Hypothalamic Actions of Tumor Necrosis Factor alpha Provide the Thermogenic Core for the Wastage Syndrome in Cachexia

TNF alpha is an important mediator of catabolism in cachexia. Most of its effects have been characterized in peripheral tissues, such as skeletal muscle and fat. However, by acting directly in the hypothalamus, TNF alpha can activate thermogenesis and modulate food intake. Here we show that high concentration TNF alpha in the hypothalamus leads to increased O(2) consumption/CO(2) production, increased body temperature, and reduced caloric intake, resulting in loss of body mass. Most of the thermogenic response is produced by beta 3-adrenergic signaling to the brown adipose tissue (BAT), leading to increased BAT relative mass, reduction in BAT lipid quantity, and increased BAT mitochondria density. The expression of proteins involved in BAT thermogenesis, such as beta 3-adrenergic receptor, peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha, and uncoupling protein-1, are increased. In the hypothalamus, TNF alpha produces reductions in neuropeptide Y, agouti gene-related peptide, proopiomelanocortin, and melanin-concentrating hormone, and increases CRH and TRH. The activity of the AMP-activated protein kinase signaling pathway is also decreased in the hypothalamus of TNF alpha-treated rats. Upon intracerebroventricular infliximab treatment, tumor-bearing and septic rats present a significantly increased survival. In addition, the systemic inhibition of beta 3-adrenergic signaling results in a reduced body mass loss and increased survival in septic rats. These data suggest hypothalamic TNF alpha action to be important mediator of the wastage syndrome in cachexia. (Endocrinology 151: 683-694, 2010)

Modulation of Bone Morphogenetic Protein-9 Expression and Processing by Insulin, Glucose, and Glucocorticoids: Possible Candidate for Hepatic Insulin-Sensitizing Substance

Bone morphogenetic protein 9 (BMP-9), a member of the TGF-beta superfamily predominantly expressed in nonparenchymal liver cells, has been demonstrated to improve glucose homeostasis in diabetic mice. Along with this therapeutic effect, BMP-9 was proposed as a candidate for the hepatic insulin-sensitizing substance ( HISS). Whether BMP-9 plays a physiological role in glucose homeostasis is still unknown. In the present study, we show that BMP-9 expression and processing is severely reduced in the liver of insulin-resistant rats. BMP-9 expression and processing was directly stimulated by in situ exposition of the liver to the combination of glucose and insulin and oral glucose in overnight fasted rats. Additionally, prolonged fasting ( 72 h) abrogated refeeding-induced BMP-9 expression and processing. Previous exposition to dexamethasone, a known inductor of insulin resistance, reduced BMP-9 processing stimulated by the combination of insulin and glucose. Finally, we show that neutralization of BMP-9 with an anti-BMP-9 antibody induces glucose intolerance and insulin resistance in 12-h fasted rats. Collectively, the present results demonstrate that BMP-9 plays an important role in the control of glucose homeostasis of the normal rat. Additionally, BMP-9 is expressed and processed in an HISS-like fashion, which is impaired in the presence of insulin resistance. BMP-9 regulation according to the feeding status and the presence of diabetogenic factors reinforces the hypothesis that BMP-9 might exert the role of HISS in glucose homeostasis physiology. ( Endocrinology 149: 6326-6335, 2008)

Glucocorticoids in Vivo Induce Both Insulin Hypersecretion and Enhanced Glucose Sensitivity of Stimulus-Secretion Coupling in Isolated Rat Islets

