Optimised planning and scheduling of grid resources

This article will present the concept and implementation of a resource management system (RMS). The central component of the RMS is the resource broker GORBA that plans resource allocation by a combination of heuristic processes and evolutionary algorithms. For resource planning, schedules are generated, which distribute the grid jobs to the grid resources in a defined time window. A test environment with extensive visualisation options was developed for GORBA, which will be presented in detail. Using this test environment, benchmark runs were carried out, which are needed to evaluate and further develop GORBA. Automated resource planning and the graphic visualisation options facilitate the usability of a grid environment

Optimised planning and scheduling of grid resources

This article will present the concept and implementation of a resource management system (RMS). The central component of the RMS is the resource broker GORBA that plans resource allocation by a combination of heuristic processes and evolutionary algorithms. For resource planning, schedules are generated, which distribute the grid jobs to the grid resources in a defined time window. A test environment with extensive visualisation options was developed for GORBA, which will be presented in detail. Using this test environment, benchmark runs were carried out, which are needed to evaluate and further develop GORBA. Automated resource planning and the graphic visualisation options facilitate the usability of a grid environment

GZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in non-metastatic colorectal tumors and predict poor clinical outcome.

CD8(+) T cells are a major prognostic determinant in solid tumors, including colorectal cancer (CRC). However, understanding how the interplay between different immune cells impacts on clinical outcome is still in its infancy. Here, we describe that the interaction of tumor infiltrating neutrophils expressing high levels of CD15 with CD8(+) T effector memory cells (T(EM)) correlates with tumor progression. Mechanistically, stromal cell-derived factor-1 (CXCL12/SDF-1) promotes the retention of neutrophils within tumors, increasing the crosstalk with CD8(+) T cells. As a consequence of the contact-mediated interaction with neutrophils, CD8(+) T cells are skewed to produce high levels of GZMK, which in turn decreases E-cadherin on the intestinal epithelium and favors tumor progression. Overall, our results highlight the emergence of GZMK(high) CD8(+) T(EM) in non-metastatic CRC tumors as a hallmark driven by the interaction with neutrophils, which could implement current patient stratification and be targeted by novel therapeutics

Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability

Rationale: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of histone deacetylase 9 (HDAC9) in atherosclerosis and its clinical complications including stroke and myocardial infarction. Objective: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection. Methods and Results: We studied the effects of Hdac9 on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further employed two-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic Hdac9 deficiency reduces lesional macrophage content whilst increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKKα and β resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting pro-inflammatory responses in macrophages. Transcriptional profiling using RNA-Seq revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKβ. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL-1β and IL-6. Conclusions: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation