En resa i kollektivtrafiken börjar och slutar alltid med en resa till och från hållplatsen. Denna resa kan ha en stor påverkan på den totala restiden, och är avgörande för om kollektivtrafiken ses som ett attraktivt transportmedel. Samtidigt behöver andelen kollektivtrafikresenärer och cyklister öka i städer för att minska utsläppen, trängsel och göra städer mer tillgängliga och attraktiva. Syftet med den här rapporten är att undersöka förutsättningar, möjligheten och intresset av att införa ett hyrcykelsystem på tågstationer i Stockholmsområdet. Mer specifikt undersöks hur uthyrningssystemet kan integreras med kollektivtrafiksystemet. Metoden för undersökningen börjar med teoretisk bakgrund genom en litteraturstudie om hur hyrcykelsystem historiskt sett har fungerat i Europa och hur det fungerar idag. Utöver det har Region Stockholms politiska mål kopplade till ämnet sammanställts, och dessutom har klimatpåverkan av elcyklar kartlagts. Efter litteraturstudien har förutsättningarna, möjligheten och intresset för ett hyrcykelsystem på tågstationer separat undersökts med tre olika metoder. Genom en fallstudie med platsbesök på 4 olika tågstationer, analyserades fysiska miljön för att undersöka förutsättningarna. Vidare undersöktes intresset bland kollektivtrafikresenärer genom en kvalitativ och kvantitativ enkät, som skickades ut i Facebookgrupper för tågpendlare och studenter. Datan från enkäten bearbetades i Excel och i Python. Till sist undersöktes möjligheten att införa ett hyrcykelsystem genom en intervju med en anställd på Mälardalstrafik som arbetar med periodbiljetten Movingo. Resultaten från enkätstudien visar att färdemedelsvalet för tågresenärers första och sista sträcka med en stor majoritet består av kollektivtrafik och gång, och att det är färre som cyklar på sista sträckan än första sträckan. Vidare visar det att lite mindre än hälften tror att uthyrning av mikromobilitetsfordon på tågstationen skulle kunna minska dess restid, men det skiljer sig åt beroende på om de som svarar är interregionala/regionala tågresenärer eller studenter. Svaren skiljer sig också åt beroende på vilket färdmedel mikromobilitetsfordonet ersätter, där de som idag går sista sträckan är mer positiva än de som åker kollektivtrafik sista sträckan. Till sist visas det av enkätstudien att det är en signifikant skillnad i inställning till uthyrningstjänsten om den är rabatterad eller integrerad med kollektivtrafiktjänsten, och en integrerad resa är viktigare för resenärerna än en rabatterad resa. Resultatet från intervjun visar att det finns en möjlig framtid då mikromobilitetsfordon kan integreras med tågtrafiken och kollektivtrafiken i ett biljettsystem, men det finns stora utmaningar som måste mötas innan det är en möjlighet. Det måste säkerställas att fordonen finns över hela systemet och att kunderna är säkra på att deras mikromobilitetsfordon de har betalat för finns där de förväntar dem. Dessutom måste det säkerställas att politiska viljan finns för integrationen.  Slutsatsen blir att integrerade mikromobilitetslösningar kan bidra till Stockholms mål för hållbara transporter, men att deras effektivitet varierar beroende på användarnas resvanor och stationernas omgivning. Det finns ett intresse för cykeluthyrning, speciellt om det integreras med kollektivtrafikbiljetter. För att maximera användningen av systemet och respekt för fordonen bör det vara skattefinansierat respektive avgiftsbelagt.

Heme is vital to a variety of cellular functions in bacteria ranging from energy generation to iron reserve. Group A streptococcus (GAS) is a prevalent bacterial pathogen that is responsible for an array of human diseases ranging from simple, self-limiting, mucosal and skin infections to invasive and systemic manifestations. GAS needs iron for growth and can satisfy this nutritional requirement by scavenging the metal from heme. The pathogen produces powerful hemolysins that facilitate heme release during infection. Heme is captured and relayed through the GAS cell wall and cytoplasmic membrane by dedicated receptors and transporters. To-date, the fate of the acquired heme is unknown in Streptococci. Although heme is nutritionally beneficial for GAS growth, its pro-oxidant and lipophilic nature makes it a liability with damaging effects on cellular components. The conundrum associated with heme use is particularly pertinent to GAS pathophysiology since invasive GAS infections involve massive hemolysis and the generation of unescorted heme in excess. In this dissertation, I aimed to describe the mechanisms that GAS uses for heme catabolism while managing its toxicity. I conducted a biochemical characterization of a new enzyme, HupZ in GAS that degrades heme in vitro. Similar to the heme oxygenase-1 (HO-1), HupZ activity leads to the formation of iron, CO, and a biliverdin-like product. I also investigated the impact of heme on GAS physiology and identified key mediators in the repair and detoxification process. This study demonstrated that heme exposure leads to a general stress response that involves the activation of antioxidant defense pathways to restore redox balance. Further, I studied a 3-gene cluster, pefRCD (porphyrin-regulated efflux RCD), which was activated by environmental heme, and provided support to my hypothesis that the pefRCD gene encodes a heme-sensing regulator (PefR) and heme efflux system (PefCD). I showed that the pef system protects GAS cells from heme-induced damage to the membrane and DNA by preventing cellular accumulation of heme. In conclusion, this dissertation addresses key knowledge gaps in GAS physiology and provides new insights into heme metabolism of GAS.

Alzheimer’s disease (AD), one of the major causes of disability and mortality in Western societies, is a progressive age-related neurodegenerative disorder. Increasing evidence suggests the etiology of AD may involve disruptions of zinc (Zn) homeostasis. We hypothesize that disruption of Zn homeostasis leads to alterations of Zn transporter (ZnT) proteins, resulting in increased production of neurotoxic amyloid beta (Aβ) peptide in AD brain. To address this hypothesis we carried out the following studies. 1. We characterized alterations of ZnT-1, ZnT-4 and ZnT-6 in the brain of preclinical AD (PCAD) subjects, who show no overt clinical manifestations of AD but demonstrate significant AD pathology at autopsy. 2. We identified the presence of ZnT-2 in human brain and compared protein levels in the brains of subjects with PCAD, mild cognitive impairment (MCI), early (EAD), and late-stage AD (LAD) to those in age matched normal control (NC) subjects. 3. We examined the relationship between protein levels of ZnT-1, ZnT-2, ZnT-4, ZnT-6 and Aβ produced by H4 human neuroglioma cells (H4-APP) transfected to overexpress amyloid precursor protein (APP), treated with short interfering RNA (siRNA) against each ZnT. Our data show a significant decrease (P < 0.05) of ZnT-1 and a significant increase of ZnT-6 in hippocampus/parahippo-campal gyrus (HPG) of PCAD subjects. In PCAD cerebellum (CER) the data show a significant increase of ZnT-4 and ZnT-6 compared to NC subjects. Levels of ZnT-2 were also significantly decreased in HPG of PCAD subjects compared to NC subjects. In addition, levels of ZnT-2 were significantly (P < 0.05) elevated in SMTG of PCAD and MCI subjects, compared to NC subjects. ZnT-2 was significantly (P < 0.05) elevated in HPG of EAD and LAD, and in SMTG of LAD brains, but was significantly (P < 0.05) decreased in LAD CER compared to NC subjects. siRNA mediated attenuation of each ZnT protein studied (ZnT-2, ZnT-4 and ZnT-6) led to significantly (P < 0.05) decreased production of Aβ compared to controls. Our results suggest alterations in Zn transport may play a role in Aβ processing and contribute to the neuropathology of AD.

