Role of Ret Signaling in the Regulation of the Nigrostriatal Dopaminergic System in Mice

Glial cell line-derived neurotrophic factor (GDNF) enhances survival of dopamine (DA) neurons in vitro, protects DAergic neurons in animal models of Parkinson s disease (PD), stimulates DA neuron function, regulates postnatal development and supports DA neurons during adulthood. GDNF utilizes a multireceptor complex consisting of a ligand-binding co-receptor GDNF family receptor alpha 1 (GFRα1) and a signal-transducing receptor. The major signaling receptor of GDNF is the receptor tyrosine kinase Ret, although alternative signaling receptors have been found. GDNF and its receptors are considered important targets for developing new therapies that would ameliorate the degeneration of DA neurons and loss of DA that underlie movement impairments in PD. The present study investigated the role and significance of Ret signaling in the nigrostriatal DAergic system using mutant mice with a point mutation in Ret, which leads to constitutive activation of the Ret receptor tyrosine kinase and causes the cancer syndrome called multiple endocrine neoplasia type B (MEN2B). Immunohistochemical, neurochemical and molecular alterations in the DAergic system, as well as the behavior of the MEN2B mice, were studied. Particularly, we explored striatal DAergic neurotransmission in the MEN2B mice by using classical pharmacological tools as well as in vivo voltammetry. Also, in order to clarify the role of Ret in neuroprotection we studied effects of toxins on the DAergic system of MEN2B mice. We found markedly increased tissue DA concentrations, increased number of DA cells in the substantia nigra, elevated TH and DAT levels in the striatum and increased sensitivity to the stimulatory effects of cocaine in the MEN2B mice with constitutively active Ret. Also, synthesis, storage, release and uptake of DA in the striatum were found to be enhanced in the MEN2B mice. Finally, constitutive Ret activity protected DA cell bodies against neurotoxicity but was ineffective in protecting their axonal terminals in the striatum. In conclusion, this study showed that the constitutive Ret signaling supports and protects brain DA neurons, and promotes the DAergic phenotype, implicating Ret as an important signaling receptor for GDNF in the brain DAergic system.Dopamiini on monessa suhteessa tärkeä aivojen välittäjäaine. Se osallistuu muun muassa motoristen toimintojen säätelyyn, ja Parkinsonin tauti aiheutuu juuri dopamiinia tuottavien hermosolujen asteittaisesta kuolemisesta. Gliasolulinjaperäisen hermokasvutekijän (GDNF) on osoitettu toimivan Parkinsonin taudissa tuhoutuvien keskiaivojen dopaminergisten hermosolujen ylläpitäjänä. GDNF:n on erilaisissa Parkinsonin taudin malleissa suojellut kyseisiä soluja hermomyrkkyjen vaikutuksilta, ja myös ihmisillä tehdyissä kliinisissä kokeissa GDNF-terapialla on saatu lupaavia, joskin vaihtelevia tuloksia. GDNF-järjestelmään vaikuttavat lääkeaineet ovat yksi lupaava tulevaisuuden terapiamuoto Parkinsonin taudissa, sillä nykyisistä hoidoista poiketen kasvutekijäjärjestelmän aktivaatiolla voidaan arvella olevan taudin kehittymistä hidastava, ellei jopa tautia parantava vaikutus. Tässä väitöskirjatyössä on tutkittu hiiriä, joilla GDNF:n vaikutukset soluun välittävä tyrosiinikinaasireseptori, Ret, on mutaation seurauksena jatkuvasti aktiivinen - siis ilman GDNF:ää. Tutkimuksessa havaittiin, että näissä nk. MEN2B (Multiple Endocrine Neoplasia type 2B) hiirissä striatumin dopamiinitasot ovat nousseet ennennäkemättömän suuriksi Parkinsonin taudin kannalta olennaisessa aivonalueessa, striatumissa. Tämä johtuu voimakkaasti lisääntyneestä dopamiinin tuotannosta ja sitä syntetisoivan entsyymin, tyrosiinihydroksylaasin, määrän kohoamisesta. Myös dopamiinihermosolujen lukumäärä ja dopamiinihermovälitys on MEN2B hiirillä lisääntynyt verrokkihiiriin verrattuna. Lisäksi tutkimuksessa havaittiin, että MEN2B-hiiret ovat normaalia vastustuskykyisempiä dopamiinisoluja tuhoavalle hermomyrkylle, joka vahvasti viittaa alentuneeseen herkkyyteen kehittää Parkinsonin tauti. Tutkimus osoittaa, että Ret-tyrosiinikinaasia aktivoivillä lääkeaineilla voi olla merkitystä Parkinsonin taudin hoidossa ja taudin etenemisen hidastamisessa

Impact of Digitization on Media and Media Presence of Debut Bands within Hard Rock and Metal Genres

Master's thesis Music Management MU501 - University of Agder 2018Since its introduction to the market, digital technology has continuously challenged various industries and their business models, including that of the media industry. Although the media industry was formerly ascribed the role of a gatekeeper and tastemaker for music, in a world in which the digital realm is profoundly related to daily life and new devices, platforms, and forms of media regularly emerge, it is questionable whether media industry channels can continue in the same role. The aim of this study is to understand and evaluate how the current status of media industries is affected by digitization. In particular, the project focuses on the role of newspapers, magazines, and their online counterparts within contemporary music journalism and publicity practices, and the way in which the relationships between these affect media presences of debut bands within the hard rock and metal genres. This thesis is based on a study of literature and reports from various bodies such as Reuters Institute and IFPI as well as of recent articles and discussions in relevant media outlets. The study also draws on in-depth interviews with high-ranking figures in the media and publicity spheres. The discussion chapter of this thesis reflects on findings from the above-mentioned research and attempts to anticipate future developments within the media industry; it also identifies opportunities and provides possible strategies for improving the media presence of debut artists within the hard rock and metal genres

Mice Deficient in Transmembrane Prostatic Acid Phosphatase Display Increased GABAergic Transmission and Neurological Alterations

Peer reviewe

GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function

Peer reviewe

Impact of Digitization on Media and Media Presence of Debut Bands within Hard Rock and Metal Genres

Master's thesis Music Management MU501 - University of Agder 2018Since its introduction to the market, digital technology has continuously challenged various industries and their business models, including that of the media industry. Although the media industry was formerly ascribed the role of a gatekeeper and tastemaker for music, in a world in which the digital realm is profoundly related to daily life and new devices, platforms, and forms of media regularly emerge, it is questionable whether media industry channels can continue in the same role. The aim of this study is to understand and evaluate how the current status of media industries is affected by digitization. In particular, the project focuses on the role of newspapers, magazines, and their online counterparts within contemporary music journalism and publicity practices, and the way in which the relationships between these affect media presences of debut bands within the hard rock and metal genres. This thesis is based on a study of literature and reports from various bodies such as Reuters Institute and IFPI as well as of recent articles and discussions in relevant media outlets. The study also draws on in-depth interviews with high-ranking figures in the media and publicity spheres. The discussion chapter of this thesis reflects on findings from the above-mentioned research and attempts to anticipate future developments within the media industry; it also identifies opportunities and provides possible strategies for improving the media presence of debut artists within the hard rock and metal genres

SIGNIFICANCE OF THERAPY LENGTH WITH NORFLOXACIN TREATMENT OF LOWER URINARY TRACT INFECTION

The aim of the paper was to examine the significance of the therapy with Norfloxacin as mono therapy in the treatment of the lower urinary tract infection and to examine the effectiveness of this antibiotic nowadays as it has not been used for a long time (it was not available on our market).Eighty patients with the lower urinary tract infection were examined. Patients were divided into two groups according to the length of therapy and the age of patients. Before and after the therapy, some examinations were done: clinical check – up, urinary analysis (general check – up), KSL, SE, urea, creatinin, urinoculture, urinary tract EHO.There was no statistically significant difference in the number of patients with the lower urinary tract infections after 3 and 7 days of therapy with Norfloxacin. Often, the cause of this infection was Escherichia coli. The highest frequency of this infection was reported in the aged and female population. There was no statistically significant difference in the number of the patients with the lower urinary tract infection after the therapy with Norfloxacin in relation to the age.There were no differences in the effects of the medicine between the group whose therapy lasted for 3 days and the group whose therapy lasted for 7 days. There was no difference in the effects of the medicine without regard to the age of the patients, too

Synthesis, X-ray structure and strong in vitro cytotoxicity of novel organoruthenium complexes

Two p-cymene ruthenium chlorido complexes containing isobutyl (C1) and isoamyl (C2) esters of (S,S)ethylenediamine-N,N'-di-2-(3-cyclohexyl) propanoic acid as ligands were prepared from p-cymene ruthenium dichloride dimer and corresponding ester. All compounds have been characterized by elemental analysis, IR, ESI-MS, H-1 and C-13 NMR spectroscopy. Single crystal X-ray structure diffraction analysis of C1 shows the usual piano-stool geometry of complexes, with coordination of ester ligand via nitrogen donor atoms. Ligands exhibit moderate anticancer activity (IC50 gt 50 mu M), while the complexes were significantly more cytotoxic towards various cancer cell lines, including B16, A375, HCT116, A549 and MCF7 cells (IC50 min.-max. 2.9-8.0 mu M). We stress that cisplatin resistant HCT116 cell line was highly sensitive to the treatment with C1 and C2 (IC50 values: 4.4 and 5.5 mu M versus IC50 gt 120 mu M for cisplatin). In parallel, primary fibroblasts-MRC-5 were remarkably less affected by these compounds. (C) 2013 Elsevier B. V. All rights reserved