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1
Raihan, Sheikh Zahir. "Desensitisation of the human long chain fatty acid receptors FFA1 and FFA4." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8144/.
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G protein-coupled receptors (GPCRs) constitute the largest, most ubiquitous and most versatile family of membrane proteins encoded by the human genome. Due to diverse ligands and multiple physiological activities, this set of receptors has frequently been explored as potential drug targets. Deorphanisation of GPCRs successfully identified FFA1 and FFA4 (previously named GPR40 and GPR120) as long chain free fatty acid receptors. With diverse expression patterns and close association to pathophysiology of metabolic diseases, both receptors are being studied to understand both receptor pharmacology and their potential for drug development. Due to the overlap in the activation of FFA1 and FFA4 by endogenous fatty acid ligands, selective synthetic ligands have been developed for these receptors. Using a number of biochemical and biophysical assays, I have characterised TUG-770, TUG-905 and GW-1100 as FFA1 ligands and TUG-891, TUG-1197 and TUG-1275 as FFA4 ligands. TUG-905 was found to be most potent and selective FFA1 agonist and GW-1100 showed insurmountable antagonism at FFA1. At FFA4, TUG-1197 was found to be a highly potent and selective agonist. TUG-1275 showed insurmountable antagonism at FFA4 in β-arrestin2 recruitment, receptor internalisation and inositol monophosphate accumulation studies and showed complete selectivity for hFFA4. Agonist exposure rapidly phosphorylated FFA4 in an agonist-concentration-dependent fashion which was totally blocked by TUG-1275. The protein kinase C activator PMA was also noted to phosphorylate FFAA in a concentration-dependent manner. Thus both homologous and heterologous phosphorylation is involved in FFA4 regulation. The FFA4-agonist TUG-891 produced robust internalisation of FFA4 as detected by each of confocal microscopy, and both cell surface ELISA and biotinylation. PMA was able to internalise FFA4 although it was unable to recruit β-arrestin2 to FFA4 suggesting that this internalisation might not be β-arrestin2-dependent. Constitutive internalisation was seen for FFA1, where the selective FFA1 antagonist GW-1100 had no effect. Repeated agonist-exposure desensitised both FFA1 and FF4 as revealed in single-cell calcium imaging studies. Although there was a small reduction of FFA4-internalisation and a slight elevation of total calcium levels from a single-chronic exposure of agonist, elimination of β-arrestin1/2 from HEK293 cells by genome editing did not significantly change the desensitisation of FFA4 to repeated exposure of agonist and did not prevent agonist-promoted internalisation. These studies indicate that β-arrestins are not the sole factors in desensitisation of human FFA4. Gαq/11 elimination by genome editing completely blocked intracellular calcium mobilisation and accumulation of inositol monophosphates mediated by both FFA1 and FFA4 indicating that Gαq/11 coupling to agonist-activated receptors is essential for this functional signalling outcome via both receptors. FFA4 expressed in Gαq/11-null cells was found to be phosphorylated by agonist, indicating that phosphorylation-mediated desensitisation of this receptor is not dependent on Gαq/11 proteins. FRET and BRET experiments revealed for the first time homo and hetero-oligomerisation of both FFA1 and FFA4. Although ligand regulation of oligomerisation was not investigated these preliminary observations of oligomerisation may help in the future to answer many questions of regulation and desensitisation of these receptors. The selective FFA1 and FFA4 ligands characterised here in this project might be used as tool compounds to further explore the physiology and pharmacology of these therapeutically important receptors.
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Patient, Guillaume. "Étude in silico de la structure et des interactions protéine-ligand de FFA4 à des fins de Drug Design." Electronic Thesis or Diss., Université de Lille (2022-....), 2024. http://www.theses.fr/2024ULILS073.
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Les récepteurs couplés aux protéines G (GPCR) sont des cibles médicamenteuses importantes, représentant 35 % du total des cibles médicamenteuses approuvées. Ces récepteurs sont des protéines transmembranaires impliquées dans la signalisation cellulaire de stimuli externes (hormones, neurotransmetteurs, ions...) et induisent l'activation de la protéine G associée via l'échange GDP/GTP. Au cours des 20 dernières années, des RCPG désorphanisés ont été mis en évidence comme étant actifs dans le métabolisme des lipides : des études ont montré que la modulation de l'activité du GPR 120 (FFA4), principalement exprimé dans la langue et l'intestin, a un impact sur la prise (alimentation) et l'absorption des lipides chez la souris, représentant ainsi une nouvelle approche pour promouvoir des traitements dans la prévention de l'obésité et des maladies cardiovasculaires. En complément des études classiques de chimie pharmaceutique, en collaboration avec l'équipe du Pr. Naim Khan de l'Université de Bourgogne, des méthodes in silico ont été appliquées à l'étude des caractéristiques structurelles de la protéine. Le manque d'informations structurelles sur le FFA4 et les essais limités de médicaments contribuent à l'application de méthodes in silico pour déterminer les caractéristiques structurelles et les interactions dynamiques de la protéine. La modélisation par homologie de différents états de FFA4 (inactif, intermédiaire et actif) a été réalisée et la protéine G associée a été modélisée pour l'état actif du récepteur. Des études dynamiques du récepteur en membrane ont permis d'affiner le domaine d'hélices transmembranaires (TM). L'identification du site actif et des interactions avec les ligands ont permis des études préliminaires de docking du TUG-891, un agoniste sélectif puissant du FFA4, et a mis en évidence des interactions ioniques avec les résidus chargés positivement dans la poche de liaison. Des structures cryo-EM expérimentales ont été publiées au cours de nos études in silico. Alors que les structures expérimentales ont confirmé les propriétés structurelles de FFA4 observées dans notre modèle par homologie, des informations complémentaires sur la liaison des ligands peuvent être dérivées de notre modèle pour l'activation de FFA4.Des études de docking de 4 ligands agonistes (TUG-891, acide oléique, acide linoléique et acide linolénique) ont été réalisées et les résultats ont été affinés en utilisant la dynamique moléculaire avec le champ de force AMBER 14IPQ pour prendre en compte les interactions ioniques entre les résidus chargés positivement dans la poche de liaison et le groupe d'acide carboxylique des ligands. Les expériences de dynamique moléculaire pour les différents systèmes protéine-ligand permettent d'identifier le mode de liaison le plus stable et nous ont permis de déterminer les contraintes pharmacophoriques pour un criblage virtuel à haut débit. Les composés les plus prometteurs ont été sélectionnés pour des tests biologiques<br>G protein-coupled receptors (GPCRs) are important drug targets, accounting for 35% of all approved drug targets. These receptors are transmembrane proteins involved in cell signaling of external stimuli (hormones, neurotransmitters, ions...) and induce activation of the associated G protein via GDP/GTP exchange. Over the last 20 years, deorphanized GPCRs have been shown to be active in lipid metabolism: studies have shown that modulating the activity of GPR 120 (FFA4), mainly expressed in the tongue and intestine, has an impact on lipid intake (feeding) and absorption in mice, representing a new approach to promoting treatments for the prevention of obesity and cardiovascular disease. In addition to classical pharmaceutical chemistry studies, in collaboration with Prof. Naim Khan's team at the University of Burgundy, in silico methods were applied to study the structural characteristics of the protein.The lack of structural information on FFA4 and limited drug testing contribute to the application of in silico methods to determine the structural features and dynamic interactions of the protein. Homology modeling of different FFA4 states (inactive, intermediate and active) was carried out, and the associated G protein was modeled for the receptor's active state. Dynamic studies of the receptor in the membrane were used to refine the transmembrane (TM) helix domain. Identification of the active site and ligand interactions enabled preliminary docking studies of TUG-891, a potent selective FFA4 agonist, and revealed ionic interactions with positively charged residues in the binding pocket. Experimental cryo-EM structures were published during our in silico studies. While the experimental structures confirmed the structural properties of FFA4 observed in our homology model, further information on ligand binding can be derived from our model for FFA4 activation. Docking studies of 4 agonist ligands (TUG-891, oleic acid, linoleic acid and linolenic acid) were carried out and the results refined using molecular dynamics with the AMBER 14IPQ force field to take account of ionic interactions between the positively charged residues in the binding pocket and the carboxylic acid group of the ligands. Molecular dynamics experiments for the different protein-ligand systems identified the most stable binding mode, and enabled us to determine pharmacophore constraints for high-throughput virtual screening. The most promising compounds have been selected for biological testing
3
Riaz, Sajjad Ali. "Evaluation of signalling and phosphorylation responses of the human histamine H₄ receptor (H₄R) and the human free fatty acid receptor 4 (FFA4)." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37696.
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The knowledge that G protein-coupled receptors (GPCRs) are regulated by phosphorylation in a process that results in the recruitment of arrestins, leading to receptor desensitisation is now well known. The histamine H₄ receptor (H₄R) and the free fatty acid receptor 4 (FFA4) are family A GPCRs that both have the ability to become phosphorylated in their third intracellular loops and C-terminal tails by kinases found in the cytosolic milieu of the cells and tissues they are expressed in. Investigations into the phosphorylation status of the histamine H4 receptor have revealed a receptor that is highly phosphorylated even in the basal state. The endogenous, full agonist for the human H₄R, histamine, induced a robust increase in receptor phosphorylation. However, the β-arrestin-biased agonist JNJ7777120 did not. Extending this study using mass spectrometry revealed the individual sites of phosphorylation. Histamine and JNJ7777120 also caused H₄R internalisation. Our data suggests a similar level of endocytosis induced by histamine and JNJ7777120 at 5 or 30 min stimulation. Thus, we show that JNJ7777120, while previously demonstrating its differing effects on H₄R signalling, also shows differences in the phosphorylation of the H₄R when compared to histamine. Using the wild type FFA4 receptor and its phosphorylation-deficient mutants, we show the importance of phosphorylation in the recruitment of arrestin to the receptor as well as delineating G protein-dependent and independent downstream signalling pathways. Knowledge of the different signalling cascades and their mechanism of activation would be useful in the design of biased ligands for therapeutic benefits in order to develop safer and more efficacious drugs. The use of a FFA4 receptor which is phosphorylation-deficient and, therefore, couples to arrestin-3 in a reduced manner may be useful in proof-of-concept studies where the downstream signalling in a physiological setting is mediated by arrestin as opposed to G proteins. Further evidence of the importance of phosphorylation is provided by my work with the phosphomimetic FFA4 mutant receptor, which I show does not faithfully mimic phosphorylated serine and/or threonine residues resulting, in a reduced ability to couple to arrestin-3.
4
Lamodière, Elisabeth. "Nouveaux concepts dans la pharmacologie des récepteurs aux acides gras à chaîne courte FFA2 et FFA3." Phd thesis, Université de Bourgogne, 2011. http://tel.archives-ouvertes.fr/tel-00668234.
