Global ETD Search

181	Investigating Amyloid β toxicity in Drosophila melanogaster Jonson, Maria January 2017 (has links) In this thesis Drosophila melanogaster (the fruit fly) has been used as a model organism to study the aggregation and toxic properties of the human amyloid β (Aβ) peptide involved in the onset of Alzheimer's disease (AD). AD is one of many misfolding diseases where the important event of a protein to adopt its’ specific three-dimensional structure has failed, leading to aggregation and formation of characteristic amyloid fibrils. AD has a complex pathology and probably reflects a variety of related molecular and cellular abnormalities, however, the most apparent common denominator so far is abnormal Amyloid-β precursor protein (APP) processing, resulting in a pool of various Aβ-peptides. In AD, the Aβ peptide misfolds, aggregates and forms amyloid plaques in the brain of patients, resulting in progressive neurodegeneration that eventually leads to death. By expressing the human Aβ protein in the fly, we have studied the mechanisms and toxicity of the aggregation in detail and how different cell types in the fly are affected. We have also used this model to investigate the effect of potential drugs that can have a positive impact on disease progression. In the first and second work in this thesis, we have, in a systematic way, proved that the length of the Aβ-peptide is essential for its toxicity and propensity to aggregate. If the peptide expressed ends at amino acid 42 it is extremely toxic to the fly nervous system. However, this toxicity can be completely abolished by expressing a variant that is shorter than 42 amino acids (1-37 to 1-41 aa), or be significantly reduced by expressing a longer variant (1-43 aa). Toxicity can be partly mitigated in trans by co-expressing the 1-42 variant with a 1-38 variant. This supports the theory that the disease progression could be inhibited if the formation of Aβ 1-42 is decreased. In the third work we demonstrate that amyloid aggregates can be found in various cell types of Drosophila, however, the toxicity seem to be selective to neurons. Our results indicate that the aggregates of glial expressing flies have a more mature structure, which appear to be less toxic. This also suggests that glial cells might spread Aβ aggregates without being harmed. The last work in this thesis investigates how curcumin (turmeric) can affect Aβ aggregation and toxicity. Curcumin appears to shift the equilibrium between the less stable aggregates and mature fibers toward the final stage resulting in an improved lifespan for treated flies. In summary, this thesis demonstrates that the toxicity of Aβ in Drosophila is highly dependent on the Aβ variant expressed, the structure of the protein aggregates and which cell type that expresses the protein. We have also shed light on the potential of using Drosophila when it comes to examining possible therapeutic substances as a tool for drug discovery. Chemical Sciences Kemi Cell and Molecular Biology Cell- och molekylärbiologi Pharmacology and Toxicology Farmakologi och toxikologi
182	Molecular Mechanisms of Reward and Aversion Klawonn, Anna January 2017 (has links) Various molecular pathways in the brain shape our understanding of good and bad, as well as our motivation to seek and avoid such stimuli. This work evolves around how systemic inflammation causes aversion; and why general unpleasant states such as sickness, stress, pain and nausea are encoded by our brain as undesirable; and contrary to these questions, how drugs of abuse can subjugate the motivational neurocircuitry of the brain. A common feature of these various disease states is involvement of the motivational neurocircuitry - from mesolimbic to striatonigral pathways. Having an intact motivational system is what helps us evade negative outcomes and approach natural positive reinforcers, which is essential for our survival. During disease-states the motivational neurocircuitry may be overthrown by the molecular mechanisms that originally were meant to aid us. In study I, to investigate how inflammation is perceived as aversive, we used a behavioral test based on Pavlovian place conditioning with the aversive inflammatory stimulus E. coli lipopolysaccharide (LPS). Using a combination of cell-type specific gene deletions, pharmacology, and chemogenetics, we uncovered that systemic inflammation triggered aversion by MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Moreover, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, inflammation-induced aversion was not an indirect consequence of fever or anorexia but constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic circuitry is a key mechanism underlying inflammation-induced aversion. In study II, we