<p>Value at Risk (VaR) approach has been extensively used by investment and commercial banks since its development by JP Morgan in 1990s. As time passes, it has become interesting to investigate whether VaR could be used also by other financial intermediaries like pension funds and insurance companies. The aim of this paper is to outline Value at Risk (VaR) methodology by giving more emphasis on parametric approach which is used for empirical section and to investigate the applicability and usefulness of VaR in pension funds. After providing theoretical framework for VaR approach, the paper continues with pension fund systems in general and especially highlights AP funds of Swedish National pension fund system by trying to show why VaR could be an invaluable risk management tool for these funds together with other traditional risk measures used. Based on this given theoretical frame, a practical application of VaR –parametric or covariance/variance method- is executed on 50 biggest investments in the fixed income and equity portfolios of three selected Swedish national pension funds – AP1, AP2 and AP3. Results of one day VaR (DEAR) estimations on 30/12/2005 for each fund have been presented and it is aimed to show the additional information that could be obtained by using VaR and which is not always apparent from other risk measures employed by funds. According to the two traditional risk measures which are active risk and Sharpe ratio; AP2 and AP3 lie in the same risk level for 2005 which can create a contradiction by considering their different returns. On the other hand, obtained DEAR estimates show their different risk exposures even with the 50 biggest investments employed. The results give a matching relationship between return of funds and DEAR estimates meaning that; the fund with the highest return has the highest DEAR value and the fund with the lowest return has the lowest DEAR value; which is consistent with the main rule- “higher risk, higher return”. Thus, we can conclude that VaR could be applied additionally to get a better picture about real risk exposures and also to get valuable information on expected possible loss together with other traditional risk measures used.</p><p>Key words: Value at Risk, DEAR, Pension funds, Risk management, Swedish pension plan, AP1, AP2, AP3</p>

The adipose tissue lipid chaperones aP2 and mal1, also known as fatty acid binding proteins (FABPs), are significant molecules contributing to metabolic homeostasis, whereby their absence promotes physiological changes that improve systemic metabolism. Identification of palmitoleate as a lipokine generated in aP2-mal1 deficiency--originating from adipose and directing the lipogenic program in liver, established a role for these chaperones in linking adipocyte and hepatic function. We have recently demonstrated a functional role for secreted aP2 in the activation of gluconeogenesis and hepatic glucose output, further designating this molecule as an adipocyte-derived regulatory factor that influences liver metabolism. Key molecules linking the metabolism of nutrients in energy generating pathways are the nucleotide cofactors NAD and NADH. Together, these molecules function to coordinate the maintenance of redox reactions during normal cellular metabolism and act as required substrates for enzymes such as sirtuins and poly ADP-ribose polymerases. Using global metabolite profiling, we show that combined deficiency of the adipose tissue lipid chaperones aP2 and mal1 leads to a hepatic nucleotide imbalance resulting from metabolic reprogramming in liver. We demonstrate that this reprogramming of metabolite flux is accompanied by significant alterations in liver NAD metabolism and establish a role for aP2 in directing substrate utilization through inhibition of the rate-limiting enzyme for NAD synthesis, nicotinamide phosphoribosyltransferase. Several models for the proposed regulatory pathways that link nutrient metabolism to aging include mechanisms that are NAD dependent. Accordingly, we found that long-term FABP deficiency confers a strong resistance to aging related metabolic deterioration. Together, the findings presented in this thesis support a considerable role for FABPs in the regulation of NAD metabolism and healthspan.

