Functional Magnetic Resonance Imaging (fMRI) based studies are rapidly expanding in the field of preclinical research. The majority of these studies use Echo Planar Imaging (EPI) to measure Blood Oxygenation Level Dependent (BOLD) signal contrasts in the brain. In such studies the magnitude and statistical significances of these contrasts are then related to brain function and cognition. It is assumed that any observed signal contrast is ultimately due to differences in biological state and that scanner performance is stable and repeatable between subjects and studies. However, due to confounding issues introduced by in vivo subjects, little work has been undertaken to test this basic assumption. As the BOLD signal contrasts generated in such experiments are often very low, even small changes in scanner performance may dominate the BOLD contrast, distorting any biological conclusions drawn. A series of fMRI phantoms were produced to measure scanner performance independent of biological subjects. These phantoms produce specified signal contrast levels on demand during an fMRI scan by means of current-induced magnetic field gradients. These were used to generate data sets that emulated the BOLD signal contrast of in vivo imaging. Two studies examining scanner performance were then conducted on high-field preclinical MRI scanners. Firstly, in a longitudinal study on a single scanner, measurements were taken over a number of days across a week long period and then every two months over a year long period. Secondly, the behaviour of four preclinical scanners (three at 7T, one at 9.4T) was comparatively assessed. Measurements of several imaging parameters including contrast generated and functional contrast to noise ratio (fCNR) were obtained in both studies. If the scanners involved are truly comparable then they should generate similar measurement values. Across both studies parameter measurements showed significant differences for identical contrast settings on the phantom. Although signal contrast itself proved very comparable across the studies fCNR proved to be highly variable. As well as these measurements of longer tem behaviour proving variable, short and mid-term signal stability displayed a wide range of variability. Variations in the level and quality of both signal and noise were observed. Modelling of signal changes based on fundamental physical principles was also performed for comparison. The impact of these behaviours and variations on in vivo studies could result in skewed biological conclusions at any single site, with some sites exhibiting greater problems than others. The multisite results suggest potential difficulties when comparing biological conclusions between sites, even when using identical imaging parameters. In summary, these results suggest that a cautious approach should be taken with the conclusions of both fMRI and associated resting state connectivity studies that use EPI as their acquisition sequence. Improvements to both the experimental design of studies and regular quality monitoring of scanners should be undertaken to minimise these effects. Clinical MRI scanners should also be assessed for similar aberrations in behaviour.

abstract: The objective of this research was to predict the persistence of potential future contaminants in indirect potable reuse systems. In order to accurately estimate the fates of future contaminants in indirect potable reuse systems, results describing persistence from EPI Suite were modified to include sorption and oxidation. The target future contaminants studied were the approximately 2000 pharmaceuticals currently undergoing testing by United States Food and Drug Administration (US FDA). Specific organic substances such as analgesics, antibiotics, and pesticides were used to verify the predicted half-lives by comparing with reported values in the literature. During sub-surface transport, an important component of indirect potable reuse systems, the effects of sorption and oxidation are important mechanisms. These mechanisms are not considered by the quantitative structure activity relationship (QSAR) model predictions for half-lives from EPI Suite. Modifying the predictions from EPI Suite to include the effects of sorption and oxidation greatly improved the accuracy of predictions in the sub-surface environment. During validation, the error was reduced by over 50% when the predictions were modified to include sorption and oxidation. Molecular weight (MW) is an important criteria for estimating the persistence of chemicals in the sub-surface environment. EPI Suite predicts that high MW compounds are persistent since the QSAR model assumes steric hindrances will prevent transformations. Therefore, results from EPI Suite can be very misleading for high MW compounds. Persistence was affected by the total number of halogen atoms in chemicals more than the sum of N-heterocyclic aromatics in chemicals. Most contaminants (over 90%) were non-persistent in the sub-surface environment suggesting that the target future drugs do not pose a significant risk to potable reuse systems. Another important finding is that the percentage of compounds produced from the biotechnology industry is increasing rapidly and should dominate the future production of pharmaceuticals. In turn, pharmaceuticals should become less persistent in the future. An evaluation of indirect potable reuse systems that use reverse osmosis (RO) for potential rejection of the target contaminants was performed by statistical analysis. Most target compounds (over 95%) can be removed by RO based on size rejection and other removal mechanisms. / Dissertation/Thesis / Ph.D. Civil and Environmental Engineering 2011

