Staphylococcus aureus gene expression in a rat model of infective endocarditis

Background: Diabetes mellitus is a frequent underlying comorbidity in patients with Staphylococcus aureus endocarditis, and it represents a risk factor for complications and a negative outcome. The pathogenesis of staphylococcal endocardial infections in diabetic hosts has been poorly characterized, and little is known about S. aureus gene expression in endocardial vegetations. Methods: We utilized a rat model of experimental S. aureus endocarditis to compare the pathogenesis of staphylococcal infection in diabetic and nondiabetic hosts and to study the global S. aureus transcriptome in endocardial vegetations in vivo. Results: Diabetic rats had higher levels of bacteremia and larger endocardial vegetations than nondiabetic control animals. Microarray analyses revealed that 61 S. aureus genes were upregulated in diabetic rats, and the majority of these bacterial genes were involved in amino acid and carbohydrate metabolism. When bacterial gene expression in vivo (diabetic or nondiabetic endocardial vegetations) was compared to in vitro growth conditions, higher in vivo expression of genes encoding toxins and proteases was observed. Additionally, genes involved in the production of adhesins, capsular polysaccharide, and siderophores, as well as in amino acid and carbohydrate transport and metabolism, were upregulated in endocardial vegetations. To test the contribution of selected upregulated genes to the pathogenesis of staphylococcal endocarditis, isogenic deletion mutants were utilized. A mutant defective in production of the siderophore staphyloferrin B was attenuated in the endocarditis model, whereas the virulence of a surface adhesin (ΔsdrCDE) mutant was similar to that of the parental S. aureus strain. Conclusions: Our results emphasize the relevance of diabetes mellitus as a risk factor for infectious endocarditis and provide a basis for understanding gene expression during staphylococcal infections in vivo. Electronic supplementary material The online version of this article (doi:10.1186/s13073-014-0093-3) contains supplementary material, which is available to authorized users

Biallelic LZTR1 Mutations Activate RAS- MAPK Signaling and Cause Hypertrophic Cardiomyopathy in iPSC-Derived Cardiomyocytes of a Novel Type of Noonan Syndrome

Noonan syndrome is a multisystemic disorder with variable expressivity, characterized by typical craniofacial features, physical and mental retardation with cardiovascular abnormalities. Noonan syndrome is the most common mono-genetic congenital heart disease and manifests as pulmonary valve stenosis, atrial and/or ventricular septum defect, and hypertrophic cardiomyopathy. In most cases, Noonan syndrome is caused by autosomal dominant germline mutations leading to hyperactivity of the RAS-MAPK pathway. Despite the epidemiological relevance, the understanding of variable expressivity, pathophysiological changes, and mechanisms, especially of congenital heart diseases, and effective causal therapies remains limited. This study focuses on two siblings with a particularly pronounced form of hypertrophic cardiomyopathy caused by a recently discovered autosomal recessive mutations in leucine zipper like transcription regulator 1. Obtained skin biopsies from both siblings were reprogrammed to establish a Noonan syndrome disease model with induced pluripotent stem cells and differentiated cardiomyocytes. With the patient-specific cardiomyocytes, the disease phenotype of the autosomal recessive Noonan Syndrome was characterized comprehensively comprising genetic, cell biological, morphological, and functional characteristics. With pure, stable, and functional cultures of induced pluripotent stem cells and differentiated cardiomyocytes an autosomal recessive Noonan syndrome disease model was successfully established. Comprehensive analyses showed that the patient-specific cardiomyocytes recapitulate the hypertrophic phenotype in vitro and reveal disturbances in calcium handling, attenuated by verapamil treatment. Long-term treatment with verapamil could not influence the hypertrophic phenotype, considering this treatment as a symptomatic, non-causal treatment option. Additionally, a connection between leucine zipper like transcription regulator 1 loss-of- function and increased RAS-MAPK signaling activity was identified with transcriptome and proteome analysis. Protein expression alterations led to the generation of a specific protein signature of autosomal recessive Noonan syndrome with the potential to optimize the molecular classification and deciphering of pathogenesis. The reported human stem cell model of Noonan syndrome improves the current knowledge of the pathophysiological mechanisms, especially associated hypertrophic cardiomyopathy, and further serves as a platform for personalized medicine.2023-03-0

High Order Correction Terms for The Peak-Peak Correlation Function in Nearly-Gaussian Models

One possible way to investigate the nature of the primordial power spectrum fluctuations is by investigating the statistical properties of the local maximum in the density fluctuation fields. In this work we present a study of the mean correlation function, $\xi_r$, and the correlation function for high amplitude fluctuations (the peak-peak correlation) in a slighlty non-Gaussian context. From the definition of the correlation excess, we compute the Gaussian two-point correlation function and, using an expansion in Generalized Hermite polynomials, we estimate the correlation of high density peaks in a non-Gaussian field with generic distribution and power spectrum. We also apply the results obtained to a scale-mixed distribution model, which correspond to a nearly Gaussian model. The results reveal that, even for a small deviation from Gaussianity, we can expect high density peaks to be much more correlated than in a Gaussian field with the same power spectrum. In addition, the calculations reveal how the amplitude of the peaks in the fluctuations field is related to the existing correlations. Our results may be used as an additional tool to investigate the behavior of the N-point correlation function, to understand how non-Gaussian correlations affect the peak-peak statistics and extract more information about the statistics of the density field.Comment: Accepted for publication in A&

European Philanthropy Manifesto In Short

This European Philanthropy Manifesto is a call to policymakers in Europe to work towards a Single Market for Philanthropy by taking these 4 steps: EMPOWER philanthropyFACILITATE cross-border philanthropyENGAGE with philanthropyPARTNER with philanthropy for public goodThis paper is a practical guide for philanthropy representatives on how to relay the key messages in the Manifesto towards policymakers at national, European and international levels

Philanthropic Organisations using the entire toolbox for more impact : Paper on foundation practice, as well as regulatory and policy environment

Philanthropic organisations have a great role to play when it comes to achieving and generating positive social change. Foundations can adopt diverse strategies and benefit from an extensive toolbox of non-financial and financial resources from their programme activities and the investments of their endowments.There is a growing realisation that involvement in impact investing may offer a chance to build on their organisational, social and environmental impact. On one hand, philanthropic organisations are seeing opportunities to expand their toolbox by incorporating impact investing approaches into their grantmaking capacity. On the other hand, a wider societal shift in expectations for investments of their endowments to create more than financial returns has led to a growing interest in this area amongst philanthropic organisations when investing their endowments. Several foundations have also taken a new strategic direction to take a holistic approach towards their programme and endowment investing side.This paper is jointly crafted by the key European philanthropy networks working in the field of philanthropic organisations and impact investing: Impact Europe: the European investing for impact network, and Philea - Philanthropy Europe Association. It builds on both organisations' resources and joint actions, in particular a multi-year joint working group on philanthropic organisations' use of the full spectrum of capital, which provided valuable insights and case studies

Climate philanthropy networks : Shaping and supporting the philanthropy ecosystem in the field of climate

This mapping shows the growing diversity and number of networks that have embraced the mission to support and grow the development of the philanthropy ecosystem in the field of climate. The twenty-one organisations presented range from those that are solely dedicated to climate issues to more general networks that work in a range of areas. Each profile gives a flavor of the organisation or platform's activities and goals. This mapping exercise is part of the activities of the Philanthropy Coalition for Climate (https://philea.eu/how-we-can-help/initiatives/philanthropy-coalition-for-climate/), a group of foundations, philanthropy infrastructure organisations and other partners gathered around the aim to empower philanthropy to drive bold climate action and transformational change in Europe and beyond