On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors

The ligand binding domain (LBD) of nuclear hormone receptors adopts a very compact, mostly alpha-helical structure that binds specific ligands with very high affinity. We use circular dichroism spectroscopy and high-temperature molecular dynamics Simulations to investigate unfolding of the LBDs of thyroid hormone receptors (TRs). A molecular description of the denaturation mechanisms is obtained by molecular dynamics Simulations of the TR alpha and TR beta LBDs in the absence and in the presence of the natural ligand Triac. The Simulations Show that the thermal unfolding of the LBD starts with the loss of native contacts and secondary Structure elements, while the Structure remains essentially compact, resembling a molten globule state. This differs From most protein denaturation simulations reported to date and suggests that the folding mechanism may start with the hydrophobic collapse of the TR LBDs. Our results reveal that the stabilities of the LBDs of the TR alpha and TR beta Subtypes are affected to different degrees by the binding of the isoform selective ligand Triac and that ligand binding confers protection against thermal denaturation and unfolding in a subtype specific manner. Our Simulations indicate two mechanisms by which the ligand stabilizes the LBD: (1) by enhancing the interactions between H8 and H 11, and the interaction of the region between H I and the Omega-loop with the core of the LBD, and (2) by shielding the hydrophobic H6 from hydration.

Two- and three-dimensional shape fabric analysis by the intercept method in grey levels

The count intercept is a robust method for the numerical analysis of fabrics Launeau and Robin (1996). It counts the number of intersections between a set of parallel scan lines and a mineral phase, which must be identified on a digital image. However, the method is only sensitive to boundaries and therefore supposes the user has some knowledge about their significance. The aim of this paper is to show that a proper grey level detection of boundaries along scan lines is sufficient to calculate the two-dimensional anisotropy of grain or crystal distributions without any particular image processing. Populations of grains and crystals usually display elliptical anisotropies in rocks. When confirmed by the intercept analysis, a combination of a minimum of 3 mean length intercept roses, taken on 3 more or less perpendicular sections, allows the calculation of 3-dimensional ellipsoids and the determination of their standard deviation with direction and intensity in 3 dimensions as well. The feasibility of this quick method is attested by numerous examples on theoretical objects deformed by active and passive deformation, on BSE images of synthetic magma flow, on drawing or direct analysis of thin section pictures of sandstones and on digital images of granites directly taken and measured in the field. (C) 2010 Elsevier B.V. All rights reserved.

Co/Mg/Al hydrotalcite-type precursor, promoted with La and Ce, studied by XPS and applied to methane steam reforming reactions

Catalysts` precursor of Co/Mg/Al promoted with Ce and La were tested in the steam reforming of methane (SRM). The addition of promoters was made by anion-exchange. The oxides characterization was made by X-ray Photoelectron Spectroscopy (XPS) analysis that confirmed Co(2+) species in free form on surface and interacted with Mg and Al in the form of solid solution. In the SRM with high fed molar ratio of H(2)O:CH(4) = 4:1, the catalysts showed a great affinity with water and immediately deactivated by oxidation of the active sites. In the stoichiometric ratio of H(2)O:CH(4) = 2: 1 the catalysts were active and presented low carbon deposition during the time reaction tested. Also a test with low fed molar ratio H(2)O:CH(4) = 0.5:1 was carried out to evaluate the stability of the catalysts by CH(4) decomposition and all the catalysts were stable during 6 h of reaction. Promoted catalysts presented lower carbon deposition. (C) 2009 Elsevier B. V. All rights reserved.

