Memoria para optar al título Bioquímico / Como parte del sistema inmune innato existe un grupo de receptores de reconocimiento de patrones (PRRs) capaces de detectar aquellos patrones moleculares asociados a patógenos (PAMPs). Entre estos PRRs, destacan los receptores de tipo Toll o TLRs. Dentro de esta familia de receptores, TLR2 reconoce PAMPs derivados de bacterias gram positivas, los que promueven la activación de la vía de señalización intracelular dependiente del adaptador molecular MyD88, que conduce a la activación de IKK y de las MAPKs, las que tienen un impacto fundamental sobre la expresión de citoquinas proinflamatorias. El estudio de los mecanismos fisiológicos de control de esta vía de señalización constituye un área de investigación relevante en inmunología. En este sentido, los glucocorticoides, anti-inflamatorios naturales, ejercen su efecto vía un receptor citoplasmático (GR) mediante procesos de trans-represión y de expresión de proteínas reguladoras. A pesar de esto, se desconoce su efecto sobre las vías de inducción de citoquinas pro-inflamatorias mediadas por TLR2, tal como la vía de p38. Basados en estos antecedentes, el objetivo general de esta memoria de título consistió en determinar la participación de p38 en la producción de TNF-α en células A549, inducida por un agonista de TLR2, Pam3Cys-Ser-Lys4, en presencia o ausencia de dexametasona. Los objetivos específicos se centraron en: 1) determinar la expresión de TNF-α, a nivel de transcrito y proteína, en células activadas con el agonista sintético Pam3Cys-Ser-Lys4, en presencia o ausencia de dexametasona 2) evaluar la fosforilación de la proteína quinasa p38 en células estimuladas con Pam3Cys-Ser-Lys4, en presencia o ausencia de dexametasona y 3) evaluar la contribución de la proteína quinasa p38 sobre la expresión de TNF-α en células estimuladas con Pam3Cys-Ser-Lys4, en presencia o ausencia de dexametasona. Los resultados obtenidos indican que la activación de TLR2 por Pam3Cys-Ser-Lys4 induce un aumento en la expresión de TNF-α, el que no es reprimido por dexametasona. Se observó una activación de la vía p38 inducida por Pam3Cys-Ser-Lys4, que está involucrada en la expresión de TNF-α. Por otro lado, constatamos que dexametasona ejerce su efecto anti-inflamatorio clásico mediante la expresión de moléculas reguladoras de la vía de p38, como la fosfatasa MKP-1. Sin embargo, no podemos descartar un efecto independiente de la expresión de genes regulados por el glucocorticoide. Además, observamos que dexametasona no actuaría en los eventos tempranos de señalización de la vía de TLR2, como lo constatamos con la fosforilación de p38. Estos datos demostrarían un mecanismo a través del cual los glucocorticoides regulan procesos inflamatorios inducidos por TLR2, con un impacto relevante en el desarrollo de la inmunidad innata y la inflamación / As part of innate immune system, it exists a group of pattern-recognition receptors (PRRs) capable of detecting those molecular pattern associated to pathogens (pathogenassociated molecular patterns; PAMPs). Among these PRRs, Toll-like receptors (TLRs) stand out. Inside this receptor family, TLR2 recognizes PAMPs derived from gram positive bacteria, thus promoting activation of MyD88-dependent intracellular pathway. It leads to IKK and MAPKs activation, which have a fundamental impact on the expression of proinflammatory cytokines. The study of the physiological control mechanisms of this pathway constitutes an area of relevant research in immunology. In this sense, glucocorticoids, natural anti-inflammatory molecules, exert its effect by a cytoplasmatic receptor (GR) by trans-repression mechanism and regulatory proteins expression. In spite of this, the effect of glucocorticoid on the TLR2-mediated pro-inflammatory cytokine pathway induction, specially on