Profilin-1 Is Expressed in Human Atherosclerotic Plaques and Induces Atherogenic Effects on Vascular Smooth Muscle Cells

.Here we monitored profilin-1 expression in human atherosclerotic plaques by immunofluorescent staining. The effects of recombinant profilin-1 on atherogenic signaling pathways and cellular responses such as DNA synthesis (BrdU-incorporation) and chemotaxis (modified Boyden-chamber) were evaluated in cultured rat aortic and human coronary vascular smooth muscle cells (VSMCs). Furthermore, the correlation between profilin-1 serum levels and the degree of atherosclerosis was assessed in humans.<0.001 vs. no atherosclerosis or control group).Profilin-1 expression is significantly enhanced in human atherosclerotic plaques compared to the normal vessel wall, and the serum levels of profilin-1 correlate with the degree of atherosclerosis in humans. The atherogenic effects exerted by profilin-1 on VSMCs suggest an auto-/paracrine role within the plaque. These data indicate that profilin-1 might critically contribute to atherogenesis and may represent a novel therapeutic target

A stencil-based implementation of Parareal in the C++ domain specific embedded language STELLA

In view of the rapid rise of the number of cores in modern supercomputers, time-parallel methods that introduce concurrency along the temporal axis are becoming increasingly popular. For the solution of time-dependent partial differential equations, these methods can add another direction for concurrency on top of spatial parallelization. The paper presents an implementation of the time-parallel Parareal method in a C++ domain specific language for stencil computations (STELLA). STELLA provides both an OpenMP and a CUDA backend for a shared memory parallelization, using the CPU or GPU inside a node for the spatial stencils. Here, we intertwine this node-wise spatial parallelism with the time-parallel Parareal. This is done by adding an MPI-based implementation of Parareal, which allows us to parallelize in time across nodes. The performance of Parareal with both backends is analyzed in terms of speedup, parallel efficiency and energy-to-solution for an advection-diffusion problem with a time-dependent diffusion coefficient

Genome-Wide Phylogenetic Comparative Analysis of Plant Transcriptional Regulation: A Timeline of Loss, Gain, Expansion, and Correlation with Complexity

Evolutionary retention of duplicated genes encoding transcription-associated proteins (TAPs, comprising transcription factors and other transcriptional regulators) has been hypothesized to be positively correlated with increasing morphological complexity and paleopolyploidizations, especially within the plant kingdom. Here, we present the most comprehensive set of classification rules for TAPs and its application for genome-wide analyses of plants and algae. Using a dated species tree and phylogenetic comparative (PC) analyses, we define the timeline of TAP loss, gain, and expansion among Viridiplantae and find that two major bursts of gain/expansion occurred, coinciding with the water-to-land transition and the radiation of flowering plants. For the first time, we provide PC proof for the long-standing hypothesis that TAPs are major driving forces behind the evolution of morphological complexity, the latter in Plantae being shaped significantly by polyploidization and subsequent biased paleolog retention. Principal component analysis incorporating the number of TAPs per genome provides an alternate and significant proxy for complexity, ideally suited for PC genomics. Our work lays the ground for further interrogation of the shaping of gene regulatory networks underlying the evolution of organism complexity

