The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition:a fMRI study

The functional catechol-O-methyltransferase (COMT Val108/158Met) polymorphism has been shown to have an impact on tasks of executive function, memory and attention and recently, tasks with an affective component. As oestrogen reduces COMT activity, we focused on the interaction between gender and COMT genotype on brain activations during an affective processing task. We used functional MRI (fMRI) to record brain activations from 74 healthy subjects who engaged in a facial affect recognition task; subjects viewed and identified fearful compared to neutral faces. There was no main effect of the COMT polymorphism, gender or genotypegender interaction on task performance. We found a significant effect of gender on brain activations in the left amygdala and right temporal pole, where females demonstrated increased activations over males. Within these regions, Val/Val carriers showed greater signal magnitude compared to Met/Met carriers, particularly in females. The COMT Val108/158Met polymorphism impacts on gender-related patterns of activation in limbic and paralimbic regions but the functional significance of any oestrogen-related COMT inhibition appears modest. Copyright © 2008 CINP.

Synthesis and evaluation of nanoparticle-polymer composites

This thesis describes the synthesis of functionalised polymeric material by variety of free-radical mediated polymerisation techniques including dispersion emulsion, seeded emulsion, suspension and bulk polymerisation reactions. Organic fluorophores and nanoparticles such as quantum dots were incorporated within polymeric materials, in particular, thiol-functionalised polymer microspheres, which were fluorescently labelled either during synthesis or by covalent attachment post synthesis. The resultant fluorescent polymeric conjugates were then assessed for their utility in biological systems as an analytical tool for cells or biological structures. Quantum dot labelled, thiol-functionalised microspheres were assessed for their utility in the visualisation and tracking of red blood cells. Determination of the possible internalisation of fluorescent microspheres into red blood cells was required before successful tracking of red blood cells could take place. Initial work appeared to indicate the presence of fluorescent microspheres inside red blood cells by the process of beadfection. A range of parameters were also investigated in order to optimise beadfection. Thiol-functionalised microspheres labelled successfully with organic fluorophores were used to image the tear film of the eye. A description of problems encountered with the covalent attachment of hydrophilic, thiol-reactive fluorescent dyes to a variety of modified polymer microspheres is also included in this section. Results indicated large microspheres were particularly useful when tracking the movement of fluid along the tear meniscus. Functional bulk polymers were synthesised for assessment of their interaction with titanium dioxide nanoparticles. Thiol-functionalised polymethyl methacrylate and spincoated thiouronium-functionalised polystyrene appeared to facilitate the attachment of titanium dioxide nanoparticles. Interaction assays included the use of XPS analysis and processes such as centrifugation. Attempts to synthesise 4-vinyl catechol, a compound containing hydroxyl moieties with potential for coordination with titanium dioxide nanoparticles, were also carried out using 3,4-dihydroxybenzaldehyde as the starting material.

4-hydroxy estradiol-induced oxidant-mediated signaling is involved in the development of breast cancer

Breast cancer is a disease associated with excess exposures to estrogens. While the mode of cancer causation is unknown, others have shown that oxidative stress induced by prolonged exposure to estrogens mediates renal, liver, endometrial and mammary tumorigenesis though the mechanism(s) underling this process is unknown. In this study, we show that 4-hydroxyl 17β-estradiol (4-OHE2), a catechol metabolite of estrogen, induces mammary tumorigenesis in a redox dependent manner. We found that the mechanism of tumorigenesis involves redox activations of nuclear respiratory factor-1 (NRF1); a transcriptions factor associated with regulation of mitochondria biogenesis and oxidative phosphorylation (OXPHOS), as well as mediation of cell survival and growth of cells during periods of oxidative stress. Key findings from our study are as follows: (i) Prolonged treatments of normal mammary epithelial cells with 4-OHE2, increased the formation of intracellular reactive oxygen species (ROS). (ii) Estrogen-induced ROS activates redox sensitive transcription factors NRF1. (iii) 4-OHE2 through activation of serine-threonine kinase and histone acetyl transferase, phosphorylates and acetylate NRF1 respectively. (iv) Redox mediated epigenetic modifications of NRF1 facilitates mammary tumorigenesis and invasive phenotypes of breast cancer cells via modulations of genes involved in proliferation, growth and metastasis of exposed cells. (v) Animal engraftment of transformed clones formed invasive tumors. (vi) Treatment of cells or tumors with biological or chemical antioxidants, as well as silencing of NRF1 expressions, prevented 4-OHE2 induced mammary tumorigenesis and invasive phenotypes of MCF-10A cells. Based on these observations, we hypothesize that 4-OHE2 induced ROS epigenetically activate NRF1 through its phosphorylation and acylation. This, in turn, through NRF1-mediated transcriptional activation of the cell cycle genes, controls 4-OHE2 induced cell transformation and tumorigenesis.^

