100,779 research outputs found
The responses of conventional T cells and mucosal-associated invariant T cells to nontypeable Haemophilus Influenzae infection
No full textNontypeable Haemophilus influenzae (NTHi) is a component of the normal lung microbiome, but is also highly associated with respiratory tract infections and exacerbations of major chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). It is not known how commensal bacteria can become pathogenic and cause inflammation in the lung, but is likely due to a breakdown in local immunity. T cell immunity may be key to controlling NTHi infection, although the responses of T cells to NTHi are not well understood. Mucosal-associated invariant T (MAIT) cells are a newly-discovered subset of innate-like T cells, which may play a role in controlling NTHi, as they recognise non-peptide antigens derived from the highly conserved vitamin B2 pathway. The role of MAIT cells in lung immunity to NTHi is also unclear.The aim of this thesis was to study the cytokine and cytotoxic responses of MAIT cells to NTHi infection, comparing these responses to those of conventional T cells. The antigen presentation and co-stimulatory mechanisms that regulate MAIT cell activation have also been explored.Conventional T cell and MAIT cell responses to NTHi were investigated using a human ex vivo lung tissue explant model and an autologous monocyte-derived macrophage (MDM)-T cell co-culture model. Cytokine and cytotoxic responses were measured by a combination of flow cytometry, ELISA and ELISpot. Blocking antibodies were used to determine the role of antigen presentation and cytokine signalling in conventional T cell and MAIT cell activation. Lung MAIT cells significantly upregulated the cytokines; IFNγ, IL-17a and TNFα, and the cytotoxic markers; granzyme B and CD107a, following NTHi infection. A greater proportion of MAIT cells were active compared to conventional T cells. In the blood-derived MDM-T cell co-culture, IFNγ expression by MAIT cells was dependent on MR1 antigen presentation and IL-12 signalling in a time-dependent manner. Cytotoxic responses were regulated by MR1 but also by a novel mechanism where IL-12 and IL-7 signalling synergised to induce granzyme B expression by upregulation of the IL-12 receptor. In contrast, conventional T cell responses predominantly relied on antigen presentation for activation. MAIT cell responses were also impaired by treatment with corticosteroids, which are commonly used to manage inflammation in chronic lung diseases, but are associated with a higher risk of developing pneumonia in COPD patients.Overall, the data in this thesis provide evidence for a role for MAIT cells in controlling NTHi infection in the lung and also highlight key differences in the regulation of innate and adaptive T cells. A further understanding of the mechanism underpinning T cell responses to NTHi infection may yield new therapeutic opportunities and improve the outcome for patients with respiratory diseases
Security for Whom? Changing Discourses on Food in Europe
No full textAfter the CAP reform of 1992 a (partial) consensus had been progressively reached in Europe among stakeholders over multifunctionality, an approach combining liberalization – which would make agriculture more reactive to market signals – with the principle of rewarding farmers for the positive impact of their activity both on the environment and on society. The mid-term review of CAP done in 2003, almost fully decoupling production from subsidies, has brought out scenarios of agricultural restructuring based on a dualism between mass agriculture, more and more integrated into global markets and aligned with the agribusiness and the retail chains, and agriculture for rural development, more and more diversified, integrated with the territory, adopting sustainable processes, developing new models of entrepreneurship based on internalization of operations (processing, selling to consumers, producing feed for animals), on more intense communication toward citizens, consumers and tourists, and on an active search for market niches and hybrid market coalitions.
The food crisis has changed radically the policy agenda and the public debate on Agriculture. Having occupied a central position in the media, the issue has suddenly unified aspects formerly held separate – food security in the world, internal food prices, climate change, biofuels, sustainable agriculture, food quality, GMOs – into one discourse. It has unified the concerns for real income erosion of low and middle class families with the concerns for the hunger in the world. It has put into question the power of supermarket chains and their monopolistic behavior. It has made more acute the dilemmas emerging within the alternative food movements, related to the links and trade-offs between alternative food products price, small farmers’ incomes, consumers’ incomes, sustainability, consumption styles.