Nef, an accessory protein of HIV-1, is a critical determinant of viral pathogenicity. The pathogenic effects of Nef are in large part dependent on its ability to decrease the amount of CD4 on the surface of infected cells. Early studies suggested that Nef induces downregulation by linking the cytosolic tail of CD4 to components of the host-cell protein-trafficking machinery. However, the specific sorting pathway that Nef uses to modulate CD4 expression remained uncertain. According to one model, Nef was thought to interfere with the transport of newly synthesized CD4 from the TGN to the cell-surface. Another model claimed that Nef facilitated the removal of CD4 from the plasma membrane. The primary goal of this thesis was to determine which of these models was correct. To accomplish this objective, a novel Nef-CD4 system was developed in Drosophila S2 cells. Nef was not only able to downregulate human CD4 in S2 cells, but it did so in a manner that was phenotypically indistinguishable from its activity in human cells. An RNAi screen targeting protein-trafficking genes in S2 cells revealed a requirement for clathrin and the clathrin-associated, plasma membrane-localized AP-2 complex in the Nef-mediated downregulation of CD4. In contrast, depletion of the related AP-1 and AP-3 complexes, which direct transport from the TGN and endosomes, had no effect. The requirement for AP-2 was subsequently confirmed in a human cell line. Yeast three-hybrid and GST pull-down assays were then used to demonstrate a robust, direct interaction between Nef and AP-2. This interaction was found to depend on a [D/E]xxxL[L/I]-type dileucine motif, located in the C-terminal loop of Nef, that is essential for CD4 downregulation. While mapping the binding site of AP-2 on Nef, a second determinant of interaction in the C-terminal loop was identified. Mutation of this motif, which conforms to a consensus [D/E]D diacidic sequence, prevented Nef from binding to AP-2 and down-regulating CD4. However, the same mutations did not affect the ability of Nef to interact with either AP-1 or AP-3, providing further evidence that these complexes are not required for the modulation of CD4 expression. Additional experiments indicated that the Nef diacidic motif most likely binds to a basic patch on AP-2 α-adaptin that is not present in the homologous AP-1 γ and AP-3 δ subunits. As with the Nef diluecine and diacidic motifs, the α-adaptin basic patch was shown to be necessary for CD4 downregulation. Moreover, all three of these motifs were needed for the cooperative assembly of a CD4-Nef-AP-2 tripartite complex, which was observed here for the first time using a yeast four-hybrid system. The data in this thesis uniformly support an endocytic model of Nef-mediated CD4 downregulation. Indeed, there is now strong evidence that Nef simultaneously binds CD4 and AP-2, thereby connecting the receptor to the cellular endocytic machinery and promoting its rapid internalization from the plasma membrane. In addition, the identification of novel motifs required for this process has provided new insights on endocytosis, and may facilitate the development of pharmacological inhibitors of Nef function.

WRINKLED1 (WRI1), a member of the APETALA2 (AP2) class of transcription factors regulates fatty acid biosynthesis and triacylglycerol (TAG) accumulation in plants. Among the four known Arabidopsis WRI1 paralogs, only WRI2 was unable to complement and restore fatty acid content in wri1-1 mutant seeds. Avocado (Persea americana) mesocarp, which accumulates 60-70% dry weight oil content, showed high expression levels for orthologs of WRI2, along with WRI1 and WRI3, during fruit development. While the role of WRI1 as a master regulator of oil biosynthesis is well-established, the function of WRI1 paralogs is poorly understood. Comprehensive and comparative in silico analyses of WRI1 paralogs from avocado (a basal angiosperm) with higher angiosperms Arabidopsis (dicot), maize (monocot) revealed distinct features. Predictive structural analyses of the WRI orthologs from these three species revealed the presence of AP2 domains and other highly conserved features, such as intrinsically disordered regions associated with predicted PEST motifs and phosphorylation sites. Additionally, avocado WRI proteins also contained distinct features that were absent in the nonfunctional Arabidopsis ortholog AtWRI2. Through transient expression assays, we demonstrated that both avocado WRI1 and WRI2 are functional and drive TAG accumulation in Nicotiana benthamiana leaves. We predict that the unique features and activities of ancestral PaWRI2 were likely lost in orthologous genes such as AtWRI2 during evolution and speciation, leading to at least partial loss of function in some higher eudicots. This study provides us with new targets to enhance oil biosynthesis in plants.

