Canadian Institutes of Health Research.

No abstract

Mapping combined with till provenance studies have resulted in a re-appraisal of the pre-Devensian glacial stratigraphy of Norfolk, England. The traditional model invoked two formations, a North Sea Drift Formation (NSDF) overlain by a Lowestoft Formation, formed by co-existing icesheets originating in Scandinavia and Northern Britain respectively. The NSDF included three diamictons, the First, Second and Third Cromer tills.The Briton's Lane Sands and Gravels were considered to overlie the Lowestoft Formation. However, our work has shown this stratigraphy to be untenable, and we propose a model of several glaciations instead of co-existing ice-sheets. In our revised stratigraphy, the oldest formation, the Happisburgh Formation (including the Happisburgh or First Cromer Till) includes massive, sandy tills derived from northern Britain. The overlying Lowestoft Formation, including the Second Cromer (Walcott) Till is confirmed as derived from the west, introducing much Jurassic material as well as Chalk. The Sheringham Cliffs Formation includes both brown sandy tills (the Third Cromer Till) and 'marly drift', in a variety of tectonic relationships, and derived from the north and NNW. Finally the Briton's Lane Formation is the only formation to include Scandinavian erratics.Dating of the four formations is at varying levels of confidence, with the Lowestoft Formation most confidently confirmed as MIS 12. The Happisburgh Formation is believed to represent an earlier glaciation, and MIS 16 is proposed. The Sheringham Cliffs Formation is tentatively believed to date from MIS 10, and the Briton's Lane Formation is assigned to MIS 6.

Recent investigations from modern environments demonstrate that many terminal moraines do not simply record a single glacial maximum, but instead reveal a complex pattern of ice-marginal behaviour including polyphase retreat. Within this study, we examine the geomorphology, geology and internal structure of a terminal moraine complex -the 'Cromer Ridge' in north Norfolk to reconstruct patterns of ice-marginal behaviour. Previously, this landform was interpreted as the limit of a southern extension of the British Ice Sheet during a Middle Pleistocene glaciation. Evidence presented here reveals a more complicated pattern of ice-marginal behaviour with the 'Cromer Ridge' reinterpreted as a 'complex' comprising several ridge elements. We propose that the maximum ice extent lay further to the south, with the size and morphology of the largest ridge element (the 'Cromer Ridge' as previously defined) a facet of thrust-stacking at an ice-marginal stillstand. We recognise multiple oscillations of the ice-front recorded against a twelve-stage model for the decay of the southern margins of a fast-flowing lobe of North Sea ice. Changes in ice-marginal dynamics are identified by the superimposition and lateral and vertical evolution of glacitectonic styles. Differences between these various states, and switches between 'shallow' and 'deep' thinskinned glacitectonics, are strongly influenced by sub-marginal and proglacial water availability. Examination of the evidence for the morphostratigraphic proposals for the glacitectonic assemblage, within the context of the above interpretation, suggests that many of the 'glacigenic landforms' are erosional and a MIS 12 age of formation is favored although several anomalies remain to be explained. IntroductionTerminal moraines are an important landform within the glacial landsystem and are widely recognised within both contemporary (Boulton et al., 1996(Boulton et al., , 1999Bennett, 2001; Evans and Twigg, 2002; Evans, 2005;Benediktsson et al., 2010) and relict glacial environments (van der Meer, 1987; Lee, J.R., Phillips, E., Booth, S.J., Rose, J., Jordan, H.M., Pawley, S.M., Warren, M., Lawley, R.S. 2013. A polyphase glacitectonic model for ice-marginal retreat and terminal moraine development: the Middle Pleistocene British Ice Sheet, northern Norfolk, UK. Proceedings of the Geologists' Association, 124, 753-777. PRE-PROOF ACCEPTEF MANUSCRIPT.2 Hart, 1990;Van der Wateren, 1995;Harris et al., 1997;Phillips et al., 2002;Wilson, 2002;Thomas and Chiverrell, 2007;Johnson et al., 2013). Previously, they have been considered as providing a visible record of a maximum extent of glacier advance, although many now consider them to provide a more dynamic record of glacier retreat (e.g. Thomas, 1984;Thomas et al., 2004;Thomas and Chiverrell, 2007;Lüthgens and Böse, 2011; Clark et al., 2012).The formation of terminal moraines typically involves the complex interplay between ice-marginal to sub-marginal sedimentation and glacitectonics; the latter including proglacial and sub-margina...

