Multiple human single-stranded DNA binding proteins function in genome maintenance : structural, biochemical and functional analysis

DNA exists predominantly in a duplex form that is preserved via specific base pairing. This base pairing affords a considerable degree of protection against chemical or physical damage and preserves coding potential. However, there are many situations, e.g. during DNA damage and programmed cellular processes such as DNA replication and transcription, in which the DNA duplex is separated into two singlestranded DNA (ssDNA) strands. This ssDNA is vulnerable to attack by nucleases, binding by inappropriate proteins and chemical attack. It is very important to control the generation of ssDNA and protect it when it forms, and for this reason all cellular organisms and many viruses encode a ssDNA binding protein (SSB). All known SSBs use an oligosaccharide/oligonucleotide binding (OB)-fold domain for DNA binding. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating strand-exchange proteins and helicases, and mediation of protein–protein interactions. Recently two additional human SSBs have been identified that are more closely related to bacterial and archaeal SSBs. Prior to this it was believed that replication protein A, RPA, was the only human equivalent of bacterial SSB. RPA is thought to be required for most aspects of DNA metabolism including DNA replication, recombination and repair. This review will discuss in further detail the biological pathways in which human SSBs function.

GameFlow : a model for evaluating player enjoyment in games

Although player enjoyment is central to computer games, there is currently no accepted model of player enjoyment in games. There are many heuristics in the literature, based on elements such as the game interface, mechanics, gameplay, and narrative. However, there is a need to integrate these heuristics into a validated model that can be used to design, evaluate, and understand enjoyment in games. We have drawn together the various heuristics into a concise model of enjoyment in games that is structured by flow. Flow, a widely accepted model of enjoyment, includes eight elements that, we found, encompass the various heuristics from the literature. Our new model, GameFlow, consists of eight elements -- concentration, challenge, skills, control, clear goals, feedback, immersion, and social interaction. Each element includes a set of criteria for achieving enjoyment in games. An initial investigation and validation of the GameFlow model was carried out by conducting expert reviews of two real-time strategy games, one high-rating and one low-rating, using the GameFlow criteria. The result was a deeper understanding of enjoyment in real-time strategy games and the identification of the strengths and weaknesses of the GameFlow model as an evaluation tool. The GameFlow criteria were able to successfully distinguish between the high-rated and low-rated games and identify why one succeeded and the other failed. We concluded that the GameFlow model can be used in its current form to review games; further work will provide tools for designing and evaluating enjoyment in games.

Panem et circenses : law, law and power in The Hunger Games

Like many cautionary tales, The Hunger Games takes as its major premise an observation about contemporary society, measuring its ballistic arc in order to present graphically its logical conclusions. The Hunger Games gazes back to the panem et circenses of Ancient Rome, staring equally cynically forward, following the trajectory of reality television to its unbearably barbaric end point – a sadistic voyeurism for an effete elite of consumers. At each end of the historical spectrum (and in the present), the prevailing social form is Arendt’s animal laborans. Consumer or consumed, Panem’s population is (with the exception of the inner circle) either deprived of the possibility of, or distracted from, political action. Within the confines of the Games themselves, Law is abandoned or de‐realised: Law – an elided Other in the pseudo‐Hobbesian nightmare that is the Arena. The Games are played out, as were gladiatorial combats and other diversions of the Roman Empire, against a background resonant of Juvenal’s concern for his contemporaries’ attachment to short term gratification at the expense the civic virtues of justice and caring which are (or would be) constitutive of a contemporary form of Arendt’s homo politicus. While the Games are, on their face, ‘reality’ they are (like the realities presented in contemporary reality television) a simulated reality, de‐realised in a Foucauldian set design constructed as a distraction for Capitol, and for the residents of the Districts, a constant reminder of their subservience to Capitol. Yet contemporary Western culture, for which manipulative reality TV is but a symptom of an underlying malaise, is inscribed at least as an incipient Panem, Its public/political space is diminished by the effective slavery of the poor, the pre‐occupation with and distractions of materiality and modern media, and the increasing concentration of power/wealth into a smaller proportion of the population.

Step function response of non-linear spring mass systems in the presence of Coulomb damping

The transient response of non-linear spring mass systems with Coulomb damping, when subjected to a step function is investigated. For a restricted class of non-linear spring characteristics, exact expressions are developed for (i) the first peak of the response curves, and (ii) the time taken to reach it. A simple, yet accurate linearization procedure is developed for obtaining the approximate time required to reach the first peak, when the spring characteristic is a general function of the displacement. The results are presented graphically in non-dimensional form.

Solution concepts in two-person multicriteria games

In this paper, we propose new solution concepts for multicriteria games and compare them with existing ones. The general setting is that of two-person finite games in normal form (matrix games) with pure and mixed strategy sets for the players. The notions of efficiency (Pareto optimality), security levels, and response strategies have all been used in defining solutions ranging from equilibrium points to Pareto saddle points. Methods for obtaining strategies that yield Pareto security levels to the players or Pareto saddle points to the game, when they exist, are presented. Finally, we study games with more than two qualitative outcomes such as combat games. Using the notion of guaranteed outcomes, we obtain saddle-point solutions in mixed strategies for a number of cases. Examples illustrating the concepts, methods, and solutions are included.