Reactive Oxygen Species via Redox Signaling to PI3K/AKT Pathway Contribute to the Malignant Growth of 4-Hydroxy Estradiol-Transformed Mammary Epithelial Cells

The purpose of this study was to investigate the effects of 17-β-estradiol (E2)-induced reactive oxygen species (ROS) on the induction of mammary tumorigenesis. We found that ROS-induced by repeated exposures to 4-hydroxy-estradiol (4-OH-E2), a predominant catechol metabolite of E2, caused transformation of normal human mammary epithelial MCF-10A cells with malignant growth in nude mice. This was evident from inhibition of estrogen-induced breast tumor formation in the xenograft model by both overexpression of catalase as well as by co-treatment with Ebselen. To understand how 4-OH-E2 induces this malignant phenotype through ROS, we investigated the effects of 4-OH-E2 on redox-sensitive signal transduction pathways. During the malignant transformation process we observed that 4-OH-E2 treatment increased AKT phosphorylation through PI3K activation. The PI3K-mediated phosphorylation of AKT in 4-OH-E2-treated cells was inhibited by ROS modifiers as well as by silencing of AKT expression. RNA interference of AKT markedly inhibited 4-OH-E2-induced in vitro tumor formation. The expression of cell cycle genes, cdc2, PRC1 and PCNA and one of transcription factors that control the expression of these genes – nuclear respiratory factor-1 (NRF-1) was significantly up-regulated during the 4-OH-E2-mediated malignant transformation process. The increased expression of these genes was inhibited by ROS modifiers as well as by silencing of AKT expression. These results indicate that 4-OH-E2-induced cell transformation may be mediated, in part, through redox-sensitive AKT signal transduction pathways by up-regulating the expression of cell cycle genes cdc2, PRC1 and PCNA, and the transcription factor – NRF-1. In summary, our study has demonstrated that: (i) 4-OH-E2 is one of the main estrogen metabolites that induce mammary tumorigenesis and (ii) ROS-mediated signaling leading to the activation of PI3K/AKT pathway plays an important role in the generation of 4-OH-E2-induced malignant phenotype of breast epithelial cells. In conclusion, ROS are important signaling molecules in the development of estrogen-induced malignant breast lesions.

Degradação fotocatalítica oxidativa do fenol utilizando carvão obtido da pirólise de diferentes biomassas

The modern industrial progress has been contaminating water with phenolic compounds. These are toxic and carcinogenic substances and it is essential to reduce its concentration in water to a tolerable one, determined by CONAMA, in order to protect the living organisms. In this context, this work focuses on the treatment and characterization of catalysts derived from the bio-coal, by-product of biomass pyrolysis (avelós and wood dust) as well as its evaluation in the phenol photocatalytic degradation reaction. Assays were carried out in a slurry bed reactor, which enables instantaneous measurements of temperature, pH and dissolved oxygen. The experiments were performed in the following operating conditions: temperature of 50 °C, oxygen flow equals to 410 mL min-1 , volume of reagent solution equals to 3.2 L, 400 W UV lamp, at 1 atm pressure, with a 2 hours run. The parameters evaluated were the pH (3.0, 6.9 and 10.7), initial concentration of commercial phenol (250, 500 and 1000 ppm), catalyst concentration (0, 1, 2, and 3 g L-1 ), nature of the catalyst (activated avelós carbon washed with dichloromethane, CAADCM, and CMADCM, activated dust wood carbon washed with dichloromethane). The results of XRF, XRD and BET confirmed the presence of iron and potassium in satisfactory amounts to the CAADCM catalyst and on a reduced amount to CMADCM catalyst, and also the surface area increase of the materials after a chemical and physical activation. The phenol degradation curves indicate that pH has a significant effect on the phenol conversion, showing better results for lowers pH. The optimum concentration of catalyst is observed equals to 1 g L-1 , and the increase of the initial phenol concentration exerts a negative influence in the reaction execution. It was also observed positive effect of the presence of iron and potassium in the catalyst structure: betters conversions were observed for tests conducted with the catalyst CAADCM compared to CMADCM catalyst under the same conditions. The higher conversion was achieved for the test carried out at acid pH (3.0) with an initial concentration of phenol at 250 ppm catalyst in the presence of CAADCM at 1 g L-1 . The liquid samples taken every 15 minutes were analyzed by liquid chromatography identifying and quantifying hydroquinone, p-benzoquinone, catechol and maleic acid. Finally, a reaction mechanism is proposed, cogitating the phenol is transformed into the homogeneous phase and the others react on the catalyst surface. Applying the model of Langmuir-Hinshelwood along with a mass balance it was obtained a system of differential equations that were solved using the Runge-Kutta 4th order method associated with a optimization routine called SWARM (particle swarm) aiming to minimize the least square objective function for obtaining the kinetic and adsorption parameters. Related to the kinetic rate constant, it was obtained a magnitude of 10-3 for the phenol degradation, 10-4 to 10-2 for forming the acids, 10-6 to 10-9 for the mineralization of quinones (hydroquinone, p-benzoquinone and catechol), 10-3 to 10-2 for the mineralization of acids.

Avaliação do desempenho da paligorsquita modificada e do carvão da pirólise do lodo de esgoto no processo de degradação fotocatalítica do fenol

The uncontrolled disposal of wastewaters containing phenolic compounds by the industry has caused irreversible damage to the environment. Because of this, it is now mandatory to develop new methods to treat these effluents before they are disposed of. One of the most promising and low cost approaches is the degradation of phenolic compounds via photocatalysis. This work, in particular, has as the main goal, the customization of a bench scale photoreactor and the preparation of catalysts via utilization of char originated from the fast pyrolysis of sewage sludge. The experiments were carried out at constant temperature (50°C) under oxygen (410, 515, 650 and 750 ml min-1). The reaction took place in the liquid phase (3.4 liters), where the catalyst concentration was 1g L-1 and the initial concentration of phenol was 500 mg L-1 and the reaction time was set to 3 hours. A 400 W lamp was adapted to the reactor. The flow of oxygen was optimized to 650 ml min-1. The pH of the liquid and the nature of the catalyst (acidified and calcined palygorskite, palygorskite impregnated with 3.8% Fe and the pyrolysis char) were investigated. The catalytic materials were characterized by XRD, XRF, and BET. In the process of photocatalytic degradation of phenol, the results showed that the pH has a significant influence on the phenol conversion, with best results for pH equal to 5.5. The phenol conversion ranged from 51.78% for the char sewage sludge to 58.02% (for palygorskite acidified calcined). Liquid samples analyzed by liquid chromatography and the following compounds were identified: hydroquinone, catechol and maleic acid. A mechanism of the reaction was proposed, whereas the phenol is transformed into the homogeneous phase and the others react on the catalyst surface. For the latter, the Langmuir-Hinshelwood model was applied, whose mass balances led to a system of differential equations and these were solved using numerical methods in order to get estimates for the kinetic and adsorption parameters. The model was adjusted satisfactorily to the experimental results. From the proposed mechanism and the operating conditions used in this study, the most favored step, regardless of the catalyst, was the acid group (originated from quinone compounds), being transformed into CO2 and water, whose rate constant k4 presented value of 0.578 mol L-1 min-1 for acidified calcined palygorskite, 0.472 mol L-1 min-1 for Fe2O3/palygorskite and 1.276 mol L-1 min-1 for the sludge to char, the latter being the best catalyst for mineralization of acid to CO2 and water. The quinones were adsorbed to the acidic sites of the calcined palygorskite and Fe2O3/palygorskite whose adsorption constants were similar (~ 4.45 L mol-1) and higher than that of the sewage sludge char (3.77 L mol-1).

