Rheumatoid arthritis (RA) is a common chronic inflammatory disease that affects about 1% of the Western population. Glucocorticoids (GC) are widely used for the treatment of RA and other immune-mediated diseases, such as asthma, but their use is associated with adverse effects on bone metabolism. Because of that, new selective GC receptor (GR) agonists (SEGRAs) with the potential for an improved risk/benefit profile have been developed. Compound A (CpdA) is a novel SEGRA, which showed an improved risk/benefit profile concerning glucose metabolism, however the effects on bone are not well investigated yet. Initial in vitro studies of our group showed bone-sparing potential of CpdA. The aim of this study was to investigate whether CpdA also possesses beneficial effects on bone in vivo. Therefore, the first step was to explore the effects of CpdA on healthy bone metabolism, followed by the analysis of the anti-inflammatory potential in a murine model of RA. To mimic the effects of continuous therapy, bone loss was induced in FVB/N mice by implanting slow-release pellets containing placebo, prednisolone (PRED; 3.5 mg), or CpdA (3.5 mg). After four weeks, mice were killed and the effects on the skeleton were examined. By performing in vitro studies with human bone marrow stromal cells (BMSC) and murine osteocyte-like cells (MLO-Y4 cells), the underlying mechanisms were assessed. Here, we focused on the RANKL/OPG ratio as a marker for the osteoclastogenic potential as well as on the Wnt signaling pathway. Whereas PRED reduced the total and trabecular bone density in the femur and in the spine, CpdA did not influence these parameters. These results were confirmed by histomorphometry as the mineral apposition rate was decreased by PRED whereas the number of osteoclasts was increased. Reduced bone formation was furthermore paralleled by a decline in the serum bone formation marker pro-collagen type 1 N-terminal peptide (P1NP) and decreased skeletal expression of osteoblast markers, as well as increased serum levels of the osteoblast inhibitor dickkopf-1 (Dkk-1). Additionally, serum CTX-1 and the RANKL/OPG ratio in the bone tissue were increased by PRED. None of these effects were observed with CpdA. Moreover, CpdA did not increase the RANKL/OPG ratio in MLO-Y4 cells and failed to transactivate Dkk-1 expression in bone tissue, BMSC, and osteocytes. To analyze the anti-inflammatory properties of CpdA, arthritis was induced in DBA/1 mice by injection of type II collagen. After disease onset, mice were treated for ten days with PBS (placebo), dexamethasone (DEX; 100 µg/mouse), or CpdA (300 µg/mouse). The latter was able to decrease disease activity, paw swelling, and paw temperature, but was less potent compared to DEX. In addition, T cells isolated from CpdA- and DEX-treated animals were less active based on proliferation rates after stimulation with type II collagen and produced smaller amounts of interferon-γ as compared to T cells from PBS-treated mice. The weaker potency of CpdA as compared to DEX in preventing infiltration of inflammatory cells, induction of osteoclastogenesis, and destruction of articular cartilage was confirmed by histological assessment of the joints. While CpdA was unable to prevent inflammation-induced bone loss, it did not aggravate bone loss or alter bone density in healthy control mice. In conclusion, this study underlines the bone-sparing potential of CpdA compared to conventional GC in a murine model of GC-induced bone loss. Even though a moderate anti-inflammatory potential of CpdA was demonstrated, it was unable to prevent inflammation-induced bone loss. Despite the bone-sparing effects of CpdA in healthy mice, its narrow therapeutic window limits its use in clinical practice. Nevertheless, this study highlights important