Les mycotoxines sont des métabolites secondaires de moisissures contaminant de façon naturelle de nombreuses denrées alimentaires, notamment les céréales. Le déoxynivalénol (DON), produit par Fusarium sp., est la mycotoxine la plus répandue dans le monde. Du fait de sa grande stabilité chimique, le DON est difficile à éliminer, et se retrouve dans les céréales et les produits finis ou il induit des effets toxiques pour l'homme et l'animal. De nouvelles stratégies de lutte sont mises en places, telle la transformation biologique utilisant des bactéries ou des plantes. En effet certaines bactéries possèdent des enzymes capables de transformer le DON en de nouveaux composés, le déepoxy-déoxynivalénol (DOM-1) et le 3-épi-déoxynivalénol (3-epi-DON). De plus, certaines plantes sont naturellement capables de transformer le DON dans le but de l'éliminer et de le détoxifier, formant ainsi le deoxynivalénol-3-ß-D-glucoside (D3G). L'objectif de cette thèse était d'évaluer la toxicité de ces dérivés du DON au niveau de l'intestin et du système immunitaire par le biais d'analyses in silico, in vitro, ex vivo et in vivo. Les tests de toxicité in vitro sur la lignée humaine intestinale cellulaire Caco-2 montrent que le DOM-1, le 3-epi-DON et le D3G n'étaient pas cytotoxiques, ils ne modifiaient ni la viabilité, ni la fonction de barrière des cellules, mesurée par la résistance électrique transépithéliale. Les tests de toxicité ex vivo sur des explants jéjunum porcin ont montré que le DOM-1, le 3-epi-DON ou le D3G n'induisaient pas de modifications histomorphologiques. En revanche, les explants exposés au DON montraient des lésions morphologiques et une régulation positive de l'expression des cytokines pro-inflammatoires. L'impact de ces trois dérivés a été également analysé sur l'expression de l'ensemble des gènes du tissu, avec une analyse microarray. Ceci a montré que ces dérivés du DON n'induisaient aucun changement dans l'expression des gènes par rapport au groupe contrôle. Le DON quand a lui exprimait différentiellement 747 sondes, correspondantes à 333 gènes impliqués dans l'immunité, la réponse inflammatoire, le stress oxydatif, la mort cellulaire, le transport moléculaire et la fonction mitochondriale. L'analyse in silico a montré que le D3G, contrairement au DON était incapable de se lier au site-A du ribosome, principale cible de la toxicité pour le DON. Les deux dérivés microbiens eux, étaient capables de se fixer au site-A au sein du ribosome, mais contrairement au DON ils ne formaient que deux liaisons hydrogènes au lieu de trois. De plus, ces trois dérivés n'induisaient pas de stress ribotoxique, d'activation des MAPKs (mitogen-activated protein kinases), et de réponse pro-inflammatoire. Une étude complémentaire a été menée in vivo pour évaluer la toxicité du DOM-1 chez le porc (gavage pendant 21 jours avec .0.14mg / kg de poids vif). Les résultats ont montré que le DOM-1, contrairement au DON n'induisait pas les effets toxiques du DON au niveau des paramètres zootechniques (pas de vomissements, aucune diminution de la consommation alimentaire ou de perte de poids), sur l'intestin et le foie (pas de dommages tissulaires), ou sur la réponse immunitaire (pas de réponse inflammatoire induite). En conclusion, nos résultats montrent l'efficacité de ces transformations enzymatiques. La déepoxydation et l'épimérisation bactérienne, ainsi que la glycosylation par les plantes permettent de sensiblement diminuer la toxicité du DON, passant par une absence de toxicité sur le ribosome avec une absence d'activation des MAPKs et de réponses