Avaliação do desempenho da paligorsquita modificada e do carvão da pirólise do lodo de esgoto no processo de degradação fotocatalítica do fenol

The uncontrolled disposal of wastewaters containing phenolic compounds by the industry has caused irreversible damage to the environment. Because of this, it is now mandatory to develop new methods to treat these effluents before they are disposed of. One of the most promising and low cost approaches is the degradation of phenolic compounds via photocatalysis. This work, in particular, has as the main goal, the customization of a bench scale photoreactor and the preparation of catalysts via utilization of char originated from the fast pyrolysis of sewage sludge. The experiments were carried out at constant temperature (50°C) under oxygen (410, 515, 650 and 750 ml min-1). The reaction took place in the liquid phase (3.4 liters), where the catalyst concentration was 1g L-1 and the initial concentration of phenol was 500 mg L-1 and the reaction time was set to 3 hours. A 400 W lamp was adapted to the reactor. The flow of oxygen was optimized to 650 ml min-1. The pH of the liquid and the nature of the catalyst (acidified and calcined palygorskite, palygorskite impregnated with 3.8% Fe and the pyrolysis char) were investigated. The catalytic materials were characterized by XRD, XRF, and BET. In the process of photocatalytic degradation of phenol, the results showed that the pH has a significant influence on the phenol conversion, with best results for pH equal to 5.5. The phenol conversion ranged from 51.78% for the char sewage sludge to 58.02% (for palygorskite acidified calcined). Liquid samples analyzed by liquid chromatography and the following compounds were identified: hydroquinone, catechol and maleic acid. A mechanism of the reaction was proposed, whereas the phenol is transformed into the homogeneous phase and the others react on the catalyst surface. For the latter, the Langmuir-Hinshelwood model was applied, whose mass balances led to a system of differential equations and these were solved using numerical methods in order to get estimates for the kinetic and adsorption parameters. The model was adjusted satisfactorily to the experimental results. From the proposed mechanism and the operating conditions used in this study, the most favored step, regardless of the catalyst, was the acid group (originated from quinone compounds), being transformed into CO2 and water, whose rate constant k4 presented value of 0.578 mol L-1 min-1 for acidified calcined palygorskite, 0.472 mol L-1 min-1 for Fe2O3/palygorskite and 1.276 mol L-1 min-1 for the sludge to char, the latter being the best catalyst for mineralization of acid to CO2 and water. The quinones were adsorbed to the acidic sites of the calcined palygorskite and Fe2O3/palygorskite whose adsorption constants were similar (~ 4.45 L mol-1) and higher than that of the sewage sludge char (3.77 L mol-1).

Individual Differences in the Neural Response to Personal Goal Pursuit Success and Failure: A Developmental Analysis

Regulatory focus theory (RFT) proposes two different social-cognitive motivational systems for goal pursuit: a promotion system, which is organized around strategic approach behaviors and "making good things happen," and a prevention system, which is organized around strategic avoidance and "keeping bad things from happening." The promotion and prevention systems have been extensively studied in behavioral paradigms, and RFT posits that prolonged perceived failure to make progress in pursuing promotion or prevention goals can lead to ineffective goal pursuit and chronic distress (Higgins, 1997).