molecular mechanisms of GC-induced bone loss showing that by avoiding increases in the RANKL/OPG ratio or Dkk-1 in osteoblast lineage cells, GC-induced bone loss may be improved. / Rund 1% der westlichen Bevölkerung leidet an rheumatoider Arthritis, einer chronischen Entzündung der Gelenke. Für deren Behandlung werden häufig Glukokortikoide (GC) eingesetzt. Trotz ihrer potenten entzündungshemmenden Wirkung ist ihr Einsatz aufgrund der negativen Auswirkungen auf den Knochenstoffwechsel eingeschränkt. Um ein besseres Risiko/Nutzen-Profil zu erzielen, wurden selektive GC-Rezeptoragonisten (SEGRAs) entwickelt, die weiterhin potent anti-inflammatorisch wirken, während negative metabolische Effekte ausbleiben. Compound A (CpdA) ist ein Vertreter dieser Gruppe, der in Mäusen ein verbessertes Behandlungsprofil hinsichtlich des Glukosestoffwechsels zeigte. Die Wirkung auf den Knochen wurde bisher nur unzureichend untersucht. Erste in vitro Ergebnisse unserer Gruppe zeigten knochenfördernde Eigenschaften von CpdA. Ziel dieser Arbeit war es zu untersuchen, ob CpdA auch in vivo ein knochenschonendes Potenzial besitzt. Dafür wurden zunächst die Effekte von CpdA auf den gesunden Knochenstoffwechsel untersucht, um anschließend seine Wirkung in einem Mausmodell der rheumatoiden Arthritis zu testen. Um die Effekte einer Dauertherapie mit CpdA nachzustellen, wurden Slow-release-Pellets mit Plazebo, Prednisolon (PRED; 3,5 mg) beziehungsweise CpdA (3,5 mg) in FVB/N-Mäuse implantiert. Nach vier Wochen wurden die Effekte der Substanzen auf den Knochen untersucht. Um mögliche zugrundeliegende Mechanismen zu eruieren, wurden humane Knochenmarkszellen und murine Osteozyten-ähnliche Zellen (MLO-Y4-Zellen) genutzt. In diesen wurde der Einfluss der Substanzen auf das RANKL/OPG-Verhältnis, als einen Marker der Osteoklastenfunktion, sowie auf Dickkopf-1, einen Inhibitor des Wnt-Signalwegs, getestet. Während PRED die totale und trabekuläre Knochendichte im Femur und der Wirbelsäule verminderte, zeigte CpdA keinen Einfluss auf diese Parameter. Diese Ergebnisse wurden durch die histomorphometrische Analyse bestätigt und zeigten des Weiteren, dass PRED die Mineralanbaurate reduzierte während es die Anzahl der Osteoklasten erhöhte. Die verminderte Osteoblastenfunktion ging mit einer Abnahme der Knochenformationsmarker im Serum und im Knochengewebe einher. Außerdem wurden der Resorptionsmarker im Serum und das RANKL/OPG-Verhältnis im Knochengewebe von PRED erhöht. Bei CpdA-behandelten Tieren wurden keine dieser Effekte beobachtet. Zudem wurde das RANKL/OPG-Verhältnis in vitro in MLO-Y4-Zellen durch CpdA nicht beeinflusst und auch die Transaktivierung von Dkk-1 im Knochengewebe, in Knochenmarkszellen und Osteozyten blieb aus, was somit eine mögliche Erklärung für die knochenschonende Wirkung von CpdA darstellen könnte. Um die entzündungshemmenden Eigenschaften von CpdA zu untersuchen, wurde mittels einer Kollageninjektion Arthritis in DBA/1-Mäusen induziert. Nachdem die Mäuse eine Arthritis entwickelt hatten, wurden sie jeden zweiten Tag über eine Dauer von zehn Tagen mit PBS (Vehikel), Dexamethason (DEX; 100 µg/Maus) oder CpdA (300 µg/Maus) behandelt. CpdA war in der Lage die Krankheitsaktivität, die Pfotendicke und die Pfotentemperatur zu senken. Dabei war es aber nicht so effektiv wie DEX. Außerdem konnte gezeigt werden, dass T-Zellen, die aus CpdA- und DEX- behandelten Tieren isoliert und mit Kollagen stimuliert wurden, basierend auf ihrer Proliferationsrate weniger aktiv waren und geringere Mengen an Interferon-γ produzierten, als T-Zellen, die aus PBS-behandelten Tieren entnommen wurden. Das schwächere entzündungshemmende Potenzial von CpdA, verglichen mit DEX, wurde mittels der histologischen Analyse der Gelenke bestätigt. Es konnte eine höhere Infiltration von Entzündungszellen, sowie