Studies of the mechanism of action of anitumour compounds

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

The synthesis and mechanism of action of organic accelerators of the sulphur vilcanisation of rubber

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Unravelling the theories of pre-eclampsia:Are the protective pathways the new paradigm?

Pre-eclampsia is a vascular disorder of pregnancy where anti-angiogenic factors, systemic inflammation and oxidative stress predominate, but none can claim to cause pre-eclampsia. This review provides an alternative to the 'two-stage model' of pre-eclampsia in which abnormal spiral arteries modification leads to placental hypoxia, oxidative stress and aberrant maternal systemic inflammation. Very high maternal soluble fms-like tyrosine kinase-1 (sFlt-1 also known as sVEGFR) and very low placenta growth factor (PlGF) are unique to pre-eclampsia; however, abnormal spiral arteries and excessive inflammation are also prevalent in other placental disorders. Metaphorically speaking, pregnancy can be viewed as a car with an accelerator and brakes, where inflammation, oxidative stress and an imbalance in the angiogenic milieu act as the 'accelerator'. The 'braking system' includes the protective pathways of haem oxygenase 1 (also referred as Hmox1 or HO-1) and cystathionine-γ-lyase (also known as CSE or Cth), which generate carbon monoxide (CO) and hydrogen sulphide (H2S) respectively. The failure in these pathways (brakes) results in the pregnancy going out of control and the system crashing. Put simply, pre-eclampsia is an accelerator-brake defect disorder. CO and H2S hold great promise because of their unique ability to suppress the anti-angiogenic factors sFlt-1 and soluble endoglin as well as to promote PlGF and endothelial NOS activity. The key to finding a cure lies in the identification of cheap, safe and effective drugs that induce the braking system to keep the pregnancy vehicle on track past the finishing line.

Mechanisms of action of microbicides

This chapter describes the sites and mechanisms of action of the major groups of microbicides, relating their physical and chemical properties to interactions with microbial structures. It considers the physical, cellular and molecular methods for studying the mechanisms of action of chemical microbicides. These range from the uptake, binding and penetration of microbial cells, to the interaction with microbial structures, including the cell wall, membrane, nucleic acids, cytoplasm and enzymes. Key features of the mechanisms of action of the major groups of microbicides are described covering oxidizing agents, alkylating agents, metal ion-binding agents, nucleic acid-binding agents, protein denaturants and agents that interact with lipids. © 2013 Blackwell Publishing Ltd.

Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action

Colon and pancreatic cancers contribute to 90,000 deaths each year in the USA. These cancers lack targeted therapeutics due to heterogeneity of the disease and multiple causative factors. One important factor that contributes to increased colon and pancreatic cancer risk is gastrin. Gastrin mediates its actions through two G-protein coupled receptors (GPCRs): cholecystokinin receptor A (CCK-A) and CCK-B/gastrin receptor. Previous studies have indicated that colon cancer predominantly expresses CCK-A and responds to CCK-A isoform antagonists. However, many CCK-A antagonists have failed in the clinic due to poor pharmacokinetic properties or lack of efficacy. In the present study, we synthesized a library of CCK-A isoform-selective antagonists and tested them in various colon and pancreatic cancer preclinical models. The lead CCK-A isoform, selective antagonist PNB-028, bound to CCK-A at 12 nM with a 60-fold selectivity towards CCK-A over CCK-B. Furthermore, it inhibited the proliferation of CCK-A-expressing colon and pancreatic cancer cells without affecting the proliferation of non-cancerous cells. PNB-028 was also extremely effective in inhibiting the growth of MAC-16 and LoVo colon cancer and MIA PaCa pancreatic cancer xenografts in immune-compromised mice. Genomewide microarray and kinase-array studies indicate that PNB-028 inhibited oncogenic kinases and angiogenic factors to inhibit the growth of colon cancer xenografts. Safety pharmacology and toxicology studies have indicated that PNB-028 is extremely safe and has a wide safety margin. These studies suggest that targeting CCK-A selectively renders promise to treat colon and pancreatic cancers and that PNB-028 could become the next-generation treatment option.

Modes of action of antibacterial agents

This chapter describes the modes of action of the major antibiotics and synthetic agents used to treat bacterial infections. Particular attention is given to the biochemical mechanisms by which the agents interfere with biosynthetic processes and the basis for their selective antibacterial action. Interference with the biosynthesis and assembly of structural components of the bacterial cell wall provides the basis for many important groups of antibiotics, including the agents targeting steps in peptidoglycan synthesis. Other agents exploit more subtle differences between bacteria and mammalian cells in fundamental processes such as DNA, RNA and protein synthesis.

Közjó és demokrácia. Két közgazdaságtani elmélet a demokráciáról (Common good and democracy. Two economic theories of democracy)

A tanulmány a demokrácia két közgazdaságtani elméletét mutatja be. A demokrácia klasszikus elmélete a közjó fogalmára épült: a klasszikus politikai filozófia érvelése szerint a demokrácia intézménye a közjó megvalósulásának eszköze. Schumpeter bírálta a klasszikus elméletet: a közgazdasági szemléletet alkalmazva a közjó értelmezésére leválasztotta a demokráciáról a közjó fogalmát. Schumpeter szerint a demokrácia szubsztantív felfogása nem tartható, ezért ehelyett a demokrácia procedurális értelmezését kínálta fel. Az alkotmányos közgazdaságtan nem fogadja el sem a közjó és demokrácia fogalmainak elválasztását, sem a közjó szubsztantív értelmezését, ehelyett a közjónak és a demokráciának egyaránt procedurális értelmezését javasolja. _____ This essay deals with two economic theories of democracy. The classical doctrine of democracy was built on the concept of the common good, classical political philosophy arguing that the institution of democracy was the instrument for realizing the common good. This theory was criticized by Schumpeter, who applied the method of modern economics to analysis of the concept, which he separated from democracy, arguing that the substantive concept of democracy was untenable, and proposing to replace it with the procedural concept of democracy. Constitutional economics does not accept such separation of the concepts of democracy and the common good, but it does not accept the substantive interpretation of the common good either. Rather, it proposes a procedural concept of both the common good and of democracy.

