Expression of fibromodulin in carotid atherosclerotic plaques is associated with diabetes and cerebrovascular events.

The small leucine-rich proteoglycans fibromodulin and lumican are functionally related extracellular matrix proteins involved in the regulation of collagen fiber formation. Fibromodulin-deficient apolipoprotein E-null mice have decreased vascular retention of lipids and reduced development of atherosclerosis suggesting that fibromodulin may influence the disease process. The aim of the present study was to investigate if fibromodulin and lumican are expressed in human carotid plaques and to determine if their expression is associated with the occurrence of preoperative symptoms and with risk for postoperative cardiovascular events

The Novel Collagen Matrikine, Endotrophin, is Associated with Mortality and Cardiovascular Events in Patients with Atherosclerosis

Background: Rupture of atherosclerotic plaques is the major cause of acute cardiovascular events. The biomarker PRO-C6 measuring Endotrophin, a matrikine of collagen type VI, may provide valuable information detecting subjects in need of intensified strategies for secondary prevention. Objective: In this study, we evaluate endotrophin in human atherosclerotic plaques and circulating levels of PRO-C6 in patients with atherosclerosis, to determine the predictive potential of the biomarker. Methods: Sections from the stenotic human carotid plaques were stained with the PRO-C6 antibody. PRO-C6 was measured in serum of patients enrolled in the Carotid Plaque Imagining Project (CPIP) (discovery cohort, n = 577) and the innovative medicines initiative surrogate markers for micro- and macrovascular hard end-points for innovative diabetes tools (IMI-SUMMIT, validation cohort, n = 1,378). Median follow-up was 43 months. Kaplan–Meier curves and log-rank tests were performed in the discovery cohort. Cox proportional hazard regression analysis (HR with 95% CI) was used in the discovery cohort and binary logistic regression (OR with 95% CI) in the validation cohort. Results: PRO-C6 was localized in the core and shoulder of the atherosclerotic plaque. In the discovery cohort, PRO-C6 independently predicted future cardiovascular events (HR 1.089 [95% CI 1.019 −1.164], p = 0.01), cardiovascular death (HR 1.118 [95% CI 1.008 −1.241], p = 0.04) and all-cause death (HR 1.087 [95% CI 1.008 −1.172], p = 0.03). In the validation cohort, PRO-C6 predicted future cardiovascular events (OR 1.063 [95% CI 1.011 −1.117], p = 0.017). Conclusion: PRO-C6 is present in the atherosclerotic plaque and associated with future cardiovascular events, cardiovascular death and all-cause mortality in two large prospective cohorts

Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology

Antibiotics have been extensively used to treat bacterial infections since Alexander Fleming’s discovery of penicillin 1928. Disease causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. According to the world health organization (WHO) there are about 440 000 new cases of multidrug-resistant tuberculosis emerging annually, causing at least 150 000 deaths. Consequently there is an immense need to develop new types of compounds with new modes of action for the treatment of bacterial infections. Presented herein is a class of antibacterial ring-fused 2-pyridones, which exhibit inhibitory effects against both the pili assembly system in uropathogenic Escherichia coli (UPEC), named the chaperone usher pathway, as well as polymerization of the major curli subunit protein CsgA, into a functional amyloid fibre. A pilus is an organelle that is vital for the bacteria to adhere to and infect host cells, as well as establish biofilms. Inhibition of the chaperone usher pathway disables the pili assembly machinery, and consequently renders the bacteria avirulent. The focus of this work has been to develop synthetic strategies to more efficiently alter the substitution pattern of the aforementioned ring-fused 2-pyridones. In addition, asymmetric routes to enantiomerically enriched key compounds and routes to compounds containing BODIPY and coumarin fluorophores as tools to study bacterial virulence mechanisms have been developed. Several of the new compounds have successfully been evaluated as antibacterial agents. In parallel with this research, manipulations of the core structure to create new heterocycle based central fragments for applications in medicinal chemistry have also been performed.  

Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology

Antibiotics have been extensively used to treat bacterial infections since Alexander Fleming’s discovery of penicillin 1928. Disease causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. According to the world health organization (WHO) there are about 440 000 new cases of multidrug-resistant tuberculosis emerging annually, causing at least 150 000 deaths. Consequently there is an immense need to develop new types of compounds with new modes of action for the treatment of bacterial infections. Presented herein is a class of antibacterial ring-fused 2-pyridones, which exhibit inhibitory effects against both the pili assembly system in uropathogenic Escherichia coli (UPEC), named the chaperone usher pathway, as well as polymerization of the major curli subunit protein CsgA, into a functional amyloid fibre. A pilus is an organelle that is vital for the bacteria to adhere to and infect host cells, as well as establish biofilms. Inhibition of the chaperone usher pathway disables the pili assembly machinery, and consequently renders the bacteria avirulent. The focus of this work has been to develop synthetic strategies to more efficiently alter the substitution pattern of the aforementioned ring-fused 2-pyridones. In addition, asymmetric routes to enantiomerically enriched key compounds and routes to compounds containing BODIPY and coumarin fluorophores as tools to study bacterial virulence mechanisms have been developed. Several of the new compounds have successfully been evaluated as antibacterial agents. In parallel with this research, manipulations of the core structure to create new heterocycle based central fragments for applications in medicinal chemistry have also been performed.  