eine erhöhte Osteoklastogenese und Knorpelzerstörung in CpdA-behandelten Tieren beobachtet werden. Obwohl CpdA nicht in der Lage war, vor dem entzündungsbedingten Knochenverlust zu schützen, verschlimmerte es weder den Knochenverlust, noch veränderte es die Knochendichte in gesunden Kontrollmäusen. Diese Studie zeigt das knochenschonende Potenzial von CpdA in einem Mausmodell des GC-induzierten Knochenverlustes und bestätigt die moderaten entzündungshemmenden Eigenschaften von CpdA in vivo. Trotz der knochenschonenden Effekte von CpdA in gesunden Mäusen wird sein Einsatz in der klinischen Praxis durch die schmale therapeutische Breite erschwert. Trotz alledem deutet unsere Studie mit CpdA auf wichtige molekulare Mechanismen hin. Somit könnte durch das Verhindern der Erhöhung des RANKL/OPG-Quotienten oder von Dkk-1 in osteogenen Zellen, der durch GC verursachte Knochenverlust möglicherweise verhindert werden.

This study investigates how Persian compound verbs are processed in the mental lexicon, through which we can infer how they are stored, organized, and accessed. The study focuses on investigating Persian compound verbs in light of psycholinguistic theories on polymorphemic word processing as well as linguistic theories of complex predicates. The psycholinguistic section details three experiments addressing the following three research questions: (1) whether compound verb constituents show significant priming in the masked-priming paradigm; (2) whether priming effects are constrained by semantic transparency; and (3) whether priming effects are due to morphological relatedness. This study revealed several findings: (1) compound verbs in Persian are decomposed into their constituents at early stages of processing, (2) at early stages of processing, decomposition is based on purely orthographic similarity, (3) although both transparent and opaque compound constituents were facilitated while processing, transparency had an impact on processing in the early stages of processing. Finally, the findings seem to support a parallel input effect or competing alternative effect for the verbal constituent of the transparent compound verb, as reflected in the slower facilitation for the verbal constituent compared to the nominal constituent. In theoretical studies on Persian complex predicates, the compound verb formation can be either lexical or syntactic. The overall evidence reflected in the linguistic data for Persian complex predicates presented in this dissertation as well as the results of the experimental studies carried out in this research seem to point towards lexical compounding in Persian compound verb formation. The evidence comes from (1) the nominalization of the compound, i.e. the possibility of using the compound verb as a noun; (2) the atelicity feature, i.e. the possibility of using the compound verb after the progressive expression dar haale ‘in the process of’, which indicates an incomplete action; and (3) the nonreferentiality of the nominal constituent in the compound verb, i.e. the nominal constituent cannot be followed by a pronoun that refers to it. On the other hand, the results of the experimental studies reported in this dissertation seem to support a lexical approach to compound verbs in Persian. The technique used in these experimental studies was masked priming paradigm, which investigates the prelexical and lexical processing. The results reveal constituent priming effects under masked priming technique. This indicates that Persian compound verb constituents are accessed at the prelexical stage of processing. Syntactic calculations are said to be done at later stages of processing. Therefore, the early processing of compound verb constituents leads us to the argument for the lexicality of Persian compound verbs.