Integration of Ligand- and Target-Based Virtual Screening for the Discovery of Cruzain Inhibitors

A myriad of methods are available for virtual screening of small organic compound databases. In this study we have successfully applied a quantitative model of consensus measurements, using a combination of 3D similarity searches (ROCS and EON), Hologram Quantitative Structure Activity Relationships (HQSAR) and docking (FRED, FlexX, Glide and AutoDock Vina), to retrieve cruzain inhibitors from collected databases. All methods were assessed individually and then combined in a Ligand-Based Virtual Screening (LBVS) and Target-Based Virtual Screening (TBVS) consensus scoring, using Receiving Operating Characteristic (ROC) curves to evaluate their performance. Three consensus strategies were used: scaled-rank-by-number, rank-by-rank and rank-by-vote, with the most thriving the scaled-rank-by-number strategy, considering that the stiff ROC curve appeared to be satisfactory in every way to indicate a higher enrichment power at early retrieval of active compounds from the database. The ligand-based method provided access to a robust and predictive HQSAR model that was developed to show superior discrimination between active and inactive compounds, which was also better than ROCS and EON procedures. Overall, the integration of fast computational techniques based on ligand and target structures resulted in a more efficient retrieval of cruzain inhibitors with desired pharmacological profiles that may be useful to advance the discovery of new trypanocidal agents.

Medical treatment and the good death: an ethical analysis of euthanasia, physician assisted suicide, and the right to die

Frequent advances in medical technologies have brought fonh many innovative treatments that allow medical teams to treal many patients with grave illness and serious trauma who would have died only a few years earlier. These changes have given some patients a second chance at life, but for others. these new treatments have merely prolonged their dying. Instead of dying relatively painlessly, these unfortunate patients often suffer from painful tenninal illnesses or exist in a comatose state that robs them of their dignity, since they cannot survive without advanced and often dehumanizing forms of treatment. Due to many of these concerns, euthanasia has become a central issue in medical ethics. Additionally, the debate is impacted by those who believe that patients have the right make choices about the method and timing of their deaths. Euthanasia is defined as a deliberate act by a physician to hasten the death of a patient, whether through active methods such as an injection of morphine, or through the withdrawal of advanced forms of medical care, for reasons of mercy because of a medical condition that they have. This study explores the question of whether euthanasia is an ethical practice and, as determined by ethical theories and professional codes of ethics, whether the physician is allowed to provide the means to give the patient a path to a "good death," rather than one filled with physical and mental suffering. The paper also asks if there is a relevant moral difference between the active and passive forms of euthanasia and seeks to define requirements to ensure fully voluntary decision making through an evaluation of the factors necessary to produce fully informed consent. Additionally, the proper treatments for patients who suffer from painful terminal illnesses, those who exist in persistent vegetative states and infants born with many diverse medical problems are examined. The ultimate conclusions that are reached in the paper are that euthanasia is an ethical practice in certain specific circumstances for patients who have a very low quality of life due to pain, illness or serious mental deficits as a result of irreversible coma, persistent vegetative state or end-stage clinical dementia. This is defended by the fact that the rights of the patient to determine his or her own fate and to autonomously decide the way that he or she dies are paramount to all other factors in decisions of life and death. There are also circumstances where decisions can be made by health care teams in conjunction with the family to hasten the deaths of incompetent patients when continued existence is clearly not in their best interest, as is the case of infants who are born with serious physical anomalies, who are either 'born dying' or have no prospect for a life that is of a reasonable quality. I have rejected the distinction between active and passive methods of euthanasia and have instead chosen to focus on the intentions of the treating physician and the voluntary nature of the patient's request. When applied in equivalent circumstances, active and passive methods of euthanasia produce the same effects, and if the choice to hasten the death of the patient is ethical, then the use of either method can be accepted. The use of active methods of euthanasia and active forms of withdrawal of life support, such as the removal of a respirator are both conscious decisions to end the life of the patient and both bring death within a short period of time. It is false to maintain a distinction that believes that one is active killing. whereas the other form only allows nature to take it's course. Both are conscious choices to hasten the patient's death and should be evaluated as such. Additionally, through an examination of the Hippocratic Oath, and statements made by the American Medical Association and the American College of physicians, it can be shown that the ideals that the medical profession maintains and the respect for the interests of the patient that it holds allows the physician to give aid to patients who wish to choose death as an alternative to continued suffering. The physician is also allowed to and in some circumstances, is morally required, to help dying patients whether through active or passive forms of euthanasia or through assisted suicide. Euthanasia is a difficult topic to think about, but in the end, we should support the choice that respects the patient's autonomous choice or clear best interest and the respect that we have for their dignity and personal worth.

