Invasão da Tilápia-do-Nilo no Estado do Amapá: uma ameaça aos peixes nativos da Bacia Igarapé Fortaleza.

2016

Manejo de açaizais de grotas.

2015

Neuroprotective and immunomodulatory properties of the new PPARγ agonist MDG548: an in vitro and in vivo study in PD models

Neuroinflammation is a key component of Parkinson’s disease (PD) neuropathology. Skewed microglia activation with pro-inflammatory prevailing over anti-inflammatory phenotypes may contribute to neurotoxicity via the production of cytokines and neurotoxic species. Therefore, microglia polarization has been proposed as a target for neuroprotection. The peroxisome proliferator-activated receptor gamma (PPARγ) is expressed in microglia and peripheral immune cells, where it is involved in macrophages polarization and in the control of inflammatory responses, by modulating gene transcription. Several studies have shown that PPARγ agonists are neuroprotective in experimental PD models in rodents and primates. however safety concerns have been raised about PPARγ agonists thiazolidinediones (TZD) currently available, prompting for the development of non-TZD compounds. Aim of this study was to characterize a novel PPARγ agonist non TZD, MDG548, for its potential neuroprotective effect in PD models and its immunomodulatory activity as the underlying mechanism of neuroprotection. The neuroprotective activity of MDG548 was assessed in vivo in the subacute MPTP model and in the chronic MPTP/probenecid (MPTPp) model of PD. MDG548 activity on microglia activation and phenotype was investigated in the substantia nigra pars compacta (SNc) via the evaluation of pro- (TNF-α and iNOS) and anti-inflammatory (CD206) molecules, with fluorescent immunohistochemistry. Moreover, cultured murine microglia MMGT12 were treated with MDG548 in association with the inflammagen LPS, pro- and anti-inflammatory molecules were measured in the medium by ELISA assay and phagocytosis was evaluated by fluorescent immunohistochemistry for CD68. MDG548 arrested dopaminergic cells degeneration in the SNc in both the subacute MPTP and the chronic MPTPp models of PD, and reverted MPTPp-induced motor impairment. Moreover, MDG548 reduced microglia activation, iNOS and TNF-α production, while induced CD206 in microglia. In cultured unstimulated microglia, LPS increased TNF-α production and CD68 expression, while decreased CD206 expression. MDG548 reverted LPS effect on TNF-α and CD206 restoring physiological levels, while strongly increased CD68 expression. Results suggest that the PPARγ agonist MDG548 is neuroprotective in experimental models of PD. MDG548 targets microglia polarization by correcting the imbalance between pro- over antiinflammatory molecules, offering a novel immunomodulatory approach to neuroprotection.

Influence of different neuroprotective drugs on dopamine neurotoxicity induced by 3,4-methylenedioxymethamphetamine and MPTP in mice

Introduction: Parkinson‟s disease (PD) is characterized by a chronic progressive loss of nigrostriatal dopaminergic neurons that is associated with chronic neuroinflammation. Current treatments for PD can significantly improve symptoms but do not cure the disease or slow its progression. An approach used in existing therapies is based on the inhibition of monoamine oxidase (MAO), enzyme involved in the metabolic degradation of dopamine. Although, preclinical studies showed that MAO-B inhibitors have neuroprotective activity in cellular and animal models of PD, clinical trials did not completely confirm this result. Therefore a large number of new molecules, with more potent MAO-B inhibitory activity and a possible neuroprotective effect, have been proposed to replace the pre-existing MAO-B inhibitors. The profile of the recent MAO inhibitor, SZV558, appears to be particularly interesting because of its pharmacodynamic, favorable for disease-modifying properties and its irreversible MAO-B enzyme bind. The enhancement of adult neurogenesis could be of great clinical interest in the management of neurodegenerative disorders. In line with this, the metformin, a well-known antidiabetic drug, has recently been proposed to promote neurogenesis and to have a neuroprotective effect on the neurodegenerative processes induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in a mice PD model. Although, PD has multiple origins, one hypothesis is that amphetamine-related drugs may be part of the wide array of factors leading to the dopaminergic neuron degeneration that causes the disease. These hypothesis are supported by different results that showed a persistent, long-term dopaminergic toxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in mice. Moreover, the MDMA, altering the dopaminergic transmission, may affect neurogenesis and synaptogenesis. On these basis, considering that the young brain is particularly sensitive to drug-induced neurotoxicity, the consumption of MDMA during the adolescence might increase the vulnerability of dopaminergic neurons. However, the use of amphetamine-related drugs by adolescent and young people is often combined with caffeinated energy drinks in order to amplify their stimulant actions. Although caffeine use is safe, the combined treatment of caffeine and MDMA increases not only the DA release but also the microglia and astroglia activation. Aims: During my Ph.D. I studied the influence of neuroprotective drugs, such as MAO inhibitors and metformin, or substances, such as caffeine, on the neurodegenerative effects of two dopaminergic toxins, MDMA and MPTP, in mice. 1. In the first phase of my study, I evaluated the neuroprotective activity of the new MAO-B inhibitor SZV558, compared with well-known rasagiline, in a chronic mouse model of MPTP plus probenecid (MPTPp), which induces a progressive loss of nigrostriatal dopaminergic neurons. 2. Previous results showed that when MDMA is associated with caffeine, a more pronounced degeneration in adolescent compared with adult mice was observed. To better clarify the molecular mechanism at the base of the different neurotoxic effect of this drug association at different ages, I evaluated the neuronal nitric oxide synthase (nNOS) expression, which plays a critical role in the integration of dopaminergic and glutamatergic transmissions, in the CPu of adolescent or adult mice treated with MDMA, alone or in combination with caffeine. 3. Finally, I investigated the neuroprotective effect of metformin against dopaminergic neurotoxicity induced by MDMA in the CPu and SNc of adult mice. Conclusions: These results demonstrated that the dopaminergic neurodegenerative process may be induced or conditioned by environment stressors or substances which influence, through different ways, the development of neurodegenerative mechanisms. In the present study I evaluated the effects of 3 substances, known as potentially neuroprotective, in combination with two different neurotoxins that affect the nigrostriatal dopaminergic system. The SZV558 MAO-B inhibitor and the metformin protected the nigrostriatal pathway, usually affected in PD, by MPTP- and MDMA- induced neurotoxicity, respectively. On the other hand, caffeine, administrated with MDMA, showed a neurotoxic potential depending on the age of consumers, confirming the vulnerability of adolescent brain to consumption of drug and substances that affected the dopaminergic system. In conclusion, the study of neurodegenerative processes may be relevant to understand the human pharmacology, the origin and development of neurodegenerative disease and to predict the neurotoxic effect of drug abuse.