Magistrinio darbo tikslas: išanalizuoti kombinuotųjų lesalų, skirtų kalakutams, gamybos procesus bei pateikti rekomendacijas lesalų kokybės gerinimui bei kalakutų produktyvumo didinimui. Šio tikslo įgyvendinimui magistriniame darbe numatoma išspręsti tokius uždavinius: 1. Atlikti pašarinių žaliavų, naudojamų kalakutų kombinuotųjų lesalų, įvertinimą. 2. Atlikti lesalų gamybos procesų analizę. 3. Išanalizuoti kokybės sistemų, taikomų lesalų gamyboje, efektyvumą. 4. Atlikti kalakutų produktyvumo analizę atsižvelgiant į naudojamų lesalų kokybinius parametrus bei lesinimo programas. Išvados: 1. UAB „Marijampolės pašarai“ KŪB yra gaminami įvairūs visaverčiai lesalai, įvairioms paukščių grupėms, daugiausiai kalakučiukams-broileriams (6 lesinimo fazių lesalai) bei viščiukams broileriams ( startinis, auginimo vidurio ir pabaigos). 2. Sudarant kombinuotuosius lesalus kalakutams pagrindinis dėmesys yra kreipiamas į javų grūdų, sojos rupinių kokybę, nes lesalų struktūroje jie sudaro didžiausią dalį. 3. Žaliavų smulkintuve- malūne yra naudojamas 3 mm sietas, esant tokiam sieto diametrui pašarinių žaliavų dalelių sumalimo dydis gali kinta nuo 0,4 iki 0,5 mikrometrų. 4. Nustatant lesalų homogeniškumą į pašarus buvo įterpta po 1,0 proc. druskos. Esant tolygiam pašarinių žaliavų išsimaišymui druskos kiekio variacijos koeficientas neturėtų viršyti 5,0 proc., mūsų atliktais tyrimų duomenys rodo, kad šis rodiklis yra 7,0 proc. 5. Nekrakmolo polisacharidus skaldantys fermentai ir fitazės yra... [toliau žr. visą tekstą] / The aim of the Master’s Thesis was to analyse production processes of compound turkey feed and provide recommendations for improving the quality of compound turkey feed and the productivity of turkey. Objectives of the Master’s Thesis: 1. Evaluate raw materials used in production of compound turkey feed. 2. Analyse production processes of compound feed. 3. Analyse efficiency of quality systems used in production of compound feed. 4. Analyse turkey productivity in regard to qualitative parameters and feeding programmes. UAB „Marijampolės pašarai“ KŪB produces large variety of complete compound feed for various poultry groups, mostly for turkeys (compound feed for 6 feeding phases) and for broiler chickens (starter, developer and finisher). This thesis contains analysis of the quality and quality affecting factors of raw materials and feed additives used in compound feed production. Accomplished analysis of processes in feed production included receiving and storing of raw material, grinding of raw material and fineness of its particles, processes of conditioning, expanding and granulation. Risk factors in compound feed production were assessed as well. During development of this thesis, experiment with cross Hybrid XL turkeys was carried out, which aimed to determine influence of compound feed enriched with synthetic amino acids on the intensity of turkey growth, the feed conversion and turkey liveability. The analytical and experimental part of the thesis concluded in the... [to full text]

This study investigates how Persian compound verbs are processed in the mental lexicon, through which we can infer how they are stored, organized, and accessed. The study focuses on investigating Persian compound verbs in light of psycholinguistic theories on polymorphemic word processing as well as linguistic theories of complex predicates. The psycholinguistic section details three experiments addressing the following three research questions: (1) whether compound verb constituents show significant priming in the masked-priming paradigm; (2) whether priming effects are constrained by semantic transparency; and (3) whether priming effects are due to morphological relatedness. This study revealed several findings: (1) compound verbs in Persian are decomposed into their constituents at early stages of processing, (2) at early stages of processing, decomposition is based on purely orthographic similarity, (3) although both transparent and opaque compound constituents were facilitated while processing, transparency had an impact on processing in the early stages of processing. Finally, the findings seem to support a parallel input effect or competing alternative effect for the verbal constituent of the transparent compound verb, as reflected in the slower facilitation for the verbal constituent compared to the nominal constituent. In theoretical studies on Persian complex predicates, the compound verb formation can be either lexical or syntactic. The overall evidence reflected in the linguistic data for Persian complex predicates presented in this dissertation as well as the results of the experimental studies carried out in this research seem to point towards lexical compounding in Persian compound verb formation. The evidence comes from (1) the nominalization of the compound, i.e. the possibility of using the compound verb as a noun; (2) the atelicity feature, i.e. the possibility of using the compound verb after the progressive expression dar haale ‘in the process of’, which indicates an incomplete action; and (3) the nonreferentiality of the nominal constituent in the compound verb, i.e. the nominal constituent cannot be followed by a pronoun that refers to it. On the other hand, the results of the experimental studies reported in this dissertation seem to support a lexical approach to compound verbs in Persian. The technique used in these experimental studies was masked priming paradigm, which investigates the prelexical and lexical processing. The results reveal constituent priming effects under masked priming technique. This indicates that Persian compound verb constituents are accessed at the prelexical stage of processing. Syntactic calculations are said to be done at later stages of processing. Therefore, the early processing of compound verb constituents leads us to the argument for the lexicality of Persian compound verbs.

