Membrane glucocorticoid receptors are localised in the extracellular matrix and signal through the MAPK pathway in mammalian skeletal muscle fibres

A number of studies have previously proposed the existence of glucocorticoid receptors on the plasma membrane of many cell types including skeletal muscle fibres. However, their exact localisation and the cellular signalling pathway(s) they utilise to communicate with the rest of the cell are still poorly understood. In this study, we investigated the localisation and the mechanism(s) underlying the non-genomic physiological functions of these receptors in mouse skeletal muscle cells. The results show that the receptors were localised in the cytoplasm in myoblasts, in the nucleus in myotubes and in the extracellular matrix, in satellite cells and in the proximity of mitochondria in adult muscle fibres. Also, they bound laminin in a glucocorticoid-dependent manner. Treating small skeletal muscle fibre bundles with the synthetic glucocorticoid, beclomethasone dipropionate, increased the phosphorylation (=activation) of extracellular-signal regulated kinase 1&2, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. This occurred within 5min and depended on the fibre-type and the duration of the treatment. It was also abolished by the glucocorticoid receptor inhibitor, mifepristone, and a monoclonal antibody against the receptor. From these results we conclude that the non-genomic/non-canonical physiological functions of glucocorticoids, in adult skeletal muscle fibres are mediated by a glucocorticoid receptor localised in the extracellular matrix, in satellite cells and close to mitochondria and involve activation of the MAPK pathway

From Plan to Impact IV: Progress towards targets of the WHO Global action plan on dementia

Dementia is a global phenomenon, yet most people with a diagnosis live in low- and middle-income countries where access to services, support and care are limited. The World Health Organization (WHO) Global action plan on the public health response to dementia 2017–2025 aims to improve the lives of people with dementia and their carers, while decreasing the impact of dementia on communities and countries. Alzheimer’s Disease International (ADI) calls on the international community, in advance of the G7 and G20 planned for 2021, to recognise the growing inequality between different regions of the world in dementia prevention, diagnosis, treatment, care and support

From Plan to Impact IV: Progress towards targets of the WHO Global action plan on dementia

Dementia is a global phenomenon, yet most people with a diagnosis live in low- and middle-income countries where access to services, support and care are limited. The World Health Organization (WHO) Global action plan on the public health response to dementia 2017–2025 aims to improve the lives of people with dementia and their carers, while decreasing the impact of dementia on communities and countries. Alzheimer’s Disease International (ADI) calls on the international community, in advance of the G7 and G20 planned for 2021, to recognise the growing inequality between different regions of the world in dementia prevention, diagnosis, treatment, care and support

Novel initiator caspase reporters uncover previously unknown features of caspase-activating cells

This work was supported by Cancer Research UK (C49979/A17516) and the John Fell Fund, University of Oxford (162/001). L.A.B.-L. is a CRUK Career Development Fellow (C49979/A17516) and an Oriel College, University of Oxford, Hayward Fellow. L.A. is a PhD student supported by the Edward Penley Abraham Research Fund. M.B. is supported by Biotechnology and Biological Sciences Research Council (BB/M021084/1). J-P.V. and C.A. are supported by a European Research Council grant (WNTEXPORT; 294523) and the Medical Research Council (MRC U117584268).The caspase-mediated regulation of many cellular processes, including apoptosis, justifies the substantial interest in understanding all of the biological features of these enzymes. To complement functional assays, it is crucial to identify caspase-activating cells in live tissues. Our work describes novel initiator caspase reporters that, for the first time, provide direct information concerning the initial steps of the caspase activation cascade in Drosophila tissues. One of our caspase sensors capitalises on the rapid subcellular localisation change of a fluorescent marker to uncover novel cellular apoptotic events relating to the actin-mediated positioning of the nucleus before cell delamination. The other construct benefits from caspase-induced nuclear translocation of a QF transcription factor. This feature enables the genetic manipulation of caspase-activating cells and reveals the spatiotemporal patterns of initiator caspase activity. Collectively, our sensors offer experimental opportunities not available by using previous reporters and have proven useful to illuminate previously unknown aspects of caspase-dependent processes in apoptotic and non-apoptotic cellular scenarios.Publisher PDFPeer reviewe

