The Thyroid Hormone Receptor (TR) beta-Selective Agonist GC-1 Inhibits Proliferation But Induces Differentiation and TR beta mRNA Expression in Mouse and Rat Osteoblast-Like Cells

Previous studies showed anabolic effects of GC-1, a triiodothyronine (T3) analogue that is selective for both binding and activation functions of thyroid hormone receptor (TR) beta 1 over TR alpha 1, on bone tissue in vivo. The aim of this study was to investigate the responsiveness of rat (ROS17/2.8) and mouse (MC3T3-E1) osteoblast-like cells to GC-1. As expected, T3 inhibited cellular proliferation and stimulated mRNA expression of osteocalcin or alkaline phosphatase in both cell lineages. Whereas equimolar doses of T3 and GC-1 equally affected these parameters in ROS17/2.8 cells, the effects of GC-1 were more modest compared to those of T3 in MC3T3-E1 cells. Interestingly, we showed that there is higher expression of TR alpha 1 than TR beta 1 mRNA in rat (similar to 20-90%) and mouse (similar to 90-98%) cell lineages and that this difference is even higher in mouse cells, which highlights the importance of TR alpha 1 to bone physiology and may partially explain the modest effects of GC-1 in comparison with T3 in MC3T3-E1 cells. Nevertheless, we showed that TR beta 1 mRNA expression increases (similar to 2.8- to 4.3-fold) as osteoblastic cells undergo maturation, suggesting a key role of TR beta 1 in mediating T3 effects in the bone forming cells, especially in mature osteoblasts. It is noteworthy that T3 and GC-1 induced TR beta 1 mRNA expression to a similar extent in both cell lineages (similar to 2- to 4-fold), indicating that both ligands may modulate the responsiveness of osteoblasts to T3. Taken together, these data show that TR beta selective T3 analogues have the potential to directly induce the differentiation and activity of osteoblasts.

Dizionario veterinario. 1. tr. italiana arricchita di aggiunte a cura dei professori Eduardo Chiari ... [e] Venceslao Lari ...

At head of title: P. Cagny e H. J. Gobert.

Improvement Of The Physical Performance Is Associated With Activation Of No/pgc-1α/mttfa Signaling Pathway And Increased Protein Expressions Of Electron Transport Chain In Gastrocnemius Muscle From Rats Supplemented With L-arginine.

To examine the influence of l-arginine supplementation in combination with physical training on mitochondrial biomarkers from gastrocnemius muscle and its relationship with physical performance. Male Wistar rats were divided into four groups: control sedentary (SD), sedentary supplemented with l-arginine (SDLA), trained (TR) and trained supplemented with l-arginine (TRLA). Supplementation of l-arginine was administered by gavage (62.5mg/ml/day/rat). Physical training consisted of 60min/day, 5days/week, 0% grade, speed of 1.2km/h. The study lasted 8weeks. Skeletal muscle mitochondrial enriched fraction as well as cytoplasmic fractions were obtained for Western blotting and biochemical analyses. Protein expressions of transcriptor coactivator (PGC-1α), transcriptor factors (mtTFA), ATP synthase subunit c, cytochrome oxidase (COXIV), constitutive nitric oxide synthases (eNOS and nNOS), Cu/Zn-superoxide dismutase (SOD) and manganese-SOD (Mn-SOD) were evaluated. We also assessed in plasma: lipid profile, glycemia and malondialdehyde (MDA) levels. The nitrite/nitrate (NOx(-)) levels were measured in both plasma and cytosol fraction of the gastrocnemius muscle. 8-week l-arginine supplementation associated with physical training was effective in promoting greater tolerance to exercise that was accompanied by up-regulation of the protein expressions of mtTFA, PGC-1α, ATP synthase subunit c, COXIV, Cu/Zn-SOD and Mn-SOD. The upstream pathway was associated with improvement of NO bioavailability, but not in NO production since no changes in nNOS or eNOS protein expressions were observed. This combination would be an alternative approach for preventing cardiometabolic diseases given that in overt diseases a profound impairment in the physical performance of the patients is observed.

Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms

Background: Thyroid receptors, TRa and TR beta, are involved in important physiological functions such as metabolism, cholesterol level and heart activities. Whereas metabolism increase and cholesterol level lowering could be achieved by TR beta isoform activation, TRa activation affects heart rates. Therefore, beta-selective thyromimetics have been developed as promising drug-candidates for treatment of obesity and elevated cholesterol level. GC-1 [ 3,5-dimethyl-4-(4'-hydroxy- 3'-isopropylbenzyl)-phenoxy acetic acid] has ability to lower LDL cholesterol with 600-to 1400-fold more potency and approximately two-to threefold more efficacy than atorvastatin (Lipitor(C)) in studies in rats, mice and monkeys. Results: To investigate GC-1 specificity, we solved crystal structures and performed molecular dynamics simulations of both isoforms complexed with GC-1. Crystal structures reveal that, in TRa Arg228 is observed in multiple conformations, an effect triggered by the differences in the interactions between GC-1 and Ser277 or the corresponding asparagine (Asn331) of TR beta. The corresponding Arg282 of TR beta is observed in only one single stable conformation, interacting effectively with the ligand. Molecular dynamics support this model: our simulations show that the multiple conformations can be observed for the Arg228 in TR alpha, in which the ligand interacts either strongly with the ligand or with the Ser277 residue. In contrast, a single stable Arg282 conformation is observed for TR beta, in which it strongly interacts with both GC-1 and the Asn331. Conclusion: Our analysis suggests that the key factors for GC-1 selectivity are the presence of an oxyacetic acid ester oxygen and the absence of the amino group relative to T(3). These results shed light into the beta-selectivity of GC-1 and may assist the development of new compounds with potential as drug candidates to the treatment of hypercholesterolemia and obesity.

A TR beta-selective agonist confers resistance to diet-induced obesity

Thyroid hormone receptor beta (TR beta also listed as THRB oil the MGI Database)-selective agonists activate brown adipose tissue (BAT) thermogenesis, while only minimally affecting cardiac activity or lean body mass. Here, we tested the hypothesis that daily administration of the TR beta agonist GC-24 prevents the metabolic alterations associated with a hypercaloric diet. Rats were placed on a high-fat diet and after a month exhibited increased body weight (BW) and adiposity, fasting hyperglycemia and glucose intolerance, increased plasma levels of triglycerides, cholesterol, nonesterified Fatty acids and interleukin-6. While GC-24 administration to these animals did not affect food ingestion or modified the progression of BW gain, it did increase energy, g the increase in adiposity Without expenditure, eliminating causing cardiac hypertrophy Fasting hyperglycemia remained unchanged, but treatment with GC-24 improved glucose I tolerance by increasing insulin Sensitivity and also normalized plasma triglyceride levels. plasma cholesterol levels were only Partially normalized and liver cholesterol content remained high in the GC-24-treated animals. Gene expression in liver, skeletal muscle, and white adipose tissue was only minimally affected by treatment with GC-24, with the main target being BAT In conclusion, during high-fat feeding treatment with the TR beta-selective agonist, GC-24 only partially improves metabolic control probably as a result Of accelerating the resting metabolic rate. Journal of Endocrinology (2009) 203, 291-299

Contractile activity per se induces transcriptional activation of SLC2A4 gene in soleus muscle: involvement of MEF2D, HIF-1a, and TR alpha transcriptional factors