Analysis of Parameter Values in the van der Waals and Platteeuw Theory for Methane Hydrates Using Monte Carlo Molecular Simulations

The van der Waals and Platteuw (vdVVP) theory has been successfully used to model the thermodynamics of gas hydrates. However, earlier studies have shown that this could be due to the presence of a large number of adjustable parameters whose values are obtained through regression with experimental data. To test this assertion, we carry out a systematic and rigorous study of the performance of various models of vdWP theory that have been proposed over the years. The hydrate phase equilibrium data used for this study is obtained from Monte Carlo molecular simulations of methane hydrates. The parameters of the vdWP theory are regressed from this equilibrium data and compared with their true values obtained directly from simulations. This comparison reveals that (i) methane-water interactions beyond the first cage and methane-methane interactions make a significant contribution to the partition function and thus cannot be neglected, (ii) the rigorous Monte Carlo integration should be used to evaluate the Langmuir constant instead of the spherical smoothed cell approximation, (iii) the parameter values describing the methane-water interactions cannot be correctly regressed from the equilibrium data using the vdVVP theory in its present form, (iv) the regressed empty hydrate property values closely match their true values irrespective of the level of rigor in the theory, and (v) the flexibility of the water lattice forming the hydrate phase needs to be incorporated in the vdWP theory. Since methane is among the simplest of hydrate forming molecules, the conclusions from this study should also hold true for more complicated hydrate guest molecules.

CFT(4) partition functions and the heat kernel on AdS(5)

We consider four-dimensional CFTs which admit a large-N expansion, and whose spectrum contains states whose conformal dimensions do not scale with N. We explicitly reorganise the partition function obtained by exponentiating the one-particle partition function of these states into a heat kernel form for the dual string spectrum on AdS(5). On very general grounds, the heat kernel answer can be expressed in terms of a convolution of the one-particle partition function of the light states in the four-dimensional CFT. (C) 2013 Elsevier B.V. All rights reserved.

CALCULATION OF SPIN-REORIENTATION TEMPERATURE IN ND2FE14B

The spin-reorientation phenomenon in Nd2Fe14B has been investigated using an angular dependent free energy approach. A magnetic Hamiltonian which includes the crystal electric field term and the exchange term has been established using realistic band structure results. The temperature dependence of the molecular field is accounted for by introducing the Brillouin function and the magnetic Hamiltonian is diagonalized within the ground state multiplet of the Nd ion. The eigenstates are then used to form the partition function for the free energy. At each temperature, the direction of the molecular field is obtained by searching for the minimum in the angular parameter space of the free energy. Our calculations show that for Nd2Fe14B, the net magnetic anisotropy direction is canted away from the c axis at a temperature close to the experimentally reported spin-reorientation temperature of 150 K. The temperature dependence of the magnetic structure is found to be very sensitive to the size of the second order crystal field parameter B20.

Coalitional Games and Contracts Based on Individual Deviations

We study what coalitions form and how the members of each coalition split the coalition value in coalitional games in which only individual deviations are allowed. In this context we employ three stability notions: individual, contractual, and compensational stability. These notions differ in terms of the underlying contractual assumptions. We characterize the coalitional games in which individually stable outcomes exist by means of the top-partition property. Furthermore, we show that any coalition structure of maximum social worth is both contractually and compensationally stable.

Synaptic dysfunction in early encephalopathies : from genes to function

Tese de doutoramento, Medicina (Neurologia), Universidade de Lisboa, Faculdade de Medicina, 2015

A role for hippocampal PSA-NCAM and NMDA-NR2B receptor function in flavonoid-induced spatial memory improvements in young rats

The increase in incidence and prevalence of neurodegenerative diseases highlights the need for a more comprehensive understanding of how food components may affect neural systems. In particular, flavonoids have been recognized as promising agents capable of influencing different aspects of synaptic plasticity resulting in improvements in memory and learning in both animals and humans. Our previous studies highlight the efficacy of flavonoids in reversing memory impairments in aged rats, yet little is known about the effects of these compounds in healthy animals, particularly with respect to the molecular mechanisms by which flavonoids might alter the underlying synaptic modifications responsible for behavioral changes. We demonstrate that a 3-week intervention with two dietary doses of flavonoids (Dose I: 8.7 mg/day and Dose II: 17.4 mg/day) facilitates spatial memory acquisition and consolidation (24 recall) (p < 0.05) in young healthy rats. We show for the first time that these behavioral improvements are linked to increased levels in the polysialylated form of the neural adhesion molecule (PSA-NCAM) in the dentate gyrus (DG) of the hippocampus, which is known to be required for the establishment of durable memories. We observed parallel increases in hippocampal NMDA receptors containing the NR2B subunit for both 8.7 mg/day (p < 0.05) and 17.4 mg/day (p < 0.001) doses, suggesting an enhancement of glutamate signaling following flavonoid intervention. This is further strengthened by the simultaneous modulation of hippocampal ERK/CREB/BDNF signaling and the activation of the Akt/mTOR/Arc pathway, which are crucial in inducing changes in the strength of hippocampal synaptic connections that underlie learning. Collectively, the present data supports a new role for PSA-NCAM and NMDA-NR2B receptor on flavonoid-induced improvements in learning and memory, contributing further to the growing body of evidence suggesting beneficial effects of flavonoids in cognition and brain health.