No description available.

Catharanthus roseus (Madagascar periwinkle) is the exclusive source of an array of terpenoid indole alkaloids (TIAs) that are used in the treatments of hypertension and certain types of cancer. TIA biosynthesis is under stringent spatiotemporal control and is induced by jasmonate (JA) and fungal elicitors. Tryptamine, derived from the indole branch, and secologanin from the iridoid branch are condensed to form the first TIA, strictosidine. Biosynthesis of TIA is regulated at the transcriptional level and several transcription factors (TFs) regulating the expression of genes encoding key enzymes in the pathway have been isolated and characterized. The JA-responsive APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF), ORCA3, and the basic helix-loop-helix (bHLH) factor, CrMYC2, are the key activators of the TIA biosynthesis. Recently, two other TFs, the bHLH IRIDOID SYNTHESIS 1 (BIS1) and BIS2 were also identified as regulators of TIA pathway. Analysis of C. roseus genome sequence has revealed that ORCA3 forms a physical cluster with two uncharacterized AP2/ERFs, ORCA4 and ORCA5. In plants, physically linked clusters of TFs are less characterized. Moreover, the regulation of TF clusters is relatively unexplored. My research uncovered that the ORCA gene cluster is differentially regulated. ORCA4 and ORCA5, while functionally overlapping with ORCA3, regulate an additional set of TIA pathway genes. ORCA4 or ORCA5 overexpression has resulted in significant increase of TIA accumulation in C. roseus hairy roots. In addition, ORCA5 directly regulates the expression of ORCA4 and indirectly regulates ORCA3, likely via unknown factor(s). Interestingly, ORCA5 also activates the expression of ZCT3, a negative regulator of the TIA pathway. In addition CrMYC2 is capable of activating ORCA3 and co-regulating pathway genes concomitantly with ORCA3. Several lines of evidence suggest that, in addition to the transcriptional control, biosynthesis of TIAs is also controlled at the posttranslational level, such as protein phosphorylation. Available literature indicates that a mitogen-activated protein kinase (MAPK) cascade is involved in this process. Analysis of C. roseus MAP kinome, identified two independent MAPK cascades regulating the indole and iridoid branches of the TIA pathway. We showed that the ORCA cluster and CrMYC2 act downstream of a MAP kinase cascade consisting of CrMAPKK1, CrMAPK3 and CrMAPK6. Overexpression of CrMAPKK1 in C. roseus hairy roots upregulates TIA pathway genes expressions and boosts TIA accumulation. The other cascade, consisting of CrMAPKK6 and CrMAPK13, mostly regulates the iridoid branch of the TIA pathway. Overexpression of CrMAPK13 in C. roseus hairy roots significantly upregulates iridoid pathway genes and boosts tabersonine accumulation. Moreover, we recently identified the third MAPK cascade, consisting of CrMAPKK1 and CrMAPK20, that negatively regulates the indole branch of the TIA pathway. Overexpression of CrMAPK20 in C. roseus hairy roots represses the genes regulated by CrMYC2-ORCAs and reduces catharanthine accumulation. These findings significantly advance our understanding of transcriptional and post-translational regulatory mechanisms that govern TIA biosynthesis in C. roseus.

No description available.