From theory-inspired to theory-based interventions : A protocol for developing and testing a methodology for linking behaviour change techniques to theoretical mechanisms of action

This research is funded by UK Medical Research Council grant number MR/L011115/1

From Theory-Inspired to Theory-Based Interventions : A Protocol for Developing and Testing a Methodology for Linking Behaviour Change Techniques to Theoretical Mechanisms of Action

This research is funded by UK Medical Research Council grant number MR/L011115/1. We would like to thank the 105 experts in behaviour change who have committed their time and offered their expertise for study 2 of this research. We are also very grateful to all those who sent us peer-reviewed behaviour change intervention descriptions for study 1. Finally, we would like thank Dr. Emma Beard and Dr. Dan Dediu for their statistical input and to all the researchers, particularly Holly Walton, who have assisted in the coding of papers for study 1.

Prospects for probabilistic theories of natural information

Peer reviewed

Vagal blocking for obesity control : a possible mechanism-of-action

Peer reviewed

British Romantic Criticism and the Fine Arts: A Study in Philosophical Theories of Literary Unity

This dissertation is an exploration of how a small but important group of Romantic critics, finding fault in the ideal of three unities developed by neoclassical Academicians and wrongly attributed to Aristotle, turned to the terminology and practices of the fine arts to emphasize their conception of organic unity in literature. The Romantic analogy to painting in particular enables a philosophical criticism of literature to present the aesthetic semblance of painting, the comprehension of a multitude of details in a harmonious whole that is a natural unity to its medium, as a paradigm of modern-romantic poetry and its aspirations to similar complexity, particularity, and imaginative colour. Further, in extension of the French Querelle des anciens et des modernes of the seventeenth century, the division of ancient and romantic art by Romantic critics like August Schlegel, Samuel Taylor Coleridge, and William Hazlitt not only establishes an ethnological and historical difference between the artistic productions of these two cultural periods but also allows, unlike the neoclassical unities, a non-anachronistic philosophical vocabulary of whole and parts or of the general and particular in the criticism of poetry, which involution provides a “rule” more consonant with the laws of the imagination rather than with the rhetorical and absolutist dicta that were thither available in the literary canon.

Attenuation of monocyte chemotaxis--a novel anti-inflammatory mechanism of action for the cardio-protective hormone B-type natriuretic peptide

B-type natriuretic peptide (BNP) is a prognostic and diagnostic marker for heart failure (HF). An anti-inflammatory, cardio-protective role for BNP was proposed. In cardiovascular diseases including pressure overload-induced HF, perivascular inflammation and cardiac fibrosis are, in part, mediated by monocyte chemoattractant protein (MCP)1-driven monocyte migration. We aimed to determine the role of BNP in monocyte motility to MCP1. A functional BNP receptor, natriuretic peptide receptor-A (NPRA) was identified in human monocytes. BNP treatment inhibited MCP1-induced THP1 (monocytic leukemia cells) and primary monocyte chemotaxis (70 and 50 %, respectively). BNP did not interfere with MCP1 receptor expression or with calcium. BNP inhibited activation of the cytoskeletal protein RhoA in MCP1-stimulated THP1 (70 %). Finally, BNP failed to inhibit MCP1-directed motility of monocytes from patients with hypertension (n = 10) and HF (n = 6) suggesting attenuation of this anti-inflammatory mechanism in chronic heart disease. We provide novel evidence for a direct role of BNP/NPRA in opposing human monocyte migration and support a role for BNP as a cardio-protective hormone up-regulated as part of an adaptive compensatory response to combat excess inflammation.

Territoriality and Migration in a Divided Society: Lay Theories of Citizenship and Place in Northern Ireland

The study of citizenship has increasingly focused on the ways in which spatialized understandings of the concept can be used to marginalise and exclude social groups: exclusive constructions of national boundaries, local neighbourhoods and public spaces can deny marginalised groups their social and political rights. Less attention has been paid to how constructions of place can accommodate different groups’ rights and promote peaceful coexistence. This is particularly important in locations where migration disrupts existing understandings (‘lay theories’) of the relationship between residency, identity and collective rights. The present research examines how spatialized understandings of citizenship shape perceptions of intergroup mixing in previously segregated areas of a post-conflict society. Critical Discursive Social Psychological (CDSP) analysis of 30 interviews with long-term residents and recent migrants to increasingly mixed areas of Belfast shows that, while all pa
rticipants acknowledged Northern Ireland’s territorialisation, different lay theories of citizenship underpin the possibility and desirability of intergroup coexistence. Long-term residents drew upon understandings of the negative citizenry of the outgroup to argue against the possibility of peaceful coexistence within their locale, while recent incomers gave evidence of their own experiences of good citizenship within the shared spaces of neighbourhood to demonstrate that this could and should be achieved. The implications of lay theories of citizenship for the study of residential migration and mixing are discussed