TGF-beta 1 induces human alveolar epithelial to mesenchymal cell transition (EMT)

Background: Fibroblastic foci are characteristic features in lung parenchyma of patients with idiopathic pulmonary fibrosis (IPF). They comprise aggregates of mesenchymal cells which underlie sites of unresolved epithelial injury and are associated with progression of fibrosis. However, the cellular origins of these mesenchymal phenotypes remain unclear. We examined whether the potent fibrogenic cytokine TGF-β1 could induce epithelial mesenchymal transition (EMT) in the human alveolar epithelial cell line, A549, and investigated the signaling pathway of TGF-β1-mediated EMT. Methods: A549 cells were examined for evidence of EMT after treatment with TGF-β1. EMT was assessed by: morphology under phase-contrast microscopy; Western analysis of cell lysates for expression of mesenchymal phenotypic markers including fibronectin EDA (Fn-EDA), and expression of epithelial phenotypic markers including E-cadherin (E-cad). Markers of fibrogenesis, including collagens and connective tissue growth factor (CTGF) were also evaluated by measuring mRNA level using RT-PCR, and protein by immunofluorescence or Western blotting. Signaling pathways for EMT were characterized by Western analysis of cell lysates using monoclonal antibodies to detect phosphorylated Erk1/2 and Smad2 after TGF-β1 treatment in the presence or absence of MEK inhibitors. The role of Smad2 in TGF-β1-mediated EMT was investigated using siRNA. Results: The data showed that TGF-β1, but not TNF-α or IL-1β, induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT in a time-and concentration-dependent manner. The process of EMT was accompanied by morphological alteration and expression of the fibroblast phenotypic markers Fn-EDA and vimentin, concomitant with a downregulation of the epithelial phenotype marker E-cad. Furthermore, cells that had undergone EMT showed enhanced expression of markers of fibrogenesis including collagens type I and III and CTGF. MMP-2 expression was also evidenced. TGF-β1-induced EMT occurred through phosphorylation of Smad2 and was inhibited by Smad2 gene silencing; MEK inhibitors failed to attenuate either EMT-associated Smad2 phosphorylation or the observed phenotypic changes. Conclusion: Our study shows that TGF-β1 induces A549 alveolar epithelial cells to undergo EMT via Smad2 activation. Our data support the concept of EMT in lung epithelial cells, and suggest the need for further studies to investigate the phenomenon

PAR2 modulators derived from GB88

PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 (3) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining affinity and selectivity, while the C-terminal substituent determines agonist/antagonist function. Here we report structurally similar PAR2 ligands with opposing functions (agonist vs antagonist) upon binding to PAR2. A biased ligand AY117 (65) was found to antagonize calcium release induced by PAR2 agonists trypsin and hexapeptide 2f-LIGRLO-NH2 (IC50 2.2 and 0.7 mu M, HT29 cells), but it was a selective PAR2 agonist in inhibiting cAMP stimulation and activating ERK1/2 phosphorylation. It showed antiinflammatory properties both in vitro and in vivo

Effects of mountain gorilla foraging activities on the productivity of their food plant species

Mountain gorillas subsist principally on foliage from the dense herbaceous understorey that is found throughout most of their habitat in the Virunga Volcanoes region. Their foraging activities cause considerable structural damage to this vegetation. Those plant species that are quantitatively most important in the gorillas' diet respond to this damage by increasing primary productivity. At a sample of spots at which gorillas had fed, these species showed significantly higher growth rates over a 6-month interval than they did at nearby spots that had not been touched by the gorillas. Stem densities of herbaceous food species at feeding spots increased markedly both in comparison to their original values and to values for the same species at untouched spots. As a result, spots at which gorillas have fed are likely to become very attractive as future feeding spots. It is unlikely that gorillas ‘manage’ their habitat in any specific fashion, largely because they do not have exclusive use of their home ranges. Their activities appear to maintain habitat productivity over the short term, on a time scale relevant to patterns of area revisits by social groups, and may contribute to long term beneficial alterations of regularly used areas, however. Effects of the type reported here may have been an important aspect of the adaptation by gorillas to terrestrial folivory. RÉSUMEÉ Les gorilles de montagne s'alimentent principalement de feuillages dans le sous-bois herbacÉ dense prÉsent presque partout dans leur habitat de la rÉgion des volcans Virunga. Leurs activitÉs alimentaires causent des dommages structurels considÉrables À cette vÉgÉtation. Les plantes des espÈces qui sont quantitativement les plus importants dans le rÉgime du gorille rÉagissent À ces dÉgats en augmentant leur productivitÉ primaire. Aux postes Échantillons oÙ les gorilles se sont nourris, ces espÈces prÉsentent des taux de croissance significantivement supÉrieurs sur un intervalle de six mois, par rapport aux postes voisins qui n'ont pas ÉtÉ touchÉs par les gorilles. Les densitÉs de tiges des espÈces herbacÉes appÉtÉes aux postes de nourrissage augmentent nettement aussi bien en comparaison avec leurs valeurs antÉrieures qu'avec celles de ces měmes espÈces dans des stations non touchÉes. En consÉquence, les postes oÙ les gorilles se sont nourris ont plus de chance de devenir des futurs postes de nourrissage trÈs attractifs. Il est peu probable que les gorilles ‘gÈrent’ leur habitat d'une quelconque faÇon, surtout parce qu'ils n'ont pas l'utilisation exclusive de leur domaine vital. Leurs activitÉs semblent maintenir À court terme la productivitÉ de leur habitat, sur une Échelle de temps comprenant les visites successives de groupes sociaux, et peuvent contribuer À long terme À des altÉrations bÉnÉfiques pour ces zones rÉguliÉrement frÉquentÉes. Des effets du type rapportÉ ici peuvent avoir ÉtÉ un ÉlÉment important de l'adaptation des gorilles À la folivorie terrestre.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75171/1/j.1365-2028.1987.tb01102.x.pd

