Universiẗat, Diss., 2004--Bielefeld.

Flygbranschen är en marknad där det idag raåder hård konkurrens. Detta betyder att flygbolag är mycket kostnadsmedvetna vilket i sin tur sätter stor press på alla parter inblandade i flygbolagens försörjningskedja - inte minst på flygcateringföretag. Flygbolag förväntar sig kvalitet, i tid, till ett så lågt pris som möjligt. I det här examensarbetet har ett flygcateringföretags försörjningskedja studerats som en fallstudie i syfte att undersöka om en utvidgning i form av ett logistikcenter kan effektivisera catering av norra Sverige. Även om anläggningslokalisering är ett i litteraturen väl studerat ämne bidrar det här examensarbetet med att belysa hur ett sådant problem kan te sig i en bransch med stränga säkerhetskrav. Exempelvis kan transporter inte samköras med andra typer av varor utan att de måste röntgas vid ankomst till flygplats, vilket kostar både tid och pengar. Leverantörer kan i flera fall inte väljas fritt utan att det innebär en ökad hanteringskostnad på grund av säkerhetsföreskrifter. Detta gör att en anläggnings lokalisering är av största vikt då andra delar av försörjningskedjan kan vara svårare att förändra än i andra branscher. I examensarbetet undersöks var en anläggning ska placeras för att minska transportkostnaderna till flygplatser i norrlandsregionen. Genom att formulera problemet som ett diskret anläggningsproblem utan kapacitetsbegränsning rekommenderas Umeå som optimal placering med hänsyn till transportkostnad baserat på vägavstånd. Hänsyn har även tagits till kvalitativa faktorer så som tillgång på arbetskraft och tillgång till infrastruktur. Vidare undersöks även lokalkostnad för en industrilokal i Umeå och personalbehovet uppskattas. Till sist har även risker med att placera en anläggning i norra Sverige undersökts. Examensarbetets slutsats är att investeringen bedömds lämplig utifrån ett transport-, lokal och personalkostnadsperspektiv. Däremot finns det risker kopplade till bemanningen på logistikcentret. Arbetsuppgifterna på logistikcentret kommer att vara relativt få och spridda över olika tider vilket gör det svårt att schemalägga personal på ett lämpligt sätt. Detta förvärras av det faktum att logistikcentret bara kommer att vara öppet under en period av sex månader varje år, vilket innebär att ny personal med största sannolikhet kommer att behöva rekryteras inför varje ny säsong.

The relationship between human erythrocyte glucose transporter (GLUT1) oligomeric structure and function was studied. GLUT1 was purified from human erythrocytes in the absence (GLUT1-DTT) or the presence (GLUT1+DTT) of dithiothreitol. Chemical cross-linking studies of lipid bilayer-resident purified GLUT1 and hydrodynamic studies of cholate-solubilized GLUT1 support the view that GLUT1-DTT is a homotetramer and GLUT1+DTT is a homodimer. Parallel studies on human erythrocyte, and studies employing conformation-specific antibodies (anti-GLUT1-DTT antibodies, ∂-IgGs), indicate that erythrocyte-resident GLUT1 resembles GLUT1-DTT (a homotetramer). While the D-glucose binding capacities of GLUT1-DTT and GLUT1+DTT are indistinguishable, GLUT1-DTT presents at least two population of binding sites to D-glucose whereas GLUT1+DTT presents only one population of sugar binding sites. The cytochalasin B (CCB) binding capacity of GLUT1-DTT (0.4 sites/monomer) is one half of that of GLUT1+DTT. GLUT1-DTT and GLUT1+DTT contain 2 and 6 free sulfhydryls per monomer respectively. The subunits (monomers) of tetrameric and dimeric GLUT1 are not linked by disulfide bridges. Erythrocyte resident GLUT1 presents at least two binding sites to D-glucose and binds CCB with a molar stoichiometry of 0.55 sites per GLUT1 monomer. Following treatment with high pH plus dithiothreitol, the sugar binding capacity of erythrocyte membrane resident transporter is unaltered but the transporter now presents only one population of binding sites to D-glucose, binds CCB with molar stoichiometry of 1.3 sites per GLUT1 monomer and displays significantly reduced affinity for ∂-IgGs. These findings demonstrate that erythrocyte resident glucose transporter is GLUT1-DTT (a GLUT1 tetramer) and that GLUT1 oligomeric structure determines GLUT1 functional properties. A model which rationalizes these findings is proposed.