investigate the role of peripheral IFN-γ in LPS induced conditioned place aversion by employing a strategy based on global and cell-type specific gene deletions, combined with measures of gene-expression. LPS induced IFN-ɣ expression in the blood, and deletion of IFN-ɣ or its receptor prevented conditioned place aversion (CPA) to LPS. LPS increased the expression of chemokine Cxcl10 in the striatum of normal mice. This induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion. Collectively, these findings demonstrate that circulating IFN-ɣ binding to receptors on brain endothelial cells which induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion. In study III, we explored the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice in CPA to various stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain and kappa opioid receptor-induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference towards most of the aversive stimuli, but were indifferent to pain. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine-dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were re-expressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in a MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli. The neurotransmitter acetylcholine has been implied in reward learning and drug addiction. However, the role of cholinergic receptor subtypes in such processes remains elusive. In study IV we investigated the function of muscarinic M4Rs on dopamine D1R expressing neurons and acetylcholinergic neurons, using transgenic mice in various reward-enforced behaviors and in a “waiting”-impulsivity test. Mice lacking M4-receptors from D1-receptor expressing neurons exhibited an escalated reward seeking phenotype towards cocaine and natural reward, in Pavlovian conditioning and an operant self-administration task, respectively. In addition, the M4-D1RCre mice showed impaired waiting impulsivity in the 5-choice-serial-reaction-time-task. On the contrary, mice without M4Rs in acetylcholinergic neurons were unable to learn positive reinforcement to natural reward and cocaine, in an operant runway paradigm and in Pavlovian conditioning. Immediate early gene expression mirrored the behavioral findings arising from M4R-D1R knockout, as cocaine induced cFos and FosB was significantly increased in the forebrain of M4-D1RCre mice, whereas it remained normal in the M4R-ChatCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Motivation Dopamine Reward Aversion Negative affect Systemic Inflammation Drug Addiction Cytokines Prostaglandin E2 Melanocortin receptor 4 Acetylcholine Muscarinic M4 receptor Neurosciences Neurovetenskaper Cell and Molecular Biology Cell- och molekylärbiologi Immunology in the medical area Immunologi inom det medicinska området Pharmacology and Toxicology Farmakologi och toxikologi
183	Characterisation of anandamide uptake in resting and activated murine cells Fredriksson Sundbom, Marcus January 2015 (has links) Modifying the metabolism of the body’s own endocannabinoids is a novel approach for analgesia. Two key catabolic enzymes are fatty acid amide hydrolase (FAAH) and inflammation-inducible cyclooxygenase 2 (COX-2). The cellular uptake of the key endocannabinoid anandamide (AEA) has been found to be regulated by its FAAH-catalysed intracellular degradation, but COX-2 has not been investigated in this respect. We aimed to find out whether or not COX-2 in an in vitro inflammation setting would be able to gate AEA uptake. To achieve this, C6 cells and Raw 264.7 cells were stimulated with LPS/INF-γ and lysates then analyzed by immunoblot in order to verify COX-2 expression. AEA cellular uptake was quantified using a radioassay with [3H]-AEA. It was found that COX-2 was not inducible in C6 cells using the LPS/INF-γ conditions studied, while it was inducible in Raw 264.7 cells. AEA uptake in the COX-2-induced Raw 264.7 cells was not reduced by inhibitors of this enzyme. FAAH appeared to be down-regulated in the stimulated Raw 264.7 cells, and this was reflected in an overall lower AEA uptake. Our interpretation of the data points to FAAH as gating AEA uptake. Additional experiments are required to validate our findings by verifying significance. Pharmacology and Toxicology Farmakologi och toxikologi
184	Quantification of Pharmaceuticals at the sub-cellular level using the NanoSIMS Dost, Maryam January 2024 (has links) Mass spectroscopy imaging (MSI) has become a vital tool in modern research due to its ability to visualize the spatial distribution of molecules within tissue samples. The collaboration between researchers at AZ, the University of Gothenburg, and Chalmers University of Technology using the NanoSIMS instrument and MSI-SIMS technology has opened up new avenues of exploration in pharmaceutical development, particularly in examining drugs and metabolites at sub-cellular levels. This groundbreaking research has the potential to significantly improve the efficacy and safety of future pharmaceutical products. NanoSIMS possesses a unique imaging and processing technique that enables high-resolution imaging of cellular structures and subcellular compartments. This powerful tool allows for the visualization and measurement of elements and isotopes at the subcellular level. The technique involves bombarding a sample with a focused primary ion beam, which causes the emission of secondary ions. These secondary ions are then analyzed to determine the elemental and isotopic composition of the sample. NanoSIMS is particularly useful for analyzing biomolecules since traditional Mass spectrometry methods cannot provide information about how molecules behave at the cellular level. Given that many of the drugs used today have intra-cellular targets, hence understanding the drug's cellular pathways is extremely important, especially in cases where the risk for organ toxicity is high due to the high dosage of the drugs. Our data from the image analysis indicated the presence of amiodarone inside the lysosomes; however, the lack of enrichment from the 13C portion of the dual-labeled molecule made it difficult to reach a variation below the LOD. Since our LOD is relatively high when working with 13C12C, we focused on the fact that accuracy, precision, and sensitivity would be the most crucial factors in our study. After adjusting these parameters, we obtained an image that made the measurement possible. This project aims to utilize a dual-labeled drug (13C and 127I) to bridge the absolute quantification ability of the 13C labeling scheme to the more sensitive labeling scheme. The focus of this study lies therefore on optimization and the relationship between Spatial resolution, Sensitivity, Mass Resolution, Accuracy, and Precision. This technique is extremely promising, but the limit of detection is relatively high mainly due to the high percentage of carbon in the sample. Despite this fact, we were able to present some valuable data. Our analysis showed that the sensitivity of the 127I is much better than 13C, however, we produced an image where the ratio between the labels was above the detection limit. Using this data, a Relative sensitivity factor (RSF) value was measured, and the concentration of the drug could be estimated by applying the quantification equation. Mass spectroscopy imaging AstraZeneca Nanosims Therapeutics pharmacokinetics pharmacodynamics Quantitative Visualization calibration curve RSF pharmacology Data Analysis Chemistry Quantification isotopes Pharmaceuticals subcellular drug drug target nucleotide biodistribution Bioanalytical electrochemistry spectroscopy mass spectrometry analytical separations Analytical Chemistry ROI Bioanalytical Chemistry Masspektroskopi avbildning AstraZeneca Nanosims Terapeutik farmakokinetik farmakodynamik Kvantitativ visualisering kalibreringskurva RSF farmakologi Dataanalys Kemi Kvantifiering isotoper Läkemedel subcellulär läkemedel läkemedelsmål bioskopisk elektrofördelning nukleotid bioskopisk bioskopisk distribution masspektrometri analytiska separationer analytisk kemi bioanalytisk kemi Analytical Chemistry Analytisk kemi
185	Fysisk aktivitet eller Farmakologi för en hälsosammare behandlingsupplevelse enligt individer med ADHD? : Retrospektiv intervjustudie / Physical activity or Pharmacology for a healthier treatment experience according to individuals with ADHD? : Retrospective Interview Study Blomster, Kaisa January 2020 (has links) Introduktion: ADHD är en uppmärksamhet -och hyperaktiv störning, där 90 % i Sverige behandlas med det farmakologiska läkemedlet Metylfenidat (MPH). En stor andel med ADHD utvecklar psykiatrisk komorbiditet i form av psykisk ohälsa (frånvaro av mentalt välbefinnande). Patofysiologin hur MPH påverkar hjärnan är okänd och behandlingsformen har diskuterats som bristfällig på grund av förekommande bieffekter. Fysisk aktivitet har föreslagits som ett hälsosammare behandlingsalternativ, då evidens visat att fysisk aktivitet kan förbättra ADHD-symptom och samsjuklighet av psykisk ohälsa. Det finns inga studier som undersökt hur individer med ADHD upplever nuvarande- och önskar behandling. Syftet med denna studie blev därför att undersöka upplevda erfarenheter av ADHD och hur det farmakologiska läkemedlet MPH och fysisk aktivitet upplevs ha påverkat diagnosens symptom och individernas psykiska hälsa samt att ta reda på vilken behandling individerna önskar utifrån deras livserfarenheter. Metoden utgick från ett fenomenologiskt ramverk med hjälp av en deskriptiv kvalitativ tvärsnittsstudie, där data extraherades genom en innehållsanalys med en induktiv ansats. Urvalet selekterades genom snöbollsurval, där inklusionskriteriet var att deltagarna blivit diagnostiserad med ADHD och har erfarenheter av MPH och fysisk aktivitet. Resultatet visade att symptom för ADHD var problematik med koncentration-, hyperaktivitet-, uppmärksamhet- och systematiska svårigheter, där symptom försämrat den psykiska hälsan. Det framgick att både MPH och fysisk aktivitet effektiviserade symptom mot koncentration, hyperaktivitet och uppmärksamhet, varav KBT (kognitiv beteendeterapi) förbättrade systematiska svårigheter. Vidare bidrog MPH med fysiska, mentala och beteendeföränderliga bieffekter som försämrade den psykiska hälsan. Fysisk aktivitet visade däremot förbättra den psykiska hälsan, där inaktivitet framgick som en central nackdel för förvärring av symptom och psykisk hälsa. Deltagarnas önskan var att behandling bör uppföljas och baseras på en överenskommelse som anpassas efter individuella svårigheter och hälsotillstånd. Slutsatsen med studien kom fram till att behandlas med fysisk aktivitet i kombination med KBT skulle vara hälsosammare som första behandling mot samtliga ADHD-symptom och psykisk hälsa. I andra hand var det deltagarnas önskan att applicera MPH vid akut behov, och är därav förslag att forska fram MPH som engångsbehandling som kan användas vid inaktiva tillstånd. Studien kom fram till att inkludering av fler idrottsvetenskapliga tjänster till vård och skola behövs för mer kompetens om vikten av fysisk aktivitet för individer som har ADHD. / Introduction: ADHD is an attention-deficit/hyperactivity disorder, where 90% in Sweden is treated with the pharmacological drug Methylphenidate (MPH). People diagnosed with ADHD develop often psychiatric comorbidity in form of mental illness. The pathophysiology behind how MPH influence the brain is unknown and the treatment have been discussed as deficient due to side effects. Physical activity has been suggested as a healthier treatment option, as evidence shows that physical activity can improve ADHD-symptoms and comorbidity of mental illness. There are no studies that have invastigate how individuals with ADHD experience current- and desired treatment. The aim of this study was therefore to investigate the experiences of having ADHD and how the pharmacological treatment MPH and physical activity has affected the symptoms and mental health, and also find out what treatment the individuals want based on their life experiences. The method was derived from a phenomenological framework using a descriptive qualitative cross-sectional study. Data was analyzed with an inductive approach using an interpretive analysis. Participants was recruited through a snowball selection, where the inclusion criteria stated that participants been diagnosed with ADHD and have experience of MPH and physical activity. The results showed that the frequent occurring symptoms of ADHD were difficulties with concentration-, hyperactivity-, attention- and systematic symptoms, where symptoms had shown a negative effect on the mental health. It appeared that both MPH and physical activity made symptom improvement against concentration-, hyperactivity- and attention difficulties, while CBT (Cognitive Behavioral Therapy) improved systematic difficulties. MPH contributed to side effects that affected physiological-, psychological- and behavioral aspects, which all were perceived to have a negative influence on mental health. In contrast, physical activity improved mental health and showed no evidence of side effects, except when physical activity was absent from daily life. Inactivity appeard to be a central disadvantage for worsening symptoms and mental health. The participants desired that their treatment should be tailored to individual difficulties and health condition in a collaborative way and with follow-up from the health care worker. The study concluded that physical activity in combination with CBT would be a healthier as first treatment option to reduce symptoms of ADHD and improve mental heatlh. Additionally, the participants desired treatment with MPH in form of single doses for urgent need, and it is therefore to suggest development of such treatment option. Furthermore, the study proposes more services for sport science within healthcare and schools for containing applicable knowledge in physical activity for dose with ADHD. ADHD Symptoms Difficulties Attention Deficit Hyperactivity Disorder Hyperactive Impulsivity Concentration Attention Systematic Physical activity Training Exercise Inactivity Mental Health Neuropsychology Physiology Pharmacology Methylphenidate MPH Treatment experience Well-being Health Health promotion Side effect Symptom effect Interview study Qualitative Content analysis Phenomenology Medicine ADHD Symptom Symptomsvårigheter Uppmärksamhet- och Hyperaktiv störning hyperaktivitet Impulsivitet Koncentration Uppmärksamhet Systematik Hälsa Psykisk Hälsa Psykisk ohälsa Psykiatrisk komorbiditet Samsjuklighet Neuropsykologi Fysiologi Fysisk aktivitet Rörelse Träning Inaktivitet Farmakologi Metylfenidat MPH Behandlingsupplevelse Välmående Hälsa Hälsofrämjande Hälsotillstånd Bieffekt Symptomeffekt Intervjustudie Kvalitativ Idrottsvetenskap Innehållsanalys Fenomenologi Medicin Läkemedel Sport and Fitness Sciences Idrottsvetenskap