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第24044号 / 生博第470号 / 新制||生||63(附属図書館) / 京都大学大学院生命科学研究科統合生命科学専攻 / (主査)教授 河内 孝之, 教授 荒木 崇, 教授 中野 雄司 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

Conditions which promote reversible growth arrest, such as hypoxia and high cell density, lead to activation of a diverse network of proteins known as growth arrest specific (GAS) genes. Fatty acid binding protein 4 (FABP4), a lipid chaperone involved in the regulation of metabolic and inflammatory responses, has been shown to be part of the GAS program. While the induction of FABP4 in oxygen-deprived environments is well characterized, its functionality and regulation in such conditions remains unclear. In this study, we describe how mis-expression of FABP4 affects cell viability and survival within low oxygen conditions. Loss of FABP4 using shRNA was shown to be associated with a significant increase in oxidative stress and lipid peroxidation, a reduction in lipid droplet formation and a greater incidence of apoptosis. Hypoxia-mediated expression of FABP4 was also found to be positively correlated with cellular levels of C/EBP-beta, an essential activator of p20K in quiescence. FABP4 and p20K are both lipocalins that have been shown to share similar induction patterns and ability to assist in the maintenance of lipid trafficking in cellular stress circumstances. Unexpectedly, the depletion of FABP4 or p20K results in loss of the other in limited oxygen concentrations. This occurs independently of disruption to the broad GAS gene program, suggesting the two proteins may be co-regulated in a shared hypoxic-signalling pathway. C/EBP-beta appears to be the transcriptional activator shared by FABP4 and p20K in quiescence, and the three may be part of an intricate system to sense and respond to reactive oxygen species and lipid radicals. However, the forced expression of either FABP4 or p20K when the other is repressed only moderately restores cell survival through alleviating oxidative stress, indicating the two are both necessary for optimal response to hypoxia. In all, these studies suggest that analogous to the p20K lipocalin, FABP4 plays a critical role in lipid homeostasis and cell survival in conditions of limited oxygen concentrations, and its stimulation is dependent on C/EBP-beta activity. / Thesis / Master of Science (MSc) / A study investigating the role of FABP4 and p20K in conditions of reversible growth arrest with an emphasis on cell survival, lipid homeostasis and mitigating the effects of oxidative stress, and regulation of the two lipocalins by C/EBP-beta.

[ES] Las plantas monocárpicas se definen como aquellas que florecen, producen semillas y mueren después de un solo ciclo reproductivo. Muchos cultivos de importancia agroeconómica siguen estrategia reproductiva. En estas plantas, después de producir un cierto número de semillas, el meristemo apical del tallo (SAM) cesa su actividad, siendo esta la antesala de su senescencia y muerte. Este fenómeno, estudiado en diferentes especies de plantas monocárpicas, se conoce como Parada Proliferativa (PA). Se encuentra influenciado por múltiples factores, que incluyen la influencia del desarrollo de frutos y semillas, así como las condiciones ambientales de luz, humedad, etc. Todos estos factores son finalmente integrados a nivel genético en la planta. En este contexto, en Aabidopsis thaliana se ha descrito una ruta dependiente de la edad encargada de la modulación del PA, la ruta FUL-AP2. Se ha demostrado que el miR172 y FRUITFUL (FUL) incrementan su expresión con la edad de la planta y regulan negativamente APETALA2 (AP2), que es responsable de mantener la actividad meristemática a través de la acción de WUSCHEL (WUS). En este sentido, se ha sugerido que otros miembros de la subfamilia euAP2, TOE1, TOE2, TOE3, SMZ y SNZ, conocidos colectivamente como AP2-like genes, también juegan un papel crucial en la modulación de la PA. No obstante, estos han sido definidos principalmente como reguladores de la transición floral, y su implicación en la modulación del PA no está bien establecida. Por otro lado, Pisum sativum ha sido, históricamente, una especie ampliamente estudiada a nivel fisiológico en lo que concierne a PA. Sin embargo, hoy aún existen numerosas cuestiones, ambigüedades y discrepancias acerca de la regulación del PA en esta