Quantification of the 15 major human bile acids and their precursor 7α-hydroxy-4-cholesten-3-one in serum by liquid chromatography-tandem mass spectrometry

Bile acids are increasingly gaining attention since they were discovered to be activators of the transcription factor farnesoid X receptor (FXR) in addition to their well-established role in dietary lipid emulsification. Moreover, the differential activation potency of bile acids on FXR, which is due to structural variation of the ligands, generates the need for new analytical tools that are sensitive and specific enough to quantify the individual species of this complex class of compounds. Because bile acids undergo enterohepatic circulation, the additional assessment of a bile acid precursor as a marker for bile acid biosynthesis is used to differentiate between newly synthesised bile acids and bile acids reabsorbed from the intestine. This paper describes two new methods using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantification of the major unconjugated bile acids in human serum (cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid and ursodeoxycholic acid) with their glycine- and taurine-conjugates as well as their precursor 7α-hydroxy-4-cholesten-3-one (C4). Intra- and inter-day variation was less than 12% and accuracy was between 84% and 102% for all analytes. Extraction recovery was between 78% and 100% for the bile acids whereas it was 62% for C4 and limit of quantification values ranged from 2nmol/l to 50nmol/l for all compounds. These two methods have the practical advantage of requiring low sample volume (100μl serum for each method) and identical eluents, stationary phase as well as ionisation technique, so that they can be used in a combined way. Moreover, they provide information on the composition of the bile acid pool on one hand and on the relative amount of newly synthesised bile acids on the other, which taken together, gives new insights in the investigation of bile acid metabolism

A consciência nas obras de Fiódor Dostoiévski

The beginning of the project is in the form of chronicle, my meeting with Fyodor Dostoevsky and the whole process that motivated this study, with the aim of passing to the reader through literature, part of my feeling towards the Russian author. Then, in the first essay, I begin the theoretical analysis of man's impulse and attitude toward killing God to become a new God, driven by Crime and Punishment along with Nietzsche's philosophical reflections in his books Antichrist and Aurora. . At the end of the preceptor essay, the latter is closely related to the former as a way of demonstrating the problems of conscience in relation to the mortifying attitude of murdering the divine figure. Concluding the relationship between Crime and Punishment and Nietzsche's works, the third essay is introduced, with the object of historically exposing Dostoevsky's influence on Nietzsche, explaining passages of the Russian writer in The Demons as a possible germ of the Nietzschean concept and its announcement. to the hyperbaric. Changing eyes, the following essay explores through the tale an unpleasant story written by the Russian author, as is evident in the impossibility of the Hegelian idea of liberal precepts being applied in nineteenth-century Russia. Finalizing, as the last essay, is the writing about the depth of the unconscious, presenting by the bias of the work The Ridiculous Man's Dream, the anticipation of ideas related to psychology even before the Freudian concretization.Trabalho de Conclusão de Curso (Graduação)Encontra-se no inicio do projeto na forma de crônica, meu encontro com Fiódor Dostoiévski e todo o processo que motivou este estudo, com objetivo de transpassar para o leitor através da literatura, parte do meu sentimento em relação ao autor russo. Em seguida, no primeiro ensaio, dou inicio à análise teórica sobre o impulso do homem e sua atitude referente a matar Deus para se tornar um novo Deus, movido pela obra Crime e Castigo juntamente as reflexões filosóficas de Nietzsche, em seus livros o anticristo e Aurora. Ao finalizar o ensaio preceptor, tem-se o segundo estritamente relacionado ao primeiro, como forma de demonstrar os problemas da consciência em relação à atitude mortificante de assassinar a figura divina. Concluindo a relação entre Crime e castigo e as obras de Nietzsche, adentra-se o terceiro ensaio, com o objeto de expor historicamente a influência de Dostoiévski perante Nietzsche, explicitando passagens do escritor russo em Os demônios como possível germe do conceito nietzschiano e seu anúncio ao hiperbóreo. Mudando os olhos de direção, o ensaio seguinte explana através do conto uma história desagradável escrito pelo autor russo, como fica evidente a impossibilidade da ideia hegeliana dos preceitos liberais serem aplicados na Rússia do século XIX. Finalizando, como derradeiro ensaio, encontra-se o escrito sobre a profundeza do inconsciente, apresentando pelo viés da obra O sonho do homem ridículo, a antecipação de ideias referentes a psicologia antes mesmo da concretiza freudiana

Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment

Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy

De cutorum chirurgia per insitionem libri 2

[Früherer Titel:] De cutorum chirurgia per insitionem libri 2Bibliografischer Nachweis: VD16 T 69Erscheinungsvermerk in Vorlageform: Francofvrti, Excudebat Iohannes Sauris, impensis Petri KopffijTbl. in Rot- u. Schwarzdr

Francofvrti : Excudebat Iohannes Sauris, impensis Petri Kopffij

[Fr\ufcherer Titel:] De cutorum chirurgia per insitionem libri 2Bibliografischer Nachweis: VD16 T 69Erscheinungsvermerk in Vorlageform: Francofvrti, Excudebat Iohannes Sauris, impensis Petri KopffijTbl. in Rot- u. Schwarzdr