Topological changes in a two-dimensional foam cluster

Cox, S.J., Vaz, M.F. and Weaire, D. (2003) Topological changes in a two-dimensional foam cluster. The European Physical Journal E - Soft Matter . 11:29-35.

Metallic foam processing from the liquid state

Cox, S.J., Bradley, G. and Weaire, D. (2001) Metallic foam processing from the liquid state: the competition between solidification and drainage. Eur. Phys. J. AP 14:87-97. Sponsorship: This research was supported by the Prodex programme of ESA, and is a contribution to ESA contract C14308/AO-075-99. SJC was supported by Enterprise Ireland and a Marie Curie fellowship. GB was supported by the HPC Programme of TCD.

The role of payout ratio in the relationship between stock returns and dividend yield

ap Gwilym, Owain, McManus, Ian, and Thomas, Stephen, 'The role of payout ratio in the relationship between stock returns and dividend yield', Journal of Business Finance & Accounting (2004) 31(9-10) pp.1355-1387 RAE2008

Fractional versus decimal pricing: Evidence from the UK Long Gilt futures market

ap Gwilym, Owain, McManus, Ian, and Thomas, Stephen, 'Fractional versus decimal pricing: Evidence from the UK Long Gilt futures market', Journal of Futures Markets (2005) 25(5) pp.419-442 RAE2008

Does the Fed Model travel well?

ap Gwilym, Owain, et al., 'Does the Fed Model travel well?', Journal of Portfolio Management (2006) 33(1) pp.68-75 RAE2008

International evidence on the payout ratio, earnings, dividends and returns

ap Gwilym, Owain, et al., 'International evidence on the payout ratio, earnings, dividends and returns', Financial Analysts Journal (2006) 62(1) pp.36-53 RAE2008

Sy abl fodd Sibli fain: Sibyl in Medieval Wales

Haycock, Marged, 'Sy abl fodd Sibli fain: Sibyl in Medieval Wales', In: Heroic Poets and Poetic Heroes in Celtic Tradition, Joseph Falaky Nagy and Leslie Ellen Jones (eds), (Dublin: Four Courts Press), pp.115-130, 2005 RAE2008

The rheology of collapsing zeolites amorphized by temperature and pressure

Greaves, G.; Meneau, F.; ap Gwynn, I.A.; Wade, S., (2003). The rheology of collapsing zeolites amorphized by temperature and pressure. Nature Materials 2, 622-629. RAE2008

A Local Circuit Model of Learned Straitial and Dopamine Cell Responses under Probabilistic Schedules of Reward

