. Aineistossa on mukana useita erilaisia tekstityyppejä: komiteanmietintöjä ja työryhmäraportteja, korkeakoululaitoksen kehittämissuunnitelmia, muita suunnitteluasiakirjoja, tutkimuksia, selvityksiä, puheenvuoroja ja esitelmiä sekä lehtikirjoituksia. Täydentävänä aineistona on lisäksi käytetty tilastoja. Tutkimusaineistoa on analysoitu diskurssianalyysillä. Keskeisenä lähtökohtana analyysissa on, että tekstien avulla tuotetaan avointa yliopistoa koskevia käsityksiä ja merkityksiä. Nämä merkitykset myös muuttuvat ajassa. Aineiston analyysin tuloksena avoimen yliopiston historiassa voidaan erottaa erilaisia vaiheita ja näiden vaiheiden välisiä taitekohtia. Ensimmäiseksi murrokseksi avoimen yliopiston historiassa voidaan paikantaa avoimen yliopiston synty, joka ajoittui 1970-luvun alkupuoliskolle. Avoin yliopisto sai vakiintuneet puitteensa vasta 1980-luvun puolivälissä, jolloin se organisoitiin osaksi yliopistojen täydennyskoulutusta. Tämä voidaan nähdä avoimen yliopiston historian toisena murroksena. Kolmas murros ajoittui 1990-luvulle, jolloin avoimen yliopiston resursointi muuttui ja nuoret tulivat sen näkyväksi opiskelijaryhmäksi. Tämä murros problematisoi avoimen yliopiston ja tutkintokoulutuksen suhteen aiemmasta poikkeavalla tavalla ja avoimen yliopiston tutkintoväylä nousi keskeiseksi keskusteluteemaksi. Tämä jännite purkautui tultaessa 2000-luvulle, ja tutkinnonuudistuksen yhteydessä avoimen yliopiston väylä sai paikkansa suhteessa kahden syklin tutkintoihin. Nyt elämme tutkinnonuudistuksen jälkeistä aikaa, jolloin avoimen yliopiston väylä vertautuu paljolti maisterikoulutuksiin. Kysymys aikuisten asemasta suhteessa tutkintokoulutukseen on kuitenkin edelleen ajankohtainen. Esillä ovat etenkin kysymykset aiemmin opitun tunnustamisesta, aikuisten ohjauksesta sekä avoimen yliopiston suhteesta työ- ja elinkeinoelämään. Keskustelussa avoimesta yliopistosta on paikannettavissa erilaisia positioita, jotka määrittävät avoimen yliopiston merkitystä ja tehtävää. Näitä positioita voidaan nimittää diskursseiksi, jotka konstituoivat avoimen yliopiston paikkaa yliopistokoulutuksen kentällä. Aineistosta on paikannettu neljä eri diskurssia: (1) akateemisia arvoja painottava yliopistollinen diskurssi, (2) osallistumisen tasa-arvoa korostava sivistyksellisen demokratian diskurssi, (3) yksilöllisiä mahdollisuuksia ja innovatiivisuutta korostava joustavuuden diskurssi sekä (4) työelämää, taloudellisuutta ja statusta korostava tehokkuuden diskurssi. Nämä diskurssit käyvät aineiston teksteissä keskinäisiä neuvotteluja ja kantavat merkityksiä suhteessa toisiinsa. Diskurssien välisiä suhteita voidaan kuvata kahden eri dimension kautta. Yhtäältä vastakkaisiksi arvoiksi asettuvat akateeminen eksklusiivisuus ja koulutuksellinen tasa-arvo. Toisena ulottuvuutena on koulutuksen arvottaminen sivistyksen versus hyödyn näkökulmasta. Avoimen yliopiston tehtävä tasa-arvon edistäjänä on eri aikoina mielletty eri tavoin. Avoimen yliopiston historiassa sen merkitystä ja tehtävää on kehystetty erilaisin puhetavoin, ja eri diskurssipositioiden vuoropuhelun kautta myös avoimen yliopiston tasa-arvotehtävästä on eri aikoina keskusteltu eri tavoin. Avoimen yliopiston alkuvaiheessa sen tehtävänä näyttäytyi sivistyksellisen demokratian turvaajana toimiminen. Kun avoimen yliopiston kurssit käynnistyivät, määrittyi toiminta selkeästi aikuisten koulutukseksi. Avoin yliopisto määrittyikin nyt aikuisten toiseksi mahdollisuudeksi hankkia koulutusta, jota vaille he olivat nuorempina jääneet. Avoimen yliopiston puitteiden lukkoonlyömisen jälkeen keskustelussa nousi vahvasti esiin toiminnan ja opetusmuotojen kehittäminen. Avoin yliopisto määrittyikin nyt aikuisten monipuoliseksi ja joustavaksi koulutusmahdollisuudeksi. Tasa-arvoisten mahdollisuuksien luominen näyttäytyi innovatiivisena, dynaamisena ja eteenpäinpyrkivänä toimintana, jossa otettiin huomioon aikuisten erilaiset tarpeet. Relander-ohjelman myötä avoimen yliopiston julkilausuttu tehtävä nimenomaan aikuisten kouluttajana kuitenkin muuttui. Avoin yliopisto näyttäytyi nyt yksilöllisiä tarpeita palvelevana mahdollisuuksien talona, jossa oli sijaa kaikille. Tärkeäksi määrittyi myös opiskelun tavoitteiden ja motiivien moninaisuus. Tutkinnon suorittamisen avoimen yliopiston opintojen kautta tuli olla realistisesti mahdollista. Viimeisimmän murroksen jälkeen avoin yliopisto määrittyy yhä selvemmin työelämän sekä alueellisten tarpeiden kautta. Avoin yliopisto näyttäytyy joustavana ja erilaisia tarpeita palvelevana opiskelufoorumina. Avoin yliopisto palvelee paitsi yksilöiden, myös työelämän ja yritysten tarpeita sekä on osaltaan turvaamassa alueiden kilpailukykyä ja elinvoimaisuutta. Tässä tutkimuksessa tarkastellaan avointa yliopistoa, sen historiaa ja siitä käytyä keskustelua erityisesti tasa-arvon näkökulmasta. Yhtenä keskeisenä tuloksena on, että avoimen yliopiston paikka on ollut aina jollakin tavalla marginaalissa. Tätä ilmentää mm. yliopistollisuuden ja tasa-arvon välinen jännite, jonka ympärille avointa yliopistoa koskeva keskustelu paljolti on järjestynyt. Ylipäätään aikuisten asemaa yliopistossa määrittää tietty epämukavuus ja täyden legitimiteetin puute erityisesti suhteessa tutkintokoulutukseen. Aikuisten koulutuksesta puhutaan yliopiston yhtenä perustehtävänä ja retorisesti voidaan todeta tämän tehtävän tärkeys. Aikuinen opiskelija aiempine osaamisineen ja osaamistarpeineen positioituu kuitenkin yliopistokoulutuksen ja työelämän väliselle rajapinnalle. Aikuisen paikka määrittyykin yliopiston ytimeen nähden selvästi marginaaliin.