The paper, after an outline the current situation in the EU in relation to food availability, food provisioning, food security issues, and the policies that are in place to foster food security for Europe, will analyze how, for effect of the food crisis debate, discourses about food and agriculture and discourse coalitions are changing, and which effect they have had or may have on policy arrangements at national and at EU level. In particular, the paper will analyze how main actors (EU commission, member states, NGOs, food movements, farmers’ unions, agribusiness, supermarket chains, scientists) articulate their positions and their strategies on issues such as the degree of protection of internal markets, the level of public support to agriculture, research and technology policies, models of agriculture, consumption styles. The paper will also discuss how actors belonging to the ‘mass production coalition’ use issues such as world hunger, internal food prices, climate change, the oil crisis to refurbish the image of industrial agriculture and its legitimization. A concluding section will discuss the prospects for alternative food networks in the new scenario and will outline some principles for a research agenda
Sphingosine kinase 2 promotes acute lymphoblastic leukemia by enhancing MYC expression
No full textAbstract not availableCraig T. Wallington-Beddoe, Jason A. Powell, Daochen Tong, Stuart M. Pitson, Kenneth F. Bradstock and Linda J. Bendal
Chapter 5:Atmospheric Chemistry of Halogenated Organic Compounds
No full textHalogenated organic compounds play an important role in atmospheric chemistry. We provide an overview of the atmospheric chemistry of halogenated organic compounds starting with a discussion of sources, emissions, and atmospheric concentrations. The chemistry associated with formation and loss of stratospheric ozone and processes related to halogenated organics is described. A discussion of the atmospheric chemistry of halogenated alkanes, alkenes, oxygenates, sulfur-, nitrogen-, and phosphorus-containing organics is provided. The contribution of halogenated organics to radiative forcing of climate change and the environmental impact of halogenated organic compounds is described.</p
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
Targeting sphingolipid metabolism as an approach for combination therapies in haematological malignancies
No full textLink to a related website: https://doi.org/10.1038/s41420-020-00380-1, Author CorrectionConventional chemotherapy-based drug combinations have, until recently, been the backbone of most therapeutic strategies for cancer. In a time of emerging rationale drug development, targeted therapies are beginning to be added to traditional chemotherapeutics to synergistically enhance clinical responses. Of note, the importance of pro-apoptotic ceramide in mediating the anti-cancer effects of these therapies is becoming more apparent. Furthermore, reduced cellular ceramide in favour of pro-survival sphingolipids correlates with tumorigenesis and most importantly, drug resistance. Thus, agents that manipulate sphingolipid metabolism have been explored as potential anti-cancer agents and have recently demonstrated exciting potential to augment the efficacy of anti-cancer therapeutics. This review examines the biology underpinning these observations and the potential use of sphingolipid manipulating agents in the context of existing and emerging therapies for haematological malignancies.Alexander C. Lewis, Craig T. Wallington-Beddoe, Jason A. Powell and Stuart M. Pitso
Modeling Shifts of Attention During Spatial Language Comprehension
No full textKluth T, Burigo M, Knoeferle P. Modeling Shifts of Attention During Spatial Language Comprehension. In: Tenbrink T, Foltz A, Wallington A, Redondo JO, Ryan J, Bedford E, eds. UK-CLC 2016 Conference Proceedings. Bangor, Gwynedd: Bangor University; 2016: 71
Oncogenic properties of sphingosine kinases in haematological malignancies
No full textThe sphingosine kinases (SphKs) have relatively recently been implicated in contributing to malignant cellular processes with particular interest in the oncogenic properties of SPHK1. Whilst SPHK1 has received considerable attention as a putative oncoprotein, SPHK2 has been much more difficult to study, with often conflicting data surrounding its role in cancer. Initial studies focused on non-haemopoietic malignancies, however a growing body of literature on the role of sphingolipid metabolism in haemopoietic malignancies is now emerging. This review provides an overview of the current state of knowledge of the SphKs and the bioactive lipid sphingosine 1-phosphate (S1P), the product of the reaction they catalyse. It then reviews the current literature regarding the roles of S1P and the SphKs in haemopoietic malignancies and discusses the compounds currently available that modulate sphingolipid metabolism and their potential and shortcomings as therapeutic agents for the treatment of haematological malignancies.Craig T. Wallington-Beddoe, Kenneth F. Bradstock and Linda J. Bendal