186	Preventing fatal effects of overworking : Product design solution Adawi, Rahim January 2018 (has links) “Overworking to death” is a phenomenon that has been noticeable in developing countries. The cause of death is mainly through ischemic strokes. While the victims’ occupations differed, they all shared a common characteristic, being positioned in a sedentary work, ranging from IT workers to doctors. This project’s aim was to develop a product that prevented or decreased the strokes that derived from sedentary overwork. This was mainly tackled by preventing one of the three causes of developing blood props, slowed blood flow. In order to gather rich data of the phenomenon, a qualitative study was conducted in China, during two months. By doing an extensive structured sampling, information rich data could be gathered during a short period of time. Data were derived from observations, questionnaires and an interview, which then was interpreted to customer needs and the final product specification. The final product became a trouser with an in built dynamic compression mechanic, that can compress the veins mostly during sitting activities, in order to prevent blood stasis. The compression mechanic works like the Chinese finger trap; compressing the calves while sitting and stretching the legs forward. It is made only out of polysaccharides fibres; cotton and corn. / "Guolaosi" eller död från överarbete är ett fenomen som i regel uppkommer bland utvecklingsländer. Dödsorsaken är huvudsakligen genom stroke. Offrens yrken varierar allt från professorer, IT-arbetare till läkare. De delar dock en sak gemensamt; att arbeta under långa perioder stillasittande. Projektets mål var att utveckla en produkt som minskar dödliga följderna av sedentära överarbete, genom att förebygga en av de tre orsakerna för att utveckla blodproppar; saktad blodström. Målgruppen var då kineser av de yrken som hade tidigare drabbats av fenomenet. För att samla informationsrika data om fenomenet genomfördes en kvalitativ studie i Kina under två månader. Genom att göra en omfattande strukturerad provtagning kunde informationsrika data samlas under en kort tidsperiod. Fältstudien bestod av observationer, frågeformulär och en intervju, som då tolkades till kundbehov och eventuellt produktspecifikationen. Den slutliga produkten kom att bli ett par byxor med en inbyggd dynamisk komprimeringsmekanism, som kan komprimera venerna under sittande aktiviteter, för att förhindra saktad blodström. Kompressionsmekanismen fungerar som den kinesiska fingerfällan. Den komprimerar blodkärlen medan personen sitter och sträcker benen framåt. Produkten är konstruerad på så sätt att den kan tillverkas endast av polysackariders tråd, från bomull och majs. Vilket är lämpligt för Kinas lokala resurser. stroke DVT overworking karoshi guolaosi prolonged inactivity sedentary death product design China Sweden Sida MFS field study trouser pants sampling observation questionnaire interview blood circulation stasis cardiovascular disease cotton corn agenda 2030 Chinese finger trap textile fibre yarn soil erosion muscle pump mechanism gradual compression stockings GECS PECS pressure distribution blood clot veins therapy stool chair PE PTS economy class syndrome methodology plastic sample concept sketch stroke DVT överarbete karoshi guolaosi förlängd inaktivitet stillasittande död produkt design Kina Sverige Sida MFS fältstudie byxa byxor provtagning observation frågeformulär intervju blodcirkulation stasis kardiovaskulär sjukdom bomull majs agenda 2030 kinesisk fingerfälla textil fiber garn jord erosion muskel pump mekanism gradvis komprimering strumpor stödstrumpa tryck kraft GECS PECS tryckfördelning blod blodproppar vener terapi pall stol PE PTS ekonomi klass syndrom metodik plast prov koncept skiss Design Design Pharmacology and Toxicology Farmakologi och toxikologi Occupational Therapy Arbetsterapi Cardiac and Cardiovascular Systems Kardiologi Environmental Sciences Miljövetenskap Medical Ergonomics Medicinsk ergonomi Textile, Rubber and Polymeric Materials Textil-, gummi- och polymermaterial Composite Science and Engineering Kompositmaterial och -teknik Medical Materials Medicinska material och protesteknik

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