The role and genetic control of non-coding RNAs in bacterial infection

Promoters are genetic elements that facilitate the transcription of a gene and they have been found in front of non-coding RNA (ncRNA) genes in different organ-isms, e.g. the model plant Arabidopsis thaliana. A similar element, DUSE, has been found in front of ncRNAs in the social amoeba Dictyostelium discoideum and a part of this project has been to analyze the function of this putative promoter element through cloning and expression studies. A construct to analyze the func-tion of DUSE was successfully designed and introduced into D. discoideum but full expression studies were not finished because of shortage of time. However, the first preliminary tests with northern blot showed a distinct loss in the expres-sion of a model gene when the putative promoter was rendered non-functional by site-directed mutagenesis, indicating that DUSE truly functions as a promoter. The main part of this project has been to set up an infection system for Legio-nella pneumophila utilizing the social amoeba Dictyostelium discoideum as a host organism. A big focus of the infection studies has been to study the RNA interfe-rence response to infection by utilizing two D. discoideum knock out strains and SOLiD sequencing. Deep sequencing using the SOLiD technique has been carried out on infected- and uninfected cells to compare the difference in the small RNA population and to analyze the response to infection. The infection system was successfully set up with good confirmation of intra-cellular bacteria by two different screening methods. The infection efficiency showed to differ substantially between the tested strains AX4 and AX2, 10,0% to 3,4% respectively. The protein Dicer B has shown to play a big role in the bioge-nesis of miRNA and a D. discoideum strain with this gene knocked out showed to be more resistant to infection, having an infection efficiency of only 1.2%. At the same time, the growth of this knock out strain was inhibited when grown in prox-imity to L. pneumophila. This could indicate that there are miRNA(s) that are in-volved in the amoeba’s response to bacterial infection. SOLiD sequencing showed that the non-coding Class I RNA gene, DdR-31,was the gene most affected in infected cells compared to uninfected cells also indicat-ing the role for a non-coding RNA in infection

Downscale product line extensions : a literature review

Nedåtgående vertikala produktlinjebreddningar (NVP) är ett sätt för företag att nå ut till konsumenter som inte har betalningsviljan för dess nuvarande produkter. NVP görs genom att minska kvaliteten på en produkt inom en viss produktlinje och sedan sälja den till ett lägre pris. Riskerna med NVP tycks däremot vara påtagliga och okunskapen stor hos företagsledare. Misslyckade lanseringar kan resultera i att en av företagets viktigaste tillgångar – nämligen varumärket – riskerar att skadas. Denna studie undersöker hur litteraturen beskriver följdeffekterna av en NVP. Studien genomfördes med en kvalitativ forskningsstrategi och analyserar såväl kvantitativa som kvalitativa studier för att sammanställa de effekter som följs av en NVP. Analysen av artiklarna belyser de vinster och risker litteraturen beskriver att en NVP kan få för varumärken och deras befintliga produktlinjer. Empirin har samlats in utifrån granskade vetenskapliga artiklar och tolkats med hjälp av en teoretisk begreppsapparat som till stor del bygger på positionering genom varumärkeskategorier. Studien visar att lanseringen av en NVP kan leda till ökade försäljningsvolymer för företaget och dess varumärken, men också att risker som återfinns som följd av NVP är utspädning av varumärket och därigenom att konsumenters relation till varumärket försämras. De vinster och risker som påträffats visar att företag bör tänka till en gång extra innan de väljer att genomföra en NVP. Detta tycks vara av särskild vikt för företag som har lyx- och premiumvarumärken i sin portfölj. Denna uppsats beskriver möjliga strategier för att minska risker vid lanseringen av en NVP och visar hur effekterna av en NVP kan skilja sig mellan en funktionell, premium och lyx-klassad produktlinje.Downscale product-line extensions (DLE) are possible strategies for companies to reach out to the consumers that have a lower willingness to pay than the current pricing of its products. DLE implies that a company lowers the quality of a product in a product-line to sell it at a lower price point. The strategy seems to come with potential risks and the knowledge among company managers about this risk seems to be insufficient. Unsuccessful launchings may result in damaging one of a company’s most valuable assets, the brand. The study examines how the effects of DLE is described in the current literature. This literature review was conducted using a qualitative research strategy and the empirical data was collected from peer-reviewed scholarly articles. Both qualitative and quantitative articles were analyzed to compile effects as a result of DLE. Brand concepts were formed in order to analyze the empirical data collected. The findings suggest that a DLE may lead to increased sales for a company and its brands. Potential risks include brand dilution effects and deteriorated consumer relationships to the brands. The findings furthermore suggest that business management should carefully consider the risks before trying to expand through DLE. Careful consideration seems to be of extra importance for luxury and premium brands. This essay describes possible strategies for companies to apply in order to lower the possible risk related to DLE. The effects appear to be different for functional, premium and luxury product-lines

Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients—a description of the DAPACARD study

Background: Diabetes increases the risk for cardiovascular (CV) events. It has recently been shown that the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to a reduction in CV outcomes in patients with type 2 diabetes mellitus (T2DM), including mortality and heart failure hospitalization. The exact mechanisms of how SGLT2 inhibitors lead to this CV risk reduction remain incompletely understood. The study of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency and myocardial contractile work in type 2 diabetes patients (DAPACARD) (NCT03387683) explores the possible effects of dapagliflozin, an SGLT2 inhibitor, on cardiac work, metabolism, and biomarker levels.Methods: DAPACARD is an international, randomized, double-blind trial that aims to examine the effects of dapagliflozin versus matching placebo in 52 patients with T2DM that are on stable metformin therapy prior to and during the 6 weeks of treatment. The primary efficacy endpoint is change in global longitudinal strain of the left ventricle (GLSLV) measured with magnetic resonance imaging (MRI) between baseline (pre-treatment) and end of study (on-treatment). The secondary endpoint is the corresponding change in myocardial efficiency measured as external left ventricular work divided by total left ventricular work, which is estimated using [11C]-acetate clearance using positron emission tomography (PET).Conclusion: The DAPACARD study is an extensive investigation of cardiac function and metabolism, by advanced imaging with PET and MRI, as well as biomarkers, performed in order to further explore how the SGLT2 inhibitor dapagliflozin could influence cardiovascular outcomes in patients with T2DM.</p

Diversity and evolution of potato mop-top virus

Nearly complete sequences of RNA-CP and 3'-proximal RNA-TGB were determined for 43 samples of potato mop-top virus (PMTV) originating from potato tubers and field soil from Sweden, Denmark and the USA. The results showed limited diversity and no strict geographical grouping, suggesting only a few original introductions of PMTV from the Andes. Two distinguishable types of RNA-CP and RNA-TGB were found in the samples, but no specific combination of them correlated with spraing symptoms in tubers. Lack of positive selection in the coding sequences indicates that there is no specific molecular adaptation of PMTV to new vectors or hosts

Effects of 6 weeks of treatment with dapagliflozin, a sodium- glucose co-transporter-2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo-controlled, exploratory study

Aim: To explore the early effects of dapagliflozin on myocardial function and metabolism in patients with type 2 diabetes without heart failure.Materials and methods: Patients with type 2 diabetes on metformin treatment were randomized to double-blind, 6-week placebo or dapagliflozin 10 mg daily treatment. Investigations included cardiac function and structure with myocardial resonance imaging; cardiac oxygen consumption, perfusion and efficiency with [11 C]-acetate positron emission tomography (PET); and cardiac and hepatic fatty acid uptake with [18 F]-6-thia-heptadecanoic acid PET, analysed by ANCOVA as least square means with 95% confidence intervals.Results: Evaluable patients (placebo: n = 24, dapagliflozin: n = 25; 53% males) had a mean age of 64.4 years, a body mass index of 30.2 kg/m2 and an HbA1c of 6.7%. Body weight and HbA1c were significantly decreased by dapagliflozin versus placebo. Dapagliflozin had no effect on myocardial efficiency, but external left ventricular (LV) work (-0.095 [-0.145, -0.043] J/g/min) and LV oxygen consumption were significantly reduced (-0.30 [-0.49, -0.12] J/g/min) by dapagliflozin, although the changes were not statistically significant versus changes in the placebo group. Change in left atrial maximal volume with dapagliflozin versus placebo was -3.19 (-6.32, -0.07) mL/m2 (p = .056). Peak global radial strain decreased with dapagliflozin versus placebo (-3.92% [-7.57%, -0.28%]; p = .035), while peak global longitudinal and circumferential strains were unchanged. Hepatic fatty acid uptake was increased by dapagliflozin versus placebo (0.024 [0.004, 0.044] μmol/g/min; p = .018), while cardiac uptake was unchanged.Conclusions: This exploratory study indicates reduced heart work but limited effects on myocardial function, efficiency and cardiac fatty acid uptake, while hepatic fatty acid uptake increased, after 6 weeks of treatment with dapagliflozin.</p

Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients - a description of the DAPACARD study

