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  • 51.
    Flos Berga, Mario
    University of Skövde, School of Bioscience.
    Effect of Ibuprofen on the growth of Pseudokirchneriella subcapitata2022Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Pharmaceuticals are an important class of pollutants in aquatic ecosystems. Detected concentration are typically in the range 1 ng/L – 1 μg/L. Traditional wastewater treatment does not provide a complete removal of these contaminants; hence, they may have a negative impact on the environment. In addition, microalgae are an ecologically-meaningful target group of species for bioindication purposes as well as primary production and oxygen supply. The present work aimed to investigate the effect of Ibuprofen on the green alga Pseudokirchneriella subcapitata. Algal cultures were exposed to five different concentrations of the drug (5, 15, 45, 135, 405 mg/L) for four days. Absorbance measured at 680 nm was determined every day and obtained data were transformed into cell concentration (cells/mL) by a previously prepared calibration curve. Specific growth rate, generation time, percent inhibition and effective concentration were calculated. Moreover, one way ANOVA with Tukey’s test were applied to observe differences between groups and time periods. Based on this study, all the cultures treated with Ibuprofen had a growth inhibition as well as presenting a lag phase. Increasing the Non-Steroidal Anti-Inflammatory drug (NSAID) concentration reduced the growth rate and consequently, increased the percent inhibition in a concentration-dependent manner. According to this report, new research should be focused on the development of hybrid systems for degradation and removal of pharmaceuticals. NSAID pollution may lead to a reduction in the diversity and number of functional groups of eukaryotic algae. Finally, more research should be devoted to the toxicity of drugs in a variety of test organisms and development of reliable methods for toxicity test at low and chronic exposures to achieve more realistic conclusions.

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  • 52.
    Fransson, Cristian
    University of Skövde, School of Bioscience.
    The initial steps in the pursuit to diagnose trimethylaminuria with liquid chromatography-tandem mass spectrometry and UniSpray ionization at CMMS2022Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Trimethylaminuria is an autosomal recessive disorder characterized by a decreased oxidation capacity of trimethylamine to trimethylamine-N-oxide in the liver. The condition is diagnosed by estimating concentrations of trimethylamine and trimethylamine-N-oxide in human urine and then evaluating their respective creatinine ratios and the oxidation efficiency percentage. Values previously retrieved with liquid chromatography-tandem mass spectrometry with electrospray ionization but not the novel ionization interface UniSpray. Thus, this project aims to initiate the development of a liquid chromatography-tandem mass spectrometry diagnostic method for trimethylaminuria with UniSpray ionization. The analytes were extracted from urine with a liquid-liquid extraction method and separated with hydrophilic interaction liquid chromatography using an isocratic profile with 5 mM of ammonium formate in water and methanol and multiple reaction monitoring. Overall, the mean coefficient of variation and recovery percentage from trimethylamine spiked urine samples were lower than expected, whereas the intra-precision for trimethylamine-N-oxide was acceptable. Three urine samples had estimated oxidation percentages, but only one had derived comparable creatinine ratios to an external laboratory. Due to the inadequacy of comparative data and the precision and recovery percentage deviations, the results presented in this report need cautious interpretation. Future development of the method could include manual tuning, reconsidering the calibration curve and reference values, and comparisons to the extraction method. Although there are apparent discrepancies in the precision and reliability of the derived trimethylamine and trimethylamineN-oxide concentrations, the initial steps in the pursuit of a liquid chromatography-tandem mass spectrometry diagnostic method for trimethylaminuria provide a practical foundation to continue the development.

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  • 53.
    Gallwitz, Maike
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Rapid species-specific diversification of the mast cell chymase locus during mammalian evolution.2006In: Immunogenetics, Vol. 58, p. 641-654Article in journal (Refereed)
  • 54.
    Gau, Rémi
    et al.
    Institute of Psychology, Université Catholique de Louvain, Louvain la Neuve, Belgium. Electronic address remi.gau@uclouvain.be.
    Noble, Stephanie
    Radiology & Biomedical Imaging, Yale University, New Haven CT, USA.
    Heuer, Katja
    Center for Research and Interdisciplinarity, Université of Paris, Paris, France; Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
    Bottenhorn, Katherine L
    Department of Psychology, Florida International University, Miami, FL, USA.
    Bilgin, Isil P
    Biomedical Engineering, Cybernetics, University of Reading, Reading, UK; Allied Health Professions Institute, University of the West of England, Bristol, UK.
    Yang, Yu-Fang
    Department of Psychology, University of Würzburg, Würzburg, Germany.
    Huntenburg, Julia M
    Systems Neuroscience Lab, Champalimaud Research, Lisbon, Portugal.
    Bayer, Johanna M M
    Centre for Youth Mental Health, University of Melbourne, Melbourne, Australia; Orygen Youth Health, Melbourne, Australia.
    Bethlehem, Richard A I
    Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK; Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, UK.
    Rhoads, Shawn A
    Department of Psychology, Georgetown University, Washington DC, USA.
    Vogelbacher, Christoph
    Laboratory for Multimodal Neuroimaging, Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
    Borghesani, Valentina
    Centre de Recherche de lInstitut Universitaire de Gériatrie de Montréal, Université de Montréal, Montréal, QC, Canada.
    Levitis, Elizabeth
    Section on Developmental Neurogenomics, National Institute of Mental Health, Bethesda, MD, USA; Centre for Medical Image Computing, Department of Computer Science, University College London, London, UK.
    Wang, Hao-Ting
    Sackler Centre for Consciousness Science, University of Sussex, Brighton, UK; Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK; Sussex Neuroscience, University of Sussex, Brighton, UK.
    Van Den Bossche, Sofie
    Department of Data Analysis, Faculty of Psychology and Educational Sciences, Ghent University, Ghent, Belgium.
    Kobeleva, Xenia
    Department of Neurology, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
    Legarreta, Jon Haitz
    Computer Science, Université de Sherbrooke, Sherbrooke, QC, Canada.
    Guay, Samuel
    Université de Montréal, Montréal, QC, Canada.
    Atay, Selim Melvin
    Neuroscience and Neurotechnology, Middle East Technical University, Ankara, Turkey.
    Varoquaux, Gael P
    Parietal, INRIA, Saclay, France; Montréal Neurological Institute, McGill University, Montréal, QC, Canada.
    Huijser, Dorien C
    Erasmus School of Social and Behavioural Sciences, Erasmus University Rotterdam, Rotterdam, the Netherlands; Developmental and Educational Psychology, Leiden University, Leiden, the Netherlands.
    Sandström, Malin S
    INCF, Karolinska Institute, Stockholm, Sweden.
    Herholz, Peer
    NeuroDataScience - ORIGAMI laboratory, Faculty of Medicine and Health Sciences McGill University Montréal, QC Canada.
    Nastase, Samuel A
    Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA.
    Badhwar, AmanPreet
    Centre de Recherche de lInstitut Universitaire de Gériatrie de Montréal, Université de Montréal, Montréal, QC, Canada; Multiomics Investigation of Neurodegenerative Diseases (MIND) Lab, Université de Montréal, Montréal, QC, Canada; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, QC, Canada.
    Dumas, Guillaume
    Department of Psychiatry, Université de Montréal, Montréal, QC, Canada; Mila, Université de Montréal, Montréal, QC, Canada.
    Schwab, Simon
    Department of Biostatistics & Center for Reproducible Research, University of Zurich, Zurich, Switzerland.
    Moia, Stefano
    Basque Center on Cognition, Brain and Language, San Sebastián-Donostia, Spain; University of the Basque Country (EHU UPV), San Sebastián-Donostia, Spain.
    Dayan, Michael
    Human Neuroscience Platform, Fondation Campus Biotech Geneva, Geneva, Switzerland.
    Bassil, Yasmine
    Graduate Division of Biological & Biomedical Sciences, Emory University, Atlanta, GA, USA.
    Brooks, Paula P
    Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA.
    Mancini, Matteo
    Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK; Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, UK; NeuroPoly Lab, Polytechnique Montréal, Montréal, QC, Canada.
    Shine, James M
    Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
    OConnor, David
    Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
    Xie, Xihe
    Department of Neuroscience, Weill Cornell Medicine, New York City, NY, USA.
    Poggiali, Davide
    Padova Neuroscience Center, University of Padova, Padova, Italy.
    Friedrich, Patrick
    Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany.
    Heinsfeld, Anibal S
    Computational Neuroimaging Lab, University of Texas at Austin, Austin, TX, USA; Department of Computer Science, University of Texas at Austin, Austin, TX, USA.
    Riedl, Lydia
    Department of Psychiatry and Psychotherapy, Philipps Universität, Marburg, Germany.
    Toro, Roberto
    Center for Research and Interdisciplinarity, Université of Paris, Paris, France; Neuroscience Department, Institut Pasteur, Paris, France.
    Caballero-Gaudes, César
    Basque Center on Cognition, Brain and Language, San Sebastián-Donostia, Spain.
    Eklund, Anders
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Department of Computer and Information Science, The Division of Statistics and Machine Learning. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Garner, Kelly G
    Queensland Brain Institute, The University of Queensland, St Lucia, Australia; School of Psychology, University of Birmingham, Birmingham, UK; School of Psychology, The University of Queensland, St Lucia, Australia.
    Nolan, Christopher R
    School of Psychology, University of New South Wales, Sydney, Australia.
    Demeter, Damion V
    Psychology Department, The University of Texas at Austin, Austin, TX, USA.
    Barrios, Fernando A
    Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico.
    Merchant, Junaid S
    Neuroscience and Cognitive Science Program, University of Maryland, College Park, MD, USA; Department of Psychology, University of Maryland, College Park, MD, USA.
    McDevitt, Elizabeth A
    Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA.
    Oostenveld, Robert
    Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands; NatMEG, Karolinska Institutet, Stockholm, Sweden.
    Craddock, R Cameron
    Department of Diagnostic Medicine, The University of Texas at Austin Dell Medical School, Austin, TX, USA.
    Rokem, Ariel
    Psychology and eScience Institute, University of Washington, Seattle, WA, USA.
    Doyle, Andrew
    McGill Centre for Integrative Neuroscience, McGill University, Montréal, QC, Canada.
    Ghosh, Satrajit S
    McGovern Institute for Brain Research, MIT, Cambridge, MA, USA; Department of Otolaryngology - Head and Neck Surgery, Harvard Medical School, Boston, MA, USA.
    Nikolaidis, Aki
    Center for the Developing Brain, Child Mind Institute, New York City, NY, USA.
    Stanley, Olivia W
    Centre for Functional and Metabolic Mapping, University of Western Ontario, London, ON, Canada; Department of Medical Biophysics, University of Western Ontario, London, ON, Canada.
    Uruñuela, Eneko
    Basque Center on Cognition, Brain and Language, San Sebastián-Donostia, Spain; University of the Basque Country (EHU UPV), San Sebastián-Donostia, Spain.
    Brainhack: Developing a culture of open, inclusive, community-driven neuroscience2021In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 109, no 11, p. 1769-1775Article in journal (Refereed)
    Abstract [en]

    Brainhack is an innovative meeting format that promotes scientific collaboration and education in an open, inclusive environment. This NeuroView describes the myriad benefits for participants and the research community and how Brainhacks complement conventional formats to augment scientific progress.

