Ore depositional processes in the formation of the Navan zinc/lead deposit, Co. Meath, Ireland

Strathclyde theses - ask staff. Thesis no.: T678

Clinical psychologists\u27 endorsements of mental disorder ideology as a function of personal sociopolitical values.

The sociopolitical underpinnings of psychiatric theory are examined both theoretically and empirically. In the theoretical analysis, the view of mental disorder as a value-free conception is shown to be rooted in logical-positivism, an epistemology which has been strongly criticized for positing a realm of science beyond values. It is argued that psychiatric theory, live all knowledge, contains values which promote particular sociopolitical interests. Traditional mental disorder conceptions are outlined as supporting the interests of dominant sectors of society by focusing on the intra-individual concomitants of psychiatric distress and minimizing the importance of the social context in which human suffering arises. By directing attention away from adverse societal factors, such as inequality and powerlessness, these asocial models protect the sociopolitical system from criticism and reform. An empirical investigation was conducted in order to investigate the relationship between mental health clinicians\u27 personal sociopolitical values and their endorsement of asocial theoretical formulations. Research questionnaires were mailed to 810 clinical psychologists throughout the United States. Participants were required to complete three measures of sociopolitical values, read four clinical case vignettes, assess whether the case descriptions indicated evidence of a mental disorder, and rate the extent to which each of Biological, Psychological, Interpersonal/Situational and Societal factors were relevant to the vignette subjects\u27 problems. One hundred and thirty useable questionnaires were returned. Results indicated that the Societal factor was assigned less importance than all other mental health factors, supporting the contention that clinicians minimize socio-contextual variables in their theoretical models. Higher mental disorder ratings were somewhat associated with greater endorsement of Biological and Psychological mental health factors, providing some support for the thesis that mental disorder conceptions are asocially based. Overall the mental health framework of psychologists with differing sociopolitical values were quite similar. However, endorsement of the Societal factor was moderately associated with liberalism and the endorsement of the Psychological factor was somewhat associated with conservatism, suggesting that the more conservative practitioners employed more asocial models. Recommendations for clinical practice are outlined from a socio-cultural perspective. Source: Dissertation Abstracts International, Volume: 56-11, Section: B, page: 6411. Adviser: James Porter. Thesis (Ph.D.)--University of Windsor (Canada), 1994

Intracellular energy variability modulates cellular decision-making capacity

Cells are able to generate phenotypic diversity both during development and in response to stressful and changing environments, aiding survival. The biologically and medically vital process of a cell assuming a functionally important fate from a range of phenotypic possibilities can be thought of as a cell decision. To make these decisions, a cell relies on energy dependent pathways of signalling and expression. However, energy availability is often overlooked as a modulator of cellular decision-making. As cells can vary dramatically in energy availability, this limits our knowledge of how this key biological axis affects cell behaviour. Here, we consider the energy dependence of a highly generalisable decision-making regulatory network, and show that energy variability changes the sets of decisions a cell can make and the ease with which they can be made. Increasing intracellular energy levels can increase the number of stable phenotypes it can generate, corresponding to increased decision-making capacity. For this decision-making architecture, a cell with intracellular energy below a threshold is limited to a singular phenotype, potentially forcing the adoption of a specific cell fate. We suggest that common energetic differences between cells may explain some of the observed variability in cellular decision-making, and demonstrate the importance of considering energy levels in several diverse biological decision-making phenomena

Platinum group element signatures in the North Atlantic Igneous Province: Implications for mantle controls on metal budgets during continental breakup

The North Atlantic Igneous Province (NAIP) is a large igneous province (LIP) that includes a series of lava suites erupted from the earliest manifestations of the (proto)-Icelandic plume, through continental and ultimately oceanic rifting. The lavas of one of these sub-provinces, the British Palaeogene Igneous Province (BPIP), were some of the first lavas to be erupted in the NAIP and overlie a thick crustal basement and sedimentary succession with abundant S-rich mudrocks. We present the first platinum-group element (PGE) and Au analyses of BPIP flood basalts from the main lava fields of the Isle of Mull and Morvern and the Isle of Skye, in addition to a suite of shallow crustal dolerite volcanic plugs on Mull, and other minor lavas suites. BPIP lavas display both Ssaturated and S-undersaturated trends which, coupled with elevated PGE abundances (> MORB), suggest that the BPIP is one of the most prospective areas of the NAIP to host Ni-Cu-PGE-(Au) mineralisation in conduit systems. Platinum-group element, Au and chalcophile element abundances in lavas from West and East Greenland, and Iceland, are directly comparable to BPIP lavas, but the relative abundances of Pt and Pd vary systematically between lavas suites of different ages. The oldest lavas (BPIP and West Greenland) have a broadly chondritic Pt/Pd ratio (~ 1.9). Lavas from East Greenland have a lower Pt/Pd ratio (~ 0.8) and the youngest lavas from Iceland have the lowest Pt/Pd ratio of the NAIP (~ 0.4). Hence, Pt/Pd ratio of otherwise equivalent flood basalt lavas varies temporally across the NAIP and appears to be coincident with the changing geodynamic environment of the (proto)-Icelandic plume through time. We assess the possible causes for such systematic Pt/Pd variation in light of mantle plume and lithospheric controls, and suggest that this reflects a change in the availability of lithospheric mantle Pt-rich sulphides for entrainment in ascending plume magmas. Hence the precious metal systematics and potential prospectivity of a LIP may be affected by contamination of plume-derived magmas by subcontinental lithospheric mantle at the margins of cratons that has been enriched by Palaeoproterzoic orogenesis