Lima GA, Anhe GF, Giannocco G, Nunes MT, Correa-Giannella ML, Machado UF. Contractile activity per se induces transcriptional activation of SLC2A4 gene in soleus muscle: involvement of MEF2D, HIF-1a, and TR alpha transcriptional factors. Am J Physiol Endocrinol Metab 296: E132-E138, 2009. First published October 28, 2008; doi: 10.1152/ajpendo.90548.2008.-Skeletal muscle is a target tissue for approaches that can improve insulin sensitivity in insulin-resistant states. In muscles, glucose uptake is performed by the GLUT-4 protein, which is encoded by the SLC2A4 gene. SLC2A4 gene expression increases in response to conditions that improve insulin sensitivity, including chronic exercise. However, since chronic exercise improves insulin sensitivity, the increased SLC2A4 gene expression could not be clearly attributed to the muscle contractile activity per se and/or to the improved insulin sensitivity. The present study was designed to investigate the role of contractile activity per se in the regulation of SLC2A4 gene expression as well as in the participation of the transcriptional factors myocyte enhancer factor 2D (MEF2D), hypoxia inducible factor 1a (HIF-1a), and thyroid hormone receptor-alpha (TR alpha). The performed in vitro protocol excluded the interference of metabolic, hormonal, and neural effects. The results showed that, in response to 10 min of electrically induced contraction of soleus muscle, an early 40% increase in GLUT-4 mRNA (30 min) occurred, with a subsequent 65% increase (120 min) in GLUT-4 protein content. EMSA and supershift assays revealed that the stimulus rapidly increased the binding activity of MEF2D, HIF-1a, and TR alpha into the SLC2A4 gene promoter. Furthermore, chromatin immunoprecipitation assay confirmed, in native nucleosome, that contraction induced an approximate fourfold (P < 0.01) increase in MEF2D and HIF-1a-binding activity. In conclusion, muscle contraction per se enhances SLC2A4 gene expression and that involves MEF2D, HIF-1a, and TR alpha transcription factor activation. This finding reinforces the importance of physical activity to improve glycemic homeostasis independently of other additional insulin sensitizer approaches.

Sistema e-Mec:reinven????o processual da educa????o superior em tr??s dimens??es da gest??o p??blica: jur??dica, organizacional e tecnol??gica

Com o objetivo de elevar a qualidade do ensino superior do pa??s, em 2006 o Minist??rio da Educa????o (MEC) iniciou um movimento de ???reinven????o processual??? em tr??s dimens??es: i) jur??dica, com a reformula????o da legisla????o aplic??vel aos processos regulat??rios da educa????o superior; ii) organizacional, implementando mudan??as na din??mica e no desenho das rotinas de trabalho; e iii) tecnol??gica, com a implementa????o do sistema eletr??nico e-MEC de operacionaliza????o dos procedimentos de regula????o. A tr??plice iniciativa permitiu, a um s?? tempo, trazer seguran??a jur??dica, transpar??ncia, credibilidade e celeridade ao processo. Isso possibilitou a cria????o de ambiente prop??cio ao salto qualitativo que o MEC pretendia dar em rela????o tanto ao condicionamento do funcionamento de institui????es e cursos superiores quanto ?? comprova????o da excel??ncia de sua opera????o. O objetivo final??stico foi atingido de maneira satisfat??ria, podendo-se dizer que est?? em curso a institucionaliza????o de uma cultura da qualidade da educa????o superior

Texto para discuss??o 47: tr??s exemplos de mudan??a na gest??o de suprimentos na Administra????o P??blica Federal: UFSM, GHC e 4?? RCC

O presente estudo foi realizado visando proporcionar melhor conhecimento de algumas mudan??as que est??o ocorrendo na gest??o de suprimentos no ??mbito da administra????o p??blica. Trata-se da descri????o e an??lise de tr??s iniciativas, em institui????es espec??ficas, premiadas em edi????es do Concurso de Inova????es na Gest??o P??blica Federal ??? Pr??mio Helio Beltr??o. Essas iniciativas referem-se a: ???Sistema integrado de administra????o de materiais???, da Universidade Federal de Santa Maria (UFSM), ???Racionaliza????o do almoxarifado???, do 4o Regimento de Carros de Combate (4oRCC), do Comando Militar do Sul e ???Pol??tica de Materiais???, do Grupo Hospitalar Concei????o (GHC), do Rio Grande do Sul. As tr??s experi??ncias foram vencedoras do concurso entre 1996 e 1999