p38, is unknown. Based on these precedents, the general aim of this study was determining the role of p38 in TNF-α production in A549 cells induced with Pam3Cys-Ser-Lys4, a TLR2 agonist, in presence or absence of dexametasona. The specific objectives were centered to: 1) determine TNF-α expression, at messenger and protein level; 2) evaluate the p38 protein kinase phosphorylation and 3) evaluate the contribution of p38 protein kinase on TNF-α expression under the stimulation with Pam3Cys-Ser-Lys4, in presence or absence of dexamethasone. The results indicate that the activation of TLR2 by Pam3Cys-Ser-Lys4 induces an increase in TNF-α expression, which is not suppressed for dexamethasone. It also was observed an activation of p38 pathway induced by Pam3Cys-Ser-Lys4, that was involved in TNF-α expression. On the other hand, that dexametasona exert its classic anti-inflammatory effect by means of expression of regulatory molecules of the p38 pathway, as phosphatase MKP-1. Nevertheless, we can’t reject an independent effect from the expression of glucocorticoid regulated genes. Besides, dexamethasona wouldn’t work on early events of TLR2 signalling pathway, as we observed for p38 phosphorylation. This data would show a mechanism by which glucocorticoids regulates the TLR2- induced inflammatory processes, with a relevant impact in the processes involved in the development of the innate immunity and inflammation

Diversos estudos buscam identificar novas moléculas com ações regulatórias sobre a via de sinalização da insulina e consequentemente na homeostase da glicose. Assim, este trabalho visa avaliar o potencial de extratos de frutos no controle da homeostase glicêmica. Os frutos avaliados foram o morango (cv. Toianoca, Camarosa, Oso Grande e Camino Real), a amora-preta e a framboesa vermelha, em dois tempos de amostragem, sendo considerado como tempo A1 e tempo A2. As amostras foram caracterizadas quanto ao seu conteúdo de fenólicos totais, conteúdo de antocianinas monoméricas, capacidade antioxidante, avaliada pelos métodos DPPH e ORAC, ácido elágico total, capacidade de inibição da alfa-glicosidase e captação de glicose e lipólise em tecido adiposo de camundongos (ensaio explante). Dentre os frutos, no primeiro tempo de amostragem, a amora-preta e o morango, cv Oso Grande, foram os que apresentaram maior conteúdo de fenólicos totais (62,36 e 34,89 mg AG/g, respectivamente) no entanto não foram mantidos esses valores no segundo tempo de amostragem, com concentração 30% e 60% inferior, respectivamente; e maior concentração de antocianinas monoméricas (45,33 mg/g e 3,09 mg/g, respectivamente). Em relação a inibição da enzima alfa-glicosidase, avaliado em extrato metanólico, o fruto framboesa vermelha e o morango cv. Camino Real foram as que apresentaram alto potencial inibitório nos dois tempos de amostragem (IC50 0,47 mg FT e IC50 0,57 mg FT para framboesa vermelha e IC50 0,50 mg FT e IC50 0,46 mg FT para Camino Real). Quando avaliado os extratos enriquecidos em fenólicos, o valor de IC50 com maior potencial dentre os frutos avaliados foi da amora-preta, nos dois tempos A1 e A2 (0,0023 mg FT e 0,0021 mg FT, respectivamente). Para captação de glicose em tecido adiposo explate, ao utilizar a insulina para estimular a captação de glicose juntamente com o tratamento (extrato), esse estimulo foi efetivo no aumento da captação de glicose somente com as amostras cv. Camino Real e cv. Oso Grande. Isso pode ser explicado pela alta correlação encontrada de antocianinas identificadas no fruto, como pelargonidina-3-O-glicosídeo. Por outro lado, somente a amora-preta A1 aumentou a lipólise em condição basal, mas nenhuma fruta foi eficiente para reduzir a lipólise em condição estimulada pelo isoproterenol. Sendo assim, frutas vermelhas podem ser boas fontes de compostos