Real-Time Flood Forecasting Systems In Flanders

As a highly urbanized and flood prone region, Flanders has experienced multiple floods causing significant damage in the past. In response to the floods of 1998 and 2002 the Flemish Environment Agency, responsible for managing 1 400 km of unnavigable rivers, started setting up a real time flood forecasting system in 2003. Currently the system covers almost 2 000 km of unnavigable rivers, for which flood forecasts are accessible online (www.waterinfo.be). The forecasting system comprises more than 1 000 hydrologic and 50 hydrodynamic models which are supplied with radar rainfall, rainfall forecasts and on-site observations. Forecasts for the next 2 days are generated hourly, while 10 day forecasts are generated twice a day. Additionally, twice daily simulations based on percentile rainfall forecasts (from EPS predictions) result in uncertainty bands for the latter. Subsequent flood forecasts use the most recent rainfall predictions and observed parameters at any time while uncertainty on the longer-term is taken into account. The flood forecasting system produces high resolution dynamic flood maps and graphs at about 200 river gauges and more than 3 000 forecast points. A customized emergency response system generates phone calls and text messages to a team of hydrologists initiating a pro-active response to prevent upcoming flood damage. The flood forecasting system of the Flemish Environment Agency is constantly evolving and has proven to be an indispensable tool in flood crisis management. This was clearly the case during the November 2010 floods, when the agency issued a press release 2 days in advance allowing water managers, emergency services and civilians to take measures.

Does active management add value?: the Brazilian mutual fund market

Does active management add or destroy value? With a sample of 699 with four different main categories: stocks, fixed income, hedge and exchange rate mutual funds we conclude that the active management add value to investors in stocks and hedge funds. But in fixed income mutual funds the evidence is against the active management. We also analyze the determinants of significant alphas. For stocks and hedge funds the evidence suggests that old, big and active funds generate biggest alphas. In fixed income funds the evidence is not clear, only a positive relationship between size and alphas could be found.

Estudo in silico da interação da albumina de soro humano com o ibuprofeno

Currently, computational methods have been increasingly used to aid in the characterization of molecular biological systems, especially when they relevant to human health. Ibuprofen is a nonsteroidal antiinflammatory or broadband use in the clinic. Once in the bloodstream, most of ibuprofen is linked to human serum albumin, the major protein of blood plasma, decreasing its bioavailability and requiring larger doses to produce its antiinflamatory action. This study aimes to characterize, through the interaction energy, how is the binding of ibuprofen to albumin and to establish what are the main amino acids and molecular interactions involved in the process. For this purpouse, it was conducted an in silico study, by using quantum mechanical calculations based on Density Functional Theory (DFT), with Generalized Gradient approximation (GGA) to describe the effects of exchange and correlation. The interaction energy of each amino acid belonging to the binding site to the ligand was calculated the using the method of molecular fragmentation with conjugated caps (MFCC). Besides energy, we calculated the distances, types of molecular interactions and atomic groups involved. The theoretical models used were satisfactory and show a more accurate description when the dielectric constant ε = 40 was used. The findings corroborate the literature in which the Sudlow site I (I-FA3) is the primary binding site and the site I-FA6 as secondary site. However, it differs in identifying the most important amino acids, which by interaction energy, in order of decreasing energy, are: Arg410, Lys414, Ser 489, Leu453 and Tyr411 to the I-Site FA3 and Leu481, Ser480, Lys351, Val482 and Arg209 to the site I-FA6. The quantification of interaction energy and description of the most important amino acids opens new avenues for studies aiming at manipulating the structure of ibuprofen, in order to decrease its interaction with albumin, and consequently increase its distribution

Cross-sectional association between healthy and unhealthy food habits and leisure physical activity in adolescents