BackgroundEpigenetic adjustments of the chromatin architecture through histone modifications are reactive to the environment and can establish chromatin states which are permissive or repressive to gene expression. Epigenetic regulation of gene expression is cell specific and therefore, it is important to understand its contribution to individual cellular responses in tissues like the airway epithelium which forms the mucosal barrier to the inhaled environment within the lung. The airway epithelium of asthmatics is abnormal with dysregulation of genes such as epidermal growth factor receptor (EGFR), the ΔN isoform of the transcription factor p63 (ΔNp63), and signal transducer and activator of transcription 6 (STAT6), integral to differentiation, proliferation, and inflammation. It is important to establish in diseases like asthma how histone modifications affect tissue responses such as proliferation and differentiation.ObjectivesTo characterize the global histone acetylation and methylation status in the epithelium of asthmatic compared to healthy subjects and to identify the impact of these variations on genes involved in epithelial functions.MethodsWhole lungs were obtained from healthy and asthmatic subjects (n = 6) from which airway epithelial cells (AECs) were isolated and airway sections were taken for analysis of histone lysine acetylation and methylation by immunohistochemistry. AECs were subjected to chromatin immunoprecipitation (ChIP) using anti-H3K18ac and anti-H3K4me2 antibodies followed by RT-PCR targeting ΔNp63, EGFR, and STAT6. AECs were also treated with TSA and changes in ΔNp63, EGFR, and STAT6 expression were determined.ResultsWe identified an increase in the acetylation of lysine 18 on histone 3 (H3K18ac) and trimethylation of lysine 9 on histone 3 (H3K9me3) in the airway epithelium of asthmatic compared to healthy subjects. We found increased association of H3K18ac around the transcription start site of ΔNp63, EGFR, and STAT6 in AECs of asthmatics. However, we were unable to modify the expression of these genes with the use of the HDAC inhibitor TSA in healthy subjects.DiscussionThe airway epithelium from asthmatic subjects displays increased acetylation of H3K18 and association of this mark around the transcription start site of ΔNp63, EGFR, and STAT6. These findings suggest a complex interaction between histone modifications and gene regulation in asthma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0254-y) contains supplementary material, which is available to authorized users.

No abstract

As the lung develops, epithelial-mesenchymal crosstalk is essential for the developmental processes that drive cell proliferation, differentiation, and extracellular matrix (ECM) production within the lung epithelial-mesenchymal trophic unit (EMTU). In asthma, a number of the lung EMTU developmental signals have been associated with airway inflammation and remodeling, which has led to the hypothesis that aberrant activation of the asthmatic EMTU may lead to disease pathogenesis. Monoculture studies have aided in the understanding of the altered phenotype of airway epithelial and mesenchymal cells and their contribution to the pathogenesis of asthma. However, 3-dimensional (3D) co-culture models are needed to enable the study of epithelial-mesenchymal crosstalk in the setting of the in vivo environment. In this review, we summarize studies using 3D co-culture models to assess how defective epithelial-mesenchymal communication contributes to chronic airway inflammation and remodeling within the asthmatic EMTU.

The effect of three different substrates, laminin, fibronectin and reconstituted basement membrane, on isolated mouse pre-Sertoli cells maintained in vitro has been investigated. Cultures were monitored on a daily basis by phase contrast microscopy, and processed for light and electron microscopy at the end of the culture period. Extra-cellular matrix components have been found to influence Sertoli cell differentiation: both fibronectin and laminin promoted cell adhesion and differentiation, though laminin cultures showed poor viability. Pre-Sertoli cells cultured on reconstituted basement membrane showed the highest degree of differentiation, developing a polarized epithelial phenotype and forming cord-like aggregates; such cultures provide a model system for the investigation of factors involved with gonadal differentiation.