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  • 55.
    Geetha, Bandhumithra
    University of Skövde, School of Bioscience.
    The severity of human papillomavirus- 16/18 infection and its prevention to cervical cancer: A systematic review and meta-analysis2022Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Infectious diseases caused by human papillomavirus (HPV) are among the most common sexually transmitted diseases in the world. Currently, all countries of the WHO Eastern Mediterranean Region (EMRO) except the United Arab Emirates and Libya do not have a national vaccination program including the HPV vaccine. Cervical cancer risk can be reduced through the use of prophylactic HPV vaccines. Hence, the aim of this study was to examine the severity of HPV-16/18 infection in cervical cancer through a systematic review and to evaluate the effectiveness of vaccines against HPV-16/18 variants to prevent cervical cancer via a meta-analysis. Both the systematic review and meta-analysis contain nine relevant studies with 66154 and 78308 cervical cancer participants respectively. Statistical analyses were performed using pooled odds ratios (OR) with 95% confidence intervals (95% CI). Publication bias was examined using the funnel plot graph. The findings stated that overall 70% of cervical cancer was attributed to either HPV 16 or HPV 18. Heterogeneity for this meta-analysis was found to be I2= 80% with a p-value<0.01 and overall OR (odds ratio) was 0.09 (95% CI= 0.04-0.20) for the random effect model. The lower odds ratio (less than 1) indicated fewer occurrences of cervical cancer in the HPV 16/18 vaccinated group than in the unvaccinated individuals. The overall vaccination efficiency was found to be 91% from the odds ratio ((1-0.09)x100=91). Thus, the present findings support that a prophylactic vaccine against HPV16/18 prevents the severity of HPV-associated cervical cancer.

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  • 56.
    Ghareh Baghi, Ghareh Baghi
    Linköping University, Department of Biomedical Engineering. Linköping University, The Institute of Technology.
    Assessment of Valvular Aortic Stenosis by Signal Analysis of the Phonocardiogram2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aortic stenosis (AS) is one of the most prevalent valvular heart diseases in elderly people. According to the recommendations of both the American Heart Association and the European Society of Cardiology, severity assessment of AS is primarily based on echocardiographic findings. The experience of the investigator here play important roles in the accuracy of the assessment, and therefore in the disease management. However, access to the expert physicians could be limited, especially in rural health care centers of developing countries.

    This thesis aims to develop processing algorithms tailored for phonocardiographic signal with the intension to obtain a noninvasive diagnostic tool for AS assessment and severity grading. The algorithms employ a phonocardiogram as input signal and perform analysis for screening and diagnostics. Such a decision support system, which we call “the intelligent phonocardiography”, can be widely used in primary healthcare centers.

    The main contribution of the thesis is to present innovative models for the phonocardiographic analysis by taking the segmental characteristics of the signal into consideration. Three novel methodologies are described, based on the presented models, to perform robust classification. In the first attempt, a novel pattern recognition framework is presented for screening of AS-related murmurs. The framework offers a hybrid model for classifying cyclic time series in general, but is tailored to detect the murmurs as a special case study. The time growing neural network is another method that we use to classify short time signals with abrupt frequency transition. The idea of the growing frames is extended to the cyclic signals with stochastic properties for the screening purposes. Finally, a combined statistical and artificial intelligent classifier is proposed for grading the severity of AS.

    The study suggests comprehensive statistical validations not only for the evaluation and representation of systolic murmurs but also for setting the methodology design parameters, which can be considered as one of the significant features of the study. The resulting methodologies can be implemented by using web and mobile technologies to be utilized in distributed healthcare system.

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  • 57.
    Ghebresus, Awet Ambesaghir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Division for Clinical Pharmacology,Department of Laboratory Medicine, Karolinska Institutet .
    Pharmacodynamic, Pharmacokinetic and Pharmacogenetic Studies of Nandrolone Decanoate2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction: Nandrolone is one of the most abused androgenic anabolic steroid. Nandrolone is, inside the body, primarily metabolized into 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE). Nandrolone abuse has been shown to cause alterations in the lipid- and endocrine profile, also to induce endothelial dysfunction. The mechanisms behind the alterations in these endogenous substances are not known, but one might speculate that alteration in gene expression may partly play a role.

    Aim: To analyze how a single dose of nandrolone affect the oxidative stress, the cholesterol and endocrine profile in healthy volunteers, and to analyze the androgenic effect as determined by testosterone and LH/FS levels in relation to genetic variations, in order to increase the knowledge on nandrolone side effects in humans.

    Materials and Methods: Elevenhealthy subjects were included. Genotyping was done using TaqMan allelic discrimination method and quantitative PCR. Real-time PCR was conducted to quantify the gene expression of HMGCR and the SOD’s. The cholesterol profile and hormone levels were analyzed at the Division of Clinical Chemistry and the hematocrit profile were measured at the Anti-Doping Laboratory according to WADA’s technical document TD2014 BAR.

    Results: Several correlations between lipoproteins and hormones were found. The gene expression of HMGCR was induced but showed no correlation with other results. Significant alterations were found on the serum levels of LH, FSH, testosterone, total cholesterol, LDL, ApoB and SHBG. Association between UGT2B17 ins/del polymorphism and a slower decrease of serum testosterone showed significance. The hematocrit profile was not altered whereas an increase in lymphocyte count was noted.

    Conclusions: One single dose of nandrolone causes a perturbation in the blood lipid- and endocrine profile. Genetic polymorphism may partly affect the serum levels of testosterone post nandrolone administration.

  • 58.
    Ghiasvand, Mohammad
    University of Skövde, School of Bioscience.
    Bacterial cell detection limits using Oxford Nanopore’s MinION2022Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Sepsis is a potentially fatal emergency medical condition that reflects the presence of the body’s systematic inflammation. Around 260 biomarkers have been determined to sepsis. The gold standard of blood culturing has remained the best technique for finding sepsis etiology up to this data. However, some vital drawbacks, such as laboriousness, have encouraged a global attempt to find new techniques. This study aimed to optimize a method from which earlier sepsis diagnosis compared to the gold standard could be resulted. DNA was extracted from both spiked and non-spiked whole blood samples. After quality control of the DNA elutions, library preparation and nanopore sequencing using the MinION device were carried out. Basecalling and demultiplexing were done using Guppy GPU and barcoded FASTQ-files were analyzed using What’s-In-My-Pot and Kraken2 taxonomy classification programs. Three different DNA extraction methods were compared from which the second and third methods opted as the optimized methods. Although spiked species were not found in the used taxonomy classification databases, their respective families were spotted. Kraken2 program indicated a relationship between the read percentage of the families and the spiking level of initial blood samples. On the other hand, What’s-In-My-Pot did not show such a trend and only the highest spiking concentration had indicated the families within the reads. A possible justification for not finding the species within the reads is the patchiness of the two databases. Despite the failure in determining the species within FASTQ-files, the whole experiment has gathered valuable experiences for future studies.

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  • 59.
    Ghobadi, Bita
    University of Skövde, School of Bioscience.
    Suggestions for optimal biomarker miRNA extraction from plasma of sepsis patients2020Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Sepsis is a life-threatening organ disfunction, which is caused by a dysfunctional immuneresponse and develops when an infection overwhelms the body’s defense mechanism and causesand uncontrolled inflammatory response. Biomarkers have a great impact on helping diagnosisand treatments of sepsis. The biomarkers, like miRNA, are needed for both more accurate andquicker diagnosis of sepsis in patients. The future diagnostics are looking at other types ofbiomarkers, e.g. miRNA, but low amounts of miRNA are present in biofluids and make itchallenging to quantify. A new methodology is needed which is both accurate and does notrequire a lot of fluid. The aim of this project was to identify which kit of two kits and which oftwo volumes of plasma would lead to the highest concentration of miRNA and highest quality ofmiRNA extracted. This was quantified by using two different volumes, 100 μl and 200 μl, andextracting the two volumes with both exoRNeasy Serum/Plasma midi kit (Qiagen) and TotalRNA Purification kit (Norgen). There was no statistical difference between median miRNAconcentrations between the two volumes within the Qiagen kit. However, the mean miRNAconcentration (0.833 ng/μl) obtained from the Norgen kit (100 μl plasma starting volume) wasstatistically higher than the mean miRNA concentration (0.570 ng/μl) obtained from the samekit with 200 μl, p = 0.033. The optimal kit and volume of this study is the Norgen kit with 100 μl.Further studies are needed to verify these results.