The Middle Pleistocene glacial evolution of northern East Anglia, UK: a dynamic tectonostratigraphic-parasequence approach

The Middle Pleistocene glacial history of northern East Anglia is a controversial topic with differing opinions surrounding chronology, provenance and the relative stratigraphic framework. Reconciling the stratigraphic framework of the region is an essential first step to developing onshore–offshore geological models and a robust event-driven chronological framework. Within this study a dynamic tectonostratigraphic–parasequence methodology is applied to deposits traditionally attributed to the Anglian Glaciation (Marine Isotope Stage 12). This approach offers an insight into ice-bed coupling during glaciation and how evolving boundary conditions influenced glacier dynamics. Six major tectonostratigraphic–parasequence assemblages (A1–A6) are recognized in northern East Anglia and correlate with successive advances into the region of North Sea or Pennine lobes of the British Ice Sheet. Individual tectonostratigraphic–parasequence assemblages are bound at their base by a sedimentary contact or, more commonly, a glacitectonic zone. The geometry and structural characteristics of these glacitectonic zones reflect temporal and spatial variations in ice-bed coupling (traction), a function of substrate rheology and, in turn, variations in lithology, porewater availability and thermo-mechanical properties. The role of permafrost may also be significant, promoting proglacial/ice-marginal thrust stacking in front of advancing ice and enhanced ice-bed decoupling during subsequent overriding and subglacial till accretio

BRITICE Glacial Map, version 2: a map and GIS database of glacial landforms of the last British-Irish Ice Sheet

During the last glaciation, most of the British Isles and the surrounding continental shelf were covered by the British–Irish Ice Sheet (BIIS). An earlier compilation from the existing literature (BRITICE version 1) assembled the relevant glacial geomorphological evidence into a freely available GIS geodatabase and map (Clark et al. 2004: Boreas 33, 359). New high-resolution digital elevation models, of the land and seabed, have become available casting the glacial landform record of the British Isles in a new light and highlighting the shortcomings of the V.1 BRITICE compilation. Here we present a wholesale revision of the evidence, onshore and offshore, to produce BRITICE version 2, which now also includes Ireland. All published geomorphological evidence pertinent to the behaviour of the ice sheet is included, up to the census date of December 2015. The revised GIS database contains over 170 000 geospatially referenced and attributed elements – an eightfold increase in information from the previous version. The compiled data include: drumlins, ribbed moraine, crag-and-tails, mega-scale glacial lineations, glacially streamlined bedrock (grooves, roches moutonnées, whalebacks), glacial erratics, eskers, meltwater channels (subglacial, lateral, proglacial and tunnel valleys), moraines, trimlines, cirques, trough-mouth fans and evidence defining ice-dammed lakes. The increased volume of features necessitates different map/database products with varying levels of data generalization, namely: (i) an unfiltered GIS database containing all mapping; (ii) a filtered GIS database, resolving data conflicts and with edits to improve geo-locational accuracy (available as GIS data and PDF maps); and (iii) a cartographically generalized map to provide an overview of the distribution and types of features at the ice-sheet scale that can be printed at A0 paper size at a 1:1 250 000 scale. All GIS data, the maps (as PDFs) and a bibliography of all published sources are available for download from: https://www.sheffield.ac.uk/geography/staff/clark_chris/britice

Elucidating the non-apoptotic role of the caspases in the Drosophila intestinal system

