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Mice have the ability to convert dietary phylloquinone (vitamin K1) into menaquinone-4 (vitamin K2) and store the latter in tissues. A prenyltransferase enzyme, UbiA prenyltransferase domain-containing 1 (UBIAD1), is involved in this conversion. There is evidence that UBIAD1 has a weak side chain cleavage activity for phylloquinone but a strong prenylation activity for menadione (vitamin K3), which has long been postulated as an intermediate in this conversion. Further evidence indicates that when intravenously administered in mice phylloquinone can enter into tissues but is not converted further to menaquinone-4. These findings raise the question whether phylloquinone is absorbed and delivered to tissues in its original form and converted to menaquinone-4 or whether it is converted to menadione in the intestine followed by delivery of menadione to tissues and subsequent conversion to menaquinone-4. To answer this question, we conducted cannulation experiments using stable isotope tracer technology in rats. We confirmed that the second pathway is correct on the basis of structural assignments and measurements of phylloquinone-derived menadione using high resolution MS analysis and a bioassay using recombinant UBIAD1 protein. Furthermore, high resolution MS and (1)H NMR analyses of the product generated from the incubation of menadione with recombinant UBIAD1 revealed that the hydroquinone, but not the quinone form of menadione, was an intermediate of the conversion. Taken together, these results provide unequivocal evidence that menadione is a catabolic product of oral phylloquinone and a major source of tissue menaquinone-4.

Vitamin K occurs in the natural world in several forms, including a plant form, phylloquinone (PK), and a bacterial form, menaquinones (MKs). In many species, including humans, PK is a minor constituent of hepatic vitamin K content, with most hepatic vitamin K content comprising long-chain MKs. Menaquinone-4 (MK-4) is ubiquitously present in extrahepatic tissues, with particularly high concentrations in the brain, kidney and pancreas of humans and rats. It has consistently been shown that PK is endogenously converted to MK-4 (refs 4-8). This occurs either directly within certain tissues or by interconversion to menadione (K(3)), followed by prenylation to MK-4 (refs 9-12). No previous study has sought to identify the human enzyme responsible for MK-4 biosynthesis. Previously we provided evidence for the conversion of PK and K(3) into MK-4 in mouse cerebra. However, the molecular mechanisms for these conversion reactions are unclear. Here we identify a human MK-4 biosynthetic enzyme. We screened the human genome database for prenylation enzymes and found UbiA prenyltransferase containing 1 (UBIAD1), a human homologue of Escherichia coli prenyltransferase menA. We found that short interfering RNA against the UBIAD1 gene inhibited the conversion of deuterium-labelled vitamin K derivatives into deuterium-labelled-MK-4 (MK-4-d(7)) in human cells. We confirmed that the UBIAD1 gene encodes an MK-4 biosynthetic enzyme through its expression and conversion of deuterium-labelled vitamin K derivatives into MK-4-d(7) in insect cells infected with UBIAD1 baculovirus. Converted MK-4-d(7) was chemically identified by (2)H-NMR analysis. MK-4 biosynthesis by UBIAD1 was not affected by the vitamin K antagonist warfarin. UBIAD1 was localized in endoplasmic reticulum and ubiquitously expressed in several tissues of mice. Our results show that UBIAD1 is a human MK-4 biosynthetic enzyme; this identification will permit more effective decisions to be made about vitamin K intake and bone health.

