Statistical Performance Analysis of an Ant-Colony Optimisation Application in S-NET

Kenneth MacKenzie, Philip K. F. Hölzenspies, Kevin Hammond, Raimund Kirner, Vu Thien Nga Nguyen, Iraneus te Boekhorst, Clemens Grelck, Raphael Poss, Merijn Verstraaten, 'Statistical Performance Analysis of an Ant-Colony Optimisation Application in S-NET'. Paper presented at the 2nd Workshop on Feedback-Directed Compiler Optimization for Multi-Core Architectures. Berlin, Germany, 12 January 2013.We consider an ant-colony optimsation problem implemented on a multicore system as a collection of asynchronous stream- processing components under the control of the S-NET coordina- tion language. Statistical analysis and visualisation techniques are used to study the behaviour of the application, and this enables us to discover and correct problems in both the application program and the run-time system underlying S-NET

PhOTO Zebrafish: A Transgenic Resource for In Vivo Lineage Tracing during Development and Regeneration

Background: Elucidating the complex cell dynamics (divisions, movement, morphological changes, etc.) underlying embryonic development and adult tissue regeneration requires an efficient means to track cells with high fidelity in space and time. To satisfy this criterion, we developed a transgenic zebrafish line, called PhOTO, that allows photoconvertible optical tracking of nuclear and membrane dynamics in vivo. Methodology: PhOTO zebrafish ubiquitously express targeted blue fluorescent protein (FP) Cerulean and photoconvertible FP Dendra2 fusions, allowing for instantaneous, precise targeting and tracking of any number of cells using Dendra2 photoconversion while simultaneously monitoring global cell behavior and morphology. Expression persists through adulthood, making the PhOTO zebrafish an excellent tool for studying tissue regeneration: after tail fin amputation and photoconversion of a ~100µm stripe along the cut area, marked differences seen in how cells contribute to the new tissue give detailed insight into the dynamic process of regeneration. Photoconverted cells that contributed to the regenerate were separated into three distinct populations corresponding to the extent of cell division 7 days after amputation, and a subset of cells that divided the least were organized into an evenly spaced, linear orientation along the length of the newly regenerating fin. Conclusions/Significance: PhOTO zebrafish have wide applicability for lineage tracing at the systems-level in the early embryo as well as in the adult, making them ideal candidate tools for future research in development, traumatic injury and regeneration, cancer progression, and stem cell behavior

Human heme oxygenase-1 deficiency: A lesson on serendipity in the discovery of the novel disease

金沢大学大学院医学系研究科血管病態制御学The first case of human heme oxygenase (HO)-1 deficiency was reported by Yachie et al. at our laboratory in the Department of Pediatrics, Angiogenesis and Vascular Development, Kanazawa University Graduate School of Medical Science, in 1999. In the present paper I would like to review this novel disease. Our studies into HO-1 deficiency were called by us \u27Kanazawa version Project X\u27. From the story of our successful discovery we have learned that serendipity is a very important spiritual factor. Serendipity is the making of fortunate and unexpected discoveries by chance (from its possession by the heroes in the Persian fairy tale The Three Princes of Serendip). © 2007 Blackwell Publishing Asia

Synthesis and structural characterization of a mimetic membrane-anchored prion protein

During pathogenesis of transmissible spongiform encephalopathies (TSEs) an abnormal form (PrPSc) of the host encoded prion protein (PrPC) accumulates in insoluble fibrils and plaques. The two forms of PrP appear to have identical covalent structures, but differ in secondary and tertiary structure. Both PrPC and PrPSc have glycosylphospatidylinositol (GPI) anchors through which the protein is tethered to cell membranes. Membrane attachment has been suggested to play a role in the conversion of PrPC to PrPSc, but the majority of in vitro studies of the function, structure, folding and stability of PrP use recombinant protein lacking the GPI anchor. In order to study the effects of membranes on the structure of PrP, we synthesized a GPI anchor mimetic (GPIm), which we have covalently coupled to a genetically engineered cysteine residue at the C-terminus of recombinant PrP. The lipid anchor places the protein at the same distance from the membrane as does the naturally occurring GPI anchor. We demonstrate that PrP coupled to GPIm (PrP-GPIm) inserts into model lipid membranes and that structural information can be obtained from this membrane-anchored PrP. We show that the structure of PrP-GPIm reconstituted in phosphatidylcholine and raft membranes resembles that of PrP, without a GPI anchor, in solution. The results provide experimental evidence in support of previous suggestions that NMR structures of soluble, anchor-free forms of PrP represent the structure of cellular, membrane-anchored PrP. The availability of a lipid-anchored construct of PrP provides a unique model to investigate the effects of different lipid environments on the structure and conversion mechanisms of PrP