Obesity and Diabetes, the major cause for morbidity and mortality in United States raises a general curiosity regarding health care expenses when talked about treating them. Every year approximately 300,000 US adults die of reasons associated to obesity and diabetes, becoming the sixth leading cause of death. The prevalence of those diagnosed with diabetes witnessed an exponential curve in the last decade and for the year 2011 about 8.3% of the population in the US has been diagnosed with diabetes and it is predicted that in the year 2030 the prevalence of diabetes is to reach 4.4% globally. Type 2 diabetes is a condition, which develops when the body no longer makes enough insulin or when the insulin so produced does not work effectively. In reaction to the increase in obesity, treatments for obesity became more common especially the pharmacological treatments. Since this treatment also required one to change their lifestyle and food habits, bariatric surgeries were considered as an option to treat obesity and diabetes. A range of surgical procedures have been used to stimulate weight loss for obese patients. These procedures resulted in weight loss by restricting the size of the stomach (Gastric Banding) or bypassing a portion of the intestine (Gastric Bypass). Roux-en-Y Gastric Bypass (RYGB) accomplishes weight loss during a combination of gastric restriction and malabsorption. Reduction of the stomach to a small gastric pouch results in feelings of satiety. The RYGB procedure has been performed regularly since the early 1980s; it was first performed laparoscopically in the early 1990s. Ileal interposition (IT) is a surgical procedure where a section of ileum is snipped and moved closer to the jejunum. It is said that the food takes just ten minutes to reach the ileum instead of an hour after this procedure. The ileum produces Glucagon like Peptide-1 (GLP-1) which helps in insulin secretion. Glucose is a key stimulator for mammals and is derived from the diet consumed, transferred from the circulation into the target cells. Glucose penetrates the eukaryotic cells through membrane associated carrier proteins, the Na+ coupled glucose transporter (SGLT-1) and the glucose transporter (GLUT). These transporters are structurally and functionally distinct. The main research question was "are the receptors involved in glucose transport across the membrane (GLUT2 and SGLT1) important for Ileal Interposition"? With experiments like real time PCR (qPCR) and immunohistochemistry (IHC), we have observed the differences in the expression of these receptors with respect to the location and organ. Ileal interposition showed a significant difference (p<0.01) compared to sham-operated rats in the expression of GLUT2 in the gluconeogenic organs. The increased GLUT2 levels in ileal interposition may explain glucose sensitivity and these data emphasize the need for GLUT2 to maintain a positive glucose homeostasis and further study on SGLT1/GLUT2 influence on gluconeogenesis.

Doctor of Philosophy / Biochemistry and Molecular Biophysics Interdepartmental Program / Subbaratnam Muthukrishnan / In this study, I have used dsRNA-mediated down-regulation of transcripts/proteins of several potential targets in the model beetle, Tribolium castaneum to identify a molecular target of the “chitin inhibitor”, diflubenzuron (DFB). The elytron of the red flour beetle, T. castaneum, was chosen as the model tissue for studying the mode of action of DFB and its molecular target(s). We have standardized the protocol for topical administration of DFB on precisely aged prepupae to achieve the desired level of mortality (90-95%) on day 5 of the pharate adult stage. Exposure of prepupae to DFB at 1000 ppm results in a near complete loss of chitin in the newly forming adult procuticle of the elytron and the body wall. Global analysis of transcripts by RNA Seq was carried out to look for differential expression of several critical genes of cuticle assembly in these insects compared to mock-treated controls. Interestingly, genes directly involved in the biosynthetic pathway of chitin were not among those affected by DFB. However, immunolocalization studies have shown that several proteins of chitin metabolism including chitin synthase A, which is involved in the synthesis of cuticular chitin, are present in near normal amounts but are mislocalized in DFB-treated insects. Assays for chitin synthase using elytral extracts have indicated that the enzyme preparations from DFB-treated insects are catalytically inactive. By using RNA interference and competition studies with fluorescently-tagged glibenclamide (a sulfonylurea compound) or DFB, we have identified a long-sought molecular receptor of DFB as an ABCC class transporter. DFB-treatment and RNAi of a specific ABCC-type transporter gene lead to identical phenotypes including loss of chitin, loss of laminar architecture of the cuticle, and mislocalization of CHS from its normal plasma membrane location to intracellular locations presumably by affecting vesicular transport. Further, using an in vitro chitin synthesizing system consisting of microsomes prepared from elytral tissue, which exhibits all of the hallmarks of cuticular chitin-synthesizing epidermal cells including sensitivity to DFB, further insights into the mechanistic details of how this class of insecticides inhibits chitin synthesis have been obtained.

No description available.

Alzheimer´s disease (AD) is an age-related, irreversible and progressive neurodegenerative pathology that deteriorates cognitive function including learning and memory. AD is characterised neuropathologically by the presence of neuritic plaques (Aβ), neurofibrillary tangles (NFTs), synaptic loss and neuronal death. AD affects specific brain regions involved in mnestic function such as the neocortex and the hippocampus. The dorsal (DR) and the median raphe (MR) nuclei give rise to serotonergic (5-HT) projections that innervate multiple brain regions including the cortex and the hippocampus, playing an important role in learning and memory processes. For a long time the degeneration of cholinergic (ACh) system was considered as the main neurochemical changes in AD brains, however, more recent studies highlight the involvement of other neurotransmitter systems including 5-HT. This thesis entitled “Altered serotonergic neurotransmission as a main player in the pathophysiology of Alzheimer’s disease: structural and ultrastructural studies in a triple transgenic mouse model of the disease” demonstrates that there exist specific alterations in the serotonergic projections of the hippocampus during the progression of AD using the triple transgenic (3xTg-AD) mouse model of the disease, which closely resemble human AD. Mr. Harun N. Noristani is submitting this thesis to the University of Manchester for the degree of PhD in the Faculty of Life Science. The results obtained in this thesis show for the first time a biphasic increase in serotonergic fibre sprouting in the 3xTg-AD mouse model of AD that occurs in parallel with evident intraneuronal/extracellular Aβ deposition in the hippocampus (Chapter 3). In addition, serotonergic fibre sprouting correlated with reduced perforated synapses in the hippocampus, suggesting a structural remodeling process to maintain hippocampal connectivity (Chapter 4). Increased 5-HT neurotransmission (via high dietary intake of tryptophan, 5-HT precursor) reduced intraneuronal Aβ accumulation in the hippocampus, suggesting a direct role of 5-HT neurotransmission in modifying AD neuropathology (Chapter 5). Given the protective role of increased 5-HT neurotransmission, treatment with 5-HT enhancing drugs may be beneficial in reducing the underlying pathology as well as improving the behavioural and cognitive abnormalities associated with AD. Nevertheless, the role of specific 5-HT receptors responsible for such neuro-protective effect of 5-HT in AD awaits further research.

Background: Elucidating the role of intestinal drug transporter function in drug development is crucial, as transporter proteins can impact on drug absorption, efficacy and adverse events. In Vitro-In Vivo Extrapolation linked to Physiologically-Based Pharmacokinetic (IVIVE-PBPK) models aim to predict the in vivo impact of transporters from in vitro cell–based transport data and expression-based scaling factors. Currently, these models depend on relative measurements of transporter expression i.e., mRNA or immunoblotting. There is a critical need for physiologically relevant measures of transporter protein abundance to populate these biological frameworks. Objectives: The key objectives were to develop and validate a targeted proteomics workflow to quantify transporter protein abundances in human enterocytes and Caco-2 cells with a QconCAT technique. A cross-laboratory comparison on matched samples was also performed to assess between-laboratory bias in abundance determination. Together with abundance data from each laboratory, BCRP and P-gp transporter activities from Caco-2 cells were used to identify function-abundance relationships, to facilitate the potential development of abundance-function scaling factors. Results: Development of a differential centrifugation technique to obtain plasma membranes was undertaken using MDCK-II and Caco-2 cells. The plasma membrane fraction showed little enrichment from the preceding total membrane fraction and was contaminated with endoplasmic reticulum, as assessed by marker enzyme activities. There were also no differences in Na/K-ATPase, BCRP and P-gp abundances between plasma and total membrane fractions in Caco-2 cells. This may be due to losses of protein from the target membrane fraction, thus, a theoretical framework combining protein assay (BCA) and transporter abundance determinations was proposed. Pilot data on the generation of recovery correction factors using Villin and Na/K-ATPase abundances, to account for protein losses is also presented. The abundances of 6 transporters in jejunal enterocyte membranes (n=3), including the key efflux proteins BCRP (2.56±0.82 fmol/μg), P-gp (1.89±1.07 fmol/μg) and MRP2 (0.59±0.246 fmol/μg) were determined with precision. In addition, peptide losses during protein digestion stages were accounted for in abundance determinations. A cross laboratory comparison of transporter abundances from intestinal (n=4) and Caco-2 cells (n=7) measured in our laboratory and Bertin Pharma (BPh), showed that P-gp abundances were highly correlated (rs=0.72), yet BPh abundances were systematically lower than determined in our laboratory (2.0±2.08 versus. 4.8±3.51 fmol/μg, respectively). No differences or correlations were found for Na/K-ATPase and BCRP abundances between laboratories. A jejunal-Caco-2 cell relative expression factor (REF) for each protein for both laboratories was generated. The P-gp REF was similar for BPh and our laboratory (0.37 vs. 0.4, respectively) however, for BCRP there was a distinct difference (1.11 versus 2.22, respectively). These findings provide the first evidence that employing expression factors generated from abundances quantified in different laboratories may produce altered IVIVE-PBPK outcomes. Functional studies in Caco-2 cells using E-3-S and vinblastine as probes for BCRP and P-gp, respectively, show that protein abundance is more closely correlated to transporter activity than mRNA expression. In addition, it was only possible to verify that increasing P-gp abundances in Caco-2 cells were ranked alongside vinblastine intrinsic clearance, as there was little consistency when estimating Km between the different Caco-2 cell models expressing increasing P-gp abundances, which may be attributed to limited absorptive transport saturation. Thus, forming any conclusions with confidence on concentration dependent abundance-activity relationships was difficult. These data suggest the value of REF scaling factors based on protein abundances, but emphasises the need to generate these from both in vitro and in vivo samples, using the same proteomic workflow. Further work to verify abundance-function relationships is required. Conclusion: A targeted proteomic workflow has been developed allowing quantification of protein abundances for key drug transporters in human gut tissues and cell models. The study has highlighted important areas including losses of targeted proteins, contamination of plasma membrane fractions and standardisation between laboratories that need to be addressed before implementation of transporter abundances into PBPK models is undertaken. Nevertheless, the evidence for a close relationship between transporter abundance and function indicate the potential value of this data for generation of robust REF scaling factors.