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Les maladies métaboliques, comme le diabète, la dyslipidémie ou l'obésité, constituent un problème majeur de santé publique dans les pays développés. Ces maladies très répandues restent encore difficiles à traiter malgré une recherche active. Les stratégies thérapeutiques contre ces maladies incluent le développement de nouvelles molécules ciblant les récepteurs aux acides gras, étant donné leur rôle essentiel dans l'homéostasie du métabolisme. C'est dans ce contexte que s'inscrit ce travail portant sur deux récepteurs couplés aux protéines G, les récepteurs aux acides gras à courte chaîne 2 et 3 ou free fatty acid receptors 2 (FFA2) et 3 (FFA3). Nous avons tout d'abord cherché à déterminer le profil d'expression des deux récepteurs. Ensuite, nous avons établi des lignées cellulaires stable exprimant FFA2 ou FFA3 afin d'étudier la pharmacologie d'agonistes synthétiques et endogènes de ces récepteurs. Après avoir identifié les voies de signalisation engendrées par l'activation des récepteurs, nous avons démontré que les agonistes synthétiques étaient des activateurs allostériques, c'est-à-dire qu'ils se liaient aux récepteurs sur un site distinct de celui des ligands endogènes. Pour identifier les résidus d'acides aminés nécessaires à la reconnaissance des ligands, nous avons généré une gamme de mutants ponctuels de ces récepteurs par mutagénèse dirigée. En analysant l'effet des mutations dans des tests fonctionnels, nous avons pu déterminer avec précision où se liaient les ligands et ainsi pu dessiner par informatique des modèles structuraux des récepteurs qui pourront être utilisés pour le drug design de futures molécules agonistes de ces récepteurs.
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Moussaud, Elisabeth. "Nouveaux concepts dans la pharmacologie des récepteurs aux acides gras à chaîne courte FFA2 et FFA3." Thesis, Dijon, 2011. http://www.theses.fr/2011DIJOS014/document.
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Les maladies métaboliques, comme le diabète, la dyslipidémie ou l’obésité, constituent un problème majeur de santé publique dans les pays développés. Ces maladies très répandues restent encore difficiles à traiter malgré une recherche active. Les stratégies thérapeutiques contre ces maladies incluent le développement de nouvelles molécules ciblant les récepteurs aux acides gras, étant donné leur rôle essentiel dans l’homéostasie du métabolisme. C’est dans ce contexte que s’inscrit ce travail portant sur deux récepteurs couplés aux protéines G, les récepteurs aux acides gras à courte chaîne 2 et 3 ou free fatty acid receptors 2 (FFA2) et 3 (FFA3). Nous avons tout d'abord cherché à déterminer le profil d'expression des deux récepteurs. Ensuite, nous avons établi des lignées cellulaires stable exprimant FFA2 ou FFA3 afin d’étudier la pharmacologie d’agonistes synthétiques et endogènes de ces récepteurs. Après avoir identifié les voies de signalisation engendrées par l’activation des récepteurs, nous avons démontré que les agonistes synthétiques étaient des activateurs allostériques, c’est-à-dire qu’ils se liaient aux récepteurs sur un site distinct de celui des ligands endogènes. Pour identifier les résidus d’acides aminés nécessaires à la reconnaissance des ligands, nous avons généré une gamme de mutants ponctuels de ces récepteurs par mutagénèse dirigée. En analysant l’effet des mutations dans des tests fonctionnels, nous avons pu déterminer avec précision où se liaient les ligands et ainsi pu dessiner par informatique des modèles structuraux des récepteurs qui pourront être utilisés pour le drug design de futures molécules agonistes de ces récepteurs<br>Metabolic diseases, such as diabetes, dyslipidemia or obesity, are more and more weighing on public health expenses in developed countries. Despite active research, these widespread diseases remain difficult to handle. Promising new therapeutic strategies against metabolic diseases include the development of drugs targeting the free fatty acid receptors, as key players in metabolism homeostasis. In this context, the current PhD thesis focuses on the study of two G protein-coupled receptors, namely the short-chain free fatty acid receptors 2 (FFA2) and 3 (FFA3). First, we investigated the expression of the two receptors of interest in a variety of cell types. Then, in order to study the pharmacology and the binding mode of endogenous and synthetic agonists on FFA2 and FFA3, we established stable cell lines expressing each receptor. Once we identified the signaling pathways engendered in response to receptor activation, we showed that synthetic agonists were allosteric activators of the receptors, in the sense that they bind to the receptors at a distinct site from short-chain fatty acids, i.e. the endogenous agonists. To identify the aminoacid residues that were involved in ligand binding, we generated a variety of point mutated receptors by site-directed mutagenesis. By analyzing the effects of the mutations in functional tests, we determined precisely the aminoacid residues that were essential for ligand binding. From these results, we designed in silico structural models which may aid future drug design efforts for the discovery of new FFA2 and FFA3 agonists
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Josefsson, Ragnar, and Joel Storm. "Materialförsörjning hos FFAB." Thesis, Linköpings universitet, Kommunikations- och transportsystem, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-151067.
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Denna rapport är en fallstudie som har gjorts på det båttillverkande företaget FFAB. FFAB har svårigheter att styra materialflödet, från varumottag till montering, på ett standardiserat och förutsägbart vis. Som en följd av detta har montörerna svårt att hitta alla komponenter de behöver vilket spiller tid från själva monteringsarbetet. Syftet med fallstudien har således varit att klargöra materialförsörjningen till en av FFABs produktionslinor och ge förbättringsförslag för att reducera andelen icke-värdeskapande aktiviteter kopplat till produktionsprocessen. Fallstudien fann fem grundorsaker till icke-värdeskapande aktiviteter; oreda, materialpresentationen, monteringsstrukturen, informationssystemet och kittningen. Åtgärderna till de rådande problemen och därmed vår slutsats blev att införa 5S för att få bukt på den oreda som finns vid samtliga lagerpunkter, att standardisera kittningen och systematiken på materialfasaderna och att i större utsträckning involvera montörerna i planeringsarbetet.
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LAGRANGE, Jean-Baptiste Henri Raymond. "Study of zero-chromaticity in FFAG accelerators." 京都大学 (Kyoto University), 2012. http://hdl.handle.net/2433/157577.
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Vanderbos, Sara. "Factors that influence secondary students to join the Collegiate FFA." DigitalCommons@USU, 2013. https://digitalcommons.usu.edu/etd/1489.
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Student involvement on college campuses is important for the professional growth, leadership development and learning of today's college student. This research sought to determine the factors that influence former high school FFA members' reasons for joining and participating in the Collegiate FFA.
The study showed that students who are involved in the National FFA at the secondary level are more likely to join Collegiate FFA while attending a university that offers the Collegiate FFA option. These students were actively engaged on campus and were interested in helping others. Collegiate FFA programs, the National FFA, and universities across the country should begin their recruitment efforts with current high school FFA members.
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Yamakawa, Emi. "Study of serpentine acceleration in zero-chromatic FFAG accelerators." 京都大学 (Kyoto University), 2013. http://hdl.handle.net/2433/174929.
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PLANCHE, Thomas. "Study of zero-chromatic FFAG synchrotron for muon acceleration." 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/131890.
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Bryant, Bradley Wayne. "History of the Virginia FFA Association." Diss., Virginia Tech, 2001. http://hdl.handle.net/10919/26640.
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Part of this research focused on the predecessors of the FFA by outlining the history and purposes of agricultural organizations formed since the late 1700s. The past two centuries of American agricultural history is rich with efforts to educate and improve agricultural practices through organized groups of farmers and other rural leaders. Early in the development of agricultural societies, experimentation and successful practices were shared with others in the local organization and works were often published in journals or newspapers for educational and informational purposes. Regular meetings and fellowship were also a major focus of the early groups. The national organizations that formed later such as the Grange, included the fraternal, social, and educational aspects while maintaining a focus on the economics of farming.
The boys’ and girls’ club movement provided opportunities for youth to meet, learn, and participate in agricultural competitions. The center of activities for youth organizations quickly shifted from community groups to agricultural education programs in the public schools. Clubs that formed within agricultural education programs in Virginia soon united to create the Future Farmers of Virginia. The FFV and FFA that followed initiated the use of certain symbols, colors, and ritual ceremonies that can be traced directly to the agricultural societies. This research identified many agricultural societies and youth clubs that had a profound influence on the development of the National FFA Organization.
The major purpose of this study was to describe the establishment of the Future Farmers of American and to document the accomplishments of Virginia FFA members at the state and national levels. The objectives of the study were:
To describe the historical events and circumstances that led to the establishment of the Future Farmers of Virginia and the Future Farmers of America,
To document Virginia FFA history by recording achievements of members and chapters at the state level,
To document the achievements of Virginia FFA members and chapters at the national level, and
To provide a history of the Virginia FFA Association from 1925 to the present.
The Virginia FFA Association is rich with historical information that ranges from the formation of the Future Farmers of Virginia in 1925, the forming of a national organization in 1928, and 75 years of accomplishments by Virginia FFA members.<br>Ph. D.
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Fiorini, Brian. "FFA state finals committee chairman guide /." Click here to view, 2009. http://digitalcommons.calpoly.edu/dscisp/13.
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Thesis (B.S.)--California Polytechnic State University, 2009.<br>Project advisor: Stan Henderson. Title from PDF title page; viewed on Jan. 21, 2010. Includes bibliographical references. Also available on microfiche.
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Junfeng, Shi. "The lipid sensor Ffar4 regulates muscle-based diet-induced thermogenesis." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225536.
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Watson, Sarah-Jane. "Pharmacological characterisation of the fatty acid receptors GPR120 and FFA1." Thesis, University of Nottingham, 2013. http://eprints.nottingham.ac.uk/13802/.
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In recent years, two G protein coupled receptors have been de-orphanised which respond to long chain free fatty acids (FFAs), and so are able to mediate the signalling of these important nutrient molecules. FFA1 (GPR40) is predominantly expressed in pancreatic -cells, while the expression profile of GPR120 includes gut endocrine cells and adipose tissue. These distributions, together with the potential of both receptors to stimulate insulin and incretin hormone secretion, singled them out as potential drug targets for type 2 diabetes and obesity. The aim of this thesis was to evaluate the pharmacology of these receptors and their signalling properties, including the development of fluorescent FFA receptor ligands to evaluate agonist binding using imaging techniques. GPR120 has been identified to exist as two splice isoforms in humans, differing by a short insertion in the third intracellular loop, but no full isoform specific characterisation of receptor signalling and trafficking had been undertaken. This work therefore studied the GPR120S and GPR120L isoforms in terms of both G protein dependent and arrestin dependent signalling, and trafficking. It was found that the long GPR120L isoform exhibited reduced G protein signalling, but similar arrestin recruitment and lysosomal intracellular trafficking profiles as GPR120S. Potentially, expression of the long GPR120 isoform provides a mechanism to direct signalling to the arrestin pathway, for example to produce anti-inflammatory effects in macrophages. As the expression profile of GPR120 overlaps with that of FFA1, for example in colonic endocrine cells, a series of constrained GPR120 homo-dimers and GPR120:FFA1 heterodimers were created using irreversible bimolecular fluorescence complementation, and the potential for novel pharmacology was investigated by monitoring dimer internalisation. However, there was no evidence that such dimerisation altered the pharmacology of the ligand tested. Second, a model of the GPR120S ligand binding site was tested using point mutagenesis of the receptor. This mutagenesis validated key features of the model, including the role of Arg99 in co-ordinating the agonist carboxylate group, and interactions of the agonists with the conserved transmembrane VI Trp “toggle-switch” involved in receptor activation. Another mutation (Asn215) provided evidence for ligand-specific binding modes within the pocket. This study showed the complexity of testing mutants designed to interfere with ligand binding indirectly through signalling assays and highlighted the requirement for a FFA receptor binding assay to measure ligand affinity directly. In the absence of radioligands of suitable selectivity and affinity, a novel fluorescent ligand, based on the FFA1/GPR120 agonist GW9508, was used to successfully develop a whole cell FFA1 competition binding assay for the first time, obtaining FFA1 affinity estimates for a range of synthetic ligands. Fluorescent ligand binding was further investigated using fluorescence correlation spectroscopy and photon counting histogram analysis, defining the diffusion characteristics of FFA1 receptors in the membrane of single living cells, and providing preliminary evidence for their dimerisation.
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Garland, James Matthew. "Beam dynamics studies of the EMMA linear non-scaling FFAG." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/beam-dynamics-studies-of-the-emma-linear-nonscaling-ffag(5b375a2d-0636-422d-a0d6-2cc941ebd01f).html.
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The development of charged particle accelerators is today reaching far beyond the realm of fundamental particle physics research. Many non-trivial social and political problems may find part of their solution lies in accelerator physics. For example, with fossil fuels becoming ever more controversial and expensive to obtain, the use of Accelerator Driven Sub-critical Reactors (ADSR) powered by rapid cycling, high current proton accelerators and thorium fuel could become part of the energy solution. Through the simplicity of the Bragg peak, cancer therapy could be enhanced through the use of high repetition rate, variable energy proton accelerators small enough to use in treatment centres. The growing problem of long lived nuclear waste storage could become a moot point through the use of high current, high power proton accelerators coupled with neutron spallation. These rapidly growing areas of study are fuelled by the development of the Fixed-Field Alternating-Gradient (FFAG) accelerator, and more recently the non-scaling FFAG. The FFAG has the ability to accelerate high current, low quality bunches of particles in very short time scales due to the fixed-field nature of its magnets. This rapid acceleration can be of the order 500 nanoseconds to 1 microsecond meaning a fast cycling rate of the machine is possible. This allows the realistic development of the ADSR, proton therapy machine and even the muon accelerator. The Electron Model with Many Applications (EMMA) accelerator is the world's first linear non-scaling FFAG and is an electron proof-of-principle accelerator based at Daresbury Laboratory, UK. EMMA can accelerate over its energy range of 10 - 20 MeV in approximately 5 - 10 machine revolutions (~275 - 500 nanoseconds) using fixed-frequency novel acceleration techniques. The accelerator contains fixed-field, constant gradient quadrupole magnets which provide all the bending and focussing to the particles. Due to the linear non-scaling nature of EMMA, many transverse integer tune values are crossed which typically cause resonant effects resulting in bunch degradation and loss. It was proposed and demonstrated that rapid crossing (in 5 - 10 turns) of integer tune values in EMMA did not result in transverse amplitude growth and particle loss. If the wider societal goals of the non-scaling FFAG are to be realised, protons and other heavy ions must be accelerated. Current technological limitations dictate that longer acceleration times of the order 1000's of turns would be necessary in proton machines of similar design to EMMA. Hence slower integer tune crossing was studied using acceleration in a synchrotron bucket in EMMA. It was found experimentally that below the nominal EMMA operating acceleration rate of 2.0 MV per turn, instabilities begin to manifest. This was indicated in the growth of closed orbit distortion (COD) and through simulation it was found that betatron amplitude growth coupled with COD resulted in eventual loss of particles to the physical aperture when crossing integer tunes. Through simulation, the amplitude growth of particles crossing integer tunes in the EMMA non-scaling FFAG was found to agree with a theory of resonance crossing proposed by R. Baartman. This theory shows that amplitude growth is proportional to $1/\sqrt(Q')$ where $Q'$ is the tune crossing rate of the particles. This means that the slower the acceleration, the slower an integer tune is crossed and hence more amplitude is gained. It was also shown that strength of the magnetic errors driving the resonant conditions was proportional to the amplitude growth.
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Giboudot, Yoel. "Study of beam dynamics in NS-FFAG EMMA with dynamical map." Thesis, Brunel University, 2011. http://bura.brunel.ac.uk/handle/2438/5947.
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Dynamical maps for magnetic components are fundamental to studies of beam dynamics in accelerators. However, it is usually not possible to write down maps in closed form for anything other than simplified models of standard accelerator magnets. In the work presented here, the magnetic field is expressed in analytical form obtained from fitting Fourier series to a 3D numerical solution of Maxwell’s equations. Dynamical maps are computed for a particle moving through this field by applying a second order (with the paraxial approximation) explicit symplectic integrator. These techniques are used to study the beam dynamics in the first non-scaling FFAG ever built, EMMA, especially challenging regarding the validity of the paraxial approximation for the large excursion of particle trajectories. The EMMA lattice has four degrees of freedom (strength and transverse position of each of the two quadrupoles in each periodic cell). Dynamical maps, computed for a set of lattice configurations, may be efficiently used to predict the dynamics in any lattice configuration. We interpolate the coefficients of the generating function for the given configuration, ensuring the symplecticity of the solution. An optimisation routine uses this tool to look for a lattice defined by four constraints on the time of flight at different beam energies. This provides a way to determine the tuning of the lattice required to produce a desired variation of time of flight with energy, which is one of the key characteristics for beam acceleration in EMMA. These tools are then benchmarked against data from the recent EMMA commissioning.
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Fenning, Richard. "Novel FFAG gantry and transport line designs for charged particle therapy." Thesis, Brunel University, 2012. http://bura.brunel.ac.uk/handle/2438/6860.
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This thesis describes the design of novel magnetic lattices for the transport line and gantry of a charged particle therapy complex. The designs use non-scaling Fixed Field Alternating Gradient (ns-FFAG) magnets and were made as part of the PAMELA project. The main contributions in this thesis are the near-perfect FFAG dispersion suppression design process and the designs of the transport line and the gantry lattices. The primary challenge when designing an FFAG gantry is that particles with different momenta take up different lateral positions within the magnets. This is called dispersion and causes problems at three points: the entrance to the gantry, which must be rotated without distortion of the beam; at the end of the gantry where reduced dispersion is required for entry to the scanning system; and a third of the way through the gantry, where a switch in curvature of the magnets is required. Due to their non-linear fields, dispersion suppression in conventional FFAGs is never perfect. However, as this thesis shows, a solution can be found through manipulation of the field components, meaning near-perfect dispersion suppression can be achieved using ns-FFAG magnets (although at a cost of irregular optics). The design process for an FFAG dispersion suppressor shown in this thesis is a novel solution to a previously unsolved problem. Other challenges in the gantry lattice design, such as height and the control of the optics, are tackled and a final gantry design presented and discussed. The starting point for the transport line is a straight FFAG lattice design. This is optimised and matched to a 45o bend. Fixed field solutions to the problem of extracting to the treatment room are discussed, but a time variable field solution is decided on for practical and patient safety reasons. A matching scheme into the gantry room is then designed and presented.
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Gratz, Steven J. "Factors influencing supervised agricultural experience earnings of Ohio FFA state degree recipients as reported on the Ohio FFA state degree application." The Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1080302672.
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Gratz, Steven Jon. "Factors influencing supervised agricultural experience earnings of Ohio FFA state degree recipients as reported on the Ohio FFA state degree application." Columbus, Ohio : Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1080302672.
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Thesis (Ph. D.)--Ohio State University, 2004.<br>Title from first page of PDF file. Document formatted into pages; contains xv, 166 p.; also includes graphics (some col.). Includes abstract and vita. Advisor: James J. Connors, Dept. of Agricultural Education. Includes bibliographical references (p. 124-134).
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Sergeev, Eugenia. "Investigating the molecular pharmacology of the short chain fatty acid receptor FFA2." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/8963/.
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The G protein-coupled receptor FFA2 is a key mediator of short chain fatty acid signalling, which are produced in the gut via fermentation of poorly digested carbohydrates by the gut microbiota. Therefore, FFA2 has attracted interest as a potential therapeutic target for metabolic and inflammatory diseases. However, several limitations have hindered validation of FFA2 as a drug target, including the limited understanding of the molecular determinants of ligand binding and species-specific differences in pharmacology. Herein, novel tool compounds and assay systems were developed for FFA2 and utilised to address some of these limitations. Following the characterisation of functional assays for detection of FFA2 signalling, these were employed to examine the structure-activity relationship and pharmacology of FFA2 agonists versus antagonists. To assess how the pharmacology of FFA2 ligands is defined by their mode of binding, a radioligand binding assay was developed using a tritiated form of FFA2 antagonist GLPG0974 that was utilised in combination with site-directed mutagenesis and homology modelling to explore FFA2 ligand binding sites. These studies showed that FFA2 agonist binding was defined by an essential interaction between the ligand carboxylate and an orthosteric Arg-His-Arg triad. In contrast, FFA2 antagonists only required one orthosteric arginine for high-affinity binding and could tolerate modifications of the carboxylate moiety. This knowledge was applied to develop an antagonist-based fluorescent tracer for FFA2 that was utilised in BRET binding assays but displayed complex pharmacological behaviour that was shown to be based on the bitopic nature of FFA2 antagonists. The secondary binding site of FFA2 antagonists was also related to their lack of action at rodent orthologues of FFA2, whose molecular basis was explored using homology models of human and murine FFA2. This facilitated the identification of a single lysine to arginine variation at position 2.60 that might provide a basis for antagonist selectivity. Extending these studies to agonist function demonstrated that removal of the positive charge at this position produced a signalling-biased form of FFA2, in which only coupling to Gi G proteins was fully maintained. In summary, these findings contribute to understanding the complex pharmacology of FFA2 ligands and the underlying mechanisms that define their function, and conclusions drawn from these studies may help advance future efforts to validate the therapeutic potential of targeting FFA2.
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Reboulleau, Jérôme. "Les mathématiques financières robustes, le maritime et les FFA /." [S.l.] : [s.n.], 2008. http://library.epfl.ch/theses/?nr=4216.
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Trajanoski, Zlatko. "Techniques for in vivo assessment of glucose and FFA metabolism /." Aachen : Shaker, 1998. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=015159660&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Hasswa, Raghda. "Biodiesel Production from High FFA Feedstock Using a Membrane Reactor." Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28716.
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Biodiesel is a renewable source of energy typically produced in a chemical process known as transesterification. The process involves the reaction of an alcohol with vegetable oil or animal fat in the presence of a catalyst to yield mono-alkyl esters (biodiesel) and glycerol as a by-product. The biodiesel market is amongst the fastest growing renewable energy markets and there is a genuine interest in its development from industry and academia. However, there are some challenges that are facing biodiesel and hindering its commercialization. The major ones are production cost and quality. The process must be cost-effective whilst producing biodiesel that meets international standards (ASTM D6751 and EN 14214). The main objectives of this project were to investigate the use of a continuous membrane reactor for the production of biodiesel from waste vegetable oil feedstock with high free fatty acid (FFA) content and to investigate the effect of membrane pore size on the separation of soap and triglycerides in the reactor. This was achieved through the construction and operation of a lab scale continuous membrane reactor. The membrane reactor integrates many procedures such as combining the chemical reaction and the membrane-based separation in the same unit. The biodiesel was produced by base-catalyzed transesterification. Two levels of FFA in the waste vegetable oil feedstock were studied, 4.8 and 10 mass%. Ceramic membranes were used, with membrane pore sizes ranging from 1 to 800 nm.