L'AMPK est un senseur cellulaire des réserves énergétiques de l’organisme. Les spermatozoïdes, mobilisent beaucoup d’énergie pour leur mobilité et la fécondation de l’ovocyte. L’objectif de ce travail était de caractériser et décrire des éléments clés de la voie de signalisation de l'AMPK, de comprendre leur implication dans les spermatozoïdes de coq et d’étudier comment leurs modulateurs peuvent impacter les fonctions des gamètes conservés in vitro. Nous avons montré une augmentation de la mobilité et de la réaction acrosomique dans les spermatozoïdes exposés à l'AICAR et à la metformine, des activateur de l’AMPK, y compris après avoir été congelés. Ces activateurs ont partiellement restauré les activités des enzymes antioxydantes (SOD, GPx, GR): et diminué les ROS et la LPO dans les spermatozoïdes décongelés. Nous avons établi la présence des CaMKKs (α et β) et de CaMKI dans les spermatozoïdes et leur rôle lié au calcium extracellulaire (via les canaux calcique SOCs) dans la voie de régulation de l'AMPK et dans la mobilité et la réaction acrosomique des spermatozoïdes. En conclusion, ce travail confirme le rôle de différents acteurs de signalisation liés au métabolisme énergétique et aux flux calciques dans les fonctions des spermatozoïdes. / AMPK is a cellular sensor of body energy reserves. Spermatozoa mobilize a lot of energy for their motility and the fertilization of the oocyte. The objective of this work was to characterize and describe key elements of the signaling pathway of AMPK, understand their involvement in chicken spermatozoa and study how their modulators may impact the functions of in vitro preserved gametes. We showed an increase in mobility and acrosome reaction in spermatozoa exposed to AICAR and metformin, activators of AMPK, including after freezing. These activators have partially restored the activities of antioxidant enzymes (SOD, GPx, GR): and decreased ROS and LPO in thawed spermatozoa. We have established the presence of CaMKKs (α and β) and CaMKI in sperm and their role related to extracellular calcium (via calcium channels SOCs) in the control channel of AMPK and in motility and acrosome reaction of spermatozoa. In conclusion, this work confirms the role of different signaling actors related to energy metabolism and calcium fluxes in spermatozoa functions.

The subject of the diploma thesis is a characteristic of the French N+N+N compounds of the type "relations parents-enfants" with the use of existing typology for other languages, mainly for Italian. The thesis is divided into two parts. The first part defines the concepts of composition and composite, their distribution based on different criteria. They described graphic, morphological, syntactic, and semantic properties of compounds. The second part of the thesis is dedicated to the practical research in the corpus and subsequent analysis of the acquired data. The last part contains a draft classification of French relational compounds.

