Historical geography II: traces remain

The second report in this series turns to focus on the trace in relation to life-writing and biography in historical geography and beyond. Through attention to tracing journeys, located moments and listening to the presence of ghosts (Ogborn, 2005), this report seeks to highlight the range of different ways in which historical geographers have explored lives, deaths, and their transient traces through varied biographical terrains. Continuing to draw attention in historical geography to the darkest of histories, this piece will pivot on moments of discovering the dead to showcase the nuanced ways in which historical geography is opening doors into uncharted lives and unspoken histories

VEGF promotes assembly of the p130Cas interactome to drive endothelial chemotactic signalling and angiogenesis

p130Cas is a polyvalent adapter protein essential for cardiovascular development, and with a key role in cell movement. In order to identify the pathways by which p130Cas exerts its biological functions in endothelial cells we mapped the p130Cas interactome and its dynamic changes in response to VEGF using high-resolution mass spectrometry and reconstruction of protein interaction (PPI) networks with the aid of multiple PPI databases. VEGF enriched the p130Cas interactome in proteins involved in actin cytoskeletal dynamics and cell movement, including actin-binding proteins, small GTPases and regulators or binders of GTPases. Detailed studies showed that p130Cas association of the GTPase-binding scaffold protein, IQGAP1, plays a key role in VEGF chemotactic signalling, endothelial polarisation, VEGF-induced cell migration, and endothelial tube formation. These findings indicate a cardinal role for assembly of the p130Cas interactome in mediating the cell migratory response to VEGF in angiogenesis, and provide a basis for further studies of p130Cas in cell movement

Elucidating cylindrospermopsin toxicity via synthetic analogues: An in vitro approach

© 2019 Elsevier Ltd Cylindrospermopsin (CYN) is an alkaloid biosynthesized by selected cyanobacteria, the cyto- and genotoxic properties of which have been studied extensively by in vitro and in vivo experimental models. Various studies have separately established the role of uracil, guanidine and hydroxyl groups in CYN-induced toxicity. In the present study, we have prepared five synthetic analogues that all possess a uracil group but had variations in the other functionality found in CYN. We compared the in vitro toxicity of these analogues in common carp hepatocytes by assessing oxidative stress markers, DNA fragmentation and apoptosis. All the analogues tested induced generation of reactive oxygen species, lipid peroxidation (LPO) and DNA fragmentation. However, the greatest increase in LPO and increase in caspase-3 activity, an apoptosis marker, was demonstrated by an analogue containing guanidine, hydroxyl and uracil functionalities similar to those found in CYN but lacking the complex tricyclic structure of CYN. We also report a crystal structure of an analogue lacking the hydroxyl group found in CYN which does not show intramolecular H-bonding interactions between the guanidine and the uracil functionalities. The observations made in this work supports the hypothesis that CYN toxicity is a result of an interplay between both of the uracil, hydroxyl and guanidine functional groups.This research was partially funded by the Ministry of Education and Science of Ukraine (program for support young fellows MV-1) and by the BEACON (ERDF) program and the EPSRC. Thanks are given to the EPSRC for a fellowship (DE, EP/J01821X/1), the BEACON (ERDF) program for support (PJM, DE) and to the National Mass Spectrometry Facility at Swansea.Published versio

Therapeutic target-site variability in α1-antitrypsin characterized at high resolution

The intrinsic propensity of [alpha]1-antitrypsin to undergo conformational transitions from its metastable native state to hyperstable forms provides a motive force for its antiprotease function. However, aberrant conformational change can also occur via an intermolecular linkage that results in polymerization. This has both loss-of-function and gain-of-function effects that lead to deficiency of the protein in human circulation, emphysema and hepatic cirrhosis. One of the most promising therapeutic strategies being developed to treat this disease targets small molecules to an allosteric site in the [alpha]1-antitrypsin molecule. Partial filling of this site impedes polymerization without abolishing function. Drug development can be improved by optimizing data on the structure and dynamics of this site. A new 1.8 Å resolution structure of [alpha]1-antitrypsin demonstrates structural variability within this site, with associated fluctuations in its upper and lower entrance grooves and ligand-binding characteristics around the innermost stable enclosed hydrophobic recess. These data will allow a broader selection of chemotypes and derivatives to be tested in silico and in vitro when screening and developing compounds to modulate conformational change to block the pathological mechanism while preserving function

Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis

Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E(2), due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5-aza-2′-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE(2) production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4 in control fibroblasts down-regulated COX-2 and PGE(2) production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE(2) synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4

Comments on a class of orthogonality relations relevant to fluid-structure interaction

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Probing the Nature of High-z Short GRB 090426 with Its Early Optical and X-ray Afterglows

GRB 090426 is a short duration burst detected by Swift ($T_{90}\sim 1.28$ s in the observer frame, and $T_{90}\sim 0.33$ s in the burst frame at $z=2.609$). Its host galaxy properties and some $\gamma$-ray related correlations are analogous to those seen in long duration GRBs, which are believed to be of a massive-star origin (so-called Type II GRBs). We present the results of its early optical observations with the 0.8-m TNT telescope at Xinglong observatory, and the 1-m LOAO telescope at Mt. Lemmon Optical Astronomy Observatory in Arizona. Our well-sampled optical afterglow lightcurve covers from $\sim 90$ seconds to $\sim 10^4$ seconds post the GRB trigger. It shows two shallow decay episodes that are likely due to energy injection, which end at $\sim 230$ seconds and $\sim 7100$ seconds, respectively. The decay slopes post the injection phases are consistent with each other ($\alpha\simeq 1.22$). The X-ray afterglow lightcurve appears to trace the optical, although the second energy injection phase was missed due to visibility constraints introduced by the {\em Swift} orbit. The X-ray spectral index is $\beta_X\sim 1.0$ without temporal evolution. Its decay slope is consistent with the prediction of the forward shock model. Both X-ray and optical emission is consistent with being in the same spectral regime above the cooling frequency ($\nu_c$). The fact that $\nu_c$ is below the optical band from the very early epoch of the observation provides a constraint on the burst environment, which is similar to that seen in classical long duration GRBs. We therefore suggest that death of a massive star is the possible progenitor of this short burst.Comment: 7 pages, 1 figures, 2 tables, revised version, MNRAS, in pres