Loss of Akt activity increases circulating soluble endoglin release in preeclampsia:identification of inter-dependency between Akt-1 and heme oxygenase-1

Aims - Endothelial dysfunction is a hallmark of preeclampsia. Desensitization of the phosphoinositide 3-kinase (PI3K)/Akt pathway underlies endothelial dysfunction and haeme oxygenase-1 (HO-1) is decreased in preeclampsia. To identify therapeutic targets, we sought to assess whether these two regulators act to suppress soluble endoglin (sEng), an antagonist of transforming growth factor-ß (TGF-ß) signalling, which is known to be elevated in preeclampsia. Methods and results - Vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor (FGF-2), angiopoietin-1 (Ang-1), and insulin, which all activate the PI3K/Akt pathway, inhibited the release of sEng from endothelial cells. Inhibition of the PI3K/Akt pathway, by overexpression of phosphatase and tensin homolog (PTEN) or a dominant-negative isoform of Akt (Aktdn) induced sEng release from endothelial cells and prevented the inhibitory effect of VEGF-A. Conversely, overexpression of a constitutively active Akt (Aktmyr) inhibited PTEN and cytokine-induced sEng release. Systemic delivery of Aktmyr to mice significantly reduced circulating sEng, whereas Aktdn promoted sEng release. Phosphorylation of Akt was reduced in preeclamptic placenta and this correlated with the elevated level of circulating sEng. Knock-down of Akt using siRNA prevented HO-1-mediated inhibition of sEng release and reduced HO-1 expression. Furthermore, HO-1 null mice have reduced phosphorylated Akt in their organs and overexpression of Aktmyr failed to suppress the elevated levels of sEng detected in HO-1 null mice, indicating that HO-1 is required for the Akt-mediated inhibition of sEng. Conclusion - The loss of PI3K/Akt and/or HO-1 activity promotes sEng release and positive manipulation of these pathways offers a strategy to circumvent endothelial dysfunction

The TORC1 phosphoproteome in C. elegans reveals roles in transcription and autophagy

The protein kinase complex target of rapamycin complex 1 (TORC1) is a critical mediator of nutrient sensing that has been widely studied in cultured cells and yeast, yet our understanding of the regulatory activities of TORC1 in the context of a whole, multi-cellular organism is still very limited. Using Caenorhabditis elegans, we analyzed the DAF-15/Raptor-dependent phosphoproteome by quantitative mass spectrometry and characterized direct kinase targets by in&nbsp;vitro kinase assays. Here, we show new targets of TORC1 that indicate previously unknown regulation of transcription and autophagy. Our results further show that DAF-15/Raptor is differentially expressed during postembryonic development, suggesting a dynamic role for TORC1 signaling throughout the life span. This study provides a comprehensive view of the TORC1 phosphoproteome, reveals more than 100 DAF-15/Raptor-dependent phosphosites that reflect the complex function of TORC1 in a whole, multi-cellular organism, and serves as a rich resource to the field. &nbsp;</p

Identification and optimization of small molecule antagonists of vasoactive intestinal peptide receptor-1 (VIPR1)

Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described

The Regenerative Capacity of the Zebrafish Caudal Fin Is Not Affected by Repeated Amputations

Background: The zebrafish has the capacity to regenerate many tissues and organs. The caudal fin is one of the most convenient tissues to approach experimentally due to its accessibility, simple structure and fast regeneration. In this work we investigate how the regenerative capacity is affected by recurrent fin amputations and by experimental manipulations that block regeneration. Methodology/Principal Findings: We show that consecutive repeated amputations of zebrafish caudal fin do not reduce its regeneration capacity and do not compromise any of the successive regeneration steps: wound healing, blastema formation and regenerative outgrowth. Interfering with Wnt/ß-catenin signalling using heat-shock-mediated overexpression of Dickkopf1 completely blocks fin regeneration. Notably, if these fins were re-amputated at the non-inhibitory temperature, the regenerated caudal fin reached the original length, even after several rounds of consecutive Wnt/ß-catenin signalling inhibition and re-amputation. Conclusions/Significance: We show that the caudal fin has an almost unlimited capacity to regenerate. Even after inhibition of regeneration caused by the loss of Wnt/ß-catenin signalling, a new amputation resets the regeneration capacity within the caudal fin, suggesting that blastema formation does not depend on a pool of stem/progenitor cells that require Wnt/ßcateni