127 research outputs found

    New Model of Macrophage Acquisition of the Lymphatic Endothelial Phenotype

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    Macrophage-derived lymphatic endothelial cell progenitors (M-LECPs) contribute to new lymphatic vessel formation, but the mechanisms regulating their differentiation, recruitment, and function are poorly understood. Detailed characterization of M-LECPs is limited by low frequency in vivo and lack of model systems allowing in-depth molecular analyses in vitro. Our goal was to establish a cell culture model to characterize inflammation-induced macrophage-to-LECP differentiation under controlled conditions.Time-course analysis of diaphragms from lipopolysaccharide (LPS)-treated mice revealed rapid mobilization of bone marrow-derived and peritoneal macrophages to the proximity of lymphatic vessels followed by widespread (∼50%) incorporation of M-LECPs into the inflamed lymphatic vasculature. A differentiation shift toward the lymphatic phenotype was found in three LPS-induced subsets of activated macrophages that were positive for VEGFR-3 and many other lymphatic-specific markers. VEGFR-3 was strongly elevated in the early stage of macrophage transition to LECPs but undetectable in M-LECPs prior to vascular integration. Similar transient pattern of VEGFR-3 expression was found in RAW264.7 macrophages activated by LPS in vitro. Activated RAW264.7 cells co-expressed VEGF-C that induced an autocrine signaling loop as indicated by VEGFR-3 phosphorylation inhibited by a soluble receptor. LPS-activated RAW264.7 macrophages also showed a 68% overlap with endogenous CD11b(+)/VEGFR-3(+) LECPs in the expression of lymphatic-specific genes. Moreover, when injected into LPS- but not saline-treated mice, GFP-tagged RAW264.7 cells massively infiltrated the inflamed diaphragm followed by integration into 18% of lymphatic vessels.We present a new model for macrophage-LECP differentiation based on LPS activation of cultured RAW264.7 cells. This system designated here as the "RAW model" mimics fundamental features of endogenous M-LECPs. Unlike native LECPs, this model is unrestricted by cell numbers, heterogeneity of population, and ability to change genetic composition for experimental purposes. As such, this model can provide a valuable tool for understanding the LECP and lymphatic biology

    Distributed leadership in organizations: A review of theory and research

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    The aim of this paper is to review conceptual and empirical literature on the concept of distributed leadership (DL) in order to identify its origins, key arguments, and areas for further work. Consideration is given to the similarities and differences between DL and related concepts including ‘shared’, ‘collective’, ‘collaborative’, ‘emergent’, ‘co-‘ and ‘democratic’ leadership. Findings indicate that whilst there are some common theoretical bases, the relative usage of these concepts varies over time, between countries and between sectors. In particular, DL is a notion that has seen a rapid growth in interest since the year 2000 but research remains largely restricted to the field of school education and of proportionally more interest to UK than US-based academics. Several scholars are increasingly going to lengths to indicate that in order to be ‘distributed’ leadership need not necessarily be widely ‘shared’ or ‘democratic’ and in order to be effective there is a need to balance different ‘hybrid configurations’ of practice. The article highlights a number of areas for further attention, including three factors relating to the context of much work on DL (power and influence; organisational boundaries and context; and ethics and diversity), and three methodological and developmental challenges (ontology; research methods; and leadership development, reward and recognition). It is concluded that descriptive and normative perspectives that dominate the literature should be supplemented by more critical accounts that recognise the rhetorical and discursive significance of DL in (re)constructing leader-follower identities, mobilising collective engagement and challenging or reinforcing traditional forms of organisation

    Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

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    To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC
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