Before choosing, it helps to know both the expected value signaled by a predictive cue and the associated uncertainty that the reward will be forthcoming. Recently, Fiorillo et al. (2003) found the dopamine (DA) neurons of the SNc exhibit sustained responses related to the uncertainty that a cure will be followed by reward, in addition to phasic responses related to reward prediction errors (RPEs). This suggests that cue-dependent anticipations of the timing, magnitude, and uncertainty of rewards are learned and reflected in components of the DA signals broadcast by SNc neurons. What is the minimal local circuit model that can explain such multifaceted reward-related learning? A new computational model shows how learned uncertainty responses emerge robustly on single trial along with phasic RPE responses, such that both types of DA responses exhibit the empirically observed dependence on conditional probability, expected value of reward, and time since onset of the reward-predicting cue. The model includes three major pathways for computing: immediate expected values of cures, timed predictions of reward magnitudes (and RPEs), and the uncertainty associated with these predictions. The first two model pathways refine those previously modeled by Brown et al. (1999). A third, newly modeled, pathway is formed by medium spiny projection neurons (MSPNs) of the matrix compartment of the striatum, whose axons co-release GABA and a neuropeptide, substance P, both at synapses with GABAergic neurons in the SNr and with the dendrites (in SNr) of DA neurons whose somas are in ventral SNc. Co-release enables efficient computation of sustained DA uncertainty responses that are a non-monotonic function of the conditonal probability that a reward will follow the cue. The new model's incorporation of a striatal microcircuit allowed it to reveals that variability in striatal cholinergic transmission can explain observed difference, between monkeys, in the amplitutude of the non-monotonic uncertainty function. Involvement of matriceal MSPNs and striatal cholinergic transmission implpies a relation between uncertainty in the cue-reward contigency and action-selection functions of the basal ganglia. The model synthesizes anatomical, electrophysiological and behavioral data regarding the midbrain DA system in a novel way, by relating the ability to compute uncertainty, in parallel with other aspects of reward contingencies, to the unique distribution of SP inputs in ventral SN.

Characterisation and application of fruit by-products as novel ingredients in gluten-free products

The physicochemical and nutritional properties of two fruit by-products were initially studied. Apple pomace (AP) contained a high level of fibre and pectin. The isolated AP pectin had a high level of methylation which developed viscous pastes. Orange pomace also had high levels of fibre and pectin, and it was an abundant source of minerals such as potassium and magnesium. Due to the fibrous properties of orange pomace flour, proofing and water addition were studied in a bread formulation. When added at levels greater than 6%, the loaf volume decreased. An optimised formulation and proofing time was derived using the optimisation tool; these consisted of 5.5% orange pomace, 94.6% water inclusion and with 49 minutes proofing. These optimised parameters doubled the total dietary fibre content of the bread compared to the original control. Pasting results showed how orange pomace inclusions reduced the final viscosity of the batter, reducing the occurrence of starch gelatinisation. Rheological properties i.e. the storage modulus (G') and complex modulus (G*) increased in the orange pomace batter compared to the control batter. This demonstrates how the orange pomace as an ingredient improved the robustness of the formulation. Sensory panellists scored the orange pomace bread comparably to the control bread. Milled apple pomace was studied as a potential novel ingredient in an extruded snack. Parameters studied included apple pomace addition, die head temperature and screw speed. As screw speed increased the favourable extrudate characteristics such as radical expansion ratio, porosity and specific volume decreased. The inclusion of apple pomace had a negative effect on extrudate characteristics at levels greater than 8% addition. Including apple pomace reduced the hardness and increased the crispiness of the snack. The optimised and validated formulation and extrusion process contained the following parameters: 7.7% apple pomace, 150°C die head temperature and a screw speed of 69 rpm.

Investigating the role of Fas (CD95) signalling in the modification of innate immune induced inflammation

Background/Aim: It has been demonstrated that a number of pathologies occur as a result of dysregulation of the immune system. Whilst classically associated with apoptosis, the Fas (CD95) signalling pathway plays a role in inflammation. Studies have demonstrated that Fas activation augments TLR4-mediated MyD88-dependent cytokine production. Studies have also shown that the Fas adapter protein FADD is required for RIG-I-induced IFNβ production. As a similar signalling pathway exists between RIG-I, TLR3 and the MyD88- independent of TLR4, we hypothesised that Fas activation may modulate both TLR3- and TLR4-induced cytokine production. Results: Fas activation reduced poly I:C-induced IFNβ, IL-8, IL-10 and TNFα production whilst augmenting poly I:C-, poly A:U- and Sendai virus-induced IP-10 production. TLR3-, RIG-I- and MDA5-induced IP-10 luciferase activation were inhibited by the Fas adapter protein FADD using overexpression studies. Poly I:C-induced phosphorylation of p-38 and JNK MAPK were reduced by Fas activation. Overexpression of FADD induced AP-1 luciferase activation. Point mutations in the AP-1 binding site enhanced poly I:C-induced IP- 10 production. LPS-induced IL-10, IL-12, IL-8 and TNFα production were enhanced by Fas activation, whilst reducing LPS-induced IFNβ production. Absence of FADD using FADD-/- MEFs resulted in impaired IFNβ production. Overexpression studies using FADD augmented TLR4-, MyD88- and TRIF-induced IFNβ luciferase activation. Overexpression studies also suggested that enhanced TLR4-induced IFNβ production was independent of NFκB activation. Conclusion: Viral-induced IP-10 production is augmented by Fas activation by reducing the phosphorylation of p-38 and JNK MAPKs, modulating AP-1 activation. The Fas adapterprotein FADD is required for TLR4-induced IFNβ production. Studies presented here demonstrate that the Fas signalling pathway can therefore modulate the immune response. Our data demonstrates that this modulatory effect is mediated by its adapter protein FADD, tailoring the immune response by acting as a molecular switch. This ensures the appropriate immune response is mounted, thus preventing an exacerbated immune response.