Although glucocorticoids are widely used as antiinflammatory agents in clinical therapies, they may cause serious side effects that include insulin resistance and hyperinsulinemia. To study the potential functional adaptations of the islet of Langerhans to in vivo glucocorticoid treatment, adult Wistar rats received dexamethasone (DEX) for 5 consecutive days, whereas controls (CTL) received only saline. The analysis of insulin release in freshly isolated islets showed an enhanced secretion in response to glucose in DEX-treated rats. The study of Ca(2+) signals by fluorescence microscopy also demonstrated a higher response to glucose in islets from DEX-treated animals. However, no differences in Ca(2+) signals were found between both groups with tolbutamide or KCl, indicating that the alterations were probably related to metabolism. Thus, mitochondrial function was explored by monitoring oxidation of nicotinamide dinucleotide phosphate autofluorescence and mitochondrial membrane potential. Both parameters revealed a higher response to glucose in islets from DEX-treated rats. The mRNA and protein content of glucose transporter-2, glucokinase, and pyruvate kinase was similar in both groups, indicating that changes in these proteins were probably not involved in the increased mitochondrial function. Additionally, we explored the status of Ca(2+)-dependent signaling kinases. Unlike calmodulin kinase II, we found an augmented phosphorylation level of protein kinase C alpha as well as an increased response of the phospholipase C/inositol 1,4,5-triphosphate pathway in DEX-treated rats. Finally, an increased number of docked secretory granules were observed in the beta-cells of DEX animals using transmission electron microscopy. Thus, these results demonstrate that islets from glucocorticoid-treated rats develop several adaptations that lead to an enhanced stimulus-secretion coupling and secretory capacity. (Endocrinology 151: 85-95, 2010)

HIERARCHICAL DECOMPOSITION OF MULTICLASS PROBLEMS

Several popular Machine Learning techniques are originally designed for the solution of two-class problems. However, several classification problems have more than two classes. One approach to deal with multiclass problems using binary classifiers is to decompose the multiclass problem into multiple binary sub-problems disposed in a binary tree. This approach requires a binary partition of the classes for each node of the tree, which defines the tree structure. This paper presents two algorithms to determine the tree structure taking into account information collected from the used dataset. This approach allows the tree structure to be determined automatically for any multiclass dataset.

Ligand dissociation from estrogen receptor is mediated by receptor dimerization: Evidence from molecular dynamics simulations

Estrogen Receptor (ER) is an important target for pharmaceutical design. Like other ligand-dependent transcription factors, hormone binding regulates ER transcriptional activity. Nevertheless, the mechanisms by which ligands enter and leave ERs and other nuclear receptors remain poorly understood. Here, we report results of locally enhanced sampling molecular dynamics simulations to identify dissociation pathways of two ER ligands [the natural hormone 17 beta-estradiol (E-2) and the selective ER modulator raloxifene (RAL)] from the human ER alpha ligand-binding domain in monomeric and dimeric forms. E-2 dissociation occurs via three different pathways in ER monomers. One resembles the mousetrap mechanism (Path I), involving repositioning of helix 12 (H12), others involve the separation of H8 and H11 (Path II), and a variant of this pathway at the bottom of the ligand-binding domain (Path II`). RAL leaves the receptor through Path I and a Path I variant in which the ligand leaves the receptor through the loop region between H11 and H12 (Path I`). Remarkably, ER dimerization strongly suppresses Paths II and II` for E-2 dissociation and modifies RAL escape routes. We propose that differences in ligand release pathways detected in the simulations for ER monomers and dimers provide an explanation for previously observed effects of ER quaternary state on ligand dissociation rates and suggest that dimerization may play an important, and hitherto unexpected, role in regulation of ligand dissociation rates throughout the nuclear receptor family.

Analysis of Agonist and Antagonist Effects on Thyroid Hormone Receptor Conformation by Hydrogen/Deuterium Exchange

Thyroid hormone receptors (TRs) are ligand-gated transcription factors with critical roles in development and metabolism. Although x-ray structures of TR ligand-binding domains (LBDs) with agonists are available, comparable structures without ligand (apo-TR) or with antagonists are not. It remains important to understand apo-LBD conformation and the way that it rearranges with ligands to develop better TR pharmaceuticals. In this study, we conducted hydrogen/deuterium exchange on TR LBDs with or without agonist (T(3)) or antagonist (NH(3)). Both ligands reduce deuterium incorporation into LBD amide hydrogens, implying tighter overall folding of the domain. As predicted, mass spectroscopic analysis of individual proteolytic peptides after hydrogen/deuterium exchange reveals that ligand increases the degree of solvent protection of regions close to the buried ligand-binding pocket. However, there is also extensive ligand protection of other regions, including the dimer surface at H10-H11, providing evidence for allosteric communication between the ligand-binding pocket and distant interaction surfaces. Surprisingly, C-terminal activation helix H12, which is known to alter position with ligand, remains relatively protected from solvent in all conditions suggesting that it is packed against the LBD irrespective of the presence or type of ligand. T(3), but not NH(3), increases accessibility of the upper part of H3-H5 to solvent, and we propose that TR H12 interacts with this region in apo-TR and that this interaction is blocked by T(3) but not NH(3.) We present data from site-directed mutagenesis experiments and molecular dynamics simulations that lend support to this structural model of apo-TR and its ligand-dependent conformational changes. (Molecular Endocrinology 25: 15-31, 2011)