Evaluating quality of life in mercury intoxicated people in urban-industrial environments through short-form 36 application

Context and objective: Records of contact with mercury (Hg) exist for more than 3500 years and several problems related to the use of this element can be noticed. Considering inexistence of current reports about it, quality of life perception evaluation was studied in people chronically intoxicated by mercury in an industrial environment. Design and setting: This is a cross-sectional descriptive observational study. Information from 47 urban-industrial workers from lamps manufacturing in São Paulo, clinically diagnosed as intoxicated by mercury and currently followed by the Occupational Health Service of Faculdade de Medicine da Universidade de São Paulo, with average age of 41.7 years old, was considered. Methods: SF36 questionnaire application was performed, with inferences tested by χ-square proof, by Spearman linear correlation and Mann-Whitney non-parametric test, adopting p < 0.05 as significant level. Results: In the eight domains, observed medians are 40% for physical functioning; 0 for physical function; 30% for body pain; 30% for general health; 22.2% for vitality; 50% for social functioning; 0 for emotional role and 36% for mental health. Correlation between age and SF36 domains does not reveal statistical significance, except for physical functioning, indicating that lower scores presented by older people in this domain are not followed by changes on other ones. Conclusions: Values obtained in people chronically intoxicated by mercury are actually lower, in the motor and mental scope components. Some instruments domains are higher for men than for women. Older ages are inversely associated to good performance in physical function domain. © Copyright Moreira Jr. Editora. Todos os direitos reservados.

Theorem for series in three-parameter mittag-leffler function

The new result presented here is a theorem involving series in the three-parameter Mittag-Le er function. As a by-product, we recover some known results and discuss corollaries. As an application, we obtain the solution of a fractional di erential equation associated with a RLC electrical circuit in a closed form, in terms of the two-parameter Mittag-Le er function.

Sleep desaturation and its relationship to lung function, exercise and quality of life in LAM

Background: Lymphangioleiomyomatosis (LAM) is characterised by progressive airway obstruction and hypoxaemia in young women. Although sleep may trigger hypoxaemia in patients with airway obstruction, it has not been previously investigated in patients with LAM. Methods: Consecutive women with lung biopsy proven LAM and absence of hypoxaemia while awake were evaluated with pulmonary function test, echocardiography, 6-min walk test, overnight full polysomnography, and Short Form 36 health-related quality-of-life questionnaire. Results: Twenty-five patients with (mean +/- SD) age 45 +/- 10 years, SpO(2) awake 95% +/- 2, forced expiratory volume in the first second (median-interquartile) FEV1 (% predicted) 77 (47-90) and carbonic monoxide diffusion capacity, DLCO (%) 55 (34-74) were evaluated. Six-minute walk test distance and minimum SpO(2) (median-interquartile) were, respectively, 447 m (411 -503) and 90% (82-94). Median interquartile apnoea-hypopnoea index was in the normal range 2 (1-5). Fourteen patients (56%) had nocturnal hypoxaemia (10% total sleep time with SpO(2) <90%), and the median sleep time spent with SpO(2) <90% was 136 (13-201) min. Sleep time spent with SpO(2) <90% correlated with the residual volume/total lung capacity ratio (r(s) = 0.5, p: 0.02), DLCO (r(s) = -0.7, p: 0.001), FEV1 (r(s) = -0.6, p: 0.002). Multivariate linear regression model showed that RV/TLC ratio was the most important functional variable related to sleep hypoxaemia. Conclusion: Significant hypoxaemia during sleep is common in LAM patients with normal SpO(2) while awake, especially among those with some degree of hyperinflation in lung function tests. (C) 2011 Published by Elsevier Ltd.

Structure and function in rhodopsin: Kinetic studies of retinal binding to purified opsin mutants in defined phospholipid–detergent mixtures serve as probes of the retinal binding pocket

In the current standard procedure for preparation of mammalian rhodopsin mutants, transfected COS-1 cells expressing the mutant opsin genes are treated with 5 μM 11-cis-retinal before detergent solubilization for purification. We found that binding of 11-cis-retinal to opsin mutants with single amino acid changes at Trp-265 (W265F,Y,A) and a retinitis pigmentosa mutant (A164V) was far from complete and required much higher concentrations of 11-cis-retinal. By isolation of the expressed opsins in a stable form, kinetic studies of retinal binding to the opsins in vitro have been carried out by using defined phospholipid–detergent mixtures. The results show wide variation in the rates of 11-cis-retinal binding. Thus, the in vitro reconstitution procedure serves as a probe of the retinal-binding pocket in the opsins. Further, a method is described for purification and characterization of the rhodopsin mutants after retinal binding to the opsins in vitro.