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Modifiable risk factors for overweight and obesity in children and adolescents from São Paulo, Brazil

Background: Brazil is currently experiencing a nutrition transition: the displacement of traditional diets with foods high in saturated fat, sodium, and cholesterol and an increase in sedentary lifestyles. Despite these trends, our understanding of child obesity in Brazil is limited. Thus, the aims of this study were (1) to investigate the current prevalence of overweight and obesity in a large sample of children and adolescents living in São Paulo, Brazil, and (2) to identify the lifestyle behaviors associated with an increased risk of obesity in young Brazilians.Methods: A total of 3,397 children and adolescents (1,596 male) aged 7-18 years were randomly selected from 22 schools in São Paulo, Brazil. Participants were classified as normal weight, overweight, or obese based on international age-and sex-specific body mass index thresholds. Selected sociodemographic, physical activity, and nutrition behaviors were assessed via questionnaire.Results: Overall, 19.4% of boys and 16.1% of girls were overweight while 8.9% and 4.3% were obese. Two-way analysis of variance revealed that the prevalence of overweight and obesity was significantly higher in boys and in younger children when compared to girls and older children, respectively (P < 0.05 for both). Logistic regression analysis revealed that overweight was associated with more computer usage, parental encouragement to be active, and light soft drink consumption after controlling for differences in sex, age, and parental education (P < 0.05 for all). Conversely, overweight was associated with less active transport to school, eating before sleep, and consumption of breakfast, full-sugar soft drinks, fried food and confectionery (P < 0.05 for all).Conclusions: Our results show that obesity in São Paulo children and adolescents has reached a level equivalent to that seen in many developed countries. We have also identified three key modifiable factors related to obesity that may be appropriate targets for future intervention in Brazilian youth: transport mode to school, computer usage, and breakfast consumption.

Power flow for primary distribution networks considering uncertainty in demand and user connection

This paper presents a method for calculating the power flow in distribution networks considering uncertainties in the distribution system. Active and reactive power are used as uncertain variables and probabilistically modeled through probability distribution functions. Uncertainty about the connection of the users with the different feeders is also considered. A Monte Carlo simulation is used to generate the possible load scenarios of the users. The results of the power flow considering uncertainty are the mean values and standard deviations of the variables of interest (voltages in all nodes, active and reactive power flows, etc.), giving the user valuable information about how the network will behave under uncertainty rather than the traditional fixed values at one point in time. The method is tested using real data from a primary feeder system, and results are presented considering uncertainty in demand and also in the connection. To demonstrate the usefulness of the approach, the results are then used in a probabilistic risk analysis to identify potential problems of undervoltage in distribution systems. (C) 2012 Elsevier Ltd. All rights reserved.

Direct effects of colchicine on myocardial function - Studies in hypertrophied and failing spontaneously hypertensive rats

The aging spontaneously hypertensive rat (SHR) is a model in which the transition from chronic stable left ventricular hypertrophy to overt heart failure can be observed. Although the mechanisms for impaired function in hypertrophied and failing cardiac muscle from the SHR have been studied, none accounts fully for the myocardial contractile abnormalities. The cardiac cytoskeleton has been implicated as a possible cause for myocardial dysfunction. If an increase in microtubules contributes to dysfunction, then myocardial microtubule disruption by colchicine should promote an improvement in cardiac performance. We studied the active and passive properties of isolated left ventricular papillary muscles from 18- to 24-month-old SHR with evidence of heart failure (SHR-F, n=6), age-matched SHR without heart failure (SHR-NF, n=6), and age-matched normotensive Wistar-Kyoto rats (WKY, n=5). Mechanical parameters were analyzed before and up to 90 minutes after the addition of colchicine (10(-5), 10(-4), and 10(-3) mol/L). In the baseline state, active tension (AT) developed by papillary muscles from the WKY group was greater than for SHR-NF and SHR-F groups (WKY 5.69+/-1.47 g/mm(2) [mean+/-SD], SHR-NF 3.41+/-1.05, SHR-F 2.87+/-0.26; SHR-NF and SHR-F P<0.05 versus WKY rats). The passive stiffness was greater in SHR-F than in the WKY and SHR-NF groups (central segment exponential stiffness constant, K-cs: SHR-F 70+/-25, SHR-NF 44+/-17, WKY 41+/-13 [mean+/-SD]; SHR-F P<0.05 versus; SHR-NF and WKY rats). AT did not improve after 10, 20, and 30 minutes of exposure to colchicine (10(-5), 10(-4), and 10(-3) mol/L) in any group. In the SHR-F group, AT and passive stiffness did not change after 30 to 90 minutes of colchicine exposure (10(-4) mol/L). In summary, the data in this study fail to demonstrate improvement of intrinsic muscle function in SHR with heart failure after colchicine. Thus, in the SHR there is no evidence that colchicine-induced cardiac microtubular depolymerization affects the active or passive properties of hypertrophied or failing left ventricular myocardium.