Research has begun to focus on uncovering the neural correlates of the promotion and prevention systems in an attempt to differentiate them at the neurobiological level. Preliminary research suggests that the promotion and prevention systems have both distinct and overlapping neural correlates (Eddington, Dolcos, Cabeza, Krishnan, & Strauman, 2007; Strauman et al., 2013). However, little research has examined how individual differences in regulatory focus develop and manifest. The development of individual differences in regulatory focus is particularly salient during adolescence, a crucial topic to explore given the dramatic neurodevelopmental and psychosocial changes that take place during this time, especially with regard to self-regulatory abilities. A number of questions remain unexplored, including the potential for goal-related neural activation to be modulated by (a) perceived proximity to goal attainment, (b) individual differences in regulatory orientation, specifically general beliefs about one's success or failure in attaining the two kinds of goals, (c) age, with a particular focus on adolescence, and (d) homozygosity for the Met allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism, a naturally occurring genotype which has been shown to impact prefrontal cortex activation patterns associated with goal pursuit behaviors.

This study explored the neural correlates of the promotion and prevention systems through the use of a priming paradigm involving rapid, brief, masked presentation of individually selected promotion and prevention goals to each participant while being scanned. The goals used as priming stimuli varied with regard to whether participants reported that they were close to or far away from achieving them (i.e. a "match" versus a "mismatch" representing perceived success or failure in personal goal pursuit). The study also assessed participants' overall beliefs regarding their relative success or failure in attaining promotion and prevention goals, and all participants were genotyped for the COMT Val158Met polymorphism.

A number of significant findings emerged. Both promotion and prevention priming were associated with activation in regions associated with self-referential cognition, including the left medial prefrontal cortex, cuneus, and lingual gyrus. Promotion and prevention priming were also associated with distinct patterns of neural activation; specifically, left middle temporal gyrus activation was found to be significantly greater during prevention priming. Activation in response to promotion and prevention goals was found to be modulated by self-reports of both perceived proximity to goal achievement and goal orientation. Age also had a significant effect on activation, such that activation in response to goal priming became more robust in the prefrontal cortex and in default mode network regions as a function of increasing age. Finally, COMT genotype also modulated the neural response to goal priming both alone and through interactions with regulatory focus and age. Overall, these findings provide further clarification of the neural underpinnings of the promotion and prevention systems as well as provide information about the role of development and individual differences at the personality and genetic level on activity in these neural systems.

Studio della reattività del glicerol carbonato nella sintesi di derivati fenolici

Supported by the increasing sustainable awareness, glycerol carbonate has gained much interest over the last 20 years because of its versatile reactivity and as a way to valorize waste glycerol. Numerous synthesis pathways for this molecule were identified, some of them very promising and on the verge of being applied at an industrial scale. Here, we report a study aimed at valorizing glycerol carbonate as chemical intermediate, in order to synthesize 2-hydroxymethyl-1,4-benzodioxane (HMB). This molecule finds important applications as key intermediate for the synthesis of a broad class of pharmaceuticals and therapeutic agents. Concerning the presence of a stereogenic center on the hydroxymethyl group, due to the pharmaceutical importance to obtain and isolate one single enantiomer, , nowadays HMB is obtained through batch scale process, using a multi-reaction approach and starting from reagents of the chiral pool. We carried out the reaction from a solution of glycerol carbonate and catechol 2:1. In the presence of a simple basic catalyst, at high temperatures, it was possible obtain total reactants conversion and high yield to HMB in few hours reaction time. Also, in the aim of developing a process which might adhere the principles of Green Chemistry, we avoided the use of solvents. Similar results were obtained using a 1:1 feed ratio of reactants, even if selectivity to HMB decrease, due to the presence of side reactions. A complete study of the reaction mechanism is proposed in this thesis.