O aprendizado organizacional na implementa????o de pol??ticas p??blicas industriais em tr??s estados nordestinos

O objetivo deste artigo ?? ampliar o conhecimento atual sobre os processos de aprendizado na implementa????o de pol??ticas p??blicas, procurando entender, em especial, os aspectos pol??ticos envolvidos nesses processos e como eles influenciam a evolu????o e os resultados dessas pol??ticas. Nesse sentido, com base em estudos de casos realizados sobre as pol??ticas industriais implementadas pelos estados da Bahia, do Cear?? e de Pernambuco nas ??ltimas d??cadas, conclui-se que o aprendizado de indiv??duos e grupos isoladamente dentro dos governos n??o parece garantir um efetivo aprendizado do governo na implementa????o de suas pol??ticas. Nos casos estudados, o aprendizado organizacional mostra-se como um processo no qual aspectos pol??ticos e cognitivos interagem sob as restri????es de arranjos institucionais espec??ficos. Esses aspectos pol??ticos tanto podem filtrar, retardar e at?? mesmo impedir a assimila????o organizacional do aprendizado de indiv??duos ou de grupos, como, outras vezes, podem aceler??-lo.

Validating Regulatory Sensory Processing Disorders Using the Sensory Profile and Child Behavior Checklist (CBCL 1 –5)

The objective was to validate Regulatory Sensory Processing Disorders’ criteria (DC:0-3R, 2005) using empirical data on the presence and severity of sensory modulation deficits and specific psychiatric symptoms in clinical samples. Sixty toddlers who attended a child mental health unit were diagnosed by a clinical team. The following two groups were created: toddlers with RSPD(N = 14) and those with ‘‘other diagnoses in Axis I/II of the DC:0-3R00(OD3R) (N = 46). Independently of the clinical process, parents completed the Infant Toddler Sensory Profile (as a checklist for sensory symptoms) and the Achenbach Behavior Checklist for ages 1/2–5 (CBCL 1/2–5). The scores from the two groups were compared. The results showed the following for the RSPD group: a higher number of affected sensory areas and patterns than in the OD3R group; a higher percentage of sensory deficits in specific sensory categories; and a higher severity of behavioral symptoms such as withdrawal, inattention, other externalizing problems and pervasive developmental problems in CBCL 1/2–5. The results confirmed our hypotheses by indicating a higher severity of sensory symptoms and identifying specific behavioral problems in children with RSPD. The results revealed convergent validity between the instruments and the diagnostic criteria for RSPD and supported the validity of RSPD as a unique diagnosis. The findings also suggested the importance of identifying sensory modulation deficits in order to develop an early intervention to enhance the sensory capacities of children who do not fully satisfy the criteria for some DSM-IV-TR disorders.

Aperfeiçoamento da técnica de eletroforese para análise isoenzimática de clones de seringueira (Hevea sp.)1

Este estudo foi conduzido no sentido de otimizar as técnicas de preparo de extratos de folíolos e identificar tampões e condições de corrida que proporcionassem uma boa definição dos perfis eletroforéticos de clones de seringueira. Foram testados 25 diferentes sistemas enzimáticos utilizando-se onze sistemas tamponantes. Não foram encontradas diferenças na qualidade dos zimogramas obtidos nos diferentes estádios fenológicos analisados, em amostras submetidas a diferentes condições de centrifugação e nas diferentes plantas de um mesmo clone. Extratos de folíolos liofilizados apresentaram resolução semelhante para Adh, Pgi, 6Pgdh, Lap-1, Skdh, Acp, Mdh, ßGlu, Pgm e Idh que homogenados de folíolos não liofilizados preparados até 2 dias pós-coleta. Os padrões de Got e Est apresentaram boa nitidez somente em extratos de folíolos frescos. As demais enzimas não apresentaram resolução satisfatória. Com o uso de diferentes substratos, foi possível detectar nove regiões de atividade esterásica nas condições empregadas, embora variação genética tenha sido caracterizada para apenas três locos nos clones analisados. Os fenótipos observados para esterase-7 utilizando-se ésteres derivados de naftol foram semelhantes aos padrões encontrados utilizando L-benzoil-ßnaftilamida como substrato, indicando que esta esterase seja, provavelmente, uma en-dopeptidase. A utilização de substratos fluorogênicos permitiu ainda a detecção de uma variante eletroforética de Acp em Hevea nítida e uma variante de ßGlu em Hevea rigidifolia.