Geographical Distribution and Demographic Characteristics of Gestational Trophoblastic Disease

OBJECTIVE: To outline the geographical distribution pattern of gestational trophoblastic disease (GTD) in a referral center in Bahia, Brazil, and determine the demographics of the disease.STUDY DESIGN: We conducted a study of data retrieved from medical records of 140 GTD patients referred to our Trophoblastic Diseases Center in 2002-2007, assessing geographical distribution across health care districts, demographics, referral sources, and previous pregnancy status.RESULTS: The most common GTD types were hydatidiform mole (106, 75.7%), invasive mole (32, 22.9%), choriocarcinoma (1, 0.7%), and placental site trophoblastic tumor (1, 0.7%). GTD incidence was 8.5 in 1,000 deliveries. Most patients originated from the coastal region (East district), which includes the state capital (77.9%). The 20-34 age group predominated (65%). Education level (67.9% attended elementary school only) and employment rate (42.9%) were low. Secondary hospitals were the principal source of referral (84.3%), followed by self-referrals (15.7%). Regarding previous pregnancy status, 42.1% (n = 59) had had term pregnancy, 39.3% (n = 55) no pregnancy, 15% (n = 21) miscarriage, and 0.7% (n = 1) ectopic pregnancy; 4 patients (2.9%) had previous hydatidiform mole.CONCLUSION: GTD predominated in the peak fertility age group and among patients of unfavorable sociodemographic status. (J Reprod Med 2010;55:305-310)

Genotoxicity of cigarette smoking in maternal and newborn lymphocytes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Serum Iron Parameters and Acute Experimental EHV-1 Infection in Horses

Background Research in humans has demonstrated that high serum iron (sFe) concentration can predispose to infection, and many infections subsequently result in alterations of host sFe. A decrease in sFe concentration is an early and sensitive indicator of systemic inflammation caused by tissue necrosis, bacterial infections, or endotoxemia in horses. Serum iron parameters in acute equine herpesvirus type 1 (EHV-1) infection have not been evaluated previously. Objectives To document the sFe response to EHV-1 infection and to determine whether or not significant differences in sFe concentration exist between EHV-1 infected horses that develop neurologic disease and those that do not. Animals A total of 14 horses experimentally infected with EHV-1. Methods Data were collected as an ancillary data set during a blinded experimental EHV-1 infection. Horses were infected with the rAb4 strain of EHV-1. Temperature, neurologic score, packed cell volume (PCV), and sFe parameters (sFe concentration, % saturation, and total iron-binding capacity) were recorded daily for 2weeks. Data were evaluated using Wilcoxon signed rank tests and Wilcoxon rank sum tests with Bonferroni corrections. Conclusions and Clinical Relevance Serum iron concentration decreases significantly in a biphasic pattern after EHV-1 infection. There was no significant difference in sFe concentration in horses that developed neurologic disease and those that did not in these experimentally infected animals. Serum iron parameters may be useful in monitoring the clinical course of viral infections such as EHV-1.