The ‘mosaic habitat’ concept in human evolution: past and present

The habitats preferred by hominins and other species are an important theme in palaeoanthropology, and the ‘mosaic habitat’ (also referred to as habitat heterogeneity) has been a central concept in this regard for the last four decades. Here we explore the development of this concept – loosely defined as a range of different habitat types, such as woodlands, riverine forest and savannah within a limited spatial area– in studies of human evolution in the last sixty years or so. We outline the key developments that took place before and around the time when the term ‘mosaic’ came to wider palaeoanthropological attention. To achieve this we used an analysis of the published literature, a study of illustrations of hominin evolution from 1925 onwards and an email survey of senior researchers in palaeoanthropology and related fields. We found that the term mosaic starts to be applied in palaeoanthropological thinking during the 1970’s due to the work of a number of researchers, including Karl Butzer and Glynn Isaac , with the earliest usage we have found of ‘mosaic’ in specific reference to hominin habitats being by Adriaan Kortlandt (1972). While we observe a steady increase in the numbers of publications reporting mosaic palaeohabitats, in keeping with the growing interest and specialisation in various methods of palaeoenvironmental reconstruction, we also note that there is a lack of critical studies that define this habitat, or examine the temporal and spatial scales associated with it. The general consensus within the field is that the concept now requires more detailed definition and study to evaluate its role in human evolution

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Advances in Target Design for Heavy-Ion Fusion

Over the past few years, the emphasis in heavy ion target design has moved from the distributed radiator target to the 'hybrid' target because the hybrid target allows a larger beam focal spot than the distributed radiator ({approx} 5 mm radius rather than {approx} 2 mm radius). The larger spot relaxes some of the requirements on the driver, but introduces some new target physics issues. Most notable is the use of shine shields and shims in the hohlraum to achieve symmetry rather than achieving symmetry by beam placement. The shim is a thin layer of material placed on or near the capsule surface to block a small amount of excess radiation. While we have been developing this technique for the heavy ion hybrid target, the technique can be used in any indirect drive target. We have begun testing the concept of a shim to improve symmetry using a double-ended z-pinch hohlraum on the Sandia Z-machine. Experiments using shimmed thin wall capsules have shown that we can reverse the sign of a P{sub 2} asymmetry and significantly reduce the size of a P{sub 4} asymmetry. These initial experiments demonstrate the concept of a shim as another method for controlling early time asymmetries in ICF capsules

Evaluation of Commercial Probiotic Products

Although there is a vast number of probiotic products commercially available due to their acceptability and increasing usage, their quality control has continuously been a major concern. This study aimed to assess some commercially available probiotics on the UK market for content in relation to their label claim. Seven products were used for the study. The bacteria content were isolated, identified and enumerated on selective media. The results revealed that all products evaluated contained viable probiotic bacteria but only three out of the seven products (43%) contained the claimed culture concentration or more. None of the multispecies product contained all the labelled probiotic bacteria. Misidentification of some species occurred. The results concurred with previous studies and showed that quality issues with commercial probiotics remain. Since probiotic activity is linked with probiotic concentration and is strain specific, the need exist for a global comprehensive legislation to control the quality of probiotics whose market is gaining huge momentum

Pathway-selective antagonism of proteinase activated receptor 2

BACKGROUND AND PURPOS