Design and development of a debris flow tracking Smart Rock

This thesis covers the design and development of a Smart Rock sensor package to be used in U.S. Geological Survey research of debris flow phenomena. This instrumented Rock, containing inertial sensors and pressure sensors, provides information about the movement of the flow as well as the pressures seen within the flow. The goal of the sensor package is to use this information to track the position of a particle in the flow with an accuracy of 1 m over the course of 10 s.. It is found that using an ad hoc filtering method provides the required level of accuracy. Any known positions are incorporated into the filter. Large scale motions over tens of meters can be distinguished as well as small scale motions on the order of centimeters. Thus, the data gathered by the Smart Rock can be used to help verify and refine debris flow models

Markov chain Monte Carlo analyses of longitudinal biomedical magnetic resonance data

Markov chain Monte Carlo simulation was used in an analysis of the data acquired in three longitudinal biomedical magnetic resonance studies. The first of these investigations uses a Bayesian nonlinear hierarchical random coefficients model to examine the longitudinal extracellular direct current (DC) potential and apparent diffusion coefficient (ADC) responses to focal ischaemia in the rat. The purpose is to perform a formal analysis of the temporal relationship between the two responses, and thus to examine the data for compatibility with a common latent (driving) process and, alternatively, the existence of an ADC threshold for anoxic depolarisation. The DC-potential and ADC transition parameter posterior probability distributions were generated, paying particular attention to the within-subject differences between the DC-potential and ADC transition characteristics. The results indicate that the DC-potential and ADC changes are not driven by a common latent process and, in addition, provide no evidence for a consistent ADC threshold associated with anoxic depolarisation. The second analysis uses data acquired in a nuclear magnetic resonance spectroscopic study into the effects of intestinal ischaemia and subsequent reperfusion on liver metabolism in the rat. The purpose of the analysis is to examine the temporal relationship between energy status [inorganic phosphate to adenosine triphosphate ratio (PAR)] and the pH response, the former of which is an indicator of liver energy failure. The posterior distribution obtained for the PAR-pH onset time difference indicates that the pH response precedes the change in PAR, suggesting that intracellular acidosis cannot be ruled out as a contributing factor to the observed liver failure. The third dataset was acquired in an electron spin resonance study of the Arrhenius behaviour of the rabbit muscle sarcoplasmic reticulum membrane. An MCMC Arrhenius plot changepoint analysis is used to estimate the order parameter 'transition' temperature

Hierarchical models in the analysis of trends in prevalence of congenital anomalies and risks associated with first trimester medications.

PhDAbstract Background Early identification of risk factors, in particular first trimester teratogenic medications, for congenital anomalies (CAs) is essential. Despite similarities between different CAs and between different medications, current surveillance methods in Europe examine each CA and each medication separately. This thesis aims to investigate whether the use of hierarchical statistical methods combining information in groups can improve CA surveillance methods. Methods EUROCAT is a European network of population-based CA registries, with EUROmediCAT comprising those registries with additional information on medication use in pregnancy. Trends in CAs from 2003-2012 in 18 EUROCAT registries (n=81,147) were analysed using Poisson regression models considering each CA separately and using hierarchical models combining related subgroups. First trimester medication exposures from 1995-2011 in 13 EUROmediCAT registries (n=15,058) were analysed. Firstly, groupings of medications and/or CAs were considered when determining the statistical significance of each medication-CA combination, using False Discovery Rate (FDR) procedures to adjust for multiple testing. Secondly, Bayesian hierarchical models were applied to directly model the group effects. The Australian classification system for prescribing medicines in pregnancy was used to independently identify “high risk” medications. The number of “high risk” medications identified by the FDR methods and Bayesian models were compared. Results For analysis of trends, grouping EUROCAT CA subgroups using hierarchical models did not provide additional information over that obtained from independent analyses of each subgroup. The double FDR method grouping medications by ATC3 level codes performed better than other FDR methods. Use of Bayesian hierarchical models did not produce enough of an improvement to justify the increased effort of implementing such models.This work was supported by the Medical Research Council [Award reference: 1504916] and the Wolfson Institute of Preventive Medicine

Design and Synthesis of Achiral and Chiral Imidazodiazepine (IMDZ) GABA(A)R Subtype Selective Ligands for the Treatment of CNS Disorders, as well as Asthma