Esta dissertação inicia-se com uma pesquisa sobre o conceito de modernidade, e suas denominações: Modernidade/Pós-modernidade; a seguir, recorremos à Arte Moderna, para depois adentrarmos a Estética literária no projeto da modernidade, foco da pesquisa e, para tanto, apresentamos valores literários de alguns escritores-críticos modernos. Assim, expostas as idéias em diálogo na modernidade, procedemos a formatação de um paradigma a que chamamos de paradigma Projeto da Modernidade. Discorremos sobre a crítica literária atual, e as autoras pesquisadas: a portuguesa Alice Vieira e a brasileira Lygia Bojunga Nunes. Selecionamos e realizamos um estudo paradigmático analíticocrítico em duas obras literárias para crianças e jovens, a saber: Flor de Mel de Alice Vieira e Corda bamba de Lygia Bojunga Nunes. Fizemos uma aproximação do paradigma PM formatado para este estudo ao final de cada análise, assim como uma aproximação entre Flor de Mel e Corda bamba. Dessa forma, pudemos constatar o quanto a qualidade estética do texto narrativo; desconsiderando se a obra pode ser endereçada ao receptor adulto ou criança, ou seja, se é chamada de literatura para crianças e jovens, ou não; comprova a estética literária da modernidade a que nos propusemos investigar neste estudo. This thesis starts by researching the concept of Modernity and its denominations. Modernity/Post-modernity; then, we approach Modern Art, and, later, we enter the literary esthetics in the project of Modernity, which is the focus of the research and, for that purpose, we present literary values of some modern critic-writers. So, once the ideas in Modernity dialog have been exposed, we proceed to the formatting of a paradigm which we call Project of Modernity Paradigm. We go about the current literary criticism, and the researched writers: Portuguese Alice Vieira and Brazilian Lygia Bojunga Nunes. We selected and performed an analytical-critical paradigm study in two literary works for children and youngsters, namely: Flor de Mel, by Alice Vieira and Corda bamba, by Lygia Bojunga Nunes. We did an approximation of the PM paradigm, for this study, in the end of each analysis, as well as an approximation between Flor de Mel and Corda bamba, so that we could find how much the esthetic quality of the narrative text, disregarding whether the work can be addressed to the adult or children receptors, in other words, if the literature mentioned is for children and youngsters, or not, does evidence the literary esthetics of Modernity which we proposed to investigate in this study.

Esta tese tem por objetivo apreender as relações do código verbal nas imagens das palavras, promovendo o resgate da palavra, a qual prescinde do código visual, e que descreve as sensações e percepções diferenciadas e múltiplas, mostradas em níveis graduados, do contextual ao estético; concomitantemente com os traços de modernidade, detectados nas obras selecionadas. O corpus de análise compõe-se de nove obras, dos autores brasileiros tem-se: Bartolomeu Campos de Queirós, Cecília Meireles, Clarice Lispector, Leo Cunha, Lygia Bojunga e Paulo Leminski; dos portugueses, Alice Vieira e José Saramago; e do africano, Mia Couto. Através da observação de algumas características comuns, e buscando-se apoio teórico nos autores que discorreram e discutiram criticamente a modernidade, foram captados tais traços comuns, elencados no primeiro capítulo. O segundo capítulo faz uma pequena incursão sobre os modos de processar a percepção. O terceiro apresenta as análises realizadas, categorizadas em três paradigmas, evidenciando-se os traços de modernidade, cuja presença aparece em menor ou maior grau. Desta forma, o verbal comprova a sua força e seu caráter essencial, que tanto sugere quanto mostra sensações e percepções na leitura da palavra imagética. This thesis aims at understanding the relationship of verbal code, promoting the rescue of the word, which does without the visual code, the images of words that describe the sensations and differentiated and multiple perceptions, shown in graduated levels of contextual to the aesthetic; concomitantly with traces of modernity, detected in the selected works. The corpus analysis consists of nine works, of Brazilian authors: Bartolomeu Campos de Queirós, Cecília Meireles, Clarice Lispector, Leo Cunha, Lygia Bojunga e Paulo Leminski; of Portuguese Alice Vieira e José Saramago; and African, Mia Couto. By observing some common features, we sought theoretical support in authors who discoursed and critically discussed modernity; raised the features listed in the first chapter. The second chapter makes a small incursion into the ways of processing the perception. The third presents the analyzes, categorized in three paradigms; showing traces of modernity, whose presence appears to a lesser or greater degree. Thus, the verbal proves its strength and its essential character, which both suggests as shows sensations and perceptions in imagetic word reading.

