Magnetic studies of the Late Cretaceous magmatism in Portugal : from Iberian plate kinematics to magnetic fabrics

Tese de doutoramento (co-tutela), Ciências Geofísicas e da Geoinformação (Geofísica), Université de Toulouse, Universidade de Lisboa, 2013

Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response.

RATIONALE: A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. OBJECTIVE: The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). METHODS: Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. RESULTS: The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D21 total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. CONCLUSION: The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.

Sedimentology and micromorphology of drumlin sediments at Chimney Bluffs State Park, New York, United States of America

The drumlin sediments at Chimney Bluffs, New York appear to represent a block-inmatrix style glacial melange. This melange comprises sand stringers, lenses and intraclasts juxtaposed in an apparently massive diamicton. Thin section examination of these glacigenic deposits has revealed microstructures indicative of autokinetic subglacial defonnation which are consistent with a deformable bed origin for the diamicton. These features include banding and. necking of matrix grains, oriented plasma fabrics and the formation of pressure shadows at the long axis ends of elongate clasts. Preservation of primary stratification within the sand intraclasts appears to suggest that these features were pre-existing up-ice deposits that were frozen, entrained, then deposited as part of a defonning till layer beneath an advancing ice sheet. Multi-directional micro-shearing within the sand blocks is thought to reflect the frozen nature of the sand units in such a high strain environment. It is also contended that dewatering of the sediment pile leading to the eventual immobilisation of the defonning till layer was responsible for opening sub-horizontal fissures within the diamicton. These features were subsequently infilled with mass flow poorly sorted sands and silts which were subjected to ductile defonnation during the waning stages of an actively deforming till layer. Microstructures indicative of the dewatering processes in the sand units include patches of fine-grained particles within a coarser-grained matrix and the presence of concentrated zones of translocated clays. However, these units were probably confined within an impermeable diamicton casing that prevented massive pore water influxes from the deforming till layer~ Hence, these microstructures probably reflect localised dewatering of the sand intraclasts. A layered subglacial shear zone model is proposed for the various features exhibited by the drumlin sediments. The complexity of these structures is explained in terms of ii superposing deformation styles in response to changing pore water pressures. Constructional glaciotectonics, as implied by the occurrence of sub-horizontal fissuring, is suggested as the mechanism for the stacking of the sand intraclast units within the diamicton. The usefulness of micromorphology in complimenting the traditional sedimentology of glacigenic deposits is emphasised by the current study. An otherwise massive diamicton was shown to contain microstructures indicative of the very high strain rates expected in a complexly deforming till layer. . It is quite obvious from this investigation that the classification of diamictons needs to be re-examined for evidence of microstructures that could lead to the re-interpretation of diamicton forming processes. RESUME Le pacquet de sediments drumlinaire de Chimney Bluffs, New York, represent un "bloc-en-matrice" genre de melange glaciale. Des structures microscopique comprennent l'evidence pour la defonnation intrinseque attribuee a l'origine lit non resistant du drumlin. PreselVation des structures primaires au coeur des blocs arenaces suggere que ceux sont des depots preexistant qui furent geles, entraines et par la suite sedimentes au milieu d'une couche de debris sous-glaciaires en voie de deformation. Des failles microscopiques a l'interieur des blocs arenaces appuient aussi l'idee d'un bloc cohesif (c'est-a-dire gele) au centre d'un till non resistant. Des implications significatives s'emergent de cette etude pour les conditions sous-glaciaire et les processus de la formation des drumlin.

Letter to S.D. Woodruff from George C. Flint and Co.

Letter to S.D. Woodruff from George C. Flint and Co., Upholsterers and Furniture Manufacturers of New York regarding items such as mantle glass, cornices and fabrics. They have enclosed a handwritten price list with this letter (4 pages, handwritten), Sept. 13, 1876.