The deregulation of caspase activity and stem cell properties are often correlated with the appearance and propagation of cancer, including colorectal cancer. However, the caspase-dependent regulation of the intestinal system remains poorly understood. Taking advantage of the powerful genetic tractability of Drosophila melanogaster, I aimed to decipher the functional role of the caspases within the intestinal system, in addition to their role in tumour formation. In this thesis, I demonstrated that using an apical-caspase reporter, I was able to observe widespread and stereotyped patterns of caspase activation within the intestinal system. Furthermore, this activation was non-apoptotic and occurred in non-regenerative conditions. Upon conditional knockout of the mammalian caspase-9/2 orthologue, Dronc, in intestinal progenitors, I demonstrated that Dronc was required to restrain proliferation and prevent the premature differentiation of Enteroblasts into Enteroctytes. Additionally, this activity of Dronc relied on its catalytic activity but not the canonical apoptotic pathway. Using a Dronc-protein reporter I was able to correlate these functions with its specific accumulation within the Enteroblasts. Molecularly, the non-apoptotic activity of Dronc in this context relies on the activity of the Notch and Insulin-TOR pathways. Using the Drop-seq single-cell sequencing technique, I observed the misexpression of several regional and cell-specific genes following loss of Dronc. Furthermore, these Dronc-specific effects may result in the deregulation of the intestinal microbiota. Collectively, this data provides novels insights into the caspase-dependent but non-apoptotic regulation of the intestinal system in non-regenerative conditions. Furthermore, these findings could explain the correlation between caspase-9 misexpression and the bad prognosis observed in patients suffering from colon cancer. </p

Elucidating the non-apoptotic role of the caspases in the Drosophila intestinal system

The deregulation of caspase activity and stem cell properties are often correlated with the appearance and propagation of cancer, including colorectal cancer. However, the caspase-dependent regulation of the intestinal system remains poorly understood. Taking advantage of the powerful genetic tractability of Drosophila melanogaster, I aimed to decipher the functional role of the caspases within the intestinal system, in addition to their role in tumour formation. In this thesis, I demonstrated that using an apical-caspase reporter, I was able to observe widespread and stereotyped patterns of caspase activation within the intestinal system. Furthermore, this activation was non-apoptotic and occurred in non-regenerative conditions. Upon conditional knockout of the mammalian caspase-9/2 orthologue, Dronc, in intestinal progenitors, I demonstrated that Dronc was required to restrain proliferation and prevent the premature differentiation of Enteroblasts into Enteroctytes. Additionally, this activity of Dronc relied on its catalytic activity but not the canonical apoptotic pathway. Using a Dronc-protein reporter I was able to correlate these functions with its specific accumulation within the Enteroblasts. Molecularly, the non-apoptotic activity of Dronc in this context relies on the activity of the Notch and Insulin-TOR pathways. Using the Drop-seq single-cell sequencing technique, I observed the misexpression of several regional and cell-specific genes following loss of Dronc. Furthermore, these Dronc-specific effects may result in the deregulation of the intestinal microbiota. Collectively, this data provides novels insights into the caspase-dependent but non-apoptotic regulation of the intestinal system in non-regenerative conditions. Furthermore, these findings could explain the correlation between caspase-9 misexpression and the bad prognosis observed in patients suffering from colon cancer. </p

Learning on the Fly: The Interplay between Caspases and Cancer

The ease of genetic manipulation, as well as the evolutionary conservation of gene function, has placed Drosophila melanogaster as one of the leading model organisms used to understand the implication of many proteins with disease development, including caspases and their relation to cancer. The family of proteases referred to as caspases have been studied over the years as the major regulators of apoptosis: the most common cellular mechanism involved in eliminating unwanted or defective cells, such as cancerous cells. Indeed, the evasion of the apoptotic programme resulting from caspase downregulation is considered one of the hallmarks of cancer. Recent investigations have also shown an instrumental role for caspases in non-lethal biological processes, such as cell proliferation, cell differentiation, intercellular communication, and cell migration. Importantly, malfunction of these essential biological tasks can deeply impact the initiation and progression of cancer. Here, we provide an extensive review of the literature surrounding caspase biology and its interplay with many aspects of cancer, emphasising some of the key findings obtained from Drosophila studies. We also briefly describe the therapeutic potential of caspase modulation in relation to cancer, highlighting shortcomings and hopeful promises