T cell Function in Patients with Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by dilatation of one or both ventricles together with decreased systolic function. Its etiology is still largely unknown. However, immunological alterations such as the presence of autoantibodies, elevated cytokines in plasma, and viral genomes in the myocardium have been frequently reported. The aim of this thesis was to examine T cell function in patients with DCM. First, cytokines in plasma were measured. In accordance with previous reports, plasma cytokines of TNF-alfa, IL-6, IL-10, and CRP were significantly elevated in patients with heart failure. Incorporating an etiology of DCM or ischemic heart disease together with clinical variables in a multivariate analysis, a diagnosis of DCM was found to be independently associated with lower IL-10 levels. Next, specific CD4+ T cell response, accumulated cytokines in supernatant, and lymphocyte proliferation were measured using flow cytometry-based methods following culture of isolated peripheral blood mononuclear cells, and stimulation with Staphylococcus enterotoxin B or phytohaemagglutinin. The frequency of IFN-gamma-producing CD4+ (Th1) cells was significantly lower in patients than in healthy controls. In contrast, no difference was found in the number of IL-4-producing CD4+ (Th2) cells. In addition, IL-10 production in the supernatant and lymphocyte proliferation were both significantly lower in patients. To conclude, these impairments of IFN-gamma and IL-10 are both consistent with an increased susceptibility to chronic infections and autoimmunity. Finally, we investigated the frequency of a single nucleotide polymorphism in the IFN-gamma gene, which alter the transcription level. We found a significant association between the IFN-gamma polymorphism and susceptibility to DCM. This previously unreported finding could be the first diagnostic marker of a DCM of autoimmune etiology. In its entirety, this thesis supports the concept that DCM is a late sequela of myocarditis leading to a disease of autoimmune character

Behavioral profiling of SLC38A10 knockout mice using the multivariate concentric square field™ test

Introduction: SLC38A10 is a gene that encodes the SLC38A10 protein, also known as SNAT10. The SLC38 family is evolutionary old, and SLC38A10 is one of the oldest members of the family. It is ubiquitously expressed, and its substrates are glutamine, glutamate, alanine, aspartate, and serine. However, little is known about its biological importance.Methods: In the current study, an SLC38A10 knockout mouse was run in the multivariate concentric square fieldTM (MCSF) test. The MCSF test gives the mouse a choice of areas to explore; sheltered areas, elevated and illuminated areas, or open spaces, and a behavioral profile is obtained. The multivariate data obtained were analyzed (i) for each parameter, (ii) parameters grouped into functional categories, and (iii) with a principal component analysis.Results: In the trend analysis, knockout mice had a decreased exploratory behavior compared to controls but did not show a distinct grouping in the principal component analysis.Discussion: There was not a pronounced difference in the behavioral profile in SLC38A10 knockout mice compared to their wild-type controls, although subtle alterations in zones associated with exploratory behavior and risk assessment in female and male knockout mice, respectively, could be observed. These results imply that a loss of function of the SLC38A10 protein in mice does not drastically alter behavior in the MSCF test

Cooperative regulation of extracellular signal-regulated kinase activation and cell shape change by filamin A and beta-arrestins.: FLNA AND ßarr COOPERATE TO REGULATE ERK AND CELL SHAPE

14 pagesbeta-Arrestins (betaarr) are multifunctional adaptor proteins that can act as scaffolds for G protein-coupled receptor activation of mitogen-activated protein kinases (MAPK). Here, we identify the actin-binding and scaffolding protein filamin A (FLNA) as a betaarr-binding partner using Son of sevenless recruitment system screening, a classical yeast two-hybrid system, coimmunoprecipitation analyses, and direct binding in vitro. In FLNA, the betaarr-binding site involves tandem repeat 22 in the carboxyl terminus. betaarr binds FLNA through both its N- and C-terminal domains, indicating the presence of multiple binding sites. We demonstrate that betaarr and FLNA act cooperatively to activate the MAPK extracellular signal-regulated kinase (ERK) downstream of activated muscarinic M1 (M1MR) and angiotensin II type 1a (AT1AR) receptors and provide experimental evidence indicating that this phenomenon is due to the facilitation of betaarr-ERK2 complex formation by FLNA. In Hep2 cells, stimulation of M1MR or AT1AR results in the colocalization of receptor, betaarr, FLNA, and active ERK in membrane ruffles. Reduction of endogenous levels of betaarr or FLNA and a catalytically inactive dominant negative MEK1, which prevents ERK activation, inhibit membrane ruffle formation, indicating the functional requirement for betaarr, FLNA, and active ERK in this process. Our results indicate that betaarr and FLNA cooperate to regulate ERK activation and actin cytoskeleton reorganization

Exposure to arsenic in drinking water is associated with increased prevalence of diabetes: a cross-sectional study in the Zimapán and Lagunera regions in Mexico