bioativos, principalmente antocianinas, as quais podem ter corroborado positivamente com os resultados. / Several studies seek to identify new molecules with regulatory actions on the insulin signaling pathway and consequently on glucose homeostasis. Thus, this work aims to evaluate the potential of fruit extracts in the control of glycemic homeostasis. The fruits evaluated were strawberry (cv. Toianoca, Camarosa, Oso Grande and Camino Real), blackberry and red raspberry, in two sampling times, being considered as time A1 and time A2. Fruits were evaluated for total phenolic, monomeric anthocyanins and contents, antioxidant capacity, evaluated by DPPH and ORAC methods, alpha-glycosidase inhibition capacity and glucose uptake and lipolysis in adipose tissue of mice (explant assay). Among the fruits, in the first sampling period, blackberry and strawberry, cv. Oso Grande, showed the highest total phenolic content (62.36 and 34.89 mg AG / g, respectively), with a decrease of the 30% and 60%, respectively, in the second sampling time; and higher monomeric anthocyanins concentration (45.33 mg/g and 3.09 mg/g, respectively). The methanolic extracts of raspberry and the strawberry cv Camino Real (A1 and A2) presented the highest alpha-glucosidase inhibitory potential. Otherwise, the enriched-polyphenol extract of blackberry (A1 and A2) presented the highest potential among the evaluated fruits. Adipose tissue treated with strawberry cv. Camino Real and cv. Oso Grande was effective in increasing glucose uptake stimulated by insulin. This can be explained by the high correlation with the anthocyanins pelargonidin-3-O-glycoside identified in this fruit. In addition, blackberry A1 was the only sample to increase the lipolysis in basal condition, but all other fruits were not effective to decrease lipolysis in stimulated condition. Thus, berries could be a good sources of bioactive compounds to maintain the glucose homeostasis.

Os objetivos foram avaliar os efeitos da aplicação de vitamina E pré-parto sobre a incidência de retenção de placenta e desempenho reprodutivo de vacas leiteiras. Entre maio de 2012 e abril de 2013, 890 animais, sendo 390 Holandesas (132 nulíparas e 258 vacas) e 500 mestiças Holandês x Gir (199 nulíparas e 301 vacas) foram envolvidas no estudo em três fazendas. Vacas e novilhas pré-parto foram alojadas em áreas de pastagem com piquetes rotacionados entre outubro e março e receberam 2 kg/d de concentrado, contendo fubá de milho, farelo de soja, minerais e vitaminas. De abril a setembro, as fêmeas pré-parto receberam dieta total composta de silagem de milho, fubá de milho, farelo de soja, minerais e vitaminas. Durante o período pré-parto, as fêmeas receberam 280 (Fazenda 1), 390 (Fazenda 2) e 480 (Fazenda 3) UI de vitamina E por dia via dieta. Em cada fazenda, os animais foram aleatorizados a não receberam tratamento algum (Controle), ou receberem aplicações semanais de 1.000 UI de vitamina E via intramuscular, aos 258 ± 3, 265 ± 3 e 272 ± 3 d de gestação (VitE). Amostras de sangue foram colhidas de um subgrupo de 141 fêmeas imediatamente antes de serem aleatorizadas para determinar a concentração sérica de ?-tocoferol. Amostras de sangue também foram analisadas para determinar as concentrações de cortisol e ácidos graxos não esterificados (AGNEs). As análises estatísticas foram feitas através dos procedimentos GLIMMIX, MIXED, PHREG E LIFETEST do SAS. Variáveis binárias foram analisadas por regressão logística, variáveis contínuas foram analisadas por ANOVA e variáveis relacionadas a tempo a um evento foram avaliadas através de curva de sobrevivência. O ?-tocoferol sérico não diferiu entre grupos Controle e VitE, com concentração média de 2,97 ± 0,10 ?g/mL. 53,2% das fêmeas apresentaram concentração inadequada de ?