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  • 60.
    Groenewald, Lourens
    University of Skövde, School of Bioscience.
    Manual and robotic RNA extraction from human plasma with absolute quantification of miRNA through two-tailed RT-qPCR as part of research into early diagnosis of sepsis2022Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Each hour´s delay in administering antibiotics has been shown to result in a 9% increase in the odds of mortality in sepsis cases. It is thus evident that the development of a diagnostic method that ensures an early time to diagnosis of sepsis is essential. MiRNAs have shown promise with regards to diagnostic capabilities concerning sepsis, with differential expression of circulatory miRNAs seen during various diseased states. MiRNA can be quantified directly from a blood plasma sample, greatly decreasing the time to diagnosis, as the requirement for culturing is eliminated. Quantification of miRNA by means of qPCR has proven rather challenging, due to their short length. A solution might be two-tailed RT-qPCR, a method which utilizes a two-tailed RT primer. The aim of the project was to optimize the extraction and quantification of miRNAs from minimal amounts of human blood plasma samples, as to create a standardized and reproduceable method for measuring biomarker miRNAs within human blood plasma. In this study, a significant difference between manual and semi-automated extraction of miRNA from plasma with regards to A260/A280 ratios (p = 0.00) was observed. It was also found that a correlation exists between A260/A280 ratios and miR-seps6 quantified, using the two-tailed RT-qPCR method. This method has shown to be effective at amplifying circulating miR-seps6 arising from 100 µL of human blood plasma. A linear standard curve, constructed from synthetic miR-seps 6 produced optimal amplification efficiencies, and the melt curve indicated a single product, which correlates with good specificity. As successful detection and amplification of miR-seps 6 had been achieved during this study, the next phase of the project can be initiated, where it will be attempted to detect miR-seps 6 from plasma stored in a human biological material bank (biobank). 

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  • 61.
    Halan Söderberg, Jessica
    University of Skövde, School of Bioscience.
    The GSK-3 inhibitor has no effect on production of IL-1β in LPS- and Nigericin-stimulated THP-1 macrophages2022Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Inflammation is the body's natural defense reaction and is known since ancient times. The inflammation is divided into two main phases, acute and chronic inflammation dependent on the process and cellular mechanisms of the inflammation. Inflammation has become to be an important field in research by biomedical research where it is included in many cellular processes thus being phagocytosis, chemotaxis, mitosis, and cell differentiation. Inflammasomes are pro-inflammatory intracellular multimeric protein complexes that introduce the activation of pro-inflammatory cytokines, such as interleukin-1β and interleukin-18, upon trigger by PAMPs and DAMPs signals. The most studied inflammasome is the NLRP3 inflammasome that is activated by various trigger signals, like DAMPs, ATP, uric acid crystals and amyloid-β fibrils. GSK-3β is a kinase that controls various cellular processes, such as inflammation by regulating the activity of abundant transcription factors that are valuable for cytokine production. The aim of this thesis project was to investigate if GSK-3 Inhibitor IV, SB-216763, in a concentration-dependent manner had an effect on production of IL-1β in LPS- and Nigericin-stimulated THP-1 ASC-GFP-macrophages. In addition to the gene expression analysis of IL-1β, the amount of secreted IL-1β, and the possible correlation between treated THP-1 cells with and without GSK-3 inhibitor evaluated. The gene expression analysis was performed by using qPCR and the amount of secreted IL-1β was done using sandwich enzyme-linked immunosorbent assay. The results from this study showed no significant difference in gene expression and amount secreted of IL-1β in THP-1 cells when treated with the GSK-3 Inhibitor IV, SB-216763. 

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  • 62.
    Halin Bergström, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rudolfsson, Stina H.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rat Prostate Tumor Cells Progress in the Bone Microenvironment to a Highly Aggressive Phenotype2016In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 18, no 3, p. 152-161Article in journal (Refereed)
    Abstract [en]

    Prostate cancer generally metastasizes to bone, and most patients have tumor cells in their bone marrow already at diagnosis. Tumor cells at the metastatic site may therefore progress in parallel with those in the primary tumor. Androgen deprivation therapy is often the first-line treatment for clinically detectable prostate cancer bone metastases. Although the treatment is effective, most metastases progress to a castration-resistant and lethal state. To examine metastatic progression in the bone microenvironment, we implanted androgen-sensitive, androgen receptor-positive, and relatively slow-growing Dunning G (G) rat prostate tumor cells into the tibial bone marrow of fully immune-competent Copenhagen rats. We show that tumor establishment in the bone marrow was reduced compared with the prostate, and whereas androgen deprivation did not affect tumor establishment or growth in the bone, this was markedly reduced in the prostate. Moreover, we found that, with time, G tumor cells in the bone microenvironment progress to a more aggressive phenotype with increased growth rate, reduced androgen sensitivity, and increased metastatic capacity. Tumor cells in the bone marrow encounter lower androgen levels and a higher degree of hypoxia than at the primary site, which may cause high selective pressures and eventually contribute to the development of a new and highly aggressive tumor cell phenotype. It is therefore important to specifically study progression in bone metastases. This tumor model could be used to increase our understanding of how tumor cells adapt in the bone microenvironment and may subsequently improve therapy strategies for prostate metastases in bone.

  • 63.
    Hassano, Ragad
    University of Skövde, School of Bioscience.
    GSK-3 and ROS (reactive oxygen species) inhibition modulate Vimentin expression2022Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    When exposed to pathogenic stress, cellular processes and survival are dependent on cytoskeletal proteins for structure and organisation of the cell to adapt and maintain homeostasis during inflammation. Vimentin is type III cytoskeletal protein, with an extensive cytoplasmic meshwork, across the cell and regulate the cell structure and cellular space and expressed strongly under tumorigenic events. GSK-3, a regulatory component of inflammation expressed in abundance of cell together with reactive oxygen species (ROS), a group of key complex signalling molecules that are oxygen metabolites which are partially reduced, with robust oxidising abilities, are believed to influence inflammasome formation and specifically vimentin expression upon inflammation. This project investigated the potential modulation vimentin mRNA expression utilising the two signal NLRP3 inflammasome activation theory, by inhibiting GSK-3 and ROS in signal I and or signal II in LPS and nigericin stimulated THP-1 cells, compared to non-inhibited LPS and nigericin THP-1 cells. Inhibition of GSK-3 in signal II downregulated vimentin expression, reflecting repressed phosphorylation of GSK-3 hence also the components required for vimentin; whilst upregulation of vimentin in signal I, reflects possible alternative pathways phosphorylating vimentin components. Overall upregulation of vimentin upon inhibiting ROS in both signal I and II, further proved that inflammasome activation is independent of ROS in the priming step. More research is required integrating vimentin activity and either GSK-3 or ROS, as the potential of these prominent inflammatory markers and their major regulatory presence across an abundance of cell may contribute to the future of drug development for inflammatory diseases.  

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  • 64.
    Hassen, Umaimah
    University of Skövde, School of Bioscience.
    The effect of GSK-3 inhibitor SB216763 on the expression and secretion of IL-8 in THP-1 ASC GFP macrophages cells2022Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Inflammation is a part of the innate immune system. It protects the body against foreign invaders such as bacteria and viruses. Inflammation helps to restore the body by removing harmful stimuli and starting the healing process. Inflammation is produced in response to damage-associated molecular patterns (DAMPS) or pathogen-associated molecular patterns (PAMPS). Glycogen synthase kinase 3 (GSK-3) is a key regulator of a variety of pathways, making it a promising therapeutic target. Therefore, this experiment aims to see how inhibiting GSK-3 affects the generation of IL-8 in THP-1 ASC GFP macrophage cells. For this study qPCR was used to measure IL-8 expression, while ELISA was used for protein secretion. An ANOVA test was utilized for the statistical analysis. Obtained results from this study showed that there is a significant difference between stimulated cells with LPS and nigericin against unstimulated samples both in protein and mRNA levels. When it comes to the stimulated cells against inhibited cells, the ANOVA test showed there is no significant difference between the samples both in protein and mRNA levels. This might suggest that GSK-3 does not influence the development of inflammasomes in THP-1 macrophage cells. Another possible reason is that other pathways such as the MAPK and JAK-STAT may mask potential inhibitory effects on the NLRP3 inflammasome pathway by producing even more IL-8, which interfered with qPCR and ELISA results. In conclusion, additional research is needed to confirm the involvement of GSK-3 in NLRP3 inflammation. 

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  • 65.
    Hedberg, Carina
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Kyhlstedt, Madeleine
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Samvarierar frukostfrekvens och betyg?: En kvantitativ studie om sambandet mellan frukostfrekvens och betyg hos gymnasieelever på samhälls- och naturvetenskapliga programmen2008Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpStudent thesis
    Abstract [sv]

    Sammanfattning

    Syfte och frågeställningar

    Syftet med denna studie var att undersöka om det hos gymnasieelever på samhälls- och naturvetenskapliga programmen finns ett samband mellan frukostfrekvens och prestation mätt i betyg. För att kunna uppnå syftet användes följande frågeställningar:

    • Finns det en korrelation mellan frukostfrekvens och betyg (betyg mäts i medelpoäng för svenska, engelska, matematik och samhällskunskap)?

    • Kan potentiella confounders förklara detta eventuella samband?

    Metod

    Den undersökta populationen bestod av 238 gymnasieelever i åldrarna 15-19 år. 122 av dessa var flickor och 116 var pojkar. På tre valda gymnasieskolor i Stockholms län gjordes ett riktat slumpmässigt urval bland eleverna. Studien byggde på självrapporterad data som inhämtades genom en enkät. Vi ställde frågor om exempelvis kroppsstorlek, frukostfrekvens, betyg, föräldrarnas postgymnasiala studienivå, studietid utanför lektionstid och boendeform.