Caractérisation de l’ubiquitin-fold modifier (UFM1) dans un modèle C. elegans

L’ubiquitin-fold modifier (UFM1) fait partie de la classe 1 de la famille de protéine ubiquitin-like (Ubl). UFM1 et Ub ont très peu d’homologie de séquence, mais partagent des similarités remarquables au niveau de leur structure tertiaire. Tout comme l’Ub et la majorité des autres Ubls, UFM1 se lie de façon covalente à ses substrats par l’intermédiaire d’une cascade enzymatique. Il est de plus en plus fréquemment rapporté que les protéines Ubls sont impliquées dans des maladies humaines. Le gène Ufm1 est surexprimé chez des souris de type MCP développant une ischémie myocardique et dans les îlots de Langerhans de patients atteints du diabète de type 2. UFM1 et ses enzymes spécifiques, UBA5, UFL1 et UFC1, sont conservés chez les métazoaires et les plantes suggérant un rôle important pour les organismes multicellulaires. Le Caenorhabditis elegans est le modèle animal le plus simple utilisé en biologie. Sa morphologie, ses phénotypes visibles et ses lignées cellulaires ont été décrits de façon détaillée. De plus, son cycle de vie court permet de rapidement observer les effets de certains gènes sur la longévité. Ce modèle nous permet de facilement manipuler l’expression du gène Ufm1 et de mieux connaître ses fonctions. En diminuant l’expression du gène ufm-1 chez le C.elegans, par la technique de l’ARN interférence par alimentation, nous n’avons observé aucun problème morphologique grave. Les vers ressemblaient aux vers sauvages et possédaient un nombre de progéniture normal. Cependant, les vers sauvage exposés à l’ARNi d’ufm-1 vivent significativement moins longtemps que les contrôles et ce, de façon indépendante de la voie de signalisation de l’insuline/IGF. Chez le C. elegans la longévité et la résistance au stress cellulaire sont intimement liées. Nous n’avons remarqué aucun effet d’ufm-1 sur le stress thermal, osmotique ou oxydatif, mais il est requis pour la protection contre le stress protéotoxique. Il est également nécessaire au maintien de l’intégrité neuronale au cours du vieillissement des animaux. L’ensemble de nos données nous renseigne sur les fonctions putatives du gène Ufm1.

Un criblage ciblant de nouveaux facteurs impliqués dans l’assemblage mitotique des chromosomes dans le nématode C. elegans

La division cellulaire est un processus fondamental des êtres vivants. À chaque division cellulaire, le matériel génétique d'une cellule mère est dupliqué et ségrégé pour produire deux cellules filles identiques; un processus nommé la mitose. Tout d'abord, la cellule doit condenser le matériel génétique pour être en mesure de séparer mécaniquement et également le matériel génétique. Une erreur dans le niveau de compaction ou dans la dynamique de la mitose occasionne une transmission inégale du matériel génétique. Il est suggéré dans la littérature que ces phénomènes pourraient causé la transformation des cellules cancéreuses. Par contre, le mécanisme moléculaire générant la coordination des changements de haut niveau de la condensation des chromosomes est encore incompris. Dans les dernières décennies, plusieurs approches expérimentales ont identifié quelques protéines conservées dans ce processus. Pour déterminer le rôle de ces facteurs dans la compaction des chromosomes, j'ai effectué un criblage par ARNi couplé à de l'imagerie à haute-résolution en temps réel chez l'embryon de C. elegans. Grâce à cette technique, j'ai découvert sept nouvelles protéines requises pour l'assemblage des chromosomes mitotiques, incluant la Ribonucléotide réductase (RNR) et Topoisomérase II (topo-II). Dans cette thèse, je décrirai le rôle structural de topo-II dans l'assemblage des chromosomes mitotiques et ces mécanismes moléculaires. Lors de la condensation des chromosomes, topo-II agit indépendamment comme un facteur d'assemblage local menant par la suite à la formation d'un axe de condensation tout au long du chromosome. Cette localisation est à l'opposé de la position des autres facteurs connus qui sont impliqués dans la condensation des chromosomes. Ceci représente un nouveau mécanisme pour l'assemblage des chromosomes chez C. elegans. De plus, j'ai découvert un rôle non-enzymatique à la protéine RNR lors de l'assemblage des chromosomes. Lors de ce processus, RNR est impliqué dans la stabilité des nucléosomes et alors, permet la compaction de haut niveau de la chromatine. Dans cette thèse, je rapporte également des résultats préliminaires concernant d'autres nouveaux facteurs découverts lors du criblage ARNi. Le plus important est que mon analyse révèle que la déplétion des nouvelles protéines montre des phénotypes distincts, indiquant la fonction de celles-ci lors de l'assemblage des chromosomes. Somme toute, je conclus que les chromosomes en métaphase sont assemblés par trois protéines ayant des activités différentes d'échafaudage: topoisomérase II, les complexes condensines et les protéines centromériques. En conclusion, ces études prouvent le mécanisme moléculaire de certaines protéines qui contribuent à la formation des chromosomes mitotiques.