especie. En esta tesis doctoral, pretendemos profundizar en la caracterización de diversos aspectos del PA tanto en Arabidopsis thaliana como en Pisum sativum, con intención de determinar el grado de conservación que existe en este proceso entre estas dos especies monocárpicas. En el Capítulo 1, hemos examinado el papel de todos los miembros de la subfamilia euAP2 en la modulación de la PA en Arabidopsis thaliana, así como su potencial para estrategias biotecnológicas dirigidas a la modulación de la PA. Nuestros resultados sugieren que, a excepción de SMZ, todos juegan un papel crítico en este proceso, siendo inductores de la actividad meristemática. Además, AP2 y SNZ han demostrado tener el potencial para ser usados en estrategias biotecnológicas dirigidas a aumentar la producción de frutos en plantas monocárpicas. En el capítulo 2 se han revisitado los estudios fisiológicos que históricamente han tenido como objetivo determinar el papel de los frutos en desarrollo en la inducción del PA en Pisum sativum. Nuestros resultados sugieren que el desarrollo de semillas determina el momento del PA: cuando se ha producido una determinada biomasa de semillas, la SAM entra en un estado latente. Además, a nivel transcriptómico, Arabidopsis thaliana y Pisum sativum exhiben un comportamiento similar en cuanto a la influencia de las semillas en la actividad meristemática y el PA. Finalmente, en el Capítulo 3, hemos generado herramientas para caracterizar los genes de la subfamilia euAP2 en la modulación de PA en Pisum sativum. Además, sentamos las bases para el estudio de nuevos moduladores de la ruta genética, como Flowering Locus T (FT), postulándolo así como posible florígeno y anti-florígeno de las plantas. / [CA] Les plantes monocàrpiques es definixen com aquelles que florixen, produïxen llavors i moren després d'un sol cicle reproductiu. Molts cultius d'importància agroeconómica seguixen estratègia reproductiva. En estes plantes, després de produir un cert nombre de llavors, el meristemo apical de la tija (SAM) cessa la seua activitat, sent esta l'avantsala de la seua senescència i mort. Este fenomen, estudiat en diferents espècies de plantes monocàrpiques, es coneix com a Parada Proliferativa (PA). Es troba influenciat per múltiples factors, que inclouen la influència del desenvolupament de fruits i llavors, així com les condicions ambientals de llum, humitat, etc. Tots estos factors són finalment integrats a nivell genètic en la planta. En este context, en Aabidopsis thaliana s'ha descrit una ruta dependent de l'edat encarregada de la modulació del PA, la ruta FUL-AP2. S'ha demostrat que el miR172 i FRUITFUL (FUL) incrementen la seua expressió amb l'edat de la planta i regulen negativament APETALA2 (AP2), que és responsable de mantindre l'activitat meristemàtica a través de l'acció de WUSCHEL (WUS). En este sentit, s'ha suggerit que altres membres de la subfamília euAP2, TOE1, TOE2, TOE3, SMZ i SNZ, coneguts col·lectivament com AP2-like gens, també juguen un paper crucial en la modulació de la PA. No obstant això, estos han sigut definits principalment com a reguladors de la transició floral, i la seua implicació en la modulació del PA no està ben establida. D'altra banda, Pisum sativum ha sigut, històricament, una espècie àmpliament estudiada a nivell fisiològic en el que concernix PA. No obstant això, hui encara existixen nombroses qüestions, ambigüitats i discrepàncies sobre la regulació del PA en esta espècie. En esta tesi doctoral, pretenem aprofundir en la caracterització de diversos aspectes del PA tant en Arabidopsis thaliana com en Pisum sativum, amb intenció de determinar el grau de conservació que existix en este procés entre estes dos espècies monocàrpiques. En el Capítol 1, hem examinat el paper de tots els membres de la subfamília euAP2 en la modulació de la PA en Arabidopsis thaliana, així com el seu potencial per a estratègies biotecnològiques dirigides a la modulació de la PA. Els nostres resultats suggerixen que, a excepció de SMZ, tots juguen un paper crític en este procés, sent inductors de l'activitat meristemàtica. A més, AP2 i SNZ han demostrat tindre el potencial per a ser usats en estratègies biotecnològiques dirigides a augmentar la producció de fruits en plantes monocàrpiques. En el capítol 2 s'han revisitat els estudis fisiològics que històricament han tingut com a