    Resultat

    Könsfördelningen var jämn – 51,3 % var flickor och 48,7 % var pojkar. För båda könen gällde att drygt två tredjedelar åt frukost samtliga veckans skoldagar. Anmärkningsvärt är att en av tio flickor aldrig åt frukost under en skolvecka. En stor andel elever hade betyget MVG och särskilt utmärkande var flickornas betyg i engelska där hela tre fjärdedelar hade det högsta betyget. Gällande programmen var både antalet elever och kön relativt jämnt fördelade. Medianmedelpoängen utifrån de fyra betygen i matematik, svenska, engelska och samhällskunskap var för flickor 17,5 (sd 2,5) och för pojkar 16,8 (sd 2,7). Det fanns en positiv korrelation (Spearman’s) mellan frukostfrekvens och medianmedelpoäng. För att ta hänsyn till möjliga confounders gjordes en logistisk regression. Av de oberoende variablerna visade sig endast frukostfrekvens och vilket program eleven gick vara signifikanta prediktorer för medelpoängen. Således hade de som åt frukost bättre betyg än de som inte gjorde det och de som gick naturvetenskapliga programmet hade bättre betyg än de som gick samhälls-vetenskapliga programmet. 20 % av variationen i medelpoäng förklaras alltså av de två variablerna frukostfrekvens och gymnasieprogram.

    Slutsats

    Slutsatsen är att det finns ett positivt samband mellan frukostfrekvens och prestation mätt i betyg. Även efter kontroll för confounders var denna korrelation signifikant. Även vilket gymnasieprogram eleven studerade korrelerade med medelpoäng.

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  • 66.
    Hedhammar, My
    et al.
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Rising, Anna
    Widhe, Mona
    Jansson, Ronnie
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Nordling, Kerstin
    Askarieh, Glareh
    Knight, Stefan
    Johansson, Jan
    Spider silk proteins: Recombinant production, structure-function relationships and biomedical applications2010Conference paper (Refereed)
  • 67.
    Hedhammar, My
    et al.
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Widhe, Mona
    Jansson, Ronnie
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Johansson, Ulrika
    Nordling, Kerstin
    Rising, Anna
    Johansson, Jan
    Spider Silk Proteins: Recombinant Production, Structure-Function Relationships and Biomedical Applications2011Conference paper (Refereed)
  • 68.
    Henriksson, Richard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Backman, Cristina M
    Harvey, Brandon K
    Kadyrova, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Shippenberg, Toni S
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain2014In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1839, no 11, p. 1226-1232Article in journal (Refereed)
    Abstract [en]

    The dynorphin kappa-opioid receptor system is implicated in mental health and brain/mental disorders. However, despite accumulating evidence that PDYN and/or dynorphin peptide expression is altered in the brain of individuals with brain/mental disorders, little is known about transcriptional control of PDYN in humans. In the present study, we show that PDYN is targeted by the transcription factor REST in human neuroblastoma SH-SY5Y cells and that that interfering with REST activity increases PDYN expression in these cells. We also show that REST binding to PDYN is reduced in the adult human brain compared to SH-SY5Y cells, which coincides with higher PDYN expression. This may be related to MIR-9 mediated down-regulation of REST as suggested by a strong inverse correlation between REST and MIR-9 expression. Our results suggest that REST represses PDYN expression in SH-SY5Y cells and the adult human brain and may have implications for mental health and brain/mental disorders.

  • 69.
    Herrera Hernandez, Ana Guadalupe
    University of Skövde, School of Bioscience.
    Detection of Sclerotinia sclerotiorum in oilseed rape using Oxford Nanopore sequencing and qPCR2023Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Sclerotinia sclerotiorum is a notorious phytopathogenic fungus and is the causal agent of the disease Sclerotinia stem rot (SSR) of rapeseed (Brassica napus). SSR is one of the main diseases affecting the yield and oil quality of rapeseed crops worldwide. This disease is very hard to predict and control due to all the different factors that are involved in the development of the disease. Successful disease management depends on accurate identification and early detection of plant pathogens. qPCR is a fast, specific, reproducible, and reliable technique for plant pathogen diagnostics. However, one limitation of qPCR is that it is unsuitable to identify and study unknown species, other than those intended, making the detection of unknown pathogens very difficult. An alternative solution is to apply single molecule sequencing, which can provide information at species and strain level. In this study, a total sample of 15 rapeseed leaves coming from three different fields in Sweden with known incidence of SSR disease were analyzed using qPCR and other 15 leaves, coming from the same fields, were analyzed using Oxford Nanopore sequencing to attempt to identify pathogens, S. sclerotiorum being the main target. S. sclerotiorum was not identified with none of the previous mentioned techniques in any of the samples. Perhaps, S. sclerotiorum was not present on the samples at the time of the collection, due to the unfavorable weather conditions for the release of the spores. However, some issues were present during the development of the qPCR assays that also could have affected the results. Regarding Oxford Nanopore sequencing, other fungal species were identified instead.

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  • 70.
    Hil Kafi, Abdulla
    University of Skövde, School of Bioscience.
    Effect of cardiovascular diseases on the severity of patients with renal failure2023Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Chronic kidney disease greatly raises cardiovascular disease risk. Heart disease and death risk grow proportionately with renal disease progression. Investigate the link between cardiovascular disease prevalence and chronic renal disease severity and mortality using meta-analysis. In this study, 155 publications were found after searching several databases (including PubMed and Google Scholar). 48 studies that matched the inclusion criteria were included in the literature review, however, only 20 were included in the meta-analysis. 17101 people had CKD, while 8883 had CVD or non-CVD. Using the R programming language, a meta-analysis was performed to get a pooled impact of the influence of CVD on the severity of CKD (odds ratio OR), and a funnel plot was also generated to check for publication bias. The outcomes of the meta-analysis indicate that cardiovascular disease has a moderate impact on the severity of chronic kidney disease (OR=2.28, 95% CI, 1.90-2.73). All data will give essential insights into the epidemiology of the cardiovascular disease in chronic kidney disease (CKD), disclose the influence of individual risk variables on bad outcomes, and serve as the platform for future interventional research. Further investigation of the particular (non-traditional) risk factors associated with the renal illness that contribute to accelerated atherosclerosis in this population is necessary to improve the efficacy of cardiovascular treatments for patients with CKD. The purpose of this research is to determine whether and how these variables affect the development of CKD.

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  • 71.
    Hirche, Elin
    University of Skövde, School of Bioscience.
    AM I FUNNY NOW?: The Neurological Basis of Humor Styles2019Independent thesis Basic level (degree of Bachelor), 15 credits / 22,5 HE creditsStudent thesis
    Abstract [en]

    The present thesis will provide an overview of how the four humor styles, affiliative, self-enhancing, aggressive, and self-defeating humor, are connected to different brain areas. The thesis will also include an overview of how humor in general, and especially three factors of humor including, processing, appreciation, and comprehension is connected to different brain areas. The present study found a connection between these three factors of humor and activation in the prefrontal cortex (PFC) and inferior frontal gyrus (IFG). The four humor styles were all connected to activity in the midbrain and nucleus accumbens (NAc), though they were found to differ in other parts of the brain. Affiliative humor and self-enhancing humor are humor styles found to share activation of similar brain areas, whereas self-enhancing and aggressive humor was found to the least extent share activation of the same brain areas. No neural differences in relation to the four humor styles have been found between men and woman, or between cultures.

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  • 72.
    Huoman, Johanna
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Univ Hosp Bonn, Germany.
    Sayyab, Shumaila
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Apostolou, Eirini
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Lovisa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Porcile, Lucas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Rizwan, Muhammad
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Sharma, Sumit
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Das, Jyotirmoy
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Rosén, Anders
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lerm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Epigenetic rewiring of pathways related to odour perception in immune cells exposed to SARS-CoV-2 in vivo and in vitro2022In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 17, no 13, p. 1875-1891Article in journal (Refereed)
    Abstract [en]

    A majority of SARS-CoV-2 recoverees develop only mild-to-moderate symptoms, while some remain completely asymptomatic. Although viruses, including SARS-CoV-2, may evade host immune responses by epigenetic mechanisms including DNA methylation, little is known about whether these modifications are important in defence against and healthy recovery from COVID-19 in the host. To this end, epigenome-wide DNA methylation patterns from COVID-19 convalescents were compared to uninfected controls from before and after the pandemic. Peripheral blood mononuclear cell (PBMC) DNA was extracted from uninfected controls, COVID-19 convalescents, and symptom-free individuals with SARS-CoV-2-specific T cell-responses, as well as from PBMCs stimulated in vitro with SARS-CoV-2. Subsequently, the Illumina MethylationEPIC 850K array was performed, and statistical/bioinformatic analyses comprised differential DNA methylation, pathway over-representation, and module identification analyses. Differential DNA methylation patterns distinguished COVID-19 convalescents from uninfected controls, with similar results in an experimental SARS-CoV-2 infection model. A SARS-CoV-2-induced module was identified in vivo, comprising 66 genes of which six (TP53, INS, HSPA4, SP1, ESR1, and FAS) were present in corresponding in vitro analyses. Over-representation analyses revealed involvement in Wnt, muscarinic acetylcholine receptor signalling, and gonadotropin-releasing hormone receptor pathways. Furthermore, numerous differentially methylated and network genes from both settings interacted with the SARS-CoV-2 interactome. Altered DNA methylation patterns of COVID-19 convalescents suggest recovery from mild-to-moderate SARS-CoV-2 infection leaves longstanding epigenetic traces. Both in vitro and in vivo exposure caused epigenetic modulation of pathways thataffect odour perception. Future studies should determine whether this reflects host-induced protective antiviral defense or targeted viral hijacking to evade host defence.

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  • 73.
    Hysing, Tommy
    Örebro University, Department of Clinical Medicine.
    Uppföljning av TSH`s beslutsgränser för analys av TPO-antikroppar2006Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Mätning av autoantikroppar mot tyreoperoxidas (TPO) är en

    viktig del för att diagnostisera autoimmun tyreoideafunktions rubbning. Hos det stora flertalet som har en autoimmun tyreoidea sjukdom hittar man TPO-antikroppar. Vid hypotyreos är det av betydelse att se om det finns TPO-antikroppar för att påvisa eller utesluta autoimmunitet som orsak till hypotyreosen.

    Ett problem är att det inte finns något allmänt accepterat referensintervall för TPO-antikroppar. I Sverige varierar det mellan 2 och 60 kIU/l beroende på vilken mätmetod som används.

    Syftet med denna undersökning är att se hur vanligt det är med förhöjda värden för tyreoidea stimulerande hormon (TSH) och hur fördelningen av antikroppar för tyreoidea peroxidas (TPO-antikroppar) ser ut vid normala och subnormala TSH-värden.