The organic anion transporting polypeptide 4c1 (Oatp4c1) was previously identified as a novel uptake transporter predominantly expressed at the basolateral membrane in the rat kidney proximal tubules. Its functional role was suggested to be a vectorial transport partner of an apically-expressed efflux transporter for the efficient translocation of physiological substrates into urine, some of which were suggested to be uremic toxins. In vitro studies in polarized cell lines showed that upon transfection rat Oatp4c1 localizes at the apical membrane. The objectives of this project were to further validate the subcellular localization of Oatp4c1/OATP4C1 in rat and human tissues as well as their localization and function in polarized cells. Using several complementary biochemical, molecular and proteomic methods as well as antibodies amenable to immunohistochemistry, immunofluorescence, and immunoblotting, we investigated the expression pattern of Oatp4c1 in epithelial cell lines and in the rat kidney and mammary gland (MG). Collectively, these data demonstrated that rat Oatp4c1 localized at the apical cell surface of polarized epithelium and primarily in the proximal straight tubules, the S3 segment of proximal tubule, in the juxtamedullary cortex. Drug uptake studies in Oatp4c1-expressing cells demonstrated that Oatp4c1- mediated estrone-3-sulfate (E3S) uptake was ATP-independent and pH-dependent. The increased E3S transport activity at acidic extracellular pH was ascribed to the increased maximum transport rate (Vmax). In addition, E3S transport inhibition by various substrates suggests that Oatp4c1 possesses multiple substrate binding sites. The apical localization of Oatp4c1 in the rat kidney and MG is a novel finding and implies that this transporter protein plays a role in the reabsorption, not vectorial secretion, of its substrates. In addition, the upregulation of Oatp4c1 expression during lactation indicates that it is involved in reuptake of xenobiotic from the milk, resulting in their reduced exposure to the suckling infants, or that it functions as a scavenger system. Further, studies to identify physiological substrates are needed to better understand the significance of Oatp4c1 function in renal and mammary epithelium.

ATP-binding cassette (ABC) transporters are transmembrane proteins that transport a wide variety of substrates across intra and extra-cellular membranes. A few examples of endo and xenobiotic substrates are metabolic products, lipids, sterols, and drugs. An important function of ABC transporters involved in export is to prevent intracellular the buildup of toxic products. Several ABC transporters have also been associated with drug resistance upon treatment with chemotherapeutic agents. P-glycoprotein (P-GP) and the multidrug resistant (MRP) transporters of the ABC C family are examples of transporters that confer chemo-resistance. We have studied two unique roles of ABC transporters in the liver and the heart. In the liver, maintenance of bile secretion is important during lactation to ensure proper absorption of nutrients for the offspring. Three main ABC transporters are involved in this process: ABCB11 (transports bile acids), ABCB4 (transporters phospholipids), and ABCG5/ABCG8 (transports cholesterol). In the rat, expression of ABCB11 remains the same as the size of the bile acid pool increases. However, the expression of ABCG5/ABCG8 is abolished, preventing excessive export and loss of cholesterol from the liver. The regulation of these transporters during lactation maintains the production of bile acids from cholesterol by decreasing export while preventing toxicity from bile acids by maintaining bile flow. Another protective role of ABC transporters is seen in oxidative stress-induced toxicity of cardiac tissue following treatment with Doxorubicin (DOX), a drug used in cancer treatment. Multidrug resistance protein 1 (Mrp1) can transport toxic products by conjugation with sulfate, glutathione (GSH) or glucuronide. In Mrp1-/- mice, DOX causes advanced cell damage through intracellular edema and increased apoptotic nuclei. However, P-glycoprotein expression increases upon DOX treatment, potentially compensating for the loss of Mrp1. Mrp1 can also transport GSH, GSH disulfide (GSSG), and products of oxidation, like GSH conjugates. In the absence of Mrp1, GSH levels are increased in the heart, providing protection against oxidative stress. Both of these examples in liver and heart show the diversity of ABC transporters and the role they play in preventing cell toxicity. These studies also provide insight into ways to prevent cell toxicity through manipulation of ABC transport proteins.

AR-67 is a lipophilic third generation camptothecin analogue, currently under early stage clinical trials. It acts by targeting Topoisomerase 1 (Top1), a nuclear enzyme essential for DNA replication and transcription and is present in two forms, the pharmacologically active lipophilic lactone and the charged carboxylate. In oncology patients participating in a phase I clinical trial, AR-67 lactone was the predominant species in plasma. Similarly to other camptothecins, the identified dose-limiting toxicities for AR-67 were neutropenia, thrombocytopenia and fatigue. In addition, in vitro metabolism studies indicated AR-67 lactone as a substrate for CYP3A4/5 as well as the UGT1A7 and UGT1A8 enzymes localizing in the liver and the gut. Numerous studies have demonstrated the over-expression of transporters in certain tumor types. Here, the effect of interactions between AR-67 and efflux or uptake transporters on the antitumor efficacy of AR-67 in vitro was studied. We showed that BCRP and MDR1 overexpression confers resistance to AR-67. Moreover, we demonstrated the therapeutic superiority of protracted dosing over more intense dosing regimens of AR-67 using xenografts models. Our studies indicated the schedule-dependent expression of Top1 and the preferential partitioning of AR-67 in the tumor tissue. We reason that these are factors that need to be taken into consideration when designing dosing schedules aiming to maximize efficacy. As most cytotoxic drugs, AR-67 has a narrow therapeutic window. Thus, it is essential to identify the variables influencing exposure to this camptothecin analogue. A thorough compartmental pharmacokinetic analysis was performed on the patient data obtained in a phase 1 clinical trial on AR-67. Moreover, sources of intersubject variability associated with obtaining pharmacokinetic parameter estimates were identified and a population covariate pharmacokinetic model was developed. In conclusion, the drug development of AR-67 is a work in process. Findings presented above provide an insight on the factors contributing to its efficacy and toxicity when given to cancer patients.

<p>Detta examensarbete har utförts som en del av högskoleingenjörsutbildningen Industriell organisation och ekonomi vid Tekniska Högskolan i Jönköping. Rapporten är skriven på uppdrag av Kinnarps Production AB i Jönköping som är en del av Kinnarpskoncernen. Företaget erbjuder inredningslösningar för kontor och offentliga miljöer och är idag Europas tredje största tillverkare av kontorsmöbler. Produktionen i Jönköping består främst av plåt- och stålbearbetning.</p><p>Enheten i Jönköping har investerat i en ny monteringslina inom produktionen. Där den nya monteringslinan ska placeras sker i nuläget montering av stolarna Yin och Jig. Därmed måste monteringsplatserna av stolarna flyttas. För närvarande finns ingen given yta att flytta monteringsplatserna till, vilket grundat problemet till detta arbete. Syftet med arbetet är att finna en ny plats för montering av Yin och Jig, samt att effektivisera stolarnas materialflöden. Målet är att presentera ett antal lösningsförslag, innehållande nya monteringsplatser och effektivare materialflöden. </p><p>Genom en övergripande kartläggning av produktionsanläggningen i Jönköping och en djupare kartläggning av tillverkningsprocesserna för Yin och Jig, har förståelsen för tillverkningen ökat. Tillgången till egen arbetsplats på företaget har också varit betydande för arbetets resultat. Närheten till produktionen och kontaktpersoner har lett till ett effektivare arbete och en ökad förståelse för Kinnarpskoncernen.</p><p>En djupare analys av faktorer som är betydande för Yins och Jigs materialflöden har utförts. För att erhålla effektivare materialflöden har faktorerna utvecklats och förbättrats. De faktorer som analyserats är: materialhantering, rörbock, excenterpress, svets, montering och interna transporter. Materialhanteringen är problematisk vid lagring och har förbättrats genom utveckling av lastbärare och lagringsmetod. Rörbocken har identifierats som trång sektor och dess begränsning kan förbättras genom utbildning av personal och införande av säsongsbuffert. Monteringen kommer att utformas med mer flexibla och ergonomiska arbetsplatser. För att minska de interna transporterna kommer materialflödenas ingående operationer att utvecklas mot en flödesgrupp. Detta medför att excenterpressen och robotsvetsen kommer att flyttas till ett gemensamt område med rörlaser och rörbock.</p><p>Resultatet presenterar tre lösningsförslag som baseras på materialflödesanalysen. Lösningsförslagen innehåller layouter över Yins och Jigs materialflöden och dess nya monteringsplatser. Målsättningarna för de tre layouterna skiljer sig åt. Den första layouten skapar främst ett arbetsteam där operatörer kan samarbeta vid närliggande operationer. För att uppnå detta mål har flera operationer inom Yins och Jigs flöden samordnats. Den andra och tredje layouten skapar främst minskade interna transporter. Detta har uppnåtts genom att skapa rakare materialflöden av Yin och Jig genom produktionsanläggningen.</p><p>I diskussionskapitlet av lösningsförslagen har layouternas för- och nackdelar tagits upp. I slutsatsen presenteras det starkaste lösningsförslaget.</p>

Resting frontal electroencephalographic (EEG) asymmetry has been hypothesized to be a biological marker of clinical depression but may reflect an endophenotype specific to women. Frontal EEG asymmetry was assessed in individuals (22% male) with (n = 12) and without (n = 21) a DSM-IV diagnosis of lifetime Major Depressive Disorder (MDD) or Dysthmic Disorder on 4 occasions within a two-week period. Depressed women exhibited greater relative right frontal activity at rest than never-depressed women across occasions. In contrast, depressed men displayed greater relative left frontal activity than never-depressed men. The same participants engaged in a Passive Viewing Face task while undergoing functional magnetic resonance imaging (fMRI). The present study did not replicate previous findings which show a hyperactive hemodynamic response in the amygdalae among depressed individuals. Mixed linear models indicated a lifetime depression by biological sex by amygdala activation interaction. For never-depressed control participants, frontal asymmetry is unrelated to the level of emotion-related amygdalae activation, but for lifetime depression spectrum participants, in both men and women, relatively greater amygdalae activation to emotional faces is associated with less left frontal activity as compared to those with less amygdalae activation to emotional faces. Also, when activation to emotionally expressive faces was closer to the levels of activation observed in the neutral face condition, the predicted pattern of association between frontal EEG asymmetry and depression based on the above findings was disrupted in men, but preserved in women. When levels of activation to emotion faces was considerably lower than that to neutral faces, the pattern was generally preserved for men, but not for women. Preliminary tests were also conducted in an attempt to replicate previous reports that document a positive correlation between the risk allele of the serotonin transporter gene and amygdalae activation. The present study failed to replicate this pattern, perhaps on account of the relatively small sample size available when non-Caucasian participants were excluded from the analysis.

Mastitis is often bacterial in origin. Lipoteichoic acid (LTA) and lipopolysaccharide (LPS), endotoxins from gram-positive and gram-negative bacteria, respectively, are potent inducers of mammary gland inflammation. Inflammation can alter expression of transporters responsible for transport of substrates important in synthesis of milk constituents and cellular metabolic energy. Since, gram-positive and gram-negative bacterial infections cause a different clinical course of mastitis, I investigated whether LTA and LPS differentially alter proton-coupled (MCT1) and sodium-coupled monocarboxylate transporter (SMCT1, SMCT2) expression and functional outcomes of altered expression. Human mammary epithelial cells (MCF-12A) were incubated with 1 microgram/mL LPS or LTA for 6, 12 and 24 hours and mRNA expression of TNF-alpha, IL-1β, IL-6, MCT1, SMCT1, and SMCT2 were measured using Quantitative RT-PCR. LPS decreased SMCT1, but increased SMCT2 expression after 6 h, while LTA increased MCT1 expression at 6 h, followed by gradual decrease in expression until 24 h. To know whether such differential changes in transporter expression by LPS and LTA could cause changes in cellular energy production, I quantified creatine (Cr) and high-energy phosphate substrates (CrP, ATP, ADP, AMP) and oxygen consumption rates using HPLC and Hansatech oxygen electrode, respectively. At 12 h, LPS increased concentrations of Cr, CrP, ATP and ADP, whereas LTA caused changes in CrP and ADP concentrations relative to control. Both LPS and LTA decreased oxygen consumption rates after 12 h. Furthermore, to know whether changes in transporter expression lead to differences in substrate availability, I performed uptake studies for carnitine using radiolabelled tritium L-carnitine. LPS and LTA challenge did not affect the affinity, but caused a 2-3-fold increase in maximal activity (Vmax) of carnitine transport. Although increases in Vmax were not significant, the increase in Vmax after 12 h exposure by LPS and LTA corresponds to changes in mRNA expression of the OCTN2 transporter (previously reported in the laboratory). In conclusion, LPS and LTA differentially alter mRNA expression of transporters, which leads to changes in cellular energy levels and oxygen consumption rates and possibly to changes in the functional activity of transporters. Whether such differences contribute to the different clinical course of mastitis warrants further investigation.

Background: Intrahospital transfers of intensive care patients involves multiple risks where patient safety is challenged. Aim: The aim of this study was to investigate intensive care nurses’ experiences and perceptions of patient safety during intrahospital transfers. Method: A qualitative, explorative design was utilized with a phenomenographic approach. Ten intensive care nurses with varying work experience in intensive care were interviewed. The interviews were transcribed and analysed according to the phenomenographic method. Results: The analysis of the intensive care nurses’ experiences and perceptions resulted in four categories: routines, risks, support and job allocation. Patient safety was, according to the intensive care nurses, lower during intrahospital transfers compared to the intensive care ward but perceived as good in general. Their preparations and their ability to predict risks were mostly based on their experience level. They solved emerging problems depending on the situation. According to the intensive care nurses, being new in the profession poses a greater risk. Times when the doctors are on call and night time were especially risky times for transfers. They considered good routines important for patient safety and saw possibilities for improvement. The intensive care nurses expressed both confidence and a lack thereof with regards to the transfers and perceived it as easy to ask for help. Cooperation and communication were, according to the informants, crucial for patient safety. Conclusion: The intensive care nurses’ perceptions of patient safety during intrahospital transports were mainly based on their earlier experiences. A possibility for improvement exists through the implementation of a checklist and team training in simulated scenarios. It is important to ensure that patient safety is high during intrahospital transfers irrespective of the experience level of the staff. / Bakgrund: Intrahospitala transporter av intensivvårdspatienter innebär många risker som leder till att patientsäkerheten kan sättas på spel. Syfte: Studiens syfte var att undersöka intensivvårdssjuksköterskors erfarenheter och uppfattningar av patientsäkerhet vid intrahospitala transporter. Metod: En kvalitativ, explorativ design tillämpades med fenomenografisk ansats i form av semistrukturerade intervjuer. Tio intensivvårdssjuksköterskor med varierande arbetslivserfarenhet inom intensivvården intervjuades. Intervjuerna transkriberades och analyserades enligt fenomenografisk metod. Resultat: Analysen av intensivvårdsjuksköterskornas erfarenheter och uppfattningar resulterade i fyra kategorier: rutiner, risker, stöd och arbetsfördelning. Enligt intensivvårdssjuksköterskorna var patientsäkerheten vid intrahospitala transporter sänkt jämfört med intensivvårdsavdelningen men uppfattades trots detta generellt som god. Förberedelserna intensivvårdssjuksköterskorna gjorde och förmågan att se risker berodde mycket på hur erfarna de var. De löste de problem som uppstod utifrån situationen. Enligt intensivvårdssjuksköterskorna innebar det en extra risk att vara ny i sin profession. Jourtid och nattetid var riskfyllda tidpunkter och förflyttningar av patienterna som ett speciellt riskfyllt moment. De ansåg att bra rutiner var viktigt och de såg möjligheter till förbättringar för att öka patientsäkerheten. Intensivvårdssjuksköterskorna uttryckte både en trygghet och otrygghet i samband med transporterna men uppfattade att det var lätt att be om hjälp. Samarbete och kommunikation var enligt dem avgörande för patientsäkerheten. Slutsats: Intensivvårdsjuksköterskornas uppfattningar av patientsäkerheten under intrahospitala transporter berodde till stor del på deras tidigare erfarenheter. Ett utrymme till förbättringar finns genom ett införande av en checklista samt teamträning i simulerade scenarion. Det är viktigt att säkerställa att patientsäkerheten är hög oberoende av hur erfaren personalen är.