inflammatoires. Dans ce contexte de contamination par les mycotoxines, ces méthodes de luttes alternatives semblent être des approches prometteuses. / The Fusarium sp. mycotoxin deoxynivalenol (DON) is one of the most frequently widespread mycotoxin worldwide. Due to its high structural stability, the elimination of DON, once present in cereals or feed materials, becomes difficult. Thereby, it is present in many cereals and final feed products, inducing several toxic effects on human and animals, and causing big economic losses. New strategies of to fight against mycotoxins were developed, as biological transformation, either by the use of bacteria or plants. Indeed, some microorganisms are able to transform DON in new products, by enzymatic reaction, forming the deepoxy-deoxynivalenol (DOM-1) and the 3-epi-deoxynivalenol (3-epi-DON). Moreover, some plants naturally own the capacity to glycosylate DON in the aim to detoxify it, forming the deoxynivalenol-3-ß-D-glucoside (D3G). The aim of this thesis was to assess the toxicity of these DON derivatives, on the intestine and immune response, using several approaches such as in silico, in vitro, ex vivo and in vivo models. On the human intestinal Caco-2 cell line, DOM-1, 3-epi-DON and D3G were not cytotoxic; they did not alter its viability and barrier function, as measured by the trans epithelial electrical resistance. The expression profile of DOM-1, 3-epi-DON and D3G-treated jejunal explants was similar to that of controls and these explants did not show any histomorphology alteration. On the other hand, the treatment of intestinal explants with DON, induced morphological lesions and upregulated the expression of proinflammatory cytokines. The impact of these three derivatives was also studied on intestinal explants with a pan-genomic transcriptomic analysis. Results show that the derivatives of DON did not induce any change on the gene expression in comparison to the control-treated explants. In contrary, DON-treated explants differentially expressed 747 probes, representing 323 genes involved in immune and inflammatory responses, oxidative stress, cell death, molecular transport and mitochondrial function. In silico analysis revealed that D3G, opposing to DON, was unable to bind to the A site of the ribosome, which is the main target for DON toxicity. Both DOM-1 and 3-epi-DON were able to fit into the pockets of the A site of the ribosome but only by forming two hydrogen bonds, while in this position, DON forms three hydrogen bonds. Moreover, the three derivatives do not elicit a ribotoxic stress, MAPKinase activation, and inflammatory response. Then, an in vivo study was carried out to assess the toxicity of DOM-1 on pig (feed forced during 21 days at 0.14 mg/Kg BW). The results showed that DOM-1 does not have as much toxic effects as DON on zootechnical parameters (no emesis induced, no decrease of food consumption or weight loss observed), on intestine and liver (no tissues damages), or on the immune response (no inflammatory response induced). Our data demonstrate that bacterial de-epoxidation or epimerization of deepoxy-DON modified its interaction with the ribosome, leading to an absence of MAPKinase activation and toxicity; and that the glycosylation of DON suppresses its ability to bind to the ribosome and decreases its intestinal toxicity. The mycotoxin deoxynivalenol (DON) remains an important challenge in many regions in the world. Thus, these biological detoxifications of DON seem to represent a new promising approach helping manage the problem of its contamination.