    De serumprover som ingick i undersökningen analyserades med en fluoroimmunoassay teknik på instrumentet AutoDELFIAÔ , Perkin-Elmer. Proverna valdes slumpmässigt från de rutinprover som kommer till laboratoriet.

    Mellan 8 – 13 % av de undersökta patientproverna har en lätt förhöjning (4,3 – 6,0 mIU/l) av TSH-värdena. Totalt för alla värden mer än 4,3 mIU/l är 15 %.

    Kvinnor har en högre andel av TPO-antikroppar jämfört med män vilket andra undersökningar också visat.

    Referensintervallet, < 35 kIU/l, för TPO-antikroppar är relevant gentemot frågeställningen. I den undersökta populationen är det ett prov som hamnar utanför detta intervall.

    44 % hade förhöjda värden på TPO-antikroppar vid måttligt förhöjda TSH värden, detta indikerar att analys av TPO-antikroppar bör göras när TSH visar värden > 4,3 mIU/l.

    Den metodjämförelse som gjordes mellan fluoroimmunoassay och kemiluminiscens visar på dålig korrelation.

    Denna undersökning är en pilotstudie för att kunna gå vidare med frågeställningar som

    - kan man korrigera på något sätt för de olikheter som uppenbarligen finns mellan de olika mätmetoderna

    - kan man ta bort spädningssteget i fluoroimmunoassay-metoden för att därigenom kunna sänka referensgränsen

  • 74.
    Isoz, Isabelle
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Role of yeast DNA polymerase epsilon during DNA replication2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Each cell division, the nuclear DNA must be replicated efficiently and with high accuracy to avoid mutations which can have an effect on cell function. There are three replicative DNA polymerases essential for the synthesis of DNA during replication in eukaryotic cells. DNA polymerase α (Pol α) synthesize short primers required for DNA polymerase δ (Pol δ) and DNA polymerase ε (Pol ε) to carry out the bulk synthesis. The role of Pol δ and Pol ε at the replication fork has been unclear. The aim of this thesis was to examine what role Pol ε has at the replication fork, compare the biochemical properties of Pol δ and Pol ε, and to study the function of the second largest and essential subunit of Pol ε, Dpb2.

    To identify where Pol ε replicates DNA in vivo, a strategy was taken where the active site of Pol ε was altered to create a mutator polymerase leaving a unique error-signature. A series of mutant pol ε proteins were purified and analyzed for enzyme activity and fidelity of DNA synthesis. Two mutants, M644F and M644G, exhibited an increased mutation rate and close to normal polymerase activity. One of these, the M644G gave rise to a specific increase of mismatch mutations resulting from T-dTMP mis-pairing during DNA synthesis in vitro. The M644G mutant was introduced in yeast strains carrying a reporter gene, URA3, on either side of an origin in different orientations. Mutations which inactivated the URA3 gene in the M644G mutant strains were analyzed. A strand specific signature was found demonstrating that Pol ε participates in the synthesis of the leading strand.

    Pol δ and Pol ε are both stimulated by the processivity clamp, PCNA, in in vitro replication assays. To clarify any differences they were challenged side by side in biochemical assays. Pol ε was found to require that single-stranded template (ssDNA) was entirely coated with RPA, whereas Pol δ was much less sensitive to uncoated ssDNA. The processivity of Pol δ was stimulated to a much higher degree by PCNA than of Pol ε. In presence of PCNA the processivity of Pol δ and Pol ε was comparable. In contrast, Pol ε was approximately four times slower than Pol δ when replicating a single-primed circular template in the presence of all accessory proteins and an excess of polymerase. The biochemical characterization of the system suggests that Pol ε and Pol δ are loaded onto the PCNA-primer-ternary complex by separate mechanisms. A model is proposed where the loading of Pol ε onto the leading strand is independent of the PCNA interaction motif which is required by enzymes acting on the lagging strand.

    The essential gene DPB2 encodes for the second largest subunit of Pol ε. We carried out a genetic screen in S.cerevisiae and isolated a lethal mutant allele of dpb2 (dpb2-200). When over-expressed together with the remaining three subunits of Polε, Pol2, Dpb3 and Dpb4, the dpb2-201 did not copurify. The biochemical property of Pol2/Dpb3/Dpb4 complex was compared with wild-type four-subunit Pol ε (Pol2/Dpb2/Dpb3/Dpb4) and a Pol2/Dpb2 complex in replication assays. The absence of Dpb2 in the complex did not significantly affect the specific activity or the processivity, but gave a slightly reduced efficiency in holoenzyme assays when compared to wild-type four-subunit Pol ε. We propose that Dpb2 is not essential for the enzyme activity of Pol ε.

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  • 75. Jacobsen, M
    et al.
    Kracht, SS
    Esteso, G
    Cirera, S
    Edfors, Inger
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Archibald, AL
    Bendixen, C
    Anderson, L
    Fredholm, M
    Jorgensen, CB
    Refined candidate region specified by haplotype sharing for Escherichia coli F4ab/F4ac susceptibility alleles in pigs.2010In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 41, p. 21-25Article in journal (Refereed)
    Abstract [en]

    P>Infection of the small intestine by enterotoxigenic Escherichia coli F4ab/ac is a major welfare problem and financial burden for the pig industry. Natural resistance to this infection is inherited as a Mendelian recessive trait, and a polymorphism in the MUC4 gene segregating for susceptibility/resistance is presently used in a selection programme by the Danish pig breeding industry. To elucidate the genetic background involved in E. coli F4ab/ac susceptibility in pigs, a detailed haplotype map of the porcine candidate region was established. This region covers approximately 3.7 Mb. The material used for the study is a three generation family, where the founders are two Wild boars and eight Large White sows. All pigs have been phenotyped for susceptibility to F4ab/ac using an adhesion assay. Their haplotypes are known from segregation analysis using flanking markers. By a targeted approach, the candidate region was subjected to screening for polymorphisms, mainly focusing on intronic sequences. A total of 18 genes were partially sequenced, and polymorphisms were identified in GP5, CENTB2, APOD, PCYT1A, OSTalpha, ZDHHC19, TFRC, ACK1, MUC4, MUC20, KIAA0226, LRCH3 and MUC13. Overall, 227 polymorphisms were discovered in the founder generation. The analysis revealed a large haplotype block, spanning at least 1.5 Mb around MUC4, to be associated with F4ab/ac susceptibility.

  • 76.
    Janardanan, Sruthy
    University of Skövde, School of Bioscience.
    Explorative bioinformatic analysis of cardiomyocytes in 2D &3D in vitro culture system2021Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The in vitro cell culture models of human pluripotent stem cells (hPSC)-derived cardiomyocytes (CMs) have gained a predominant value in the field of drug discovery and is considered an attractive tool for cardiovascular disease modellings. However, despite several reports of different protocols for the hPSC-differentiation into CMs, the development of an efficient, controlled and reproducible 3D differentiation remains challenging. The main aim of this research study was to understand the changes in the gene expression as an impact of spatial orientation ofhPSC-derived CMs in 2D(two-dimensional) and 3D(three-dimensional) culture conditions and to identify the topologically important Hub and Hub-Bottleneck proteins using centrality measures to gain new knowledge for standardizing the pre-clinical models for the regeneration of CMs. The above-mentioned aim was achieved through an extensive bioinformatic analysis on the list of differentially expressed genes (DEGs) identified from RNA-sequencing (RNA-Seq). Functional annotation analysis of the DEGs from both 2D and 3D was performed using Cytoscape plug-in ClueGO. Followed by the topological analysis of the protein-protein interaction network (PPIN) using two centrality parameters; Degree and Betweeness in Cytoscape plug-in CenTiScaPe. The results obtained revealed that compared to 2D, DEGs in 3D are primarily associated with cell signalling suggesting the interaction between cells as an impact of the 3D microenvironment and topological analysis revealed 32 and 39 proteins as Hub and Hub-Bottleneck proteins, respectively in 3D indicating the possibility of utilizing those identified genes and their corresponding proteins as cardiac disease biomarkers in future by further research.

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  • 77.
    Jansson, Ronnie
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Att göra spindeltråd utan spindlar2011Conference paper (Other (popular science, discussion, etc.))
  • 78.
    Jansson, Ronnie
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Konstgjord spindeltråd ― igår, idag och imorgon2011Conference paper (Other (popular science, discussion, etc.))
  • 79.
    Jansson, Ronnie
    et al.
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Johansson, Ulrika
    Widhe, Mona
    Rising, Anna
    Nygren, Per-Åke
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Johansson, Jan
    Hedhammar, My
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Recombinant spider silk with IgG-binding capacity used for cell capture2012Conference paper (Refereed)
  • 80.
    Jansson, Ronnie
    et al.
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Thatikonda, Naresh
    Nygren, Per-Åke
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Hedhammar, My
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Recombinant Affinity Silk for Presentation of Active Protein Domains2014Conference paper (Refereed)
  • 81.
    Jansson, Ronnie
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Thatikonda, Naresh
    Nygren, Per-Åke
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Wingren, Christer
    Hedhammar, My
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Towards the use of Bioactive Spider Silk in Affinity-Based Assays2017Conference paper (Other academic)
  • 82.
    Jegefalk, Annelie
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Csiffary, Thomas
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Ökat kreatinintag = Ökad kraft: en träningsstudie om kreatinets prestationshöjande effekt och korrelationen mellan styrkeökning och kreatinupptag.2007Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpStudent thesis
    Abstract [sv]

    Sammanfattning

    Syfte och frågeställningar

    Syftet med studien var att undersöka kreatinets prestationshöjande effekt på styrka efter en sex dagars kreatinuppladdning samt undersöka om en korrelation mellan kreatinupptag och styrkeförändring förelåg. Frågeställningar var:

    Hur skiljer sig den statiska styrkan i biceps efter en sex dagar lång kreatinuppladdning?

    Hur skiljer sig den dynamiska styrkan i bänkpress efter en sex dagar lång kreatinuppladdning?