Applications of Bayesian Econometrics to Financial Economics

This PhD thesis consists of four separate papers. What these papers have in common is that Bayesian Econometrics, in combination with Markov chain Monte Carlo (MCMC) methods, is applied to study various problems in financial economics. The first two papers are further related in that they both deal with portfolio selection and estimation risk, as are the last two papers in that they both deal with international aspects of extreme stock returns. The first paper, "The Impact of Estimation Error on Single-Period Portfolio Selection", examines the impact of estimation error on single-period portfolio selection. This is done under slightly more realistic assumptions than those made by Chopra and Ziemba (1993, Journal of Portfolio Management 19, 6-12) in frequently cited paper, but still using their basic approach and simulation methodology, in which simulated estimation error is added to what are assumed to be the true mean vector and covariance matrix of returns. To obtain estimation error sizes that are more consistent with those in actual estimates, a Bayesian approach based on MCMC methods is used. The paper also looks at what effects short selling constraint have on the impact of estimation error. The empirical results differ from those of Chopra and Ziemba (1993), suggesting that the effect of estimation error may have been overestimated in the past. Furthermore, when some short selling is allowed, the paper finds reason to question the traditional viewpoint that estimating the covariance matrix correctly is always less important than estimating the mean vector correctly. The second paper, "A Shrinkage Estimator of the Covariance Matrix for Improved Mean-Variance Optimization", proposes a shrinkage estimator of the covariance matrix of returns which shrinks the usual sample covariance matrix towards a K-factor principal component covariance matrix. In addition, the paper examines the gains from taking into account the uncertainty of the estimated covariance matrix when selecting portfolios. This is done through portfolio resampling based on the posterior distribution of the covariance matrix quantified with MCMC methods. In an empirical contest between estimators, where the objective is to pick portfolios with as low out-of-sample volatility as possible, the proposed estimator is found to perform better than all other competing estimators. In addition, it is found that the out-of-sample volatility can be reduced even further through portfolio resampling. The third paper, "Jump Spillover in International Equity Markets", co-authored with Hossein Asgharian, studies what is referred to as jump spillover effects between a number of international equity indices. In order to identify the latent historical jumps of each index, a univariate stochastic volatility jump-diffusion model is estimated on each index using a Bayesian approach based on MCMC methods. The paper looks at the simultaneous jump intensities of pairs of countries and the probabilities that jumps in large countries cause jumps or unusually large returns in other countries. In all cases, significant evidence of jump spillover is found. In addition, it is found that jump spillover seems to be particularly large and significant between countries that belong to the same regions and have similar industry structures, whereas, interestingly, the sample correlations between the countries have difficulties in capturing the jump spillover effects. The fourth paper, "International Jumps in Returns", examines, just as the previous paper, the international aspects of jumps in returns, but does so in an econometrically more formal manner. The paper proposes a multivariate stochastic volatility jump-diffusion model which is estimated on three groups of major North American, European, and Asian equity indices. The model assumes that returns are affected by both systemic (simultaneous across markets) and idiosyncratic (market specific) jumps. In all three cases, significant evidence of the existence of systemic jumps is found. In the North American markets (the United States and Canada), the majority of jumps are systemic, whereas in the European markets (the United Kingdom, Germany, and France) and the Asian markets (Japan and Hong Kong), the majority of jumps are idiosyncratic. In all cases, the mean sizes of systemic jumps are significantly negative, while the mean sizes of idiosyncratic jumps are not significantly different from zero. Surprisingly, the finding in all cases is that the correlation coefficients between the sizes of systemic jumps are relatively small and not significantly different from zero

The Complexity and Returns of Structured Products

In this paper we analyze if higher complexity gives lower returns in structured products. Our unique, hand collected sample consists of 499 structured products sold in Sweden that matured or were subject to early redemption during 2016. We assign a complexity score to each product based on the conditions of their payo pro les. Our sample consists of products with complexity scores 1 through 4 out of a possible 1 to 8. We perform two regressions. In a panel regression, we regress monthly returns on complexity score and nd that products of complexity score 3 earn a statistically signi cant -0.5% lower monthly returns than products of complexity 1. In the second regression, we use monthly returns that are risk-adjusted using a market factor model. The results from this regression show that products of complexity 4 and 3 perform worse than products of complexity 1 by -0.5% and -0.1%, respectively. Complexity 2 performs better by approximately 0.1%. Our results con rm what previous literature has found; that very complex structured products are di cult to value and that higher complexity can be used to hide risks and fees.MSc in Financ