Subterranean glacial spillways: an example from the karst of South Wales, UK

Many karst areas in the UK have been glaciated one or more times during the last 0.5 Ma, yet there are few documented examples of caves in these regions being affected by glacial processes other than erosion. The karst of South Wales is one area where sub or pro-glacial modification of pre-existing caves is thought to occur. Evidence from the Ogof Draenen cave system suggests that caves can sometimes act as subterranean glacial ‘underspill’ channels for melt-water. This cave, one of the longest in Britain with a surveyed length of over 70 km, underlies the interfluve between two glaciated valleys. Sediment fills and speleo-morphological observations indicate that melt-water from a high level glacier in the Afon Lwyd valley (>340m asl) filled part of the cave and over-spilled into the neighbouring Usk valley, temporarily reversing non-glacial groundwater flow directions in the cave. It is suggested that this may have occurred during a Middle Pleistocene glaciation

Iron Age to Medieval entomogamous vegetation and Rhinolophus hipposideros roost in south-eastern Wales (UK)

Karst cave systems are well developed in Wales (UK) and, in some instances, constitute important bat roosts. Ogof Draenen, near Blaenavon in south-east Wales, is the most recent major cave discovery (1994) with already > 70 km of passages explored spanning a vertical range of 148 m. With the exception of one small chamber (Siambre Ddu) located directly above the main Ogof Draenen system, very few bats have been noticed inside. Extensive accumulations of guano, attributable to Rhinolophus hipposideros, are however found in parts of the Ogof Draenen system. In places covering many square meters and sometimes building heaps > 0.5 m thick, these represent volumes not yet found in any other cave system in the British Isles. Although the date of the abandonment of the main Ogof Draenen system as a bat roost remains unknown, six radiocarbon dates on guano from Ogof Draenen place the occupation in the Iron Age to Medieval period at least. Palynological analysis was undertaken on ten samples distributed through the cave. Comparisons were made with a moss polster and a lake mud sample from the area to provide a first approximation of the regional modern pollen rain and with two modern guano samples, one from Siambre Ddu and one from Agen Allwedd cave (5 km to the north-west) to provide a temporal comparison with the fossil guano. Agen Allwedd cave currently is one of the largest active roosts for Lesser Horseshoe bats in Britain and lies close to the present northern limit of this endangered species in Europe. The main results are that the cave appears to have been used both as a summer and a winter roost; most of the Ogof Draenen guano is formed within c.1600 14C years and, if the largest heap is continuous, it has accumulated within 750 14C years, i. e. 0.16 mm.year-1; the fossil guano samples reflect a relatively closed oak forest with more abundant ivy (Hedera) and holly (Ilex) than at present; insect-pollinated plants such as Ilex, Acer, Hedera and Impatiens glandulifera are over–represented in the guano samples; in addition to the usual causes of bat roost decline (pesticides, pollution), in the case of Ogof Draenen, we may add entrance blocked by rock collapse and decline of the local forest cover as well as change in its composition

Relative antagonism of mutants of the CGRP receptor extracellular loop 2 domain (ECL2) using a truncated competitive antagonist (CGRP8-37):evidence for the dual involvement of ECL2 in the two-domain binding model

The second extracellular loop (ECL2) of the G protein-coupled receptor (GPCR) family is important for ligand interaction and drug discovery. ECL2 of the family B cardioprotective calcitonin gene-related peptide (CGRP) receptor is required for cell signaling. Family B GPCR ligands have two regions; the N-terminus mediates receptor activation, and the remainder confers high-affinity binding. Comparing antagonism of CGRP8-37 at a number of point mutations of ECL2 of the CGRP receptor, we show that the ECL2 potentially facilitates interaction with up to the 18 N-terminal residues of CGRP. This has implications for understanding family B GPCR activation and for drug design at the CGRP receptor