    Finns det någon korrelation mellan förändring av styrka och upptag av kreatin?

    Metod

    Studien genomfördes på 22 fysiskt aktiva friska svenska män och kvinnor (13 män, 9 kvinnor) som delades in i antingen en kreatingrupp (n=12) eller en kontrollgrupp (n=10). Båda grupperna genomförde tre testtillfällen (T1, T2, T3) där T1 syftades till att mäta upp deras 1RM. Vid T2 och T3 mättes deltagarnas statiska styrka i biceps (höger och vänster) samt deras dynamiska styrka i bänkpress. Mellan T2 och T3 gavs kreatingruppen 20 gram kreatin om dagen uppdelat vid 4 olika tillfällen i 6 dagar. En 24-timmars urininsamling genomfördes på samtliga deltagare i kreatingruppen under den andra dagen på kreatinuppladdningen för att mäta deras kreatinupptag.

    Resultat

    Kreatingruppens medelökning i bicepsövningen motsvarade som lägst 2,08 sekunder och som högst 9,33 sekunder där den största ökningen skedde under set 1 för höger arm. I den dynamiska bänkpressen visade kreatingruppen en ökning motsvarande 3,41 repetitioner. Inga signifikanta höjningar sågs för kontrollgruppen under något av seten. Inga korrelationer mellan kreatinupptag och styrkeförändring kunde påvisas i studien.

    Slutsats

    Resultaten från föreliggande studie indikerar på att ett oralt kreatinintag på 20 (4 tillfällen á 5 gram) gram kreatin om dagen i 6 dagar ger en förhöjd isometrisk prestation i biceps under tre set med 60 sekunders vila (p<0,05 under fem av sex set). Intaget tycks även resultera i en medelökning på 3,41 utförda repetitioner under det första setet i en dynamisk bänkpress (67 % av 1RM som belastning). Dessa resultat bör emellertid beskådas kritiskt sedan studien inte använde sig av något placebopreparat, vilket kan ha inneburit att en placeboeffekt förelåg.

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  • 83.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Byström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Davidson, Alice E.
    UCL Institute of Ophthalmology, London, UK.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kellgren, Therese
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Tuft, Stephen J.
    UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK.
    Koskela, Timo
    Koskelas Eye Clinic, Umeå, Sweden.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Hardcastle, Alison J.
    UCL Institute of Ophthalmology, London, UK.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 4, p. 463-473Article in journal (Refereed)
    Abstract [en]

    Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.

  • 84. Kagera, Irene
    et al.
    Kahenya, Peter
    Mutua, Florence
    Anyango, Gladys
    Kyallo, Florence
    Grace, Delia
    Lindahl, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Status of aflatoxin contamination in cow milk produced in smallholder dairy farms in urban and peri-urban areas of Nairobi County: a case study of Kasarani sub county, Kenya.2019In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 9, no 1, article id 1547095Article in journal (Refereed)
    Abstract [en]

    Introduction: Milk consumption in Kenya supersedes other countries in East Africa. However, milk contamination with aflatoxin M1 (AFM1) is common, but the magnitude of this exposure and the health risks are poorly understood and need to be monitored routinely. This study aimed at assessing the awareness, knowledge and practices of urban and peri-urban farmers about aflatoxins and determining the levels of aflatoxin contamination in on-farm milk in a selected area within Nairobi County. Materials and methods: A cross-sectional study was undertaken to assess aflatoxin contamination levels of milk in Kasarani sub-county. A total of 84 milk samples were collected from small-holder dairy farms and analyzed for AFM1 using Enzyme-Linked Immunosorbent Assay (ELISA). Results and Discussion: Ninety nine percent of the samples (83/84) analysed were contaminated with AFM1. The mean aflatoxin level was 84 ng/kg with 64% of the samples exceeding the EU legal limit of 50 ng/kg. Whereas 80% of the farmers were aware of aflatoxin, there was no correlation between farmers' knowledge and gender with AFM1 prevalence. Conclusion: This study concludes that AFM1 is a frequent contaminant in milk and there is need to enhance farmers awareness on mitigation.

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  • 85.
    Karlsson, Andréa
    University of Skövde, School of Bioscience.
    A novel assay for the detection of Hepatitis C virus in blood plasma, using padlock probes and rolling circle amplification2023Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Hepatitis C viral infection is a globally widespread blood-borne disease affecting the liver, causing cirrhosis and hepatocellular carcinoma. This type of liver cancer is mainly caused by chronic Hepatitis C and Hepatitis B. Specific detection with the following correct treatment is crucial to reduce the overall burden of the disease. This work focused on investigating whether the padlock probes and rolling circle amplification can detect Hepatitis C, determining the limit of detection, and if any blood components would inhibit the reactions. All oligonucleotides were tested for ligation functionality in 10% TBE-Ureal gel electrophoresis and used with rolling circle amplification and phi29 polymerase to determine if eye read-out was possible. The lowest concentration of detection was found to be 10 pM. To avoid inhibition in blood plasma, samples were pre-treated at 95 ˚C for five minutes. Eye read-out was possible after amplification, with 30% plasma at the highest and 5% plasma at the lowest in samples. In conclusion, this novel assay using padlock probes, a detection oligonucleotide, and rolling circle amplification holds promise in developing a simplified new detection technique for the diagnostics of Hepatitis C.

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  • 86.
    Khalaf, Hazem
    et al.
    Örebro University, School of Medical Sciences.
    Palm, Eleonor
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Cellular Response Mechanisms in Porphyromonas gingivalis Infection2017In: Periodontitis: A Useful Reference / [ed] Pachiappan Arjunan, InTech, 2017, p. 45-68Chapter in book (Refereed)
    Abstract [en]

    The pathogenicity of the periodontal biofilm is highly dependent on a few key species, of which Porphyromonas gingivalis is considered to be one of the most important pathogens. P. gingivalis expresses a broad range of virulence factors, of these cysteine proteases (gingipains) are of special importance both for the bacterial survival/proliferation and for the pathological outcome. Several cell types, for example, epithelial cells, endothelial cells, dendritic cells, osteoblasts, and fibroblasts, reside in the periodontium and are part of the innate host response, as well as platelets, neutrophils, lymphocytes, and monocytes/macrophages. These cells recognize and respond to P. gingivalis and its components through pattern recognition receptors (PRRs), for example, Toll-like receptors and protease-activated receptors. Ligation of PRRs induces downstream-signaling pathways modifying the activity of transcription factors that regulates the expression of genes linked to inflammation. This is followed by the release of inflammatory mediators, for example, cytokines and reactive oxygen species. Periodontal disease is today considered to play a significant role in various systemic conditions such as cardiovascular disease (CVD). The mechanisms by which P. gingivalis and its virulence factors interact with host immune cells and contribute to the pathogenesis of periodontitis and CVD are far from completely understood.

  • 87.
    Kjellman, Simon
    University of Skövde, School of Bioscience.
    16S Nanopore sequencing of Lactobacillus spp. in Apis mellifera, and investigation of their bacteriocin activity2022Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Apis mellifera is the most common honeybee species in the world. In recent years, there have been several reports of declines in wild, and domesticated populations. Central to honeybee health are the mutualistic relationships they have with their intestinal microbiome. The Lactobacillus species living in their digestive tract assist with nutrient digestion and pathogen protection. The aim of this study was to investigate which Lactobacillus spp. were present in the intestines of subspecies A. mellifera mellifera, and A. mellifera ligustica, and if they were able to inhibit growth of the pathogen Melissococcus plutonius. The 16S rRNA gene was amplified from gDNA extracted from two complete intestines per sample, in a PCR reaction with barcoded primers. Fragments were then analyzed with nanopore sequencing. In vitro assays of catalase-treated cell-free supernatants from Lactobacillus cultures were set up against living cultures of M. plutonius on KBHI agar plates and liquid broth media, in two experiments. The same seven Lactobacillus species previously found in honeybees were confirmed to be present in the bees of this study. The ratio of species was different between individual samples, which supports earlier findings suggesting the variation is dependent on factors such as individual health, food source, and sampling season. Liquid broth in vitro assay resulted in no inhibition of early growth phase, while the last cell count measure at24 h, recorded statistically significant difference in mean values between A. apinorum and negative control (p<0.001). Further research is needed to investigate optimum conditions for inhibition.

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  • 88.
    Klütsch, Cornelya
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Seppälä, E. H.
    Fall, T.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Gene Technology.
    Hedhammar, Å.
    Lohi, H.
    Savolainen, Peter
    KTH, School of Biotechnology (BIO), Gene Technology.
    Regional occurrence, high frequency but low diversity of mitochondrial DNA haplogroup d1 suggests a recent dog-wolf hybridization in Scandinavia2011In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 42, no 1, p. 100-103Article in journal (Refereed)
    Abstract [en]

    P>The domestic dog mitochondrial DNA (mtDNA)-gene pool consists of a homogenous mix of haplogroups shared among all populations worldwide, indicating that the dog originated at a single time and place. However, one small haplogroup, subclade d1, found among North Scandinavian/Finnish spitz breeds at frequencies above 30%, has a clearly separate origin. We studied the genetic and geographical diversity for this phylogenetic group to investigate where and when it originated and whether through independent domestication of wolf or dog-wolf crossbreeding. We analysed 582 bp of the mtDNA control region for 514 dogs of breeds earlier shown to harbour d1 and possibly related northern spitz breeds. Subclade d1 occurred almost exclusively among Swedish/Finnish Sami reindeer-herding spitzes and some Swedish/Norwegian hunting spitzes, at a frequency of mostly 60-100%. Genetic diversity was low, with only four haplotypes: a central, most frequent, one surrounded by two haplotypes differing by an indel and one differing by a substitution. The substitution was found in a single lineage, as a heteroplasmic mix with the central haplotype. The data indicate that subclade d1 originated in northern Scandinavia, at most 480-3000 years ago and through dog-wolf crossbreeding rather than a separate domestication event. The high frequency of d1 suggests that the dog-wolf hybrid phenotype had a selective advantage.