New perspectives on the melanocortins and their cardiovascular effects: Potential implications for the treatment of cardiovascular diseases with melanocortin analogues

The melanocortin peptides, including melanocyte-stimulating hormones, α-, β- and γ-MSH, are derived from the precursor peptide proopiomelanocortin and mediate their biological actions via five different melanocortin receptors, named from MC1 to MC5. Melanocortins have been implicated in the central regulation of energy balance and cardiovascular functions, but their local effects, via yet unidentified sites of action, in the vasculature, and their therapeutic potential in major vascular pathologies remain unclear. Therefore, the main aim of this thesis was to characterise the role of melanocortins in circulatory regulation, and to investigate whether targeting of the melanocortin system by pharmacological means could translate into therapeutic benefits in the treatment of cardiovascular diseases such as hypertension. In experiments designed to elucidate the local effects of α-MSH on vascular tone, it was found that α-MSH improved blood vessel relaxation via a nitric oxide (NO)-dependent mechanism without directly contracting or relaxing blood vessels. Furthermore, α-MSH was shown to regulate the expression and function of endothelial NO synthase in cultured human endothelial cells via melanocortin 1 receptors. In keeping with the vascular protective role, pharmacological treatment of mice with α-MSH analogues displayed therapeutic efficacy in conditions associated with vascular dysfunction such as obesity. Furthermore, α-MSH analogues elicited marked diuretic and natriuretic responses, which together with their vascular effects, seemed to provide protection against sodium retention and blood pressure elevation in experimental models of hypertension. In conclusion, the present results identify novel effects for melanocortins in the local control of vascular function, pointing to the potential future use of melanocortin analogues in the treatment of cardiovascular pathologies.

Leishmanicidal and cholinesterase inhibiting activities of phenolic compounds of Dimorphandra gardneriana and Platymiscium floribundum, native plants from Caatinga biome

In recent years, the Brazilian Health Ministry and the World Health Organization have supported research into new technologies that may contribute to the surveillance, new treatments, and control of visceral leishmaniasis within the country. In light of this, the aim of this study was to isolate compounds from plants of the Caatinga biome, and to investigate their toxicity against promastigote and amastigote forms of Leishmania infantum chagasi, the main responsible parasite for South American visceral leishmaniasis, and evaluate their ability to inhibit acetylcholinesterase enzyme (AChE). A screen assay using luciferase-expressing promastigote form and an in situ ELISA assay were used to measure the viability of promastigote and amastigote forms, respectively, after exposure to these substances. The MTT colorimetric assay was performed to determine the toxicity of these compounds in murine monocytic RAW 264.7 cell line. All compounds were tested in vitro for their anti-cholinesterase properties. A coumarin, scoparone, was isolated from Platymiscium floribundum stems, and the flavonoids rutin and quercetin were isolated from Dimorphandra gardneriana beans. These compounds were purified using silica gel column chromatography, eluted with organic solvents in mixtures of increasing polarity, and identified by spectral analysis. In the leishmanicidal assays, the compounds showed dose-dependent efficacy against the extracellular promastigote forms, with an EC50 for scoporone of 21.4µg/mL, quercetin and rutin 26 and 30.3µg/mL, respectively. The flavonoids presented comparable results to the positive control drug, amphotericin B, against the amastigote forms with EC50 for quercetin and rutin of 10.6 and 43.3µg/mL, respectively. All compounds inhibited AChE with inhibition zones varying from 0.8 to 0.6, indicating a possible mechanism of action for leishmacicidal activity.