Role of arginase in vascular function

Background Nitric oxide (NO) is central for the integrity of the cardiovascular system, the maintenance of endothelial function and the protection against ischaemic heart disease. The enzyme arginase is up-regulated during ischaemia-reperfusion and by hypoxia in cell culture and animal models which might be of pathophysiological relevance since it competes with NO synthase for their common substrate arginine. The aim of the studies was to clarify the role of arginase in cardiovascular disease related to ischaemia and hypoxia including myocardial ischaemia and reperfusion injury, heart failure and following resuscitation after cardiac arrest by investigating the therapeutic effect of arginase inhibition and its association to increased NO bioavailability. Studies I-II To study the relevance of arginase in the context of myocardial ischaemia and reperfusion two different animal models were used. In a rat model, the animals were treated with an arginase inhibitor (Nω-hydroxy-nor-L-arginine, nor-NOHA) alone or together with substances inhibiting NO or its production intravenously before the onset of ischaemia. The infarct size was reduced by 50 % following administration of the arginase inhibitor. The cardioprotective effect was completely dependent on NO synthase activity and NO activity. Ischaemia and reperfusion was associated with increased expression of arginase I in the ischaemic myocardium. Arginase inhibition induced a 10-fold increase in the citrulline/ ornithine ratio as an indirect enzyme activity measure, indicating a shift in arginine utilization from arginase towards NO synthase. In a subsequent study this concept was investigated in a large animal (pig) model of myocardial ischaemia and reperfusion with intracoronary drug administration in connection with reperfusion. Administration of nor-NOHA resulted in a profound cardioprotection comparable to that observed in rats. Parallel groups confirmed that the cardioprotective mechanism was dependent on NO production. Studies III-IV Circulating levels of arginase I were determined in patients with heart failure and following cardiopulmonary resuscitation as well as in healthy volunteers after global hypoxia in an normobaric hypoxia chamber. These conditions were all associated with increased levels of arginase I. In addition, the effect of topical application of nor-NOHA on the sublingual mucosa on microvascular perfusion was studied using a sidestream darkfield microcirculation camera. The impaired microcirculation in heart failure and in patients following resuscitation was improved by local nor-NOHA incubation via a NO-dependent mechanism. Conclusions Inhibition of arginase protects from myocardial ischaemia and reperfusion injury by a mechanism that is dependent on NO production and increased bioavailability of NO by shifting arginine utilization towards NO production. In addition, we showed that heart failure, global hypoxia and cardiopulmonary resuscitation lead to increased plasma levels of arginase I. Impaired microcirculatory perfusion in these patients is improved following topical arginase inhibition by a NO dependent mechanism. Inhibition of arginase is a promising potential treatment target for protection against myocardial ischaemia and reperfusion injury and to ameliorate microcirculatory dysfunction in critically ill patients

Sparse recovery in bounded Riesz systems with applications to numerical methods for PDEs

We study sparse recovery with structured random measurement matrices having independent, identically distributed, and uniformly bounded rows and with a nontrivial covariance structure. This class of matrices arises from random sampling of bounded Riesz systems and generalizes random partial Fourier matrices. Our main result improves the currently available results for the null space and restricted isometry properties of such random matrices. The main novelty of our analysis is a new upper bound for the expectation of the supremum of a Bernoulli process associated with a restricted isometry constant. We apply our result to prove new performance guarantees for the CORSING method, a recently introduced numerical approximation technique for partial differential equations (PDEs) based on compressive sensing

Microcirculation versus Macrocirculation in Cardiogenic Shock

Macro- and microcirculation are important parameters in cardiogenic shock. Microcirculation is relevant for monitoring organ function and prognosis. Serum lactate might be the best daily life parameter to assess microcirculation, and the crude 8-hour value can be used for outcome prediction. Any treatment should consider the consequences of microcirculation and macrocirculation