The thesis entitled “Enantiospecific synthesis of bio-active stryllactones” comprise an introduction about stryllactone and two chapters describes the synthesis of stryllactones. Trees of the genus Goniothalamus of the plant family Annonaceae in South East Asia has been known for a long time for their proven as folkloric medicine. Stryryllactones were found to exhibit moderate to significant biological activity including antitumour, antifungal as well as antibiotic properties. Because of their unique and intriguing structures and the activity associated much effort has been centered on the development of methodology for the synthesis of these compounds. The structures and relative configurations of these compounds were determined either by X-ray crystallography or by extensive NMR spectral analysis and by mass spectroscopic techniques. The research group of McLaughlin isolated and characterized a series of styryllactones, possessing significant to marginal cytotoxic activity against human tumor cell lines. The structures and relative configurations of these compounds were determined either by X-ray crystallography or by extensive NMR spectral analysis. Classification of these styryllactones is based on the structural characteristics of the six different skeletons as shown in Figure 1. Figure 1:features styryllactone the genus In this thesis, enantioselective total synthesis of styryllactones ()-9-deoxygoniopypyrone 1, ()-goniopypyrone 2, ()-7-epi-goniofufurone 3, ()-7-epigoniodiol 4 and the putative structure of ()-etharvendiol 5 is presented. a) Total synthesis of ()-9-deoxygoniopypyrone, ()-goniopypyrone, ()-7-epigoniofufurone and ()-7-epi-goniodiol: Synthesis of the styrylalctones is relied on elaboration of the trihydroxy ester 11 derived from tartaric acid. Appropriate protection of the hydroxy groups and further modifications of the ester functionality (which can be transformed into the corresponding alcohol or aldehyde) is planned for the synthesis of the styryllactones 1-5. Accordingly, the bis-dimethylamide 9 derived from D-()-tartaric acid, was transformed to the -hydroxy amide 10 using a combination of Grignard reagent addition followed by reduction of the resultant ketone. Acid mediated deprotection of the acetonide with concomitant hydrolysis of the amide to the ester is accomplished in one pot by treating 10 with p-TSA in benzene/MeOH mixture Treatment of the trihydroxy ester with 2,2-dimethoxy propane in presence of p-TSA afforded the hydroxy ester 12 which was elaborated to the styrylalctones 9deoxygoniopypyrone, 7-epi-goniodiol, 7-epi-goniofufurone and goniopypyrone (Scheme-2). (Part of this work is published: Prasad, K. R.; Dhaware, M.G. Synlett. 2007, 11121114.; Prasad, K.R.; Dhaware, M.G. Synthesis 2007, 3697) b) Stereoselective synthesis of the putative structure of (+)-etharvendiol: In 1997, Bermejo et al isolated the styryl pyrone etharvendiol 5 from the ethanolic extract of stem bark from Goniothalamus arvensis. Hitherto, no synthesis of etharvendiol is reported in the literature. In this section, approach towards the synthesis of putative structure of etharvendiol will be discussed. Synthesis of etharvendiol 5 is anticipated by the elaboration of masked tetrol 15, comprising an alkene tether and four contiguous hydroxy groups installed with definite configuration. It is relied on exploiting the hydroxy directed lactonization via the oxidation of alkene in 15, and subsequent elaboration to 7. Bis-dimethylamide 9, derived from D-()-tartaric acid was identified as the suitable precursor for the synthesis of 15. Synthesis of masked tetrol 15 is accomplished from 9 involving a combination of selective Grignard additions and stereoselective reduction (Scheme 3). (For structural formula pl see the pdf file)