Protein-Tyrosin-Phosphatasen (PTPs) as interventional targets in arteriogenesis

Protein-Tyrosin-Phosphatasen (PTPs) gelten als gegen-regulatorische Enzymgruppe von Tyrosinkinasen und sind entscheidend an der Phosphotyrosin- abhängigen Signaltransduktion beteiligt. Klassische PTPs bilden dabei eine Gruppe sowohl membranassoziierter als auch zytosolischer Hydrolasen, die sich durch ihre exklusive Phosphotyrosin-Substratspezifität auszeichnet. In der vorliegenden Arbeit wurden PTPs als potentiell therapeutische Zielstrukturen zur Beeinflussung der Kollateralisierung (Arteriogenese) untersucht. Durch die Proliferation präexistenter Gefäße und konsekutive Gefäßdurchmesserzunahme ist die Arteriogenese in der Lage, der durch eine stenotische Erkrankung hervorgerufene Minderversorgung entgegenzuwirken. In zwei funktionellen Tiermodellen, der Maus und der Ratte, wurde durch operative Modifikation der Blutflussdynamik (Karotisligatur (CCAO) bzw. 3 Gefäßverschluss (3 VO)) zerebrales Kollateralwachstum induziert. In einem konventionellen knockout der Maus bzw. durch pharmakologische Behandlung in der Ratte wurde anschließend die Bedeutung von PTPs für die Arteriogenese untersucht. Mäuse mit einem knockout der PTP Density-Enhanced Phosphatase (DEP) 1 zeigten im Vergleich zu Kontrolltieren nach Arteriogenese-induzierender CCAO-Operation eine signifikant reduzierte zerebrovaskuläre Reservekapazität (CVRC). Demgegenüber war eine morphologische Zunahme der Durchmesser zerebraler Gefäße in DEP 1 knockout-Tieren nicht nachweisbar. Genexpressionsanalysen in arteriellem Zielgewebe (Arteria cerebri anterior, ACA) zeigten eine signifikante Abnahme von Platelet-Derived Growth Factor (PDGF) B Transkripten in DEP 1 knockout Mäusen. In vitro-Experimente bestätigten eine transkriptionelle Abnahme von PDGF-B nach einem knockdown von DEP 1 in kultivierten Endothelzellen. Die Analyse eines potentiellen Effektes auf das periphere Kollateralwachstum konnte beim Vergleich von Wildtyp- und DEP-1 knockout-Mäusen nicht festgestellt werden. Die Bedeutung einer pharmakologischen pan PTP Inhibierung und die spezifische Hemmung der PTPs Src homology 2 domain tyrosine phosphatase (SHP) 1 und PTP1B erfolgte im 3-VO Modell der Ratte. Die Inhibierung der pan PTP- und PTP1B Aktivität führte, insbesondere in der posterioren Zerebralarterie (PCA), zu einer gesteigerten Gefäßproliferation und signifikant erhöhten Gefäßdurchmesserzunahme. Die PTP1B Inhibierung resultierte zudem in einer funktionell verbesserten CVRC. Die pan PTP- und die PTP1B Hemmung führten zusätzlich zu einer Hyperphosphorylierung des PDGF β Rezeptors. Zusammenfassend konnten die hier erarbeiteten Daten erstmals eine generelle Relevanz von PTPs beim Kollateralwachstum zeigen. Insbesondere PTP1B wurde dabei als negativer Regulator und potentielle therapeutische Zielstruktur zur vorteilhaften Beeinflussung der Arteriogenese identifiziert.Protein tyrosine phosphatases (PTPs) are considered as a primarily opposing enzyme group to tyrosine kinases and are therefore in particular antagonizing intracellular phosphotyrosine dependent signaling events. The group of classical PTPs is composed of membrane associated as well as cytosolic enzymes with a solely phosphotyrosine substrate specificity. Here we analyzed the impact of PTP inhibition on collateral growth (arteriogenesis). By the proliferation of pre-existing arterioles, arteriogenesis as a vascular remodeling process is leading to the development of fully functional arterial vessels to overcome ischemic related circulatory deficits. In the present work, we therefore determined the potential of PTPs as pharmacological targets to therapeutically enhance collateral growth - arteriogenesis. Using two animal models of cerebral hypoperfusion in mice (permanent occlusion of the common carotid artery (CCAO)) and rats (three-vessel-occlusion (3-VO)), cerebral collateral growth was evaluated. Based on these models of induced arteriogenesis the relevance of individual PTPs was examined via conventional PTP knockout or pharmacological intervention. In mice deficient for the receptor like PTP density-enhanced phosphatase (DEP)-1, a significantly reduced cerebrovascular reserve capacity (CVRC) was detected compared to wild- type animals. However, morphological changes, assessed by measuring the cerebral vessel diameters, were not detected. Gene expression analysis in target tissues (Arteria cerebri anterior, ACA) revealed a significant reduction in platelet-derived growth factor (PDGF)-B transcripts in DEP-1 knockout mice compared to wild-type animals. Additionally, in vitro experiments in cultured endothelial cells confirmed reduced PDGF-B expression after DEP-1 knockdown. Examining a peripheral vascular effect after femoral artery ligation did not show significant alterations comparing knockout and wild-type mice. Pan PTP inhibition and specific inhibition of Src homology 2 domain tyrosine phosphatase SHP-1 and PTP1B was performed in a 3 VO model in rats. Inhibition of both pan PTP- and PTP1B activity resulted in significantly elevated cerebrovascular diameter gain, particularly in the posterior cerebral artery (PCA). PTP1B inhibition furthermore led to improved CVRC. Under pan- PTP- and PTP1B-inhibition a hyperphosphorylation of the PDGF β-receptor was detected. Our analysis did not reveal a significant impact of SHP 1 in cerebral collateral growth. Taken together, our data point towards a to date unrecognized relevance of PTPs during the vascular remodeling process of arteriogeneis. Especially PTP1B was identified as a negative regulator and potential therapeutical target in pharmacological induced arteriogenesis

MATHICSE Technical Report : Perturbation of higher-order singular values

The higher-order singular values for a tensor of order d are defined as the singular values of the d different matricizations associated with the multilinear rank. When d≥3, the singular values are generally different for different matricizations but not completely independent. Characterizing the set of feasible singular values turns out to be difficult. In this work, we contribute to this question by investigating which first-order perturbations of the singular values for a given tensor are possible. We prove that, except for trivial restrictions, any perturbation of the singular values can be achieved for almost every tensor with identical mode sizes.This settles a conjecture from [Hackbusch and Uschmajew, 2016] for the case of identical mode sizes. Our theoretical results are used to develop and analyze a variant of the Newton method for constructing a tensor with specified higher-order singular values or, more generally, with specified Gramians for the matricizations. We establish local quadratic convergence and demonstrate the robust convergence behavior with numerical experiments

Finite element methods for the Stokes problem on complicated domains

It is a standard assumption in the error analysis of finite element methods that the underlying finite element mesh has to resolve the physical domain of the modeled process. In case of complicated domains appearing in many applications such as ground water flows this requirement sometimes becomes a bottleneck. The resolution condition links the computational complexity a priorily to the number (and size) of geometric details. Therefore even the coarsest available discretization can lead to a huge number of unknowns. In this paper, we will relax the resolution condition and introduce coarse (optimal order) approximation spaces for Stokes problems on complex domains. The described method will be efficient in the sense that the number of unknowns is only linked to the properties of the solution and not to the problem data. The presentation picks up the concept of composite finite elements for the Stokes problem presented in a previous paper of the authors. Here, the a priori error and stability analysis of the proposed mixed method is generalized to quite general, i.e. slip and leak boundary conditions that are of great importance in practical applications

Computation of Expectations by Markov Chain Monte Carlo Methods

Markov chain Monte Carlo (MCMC) methods are a very versatile and widely used tool to compute integrals and expectations. In this short survey we focus on error bounds, rules for choosing the burn in, high dimensional problems and tractability versus curse of dimension