Patient complaints as predictors of patient safety incidents

Patients remain an underused resource in efforts to improve quality and safety in healthcare, despite evidence that they can provide valuable insights into the care they receive. This study aimed to establish whether high-level patient safety incidents (HLIs) were predictable from preceding complaints, enabling complaints to be used to prevent HLIs. For this study complaints received from November 2011 through June 2012 and HLI incident reports from April through September 2012 were examined. Complaints and HLIs were categorised according to location or specialty and the themes they included. Data were analysed to look for correlations between number of complaints and HLIs in a given area. A qualitative analysis was carried out to determine whether any complaints contained information that, if acted upon earlier, could have prevented later HLIs. In the data a total of 52 complaints and 16 HLIs were included. No correlation was established between location of HLIs and complaints. Complaints commonly focused on staff attitude, diagnostic problems and delayed treatment. HLIs most often arose from failure to recognise a patient’s deterioration and escalate appropriately or incorrect patient identification. Most HLIs were not preceded by similar complaints. However, in two instances complaints did signpost future HLIs. Patient complaints can highlight specific risks to patient safety and act as an early warning system. There is a need to devise reliable means of identifying the minority of complaints that do precede serious incidents

Dynamic Boolean modelling reveals the influence of energy supply on bacterial efflux pump expression

Antimicrobial resistance (AMR) is a global health issue. One key factor contributing to AMR is the ability of bacteria to export drugs through efflux pumps, which relies on the ATP-dependent expression and interaction of several controlling genes. Recent studies have shown that significant cell-to-cell ATP variability exists within clonal bacterial populations, but the contribution of intrinsic cell-to-cell ATP heterogeneity is generally overlooked in understanding efflux pumps. Here, we consider how ATP variability influences gene regulatory networks controlling expression of efflux pump genes in two bacterial species. We develop and apply a generalizable Boolean modelling framework, developed to incorporate the dependence of gene expression dynamics on available cellular energy supply. Theoretical results show that differences in energy availability can cause pronounced downstream heterogeneity in efflux gene expression. Cells with higher energy availability have a superior response to stressors. Furthermore, in the absence of stress, model bacteria develop heterogeneous pulses of efflux pump gene expression which contribute to a sustained sub-population of cells with increased efflux expression activity, potentially conferring a continuous pool of intrinsically resistant bacteria. This modelling approach thus reveals an important source of heterogeneity in cell responses to antimicrobials and sheds light on potentially targetable aspects of efflux pump-related antimicrobial resistance.publishedVersio

Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity.

Falcipain-2 and falcipain-3 are critical hemoglobinases of Plasmodium falciparum, the most virulent human malaria parasite. We have determined the 2.9 A crystal structure of falcipain-2 in complex with the epoxysuccinate E64 and the 2.5 A crystal structure of falcipain-3 in complex with the aldehyde leupeptin. These complexes represent the first crystal structures of plasmodial cysteine proteases with small molecule inhibitors and the first reported crystal structure of falcipain-3. Our structural analyses indicate that the relative shape and flexibility of the S2 pocket are affected by a number of discrete amino acid substitutions. The cumulative effect of subtle differences, including those at "gatekeeper" positions, may explain the observed kinetic differences between these two closely related enzymes

In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi.

BackgroundCruzain, the major cysteine protease of Trypanosoma cruzi, is an essential enzyme for the parasite life cycle and has been validated as a viable target to treat Chagas' disease. As a proof-of-concept, K11777, a potent inhibitor of cruzain, was found to effectively eliminate T. cruzi infection and is currently a clinical candidate for treatment of Chagas' disease.Methodology/principal findingsWRR-483, an analog of K11777, was synthesized and evaluated as an inhibitor of cruzain and against T. cruzi proliferation in cell culture. This compound demonstrates good potency against cruzain with sensitivity to pH conditions and high efficacy in the cell culture assay. Furthermore, WRR-483 also eradicates parasite infection in a mouse model of acute Chagas' disease. To determine the atomic-level details of the inhibitor interacting with cruzain, a 1.5 A crystal structure of the protease in complex with WRR-483 was solved. The structure illustrates that WRR-483 binds covalently to the active site cysteine of the protease in a similar manner as other vinyl sulfone-based inhibitors. Details of the critical interactions within the specificity binding pocket are also reported.ConclusionsWe demonstrate that WRR-483 is an effective cysteine protease inhibitor with trypanocidal activity in cell culture and animal model with comparable efficacy to K11777. Crystallographic evidence confirms that the mode of action is by targeting the active site of cruzain. Taken together, these results suggest that WRR-483 has potential to be developed as a treatment for Chagas' disease

MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease

MicroRNA (miRNA) has the potential for cross-regulation and functional integration of discrete biological processes during complex physiological events. Utilizing the common human condition tendinopathy as a model system to explore the cross-regulation of immediate inflammation and matrix synthesis by miRNA we observed that elevated IL-33 expression is a characteristic of early tendinopathy. Using in vitro tenocyte cultures and in vivo models of tendon damage, we demonstrate that such IL-33 expression plays a pivotal role in the transition from type 1 to type 3 collagen (Col3) synthesis and thus early tendon remodelling. Both IL-33 effector function, via its decoy receptor sST2, and Col3 synthesis are regulated by miRNA29a. Downregulation of miRNA29a in human tenocytes is sufficient to induce an increase in Col3 expression. These data provide a molecular mechanism of miRNA-mediated integration of the early pathophysiologic events that facilitate tissue remodelling in human tendon after injury