It was found that the free glycerol and total glycerol content in the fatty acid methyl ester (FAME or biodiesel) produced were significantly below the maximum limit of the ASTM D6751 standard. There was no trend associating changes in membrane pore size with glycerol concentration. Additionally, it was found that the water content in the FAME produced met the ASTM D6751 standard. Furthermore, the results of the soap analysis indicated that the soap dissolved in the alcohol and passed through the membrane. Thus, soap was not completely retained in the reactor. Therefore, the soap produced as a result of using high FFA feedstock in a base-catalyzed transesterification did not affect the FAME production process and the passage of mono-, di-, and triglycerides through the membrane. The quality of the biodiesel produced in this project met the requirements for the ASTM D6751 standard.
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Rose, Matthew. "Development of a new 'soft muon tagger' for the identification of b quarks, applied to a top quark pair production cross section measurement, using the ATLAS detector at CERN." Thesis, Royal Holloway, University of London, 2013. http://repository.royalholloway.ac.uk/items/256683e9-584b-ffa5-7464-20f025b29419/7/.
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This thesis presents a study of a method for identifying b-jets by searching for “soft” muons produced within them. This method, a so-called Soft Muon Tagger, uses the quality of the match (Χ2match) between tracks left in the inner detector and the muon systems within the ATLAS detector to discriminate between muons within hadronic jets produced by the decay of b quarks, and those within light flavour jets. The complete characteristics of the tagger are investigated in a detailed study on simulated data. The scale factors between the efficiency of the tagger in simulated and collision data, dependent on the kinematics of the tagged muon, are found using J/Ψ decays. These are used in a measurement of the top quark pair production cross section in collision data. The measurement is performed on data taken during the 2011 run of the LHC, specifically in the lepton+jets top-antitop quark decay channel. A summary of this measurement is presented, and is found to be compatible with theoretical predictions for the cross section at a centre of mass energy of √s = 7 TeV, and with published ATLAS and CMS measurements using b-tagging in the lepton+jets channel. The measured cross section is: σtt ̄ = 165 ± 2(stat.) ± 17(syst.) ± 3(lumi.) pb The Χ2match-based soft muon tagger contributes a small b-tagging systematic uncertainty to the cross section measurement compared to measurements performed using lifetime based b-taggers, and has a good signal to background ratio.
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Wearmouth, Alexis. "Thomas Duff & Co and the jute industry in Calcutta, 1870-1921 : managing agents and firm strategy." Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/b86e1313-ffaf-475c-9b40-7aea9faeb8b7.
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This thesis is about the nature of the rapid growth of the jute manufacturing industry in colonial India in the age of the “imperialism of free trade”. It seeks to understand how the managing agents who controlled the jute mill companies in Calcutta internalised a competitive advantage that generated lucrative rents through a case study of the history of the Dundee-based managing agents, Thomas Duff & Co. The thesis argues that the industry experienced a pattern of extensive growth with static technology that led to rising costs and pressure on profits and dividends. Nevertheless, the pattern of entry into the industry indicates the existence of institutional barriers to entry. Managing agents like Thomas Duff & Co were able to take advantage of and shape these barriers through strategic behaviour. They created a company form that allowed the structuring of incentives to reproduce a functional managerial hierarchy and renew their competitive advantage over time. Strategic behaviour by the founding directors of Thomas Duff & Co extended to actively shaping the business environment in which the firm operated by anticipating and neutralising threats to their control of the directorate, intervening in the supply chain to manage costs and cajoling other managing agents to cooperate to manage competition. The success of these strategies led to growth, which entailed the creation of a popular base of shareholdings. This dilution of formal ownership proved to be compatible with retaining control and generating rents while minimising risk.
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Mohsen, Mona. "Virus-Like Particles (VLPs) platform for the development of an effective melanoma vaccine." Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:57fefb18-ff84-4add-b4d8-e69e9c4f46a4.
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Melanoma is the least common type of skin-cancer but the deadliest one. Cancer immunotherapy is considered a powerful tool in cancer treatment. Nevertheless, therapeutic cancer vaccines have led so far to modest immune responses with little clinical impact. The first part of this work is focused on developing a personalized melanoma vaccine platform based on VLPs and copper-free click chemistry, enabling bedside production of personalized cancer vaccines. There is currently a debate in the field whether cancer-specific, non-mutated germ-line epitopes or mutated neo-epitopes are more powerful antigens for vaccination. To address this issue, we identified melanoma-specific germ-line T-cell epitopes by immunopeptidomic and neoantigens using exome sequencing. Different VLP-based vaccine cocktails were generated, and their immunogenecity was compared in melanoma murine models. We demonstrate that both neoantigens and germ-line epitopes can induce partial protection, but the best therapeutic effect is achieved when combining both. The second part of the thesis tested a new adjuvant microcrystalline tyrosine (MCT) in combination with VLP-based vaccine (CuMV<sub>TT</sub>). MCT, is an adjuvant that has been used in licensed allergen-immunotherapy products for decades. The adjuvant potential of MCT was also compared to Alum and B-type CpGs. MCT was similarly potent as CpGs and clearly superior to Alum when CD8<sup>+</sup> T-cell responses and tumour protection were assessed. Combining a micron-sized adjuvant (MC) with nanoparticles (CuMVTT) appears a particularly attractive strategy as it optimally harnesses the drainage properties of the immune system. Thus, MCT may not only be used in marketed allergy products but may also be promising for induction of protective CTL response. Finally, we focused on delivering antigens and adjuvants in separate virus-like particles. This new technique would be beneficial when designing a personalized VLP-based vaccine as it would be handy to have a ready adjuvanted VLP which can be formulated with the patient vaccine at bed-side.
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Steinkraus, Bruno. "Deciphering cis/trans RNA regulatory interactions in vivo." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:6d095a0a-ff54-4b67-a62d-47e31d182ad5.
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Post-transcriptional regulation of the genetic programme is achieved through the sophisticated interplay between cis regulatory elements and trans interacting factors. Deciphering these interactions, especially those between microRNAs (miRNAs) and destabilising miRNA response elements (MREs), requires technologies that permit their unbiased interrogation under native, physiological conditions. Here I describe the development of miR-TRACE, a novel and versatile platform for miRNA-target identification that analyses in vivo miRNA-MRE binding. Following iterative optimisation I demonstrate the reliability of this technology in identifying bona fide miRNA targets on a candidate scale. Subsequently, I implement several experimental and computational innovations to develop miRTRACEseq, a multiplex platform enabling unbiased high-throughput analysis of miRNA-MRE interactions across the transcriptome. As a proof of concept, I applied this technology to a highly conserved candidate miRNA in S2R+ cells (miR-184) and implemented a logistic regression model to map all miR-184 MREs. This analysis confirmed known miR-184 MREs but also discovered novel targets. In parallel, during my thesis I have applied the core principles underlying miRTRACE to study the translational quiescence of bicoid (bcd) mRNA during Drosophila oogenesis. Several lines of evidence, foremost bcd's association to mRNA processing bodies (P-bodies), suggest the possibility of a miRNA-mediated mechanism underlying bcd silencing. To explore this scenario I have developed a multipronged experimental approach employing miR-TRACE, unbiased small RNA interactome capture, and computational analysis. Together, these analyses uncovered several miRNAs specifically associated with bcd RNA in ovary tissues, of which the two most notable candidates were miR-184 and miR-989. Interestingly, the levels of these miRNAs are significantly reduced in a bcd pulldown from embryos, a finding consistent with relief of bcd silencing in this tissue. This study provides the first evidence for a potential role of miRNAs in regulating the translation of bcd RNA. This opens up a completely new line of investigation in the quest for elucidating what remains one of the most enigmatic accounts of gene expression regulation during the oocyte-to-embryo developmental transition.
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Cornes, Stuart. "Halogen bonding, hydrogen bonding and Lewis acidic receptors for anion recognition." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:0725f9c4-ff44-4158-b94e-9bcaf0fa3b4d.
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This thesis describes the preparation of acyclic, macrocyclic and interlocked receptors for the recognition of anions in competitive organic and aqueous solvent media. Chapter One introduces the field of anion supramolecular chemistry, with a particular focus on the non-covalent interactions used for anion recognition and the synthesis of mechanically interlocked molecules. Chapter Two discusses the preparation of halogen bonding and hydrogen bonding acyclic and interlocked pyridinium-based receptors. Investigations into their anion selectivity trends are undertaken using 1H NMR titration experiments. The anion sensing properties of analogous hosts containing a fluorescent quinolinium motif are also described. Chapter Three presents the synthesis of acyclic and macrocyclic receptors containing the dicationic 1,2-bis(pyridinium)ethane motif. Attempts towards the preparation of interlocked receptors containing the motif are also discussed. Chapter Four focuses on a series of water-soluble receptors based around functionalised a-cyclodextrins. Isothermal titration calorimetry experiments are used to investigate differences in the thermodynamics of anion binding to halogen bonding and hydrogen bonding analogues. Chapter Five details the preparation of a [2]rotaxane containing a Lewis acidic triarylborane motif. Investigations into its anion binding properties are conducted using multinuclear NMR and UV-visible spectroscopies. Chapter Six provides the experimental details and characterisation data for the compounds discussed in Chapters Two to Five. Protocols for the titration experiments conducted are also described. Full crystallographic data is provided in the Appendix.
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Buchanan, Elizabeth Fuller. "Debt in Late Antique Egypt, 400-700 CE : approaches to a time in transition." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:5558d838-ffd4-4671-a801-0073fa017210.
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Modern scholars are deeply divided over the extent to which early Byzantine provinces such as Egypt adopted imperial Roman law. This thesis undertook a diachronic study of the published debt acknowledgements from Egypt and Nessana for the fifth through seventh centuries CE to examine the degree of adoption of imperial legal changes. The debt acknowledgements are one of the largest sets of papyri documents for this period, consisting of 283 Greek and fifty-seven Coptic documents. Having created a database of these documents, in their original Greek or Coptic plus an English translation and information from the major commentaries, I had an unparalleled opportunity to analyse change, both legal and socio-economic. The research shows that while many legal changes, including the requirement for regnal dating and changes in the liability of co-debtors, were generally adopted, there was resistance to other changes. For example, the interest rate reduction ordered by Justinian I in 528 was clearly disseminated because some documents reflect the reduction. Most people, however, continued to charge the earlier higher rates. Furthermore, some sectors of the population appear to have struggled with the imperial changes. Model formats for a simplified Greek debt acknowledgement and a very similar Coptic debt acknowledgement were developed and disseminated in the sixth century. These simplified formats did not use regnal dating or many of the other customary clauses of the formal Greek debt acknowledgment. The early development of these simplified formats, together with evidence of the privatisation and localisation of many imperial functions, including dispute resolution, support the view that the later sixth century experienced an unravelling of ties with the Roman Empire. The catastrophic seventh century, with its civil wars and Persian and Arab invasions, resulted in a shift in language from Greek to Coptic for personal legal documents. The disruption of the seventh century, however, only accelerated and finalised a process of change that was already well established in the sixth century.
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Collins, Jessica Ann. "Beyond the FFA: Understanding Face Representation within the Anterior Temporal Lobes." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/255610.