Kan egenvårdsutbildning ge kunskaper som leder till ökad livskvalitet och att fler patienter slutar röka? : En jämförelse av två olika omhändertagandenav KOL patienter i primärvården.En kvasiexperimentell studie

Syftet med studien var att jämföra livskvalitet, kunskap om KOL och antal patienter som inlett ett rökstopp där en grupp erhöll standard vård och en annan grupp förutom standard vård även fick ett strukturerat omhändertagande på en distriktssköterskeledd KOL- mottagning med undervisning i egenvård.Studien genomfördes med kvasiexperimentell design. Urvalet var 52 patienter från primärvården med diagnosen KOL. Patienterna matchades utifrån kön, sjukdomens svårighetsgrad och slumpades sen till två grupper, en interventionsgrupp och en jämförandegrupp. Jämförandegruppen erhöll standardvård medan interventionsgruppen utöver standardvård erhöll två utbildningsbesök i egenvård hos astma KOL-sjuksköterskan på en vårdcentral i mellansverige.Som datainsamlingsmetod har två enkäter använts. En enkät som innehöll frågor om kön, ålder, civilstånd, utbildning, upplevd kunskap om KOL och rökstatus samt en enkät som hade till syfte att ge information om hur andningsbesvären påverkar patientens livskvalitet. Båda grupperna har svarat på enkäterna vid två tillfällen, vid det första besöket och vid det sista besöket efter tre månader. Interventionsgruppen har däremellan fått två utbildningsbesök.Resultaten visade statistiskt säkerställda skillnader mellan grupperna gällande livskvalitet, rökstopp och kunskaper om KOL. Interventionsgruppen hade fått minskade andningsbesvär, hade ökat sin fysiska aktivitet och fått en bättre psykosocial hälsa. Medan jämförande gruppen hade försämrats något i alla dessa avseenden. I interventionsgruppen hade sex av sexton rökande patienter slutat att röka, medan ingen hade slutat av de fjorton rökande patienterna i jämförandegruppen. Patienterna i interventions- gruppen hade också väsentligen större kunskaper om sin sjukdom jämfört med patienterna i jämförandegruppen.

Desenvolvimento de formulações para produção de grés porcelanato a partir de matérias-primas da região da bacia do Parnaíba

Brazil is a great ceramic raw materials productor because of the its big number of clay deposits, in various areas of the ceramic industry. Although, the majority of the natural reservations are unknown or not studied yet, so there is no scientific technical dates that can guide their usage and industrial application, as well as the racional and optimazed way of usage by the industrial sector. The state of Maranhão has a gigant mineral wealth as esmectite, bentonite, kaolin, clays, feldspates, marine salt, iron and others, but produce only products with small agregated value compared to the porcelanato, one of the most expensives ceramic cover tiles, the reason for that is the low water absorption (lower than 0,5%), beside present amazing tecnicals features, like mechanical resistence. The main objective of the work is to do the characterization of four clays, with the finallity of find an application by the results and develop formulations to produce porcelanato using these raw materials from Timon-MA. For this were made the raw materials characterization using X ray fluorecence; X ray diffraction; Differencial thermal analysis; Dilatometric analysis and Tecnological properties, planing three formulations that were sinterized at six different temperatures: 1150, 1170, 1190, 1210, 1230 and 1250ºC for 7 minutes. After the sinteratization, the samples were submitted to tension resistance analysis. Were attained two formulations with the requested properties to produce porcelanato

Aproveitamento de resíduo de beneficiamento do caulim na produção de porcelanato cerâmico