Health-related quality of life (HRQOL; "QOL" hereafter) was evaluated in Japanese osteoporotic patients using three questionnaires; the SF-36 (MOS 36-Item Short-Form Health Survey; generic, profile-type), the EQ-5D (Euro Qol-5 Dimensions; generic, preference-based), and the JOQOL (Japanese Osteoporosis Quality of Life 1999; disease-targeted). The eight subscales and two summary scores of the SF-36 were impaired in these patients even after correction for age and sex. The scores on the EQ-5D and JOQOL correlated well with the subscales of the SF-36 that represent the physical aspects of physical function and bodily pain, which suggests that physical aspects are important determinants of overall QOL status in osteoporotic patients. Although the QOL scores did not correlate with bone mineral density, they were markedly influenced by the presence of vertebral fractures. In particular, the presence of two or more vertebral fractures greatly decreased the QOL scores. We then evaluated the QOL scores before and after treatment. The patients were either given calcium supplementation alone or calcium plus once-weekly elcatonin (Elcitonin, Asahi Kasei Pharma, Tokyo, Japan) injection. Elcatonin treatment markedly improved diverse aspects of the QOL, whereas calcium alone did not. The current data suggest that osteoporosis, especially in the presence of vertebral fracture, is associated with compromised QOL, and therapeutic intervention for osteoporosis should be evaluated in terms of QOL, as well as in terms of increases in bone mineral density and fracture prevention.

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) plays a significant role in vitamin K2 (MK-4) synthesis. We investigated the enzymological properties of UBIAD1 using microsomal fractions from Sf9 cells expressing UBIAD1 by analysing MK-4 biosynthetic activity. With regard to UBIAD1 enzyme reaction conditions, highest MK-4 synthetic activity was demonstrated under basic conditions at a pH between 8.5 and 9.0, with a DTT ≥0.1 mM. In addition, we found that geranyl pyrophosphate and farnesyl pyrophosphate were also recognized as a side-chain source and served as a substrate for prenylation. Furthermore, lipophilic statins were found to directly inhibit the enzymatic activity of UBIAD1. We analysed the aminoacid sequences homologies across the menA and UbiA families to identify conserved structural features of UBIAD1 proteins and focused on four highly conserved domains. We prepared protein mutants deficient in the four conserved domains to evaluate enzyme activity. Because no enzyme activity was detected in the mutants deficient in the UBIAD1 conserved domains, these four domains were considered to play an essential role in enzymatic activity. We also measured enzyme activities using point mutants of the highly conserved aminoacids in these domains to elucidate their respective functions. We found that the conserved domain I is a substrate recognition site that undergoes a structural change after substrate binding. The conserved domain II is a redox domain site containing a CxxC motif. The conserved domain III is a hinge region important as a catalytic site for the UBIAD1 enzyme. The conserved domain IV is a binding site for Mg2+/isoprenyl side-chain. In this study, we provide a molecular mapping of the enzymological properties of UBIAD1.

There is currently insufficient information on serum 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) concentrations, and bone mineral status in healthy adolescents to allow reference values to be set. This study aimed to provide comparable data on vitamin D status in Japanese adolescents and to assess sex differences in susceptibility to vitamin D insufficiency. Serum 25OHD and PTH concentrations were measured in 1,380 healthy adolescents (aged 12–18 years). Subjects completed a questionnaire on exercise history, diet, and lifestyle factors. Calcaneal stiffness was evaluated by quantitative ultrasound. Serum 25OHD concentrations in boys and girls were 60.8 ± 18.3 and 52.8 ± 17.0 nmol/L, respectively. Approximately 30 % of boys and 47 % of girls had suboptimal 25OHD concentrations (

53歳,女性。1999年3月中旬,発熱,再発性口内炎,咽頭痛,関節痛出現。顔面と手背,下肢に境界鮮明な暗赤色,有痛性,浮腫性紅斑を認める。病理では血管周囲性に好中球を主体とする密な細胞浸潤が認められた。末梢血好中球増多,CRP上昇。針反応陽性,フィブリノーゲン高値,シアル酸高値が認められるものの,診断基準よりSweet病と診断。 Behcet病の診断は臨床症状に頼っているところが大きいが,最近の文献では,針反応がBehcet病に特異性が高いとしてあるものが多い。針反応を重視すると,今回の症例は,症状が足りなく,診断基準を満足していないものの,Sweet病にBehcet病を合併している可能性もある。Sweet病をみた場合は針反応にも注目すべきである。

COM BASE NOS ESTUDOS DE ITALO CALVINO E DE JACQUELINE HELD, PRETENDEMOS ANALISAR A NOVELA INFANTO-JUVENIL CORDA BAMBA DE LYGIA BOJUNGA NUNES, NO QUE DIZ RESPEITO AOS ASPECTOS ESTETICOS E AO IMAGINARIO DA OBRA.