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Psychology<br>Ph.D.<br>Extensive research has supported the existence of a specialized face-processing network that is distinct from the visual processing areas used for general object recognition. The majority of this work has been aimed at characterizing the response properties of the fusiform face area (FFA) and the occipital face area (OFA), which together are thought to constitute the core network of brain areas responsible for facial identification. Although accruing evidence has shown that face-selective patches in the ventral anterior temporal lobes (vATLs), within perirhinal cortex, play a necessary role in facial identification, the relative contribution of these brain areas to the core face-processing network has remained unarticulated. The current study assessed the relative sensitivity of the anterior face patch, the OFA, and the FFA, to different aspects of person information. Participants learned to associate a name and occupation label, or a name only, with different facial identities. The sensitivity of the face processing areas to facial identity, occupation, and the amount of information associated with a face was then assessed. The results of a multivoxel pattern analysis (MVPA) revealed that distributed activity patterns in the anterior face patch contained information about facial identity, occupation, and the amount of information associated with a face, with the sensitivity of the anterior face patch to occupation and amount of information being greater than the more posterior face processing regions. When a similar analysis was conducted that included all voxels in the perirhinal cortex, sensitivity to every aspect of person information increased. These results suggest that the human ventral anterior temporal lobes may be critically involved in representing social, categorical, information about individual identities.<br>Temple University--Theses
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Navarro, Suazo Jorge Esteban. "Responsabilidad patrimonial del Estado por actuación de las FFAA y de Orden y Seguridad Pública." Tesis, Universidad de Chile, 2015. http://repositorio.uchile.cl/handle/2250/132989.
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Memoria (licenciado en ciencias jurídicas y sociales)<br>Esta memoria se estructura en dos partes y cada una de ella cuenta
con dos capítulos.
El primero trata de las generalidades y particularidades que
caracterizan a las instituciones que integran las Fuerzas Armadas y de
Orden y Seguridad Pública. Allí se destaca el hecho de tratarse de
organismos que forman parte de la Administración Pública y el de poseer
una especial característica en lo que concierne a la Responsabilidad del
Estado: La frecuencia y gravedad con que, a propósito del desarrollo de sus
actividades, se producen daños sobre las personas o sus bienes, cuestión
que se ilustra con la mención de una serie de ejemplos concretos recogidos
de la prensa. Se hace referencia también a su organización interna, en
cuanto resulta pertinente al régimen de subordinación bajo el cual se
desenvuelven sus agentes
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Fourrier, Joris. "Les accélérateurs à champ fixe et gradient alterné FFAG et leur application médicale en protonthérapie." Phd thesis, Grenoble 1, 2008. http://www.theses.fr/2008GRE10161.
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La radiothérapie utilise des faisceaux de particules dans le but d'irradier et d'éliminer les tumeurs cancéreuses tout en épargnant au maximum les tissus sains. La perte d'énergie en forme de pic de Bragg des protons dans la matière permet une amélioration balistique du dépôt de la dose par rapport aux rayons X. Le volume irradié peut ainsi être précisément ajusté au volume tumoral. Cette thèse, dans le cadre du projet RACCAM, vise à étudier et à mettre au point le design d'une installation de protonthérapie basée sur un accélérateur de particules à champ fixe et à gradient alterné FFAG dans le but de construire un aimant FFAG à secteur spiral pour validation. Nous présentons tout d'abord la protonthérapie pour définir un cahier des charges médicales définissant les critères techniques d'une installation de protonthérapie. Puis nous introduisons les accélérateurs FFAG par une présentation des projets passés et en cours dans le monde avant de développer la théorie de la dynamique faisceau dans le cas de l'optique à focalisation invariante. Nous décrivons ensuite les outils de modélisation et simulation mis au point pour étudier cette dynamique faisceau dans une optique FFAG à focalisation invariante et à secteur spiral. Nous expliquons par la suite la recherche des paramètres de l'optique ayant abouti à la construction d'un aimant prototype. Enfin, nous décrivons l'installation de protonthérapie du projet RACCAM depuis le cyclotron injecteur jusqu'au système d'extraction<br>Radiotherapy uses particle beams to irradiate and kill cancer tumors while sparing healthy tissues. Bragg peak shape of the proton energy loss in matter allows a ballistic improvement of the dose deposition compared with X rays. Thus, the irradiated volume can be precisely adjusted to the tumour. This thesis, in the frame of the RACCAM project, aims to the study and the design of a proton therapy installation based on a fixed field alternating gradient (FFAG) accelerator in order to build a spiral sector FFAG magnet for validation. First, we present proton therapy to define medical specifications leading to the technical specifications of a proton therapy installation. Secondly, we introduce FFAG accelerators through their past and on-going projects which are on their way around the world before developing the beam dynamic theories in the case of invariant focusing optics (scaling FFAG). We describe modelling and simulation tools developed to study the dynamics in a spiral scaling FFAG accelerator. Then we explain the spiral optic parameter search which has leaded to the construction of a magnet prototype. Finally, we describe the RACCAM project proton therapy installation starting from the injector cyclotron and ending with the extraction system
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Fourrier, Joris. "Les accélérateurs à champ fixe et gradient alterné FFAG et leur application médicale en protonthérapie." Phd thesis, Université Joseph Fourier (Grenoble), 2008. http://tel.archives-ouvertes.fr/tel-00338177.
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La radiothérapie utilise des faisceaux de particules dans le but d'irradier et d'éliminer les tumeurs cancéreuses tout en épargnant au maximum les tissus sains. La perte d'énergie en forme de pic de Bragg des protons dans la matière permet une amélioration balistique du dépôt de la dose par rapport aux rayons X. Le volume irradié peut ainsi être précisément ajusté au volume tumoral. Cette thèse, dans le cadre du projet RACCAM, vise à étudier et à mettre au point le design d'une installation de protonthérapie basée sur un accélérateur de particules à champ fixe et à gradient alterné FFAG dans le but de construire un aimant FFAG à secteur spiral pour validation. Nous présentons tout d'abord la protonthérapie pour définir un cahier des charges médicales définissant les critères techniques d'une installation de protonthérapie. Puis nous introduisons les accélérateurs FFAG par une présentation des projets passés et en cours dans le monde avant de développer la théorie de la dynamique faisceau dans le cas de l'optique à focalisation invariante. Nous décrivons ensuite les outils de modélisation et simulation mis au point pour étudier cette dynamique faisceau dans une optique FFAG à focalisation invariante et à secteur spiral. Nous expliquons par la suite la recherche des paramètres de l'optique ayant abouti à la construction d'un aimant prototype. Enfin, nous décrivons l'installation de protonthérapie du projet RACCAM depuis le cyclotron injecteur jusqu'au système d'extraction.
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Edgar, John Curtis. "Identifying Demographics and Personality Trends among Illinois Association FFA Major State Officers." OpenSIUC, 2020. https://opensiuc.lib.siu.edu/theses/2663.
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The primary objective of this thesis was to analyze trends among demographic profiles and personalities identified by the CliftonStrengths® assessment (formerly Clifton StrengthsFinder®) of Illinois FFA state officers in order to better understand and improve the team dynamics and training provided by National FFA facilitators and Illinois FFA staff. The population analyzed included Illinois FFA officers elected from 2006-2019. Major findings include a positive trend among male candidates advancing through the Illinois FFA major state officer election process, though also identified a trend of females being elected more during the years more females originally run for office. Geographic representation of major state officers remained fairly consistent among the Illinois FFA districts, though large differences were identified in the representation from specific Illinois FFA sections. Various trends were also identified among gender representation and personality trends from each of the different Illinois FFA districts. Personality trends were identified among Illinois FFA major state officers, and differences were identified, most notably within the Strategic Thinking Domain, between Illinois FFA major state officer talent themes and those of state FFA officers nationwide. A pendulum affect was also identified in the talent theme domains most prevalent among Illinois FFA major state officers over time.
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Silva, Maria Helena Almeida Braz da. "Modulation of TG/(GL+FFA) cycle as a therapeutic strategy to obesity." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/13330.
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Mestrado em Biologia Molecular e Celular<br>Obesity is one of the leading causes of health care issues all over the world. A large slice of the worldwide population develops co-morbidities as a consequence of this condition, such as type 2 diabetes mellitus (T2DM), atherosclerosis, fatty liver, cardiovascular diseases and even some cancers, conditions that are associated with reduced life expectancy. The inefficiency of current therapies that aim to treat obesity leads to further investigation on novel therapeutic targets for this condition, including modulation of white adipose tissue (WAT). In WAT, glucose and lipid metabolism converge into triglyceride/ glycerol + free fatty acid (TG/ (GL + FFA)) cycle, which is considered a futile cycle since it doesn’t generate products while consuming energy substrates. The decreased activity of this cycle in obesity, decreases substrates oxidation and increases free fatty acids (FFA) storage in WAT. If coupled to increased mitochondrial β-oxidation, modulation of TG/ (GL+FFA) cycling provides an attractive therapeutic target to stimulate fat mobilization and prevent WAT dysfunction. Currently there are no known strategies that simultaneously stimulate both these processes. Chenodeoxycholic acid (CDCA) is a bile acid known for its anti-obesity effects; however the mechanism of action is still controversial. CDCA activates both peroxisome proliferator activating receptor (PPAR) α and PPARγ, regulators of the transcription of key metabolic genes involved in the TG/ ( GL+FFA) cycle, mitochondrial oxidative capacity and FFA oxidation. As such, we hypothesized that CDCA mediates the coupling of futile cycles with energy expenditure in WAT, increasing simultaneously futile acid activity and mitochondrial substrates oxidation.
This work focused on evaluating the metabolic alterations of TG/ (GL+FFA) cycle, in culture 3T3-L1 cells exposed to CDCA. Specifically, we addressed if CDCA supplementation alters the TG/ (GL+FFA) cycle activity, if this was related to improved metabolic status and if mitochondrial metabolism was involved.
Cultured 3T3-L1 cells exposed to CDCA exhibit decreased lipid accumulation and an increase in uncoupling protein-1 (UCP-1) content, which in turn leads to a decrease in reactive oxygen species (ROS) generation. CDCA also leads to an increase in glyceroneogenesis, suggesting an increase activity in TG/ (GL+FFA) cycle activity. Indeed, these results show that administration of CDCA seems to be an attractive therapy to obesity and T2DM. However, a question still remains, what leads to a reduction in triglycerides (TG) accumulation? Based on our results CDCA up-regulates genes involved in β-oxidation and mitochondrial biogenesis, but there are no differences in fatty acid oxidation between control and cell exposed to CDCA. A possible explanation is that lipids are being exported to the medium. However this is an in vitro study, it would be interesting understand the destination of this lipids in vivo. Finally the possible occurrence of metabolic compartmentalization opens new perspectives in futures works.<br>A obesidade é um dos principais problemas de saúde pública a nível mundial. A grande maioria da população obesa desenvolve patologias associadas que consequentemente levam à diminuição da esperança média de vida. Estas incluem diabetes tipo 2 (T2DM), aterosclerose, esteatose hepática, doenças cardiovasculares e ainda alguns tipos de cancro, Dado que as estratégias atuais são ainda pouco eficazes, no que se refere ao tratamento da obesidade, é urgente que se investiguem novas terapias, nomeadamente a modulação do tecido adiposo branco (WAT). No WAT, as vias metabólicas da glicose e dos lípidos convergem no ciclo dos glicerolípidos/ácidos gordos livres (TG/ (GL+FFA)), sendo este considerado um ciclo fútil dado que não gera produtos enquanto consome substratos energéticos. A diminuição da atividade deste ciclo em situações de obesidade e diabetes diminui a oxidação de substratos e aumenta o armazenamento de ácidos gordos (FFA) no WAT. Assim, a estimulação deste ciclo fútil surge como um potencial alvo terapêutico. Porém, a oxidação de substratos implica a estimulação simultânea do ciclo fútil e da função mitocondrial sendo que, até à data, não existe um mecanismo capaz de acoplar estes processos. O ácido quenodesoxicólico (CDCA) é um ácido biliar conhecido pelos seus efeitos anti-obesidade, no entanto, o seu mecanismo de ação é ainda controverso. O CDCA activa dois reguladores da transcrição de genes metabólicos envolvidos no ciclo TG/ (GL+FFA), na capacidade oxidativa mitocondrial e na β-oxidação, o PPARα e o PPARγ. Assim, a nossa hipótese propõe que o CDCA medeia o acoplamento do ciclo fútil com o gasto energético no WAT, aumentando simultaneamente as taxas de atividade do ciclo fútil e de oxidação mitocondrial de substratos.