The development of historic field systems in northern England: a case study at Wallington, Northumberland
No full textWallington in central Northumberland is a late-seventeenth and early-eighteenth century country house with associated pleasure grounds. Much of the surrounding estate is agricultural land, though there are also expanses of moorland and conifer plantation. The character of Wallington’s landscape, now divided into fifteen separate farm holdings, was to a large extent shaped by estate management practices and improvements in the eighteenth-nineteenth centuries. Today’s settlement pattern is made up largely of dispersed farmsteads, with field systems which reflect the orderly rectilinear layout of planned enclosure, being separated mainly by long and fairly straight stone-faced banks. In medieval and early modern times by contrast, the landscape is thought to have been quite different, with nucleated villages set amidst irregular open fields which were farmed collectively. The process of long-term landscape change from open to enclosed field systems has been inferred across the whole of Northumberland but it can be difficult to understand in detail. Absolute dating evidence for field systems before the eighteenth century is generally lacking and the origins and development of historic earthworks including boundary banks and the remains of arable farming are poorly understood. This paper presents results of research which used retrogressive landscape analysis (based on documentary evidence, archaeological data, aerial photographs and historic cartography) to identify five areas for detailed geoarchaeological investigation and sampling with optically stimulated luminescence profiling and dating (OSL-PD). The results provide new perspectives on the development of landscape character at Wallington which have wider relevance for north-east England and beyond
Steroid-induced deficiency of mucosal-associated invariant T cells in the chronic Obstructive Pulmonary Disease lung: Implications for Nontypeable <i>Haemophilus influenzae</i> Infection
No full textRationale: Mucosal associated invariant T (MAIT) cells are a recently-described, abundant, pro-inflammatory T cell subset with unknown roles in pulmonary immunity. Non-typeable Haemophilus influenzae (NTHi) is the leading bacterial pathogen during COPD exacerbations and a plausible target for MAIT cells.Objectives: To investigate whether MAIT cells respond to NTHi and the effects of inhaled corticosteroids on their frequency and function in COPD. Methods: 11 participants with COPD receiving inhaled corticosteroids (ICS), 8 with steroid-naïve COPD and 21 healthy controls underwent phlebotomy, sputum induction, bronchoalveolar-lavage and endobronchial biopsy. Pulmonary and monocyte-derived macrophages were cultured in vitro with NTHi. Measurements: Frequencies of Va7.2+CD161+ MAIT cells, surface expression of MHC-related protein 1 (MR1) and intracellular IFN-y expression were measured by flow cytometry.Main Results: MAIT cell frequencies were reduced in peripheral blood in ICS-treated COPD (median 0.38% (IQR, 0.25-0.96) compared with health (1.8% (IQR, 1.4-2.5), P=0.001)) or steroid-naïve COPD (1.8% (1.2-2.3), P=0.04). MAIT cells were reduced in bronchial biopsies in steroid-treated COPD (0.73% (0.46-1.3)) compared with health (4.0% (1.6-5.0), P=0.02). Co-culture of live NTHi increased macrophage surface expression of MR1 and induced IFN-? from CD4 cells and CD8 cells, but most potently from MAIT cells (median IFN-y positive frequencies 2.9%, 8.6% and 27.6% respectively). In vitro fluticasone and budesonide reduced MR1 surface expression 2-fold and decreased NTHi-induced IFN-y secretion 8-fold.Conclusions: MAIT cells are deficient in blood and bronchial tissue in steroid-treated, but not steroid-naïve COPD. NTHi constitutes a target for pulmonary MAIT cell immune responses, which are significantly impaired by corticosteroids.<br/
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