Gamma-aminobutyric acid type A receptors (GABAAR) are transmembrane pentameric ligand-gated chloride ion channels that respond to GABA, the major inhibitory neurotransmitter in the central nervous systems (CNS). The benzodiazepines (BZDs) bind at the extracellular interface of the α+γ2-subunits of GABAAR. The binding of ligands at different subunits of GABAA receptors specifically at α1-6β2/3 γ2 ion channels, can affect a wide variety of brain functions. The α1-subtype selective ion channels of GABAARs are involved in the sedative, ataxic, amnesic, anticonvulsant and addictive effects, which should be avoided, with the exception of the anticonvulsant effects, when designing ligands for this BZ allosteric modulatory site. The α2/3-containing GABAARs have been implicated by many, in the anxiolytic, anticonvulsant, and antinociceptive activities. At higher doses, muscle relaxation may be mediated by interaction at α3 subtypes. It is known that α5-containing GABAARs are involved in cognition, as well as learning and memory processes. The disruption of GABA activity at α5 subtypes on GABAAR plays a role in the pathophysiology of CNS disorders such as schizophrenia, major depressive disorder (MDD), bipolar disorder and certain anxiety disorders such as OCD. The α5 subtypes in the lung play a major role in potential new treatments for asthma. Based on the privileged imidazodiazepine (IMZD) structures derived from the unified pharmacophore model of Milwaukee, the design, synthesis and biological activities of more than 120 novel chiral GABAAR α2/α3/α5 or α5 subtype selective imidazodiazepines (IMDZs) related to SH-053-2\u27F-R-CH3, and its enantiomer SH-053-2\u27F-S-CH3, as well as the key achiral ligand Hz-166 are described. The goal of this research is to develop new analogs with improved metabolic stability that also retain the desired biological properties with little or no side effects for the treatment of CNS disorders, as well as asthma. Several compounds from the α5 subtype selective group are anxiolytic, antidepressant, as well as pro-cognitive, and are targeted toward the treatment of major depressive disorders. About 20 grams of one lead compound (GL-II-73), and more than 80 analogs were designed, synthesized and evaluated. The α5 selective chiral lead amide, GL-II-73, looks very good in rodent models for the treatment of depression. It exhibited an excellent pharmacokinetic profile, as well as anti-depressant and anxiolytic activities in mice. This antidepressant effect has been realized with no side effects such as sedation nor motor impairment that benzodiazepine drugs would normally effect. In addition, the much sought after improved cognitive effects were clear in mice; this is a key in treating depression or schizophrenia. Examination of the data in the most recent study indicated that the administration of a single dose of GL-II-73 within 30 minutes could reverse the stress-induced or normal aging-related working memory deficits in old mice back up to 80-90 %, which is almost at the level of a young mouse. Whereas the old mice or stressed young mice will normally perform at about a level of 50-60 %. Furthermore, the brain cells, which had shrunk in older mice associated with aging, grew back (dendrites and spines) to a level that is similar to the young mice. This is extremely exciting and occurred after two months of the administration of GL-II-73 to the old mice in their drinking water. These results were presented by our collaborator, Dr. Etienne Sibille in an interview with the BBC, but also resulted in three papers and two patents. It is hoped the CAMH group of Sibille can push this project forward to human trials within two years as proposed. Additional research on these key compounds by several groups is ongoing. One can imagine the use of GL-II-73 or analogs in other neurodegenerative diseases of the CNS. After evaluation of a series of novel IMDZs that were α5 subtype selective for the treatment of asthma, one compound MIDD0301 (originally named GL-II-93) was found to be orally active and also as an inhalant in rodent asthma models. Ligand MIDD0301 was active in the airway smooth muscle (ASM) relaxation assay, in the airway hyper-responsiveness model, in the human and guinea pig tracheal bath assays. Moreover, it does not induce any immunotoxicity in animal models. Taken together this data suggests that this novel ligand can be a potential candidate for the treatment of asthma. About 50 grams of the ligand has been synthesized in good yield to support all the different biological assays from our collaborators. Furthermore, the large scale total synthesis of MIDD0301 was presented to the Alcami Corporation for a proposed kilogram scale synthesis of GMP material for further research on toxicity and safety. This research has resulted in three new publications over the last year. This compound provided some of the impetus to found a new company, Panthergenics, to try to get it through the FDA. Dr. Arnold and Dr. Stafford founded the company via UW-Milwaukee. In regard to the design of new α2/3 subtype selective agents to treat anxiety disorders, neuropathic pain and epilepsy, an improved large scale synthesis of Hz-166, MP-III-080, and KRM-II-81 was executed. These ligands are anxiolytic, anticonvulsant and antinociceptive agents. They were prepared under milder conditions and with much improved yields. Moreover, an alternative reduction process, which was developed for the synthesis of the key aldehyde intermediate from the ethyl ester, was optimized. This new process overcame the long-standing problem of imine reduction in good yield. These methods can be employed for larger scale reactions. In addition, there is no need for column chromatography for most of the compounds, which provided a much more practical route. With the improved synthesis, large quantities of these three α2/3-subtype selective GABAARs PAMs, which exhibited anxiolytic, anticonvulsant and antinociceptive effects in many animal tests, can be supplied with high-efficiency and quality to our collaborators. The large-scale synthesis and the analog research will permit investigation of ADME toxicity and for other behavior assays including those in primates. Studies in animal models for anxiety and epilepsy, as well as for neuropathic pain require gram quantities of compounds, which can now be provided. This will also permit the execution of long-term safety studies in order to approach the FDA

Knowledge and Management Models for Sustainable Growth

In the last years sustainability has become a topic of global concern and a key issue in the strategic agenda of both business organizations and public authorities and organisations. Significant changes in business landscape, the emergence of new technology, including social media, the pressure of new social concerns, have called into question established conceptualizations of competitiveness, wealth creation and growth. New and unaddressed set of issues regarding how private and public organisations manage and invest their resources to create sustainable value have brought to light. In particular the increasing focus on environmental and social themes has suggested new dimensions to be taken into account in the value creation dynamics, both at organisations and communities level. For companies the need of integrating corporate social and environmental responsibility issues into strategy and daily business operations, pose profound challenges, which, in turn, involve numerous processes and complex decisions influenced by many stakeholders. Facing these challenges calls for the creation, use and exploitation of new knowledge as well as the development of proper management models, approaches and tools aimed to contribute to the development and realization of environmentally and socially sustainable business strategies and practices