Dostoevsky's art: polyphony and its relationship with the word of difference

Based on Mikhail Bakhtin's work titled "Problems of Dostoevsky's Poetics," the aim of this writing is to express and articulate the concept of polyphony coined by Bakhtin in relation to the artistic works of the Russian author Fyodor Dostoevsky. In this sense, understanding Dostoevsky's works as innovative artistic creations, Bakhtin contrasts the polyphonic aesthetic construction with Western monologic works. Therefore, to comprehend the concept of polyphony, as well as the innovative expression that pervades Dostoevsky's art, it is important to highlight the characteristics that comprise this concept, in addition to relating it to Dostoevsky's own works that support it. In this regard, with a strong foundation in Bakhtin's concept of polyphony when considering Dostoevsky's artwork, the following points regarding the Russian artist's novels are noticeable. Firstly, it's crucial to emphasize that Dostoevsky's artwork is inconclusive, allowing for a multitude of interpretations, as a variety of affects reach each reader individually, with the author himself distancing as a determining and conclusive figure. In this vein, Dostoevsky moves away from the characteristic monologic tone of Western novels and creates original polyphonic-type novels. Thus, Dostoevsky's polyphonic art destabilizes the monologic model, which seeks to place the final and decisive word of the author within the mouth of a specific hero or throughout the entirety of a single work. In contrast, in Dostoevsky's works, the author's voice spreads through the characters, sometimes prominently, while at other times it may be absent. Furthermore, there are no conclusive passages in Dostoevsky's works; everything is in motion, in a state of becoming and occurrence. In this sense, the reader also becomes active and integral, being another singular individual composing the dialogic structure of Dostoevsky's art. Thus, one of the points I emphasize is the value of the word of difference, of expressing singularity, and also of the mode of thought as something constantly in motion in contact with the words of others. Therefore, the idea here is not to definitively close Dostoevsky's characters around a given moral value, or to determine what moral values Dostoevsky himself possesses as a person. Instead, the path taken is to express how each character holds a unique perspective on life, perspectives permeated by the word of difference but not defined by it in an objectified manner. Additionally, to connect the aforementioned with other thinkers, the concept of minor literature created by Gilles Deleuze and Félix Guattari has been used. The viewpoint of these philosophers aligns with Bakhtin's concept and Dostoevsky's art, as they precisely embody the active sense of difference values. To conclude this writing, I have presented how Dostoevsky himself expressed his viewpoint regarding the function of art in society.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorDissertação (Mestrado)Tomando como base a obra de Mikhail Bakhtin, intitulada Problemas da poética de Dostoiévski, o objetivo desse escrito é o de expressar e articular o conceito de polifonia cunhado por Bakhtin às obras artísticas do autor russo Fiódor Dostoiévski. Nesse sentido, compreendendo as obras de Dostoiévski como uma criação artística inovadora, Bakhtin contrapõe a forma de construção estética polifônica às obras monológicas ocidentais. Portanto, para compreender o conceito de polifonia, assim como a expressão inovadora que perpassa a arte dostoievskiana, é importante ressaltar quais são as características que compõem este conceito, além de relaciona-lo com as próprias obras de Dostoiévski que o sustenta. Nesse sentido, tendo como base forte de sustentação o conceito de polifonia criado por Bakhtin ao pensar sobre a obra de arte de Dostoiévski, nota-se os seguintes pontos referente aos romances do artista russo. De início, é de grande importância destacar que a obra de arte dostoievskiana é inconclusiva e permite, com isso, uma gama múltipla de interpretações, pois um fluxo de afetos variados atinge cada leitor a sua maneira, além do próprio artista ter se distanciado como autor determinante e conclusivo. Nessa esteira, Dostoiévski se afasta do tom monológico característico dos romances ocidentais e cria de maneira original romances de tipo polifônico. Assim, a arte polifônica de Dostoiévski desestabiliza o modelo monológico, o qual busca colocar na boca de um herói específico, ou no conjunto de uma mesma obra, a palavra final e decisiva do autor que a escreve. Em Dostoiévski, ao contrário, a palavra do autor se esparrama pelas personagens, às vezes elas aparecem de maneira relevante, como pode em alguns momentos nem estar presente. Além disso, não ocorrem passagens conclusivas nas obras de Dostoiévski, tudo está em movimento, em devir e em acontecimento. Neste sentido, o leitor também se torna ativo e pleno, é mais um indivíduo singular que compõe a estrutura dialógica da arte dostoievskiana. Desta maneira, um dos pontos que saliento é sobre o valor da palavra da diferença, da expressão da singularidade e também sobre o modo de pensamento como algo em constante movimento no contato com a palavra alheia. Portanto, a ideia aqui não é o de colocar as personagens de Dostoiévski fechadas definitivamente sobre um dado valor moral, ou sobre quais valores morais possui o próprio Dostoiévski como pessoa. Diferente disso, o caminho percorrido é o de expressar como cada personagem possui um pensamento singular sobre a vida, pensamentos estes que estão permeados pela palavra da diferença, mas que não são definidos por ela de maneira objetificada. Além disso, para fazer conexão do que foi dito acima com outro pensadores, foi utilizado o conceito de literatura menor criado por Gilles Deleuze e Félix Guattari. O ponto de vista desses filósofos se articula ao conceito de Bakhtin e à arte de Dostoiévski, pois comportam justamente o sentido dos valores ativos da diferença. Para finalizar este escrito, apresentei como o próprio Dostoiévski expressava seu ponto de vista em relação à função da arte para com a sociedade