Régulation de la division asymétrique chez C. elegans

La division asymétrique est essentielle pour générer la diversité au cours du développement et permet aussi de réguler la balance entre renouvellement et différenciation des cellules souches chez l’adulte. Dans ces deux cas de figure, elle dépend respectivement d’une polarité intrinsèque ou d’une polarité extrinsèque. C. elegans est un excellent modèle pour étudier les mécanismes cellulaires et moléculaires de la division asymétrique in vivo. Chez l’embryon, le maintien d’un axe de polarité antéro-postérieur dépend des protéines PAR conservées et localisées de façon asymétrique en deux groupes mutuellement exclusifs; le groupe antérieur avec PAR-3, PAR-6, PKC-3 et le groupe postérieur avec PAR-2 et PAR-1. L’absence d’une protéine PAR entraine une perte de polarité et une létalité embryonnaire. Lors d’un crible par ARN interférence mené par Jean-Claude Labbé pour identifier les suppresseurs de la létalité associée à la perte de PAR-2, deux cyclines de type B, CYB-2.1 et CYB-2.2 ont été trouvées. J’ai déterminé que CYB-2.1 et CYB-2.2 interviennent dans la polarité sans perturber le cycle cellulaire et agissent vraisemblablement avec leur kinase associée, CDK-1, pour stabiliser les niveaux protéiques de PAR-6. Ces travaux permettent de mieux définir les liens étroits entre polarité et cycle cellulaire. La lignée germinale de C. elegans est un excellent modèle pour étudier les divisions des cellules souches germinales in vivo. Par contre, l’absence d’orientation préférentielle de ces divisions laisse envisager que la complexité morphologique de la niche pourrait engendrer une diversité d’axe possible. J’ai étudié la régulation morphologique de cette niche, une unique cellule somatique appelée distal tip cell (DTC), qui arborise de longues extensions au stade adulte. Mes résultats préliminaires favorisent un modèle dans lequel les cellules souches et progéniteurs germinaux (CSPG) supportent la formation de ces extensions. Enfin, j’ai obtenu des conditions favorables à l’étude de la division asymétrique extrinsèque dans ce modèle, en simplifiant l’architecture de la niche dans des conditions qui préservent les divisions cellulaires des cellules souches. Mes travaux ont permis de mieux comprendre les liens unissant les différents processus biologiques impliqués dans la division asymétrique, d’une part par l’étude du rôle qu’y jouent des régulateurs clés du cycle cellulaire au cours du développement et d’autre part par la caractérisation d’une communication bidirectionnelle entre la niche et les cellules souches chez l’adulte.

Techniques for Enhancing Wind Energy Generation - A CFD Based Multibody Dynamics Approach in Horizontal Axis Wind Turbines