<p>Abstract</p> <p>Background</p> <p>Human exposures to inorganic arsenic (iAs) have been linked to an increased risk of diabetes mellitus. Recent laboratory studies showed that methylated trivalent metabolites of iAs may play key roles in the diabetogenic effects of iAs. Our study examined associations between chronic exposure to iAs in drinking water, metabolism of iAs, and prevalence of diabetes in arsenicosis-endemic areas of Mexico.</p> <p>Methods</p> <p>We used fasting blood glucose (FBG), fasting plasma insulin (FPI), oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), and insulin resistance (HOMA-IR) to characterize diabetic individuals. Arsenic levels in drinking water and urine were determined to estimate exposure to iAs. Urinary concentrations of iAs and its trivalent and pentavalent methylated metabolites were measured to assess iAs metabolism. Associations between diabetes and iAs exposure or urinary metabolites of iAs were estimated by logistic regression with adjustment for age, sex, hypertension and obesity.</p> <p>Results</p> <p>The prevalence of diabetes was positively associated with iAs in drinking water (OR 1.13 per 10 ppb, p < 0.01) and with the concentration of dimethylarsinite (DMAs^III) in urine (OR 1.24 per inter-quartile range, p = 0.05). Notably, FPI and HOMA-IR were negatively associated with iAs exposure (β -2.08 and -1.64, respectively, p < 0.01), suggesting that the mechanisms of iAs-induced diabetes differ from those underlying type-2 diabetes, which is typically characterized by insulin resistance.</p> <p>Conclusions</p> <p>Our study confirms a previously reported, but frequently questioned, association between exposure to iAs and diabetes, and is the first to link the risk of diabetes to the production of one of the most toxic metabolites of iAs, DMAs^III.</p

The Human Melanoma Proteome Atlas—Complementing the melanoma transcriptome

The MM500 meta‐study aims to establish a knowledge basis of the tumor proteome to serve as a complement to genome and transcriptome studies. Somatic mutations and their effect on the transcriptome have been extensively characterized in melanoma. However, the effects of these genetic changes on the proteomic landscape and the impact on cellular processes in melanoma remain poorly understood. In this study, the quantitative mass‐spectrometry‐based proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. The melanoma proteome landscape, obtained by the analysis of 505 well‐annotated melanoma tumor samples, is defined based on almost 16 000 proteins, including mutated proteoforms of driver genes. More than 50 million MS/MS spectra were analyzed, resulting in approximately 13,6 million peptide spectrum matches (PSMs). Altogether 13 176 protein‐coding genes, represented by 366 172 peptides, in addition to 52 000 phosphorylation sites, and 4 400 acetylation sites were successfully annotated. This data covers 65% and 74% of the predicted and identified human proteome, respectively. A high degree of correlation (Pearson, up to 0.54) with the melanoma transcriptome of the TCGA repository, with an overlap of 12 751 gene products, was found. Mapping of the expressed proteins with quantitation, spatiotemporal localization, mutations, splice isoforms, and PTM variants was proven not to be predicted by genome sequencing alone. The melanoma tumor molecular map was complemented by analysis of blood protein expression, including data on proteins regulated after immunotherapy. By adding these key proteomic pillars, the MM500 study expands the knowledge on melanoma disease

Han Kang’s The Vegetarian in direct and indirect translation : Korean to English, English to Swedish

In 2016, South Korean author Han Kang’s The Vegetarian, translated into English by Deborah Smith, was awarded the Man Booker International Prize. Following the success, South Korean critics brought to attention mistakes and inaccuracies of Deborah Smith’s work, heavily criticizing her translation, but also bringing the debate of liberal and literal translation from the academic sphere to the public eye. In Sweden, the book was translated from Deborah Smith’s English into Swedish by Eva Johansson and published under the title Vegetarianen in January 2017. This thesis uses a comparative qualitative method to investigate how Han’s novel is changed through the process of translation and indirect translation by the hands of Smith and Johansson, as well as if Smith’s translation changes through the process of working with the text. With Smith’s very liberal method of translation, her translation occasionally results in significant change of tone, atmosphere and characterization. Mistakes make it clear she did not have a sufficient comprehension of Korean, however she can be seen growing more comfortable with the language by the end of the novel. Johansson stays very loyal to Smith’s English translation due to Swedish and English being more similar languages in structure and literary tradition, she is also a very experienced translator. Despite Smith’s flawed translation, The Vegetarian has been a huge success. The author hopes that more research will be done in the areas of Korean-English translation and indirect translation from Korean, in order to further identify struggles of translators of Korean and advance Korean literature in translation.2016 prisades Sydkoreanska författaren Han Kangs The Vegetarian, översatt till engelska av Deborah Smith, med Man Booker International Prize. Följande succén bringade Sydkoreanska kritiker uppmärksamhet till misstag och oriktigheter i Deborah Smiths översättning och kritiserade den hårt, men tog också debatten om fri och exakt översättning till allmänhetens ögon. I Sverige översattes boken till svenska från Deborah Smiths engelska av Eva Johansson och släpptes under titelnVegetarianeni januari 2017. Denna uppsats använder en komparativ kvalitativ metod för att undersöka hur Hans novell förändrats under processen av direkt och indirekt översättning av Smith och Johansson, och om Smiths översättning förändrats under hennes arbete med novellen. Genom Smiths väldigt fria metod av översättning resulterar översättningen stundtals i utmärkande förändringar i ton, atmosfär och karaktärisering. Misstag gör det uppenbart att hon inte hade tillräckliga färdigheter i det koreanska språket, dock ses hon bli mer bekväm med språket i slutet av novellen. Johannson är väldigt lojal till Smiths engelska översättning då svenska och engelska är betydligt mer liknande språk i struktur och litterär tradition. Hon är också en väldigt erfaren översättare. Trots Smiths bristfällande översättning har The Vegetarianblivit en ringande succé. Författaren av denna uppsats hoppas att mer undersökning kommer att göras i området koreansk-engelsk översättning och indirekt översättning från koreanska för att ytterligare identifiera de problem som översättare av koreanska stöter på och för att avancera översatt koreansk litteratur.