Induced mutations for studying Mendelian inheritance

Sämtliche genetische Variation resultiert aus Mutationen. Die Mutationsraten können durch Bestrahlung oder chemische Behandlung um mehrere Größenordnungen erhöht werden. Die Genom-Editierung bietet neue Perspektiven für die Mutationsinduktion, da erstmals Zielsequenzen auch innerhalb großer Pflanzengenome präzise anvisiert werden können. Im weitesten Sinne sind auch Transgene, die mit gentechnischen Verfahren in ein Genom eingeschleust wurden, Mutationen, die zu neuer genetischer Variation führen. Alle Einzelgen-Mutationen nach Genom-Editierung, Transgenese oder chemischer Mutagenese werden nach den Mendelschen Regeln vererbt. Die Nachkommen können phänotypisch in diskrete Klassen eingeteilt werden, während polygene Vererbung zu kontinuierlicher Variation führt. Aber aufgrund genomweiter Studien ist eine derartige Einteilung nicht mehr gerechtfertigt. Knockout-Mutationen einzelner Gene können auf eine nicht-mendelnde Weise vererbt werden, vor allem, wenn Gene mutagen verändert werden, die für Transkriptionsfaktoren kodieren. Sogar klassische Mendel-Merkmale werden nach heutiger Kenntnis heute von zahlreichen Genen kontrolliert. Daher sollte die Mendelsche Genetik auf die genetische Variation beschränkt werden, während die phänotypische Variation als polygen angesehen werden sollte.All genetic variation results from mutations. Orders of magnitude can increase mutation rates by applying irradiation or chemical treatment. Genome editing offers new perspectives for mutation induction because mutation sites can be precisely targeted even within large plant genomes for the first time. Generally, transgenes after genetic engineering also result in new genetic variation. All single-gene mutations after genome editing, transgenesis, or chemical mutagenesis are inherited according to the Mendelian rules. Thus, offspring can be phenotypically classified into discrete classes, whereas polygenic inheritance results in continuous variation. However, genome-wide studies have blurred the boundaries between the two in recent years. Single-gene knockout mutations can be inherited non-Mendelian, mainly if transcription factor genes are targeted. Even classical Mendelian traits are now believed to be controlled by numerous genes. Therefore, Mendelian genetics should be limited to genetic variation, whereas phenotypic variation should be considered polygenic

Limited utility of qPCR-based detection of tumor-specific circulating mRNAs in whole blood from clear cell renal cell carcinoma patients

BACKGROUND: RNA sequencing data is providing abundant information about the levels of dysregulation of genes in various tumors. These data, as well as data based on older microarray technologies have enabled the identification of many genes which are upregulated in clear cell renal cell carcinoma (ccRCC) compared to matched normal tissue. Here we use RNA sequencing data in order to construct a panel of highly overexpressed genes in ccRCC so as to evaluate their RNA levels in whole blood and determine any diagnostic potential of these levels for renal cell carcinoma patients. METHODS: A bioinformatics analysis with Python was performed using TCGA, GEO and other databases to identify genes which are upregulated in ccRCC while being absent in the blood of healthy individuals. Quantitative Real Time PCR (RT-qPCR) was subsequently used to measure the levels of candidate genes in whole blood (PAX gene) of 16 ccRCC patients versus 11 healthy individuals. PCR results were processed in qBase and GraphPadPrism and statistics was done with Mann-Whitney U test. RESULTS: While most analyzed genes were either undetectable or did not show any dysregulated expression, two genes, CDK18 and CCND1, were paradoxically downregulated in the blood of ccRCC patients compared to healthy controls. Furthermore, LOX showed a tendency towards upregulation in metastatic ccRCC samples compared to non-metastatic. CONCLUSIONS: This analysis illustrates the difficulty of detecting tumor regulated genes in blood and the possible influence of interference from expression in blood cells even for genes conditionally absent in normal blood. Testing in plasma samples indicated that tumor specific mRNAs were not detectable. While CDK18, CCND1 and LOX mRNAs might carry biomarker potential, this would require validation in an independent, larger patient cohort

An Analytical Representation of the 2d Generalized Balanced Power Diagram

Tessellations are an important tool to model the microstructure of cellular and polycrystalline materials. Classical tessellation models include the Voronoi diagram and Laguerre tessellation whose cells are polyhedra. Due to the convexity of their cells, those models may be too restrictive to describe data that includes possibly anisotropic grains with curved boundaries. Several generalizations exist. The cells of the generalized balanced power diagram are induced by elliptic distances leading to more diverse structures. So far, methods for computing the generalized balanced power diagram are restricted to discretized versions in the form of label images. In this work, we derive an analytic representation of the vertices and edges of the generalized balanced power diagram in 2d. Based on that, we propose a novel algorithm to compute the whole diagram