Wind energy has emerged as a major sustainable source of energy.The efficiency of wind power generation by wind mills has improved a lot during the last three decades.There is still further scope for maximising the conversion of wind energy into mechanical energy.In this context,the wind turbine rotor dynamics has great significance.The present work aims at a comprehensive study of the Horizontal Axis Wind Turbine (HAWT) aerodynamics by numerically solving the fluid dynamic equations with the help of a finite-volume Navier-Stokes CFD solver.As a more general goal,the study aims at providing the capabilities of modern numerical techniques for the complex fluid dynamic problems of HAWT.The main purpose is hence to maximize the physics of power extraction by wind turbines.This research demonstrates the potential of an incompressible Navier-Stokes CFD method for the aerodynamic power performance analysis of horizontal axis wind turbine.The National Renewable Energy Laboratory USA-NREL (Technical Report NREL/Cp-500-28589) had carried out an experimental work aimed at the real time performance prediction of horizontal axis wind turbine.In addition to a comparison between the results reported by NREL made and CFD simulations,comparisons are made for the local flow angle at several stations ahead of the wind turbine blades.The comparison has shown that fairly good predictions can be made for pressure distribution and torque.Subsequently, the wind-field effects on the blade aerodynamics,as well as the blade/tower interaction,were investigated.The selected case corresponded to a 12.5 m/s up-wind HAWT at zero degree of yaw angle and a rotational speed of 25 rpm.The results obtained suggest that the present can cope well with the flows encountered around wind turbines.The areodynamic performance of the turbine and the flow details near and off the turbine blades and tower can be analysed using theses results.The aerodynamic performance of airfoils differs from one another.The performance mainly depends on co-efficient of performnace,co-efficient of lift,co-efficient of drag, velocity of fluid and angle of attack.This study shows that the velocity is not constant for all angles of attack of different airfoils.The performance parameters are calculated analytically and are compared with the standardized performance tests.For different angles of ,the velocity stall is determined for the better performance of a system with respect to velocity.The research addresses the effect of surface roughness factor on the blade surface at various sections.The numerical results were found to be in agreement with the experimental data.A relative advantage of the theoretical aerofoil design method is that it allows many different concepts to be explored economically.Such efforts are generally impractical in wind tunnels because of time and money constraints.Thus, the need for a theoretical aerofoil design method is threefold:first for the design of aerofoil that fall outside the range of applicability of existing calalogs:second,for the design of aerofoil that more exactly match the requirements of the intended application:and third,for the economic exploration of many aerofoil concepts.From the results obtained for the different aerofoils,the velocity is not constant for all angles of attack.The results obtained for the aerofoil mainly depend on angle of attack and velocity.The vortex generator technique was meticulously studies with the formulation of the specification for the right angle shaped vortex generators-VG.The results were validated in accordance with the primary analysis phase.The results were found to be in good agreement with the power curve.The introduction of correct size VGs at appropriate locations over the blades of the selected HAWT was found to increase the power generation by about 4%

Pre-pubertal measurements of the somatotrophic axis as predictors of milk production in Holstein-Friesian dairy cows

This study investigated possible relationships between measurements of the somatotrophic axis in pre-pubertal dairy calves and subsequent milk yields. Endogenous growth hormone (GH) release was measured through a fed and fasted period in fifty 6-month-old Holstein-Friesian heifers and they were then challenged with growth hormone-releasing factor (GRF) to assess their GH release pattern. Insulin-like growth factor-I (IGF-I), insulin and glucose concentrations were measured in relation to time of feeding. Cows were subsequently monitored through their first three lactations to record peak and 305-day milk yields. In the first lactation, milk energy output for the first 120 days of lactation was also calculated. The mean 305-day milk yield increased from 7417 +/- 191 kg in the first lactation (n = 37) to 8749 +/- 252 kg in the third (n = 25). There were no significant relationships between any measures of GH secretion and peak or 305-day yield in any lactation. A highly significant positive relationship was established between the GH peak measured 10 min post-GRF challenge and 120-day milk energy values in the first lactation. This relationship was, however, only present in the subpopulation of 12 cows culled after one or two lactations and was absent in the 25 animals remaining for the third lactation. There were no significant relationships between pre-pubertal IGF-I and fed or fasted insulin or glucose concentrations and any subsequent measurement of yield. The usefulness of GH secretagogue challenges in calves as a predictive test for future milk production is thus limited but may have some bearing on nutrient partitioning and longevity. (c) 2005 Elsevier Inc. All rights reserved.

HPA axis related genes and response to psychological therapies: genetics and epigenetics

Background Hypothalamic–pituitary–adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT). Methods Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response). Results Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response. Conclusions Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner.