Este trabalho foca-se na avaliação das alterações metabólicas no ciclo TG/ (GL+FFA), na linha celular 3T3-L1, induzidas pelo CDCA. Especificamente, avaliou-se se a exposição ao CDCA altera a atividade deste ciclo, se essa alteração está relacionada com uma melhoria no perfil metabólico e ainda se o metabolismo mitocondrial está envolvido.
As células expostas ao CDCA demonstraram uma diminuição na acumulação de lípidos e um aumento no conteúdo de proteína desacopladora-1 (UCP-1), o que por sua vez diminui a produção de espécies reactivas de oxigénio (ROS). Adicionalmente, a exposição ao CDCA induziu um aumento na gliceroneógenese, sugerindo, assim, um aumento na atividade do ciclo TG/ (GL+FFA). Dessa forma, a administração de CDCA parece ser uma estratégia terapêutica atrativa no combate à obesidade e à T2DM. No entanto, uma questão mantém-se, o que leva à redução da acumulação dos triglicerídeos (TG)? Com base nos resultados obtidos, o CDCA aumenta a expressão dos genes envolvidos na β-oxidação e na biogénese mitocondrial, mas não existem diferenças na oxidação dos FFA entre o controlo e as células expostas ao CDCA. Uma possível explicação é que os lípidos estejam a ser exportados para o meio. No entanto, este é um estudo in vitro, logo seria interessante perceber o destino destes lípidos in vivo. Finalmente a possível ocorrência de compartimentalização metabólica abre novas perspectivas para trabalhos futuros.
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Solis, Agurto Carlos Antonio. "Creación de un centro de desarrollo de capacidades y entrenamiento conjunto de las FFAA para riesgos de desastre." Master's thesis, Pontificia Universidad Católica del Perú, 2019. http://hdl.handle.net/20.500.12404/15850.
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El Comando Conjunto de las Fuerzas Armadas (CCFFAA) en las últimas décadas ha
cumplido de forma eficiente las tareas de defensa de la soberanía e integridad territorial
y su apoyo en el orden interno al Ministerio del Interior. Sin embargo, para el
cumplimiento eficiente y eficaz del 4to nuevo rol estratégico de las Fuerzas Armadas
(FFAA) y además de superar las adversidades, limitaciones y carencias demostrados
en la intervención en los últimos escenarios de desastres; se demanda la preparación
conjunta mediante un sistema de desarrollo de capacidades y entrenamiento conjunto
en todos los niveles de mando para el éxito de la misión en el Sistema Nacional de
Gestión de Riesgos de Desastre (SINAGERD). Nuestro proyecto de innovación
consiste en estudiar la viabilidad de la “Creación de un centro de desarrollo de
capacidades y entrenamiento conjunto de las FFAA para riesgos de desastre. La
estrategia metodológica para evidenciar el problema y la elaboración de la propuesta
innovadora, consta de un conjunto de herramientas como: 1) la revisión bibliográfica de
documentos oficiales de las instituciones públicas como el Ministerio de Defensa
(MINDEF), Ejercito del Perú, Instituto Nacional de Defensa Civil (INDECI) y el CCFFAA,
2) Entrevistas a grupo de expertos en Gestión de Riesgos de Desastre de instituciones
dedicadas a la investigación en el ámbito de defensa como el Centro de Estudios
Estratégicos del Ejercito (CEEEP), 3) Además de la experiencia y observación
participante en los procesos de preparación e intervención de las FFAA durante el año
2017 y 2018.<br>The Comando Conjunto de las Fuerzas Armadas (CCFFAA) in recent decades has
efficiently accomplished the tasks of defense of territorial sovereignty and integrity and
its internal support to the Ministry of Interior. However, for the efficient and effective
fulfillment of the 4th new strategic role of the Armed Forces (FFAA) and in addition to
overcoming the adversities, limitations and deficiencies demonstrated in the intervention
in the last scenarios of disasters; Joint preparation is required through a system of
capacity development and joint training at all levels of command for the success of the
mission in the National Disaster Risk Management System (SINAGERD). Our
innovation project consists in studying the viability of the “Creation of a joint capacity
development and training center of the Armed Forces for disaster risks. The
methodological strategy to highlight the problem and the development of the innovative
proposal, consists of a set of tools such as: 1) the bibliographic review of official
documents of public institutions such as the Ministry of Defense (MINDEF), Army of
Peru, National Institute of Civil Defense (INDECI) and CCFFAA, 2) Interviews with a
group of experts in Disaster Risk Management of institutions dedicated to research in
the field of defense such as the Centro de Estudios Estratégicos del Ejercito (CEEEP),
3) In addition to the experience and participant observation in the preparation and
intervention processes of the Armed Forces during the year 2017 and 2018.<br>Tesis
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Si, Ali Abderrahim. "Le recours des personnes morales de droit public à l'arbitrage." Dijon, 1998. https://nuxeo.u-bourgogne.fr/nuxeo/site/esupversions/83b4ea72-ffab-414e-9b81-8ff812895b17.
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A l'exception de la période révolutionnaire, arbitrage et droit public font traditionnellement mauvais ménage. L’ancien code de procédure civile interdisait d'y recourir (articles 1004 et 83). L’article 2060 du code civil, issue de la loi 72-626 du 5 juillet 1972, n'a pas modifié cette interdiction. Toutefois, cette interdiction a été assortie de quelques exceptions conventionnelles (convention européenne de Genève du 21 avril 1961 et convention de Washington du 18 mars 1965), législatives (articles 247 et 361 du code des marches publics, loi 86-972 du 19 aout 1986 etc. . . ) et jurisprudentielle (extension de l'arbitrage aux litiges de commerce international des personnes publiques). L’assouplissement de l'interdiction de compromettre faite aux personnes publiques est souhaitable. L’arbitrage constitue aujourd'hui une alternative au juge étatique. Il peut contribuer à l'allègement de la surcharge des juridictions, notamment administratives. Par ailleurs, vu les avantages qu'il procure aux parties (rapidité, confidentialité et compétence technique des arbitres), l'arbitrage convient mieux aux contentieux économiques. Cependant, pour mettre en œuvre cet arbitrage, encore faut-il déterminer son régime juridique. Le législateur, à l'exception des articles 247 et 361 du code des marchés publics qui renvoient au nouveau code de procédure civile, n'a pas prévu les règles auxquelles l'arbitrage devra être soumis. Il reste donc à s'interroger sur l'applicabilité de ce régime de droit commun. Dans l'ensemble, bien que droit public et arbitrage soient dominés par des finalités différentes, le régime de droit commun peut régir la procédure d'arbitrage à laquelle une personne publique est partie. Cependant, d'origine réglementaire, ces règles ne sont pas applicables si elles s'opposent à des principes généraux du droit public. En matière internationale, la question portait surtout sur la partialité du droit national de l'état contractant. Pour éviter cette partialité. Les thèses d'internationalisation (applicabilité du droit international public) et de délocalisation (applicabilité de la lex mercatoria) ont été proposées. On constate que là aussi les arbitres appliquent le régime juridique d'arbitrage de droit commun aux personnes morales de droit public, assorti de certaines adaptations quand les besoins de la collectivité le nécessitent<br>Excepted during the revolutionary period, arbitration is not in agreement with public law. The old civil procedure code prohibited arbitration (articles 1003 and 83). The paragraph 2060 of civil code has not changed this prohibition. However, arbitration is allowed by some international conventions, legal acts and case-law. So, it's hoped to introduce some flexibility to prohibition in order to allow legal persons of public law the right to arbitration. Today, an arbitrator is an alternative to a public judge. It can reduce overloaded jurisdictions, in particular, administrative ones. Moreover, arbitration is suitable for economic litigation considering its advantages. However, it is necessary to determine the juridical regime of arbitration before its application. The legislator, with the exception of act 1906, has not been informed of the rules which the arbitrator has to comply. It is necessary to study the possible applications of the ordinary common law. Although public law and arbitration are different, the common ordinary law can be applied to legal persons of public law. However, these rules cannot be applied if they are against the general principles of public law. In international matters, the problem concerns the partiality of national law of the contracting state. To avoid this partiality, the application of international public law and lex mercatoria are suggested. We note that in arbitration, common ordinary law is applied and, if necessary, adapted for community interests
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Chauveau, Amandine. "La toux en dehors d'une infection chez l'enfant : trajectoires au cours des dix premières années de vie, association avec les maladies allergiques et rôle de l'environnement périnatal." Electronic Thesis or Diss., Bourgogne Franche-Comté, 2023. http://indexation.univ-fcomte.fr/nuxeo/site/esupversions/c5effcd3-ffa9-426d-88b6-ddd6d823c850.