Background: Diabetes increases the risk for cardiovascular (CV) events. It has recently been shown that the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to a reduction in CV outcomes in patients with type 2 diabetes mellitus (T2DM), including mortality and heart failure hospitalization. The exact mechanisms of how SGLT2 inhibitors lead to this CV risk reduction remain incompletely understood. The study of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency and myocardial contractile work in type 2 diabetes patients (DAPACARD) (NCT03387683) explores the possible effects of dapagliflozin, an SGLT2 inhibitor, on cardiac work, metabolism, and biomarker levels. Methods: DAPACARD is an international, randomized, double-blind trial that aims to examine the effects of dapagliflozin versus matching placebo in 52 patients with T2DM that are on stable metformin therapy prior to and during the 6 weeks of treatment. The primary efficacy endpoint is change in global longitudinal strain of the left ventricle (GLSLV) measured with magnetic resonance imaging (MRI) between baseline (pre-treatment) and end of study (on-treatment). The secondary endpoint is the corresponding change in myocardial efficiency measured as external left ventricular work divided by total left ventricular work, which is estimated using [11C]-acetate clearance using positron emission tomography (PET). Conclusion: The DAPACARD study is an extensive investigation of cardiac function and metabolism, by advanced imaging with PET and MRI, as well as biomarkers, performed in order to further explore how the SGLT2 inhibitor dapagliflozin could influence cardiovascular outcomes in patients with T2DM

Treatments and Mortality Trends in Cases With and Without Dialysis Who Have an Acute Myocardial Infarction : An 18-Year Nationwide Experience

BACKGROUND: Patients on dialysis who have an acute myocardial infarction (AMI) have an exceedingly poor prognosis, but it is unknown to what extent guideline-recommended interventions and treatments are used and to which benefit. We aimed to assess temporal changes in the use of treatments and survival rates in dialysis patients with an AMI. METHODS AND RESULTS: All consecutive AMI cases from 1996 to 2013 enrolled in the SWEDEHEART registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) were included. The Swedish Renal Registry identified all chronic dialysis cases. Multivariable adjusted standardized 1-year mortality was estimated. An age-sex-calendar year-matched dialysis background population from the Swedish Renal Registry was used to obtain a standardized incidence ratio. All analyses were performed in 2-year blocks, where each individual could be included several times but in different time blocks; hence the term AMI cases and not patients is used. Of 289 699 cases with AMI, 1398 (0.5%) were on dialysis (73.6% hemodialysis; 26.4% peritoneal dialysis). Among dialysis cases, 29.4% were women, and 21.0% had ST-segment-elevation myocardial infarction. Through 1996 to 2013, dialysis cases had similar age (median, 70 years [interquartile range, 62-77]; P for trend, 0.14), but the proportion with diabetes mellitus increased (36.0%-55.3%; P for trend, 0.005). Dialysis cases admitted with AMI were treated more invasively and received more discharge medications in the later years. From 1995 to 2013, in-hospital and 1-year mortality decreased from 25.4% to 9.4% and from 59.6% to 41.2%, respectively. The standardized in-hospital and 1-year mortality decreased from 25.7% to 9.4% and from 54.6% to 41.2%. Yet, compared with the matched dialysis population, the odds of death remained as high in 2012/2013 as in 1996/1997 (odds ratio, 2.04; 95% CI, 1.62-2.58 and odds ratio, 1.99; 95% CI, 1.52-2.60, respectively; P for trend, 0.34). CONCLUSIONS: Over the last 18 years, more patients on dialysis with AMI have been treated with evidence-based therapies. Overall, dialysis cases with AMI have an improved in-hospital and 1-year survival in the more recent years compared with earlier years. However, this appears largely to be because of improved survival in the general dialysis population

SGLT2 inhibition reduces myocardial oxygen consumption

AIMS/HYPOTHESIS: SGLT2 inhibition is associated with a reduced risk of cardiac disease that is still largely unexplained. According to one hypothesis, improved myocardial energetics may explain the cardioprotective effects of SGLT2i. However, recent mechanistic studies that have addressed this question have lacked the power to detect discrete but still clinically significant effects. METHODS: We pooled data from two recent randomized clinical trials and performed a meta-analysis to determine the effect of SGLT2 inhibition on myocardial oxygen consumption and myocardial external efficiency measured by positron emission tomography. RESULTS: SGLT2 inhibition reduced myocardial oxygen consumption (-1.06 [95%CI: 0.22-1.89] mL/100 g/min (n = 59, p = 0.01)), but did not affect myocardial external efficiency (2.22 [95%CI: 0.66-5.11] % (n = 59, p = 0.13)). CONCLUSIONS: /interpretation: SGLT2 inhibition reduces myocardial oxygen consumption at rest, which may contribute to the drugs' cardioprotective effects