Intestinal barrier dysfunction in inflammatory bowel diseases

The etiology of human inflammatory bowel diseases (IBDs) is believed to involve inappropriate host responses to the complex commensal microbial flora in the gut, although an altered commensal flora is not completely excluded. A multifunctional cellular and secreted barrier separates the microbial flora from host tissues. Altered function of this barrier remains a major largely unexplored pathway to IBD. Although there is evidence of barrier dysfunction in IBD, it remains unclear whether this is a primary contributor to disease or a consequence of mucosal inflammation. Recent evidence from animal models demonstrating that genetic defects restricted to the epithelium can initiate intestinal inflammation in the presence of normal underlying immunity has refocused attention on epithelial dysfunction in IBD. We review the components of the secreted and cellular barrier, their regulation, including interactions with underlying innate and adaptive immunity, evidence from animal models of the barrier's role in preventing intestinal inflammation, and evidence of barrier dysfunction in both Crohn's disease and ulcerative colitis. (Inflamm Bowel Dis 2008

Uppermost Triassic to Lower Jurassic sediments of the island of Ireland and its surrounding basins

The uppermost Triassic to Lower Jurassic interval has not been extensively studied across the island of Ireland. This paper seeks to redress that situation and presents a synthesis of records of the uppermost Triassic and Lower Jurassic from both onshore and offshore basins as well as describing the sedimentological characteristics of the main lithostratigraphical units encountered. Existing data have been supplemented with a re-examination and logging of some outcrops and the integration of data from recent hydrocarbon exploration wells and boreholes. The Late Triassic Penarth Group and Early Jurassic Lias Group can be recognised across the Republic of Ireland and Northern Ireland. In some onshore basins, almost 600 m of strata are recorded, however in offshore basins thicknesses in excess of two kilometres for the Lower Jurassic have now been recognised, although little detailed information is currently available. The transition from the Triassic to the Jurassic was a period of marked global sea-level rise and climatic change (warming) and this is reflected in the lithostratigraphical record of these sediments in the basins of Northern Ireland and offshore basins of the Republic of Ireland. In general, the sediments of this interval are thicker than those in Great Britain and have potential for detailed study of climatic and sea-level fluctuation

Understanding the molecular functions of the second extracellular loop (ECL2) of the calcitonin gene-related peptide (CGRP) receptor using a comprehensive mutagenesis approach

The extracellular loop 2 (ECL2) region is the most conserved of the three ECL domains in family B G protein-coupled receptors (GPCRs) and has a fundamental role in ligand binding and activation across the receptor super-family. ECL2 is fundamental for ligand-induced activation of the calcitonin gene related peptide (CGRP) receptor, a family B GPCR implicated in migraine and heart disease. In this study we apply a comprehensive targeted non-alanine substitution analysis method and molecular modelling to the functionally important residues of ECL2 to reveal key molecular interactions. We identified an interaction network between R274/Y278/D280/W283. These amino acids had the biggest reduction in signalling following alanine substitution analysis and comprise a group of basic, acidic and aromatic residues conserved in the wider calcitonin family of class B GPCRs. This study identifies key and varied constraints at each locus, including diverse biochemical requirements for neighbouring tyrosine residues and a W283H substitution that recovered wild-type (WT) signalling, despite the strictly conserved nature of the central ECL2 tryptophan and the catastrophic effects on signalling of W283A substitution. In contrast, while the distal end of ECL2 requires strict conservation of hydrophobicity or polarity in each position, mutation of these residues never has a large effect. This approach has revealed linked networks of amino acids, consistent with structural models of ECL2 and likely to represent a shared structural framework at an important ligand-receptor interface that is present across the family B GPCRs

Transforming growth factor-β suppresses metastasis in a subset of human colon carcinoma cells.