objectiu determinar el paper dels fruits en desenvolupament en la inducció del PA en Pisum sativum. Els nostres resultats suggerixen que el desenvolupament de llavors determina el moment del PA: quan s'ha produït una determinada biomassa de llavors, la SAM entra en un estat latent. A més, a nivell transcriptómico, Arabidopsis thaliana i Pisum sativum exhibixen un comportament similar quant a la influència de les llavors en l'activitat meristemàtica i el PA. Finalment, en el Capítol 3, hem generat ferramentes per a caracteritzar els gens de la subfamília euAP2 en la modulació de PA en Pisum sativum. A més, establim les bases per a l'estudi de nous moduladors de la ruta genètica, com Flowering Locus T (FT), postulant-lo així com possible florígeno i anti-florígeno de les plantes. / [EN] Monocarpic plants are defined as those that bloom, produce seeds, and die after a single reproductive cycle. Many economically important crops belong to this reproductive strategy. In these plants, after producing a certain number of seeds, the shoot apical meristem (SAM) ceases its activity, heralding the onset of senescence and plant death. This phenomenon, studied in various monocarpic plant species, is known as Proliferative Arrest (PA), and is found to be influenced by multiple factors, involving the influence of developing fruits and seeds, as well as environmental conditions like temperature, light, and humidity. All these factors are ultimately integrated at the genetic level within the plant. In this context, an age-dependent pathway that controls SAM activity and modulates PA, known as the FUL-AP2 pathway, has been described in Arabidopsis thaliana. It has been demonstrated that the microRNA miR172 and FRUITFUL (FUL) increase with the plant's age and negatively regulate APETALA2 (AP2), which is responsible for maintaining meristematic activity through the action of WUSCHEL (WUS). In this sense, it has been suggested that other members of the euAP2 subfamily, TARGET OF EAT1 (TOE1), TOE2, TOE3, SCHLAFMÜTZE (SMZ), and SCHNARCHZAPFEN (SNZ), collectively known as AP2-like genes, also play a crucial role in modulating PA. However, they have mainly been defined as regulators of the floral transition, and their involvement in PA modulation is not well established. On the other hand, historically, Pisum sativum has been a species widely studied in relation to PA. However, this research often treated PA and senescence as the same process, and uncertainties and ambiguities persist, with discrepancies among different research groups that have treated this topic. In this doctoral thesis, we aimed to delve into the characterization of various aspects of PA in both Arabidopsis thaliana and Pisum sativum and determine the degree of conservation of this process in these two monocarpic species: In Chapter 1, we examined the role of all euAP2 subfamily members in modulating PA in Arabidopsis thaliana and explored their potential for biotechnological strategies aimed at PA modulation. Our findings suggest that, except for SMZ, all members of the euAP2 subfamily play a critical role in this process as inducers of meristematic activity. Furthermore, AP2 and SNZ have shown the potential to be considered prime candidates for use in biotechnological strategies to increase fruit production in monocarpic plants. Chapter 2 revisited the physiological studies that have historically aimed to determine the role of developing fruits in inducing PA in Pisum sativum. Our results suggest that developing seeds determine the timing of PA: when a certain seed biomass has been produced, the SAM enters a dormant state. Additionally, at the transcriptomic level, Arabidopsis thaliana and Pisum sativum exhibit similar behaviour regarding the influence of seeds on meristematic activity, suggesting that PA could be a conserved process among monocarpic plants. In Chapter 3, we generated tools for characterizing euAP2 subfamily genes in PA modulation in Pisum sativum. Furthermore, we laid the groundwork for the study of new modulators of the genetic pathway, such as Flowering Locus T (FT), suggesting its potential role of florigen and anti-florigen of the plant. / Burillo Richart, E. (2024). Characterization of Proliferative Arrest (PA) Process in Arabidopsis thaliana and Pisum sativum [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/207109