  • 89. Kyro, Cecilie
    et al.
    Olsen, Anja
    Bueno-de-Mesquita, H. B(as).
    Skeie, Guri
    Loft, Steffen
    Aman, Per
    Leenders, Max
    Dik, Vincent K.
    Siersema, Peter D.
    Pischon, Tobias
    Christensen, Jane
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Cottet, Vanessa
    Kuehn, Tilman
    Chang-Claude, Jenny
    Boeing, Heiner
    Trichopoulou, Antonia
    Naska, Androniki
    Oikonomidou, Despoina
    Masala, Giovanna
    Pala, Valeria
    Tumino, Rosario
    Vineis, Paolo
    Mattiello, Amalia
    Peeters, Petra H.
    Bakken, Toril
    Weiderpass, Elisabete
    Asli, Lene Angell
    Sanchez, Soledad
    Jakszyn, Paula
    Sanchez, Maria-Jose
    Amiano, Pilar
    Maria Huerta, Jose
    Barricarte, Aurelio
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Travis, Ruth C.
    Slimani, Nadia
    Freisling, Heinz
    Ferrari, Pietro
    Gunter, Marc J.
    Murphy, Neil
    Riboli, Elio
    Tjonneland, Anne
    Landberg, Rikard
    Plasma alkylresorcinol concentrations, biomarkers of whole-grain wheat and rye intake, in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2014In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 111, no 10, p. 1881-1890Article in journal (Refereed)
    Abstract [en]

    Whole-grain intake has been reported to be associated with a lower risk of several lifestyle-related diseases such as type 2 diabetes, CVD and some types of cancers. As measurement errors in self-reported whole-grain intake assessments can be substantial, dietary biomarkers are relevant to be used as complementary tools for dietary intake assessment. Alkylresorcinols (AR) are phenolic lipids found almost exclusively in whole-grain wheat and rye products among the commonly consumed foods and are considered as valid biomarkers of the intake of these products. In the present study, we analysed the plasma concentrations of five AR homologues in 2845 participants from ten European countries from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition. High concentrations of plasma total AR were found in participants from Scandinavia and Central Europe and lower concentrations in those from the Mediterranean countries. The geometric mean plasma total AR concentrations were between 35 and 41nmol/l in samples drawn from fasting participants in the Central European and Scandinavian countries and below 23nmol/l in those of participants from the Mediterranean countries. The whole-grain source (wheat or rye) could be determined using the ratio of two of the homologues. The main source was wheat in Greece, Italy, the Netherlands and the UK, whereas rye was also consumed in considerable amounts in Germany, Denmark and Sweden. The present study demonstrates a considerable variation in the plasma concentrations of total AR and concentrations of AR homologues across ten European countries, reflecting both quantitative and qualitative differences in the intake of whole-grain wheat and rye.

  • 90.
    Källebring, Tina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    THE EXPRESSION OF THROMBOMODULIN, TISSUE FACTOR, TISSUE FACTOR PATHWAY INHIBITOR AND ENDOTHELIAL PROTEIN C RECEPTOR IN NORMAL AND IUGR PLACENTA2005Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The aim of this study was to examine the expression of Thrombomodulin, Tissue Factor, Tissue Factor Pathway Inhibitor and Endothelial Protein C Receptor in placenta throughout the three phases of the third trimester in the normal placenta and in IUGR placenta from full term.

    Twenty-five normal placenta samples and twenty-five IUGR placenta samples were obtained and each sample was stained by immunohistochemistry using monoclonal antibodies. Each antibody was optimised for antigen retrieval method and for optimal dilution, before been applied to the test tissue.

    The results showed that each of the antibodies mentioned was expressed in normal placenta and in IUGR placenta.

    No significant difference could be established concerning the expression of each antibody mentioned between normal and IUGR placenta.

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  • 91.
    Lee, Francis
    Linköping University, Department of Thematic Studies, Technology and Social Change. Linköping University, Faculty of Arts and Sciences.
    Purity and interest: on relational work and epistemic value in the biomedical sciences2015In: Value Practices in the Life Sciences and Medicine / [ed] Isabelle Dussauge, Claes-Fredrik Helgesson, Francis Lee, Oxford: Oxford University Press, 2015, p. 207-223Chapter in book (Refereed)
  • 92. Lindqvist, Breezy M.
    et al.
    Wingren, Sten
    Motlagh, Parviz Behnam
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Whole genome DNA methylation signature of HER2-positive breast cancer2014In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, no 8, p. 1149-1162Article in journal (Refereed)
    Abstract [en]

    In order to obtain a comprehensive DNA methylation signature of HER2-positive breast cancer (HER2+ breast cancer), we performed a genome-wide methylation analysis on 17 HER2+ breast cancer and compared with ten normal breast tissue samples using the Illumina Infinium HumanMethylation450 BeadChip (450K). In HER2+ breast cancer, we found altered DNA methylation in genes involved in multicellular development, differentiation and transcription. Within these genes, we observed an overrepresentation of homeobox family genes, including several genes that have not been previously reported in relation to cancer (DBX1, NKX2-6, SIX6). Other affected genes included several belonging to the PI3K and Wnt signaling pathways. Notably, HER2, AKT3, HK1, and PFKP, genes for which altered methylation has not been previously reported, were also identified in this analysis. In total, we report 69 candidate biomarker genes with maximum differential methylation in HER2+ breast cancer. External validation of gene expression in a selected group of these genes (n = 13) revealed lowered mean gene expression in HER2+ breast cancer. We analyzed DNA methylation in six top candidate genes (AKR1B1, INA, FOXC2, NEUROD1, CDKL2, IRF4) using EpiTect Methyl II Custom PCR Array and confirmed the 450K array findings. Future clinical studies focusing on these genes, as well as on homeobox-containing genes and HER2, AKT3, HK1, and PFKP, are warranted which could provide further insights into the biology of HER2+ breast cancer.

  • 93.
    Ling, Agnes
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Immune cell infiltration and prognosis in colorectal cancer2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Colorectal cancer (CRC) is globally the second most common form of cancer among women, and third in men. It is also one of the most common causes of cancer-related death in high-income countries. Surgical resection is the basis for curative therapy but still almost half of the patients die from metastatic disease. It is therefore imperative to strive on in the search for more efficient strategies to improve patient survival. The success scores for accurate prediction of patient prognosis remain discouraging and novel markers to identify high-risk patients are called for.

    The tumour immune response has proven critical to prognosis in CRC. A high amount of tumour infiltrating lymphocytes have in studies been found to significantly improve patient outcome. The opposite has been seen in patients with sparsely infiltrated tumours. Findings in this area have driven forth the design of the Immunoscore® system, which may be implemented in clinic as a complement to the TNM staging system. Ongoing research is also focusing on which immune evading mechanisms CRC might deploy in order to progress and metastasize.

    Aim: To study immune cell infiltration in relation to prognosis in CRC. More specifically the aim has been to investigate the prognostic importance of different subsets of immune cells infiltrating the tumour, not only according to quantity but also to intratumoural subsite (tumour invasive front, tumour centre and within the tumour epithelium). The tumour immune response was also evaluated in different molecular subgroups of CRC. Another part of this thesis concerns possible molecular mechanisms involved in tumour immune escape in CRC.

    Methods: CRC cases in the Colorectal Cancer in Umeå Study (CRUMS) were evaluated using immunohistochemistry, gene expression analyses as well as methylation analyses. Cytokine and chemokine expression was evaluated in CRC tumour tissues and one CRC cell line (Caco2) and derivatives using semi-quantitative real-time PCR. Methylation was analysed using methylation-specific pyrosequencing.

    Results: We found high quantities of both cytotoxic T cells (CTLs) as well as of regulatory T cells (Tregs) to associate with a better patient outcome. The infiltration of CTLs within the tumour epithelium provided the strongest prognostic information, whilst Tregs withheld the strongest association to prognosis at the tumour invasive front and tumour centre. We could further show that a high Th1 lymphocyte infiltration was strongly associated with a better prognosis in patients with CRC, independently of intratumoural subsite. Another finding was that the extent of Th1 infiltration and patient outcome differed in different molecular subgroups of CRC. We also found down-regulation of TAP1, a protein involved in antigen presentation by MHC class I, to be significantly associated with low infiltration of various subtypes of immune cells. Down-regulation of TAP1 was also correlated to poor prognosis in patients with early stages of CRC. Furthermore, we found TAP1 expression to be inversely correlated with methylation at sites close to the TAP1 promoter region.

    Conclusion: Tumour infiltrating T lymphocytes have a significant positive impact on prognosis in CRC patients. Different subsets of T lymphocytes vary in their dependency on intratumoural subsite, in to what extent they exert their prognostic influence. We moreover found varying Th1 lymphocyte infiltration rates as well as prognostic impact thereof, in different molecular subgroups of CRC. Our results also show down-regulation of TAP1 to be a mechanism of tumour immune escape in CRC. Further findings suggest methylation of the TAP1 gene to be a putative mechanism for TAP1 down-regulation.

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  • 94.
    Lundholm, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. anders.bergh@umu.se.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 15651Article in journal (Refereed)
    Abstract [en]

    Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2(+)) and immunosuppressive M2 macrophages (CD163(+)) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies.

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  • 95.
    Lundin, Desiré
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Do the new signal transduction modulators have activity in vitro in tumor cells from ovarian carcinoma and lymphoma?2005Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    During the last decades, chemotherapy with cytotoxic drugs has played a significant role in cancer therapy. It’s important to develop new anticancer drugs, and drug sensitivity testing in vitro can be used to find the right diagnosis for the newly developed substances.

    The aim of this study was to investigate the cytotoxic activity of the new signal transduction modulators bortezomib, gefitinib and PKC412. The well-established substances cisplatin, cytarabine, doxorubicin and vincristin were investigated for comparison.

    The activity of the cytotoxic drugs was analysed in human tumor samples from patients with ovarian carcinoma (n=16) and lymphoma (n=15) by using the Fluorometric Microculture Cytotoxicity Assay (FMCA). The testing of cellular drug resistance by FMCA was accomplished successfully in 33 out of the 34 samples (97%).