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La toux est un symptôme respiratoire fréquent et non spécifique chez l’enfant, habituellement présent uniquement durant une infection aigue des voies respiratoires. Cependant, certains enfants présentent une toux par excès de sensibilité se manifestant par des épisodes de toux fréquents ou récurrents, en dehors d’une infection, et des facteurs déclenchants habituellement non tussigènes. Bien qu’un des mécanismes étiologiques de cette hypersensibilité soit l’atopie, très peu d’études se sont intéressées à la relation entre trajectoires de toux dans l’enfance et maladies allergiques ainsi qu’à leur association avec l’environnement précoce.Afin d’identifier les trajectoires de toux dans l’enfance, d’analyser leur relation avec les maladies allergiques et avec l’environnement précoce, le travail de cette thèse a porté sur deux volets complémentaires : un volet épidémiologique observationnel chez l’enfant et un volet expérimental chez le lapin. Le volet épidémiologique reposait sur l’analyse des données de la cohorte prospective européenne PASTURE (Protection against Allergy: STUdy in Rural Environment). Parmi les 961 enfants inclus dans l’étude épidémiologique, une analyse en classes latentes a permis d’identifier cinq trajectoires de toux en dehors d’une infection : peu ou pas de symptômes (59,9 %), transitoire aigue (24,1 %), transitoire modérée (6,8 %), persistante à début tardif (4,8 %), et persistante à début précoce (4,4 %). En comparaison avec la trajectoire peu ou pas de symptômes, les autres trajectoires étaient significativement associées avec les sibilants, l’asthme et la rhinite allergique. La trajectoire persistante à début précoce avait la plus forte association pour l’asthme et était inversement associée à l’environnement fermier. L’allergie alimentaire était associée aux deux trajectoires persistantes. La sensibilisation atopique était associée uniquement à la toux persistante à début tardif. La consommation de lait de ferme bouilli durant la première année de vie était la seule exposition spécifique à l’environnement fermier significativement associée à une diminution du risque de toux persistante à début précoce et de toux transitoire aigue. Des infections respiratoires répétées ou prolongées dans la première année de vie étaient significativement associées à un risque plus élevé de toux persistante à début précoce. Le volet expérimental a permis d’évaluer l’impact de l’exposition périnatale à la poussière de ferme sur la sensibilité tussigène et la réactivité bronchique chez un modèle de lapin d’inflammation bronchique d’origine allergique. Un environnement spécifique a été appliqué aux lapines gestantes et à leurs lapereaux jusqu’à la sixième semaine de vie (zone exempte d’agent pathogène pour le groupe contrôle ; étable de veaux pour le groupe ferme). Les lapereaux étaient ensuite hébergés dans une zone conventionnelle de l’animalerie et sensibilisés à l’ovalbumine par voie intrapéritonéale. La sensibilité à la toux a été évaluée par la stimulation mécanique de la toux et la réactivité bronchique par un test à la méthacholine. Nous n’avons pas retrouvé d’effet de l’exposition précoce à une étable de veaux sur la sensibilité tussigène ni la réactivité bronchique.Nos résultats suggèrent un lien étroit entre toux persistante et pathologies atopiques ainsi que l’existence de potentiels facteurs de prévention communs. Les enfants présentant une toux persistante ou récurrente devraient être orientés vers un médecin allergologue pour qu’une évaluation allergologique complète soit réalisée. Les études de prévention des pathologies atopiques devraient également s’intéresser aux symptômes de toux en dehors d’une infection afin d’évaluer la pertinence de développer des stratégies de prévention communes<br>Cough is a frequent and non-specific respiratory symptom in children. In the majority of otherwise healthy children, cough is a symptom related to a self-limiting viral upper respiratory tract infection. However, some children have cough hypersensitivy that manifests as frequent or recurrent coughs, without a respiratory infection, and triggered by normally innocuous stimuli. Although atopy is one of the etiological mechanisms of this hypersensitivity, few studies has explored the relationship between cough trajectories in children and allergic diseases, as well as their association with early environment.In order to identify trajectories of cough in childhood, to analyse their relationship with allergic diseases and with early environment, the thesis work consisted of two complementary parts: an epidemiological observational part in children and an experimental part in rabbit. The epidemiological part was based on analysis of data from the prospective European birth cohort PASTURE (Protection against Allergy: STUdy in Rural Environment). Among the 961 children included in the epidemiological study, a latent class analysis allowed to identify five trajectories of cough without a cold: never of infrequent (59.9%), acute transient (24.1%), moderate transient (6.8%), late persistent (4.8%) and early persistent (4.4%). Compared with the never/infrequent trajectory, the other trajectories were significantly associated with wheezing, asthma and allergic rhinitis. Early persistent trajectory had the strongest association with asthma and was inversely associated with farm environment. Food allergy was associated with both persistent trajectories. Atopic sensitisation was only associated with the late persistent trajectory. Consumption of boiled farm milk during the first year of life was the only farm-specific exposure significantly associated with a decreased risk of early persistent cough and acute transient cough. Repeated or prolonged respiratory tract infections during the first year of life was associated with a higher risk of early persistent cough. The experimental part allowed to evaluate the impact of perinatal exposure to farm dust on cough sensitivity and airway responsiveness in an allergic airway inflammation rabbit model. A specific environment has been applied to pregnant rabbits and their offspring until six weeks after birth (pathogen-free zone for the control group, calf barn for the farm group). Rabbit pups were then housed in a conventional zone and sensitised to ovalbumin by intraperitoneal route. Cough sensitivity was assessed by mechanical stimulation of cough and airway responsiveness by a methacholine challenge. We did not find any effect of early exposure to the calf barn on cough sensitivity or bronchial reactivity.Our results suggest 1/ a close link between persistent cough and atopic diseases and 2/ the existence of potential common preventive factors. Children having persistent or recurrent cough should be referred to an allergist for a complete allergy assessment. Prevention studies for atopic diseases should also explored symptoms of cough without a cold in order to evaluate the relevance of developing common prevention strategies
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Sharber, Casey D. "An analysis of the mutual awareness between public horticulture and the national FFA organization." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 173 p, 2007. http://proquest.umi.com/pqdweb?did=1453233021&sid=4&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Sýkora, Michal. "Optimalizace a validace metody stanovení volných mastných kyselin." Master's thesis, Vysoké učení technické v Brně. Fakulta chemická, 2016. http://www.nusl.cz/ntk/nusl-240526.
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This master thesis deals with the development of method for free fatty acids determination in natural and processed cheese. In the theoretical part the possibilities of extraction, fractionation and determination of lipid fractions, characterization of fatty acids and various methods of their determination are described, as well as determination of free fatty acids. The main scope of the experimental section is optimization and validation of the selected method for determination of free fatty acids in various cheese matrices. For extraction of lipids from the sample the method with the mixture of diethylether and petrolether according to ČSN EN ISO 1735 was selected. Thin-layer chromatography and solid phase extraction were tested and compared for separation of free fatty acids. The method according to ČSN EN ISO 5509, using methanol solution of bortrifluoride, was applied for esterification. Fatty acid methyl esters were determined by gas chromatography with flame-ionization detection.
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Borges, Gleice Rocha Ferreira. "Atividade de derivados de diindolilmetano e de uracil em receptores de ácidos graxos 1 e 4 (FFAR1 e FFAR4)." reponame:Repositório Institucional da UnB, 2018. http://repositorio.unb.br/handle/10482/32264.
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Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências Farmacêuticas, 2018.<br>Submitted by Raquel Viana (raquelviana@bce.unb.br) on 2018-07-12T18:07:51Z
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Previous issue date: 2018-07-06<br>Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).<br>Doenças metabólicas como o diabetes tipo 2 têm crescido em prevalência em todo o mundo. Diversas alternativas farmacológicas têm sido usadas, porém com importantes efeitos adversos, como exemplo, a hipoglicemia. Os receptores de ácidos graxos 1 e 4 (FFAR1 e FFAR4) têm sido investigados como possíveis alvos para o tratamento de diabéticos, porém, até o momento, nenhum fármaco com alvo nestes receptores atingiu sucesso em todas as fases clínicas. Com objetivo de encontrar novos ligantes, diversos compostos foram testados para atividade agonista e antagonista nos receptores FFAR1 e FFAR4 em ensaios de recrutamento de β-arrestina e de mobilização de cálcio. Foram encontrados quatro antagonistas e um agonista com atividade moderada para o receptor FFAR1, e um agonista moderado para FFAR4. A análise de estrutura-atividade (SAR)dos derivados de diindolilmetano mostrou que substitutos longos não foram bem tolerados na ponte de metileno e apenas substitutosaltamente eletronegativos deflúor foram tolerados na posição 4 de cada indolda molécula. Os ligantes foram também testados para a atividade adipogênica in vitro. Desses, apenas Yazh 357 mostrou um potencial adipogênicocom aumento da expressão gênica de Fabp4, Pparge Ffar4 durante o processo de diferenciação. Estudos adicionais são necessários para esclarecer o possível alvo desse ligante no processo de maturação do adipócito.<br>Metabolic diseases, liketype 2 diabetes, are increasing in prevalence worldwide. Several pharmacologic alternatives have been used, however with side effects such as the hypoglycemia. The free fatty acids receptor 1 and 4 (FFAR1 and FFAR4)have been investigatedas possible alternatives for the treatment of these patients, but so far none medicine targeting these receptors could reachsuccess in all the clinical trials. Aiming to find new ligands, many compounds were testedfor agonist and antagonist activity at FFAR1 and FFAR4 using β-arrestin recruitment and calcium mobilization assays. Four antagonists and one agonist were found with moderate activity atFFAR1, while forFFAR4 one moderate agonist was found. The structure activity relationship (SAR)of diindolylmethane derivatives showed that longsubstitutes were not well tolerated in the methylene bridge, and only the highly electronegative substitute fluorine was tolerated at position 4of each distal aromatic system of the molecule. The ligands were also testedfor their adipogenic activity in vitro. Only Yazh 357 showed an adipogenic potential, increasing the gene expression of Fabp4, Pparge Ffar4 during the differentiation process. Additional studies are necessary to clarify the possible target of this ligandin the process of adipocyte maturation.
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Wiesenthal, Stephanie Renée. "The effect of free fatty acids, FFA, on first-pass hepatic insulin extraction in vivo." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ34094.pdf.
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Gossen, Larry Alan. "A study of the membership of the national FFA alumni association: volunteering, loyalty, and benefits." Diss., Kansas State University, 2011. http://hdl.handle.net/2097/8450.
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Doctor of Philosophy<br>Curriculum and Instruction Programs<br>Steven R. Harbstreit<br>There has been little research conducted related to the National FFA Alumni Association since its establishment in 1971. The purposes of this study were to determine the demographic characteristics of the membership of the National FFA Alumni Association, determine whether differences exist regarding members’ motivation to join and engage themselves in the local FFA Alumni affiliate, and whether differences exist in members’ loyalty to the FFA Alumni at the national and local levels based on their level of engagement. This descriptive study utilized survey research to accomplish the purpose, assessing the motivational functions for volunteering and measuring loyalty to the local FFA Alumni affiliate and the National FFA Alumni Association. The population of this study was the membership of the National FFA Alumni Association for the 2009-2010 membership year (N = 49,589). A proportional stratified random sample (n = 1,000) was used to identify study participants and ensure representation from the four membership regions of the National FFA Alumni Association. Based on a final usable sample (n = 913), the researcher obtained a final response rate of 43.7% (n = 399).
The National FFA Alumni Association is comprised of predominantly white, male, college-educated, actively engaged former FFA members with an average age of 49.6 years. The results of independent sample t-tests indicated a significant difference between male and female members in the importance they place on six motivations for volunteering. Female members were considerably higher in the motivational functions of values, understanding, enhancement, social, career, and protective. A correlation analysis also indicated that age of the respondents played a role in the motivation to volunteer. Older members were less motivated in the areas of career, understanding, values, and enhancement. Paired samples t-tests determined members were significantly more loyal to the local FFA Alumni affiliate than the National FFA Alumni Association. There was also a significant difference in the loyalty of members based on their level of engagement with a local FFA Alumni affiliate with more highly engaged members expressing more loyalty to the association.
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Jenkins, III Charles Cordell. "A QUALITY AGRICULTURAL EDUCATION PROGRAM: A NATIONAL DELPHI STUDY." UKnowledge, 2008. http://uknowledge.uky.edu/gradschool_theses/516.
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The current body of knowledge concerning Agricultural Education quality in regards to its three components is not consistent and total program quality has not been defined scientifically. The purpose of this study was to determine quality indicators for instruction, SAE, and FFA according to experts (agricultural education teacher educators, state instructional staff, and high school teachers) across the United States. The conceptual framework for this study was the three circle model consisting of the three integral, intra-curricular components of Instruction, FFA, and SAE. This national study was descriptive in nature and utilized the Delphi technique to gather responses from an expert panel and combine the responses into one useful statement (Stitt-Gohdes andamp; Crews, 2004). The initial questionnaire consisted of three open-ended questions and was developed by the researcher while subsequent questionnaires were developed from the experts responses. The expert panel agreed upon 37 quality indicators for Instruction, 19 quality indicators for FFA, and 6 quality indicators for SAE.
