A functional vascular system is a prerequisite for bone repair as disturbed angiogenesis often causes non-union. Paracrine factors released from human bone marrow derived mesenchymal stromal cells (BMSCs) have angiogenic effects on endothelial cells. However, whether these paracrine factors participate in blood flow dynamics within bone capillaries remains poorly understood. Here, we used two different microfluidic designs to investigate critical steps during angiogenesis and found pronounced effects of endothelial cell proliferation as well as chemotactic and mechanotactic migration induced by BMSC conditioned medium (CM). The application of BMSC-CM in dynamic cultures demonstrates that bioactive factors in combination with fluidic flow-induced biomechanical signals significantly enhanced endothelial cell migration. Transcriptional analyses of endothelial cells demonstrate the induction of a unique gene expression profile related to tricarboxylic acid cycle and energy metabolism by the combination of BMSC-CM factors and shear stress, which opens an interesting avenue to explore during fracture healing. Our results stress the importance of in vivo - like microenvironments simultaneously including biochemical, biomechanical and oxygen levels when investigating key events during vessel repair. Statement of significance: Our results demonstrate the importance of recapitulating in vivo - like microenvironments when investigating key events during vessel repair. Endothelial cells exhibit enhanced angiogenesis characteristics when simultaneous exposing them to hMSC-CM, mechanical forces and biochemical signals simultaneously. The improved angiogenesis may not only result from the direct effect of growth factors, but also by reprogramming of endothelial cell metabolism. Moreover, with this model we demonstrated a synergistic impact of mechanical forces and biochemical factors on endothelial cell behavior and the expression of genes involved in the TCA cycle and energy metabolism, which opens an interesting new avenue to stimulate angiogenesis during fracture healing.

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Enterococciwere detected occasionally in 100 L samples ofwater abstracted froma shallowaquifer in a natural dune infiltration area for drinking water production. Enterococcus moraviensis was the species most frequently identified in these samples. Because there are no existing reports of faecal sources of E. moraviensis and the closely related E. hemoperoxidus, this study aimed to find such sources of these two species in the dunes. Faecal samples from various animal species living in the vicinity of abstraction wells, were analysed for enterococci on Slanetz and Bartley Agar. From these samples, enterococci isolates (1,386 in total) were subsequently identified using matrix assisted laser desorption ionizationtimeof flight (MALDI-TOF)mass spectrometry. E.moraviensiswas found in the faeces of geese, foxes and rabbits. Also, E. haemoperoxidus was isolated from goose faeces. Using hierarchical clustering, the species composition of Enterococcus spp. isolated from abstracted water formed one cluster with the species composition found in geese droppings. A sanitary survey supported the indication that feral geese may provide a substantial faecal load in particular parts of this dune infiltration area, close to the water abstraction system. This study confirms the faecal origin of E.moraviensis and E. haemoperoxidus from specific animals, which strengthens their significance as faecal indicators.

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Acute Myeloid Leukemia is a highly diverse disease containing many cytogenetic and molecular abnormalities. We analyzed the DNA methylation (DMP) and gene expression profiles (GEP) of 344 AML patients using an unsupervised and supervised approach. We hypothesized to better characterize the disease phenotype by combing these features as these may result in specific patterns in cancer cells which reflect biological differences. The unsupervised approach segregates patients into 18 clusters, among them six clusters that are defined by the World Health Organization, such as inv16, t(15;17), t(8;21) and CEBPA double mutants. In addition we identified four novel AML subtypes that could not be explained by the enrichment of any currently known recurrent cytogenetic, molecular, morphological or clinical feature. Two of these clusters are categorized with good stability. One of these cluster could be characterized with pathways that are involved in the accumulation of red blood cells and highly predictable using 21 GEP and 3 DMP features, whereas the other cluster is characterized with T-cell related pathways and highly predictable with 9 GEP and 4 DMP features.@en