Development of Novel Density Functionals for Thermochemical Kinetics

A new density functional theory (DFT) exchange-correlation functional for the exploration of reaction mechanisms is proposed. This new functional, denoted BMK (Boese-Martin for Kinetics), has an accuracy in the 2 kcal/mol range for transition state barriers but, unlike previous attempts at such a functional, this improved accuracy does not come at the expense of equilibrium properties. This makes it a general-purpose functional whose domain of applicability has been extended to transition states, rather than a specialized functional for kinetics. The improvement in BMK rests on the inclusion of the kinetic energy density together with a large value of the exact exchange mixing coefficient. For this functional, the kinetic energy density appears to correct `back' the excess exact exchange mixing for ground-state properties, possibly simulating variable exchange.Comment: J. Chem. Phys., in press (303431JCP, scheduled for August 15, 2004 issue); supplementary data available at http://theochem.weizmann.ac.il/web/papers/BMK.htm

Les élégies de Louise Labé : le faix d’amour et le faix de l’écriture

Placées au centre du volume des Oeuvres , les élégies de Louise Labé constituent un ensemble structuré dont la signification s'enrichit de multiples rapports entretenus avec d'autres parties du volume et, en particulier, son paratexte (titre, épître dédicatoire, textes d'hommage réunis à la fin du volume sous le titre « Escriz de divers poetes, à la louenge de Louize Labé Lionnoize »). Dans ces textes, Louise Labé ne met pas seulement en scène une persona d'amante, mais aussi une persona d'auteure réclamant l'indulgence de ses lectrices et s'offrant à les aider à chanter leur plainte. Ainsi l'aventure littéraire, avec les périls qu'elle comporte pour la femme du XVIe siècle, devient-elle thème littéraire au même titre que l'aventure amoureuse.Placed at the center of Louise Labé's Oeuvres, the elegies constitute a structured ensemble whose significance is enriched by the multiple rapports it maintains with the other parts of the work, specially with its paratext (title, dedicatory epistle, and the various texts in honor of « Louise Labé from Lyons »). In the elegies, Louise Labé presents the persona of a female lover as well as the persona of a woman writer who begs her female readers for their forgiveness while offering to help them express their love pain. Much in the same way as the « love adventure », the « literary adventure » and the danger it represents for the sixteenth-century woman becomes the subject of literature

From ab initio quantum chemistry to molecular dynamics: The delicate case of hydrogen bonding in ammonia

The ammonia dimer (NH3)2 has been investigated using high--level ab initio quantum chemistry methods and density functional theory (DFT). The structure and energetics of important isomers is obtained to unprecedented accuracy without resorting to experiment. The global minimum of eclipsed C_s symmetry is characterized by a significantly bent hydrogen bond which deviates from linearity by about 20 degrees. In addition, the so-called cyclic C_{2h} structure is extremely close in energy on an overall flat potential energy surface. It is demonstrated that none of the currently available (GGA, meta--GGA, and hybrid) density functionals satisfactorily describe the structure and relative energies of this nonlinear hydrogen bond. We present a novel density functional, HCTH/407+, designed to describe this sort of hydrogen bond quantitatively on the level of the dimer, contrary to e.g. the widely used BLYP functional. This improved functional is employed in Car-Parrinello ab initio molecular dynamics simulations of liquid ammonia to judge its performance in describing the associated liquid. Both the HCTH/407+ and BLYP functionals describe the properties of the liquid well as judged by analysis of radial distribution functions, hydrogen bonding structure and dynamics, translational diffusion, and orientational relaxation processes. It is demonstrated that the solvation shell of the ammonia molecule in the liquid phase is dominated by steric packing effects and not so much by directional hydrogen bonding interactions. In addition, the propensity of ammonia molecules to form bifurcated and multifurcated hydrogen bonds in the liquid phase is found to be negligibly small.Comment: Journal of Chemical Physics, in press (305335JCP

Psychopathy, adaptation, and disorder

In a recent study, we found a negative association between psychopathy and violence against genetic relatives. We interpreted this result as a form of nepotism and argued that it failed to support the hypothesis that psychopathy is a mental disorder, suggesting instead that it supports the hypothesis that psychopathy is an evolved life history strategy. This interpretation and subsequent arguments have been challenged in a number of ways. Here, we identify several misunderstandings regarding the harmful dysfunction definition of mental disorder as it applies to psychopathy and regarding the meaning of nepotism. Furthermore, we examine the evidence provided by our critics that psychopathy is associated with other disorders, and we offer a comment on their alternative model of psychopathy. We conclude that there remains little evidence that psychopathy is the product of dysfunctional mechanisms

Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis.

There is a need for treatments that can safely promote regulatory lymphocyte responses. T cells express GABA receptors (GABAA-Rs) and GABA administration can inhibit Th1-mediated processes such as type 1 diabetes and rheumatoid arthritis in mouse models. Whether GABAA-R agonists can also inhibit Th17-driven processes such as experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is an open question. GABA does not pass through the blood-brain barrier (BBB) making it ill-suited to inhibit the spreading of autoreactivity within the CNS. Homotaurine is a BBB-permeable amino acid that antagonizes amyloid fibril formation and was found to be safe but ineffective in long-term Alzheimer's disease clinical trials. Homotaurine also acts as GABAA-R agonist with better pharmacokinetics than that of GABA. Working with both monophasic and relapsing-remitting mouse models of EAE, we show that oral administration of homotaurine can (1) enhance CD8+CD122+PD-1+ and CD4+Foxp3+ Treg, but not Breg, responses, (2) inhibit autoreactive Th17 and Th1 responses, and (3) effectively ameliorate ongoing disease. These observations demonstrate the potential of BBB-permeable GABAA-R agonists as a new class of treatment to enhance CD8+ and CD4+ Treg responses and limit Th17 and Th1-medaited inflammation in the CNS

Hepatitis C virus pharmacogenomics in Latin American populations: implications in the era of direct-acting antivirals

In recent years, great progress has been made in the field of new therapeutic options for hepatitis C virus (HCV) infection. The new direct-acting antiviral agents (DAAs) represent a great hope for millions of chronically infected individuals because their use may lead to excellent cure rates with fewer side effects. In Latin America, the high prevalence of HCV genotype 1 infection and the significant association of Native American ancestry with risk predictive single-nucleotide polymorphisms (SNPs) in IFNL4 and ITPA genes highlight the need to implement new treatment regimens in these populations. However, the universal accessibility to DAAs is still not a reality in the region as their high cost is one of the major, although not the only, limiting factors for their broad implementation. Therefore, under these circumstances, could the assessment of host genetic markers be a useful tool to prioritize DAA treatment until global access to these new drugs can be achieved? This review will summarize the scientific evidences and the potential implications of HCV pharmacogenomics in this rapidly evolving era of anti-HCV drug development.Fil: Trinks, Julieta. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Caputo, Mariela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hulaniuk, María L.. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; ArgentinaFil: Corach, Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Flichman, Diego Martin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Nepotistic patterns of violent psychopathy: evidence for adaptation?

Psychopaths routinely disregard social norms by engaging in selfish, antisocial, often violent behavior. Commonly characterized as mentally disordered, recent evidence suggests that psychopaths are executing a well-functioning, if unscrupulous strategy that historically increased reproductive success at the expense of others. Natural selection ought to have favored strategies that spared close kin from harm, however, because actions affecting the fitness of genetic relatives contribute to an individual’s inclusive fitness. Conversely, there is evidence that mental disorders can disrupt psychological mechanisms designed to protect relatives. Thus, mental disorder and adaptation accounts of psychopathy generate opposing hypotheses: psychopathy should be associated with an increase in the victimization of kin in the former account but not in the latter. Contrary to the mental disorder hypothesis, we show here in a sample of 289 violent offenders that variation in psychopathy predicts a decrease in the genetic relatedness of victims to offenders; that is, psychopathy predicts an increased likelihood of harming non-relatives. Because nepotistic inhibition in violence may be caused by dispersal or kin discrimination, we examined the effects of psychopathy on (1) the dispersal of offenders and their kin and (2) sexual assault frequency (as a window on kin discrimination). Although psychopathy was negatively associated with coresidence with kin and positively associated with the commission of sexual assault, it remained negatively associated with the genetic relatedness of victims to offenders after removing cases of offenders who had coresided with kin and cases of sexual assault from the analyses. These results stand in contrast to models positing psychopathy as a pathology, and provide support for the hypothesis that psychopathy reflects an evolutionary strategy largely favoring the exploitation of non-relatives

Testing axiomatizations of ambiguity aversion

The study of the normative and positive theory of choice under uncertainty has made major advances through thought experiments often referred to as paradoxes: the St. Petersburg paradox, the Allais paradox, the Ellsberg paradox, and the Rabin paradox. Machina proposes a new thought experiment which posits a choice between two acts that have three outcomes. As in the Ellsberg paradox there are three events, but while the Ellsberg paradox has two (monetary) outcomes in Machina there are three. Machina shows that four prominent theories of ambiguity aversion predict indifference between the acts. Introspection, however, suggests that many people might very well strictly prefer one act over the other. This paper makes four contributions: first, to our knowledge, it is the first to experimentally implement the Machina thought experiment. Second, we employ a novel method to simultaneously elicit the certainty equivalent of an embedded lottery. Third, our results—across three experiments—indicate non-indifference, which rejects earlier theories of ambiguity aversion, but is consistent with a newer one, which we apply to explain our results. Fourth, we show that independence is a sufficient condition for indifference in the Machina paradox, and thereby explains why so many models predict indifference