-tocoferol sérico baseado em 3 ?g/mL como ponto de corte. A probabilidade das vacas terem retenção de placenta diminuiu à medida em que a concentração sérica de ?-tocoferol aumentou (P = 0,01). A produção de leite foi igual nos grupos Controle e VitE. Aplicação de vitamina E pré-parto reduziu a incidência de natimortos, retenção de placenta e mortalidade até os 200 DEL. O grupo VitE apresentou tendência (P = 0,08) de aumento na taxa de concepção à primeira IA (36,7 vs 30,1%) pela menor perda embrionária/fetal entre 30 e 60 d de gestação (12,5 vs 20,5%). Apesar de similar taxa de inseminação entre os grupos, suplementação com vitamina E pré-parto acarretou em 22% de aumento na taxa de prenhez em relação ao grupo Controle. As fêmeas no grupo VitE tiveram menores concentrações de cortisol e AGNEs ao redor do parto. Em resumo, quando as vacas e novilhas foram alimentadas com quantidades limitadas de vitamina E, 28 a 48% das recomendações do NRC para vacas no pré-parto, a suplementação com vitamina E injetável melhorou a saúde e o desempenho reprodutivo das mesmas. / Objectives were to evaluate the effects of injectable vitamin E supplementation during the last 3 weeks prepartum on the incidence of retained fetal membranes (RFM) and reproductive performance of dairy cows. Eight-hundred and ninety dairy cows and heifers, being 390 Holsteins (132 nuliparous and 258 parous) and 500 crossbred Holstein x Gyr (199 nuliparous and 301 parous) from three dairy farms were assigned to the study from May 2012 to April 2013. In all three farms, prepartum females were housed in pastures, and from October to March, cows had access to pasture and were managed under grazing and received 2 kg/d of a mixture of finely ground corn, soybean meal, and minerals and vitamins. From April to September, prepartum animals received a TMR composed of corn silage, finely ground corn, soybean meal, and minerals and vitamins. During the prepartum period, animals received 280 (Farm 1), 390 (Farm 2), and 480 (Farm 3) IU of vitamin E/d. Within each farm, cows and heifers were randomly assigned to remain as untreated controls or to receive three i.m. injections of 1,000 IU each of DL-?-tocopherol administered at 258 ± 3, 265 ± 3, and 272 ± 3 d of gestation (VitE). Blood was sampled from a subset of 141 animals immediately before enrollment to determine the _-tocopherol status. Blood was also analyzed for concentrations of cortisol and nonesterified fatty acids (NEFA). Statistical analysis was performed with SAS software using the GLIMMIX, MIXED, PHREG and LIFETEST procedures. The concentration of ?-tocopherol in serum of females did not differ between treatments and averaged 2.97 ± 0.10 ?g/mL. A total of 53.2% of the animals had inadequate concentration of serum ?-tocopherol based on the 3.0 ?g/mL cut-off for adequacy. The probability of cows to have RFM decreased as the concentration of ?-tocopherol in serum increased (P = 0,01). Milk production did not differ between Control and VitE cows. Treatment with injectable ?-tocopherol improved postpartum health by reducing the incidence of stillbirths, RFM, and death by 200 d postpartum. Cows receiving VitE tended (P = 0,08) to have improved pregnancy per insemination (P/AI) at first AI (36.7 vs. 30.1%) because of less pregnancy loss between 30 and 60 d of gestation (12.5 vs. 20.5%). Despite similar insemination rate, cows receiving VitE had 22% greater pregnancy rate than control cows, which was attributed to the improved P/AI and reduced pregnancy loss in all inseminations during the first 200 d in milk. Females in VitE had reduced concentrations of cortisol and NEFA around calving. In summary, when cows and heifers were fed limited amounts of supplemental vitamin E, 28 to 48% of the recommendations for prepartum dry cows, supplementation with injectable ?-tocopherol improved postpartum health and reproduction.