The problem with which this investigation is concerned is that of the evaluation of the effectiveness of the EPI-C model as a guide to group counseling. The purposes of the study are (1) to determine whether group counseling employing the EPI-C model results in positive gain in self-actualization, and (Z) whether group counseling using the EPI-C model is more effective than a topical discussion group or no treatment at all in producing greater positive change in subject self-actualization. This report concludes that the EPI-C model as a guide to group counseling is effective as a means of increasing reliance on inner support, increasing ascendance levels, emotional stability, and objectivity. The model also produced changes in assessed congruence of the emotional, physical and intellectual self. It demonstrated that the EPI-C model facilitated the growth of individuals on certain dimensions of self -actualization.

No description available.

This study examines the complex interplay and relationships between national climate–, energy– and nature conservation policy within the framework of offshore wind power development in Sweden. Focusing on the potential conflicts and synergies between these policy areas, the research applies theories of Policy Integration (PI) and Environmental Policy Integration (EPI) to clarify the integration between the policy areas and whether environmental concerns are prioritized. The energy sector is developing rapidly in response to the challenges of climate change, with offshore wind power emerging as a central component in sustainable energy transitions. However, the expansion of offshore wind power poses a potential threat to marine biodiversity. The study uses a qualitative content analysis of selected national policy documents in the areas of climate, energy and nature conservation to identify important goals and concepts. The results reveal synergies between climate and energy goals, demonstrating a common motivation to reduce greenhouse gas emissions and transition to renewable energy sources. Nevertheless, conflicts arise in the energy policy area, highlighting tensions between economic benefits and the responsible use of marine resources. Marine biodiversity conservation policy exhibits strong environmental policy integration, which emphasizes the paramount importance of environmental considerations in decision-making. This research offers practical insights for policymakers navigating the intricate landscape of offshore wind deployment while emphasizing the need for a balanced approach that takes into account economic, climate and biodiversity objectives.

The purpose of this study was to evaluate the correlation between personality and pain perception in healthy adults. Thirty participants completed the study. All participants were asked to scan a QR code and fill out a survey on their phones that included demographic questions and the Eysenck personality inventory (EPI). The demographics section included questions on age, sex, job activity level, and physical activity level. The researcher then evaluated their pressure pain threshold (PPT) using a handheld pressure algometer. The algometer was applied to the regions of the right paravertebral (PVM), quadratus lumborum (QL), and piriformis (PF) muscles perpendicular to the skin based on standardized palpation procedures. The participants were instructed to report when the sensation changed from “comfortable” to “mildly unpleasant pressure.” Results suggest that there was a positive correlation between PPT applied to the different muscles but there was no strong correlation found between the participants extraversion score and neuroticism score and their PPT at different muscles. This study aids in the understanding of the relationship between personality and pain sensitivity by providing a better view on which tools are the most beneficial in assessing personality and how it relates to pain in a clinical setting.

The Expanded Program on Immunization Sampling Method (known simply as EPI sampling) is a two-stage sampling procedure originally intended for quick estimation of disease prevalence in large geographical regions. The method was developed in the 1970s and all the subsequent assessments of its performance have been conducted by simulation. In her master's thesis, Reyes (2016) studied in detail the second-stage sampling of the method by developing formulas for the exact calculation of the household inclusion probabilities when sectors are used to identify the initial household to generate the EPI samples. The inclusion probabilities were used in turn to obtain exact mean, bias, variance and mean square error of any estimator of disease prevalence in the population. Thus, no extensive simulations are required and the results are exact rather than just estimates. This thesis is an extension of Reyes' (2016) work. The extension is two-fold; (a) employing strips rather than sectors because they narrow the geographic area for field workers and to use strips to select the first household for the EPI sample at the secondary stage, and (b) carrying out an analysis on simulated population and sampling plans, using both stages of the EPI method. Analyzing the simulated populations showed that equal weight estimator that samples primary units with replacement with probability proportional to size (EW1) should be used when the target characteristic is thought to be spread randomly throughout the population, and the Horvitz-Thompson estimator that samples primary units systematically with replacement (HTSYS) should be used when the disease is believed to spread from a central location or through pocketing. Comparing the strip and sector sampling methods at the secondary stage using their effective areas leads to a comparative basis in which the inclusion probabilities are identical for both methods. / Thesis / Master of Science (MSc)

No / MicroRNAs are a relatively new class of small, noncoding RNA species that represent a cornerstone of cell biology, with diverse roles ranging from embryonic development to aging. miRNAs function to regulate posttranscriptional gene expression, are critical to the normal function of cells, and as such are frequently dysregulated during disease processes. In this chapter, we discuss the biogenesis and mechanism of action of miRNA and their role in cancer initiation, promotion, and progression. In addition, we discuss the most recently identified dual roles of miRNA in epigenetic gene regulation; how they are both regulators and regulated. Finally, we discuss the emerging roles of miRNA as epigenetic anti-cancer therapeutics, the current research examining inhibition of oncogenic miRNAs, and studies now establishing the potential of replacing lost, tumor-suppressive miRNA.