    The results of this study indicated that the activity of cytotoxic drugs in tumor cells obtained from patients with ovarian carcinoma and lymphoma may be detected by the FMCA. It also suggested that bortezomib and gefitinib could represent promising agents for treatment of ovarian carcinoma and that PKC412 might be of less use for patients with this diagnose.

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  • 96.
    Lönn, Johanna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. PEAS Institute, Linköping, Sweden.
    Shahzad, Faisal
    PEAS Institute, Linköping, Sweden.
    Uhlin, Fredrik
    Department of Nephrology UHL, County Council of Östergötland, Linköping, Sweden; Department of Medicine and Health Science, Faculty of Health Science, Linköping University, Linköping, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Almroth, Gabriel
    Department of Nephrology UHL, County Council of Östergötland, Department of Medicine and Health Science, Faculty of Health Science, Linköping University, Linköping, Sweden.
    Nayeri, Fariba
    PEAS Institute, Linköping, Sweden; Department of Molecular and Clinical Medicine, Division of Infectious Diseases, University Hospital, Linköping, Sweden.
    High concentration but low biological activity of hepatocyte growth factor in patients with chronic renal failure2012In: Advances in Bioscience and Biotechnology, ISSN 2156-8456, E-ISSN 2156-8502, Vol. 3, no 4, p. 516-523Article in journal (Refereed)
    Abstract [en]

    Hepatocyte growth factor (HGF) is a renotropic, antifibrotic and regenerative factor with cytoprotective effects that is produced by mesenchymal cells and shows high affinity to components of extra cellular matrix, such as heparan sulphate proteoglycan (HS-PG), in healthy. Patients with chronic renal failure (CRF) suffer from a chronic inflammatory disorder. In order to assess the underlying mechanisms for development of CRF we aimed to assess the amounts and affinity of HGF in this patient group. Elisa, western blot and surface plasmon resonance (SPR) were used to study HGF in blood samples, as well as in isolated neutrophils, in CRF patients compared to healthy controls. Patients with CRF showed higher HGF levels in serum (P < 0.0001), but decreased affinity to HSPG (P < 0.0001), compared to healthy controls. Addition of protease inhibitors decreased the difference between patients with CRF compared to healthy individuals. HGF with potent regenerative function during injury lacks affinity to HSPG in patients with CRF that may depend on production of proteases from activated immune cells. This information might be used to highlight underlying mechanisms for chronicity and leading to new strategies for treatment of chronic injuries.

  • 97.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Studies for Better Treatment of Patients with Glioma2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In Sweden annually over 500 people will be diagnosed with the malignant brain tumor glioma. They are graded from I-IV. The majority are glioblastoma (grade IV) (GBM), these being the most aggressive type. Median survival for those treated with standard of care is expected to be around 15 months. This tumor will mainly affect those 60 years or older.

    The studies in this thesis focus on treatment of patients with malignant gliomas grade III and IV. The aim of the studies is to improve the care of glioma patients. Papers I and II explored different therapeutic options in randomized trials, to facilitate individualized treatment recommendations. Findings from studies I and II, together with additional trials, demonstrated the importance of analyzing the tumor marker O6-methylguanine DNA methyltransferase (MGMT) methylation status for survival of GBM patients treated with Temozolomide (TMZ). The third paper investigated how the analysis of this marker is implemented internationally.

    The first study (paper I, Nordic trial) investigated treatment options for patients 60 years or older with GBM. The trial compared standard radiotherapy (SRT) over 6 weeks versus hypofractionated radiotherapy (HRT) over 2 weeks versus single agent TMZ administered in up to six 4 weekly cycles. In all, 342 patients were included in the trial. This study demonstrated that those randomized to TMZ had superior survival as compared to SRT. In addition, quality of life (QoL) data also suggested a better QoL for TMZ treatment than for radiotherapy. The benefit of TMZ treatment seemed to be limited to those with the tumor molecular marker MGMT methylated (inactivated).

    The second trial (paper II, Neoadjuvant trial) studied whether integrating TMZ treatment with SRT for patients younger than 60 years with GBM (grade IV) and astrocytoma grade III would confer a survival benefit, if administered postoperatively, before the start of SRT (neoadjuvant). TMZ was provided for 2-3 four weekly cycles followed by SRT to patients randomized to neoadjuvant treatment and was compared to postoperative SRT alone. Although this trial could not illustrate any advantage of delaying the start of SRT while administering TMZ for the study cohort in general, for those included as astrocytoma grade III the median survival was found to be superior by 5 years when randomized to neoadjuvant TMZ. This trial also confirmed the importance of MGMT promoter methylation for the efficacy of TMZ.

    The third study (paper III) investigated international practices for analyzing tumor MGMT promoter methylation status. MGMT analysis can be conducted by various laboratory methods, which in some cases can provide opposing results regarding the MGMT methylation status of the patient´s tumor. This can lead to incorrect treatment recommendations. To establish which methods and cut-offs that are regularly used to determine tumor MGMT status in the clinic, an international survey was provided to those working in the field. We also inquired about opinions regarding an international consensus on how MGMT should be tested. The 152 respondents reported several methodologies and different cut-off levels also for the same method. A majority of respondents warrant international guidelines.

    In conclusion, the results of the 2 randomized trials contribute to individualized treatment recommendations for patients affected by GBM or astrocytoma grade III. The results of the survey regarding analyses of MGMT clarify the current problematic situation. The request of the respondents regarding international guidelines might contribute to their future development, so that personalized treatment recommendations can be improved.

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  • 98.
    Malmström, Annika
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Närvårdskliniken.
    Lysiak, Malgorzata
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Winther Kristensen, Bjarne
    Department of Pathology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Denmark.
    Hovey, Elizabeth
    Department of Medical Oncology, Nelune Comprehensive Cancer Centre, Prince of Wales Hospital , Randwick, Sydney, NSW, Australia University of New South Wales , Sydney, Australia.
    Henriksson, Roger
    Department of Radiation Sciences, University of Umeå , Sweden.
    Söderkvist, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Do we really know who has an MGMT methylated glioma?: Results of an international survey regarding use of MGMT analyses for glioma2020In: Neuro-Oncology Practice, ISSN 2054-2577, E-ISSN 2054-2585, Vol. 7, no 1, p. 68-76Article in journal (Refereed)
    Abstract [en]

    Glioma O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status informs clinical decision making. Worldwide different methods and cutoff levels are used, which can lead to discordant methylation results.We conducted an international survey to clarify which methods are regularly used and why. We also explored opinions regarding international consensus on methods and cutoff.The survey had 152 respondents from 25 countries. MGMT methylation status is determined for all glioblastomas in 37% of laboratories. The most common methods are methylation-specific polymerase chain reaction (msPCR) (37%) and pyrosequencing (34%). A method is selected for simplicity (56%), cost-effectiveness (50%), and reproducibility of results (52%). For sequencing, the number of CpG sites analyzed varies from 1–3 up to more than 16. For 50% of laboratories, the company producing the kit determines which CpG sites are examined, whereas 33% select the sites themselves. Selection of cutoff is equally distributed among a cutoff defined in the literature, by the local laboratory, or by the outside laboratory performing the analysis. This cutoff varies, reported from 1% to 30%, and in 1 laboratory tumor is determined as methylated in case of 1 methylated CpG site of 17 analyzed. Some report tumors as unmethylated or weakly vs highly methylated. An international consensus on MGMT methylation method and cutoff is warranted by 66% and 76% of respondents, respectively. The method preferred would be msPCR (45%) or pyrosequencing (42%), whereas 18% suggest next-generation sequencing.Although analysis of MGMT methylation status is routine, there is controversy regarding laboratory methods and cutoff level. Most respondents favor development of international consensus guidelines.

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    Do we really know who has an MGMT methylated glioma?: Results of an international survey regarding use of MGMT analyses for glioma
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  • 99. Marincevic-Zuniga, Yanara
    et al.
    Zachariadis, Vasilios
    Cavelier, Lucia
    Castor, Anders
    Barbany, Gisela
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Fogelstrand, Linda
    Heyman, Mats
    Abrahamsson, Jonas
    Lonnerholm, Gudmar
    Nordgren, Ann
    Syvanen, Ann-Christine
    Nordlund, Jessica
    PAX5-ESRRB is a recurrent fusion gene in B-cell precursor pediatric acute lymphoblastic leukemia2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 1, p. E20-E23Article in journal (Refereed)
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  • 100.
    Marinkovic, Lucija
    University of Skövde, School of Bioscience.
    Extraction of miR-223 from human blood plasma and quantification using the two-tailed RT-qPCR and absolute quantification2021Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Sepsis is a very dangerous and life-threatening disease that develops when the body’s reaction to infection causes damage to the body’s tissues and organs. It is difficult to diagnose it and it develops fast leading to a high mortality rate. Current methods rely on blood culturing and multiple biomarkers, such as C-reactive protein and procalcitonin, that take too long to produce results. A possible solution to this problem lies in specific biomarkers such as microRNAs, which are small non-coding single stranded RNA molecules that contain around 22 nucleotides and have a big role in regulating gene expression. Being specific biomarkers for particular disease makes microRNAs promising biomarkers for sepsis. The aim of the project was to optimize the process from extraction to quantification of microRNAs using the miRNeasy Serum/Plasma Advanced Kit-Qiagen Kit (manual) and to see if the Two-tailed RT-qPCR (TATAA Biocenter) technique could quantify the samples. Blood plasma from healthy donors was used for microRNA extractions and was separated into two categories- spiked-in samples and non-spiked samples. Spiked-in samples were spiked with a synthetic microRNA- miR-223 and served as a positive control. All samples were quantified using the absolute quantification and the Two-tailed RT-qPCR method (TATAA Biocenter). Quantification was successful for all samples showing that the method was optimized, parameters for optimization were within the wanted range, and quantifiable. More research is needed, however, the method has potential in becoming a simple and quick novel tool in diagnosing sepsis in the early stages and thus saving lives.

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