Orientador: Paulo Sergio Patto dos Santos / Resumo: Objetivou-se com este trabalho avaliar os efeitos na hemodinâmica, respiração, motilidade ruminal e sedação, da associação de detomidina e nalbufina em ovinos. Foram utilizados 8 ovinos hígidos, jovens, fêmeas ou machos, pesando 54,85 ± 20,31kg. Foi instalado na veia jugular esquerda um introdutor e, posteriormente, posicionado um cateter de Swan-Ganz com a extremidade distal alocada no lumen da artéria pulmonar. Foi administrado pela via intramuscular detomidina (10μg/kg) associado a nalbufina (0,1mg/kg). Foram avaliadas FC, PAS, PAD, PAM, PVC, PAPm, IC, IS, IRVS, FR, pH, PaO2, PaCO2, HCO3, TC, sedação e motilidade ruminal antes do início da administração dos fármacos (MB) e a cada quinze minutos após a aplicação durante sessenta minutos (M15, M30, M45 e M60). Houve redução do IC, FR e aumento da PAS, PAPm, temperatura central, PaCO2 e HCO3 após administração dos fármacos. A sedação foi considerada satisfatória durante 45 minutos. Com os resultados obtidos neste estudo, conclui-se que a neuroleptoanalgesia promovida pela associação de detomidina e nalbufina em ovinos, nas doses utilizadas, promove sedação satisfatória. As alterações hemodinâmicas, respiratórias e na motilidade ruminal observadas podem ser bem toleradas por animais sadios. / Abstract: The aim of this study was to evaluate the effects on hemodynamics, respiration, ruminal motility and sedation of the combination of detomidine and nalbuphine in sheep. Were used eight healthy young, female or male sheep, weighing 54.85 ± 20.31kg. A Percutaneous Sheath Introducer was placed in the left jugular vein and then a Swan-Ganz catheter was positioned with the distal port allocated to the lumen of the pulmonary artery. Association of detomidine (10µg/kg) and nalbuphine (0,1mg/kg) was administered intramuscular. HR, SAP, DAP, MAP, CVP, MPAP, CI, SI, SVRI, RR, pH, PaO2, PaCO2, HCO3, CT, sedation and ruminal motility before drug administration (MB) and at each fifteen minutes after application for sixty minutes (M15, M30, M45 and M60). There was a reduction in CI, RR and increase in SAP, mPAP, CT, PaCO2 and HCO3 after drug administration. Sedation was considered satisfactory for 45 minutes. The results of this study allowed us to conclude that neuroleptoanalgesia promoted by the association of detomidine and nalbuphine in sheep at the doses used, promotes satisfactory sedation for short procedures. The hemodynamic, respiratory and ruminal motility changes observed can be well tolerated by healthy animals. / Mestre

Hedgefonder är ett hett investeringsverktyg, specielltnui en tid präglad av låga räntor. Envanligtförekommande uppfattning är atthedgefonder skagenerera överavkastning;det faktum att de historiskt har kunnat verka under generösaregleringsformer är en av flera anledningar tillatt gemene man har högt ställda förväntningar på hedgefonder som investeringsform. Frågan är dock vad som händer med överavkastningen-vilket är varje investerares primära angelägenhet –om regleringarna stramas åt? Syftet med studien är därför att undersöka hur hedgefonder påverkas av ett minskat handlingsutrymme, det villsäga en ökad grad av reglering. Studien mäter hedgefonders överavkastning, i termer av alfa, med hjälp av Fama och Frenchs trefaktormodell, före och efter den omfattande reformen The Dodd-Frank Wall Street Reform and Consumer Protection Act. Uppsatsens data indikerar på att överavkastningen, alfa, är signifikant lägre i perioden efter införandet av reformen. Studienpåvisar även att strategierna, Event Driven och Multistrategi, har lägre överavkastning efter implementeringen av Dodd-Frank Act, medanssamma effekt inte kunde konstaterasförLång/Kort-strategin.

This Master's describes knownledge discovery from process logs by using process mining algorithms. Chosen algorithms are described in detail. These aim to create process model based on event log analysis. The goal is to design such components, which would be able to import the process and run the simulations. Results from components can be used for short term planning.

Det pågår diskussioner huruvida aktivt förvaltade fonder lyckas generera en bättre avkastning än marknaden. Ett argument för att investera i en aktivt förvaltad fond är att fondförvaltaren aktivt handlar värdepapper i syfte att uppnå hög avkastning. De här fonderna har ofta en högre avgift vilket används som motargument för att investera i den typen av fonder. Kritiker anser att en indexfond ger investerare en högre nytta eftersom de har lägre avgifter och att aktiv handel inte leder till större avkastning.  Många studier har gjorts på ämnet och den allmänna uppfattningen är att aktivt förvaltade fonder kan ge bättre avkastning än index över tid. Få studier kan dock bekräfta att det är fondförvaltarens bedrift. Fondprestation mäts enligt prestationsmåtten, Jensens Alfa, Sharpekvot och Treynorkvot. Slutsatsen liknar majoriteten av studier. Det är svårt att bekräfta hypotesen att det är fondförvaltarens skicklighet som ligger till grund till en bra fondprestation. Troligtvis beror större delen av en fonds prestation på makroekonomiska faktorer och börspsykologi. / Discussions are ongoing as to whether actively managed funds succeed in generating a better return than the market. One argument for investing in an actively managed fund is that the fund manager actively trades securities in order to achieve a high return. These funds often have a higher fee, which is used as a counter-argument to invest in this type of fund. Critics believe that an index fund provides investors with a higher benefit because they have lower fees and that active trading does not lead to greater returns.  Many studies have been done on the subject and the general perception is that actively managed funds can provide better returns than indices over time. Few studies can, however, confirm that this is the fund manager's achievement. Fund performance is measured according to performance measures such as Jensen's Alpha, Sharpe ratio and Treynor ratio. The conclusion of the study is similar to the majority of studies. It is difficult to confirm the hypothesis that it is the fund manager's skill that is the basis for a good fund performance. Most of a fund's performance probably depends on macroeconomic factors and stock market psychology.

This analysis aims to figure out if active fund management can provide a greater risk-adjusted return compared to an index. The analysis is divided into two periods, 2012-2020 and year 2020. Jensen’s alpha is the performance measure that will be used during the analysis. A t-test will be performed to figure out if active fund management is significantly different from the index. Sharpe ratio and Treynor ratio is also included as a descriptive statistic. The result shows that during the period of 2012-2020, there was only one actively managed fund with a positive alpha that was significantly different from the benchmark index SIXPRX. The Treynor ratio showed that more than half of the actively managed funds outperform index, and less than half of the funds Sharpe ratio outperformed the index. The results for year 2020 show that there are two actively managed funds that have outperformed the index alpha and are significantly different. The amount of funds that outperformed the index Treynor ratio and Sharpe ratio also increased for that period. The conclusion is that there is very little evidence proving that active managed funds provide a greater risk-adjusted return compared to index in either time periods.

JANKOVÁ, Z. A Performance Comparison of mutual funds and ETF. Mendel University in Brno, 2017. Diploma thesis. The diploma thesis is focused on performance comparison of open-end mutual funds and ETF. Selected funds are separated by region USA, World, European and Emerging markets equities. Funds are analyzed in the practical part for the period between 2007 and 2016. The first part introduced defines notion of collective investment, advantages and disadvantages. Funds are analyzed in the terms of return, risk, cost and including foreing exchange risk.

Preparation of contructs for transgenic expression of DPP-IV and FAP Bc. Dalibor Košek Abstract: DASH (Dipeptidyl peptidase-IV Activity and/or Structure Homologues) protein group involves multi-funcional molecules typically bearing enzymatic activity similar to the Dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5, identical with lymphocyte differentiation antigen CD26). In general, they cleave multiple regulatory as well as structural peptides and proteins, possessing proline residue on the penultimate position from the N-terminus. We focused on two members of this group: canonical DPP-IV and Fibroblast activation protein alpha (FAP-α). Both are typically type II plasma membrane proteins with specific tissue distribution. Soluble extrecellular forms have also been identified. Available knowledge suggest important roles of these proteins in oncogenesis, executed by their enzymatic activity but also by non-proteolytic interactions. To study their role in gliomagenesis we designed several experimental models exploiting astrocytoma cell lines with defined DPP-IV or FAP-α phenotype. Enzymatically inactive forms and analogues with different subcellular distribution will also be included. These models will allow to assess the impact of DPP-IV and FAP-α on the glial tumor development and the importance of their...