The interactive relationship between coastal erosion and flood risk

Coastal erosion and flooding are hazards that, when combined with facilitative pathways and vulnerable receptors, represent sources of coastal risk. Erosion and flooding risks are often analysed separately owing to complex relationships between driving processes, morphological response and risk receptors. We argue that these risks should be considered jointly and illustrate this through discussion of three ‘expressions’ of this interactive relationship: coastal morphology modifies flood hazard; future flood risk depends on changing shoreline position; and the simultaneous occurrence of erosion–flooding events. Some critical thoughts are offered on the general applicability of these expressions and the implications for coastal risk management policy. This research is funded by the NERC/ESRC Data, Risk and Environmental Analytical Methods (DREAM) Centre, Grant/Award Number: NE/M009009/

Impact of management regime and regime change on gravel barrier response to a major storm surge

Gravel barriers represent physiographic, hydrographic, sedimentary, and ecological boundaries between inshore and open marine offshore environments, where they provide numerous important functions. The morphosedimentary features of gravel barriers (e.g., steep, energy reflective form) have led to their characterization as effective coastal defense features during extreme hydrodynamic conditions. Consequently, gravel barriers have often been intensively managed to enhance coastal defense functions. The Blakeney Point Barrier System (BPBS), U.K., is one such example, which offers the opportunity to investigate the impact of alternative management regimes under extreme hydrodynamic conditions. The BPBS was actively re-profiled along its eastern section from the 1950s to the winter of 2005, whilst undergoing no active intervention along its western section. Combining an analysis of remotely sensed elevation datasets with numerical storm surge modeling, this paper finds that interventionist management introduces systemic differences in barrier morphological characteristics. Overly steepened barrier sections experience greater wave run-up extents during storm surge conditions, leading to more extreme morphological changes and landward barrier retreat. Furthermore, while high, steep barriers can be highly effective at preventing landward flooding, in cases where overwashing does occur, the resultant landward overtopping volume is typically higher than would be the case for a relatively lower crested barrier with a lower angled seaward slope. There is a growing preference within coastal risk management for less interventionist management regimes, incorporating natural processes. However, restoring natural processes does not immediately or inevitably result in a reduction in coastal risk. This paper contributes practical insights regarding the time taken for a previously managed barrier to relax to a more natural state, intermediary morphological states, and associated landward water flows during extreme events, all of which should be considered if gravel barriers are to be usefully integrated into broader risk management strategies.</jats:p

Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma.

BACKGROUND: Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant paediatric brain tumour. METHODS: We explore the therapeutic potential of BMI1 and MAPK/ERK inhibition in BMI1 High;CHD7 Low MB cells and in a pre-clinical xenograft model. RESULTS: We identify a synergistic vulnerability of BMI1 High;CHD7 Low MB cells to a combination treatment with BMI1 and MAPK/ERK inhibitors. Mechanistically, CHD7-dependent binding of BMI1 to MAPK-regulated genes underpins the CHD7-BMI1-MAPK regulatory axis responsible of the anti-tumour effect of the inhibitors in vitro and in a pre-clinical mouse model. Increased ERK1 and ERK2 phosphorylation activity is found in BMI1 High;CHD7 Low G4 MB patients, raising the possibility that they could be amenable to a similar therapy. CONCLUSIONS: The molecular dissection of the CHD7-BMI1-MAPK regulatory axis in BMI1 High;CHD7 Low MB identifies this signature as a proxy to predict MAPK functional activation, which can be effectively drugged in preclinical models, and paves the way for further exploration of combined BMI1 and MAPK targeting in G4 MB patients

Understanding spatio-temporal barrier dynamics through the use of multiple shoreline proxies

At the coast, risk arises where, and when, static human developments are situated within dynamic surroundings. Barrier islands are often sites of heightened coastal risk since they frequently support substantial human populations and undergo extensive morphological change owing to their low-lying form and persistence in energetic hydrodynamic and meteorological conditions. Using the mixed sand-gravel barrier of Blakeney Point, this study argues that to avoid an only partial understanding of coastal zone processes, it is necessary to make use of multiple shoreline proxies, capturing processes operating both at different timescales and different cross-shore positions. Here, five shoreline proxies were extracted from three data sources. Shoreline error was quantified and compared to observed shoreline change rates to establish proxy-specific, appropriate timescales for shoreline change analysis. The map derived Mean High Water Line at Blakeney Point revealed landward retreat of −0.61 m a−1 over the past 130 years with a shift from drift- towards swash-alignment of the barrier since 1981. Over the past 24 years, the High Water Line, Ridge Line and Vegetation Line reveal proxy-specific response to management regime change. The termination of barrier reprofiling of the eastern section of the barrier has resulted in increased sediment release to the downdrift barrier terminus, buffering retreat there at the expense of the updrift section. The Vegetation Line represents an effective proxy for storm-driven overwash with maximum shoreline retreat during surge events of 172 m, illustrating a strong event-driven component to barrier morphodynamics. By comparison to the other proxies, the LiDAR (Light Detection and Ranging) derived Mean High Water Line offers relatively limited insights into barrier dynamics, emphasising the importance of multi-proxy approaches. In the face of technological advance, we demonstrate the continued importance of critical attention towards the dependencies that exist between shoreline proxy selection and the processes that can be observed as a result.This work was funded by the NERC/ESRC Data, Risk and Environmental Analytical Methods (DREAM) CDT, Grant/Award Number: NE/M009009/1. It is also a contribution to the NERC-funded project “Physical and Biological dynamic coastal processes and their role in coastal recovery” (BLUE-coast), Grant Award Number: NE/N015924/1

Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner

Epigenetic changes are frequently observed in cancer. However, their role in establishing or sustaining the malignant state has been difficult to determine due to the lack of experimental tools that enable resetting of epigenetic abnormalities. To address this, we applied induced pluripotent stem cell (iPSC) reprogramming techniques to invoke widespread epigenetic resetting of glioblastoma (GBM)-derived neural stem (GNS) cells. GBM iPSCs (GiPSCs) were subsequently redifferentiated to the neural lineage to assess the impact of cancer-specific epigenetic abnormalities on tumorigenicity. GiPSCs and their differentiating derivatives display widespread resetting of common GBM-associated changes, such as DNA hypermethylation of promoter regions of the cell motility regulator TES (testis-derived transcript), the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C; p57KIP2), and many polycomb-repressive complex 2 (PRC2) target genes (e.g., SFRP2). Surprisingly, despite such global epigenetic reconfiguration, GiPSC-derived neural progenitors remained highly malignant upon xenotransplantation. Only when GiPSCs were directed to nonneural cell types did we observe sustained expression of reactivated tumor suppressors and reduced infiltrative behavior. These data suggest that imposing an epigenome associated with an alternative developmental lineage can suppress malignant behavior. However, in the context of the neural lineage, widespread resetting of GBM-associated epigenetic abnormalities is not sufficient to override the cancer genome

Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation.

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model

The white matter is a pro-differentiative niche for glioblastoma

Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients

Effect of Temperature and Heat Treatment on Crack Growth Acoustic Emission in 7075 Aluminum

The acoustic emission activity due to crack advance in 7075 aluminum alloys has been found to vary with both temperature and heat treatment. An Increase in temperature or overaging of material in the -T6 condition each reduces the acoustic emission activity by changing the probability of occurrence of acoustic emission events and lowering their amplitudes. These observations suggest that the acoustic emission source mechanism is not inclusion fracture but rather is a property of the ductile matrix

Capture of Neuroepithelial-Like Stem Cells from Pluripotent Stem Cells Provides a Versatile System for In Vitro Production of Human Neurons

Human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC) provide new prospects for studying human neurodevelopment and modeling neurological disease. In particular, iPSC-derived neural cells permit a direct comparison of disease-relevant molecular pathways in neurons and glia derived from patients and healthy individuals. A prerequisite for such comparative studies are robust protocols that efficiently yield standardized populations of neural cell types. Here we show that long-term self-renewing neuroepithelial-like stem cells (lt-NES cells) derived from 3 hESC and 6 iPSC lines in two independent laboratories exhibit consistent characteristics including i) continuous expandability in the presence of FGF2 and EGF; ii) stable neuronal and glial differentiation competence; iii) characteristic transcription factor profile; iv) hindbrain specification amenable to regional patterning; v) capacity to generate functionally mature human neurons. We further show that lt-NES cells are developmentally distinct from fetal tissue-derived radial glia-like stem cells. We propose that lt-NES cells provide an interesting tool for studying human neurodevelopment and may serve as a standard system to facilitate comparative analyses of hESC and hiPSC-derived neural cells from control and diseased genetic backgrounds

A high-content small molecule screen identifies sensitivity of glioblastoma stem cells to inhibition of polo-like kinase 1

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults and there are few effective treatments. GBMs contain cells with molecular and cellular characteristics of neural stem cells that drive tumour growth. Here we compare responses of human glioblastoma-derived neural stem (GNS) cells and genetically normal neural stem (NS) cells to a panel of 160 small molecule kinase inhibitors. We used live-cell imaging and high content image analysis tools and identified JNJ-10198409 (J101) as an agent that induces mitotic arrest at prometaphase in GNS cells but not NS cells. Antibody microarrays and kinase profiling suggested that J101 responses are triggered by suppression of the active phosphorylated form of polo-like kinase 1 (Plk1) (phospho T210), with resultant spindle defects and arrest at prometaphase. We found that potent and specific Plk1 inhibitors already in clinical development (BI 2536, BI 6727 and GSK 461364) phenocopied J101 and were selective against GNS cells. Using a porcine brain endothelial cell blood-brain barrier model we also observed that these compounds exhibited greater blood-brain barrier permeability in vitro than J101. Our analysis of mouse mutant NS cells (INK4a/ARF(-/-), or p53(-/-)), as well as the acute genetic deletion of p53 from a conditional p53 floxed NS cell line, suggests that the sensitivity of GNS cells to BI 2536 or J101 may be explained by the lack of a p53-mediated compensatory pathway. Together these data indicate that GBM stem cells are acutely susceptible to proliferative disruption by Plk1 inhibitors and that such agents may have immediate therapeutic value