This study investigates how Persian compound verbs are processed in the mental lexicon, through which we can infer how they are stored, organized, and accessed. The study focuses on investigating Persian compound verbs in light of psycholinguistic theories on polymorphemic word processing as well as linguistic theories of complex predicates. The psycholinguistic section details three experiments addressing the following three research questions: (1) whether compound verb constituents show significant priming in the masked-priming paradigm; (2) whether priming effects are constrained by semantic transparency; and (3) whether priming effects are due to morphological relatedness. This study revealed several findings: (1) compound verbs in Persian are decomposed into their constituents at early stages of processing, (2) at early stages of processing, decomposition is based on purely orthographic similarity, (3) although both transparent and opaque compound constituents were facilitated while processing, transparency had an impact on processing in the early stages of processing. Finally, the findings seem to support a parallel input effect or competing alternative effect for the verbal constituent of the transparent compound verb, as reflected in the slower facilitation for the verbal constituent compared to the nominal constituent. In theoretical studies on Persian complex predicates, the compound verb formation can be either lexical or syntactic. The overall evidence reflected in the linguistic data for Persian complex predicates presented in this dissertation as well as the results of the experimental studies carried out in this research seem to point towards lexical compounding in Persian compound verb formation. The evidence comes from (1) the nominalization of the compound, i.e. the possibility of using the compound verb as a noun; (2) the atelicity feature, i.e. the possibility of using the compound verb after the progressive expression dar haale ‘in the process of’, which indicates an incomplete action; and (3) the nonreferentiality of the nominal constituent in the compound verb, i.e. the nominal constituent cannot be followed by a pronoun that refers to it. On the other hand, the results of the experimental studies reported in this dissertation seem to support a lexical approach to compound verbs in Persian. The technique used in these experimental studies was masked priming paradigm, which investigates the prelexical and lexical processing. The results reveal constituent priming effects under masked priming technique. This indicates that Persian compound verb constituents are accessed at the prelexical stage of processing. Syntactic calculations are said to be done at later stages of processing. Therefore, the early processing of compound verb constituents leads us to the argument for the lexicality of Persian compound verbs.

Generally, nonlinear optics studies investigate optically-induced changes in refraction or absorption, and their application to spectroscopy or device fabrication. The photorefractive effect is a nonlinear optical effect that occurs in solids, where transport of an optically-induced free-carrier population results in an internal space-charge field, which produces an index change via the linear electrooptic effect. The photorefractive effect has been widely studied for a variety of materials and device applications, mainly because it allows large index changes to be generated with laser beams having only a few milliwatts of average power.Compound semiconductors are important photorefractive materials because they offer a near-infrared optical response, and because their carrier transport properties allow the index change to be generated quickly and efficiently. While many researchers have attempted to measure the fundamental temporal dynamics of the photorefractive effect in semiconductors using continuous-wave, nanosecond- and picosecond-pulsed laser beams, these investigations have been unsuccessful. However, studies with this goal are of clear relevance because they provide information about the fundamental physical processes that produce this effect, as well as the material's speed and efficiency limitations for device applications.In this dissertation, for the first time, we time-resolve the temporal dynamics of the photorefractive nonlinearities in two zincblende semiconductors, semi-insulating GaAs and undoped CdTe. While CdTe offers a lattice-match to the infrared material HgxCd1-xTe, semi-insulating GaAs has been widely used in optoelectronic and high-speed electronic applications. We use a novel transient-grating experimental method that allows picosecond temporal resolution and high sensitivity. Our results provide a clear and detailed picture of the picosecond photorefractive response of both materials, showing nonlinearities due to hot-carrier transport and the Dember space-charge field, and a long-lived nonlinearity that is due to the EL2 midgap species in GaAs. We numerically model our experimental results using a general set of equations that describe nonlinear diffraction and carrier transport, and obtain excellent agreement with the experimental results in both materials, for a wide variety of experimental conditions.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19005号 / 工博第4047号 / 新制||工||1623(附属図書館) / 31956 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 中條 善樹, 教授 澤本 光男, 教授 田中 一義 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM