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Tämä työ toteutettiin yhteistyössä Omexomin, Savon Voima Verkko Oy:n ja Savon Voima Oyj:n palvelukeskuksen kanssa. Työn tilaajana tässä opinnäytetyössä toimii Omexom, jonka juridisena nimenä käytetään Infratek Finland Oy. Työn tarkoituksena oli tutkia ja selvittää liittymäprosessin nykytilaa, muutosta ja haluttua tavoitetilaa. Savon Voima Verkolla noin 20 % henkilöstöstä eläköityy tulevan viiden vuoden aikana, mikä tarkoittaa melko tasaista henkilöstön uusiutumista korvausrekrytointien avulla. Tämän vuoksi on myös syytä tarkastella nykyisiä toimintoja ja toimintamalleja sekä miettiä, kuinka toimintaa voidaan kehittää. Työn tavoitteena on kuvata vanha ja uusi liittymäprosessin toimintamalli, liittymäprosessin toimintamallin muutokset sekä tuoda uusi liittymäprosessin toimintamalli esille konkreettisen kohteen kautta. Työ tuo esille kaikkien liittymäprosessiin kuuluvien henkilöiden toimenkuvat. Työssä etsitään näkökulmia prosessin toimivuudesta ja ratkaistaan vastaantulevia ongelmia niiden ilmentyessä. Työssä tuodaan selvästi ilmi molempien osapuolten tavoite- ja tahtotilat uudelta toimintamallilta. Tulevaisuudessa sähkötekninen suunnittelu tullaan laajentamaan urakoitsijoille. Töiden vastaanottaminen sekä niiden hallinta ja valvominen siirtyvät palvelukeskukselle. Tällä tavoin Savon Voima Verkko vapauttaa itseltään resursseja muuhun käyttöön. Yhteenvetona voidaan todeta, että tämä opinnäytetyö on antanut kaikille liittymäprosessiin kuuluville henkilöille selkeän näkemyksen liittymäprosessista ja sen tavoite- ja tahtotiloista. Kehityksen kannalta tämä opinnäytetyö on luonut hyvän pohjan jatkokäsittelyä varten.
Abstract Cholesterol oxidation product 4β‐hydroxycholesterol (4β‐OHC) may possibly be used as an endogenous biomarker of CYP3A enzyme activity and as CYP3A4 is involved in the metabolism of approximately 50% of the drugs in clinical use, the monitoring of CYP3A activity by 4β‐OHC plasma or serum levels, may be of clinical significance. The plasma and serum concentrations of 4α‐hydroxycholesterol (4α‐OHC), an isomer of 4β‐OHC, increase during uncontrolled storage conditions and therefore serve as an indicator of proper handling of samples. A sensitive and simple high-throughput method for the simultaneous quantification of both 4α‐OHC and 4β‐OHC in human plasma and serum was developed utilizing ultrahigh performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC/ESI-HR-MS). The chromatographic analysis was carried out on a Waters HSS T3 C18 reversed phase column with a mobile phase composed of 0,1% formic acid with 200 mg/l sodium acetate, and methanol. 4β‐OHC and 4α‐OHC and also internal standard d7‐4β‐OHC were monitored using HR-MS as sodium adducts, which could not be used as a precursor ions in conventional tandem mass spectrometry methods due to their extensive stability in collision for MS/MS. The use of HR-MS detection enabled avoiding laborious sample derivatization, which is required with triple quadrupole mass spectrometer-based methods to achieve adequate analytical sensitivity for 4β‐OHC, as the underivatized molecule is otherwise poorly ionized to other molecular ions than sodium adduct. Chromatographic separation of 4α‐OHC and 4β‐OHC was obtained and confirmed with standard samples prepared in blank surrogate matrix. The lower limits of quantitation in the assay were 0.5 ng/ml for 4β‐OHC, and 2 ng/ml for 4α‐OHC. Endogenous levels of 4β‐OHC can vary between 10 and 100 ng/ml depending on the possible induction or inhibition of CYP3A4, whereas the levels of 4α‐OHC can vary between 5 and 100 ng/ml, depending on the storage conditions of the samples. Thus, the sensitivity of the assay developed allows for the simultaneous measurement of endogenous levels of 4α‐OHC and 4β‐OHC cost-effectively and with high throughput. The method was successfully used for the determination of 4β‐OHC and 4α‐OHC concentrations in clinical plasma and serum samples collected before and after treatment with a known CYP3A4 inducer rifampicin. The endogenous levels in clinical human samples before treatment varied between 13.4 and 31.9 ng/ml for 4β‐OHC, and between 3.53 and 5.65 ng/ml for 4α‐OHC, and a three-fold increase in 4β‐OHC plasma levels was observed after the rifampicin treatment, while 4α‐OHC levels remained unaffected.
Abstract Activation of pregnane X receptor (PXR) elevates circulating 4β-hydroxycholesterol (4βHC), an agonist of liver X receptor (LXR). PXR may also regulate 25-hydroxycholesterol and 27-hydroxycholesterol. Our aim was to elucidate the roles of PXR and oxysterols in the regulation of cholesterol transporters. We measured oxysterols in serum of volunteers dosed with PXR agonist rifampicin 600 mg/day versus placebo for a week and analyzed the expression of cholesterol transporters in mononuclear cells. The effect of 4βHC on the transport of cholesterol and the expression of cholesterol transporters was studied in human primary monocyte-derived macrophages and foam cells in vitro. The expression of cholesterol transporters was measured also in rat tissues after dosing with a PXR agonist. The levels of 4βHC were elevated, while 25-hydroxycholesterol and 27-hydroxycholesterol remained unchanged in volunteers dosed with rifampicin. The expression of ATP binding cassette transporter A1 (ABCA1) was induced in human mononuclear cells in vivo. The influx of cholesterol was repressed by 4βHC, as was the expression of influx transporter lectin-like oxidized LDL receptor-1 in vitro. The cholesterol efflux and the expression of efflux transporters ABCA1 and ABCG1 were induced. The expression of inducible degrader of the LDL receptor was induced. In rats, PXR agonist increased circulating 4βHC and expression of LXR targets in peripheral tissues, especially ABCA1 and ABCG1 in heart. In conclusion, PXR activation-elevated 4βHC is a signaling molecule that represses cholesterol influx and induces efflux. The PXR-4βHC-LXR pathway could link the hepatic xenobiotic exposure and the regulation of cholesterol transport in peripheral tissues.
Abstract Background and purpose: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved. Experimental approach: We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis. Key results: Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol–cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch–Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation. Conclusions and implications: PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR–SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia.
The ground state to ground state electron-capture Q value of 159Dy (3/2−) has been measured directly using the double Penning trap mass spectrometer JYFLTRAP. A value of 364.73(19) keV was obtained from a measurement of the cyclotron frequency ratio of the decay parent 159Dy and the decay daughter 159Tb ions using the novel phase-imaging ion-cyclotron resonance technique. The Q values for allowed Gamow-Teller transition to 5/2− and the third-forbidden unique transition to 11/2+ state with excitation energies of 363.5449(14) keV and 362.050(40) keV in 159Tb were determined to be 1.18(19) keV and 2.68(19) keV, respectively. The high-precision Q value of transition 3/2−→5/2− from this work, revealing itself as the lowest electron-capture Q value, is used to unambiguously characterize all the possible lines that are present in its electron-capture spectrum. We performed atomic many-body calculations for both transitions to determine electron-capture probabilities from various atomic orbitals and found an order of magnitude enhancement in the event rates near the end point of energy spectrum in the transition to the 5/2− nuclear excited state, which can become very interesting once the experimental challenges of identifying decays into excited states are overcome. The transition to the 11/2+ state is strongly suppressed and found unsuitable for measuring the neutrino mass. These results show that the electron-capture in the 159Dy atom, going to the 5/2− state of the 159Tb nucleus, is a new candidate that may open the way to determine the electron-neutrino mass in the sub-eV region by studying electron-capture. Further experimental feasibility studies, including coincidence measurements with realistic detectors, will be of great interest.
We report the first detection of the second-forbidden, nonunique, 2(+) -> 0(+), ground-state transition in the beta decay of F-20. A low-energy, mass-separated F-20(+) beam produced at the IGISOL facility in Jyvaskyla, Finland, was implanted in a thin carbon foil and the beta spectrum measured using a magnetic transporter and a plastic-scintillator detector. The beta-decay branching ratio inferred from the measurement is b(beta) = [0.41 +/- 0.08(stat) +/- 0.07(sys)] x 10(-5) corresponding to log ft = 10.89(11), making this one of the strongest second-forbidden, nonunique beta transitions ever measured. The experimental result is supported by shell-model calculations and has significant implications for the final evolution of stars that develop degenerate oxygen-neon cores. Using the new experimental data, we argue that the astrophysical electron-capture rate on Ne-20 is now known to within better than 25% at the relevant temperatures and densities.