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

TMEM16B regulates anxiety-related behavior and GABAergic neuronal signaling in the central lateral amygdala.

TMEM16B (ANO2) is the Ca2+-activated chloride channel expressed in multiple brain regions, including the amygdala. Here we report that Ano2 knockout mice exhibit impaired anxiety-related behaviors and context-independent fear memory, thus implicating TMEM16B in anxiety modulation. We found that TMEM16B is expressed in somatostatin-positive (SOM+) GABAergic neurons of the central lateral amygdala (CeL), and its activity modulates action potential duration and inhibitory postsynaptic current (IPSC). We further provide evidence for TMEM16B actions not only in the soma but also in the presynaptic nerve terminals of GABAergic neurons. Our study reveals an intriguing role for TMEM16B in context-independent but not context-dependent fear memory, and supports the notion that dysfunction of the amygdala contributes to anxiety-related behaviors

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

Usage of Indiana University computation and data cyberinfrastructure in FY 2011/2012 and assessment of future needs

This report details the past and current cyberinfrastructure resources that have been deployed by the Research Technologies (RT) division of University Information Technologies Services to support research and scholarly activities at IU. This report also presents data and detailed analysis of system usage and services supported by RT for the FY 2011/2012 period, projects future usage trends based on these data, and provides several recommendations for the most effective ways to meet the growing need for high performance computing resources in research and scholarly endeavors.This research was supported in part by: The Pervasive Technology Institute, Indiana Metabolomics and Cytomics Initiative, and the Indiana Genomics Initiative. All of these initiatives have been supported in part by Lilly Endowment, Inc. Grant number 1U24AA014818-01 from NIAAA/NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAAA/NIH. National Science Foundation under Grants CDA-9601632, EIA-0116050, ACI-0338618l, OCI-0451237, OCI-0535258, and OCI-0504075, CNS-0723054, and CNS-0521433. Shared University Research grants from IBM, Inc. to Indiana University. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the funding agencies represented above

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

Cultivating compassion through compassion circles: learning from experience in mental health care in the NHS

Purpose: This paper aims to discuss the importance of compassion in health care and experiences of Compassion Circles (CCs) in supporting it, placing this into the national policy context of the National Health Service (NHS), whilst focusing on lessons from using the practice in mental health care. Design/methodology/approach: This conceptual paper is a discussion of the context of compassion in health care and a description of model and related concepts of CCs. This paper also discusses lessons from implementation of CCs in mental health care. Findings: CCs were developed from an initial broad concern with the place of compassion and well-being in communities and organisations, particularly in health and social care after a number of scandals about failures of care. Through experience CCs have been refined into a flexible model of supporting staff in mental health care settings. Experience to date suggests they are a valuable method of increasing compassion for self and others, improving relationships between team members and raising issues of organisational support to enable compassionate practice. Research limitations/implications: This paper is a discussion of CCs and their conceptual underpinnings and of insights and lessons from their adoption to date, and more robust evaluation is required. Practical implications: As an emergent area of practice CCs have been seen to present a powerful and practical approach to supporting individual members of staff and teams. Organisations and individuals might wish to join the community of practice that exists around CCs to consider the potential of this intervention in their workplaces and add to the growing body of learning about it. It is worth further investigation to examine the impact of CCs on current concerns with maintaining staff well-being and engagement, and, hence, on stress, absence and the sustainability of work environments over time. Social implications: CCs present a promising means of developing a culture and practice of more compassion in mental health care and other care contexts. Originality/value: CCs have become supported in national NHS guidance and more support to adopt, evaluate and learn from this model is warranted. This paper is a contribution to developing a better understanding of the CCs model, implementation lessons and early insights into impact