New molecular variants of hypothalamus-pituitary-gonad axis genes and their association with early puberty phenotype in Bos taurus indicus (Nellore)

Endocrine system plays a major role in the control of reproductive functions which are regulated by the hypothalamus-pituitary-gonad axis and its interactions. FSH and LH receptor genes are expressed at the gonads and GnRH receptor gene is expressed at the anterior pituitary gland. Misense mutations of the FSH, LH or GnRH receptors, activating or inactivating their functions in mammals, are potentially useful to allow the understanding of the role of this group of gonadotropins in reproductive phenotypes as early puberty and birth interval length. In the present study, polymorphisms in bovine exon 11 and 3`UTR of LHR, exon 10 and 3`UTR of FSHR and GnRHR genes were characterized with some of them resulting in changes in the aminoacidic chain. These polymorphic sites were found in a Bos taurus indicus (Nellore) female population by means of PCR-SSCP and DNA sequencing. Association between nucleotidic/aminoacidic changes and early puberty were determined by Chi-square analysis. It was found association between FSHR 3`UTR polymorphisms at position 2181, 2248 and 2249 bp and early puberty phenotype (p < 0.05). The presence of these new molecular markers might be considered in further studies to validate its correlation with early puberty or other reproduction associated phenotypes in cattle breeds. (C) 2007 Published by Elsevier B.V.

Morphology and anatomy of inflorescence and inflorescence axis in Paepalanthus sect. Diphyomene Ruhland (Eriocaulaceae, Poales) and its taxonomic implications

Paepalanthus sect. Diphyomene has inflorescences arranged in umbels. The underlying bauplan seems however to be more complex and composed of several distinct subunits. Despite appearing superficially very similar, the morphology and anatomy of the inflorescences can supply useful information for the understanding of the phylogeny and taxonomy of the group. Inflorescences of Paepalanthus erectifolius, Paepalanthus flaccidus, Paepalanthus giganteus, and Paepalanthus polycladus were analyzed in regard to branching pattern and anatomy. In P. erectifolius, P. giganteus and P. polycladus the structure is a tribotryum, with terminal dibotryum, and with pherophylls bearing lateral dibotrya. In P. flaccidus, the inflorescence is a pleiobotryum, with terminal subunit, and without pherophylls. Secondary inflorescences may occur in all species without regular pattern. Especially when grown in sites without a pronounced seasonality, the distinction between enrichment zone (part of the same inflorescence) and new inflorescences may be obscured. The main anatomical features supplying diagnostic and phylogenetic information are as follows: (a) in the elongated axis, the thickness of the epidermal cell walls and the cortex size; (b) in the bracts, the quantity of parenchyma cells (c) in the scapes, the shape and the presence of a pith tissue. Therefore, P. sect. Diphyomene can be divided in two groups; group A is represented by P. erectifolius, P. giganteus and P. polycladus, and group B is represented by P. flaccidus. The differentiation is based in both, inflorescence structure and anatomy. Group A presents a life cycle and anatomical features similar to species of Actinocephalus. Molecular trees also point that these two groups are closely related. However, inflorescence morphology and blooming sequence are different. Species of group B present an inflorescence structure and anatomical features shared with many genera and species in Eriocaulaceae. The available molecular and morphology based phylogenies still do not allow a precise allocation of the group in the bulk of basal species of Paepalanthus collocated in P. sect. Variabiles. The characters described and used here supply however important information towards this goal. (C) 2009 Elsevier GmbH. All rights reserved.

The Immune-Pineal Axis Stress as a Modulator of Pineal Gland Function

The temporal organization of mammals presents a daily adjustment to the environmental light/dark cycle. The environmental light detected by the retina adjusts the central clock in the suprachiasmatic nuclei, which innervate the pineal gland through a polysynaptic pathway. During the night, this gland produces and releases the nocturnal hormone melatonin, which circulates throughout the whole body and adjusts several bodily functions according to the existence and duration of darkness. We have previously shown that during the time frame of an inflammatory response, pro-inflammatory cytokines, such as tumor necrosis factor-a, inhibit while anti-inflammatory mediators, such as glucocorticoids, enhance the synthesis of melatonin, interfering in the daily adjustment of the light/dark cycle. Therefore, injury disconnects the organism from environmental cycling, while recovery restores the light/dark information to the whole organism. Here, we extend these observations by evaluating the effect of a mild restraint stress, which did not induce macroscopic gastric lesions. After 2 h of restraint, there was an increase in circulating corticosterone, indicating activation of the hypothalamus-pituitary-adrenal (HPA) axis. In parallel, an increase in melatonin production was observed. Taking into account the data obtained with models of inflammation and stress, we reinforce the hypothesis that the activity of the pineal gland is modulated by the state of the immune system and the HPA axis, implicating the darkness hormone melatonin as a modulator of defense responses.