Tidigare forskning har identifierat bristande överrapportering mellan yrkesgrupper som en av riskfaktorerna i samband med en interhospital transport. Studiens syfte var att utifrån kritiska händelser beskriva upplevelser av oro och farhågor hos sjuksköterskor inom ambulanssjukvården i samband med överrapportering av patienter som transporteras av ambulans mellan två vårdinrättningar. Metoden för studien var kritisk incidentteknik (CIT). Datainsamlingen utfördes i ett landsting i södra Sverige där sex sjuksköterskor inom ambulanssjukvård deltog. Intervjuerna transkriberades och analyserades enligt kritisk incidentteknik. I resultatet framkom fem huvudkategorier av oro och farhågor hos sjuksköterskor inom ambulanssjukvården i samband med överrapportering; Oro och farhågor för att nedgraderas till transportör, Oro och farhågor för rationalisering och slarv, Oro och farhågor för den prehospitala arbetsmiljön, Oro lindras genom att mottagande personal efterfrågar ytterligare information och Oro lindras genom tydligt medicinskt ansvar. Studien visar att oro och farhågor i samband med överrapportering av patienter som transporteras av ambulans mellan två vårdinrättningar kan relateras till ett patientansvar, yrkesrollen och arbetsmiljö. Den interhospitala transporten har en betydelsefull påverkan både på vårdrelationen till patienten och ambulanssjuksköterskans yrkesidentitet. Då sjuksköterskor inom ambulanssjukvård upplevt en adekvat och god överrapportering beskrevs det bidra till en patientsäker vård och upplevelse av lugn och trygghet i yrkesrollen. Överrapporteringen bör därför betraktas som en grundförutsättning för professionellt vårdarbete inom ambulanssjukvård.

Bakgrund: - År 2012 stod lastbilstransporter för majoriteten av alla transporter internt inom Sverige medan intermodala inlandstransporter endast stod för 2,4 procent. Samtidigt finns det en ambition på både nationell och regional nivå att flytta långväga godstransporter från landsvägen till järnvägen (Eriksson, 2016). Till skillnad från andra delar av samhället har utsläppen från interntransporter, alltså transporter inom Sverige, inte minskat under det senaste decenniet (Intelligent Logistik, 2016). Syfte: - Syftet med studien är att identifiera vilka förutsättningar som finns för intermodala transporter till och från Jönköpings län. Utifrån slutsatsen för frågeställning ett, de förutsättningar som identifierats, ska förbättringsförslag som kan öka andelen intermodala transporterna presenteras samt hur dessa förslag kan bidra med måluppfyllelse inom transportpolitiska och miljömässiga målsättningar för RJL. Metod: - Studien är uppbyggd på en kvalitativ strategi och för att besvara studiens syfte har en fallstudie på Jönköping län gjort. Den empiri som används har samlats in genom semistrukturerade intervjuer och sekundärdata från rapporter, vetenskapliga artiklar och litteratur. Studiens urval av respondenter har skett genom snöbollsurval. Slutsats: - För att intermodala transporter skall vara ekonomiskt motiverade krävs det långa avstånd vilket är ett problem för Jönköping län. Genom att förutsättningar för intermodala transporter till och från Jönköpings län har identifierats har förslag på vad RJL kan göra för att öka andelen intermodal transporter presenterats. Det innefattar både förslag som RJL direkt kan påverka i form av investering i infrastrukturen och förslag på hur de indirekt kan påverka, som att uppmuntra samarbete mellan terminaler för att skapa samordningsvinster och därmed minska break-even distansen. / Background: - In 2012, lorries transported the bulk of all shipments internally within Sweden while intermodal inland transport only accounted for 2.4 percent. At the same time, there is an ambition at national and county level to move long-distance freight transport by road to the railroad (Eriksson, 2016). Unlike other parts of society, emissions from internal transport, ie transport within Sweden, have not decreased over the past decade (Intelligent Logistics, 2016). Purpose: - The purpose of the study is to identify the conditions for intermodal transport to and from Jönköping County. Based on the conclusion of research question one, the identified conditions, proposals for improvement that can increase the proportion of intermodal transports and how these proposals can contribute to the achievement of objectives in transport policy and environmental objectives for RJL will be presented. Methodology: - The study is based on a qualitative strategy and in order to answer the purpose of the study, a case study on Jönköping County has been made. The empirical use has been collected through semi structured interviews and secondary data from reports, scientific articles and literature. The study's selection of respondents has been through snowball selections. Findings: - In order for intermodal transport to be economically justified, long distance is required, which is a problem for Jönköping County. By recognizing the conditions for intermodal transport to and from Jönköping County, proposals for what RJL can do to increase the proportion of intermodal transport has been presented. It includes both proposals that RJL can directly influence in terms of investment in the infrastructure and suggestions on how they indirectly can affect others parties.