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English, Chastity Katrina Warren. "An Analysis of LifeKnowledge® Skills and Abilities Development within North Carolina Agriscience Education Programs as Viewed by Veteran Secondary Agriscience Educators, Agriscience Education Students, and Students' Employers." Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/39220.
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The purpose of this descriptive study was to analyze the LifeKnowledge® skills development within North Carolina agriscience education programs as viewed by veteran agriscience teachers, agriscience education students, and studentsâ employers. The survey population consisted of 54 veteran agriscience education teachers, of whom 49 (91%) responded. One hundred sixty-two agriscience education students, of whom 115 (71%) responded and 162 employers, of whom 95 (59%) responded. Seventy-four LifeKnowledge® skills items and the 16 LifeKnowledge® precepts were evaluated by teachers to determine how often they provided instruction and experiences related to the development of employability skills development for students. The same 74 items and 16 precepts were evaluated by students to determine the extent to which they thought participating in their agriscience education programs and FFA increased their employability and personal skills development. Employers were asked to evaluate how often they witnessed agriscience education students exhibit the LifeKnowledge® 74 items and 16 precepts within the workplace.
The major findings for this study included that teachers, students, and employers were generally consistent, with a few exceptions, in their perceptions of the development and demonstration of the LifeKnowledge® skills and abilities. Statistically significant differences were found among the three groups on select LifeKnowledge® skills items and precepts. A majority of teachers reported that they regularly or often provided students instruction and experiences related to the LifeKnowledge® skills. Students reported that regularly or often their
participation in their local agriscience education programs and FFA had increased their employability and personal skills development. The employers reported that often, with a few regular observations, they witnessed students exhibiting the LifeKnowledge® skills within the workplace.
One of the major recommendations for this study is that LifeKnowledge® lessons be implemented for pre-service and in-service teachers and findings shared with the National FFA Organization. Another suggestion is that an employability skills curriculum should be developed for use across all career and technical education programs and core courses to develop studentsâ employability skills in response to business and industry demands. Finally, research should be conducted to determine how 4-H, career and technical student organizations, and other youth groups develop LifeKnowledge® skills.<br>Ph. D.
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Moodaley, Runisha. "Free fatty acid receptor (FFA) and lipid receptor (GPR119) signalling mediates nutrient-sensing in mouse intestine." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/free-fatty-acid-receptor-ffa-and-lipid-receptor-gpr119-signalling-mediates-nutrientsensing-in-mouse-intestine(6deac195-861b-4967-b005-20ec150df882).html.
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Medium and long chain fatty acids exhibit affinity for free-fatty acid receptor 1 (FFA1) and 4 (FFA4). FFA1 and FFA4 are expressed in the pancreas with a third lipid G-protein coupled receptor, GPR119, and all three GPCRs are also highly expressed by gastrointestinal (GI) enteroendocrine L cells, which release glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). GLP-1 is a stimulant of insulin secretion postprandially, whereas PYY slows GI motility and reduces food intake. The receptor expression patterns raise these receptors’ potential as targets for anti-diabetic and anti-obesity therapeutics. This thesis compares the pharmacology and cellular signalling of novel FFA1, FFA4 and GPR119 agonists from AstraZeneca, with that of commercially available agonists in mouse colonic mucosa. Mucosa was mounted in Ussing chambers, voltage-clamped and the resultant short-circuit current (Isc) was recorded continuously, as a measurement of vectorial epithelial ion transport in vitro. Colonic bead propulsion and charcoal-meal gavage assessments were used to measure lower and upper GI transit in vivo, respectively. FFA1, FFA4 or GPR119 selective agonism potently inhibited mucosal anion secretion via a PYY-Y1 paracrine mechanism. These anti-secretory responses showed area-specificity and the descending colon was selected for further interrogation. Here, FFA1 and FFA4 agonists displayed low maximal responses, whereas GPR119 agonists exhibited partial efficacy in comparison to PSN632408. All agonists required glucose for activity, minimising the potential for hypoglycaemia, a limitation of current anti-diabetic drugs. Furthermore, dual agonism of FFA1, FFA4 or GPR119 was additive. The FFA1 antagonist, ANT825 revealed endogenous intestinal FFA1 tone, and this was inhibited in the presence of the competitive Y1 and Y2 antagonists. FFA4 agonism slowed transit in the colon and increased transit in the small intestine, whereas FFA1 agonism had no effect on transit in vivo. As the FFA4 receptor is more broadly expressed in the GI tract compared to FFA1 and GPR119, luminal-restricted GPR119 agonists in combination with FFA1 agonists should be considered as future T2DM therapeutics.
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Clark, Travis Scott. "Influences of aspirations and expectations on contest performance at the National FFA Agricultural Mechanics Career Development Event, 2001-2006." [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-2411.
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Salomonsson, Flockhart Mikael. "Muscle glycogen depletion and resynthesis in highly trained male cyclists." Thesis, Gymnastik- och idrottshögskolan, GIH, Institutionen för idrotts- och hälsovetenskap, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:gih:diva-1860.
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Aim The aim of this study was to establish a method to create a difference between groups in muscle glycogen content as well as to investigate the effect of training in low muscle glycogen state on metabolic and physiological parameters. Method During two trials, a subject group of ten highly trained male road or mountain bike cyclists ((mean±SD) age, hight, body weight, VO2max, and VO2max·kg-1 was 28±5 years, 74.7±6.3 kg, 183±6 cm, 4876±332 mL min-1, 64.4±2.8 mL·kg-1 min-1), performed a glycogen depletion exercise followed by a night’s rest and a second exercise session. In the study, which was a crossover design, the subjects were randomly chosen to perform the first trial on a carbohydrate rich diet or a diet with no of carbohydrates. All the testing was performed on a Monark 839E ergometer bike and muscle biopsy sampling was collected before depletion exercise, before the exercise the following day and three hours post exercise. Plasma FFA and glucose was analyzed from venous blood collected at rest. Results Muscle glycogen pre depletion exercise was 623±180 and 645±133 mmol·kg dw-1 glycosyl units for non-CHO and CHO trials respectively. The depletion exercise followed by 13 hours of rest resulted in a significant decrease in muscle glycogen in the non-CHO (p<0.0001), and CHO trials (p<0.01) to 166±71 and 478±111 mmol·kg dw-1 respectively. In the non-CHO trial net glycogen depletion correlated positively with pre depletion glycogen storage. After the completion of exercise 2 and the following three hour rest period, glycogen content in non-CHO and CHO-trial was 130±52 and477±97 mmol·kg dw-1, respectively. In low glycogen state, the non-CHO trial resulted in an increase in FFA measured in blood plasma at rest and in an increase in Borg rating of perceived exertion (RPE) as well as a reduction in blood glucose during exercise. Conclusion The protocol used in the present study was successful in creating a difference in muscle glycogen storage and training in low glycogen state was associated with an increase of several physiological parameters indicating a possible impairment of endurance exercise performance.<br>Syfte Syftet med denna studie var att skapa en metod för att åstadkomma skillnader i muskelglykogen samt observera den akuta effekten av träning med låga muskelglykogennivåer på metabola och fysiologiska parametrar. Metod Vid två tillfällen fick tio vältränade mountainbike- eller landsvägscyklister ((medel±SD) ålder, längd, kroppsvikt, VO2max och VO2max·kg-1 var 28±5 years, 74,7±6,3 kg, 183±6 cm, 4876±332 mL min-1, 64,4±2,8 mL·kg min-1) genomföra ett träningspass i syfte att tömma muskelglykogendepåerna följt av en natts vila och sedan ett andra träningspass. Studien följde ett randomiserat crossover-upplägg och det ena försökstillfället genomfördes med en diet hög på kolhydrater och det andra tillfället med en diet utan kolhydrater (CHO). All testning genomfördes på en Monark 839E ergometer och muskelbiopsier togs före tömningspass, efter en natts vila före det andra träningspasset och tre timmar efter det andra träningspasset. Venösa blodprov togs i vila före biopsitagning för analys av plasma FFA och glukos. Resultat Koncentrationen av muskelglykogen före tömningspasset var 623±180 and 645±133 mmol·kg dw-1 vid försök utan respektive med CHO. Tömningspasset och 13 timmars vila resulterade i en signifikant minskning av muskelglykogen vid försök utan CHO (p<0.0001), och med CHO (p<0.01) till 166±71 och 478±111 mmol·kg dw-1. Nettominskningen av muskelglykogen vid tömningspasset utan CHO korrelerade positivt med glykogenkoncentration före tömning Efter genomförande av det andra träningspasset och tre timmars efterföljande vila var muskelglykogenmängden vid försöken utan CHO och med CHO 130±52 och477±97 mmol·kg dw-1. Vid träning med lågt muskelglykogen fanns det en kraftig ökning av fria fettsyror i blod vid vila och under arbete noterades en ökning skattning av Borg subjektivt skattad ansträngning (RPE) samt en sänkning av blodglukos. Slutsats Protokollet som användes i denna studie skapade framgångsrikt en minskning av muskelglykogen och träning med låga glykogennivåer kunde sammankopplas med flera fysiologiska parametrar som indikerar en möjlig sänkning av prestationsförmåga under uthållighetsarbete.
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Wilson, Erin Marie. "Landscape architecture in the Ag-Ed classroom: cultivating the next generation of designers." Kansas State University, 2016. http://hdl.handle.net/2097/32684.
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Master of Landscape Architecture<br>Landscape Architecture/Regional and Community Planning<br>Howard D. Hahn<br>Landscape architecture education in schools have been focused primarily on elementary and secondary Common Core courses. In many states, career-oriented programs such as agricultural education serve as a platform to teach necessary skills to be successful in all aspects of the agricultural industry. With the shift in lifestyles and technology, agricultural education (Ag-Ed) today has branched out from the traditional farm management courses to food science, natural resources, and landscaping design as well as many others. At schools like Lennox High School in Lennox, South Dakota, students learn plant identification, fundamentals of landscape design, and design graphics. How comprehensive are students' awareness of the landscape architecture profession before, during, and after taking a landscaping course? What are the possibilities of reinforcing foundational skills learned in the landscaping coursework through an outdoor learning environment similar to practical application of other vocational-type courses? How could students be presented a snapshot of the landscape architecture profession that connects the current and future curriculum taught in the Ag-Ed classroom?
In order to better understand the landscape architectural aspects of current Ag-Ed, a mixed methods approach was used. First, national, state, and local Ag-Ed curricula standards were reviewed to track how Ag-Ed courses and priorities have changed over time. Next, Ag-Ed students were surveyed before, during, and after taking the Landscaping and Horticultural course offered at Lennox High School to assess potential changes in awareness. Lastly, students currently taking the landscaping course participated in a three-day workshop where they developed ideas for their outdoor learning environment to support current and future Ag-Ed courses and landscape architecture. After the workshop, these students took a post-survey to evaluate ideas produced in the workshop, the future implementation of the workshop, and their level of awareness of the landscape architecture profession.
Results from the surveys and workshop show a refinement and increase in landscape architecture awareness, a desire for more hands-on learning conducted outside, and an enthusiasm for using their creativity to design a project for future Ag-Ed students. In subsequent years, future iterations of the workshop will advance planning and design proposals toward implementation.
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Tu, Qingshi. "Assessment of Selected Sustainability Aspects of Biodiesel Production: Water and Waste Conservation." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1342730602.
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