Chronic supplementation of beta-hydroxy-beta methylbutyrate (HM beta) increases the activity of the GH/IGF-I axis and induces hyperinsulinemia in rats

Objective: Beta-hydroxy-beta-methylbutyrate (HM beta) is a metabolite of leucine widely used for improving sports performance. Although limp is recognized to promote anabolic or anti-catabolic effects on protein metabolism, the impact of its long-term use on skeletal muscle and/or genes that control the skeletal protein balance is not fully known. This study aimed to investigate whether chronic HM beta treatment affects the activity of GH/IGF-I axis and skeletal muscle IGF-I and myostatin mRNA expression. Design: Rats were treated with HK beta (320 mg/kg BW) or vehicle, by gavage, for 4 weeks, and killed by decapitation. Blood was collected for evaluation of serum insulin, glucose and IGF-I concentrations. Samples of pituitary, liver, extensor digitorum longus (EDL) and soleus muscles were collected for total RNA or protein extraction to evaluate the expression of pituitary growth hormone (GH) gene (mRNA and protein), hepatic insulin-like growth factor I (IGF-I) mRNA, skeletal muscle IGF-I and myostatin mRNA by Northern blotting/real time-PCR, or Western blotting. Results: Chronic HM beta treatment increased the content of pituitary GH mRNA and GH, hepatic IGF-I mRNA and serum IGF-I concentration. No changes were detected on skeletal muscle IGF-I and myostatin mRNA expression. However, the HIM-treated rats although normoglycemic, exhibited hyperinsulinemia. Conclusions: The data presented herein extend the body of evidence on the potential role of HM beta-treatment in stimulating GH/IGF-I axis activity. In spite of this effect, HM beta supplementation also induces an apparent insulin resistance state which might limit the beneficial aspects of the former results, at least in rats under normal nutritional status and health conditions. (C) 2010 Growth Hormone Research Society. Published by Elsevier Ltd. All rights reserved.

Toll-like receptor 4 agonists adsorbed to aluminium hydroxide adjuvant attenuate ovalbumin-specific allergic airway disease: role of MyD88 adaptor molecule and interleukin-12/interferon-gamma axis

Background Epidemiological and experimental data suggest that bacteria] lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. Lipopolysaccharides trigger immune responses through toll-like receptor 4 (TLR4) that in turn activates two major signalling pathways via either MyD88 or TRIF adaptor proteins. The LPS is a pro-Type 1 T helper cells (Th 1) adjuvant while aluminium hydroxide (alum) is a strong Type 2 T helper cells (Th2) adjuvant, but the effect of the mixing of both adjuvants on the development of lung allergy has not been investigated. Objective We determined whether natural (LPS) or synthetic (ER-803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS-induced molecular pathways, we used TLR4-, MyD88-, TRIF-, or IL-12/IFN-gamma-deficient mice. Methods Mice were sensitized with subcutaneous injections of ovalbumin (OVA) with or without TLR4 agonists co-adsorbed onto alum and challenged with intranasally with OVA. The development of allergic lung disease was evaluated 24 h after last OVA challenge. Results Sensitization with OVA plus LPS co-adsorbed onto alum impaired in dose-dependent manner OVA-induced Th2-mediated allergic responses such as airway eosinophilia, type-2 cytokines secretion, airway hyper-reactivity, mucus hyper production and serum levels of IgE or IgG1 anaphylactic antibodies. Although the levels of IgG2a, Th1 -affiliated isotype increased, investigation into the lung-specific effects revealed that LPS did not induce a Th1 pattern of inflammation. Lipopolysaccharides impaired the development of Th2 immunity, signaling via TLR4 and MyD88 molecules and via the IL-12/IFN-gamma axis, but not through TRIF pathway. Moreover, the synthetic TLR4 agonists that proved to have a less systemic inflammatory response than LPS also protected against allergic asthma development. Conclusion Toll-like receptor 4 agonists co-adsorbed with allergen onto alum down-modulate allergic lung disease and prevent the development of polarized T cell-mediated airway inflammation.