BACKGROUND: TGFβ signaling has typically been associated with suppression of tumor initiation while the role it plays in metastasis is generally associated with progression of malignancy. However, we present evidence here for an anti-metastatic role of TGFβ signaling. METHODS: To test the importance of TGFβ signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGFβ response (FET), or tumorigenic with TGFβ response (FETα) or tumorigenic with abrogated TGFβ response via introduction of dominant negative TGFβRII (FETα/DN) and their ability to metastasize. Metastatic competency was assessed by orthotopic transplantation. Metastatic colony formation was assessed histologically and by imaging. RESULTS: Abrogation of TGFβ signaling through introduction of a dominant negative TGFβ receptor II (TGFβRII) in non-metastatic FETα human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGFβ signaling in FETα-DN cells generated enhanced cell survival capabilities in response to cellular stress in vitro. We show that enhanced cellular survival is associated with increased AKT phosphorylation and cytoplasmic expression of inhibitor of apoptosis (IAP) family members (survivin and XIAP) that elicit a cytoprotective effect through inhibition of caspases in response to stress. To confirm that TGFβ signaling is a metastasis suppressor, we rescued TGFβ signaling in CBS metastatic colon cancer cells that had lost TGFβ receptor expression due to epigenetic repression. Restoration of TGFβ signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGFβ signaling has an important role in the suppression of metastatic potential in tumors that have already progressed to the stage of an invasive carcinoma. CONCLUSIONS: The observations presented here indicate a metastasis suppressor role for TGFβ signaling in human colon cancer cells. This raises the concern that therapies targeting inhibition of TGFβ signaling may be imprudent in some patient populations with residual TGFβ tumor suppressor activity

The first discovery of crinoids and cephalopod hooklets in the British Triassic

The Late Triassic Rhaetian stage is perhaps best known in south-west Britain for the bone beds of the Westbury Formation, but there are other fossil-rich horizons within this and the underlying Blue Anchor Formation. Samples from a borehole drilled at the Filton West Chord, and collected from exposures near Bristol Parkway railway station, have yielded significant fossil material from both of these formations. The assemblage recovered from the Blue Anchor Formation is similar to those from the lower Westbury Formation, yielding roughly equal proportions of chondrichthyans and osteichthyans. Assemblages recovered from the Westbury Formation are typical of those from the upper Westbury Formation, in being dominated by osteichthyans. The borehole samples have produced the first recorded evidence of crinoids in the British Triassic, and the first evidence of coleoid cephalopods, in the form of grasping hooklets, from the Rhaetian, and indeed the first from the British Triassic

Differential cytotoxic activity of a novel palladium-based compound on prostate cell lines, primary prostate epithelial cells and prostate stem cells

The outcome for patients with advanced metastatic and recurrent prostate cancer is still poor. Therefore, new chemotherapeutics are required, especially for killing cancer stem cells that are thought to be responsible for disease recurrence. In this study, we screened the effect of a novel palladium-based anticancer agent (Pd complex) against six different prostate cancer cell lines, and primary cultures from seven Gleason 6/7 prostate cancer, three Gleason 8/9 prostate cancer and four benign prostate hyperplasia patient samples, as well as cancer stem cells selected from primary cultures. MTT and ATP viability assays were used to assess cell growth and flow cytometry to assess cell cycle status. In addition, immunofluorescence was used to detect γH2AX nuclear foci, indicative of DNA damage, and Western blotting to assess the induction of apoptosis and autophagy. The Pd complex showed a powerful growth-inhibitory effect against both cell lines and primary cultures. More importantly, it successfully reduced the viability of cancer stem cells as first reported in this study. The Pd complex induced DNA damage and differentially induced evidence of cell death, as well as autophagy. In conclusion, this novel agent may be promising for use against the bulk of the tumour cell population as well as the prostate cancer stem cells, which are thought to be responsible for the resistance of metastatic prostate cancer to chemotherapy. This study also indicates that the combined use of the Pd complex with an autophagy modulator may be a more promising approach to treat prostate cancer. In addition, the differential effects observed between cell lines and primary cells emphasise the importance of the model used to test novel drugs including its genetic background, and indeed the necessity of using cells cultured from patient samples