Nowadays, industries from all sectors have great concerns over the disposition of the residues generated along the productive process. This is not different in the mineral sector, as this generates great volumes of residues. It was verified that the kaolin improvement industry generates great volumes of residue basically constituted of kaolinite, muscovite mica and quartz, which are basic constitution elements to formularisations of ceramics masses to the production of covering of stoneware tiles type. This happens because the methodology applied to the improvement process is still very rudimentary, what causes a very low yield, only ¼ from all the material volume that enters the improvement process, in the end, is marketable. The disposal of this residue, in a general way, causes a very big negative environmental impact, what has justified the researches efforts aiming to find a rational solution to this problem. In this way, the intention of this present work is the utilization of this residue in the manufacture of products to high quality ceramics covering, stoneware tiles in an industrial scale. For this purpose, the influence of the addition of the residue to a standard ceramics mass used by a ceramics sector company, already established in the market, with the intention of verifying the possibility of use of this residue as the mass complementary raw material and even the possible partial or total substitution of one of the components of the mass for the raw material in evidence will be studied. To the accomplishment of this work, the kaolin improvement residue generated by an industry of exploitation and improvement of kaolin, located in the region of Equador-RN, in the levels 1,2,4,8, 16 and 32% will be added to the standard mass already used for the production of stoneware tiles. The raw materials used, kaolin residue and the standard mass, were characterized through DRX, FRX, DTA, TGA and dilatometry. After the sintering of the bodies of test, tests of water absorption, apparent porosity, post burning linear retraction, apparent specific mass and flexural strength (3 point bending) were realized to determinate the technological properties of these materials. The results show the studied residue can be considered raw material of great potential to the industry of floor and ceramics covering of the stoneware tiles type

Crescimento e nutrição mineral de capim-braquiária

Brachiaria decumbens, vulgarmente conhecida por capim-braquiária, é considerada uma importante planta daninha, muito agressiva e de difícil controle em áreas onde foi introduzida como forrageira e posteriormente tornou-se lavoura. Com o objetivo de estudar a produção de massa seca, a distribuição e o acúmulo de macronutrientes em plantas de capim-braquiária, foi conduzido o presente trabalho em casa de vegetação. As plantas foram cultivadas em vasos preenchidos com areia de rio lavada e peneiradas e irrigadas diariamente com solução nutritiva completa de Hoagland & Arnon a 50% da concentração original. A primeira avaliação foi realizada aos 20 dias após a emergência (DAE), e as seguintes, em intervalos de 14 dias. Foi determinada a massa seca das diferentes partes da planta. O material foi moído e analisado quanto aos teores de macronutrientes. Os resultados indicaram que a planta apresentou crescimento durante toda a fase experimental. O maior acúmulo ocorreu aos 160 DAE, sendo de 38,27 g planta-1 de massa seca. Aos 160 DAE, cerca de 37,37% da massa seca estava alocada nas raízes, 37,54% nos colmos + bainhas e 25,09% nas folhas. O acúmulo total dos macronutrientes foi crescente até os 146 dias após a emergência. Aos 76 DAE (período de maior competição dessa espécie com a maioria das culturas anuais), uma planta de capim-braquiária acumulou 1,32 grama de massa seca; 40,8 mg de K; 18,2 mg de N; 6,3 mg de Ca; 5,2 mg de Mg; 2,68 mg de P; e 2,4 mg de S.

Análise dos Processos de Flotação e Oxidação Avançada para o Tratamento de Efluente Modelo da Indústria do Petróleo

The generation of wastes in most industrial process is inevitable. In the petroleum industry, one of the greatest problems for the environment is the huge amount of produced water generated in the oil fields. This wastewater is a complex mixture and present great amounts. These effluents can be hazardous to the environmental without adequate treatment. This research is focused in the analysis of the efficiencies of the flotation and photo-oxidation processes to remove and decompose the organic compounds present in the produced water. A series of surfactants derivated from the laurilic alcohol was utilized in the flotation to promote the separation. The experiments have been performed with a synthetic wastewater, carefully prepared with xylene. The experimental data obtained using flotation presented a first order kinetic, identified by the quality of the linear data fitting. The best conditions were found at 0.029 g.L-1 for the surfactant EO 7, 0.05 g.L-1 for EO 8, 0.07 g.L-1 for EO 9, 0.045 g.L-1 for EO 10 and 0.08 g.L-1 for EO 23 with the following estimated kinetic constants: 0.1765, 0.1325, 0.1210, 0.1531 and 0.1699 min-1, respectively. For the series studied, the most suitable surfactant was the EO 7 due to the lower reagent onsumption, higher separation rate constant and higher removal efficiency of xylene in the aqueous phase (98%). Similarly to the flotation, the photo-Fenton process shows to be efficient for degradation of xylene and promoting the mineralization of the organic charge around 90% and 100% in 90 min