Staphylococcus aureus in the infantile bowel flora

The increasingly hygienic life-style in Western societies may not only have reduced infections, but may also have altered the composition of the commensal microflora, which may, in turn, have predisposed to e.g. allergy development. Here we investigated the first year s intestinal colonization pattern of a Swedish birth-cohort. Rectal swabs obtained at 3 days of age were cultured for aerobic bacteria and faecal samples obtained at 1, 2, 4 and 8 weeks and at 6 and 12 months of age were cultivated quantitatively for aerobic and anaerobic bacteria. When studying the overall colonization pattern we found that staphylococci have taken over as the first intestinal colonizer and that colonization with foremost Gram-negative bacteria has declined. When studying colonization pattern in relation to delivery mode we found that vaginally delivered infants were significantly more often colonized by E. coli during the first half year while sectio-delivered infants instead more often harbored other enterobacteria during the first weeks. Bacteroides colonization was delayed up to one year of age in sectio-delivered infants. We regard the findings as a result of reduced spread of some prototype faecal bacteria in the Swedish society today. In the absence of such traditional faecal bacteria skin bacteria like staphylococci, have have had increased chances to expand in the infantile intestinal microflora. Approxiamtely 80% of the Swedish infants studied harbored S. aureus at some time-point during the first year with a peak between two and six motnhs of age. Using the PCR-based method random amplified polymorphic DNA, RADP, we found that most infants carried a single strain that persisted several months in the microflora. Half of the infants were colonized with a S. aureus strain producing one or more superantigens (enterotoxin A-D and/or toxic shock syndrome toxin-1, TSST-1). Such colonization did not result in any overt clinical signs and it is not known whether the toxins are produced in situ in the gastrointestinal tract. Most of the S. aureus strains colonizing the infantile bowel derived from the skin flora of the parents. In almost all cases infant and parent(s) harbored the same strain. For comparison, intestinal colonization with S. aureus was studied in a cohort of 100 Italian infants. They were significantly less often colonized by S. aureus in their intestines than Swedish infants. Investigating which life-style factors predisposed to S. aureus colonization; we found that exclusive breast-feeding and having older sibling correlated positively with S. aureus colonization, while having pets correlated negatively. Adjusting for these factors we still found a significantly increased intestinal colonization by S. aureus in Swedish compared to Italian infants. The Swedish infantile intestinal S. aureus strains were investigated for susceptibility to a range of common antibiotics. Few strains were resistant to other antibiotics than penicillin V, similar to the situation for clinical S. aureus isolates from Sweden. Strains resistant to antibiotics were equally likely to persist in the infantile intestinal microflora and had similar population counts as susceptible strains. In conclusion, S. aureus has become a common persistent colonizer of the infantile bowel flora. This may be due to lack of competition from more professional faecal bacteria, such as E. coli and obligate anaerobes, whose circulation in society may have decreased due to improved hygienic standards

The West and the Rest : En undersökning av SOS Barnbyars sätt att porträttera utsatta i reklamfilmer

Authors: Karin Lindberg &amp; Erika Losciale Title: The West and the Rest Level: BA Thesis in Media and Communication Studies Location: Linnaeus University Language: Swedish In today's media, the use of stereotypes and simplifications of the world and of different groups are common. It is a part of how humans make sense of the world. The problem is that these simplifications tend to encourage false notions of reality. The way charities communicate in advertising is important in order to engage the audience to donate. This study aims to examine how the non-profit organization SOS Barnbyar Sverige portray underprivileged individuals in their commercials. We have chosen to focus on two different commercials in relation to the ongoing refugee crisis in Europe. The first commercial has no relation to the crisis and the second one is an attempt to show the viewer the situation of a refugee. We have studied the material through a qualitative semiotic method, also using colonialism, stereotypes and representation as theoretical frame- work in order to examine whether or not certain notions and simplifications are reproduced in the commercials from this organization. Our study has shown that there were a lot of colonial ideals and stereotypes to be found in SOS Barnbyars commercials, thus fueling the polarization of us and them and the Other.