Substituição do fubá de milho (Zea Mays, L.) por farinha de pupunha (Bactris Gasipaes, H. B. K.) em rações para Alevinos de Tambaqui (Colossoma Macropomum, Cuvier 1818)1

São apresentados os resultados da substituição do fubá de milho por farinha de pupunha, através do desempenho em crescimento e composição corporal de alevinos de tambaqui, alimentados durante 112dias com quatro dietas, constituídas de uma ração padrão e três níveis de substituição do fubá de milho. Osresultados demonstram que a farinha de pupunha pode substituir completamente o fubá de milho nas dietas para estes alevinos, sem afetar seu desempenho e composição corporal.

Descrição de três novas espécies do gênero Melittomma (Coleoptera: Lymexylidae) da região neotropical e considerações sobre Melittomma brasiliense (Castelnau, 1832)

Estudo taxonômico das espécies neotropicais de Melittomma é apresentado, enfatizando as espécies distribuídas no território brasileiro. Discute-se brevemente os caracteres diagnósticos de M. brasiliense com dados de sua distribuição geográfica; descrições e ilustrações de três novas espécies, Melittomma nana sp.n. distribuída pela região Neotropical, Μ. brunnea sp.n. da Amazônia Central e M. panamensis sp.n. do Panamá, são apresentadas.

Ingestão e hábitos alimentares de pré-escolares de três capitais da Amazônia Ocidental Brasileira: um enfoque especial à ingestão de Vitamina A

Com objetivo de avaliar o consumo de energia, vitamina A, zinco e proteínas, bem como os hábitos alimentares de pré-escolares das capitais de Roraima (Boa Vista),Amazonas (Manaus) e Rondônia (Porto Velho) foi realizado um inquérito alimentar em 54, 238 e 78 crianças de ambos os sexos (sub-amostra de inquérito nutricional mais abrangente),respectivamente, em creches e pré-escolas, mediante os métodos recordatório de 24 horas e de freqüência de consumo de alguns alimentos fontes de vitamina A, em entrevista com a mãe ou responsável pela criança. Os resultados mostram que os alimentos mais consumidos foram pão, bolacha e biscoito, com 98,3%, seguidos pelo açúcar (95,1%), arroz (92,4%), óleo vegetal (86,0), farinha de mandioca (77,4%), tomate (70,1%) e café (69,5%). O consumo de alimentos de origem animal foi responsável por quase dois terços do total ingerido de vitamina A. Quanto à distribuição dos alimentos fontes de vitamina A, observou-se semelhança do seu consumo nas três cidades estudadas. O percentual de adequação de consumo evidenciou que a proteína foi o único nutriente consumido em níveis superiores à recomendação da "National Research Council", enquanto o aporte dietético de vitamina A foi de 84,0%, 68,4% e 63,8%, em Boa Vista, Manaus e Porto Velho, respectivamente, com inadequação, inclusive, para energia e zinco. Observou-se um padrão alimentar monótono e limitado, com baixo consumo de fontes de vitamina A pré-formada, de hortaliças e de frutas fontes de carotenóides pró-vitamínicos A típicos da Região Amazônica, como buriti, tucumã, pupunha e manga, quase todas sazonais, que não estavam na sua época por ocasião do inquérito.

Text-book of comparative anatomy, by Arnold Lang with preface to the English translation by Ernst Haeckel, tr. into English by Henry M. Bernard and Matilda Bernard.

pt. 1