Exploring the origins of topological frustration: Design of a minimally frustrated model of fragment B of protein A

Topological frustration in an energetically unfrustrated off-lattice model of the helical protein fragment B of protein A from Staphylococcus aureus was investigated. This Gō-type model exhibited thermodynamic and kinetic signatures of a well-designed two-state folder with concurrent collapse and folding transitions and single exponential kinetics at the transition temperature. Topological frustration is determined in the absence of energetic frustration by the distribution of Fersht φ values. Topologically unfrustrated systems present a unimodal distribution sharply peaked at intermediate φ, whereas highly frustrated systems display a bimodal distribution peaked at low and high φ values. The distribution of φ values in protein A was determined both thermodynamically and kinetically. Both methods yielded a unimodal distribution centered at φ = 0.3 with tails extending to low and high φ values, indicating the presence of a small amount of topological frustration. The contacts with high φ values were located in the turn regions between helices I and II and II and III, intimating that these hairpins are in large part required in the transition state. Our results are in good agreement with all-atom simulations of protein A, as well as lattice simulations of a three- letter code 27-mer (which can be compared with a 60-residue helical protein). The relatively broad unimodal distribution of φ values obtained from the all-atom simulations and that from the minimalist model for the same native fold suggest that the structure of the transition state ensemble is determined mostly by the protein topology and not energetic frustration.

Pressure-induced protein-folding/unfolding kinetics

We use an off-lattice minimalist model to describe the effects of pressure in slowing down the folding/unfolding kinetics of proteins when subjected to increasingly larger pressures. The potential energy function used to describe the interactions between beads in the model includes the effects of pressure on the pairwise interaction of hydrophobic groups in water. We show that pressure affects the participation of contacts in the transition state. More significantly, pressure exponentially decreases the chain reconfigurational diffusion coefficient. These results are consistent with experimental results on the kinetics of pressure-denaturation of staphylococcal nuclease.

Resected RNA pseudoknots and their recognition by histidyl-tRNA synthetase

Duplexes constituted by closed or open RNA circles paired to single-stranded oligonucleotides terminating with 3′-CCAOH form resected pseudoknots that are substrates of yeast histidyl-tRNA synthetase. Design of this RNA fold is linked to the mimicry of the pseudoknotted amino acid accepting branch of the tRNA-like domain from brome mosaic virus, known to be charged by tyrosyl-tRNA synthetases, with RNA minihelices recapitulating accepting branches of canonical tRNAs. Prediction of the histidylation function of the new family of minimalist tRNA-like structures relates to the geometry of resected pseudoknots that allows proper presentation to histidyl-tRNA synthetase of analogues of the histidine identity determinants N-1 and N73 present in tRNAs. This geometry is such that the analogue of the major N-1 histidine determinant in the RNA circles faces the analogue of the discriminator N73 nucleotide in the accepting oligonucleotides. The combination of identity elements found in tRNAHis species from archaea, eubacteria, and organelles (G-1/C73) is the most efficient for determining histidylation of the duplexes. The inverse combination (C-1/G73) leads to the worst histidine acceptors with charging efficiencies reduced by 2–3 orders of magnitude. Altogether, these findings open new perspectives for understanding evolution of tRNA identity and serendipitous RNA functions.

Toward an outline of the topography of a realistic protein-folding funnel.

Experimental information on the structure and dynamics of molten globules gives estimates for the energy landscape's characteristics for folding highly helical proteins, when supplemented by a theory of the helix-coil transition in collapsed heteropolymers. A law of corresponding states relating simulations on small lattice models to real proteins possessing many more degrees of freedom results. This correspondence reveals parallels between "minimalist" lattice results and recent experimental results for the degree of native character of the folding transition state and molten globule and also pinpoints the needs of further experiments.

Artigos e possessivos na história do português paulista

Esta dissertação teve como objetivo articular um estudo do determinante diante das formas possessivas com base em um corpus histórico jornalístico composto de anúncios e cartas de leitores e redatores extraídos de jornais paulistas do século XIX. Focalizamos as formas possessivas seu/seus/sua/suas pré-nominais, observando a presença versus ausência do artigo definido e seus diferentes contextos. Nossas hipóteses buscaram resolver algumas questões teóricas relacionadas à estrutura do DP possessivo no PB, entre elas a da opcionalidade aparente do determinante e a da variação na realização de Número no interior da estrutura. Desenvolvemos respostas e análises às questões a partir da associação de dois quadros teóricos: a teoria dos Princípios & Parâmetros (CHOMSKY 1981, 1986) incluindo alguns refinamentos do Programa Minimalista (CHOMSKY 1995, 1998, 2000, 2001, 2004), e os pressupostos elaborados dentro da Sociolinguística Variacionista (cf. WEINREICH, LABOV e HERZOG (WLH) (1968); LABOV (1972, 1994, 2000)). Consideramos também estudos posteriores que conciliaram a mudança paramétrica internalista da língua (ROBERTS (2007)) com fatores extragramaticais que determinam o percurso das formas linguísticas no tempo histórico (KROCH (1989, 1994, 2000)). Para o estudo da estrutura do DP possessivo usamos a análise sobre os Bare Nouns de Cyrino & Espinal (2014). Os resultados obtidos mostraram que a média geral de ausência do determinante diante de DPs possessivos se manteve a mesma nos dois períodos analisados, configurando uma variação estável. Concluímos que não houve, portanto, indícios de oscilação no uso de uma ou outra variante que pudesse demonstrar o avanço de uma delas em detrimento de outra.

Fases en la derivación e interpretación semántico pragmática

En trabajos anteriores (Romero, 2008a y b, Alabart Lago, L., P. Díaz y G. Herrera, 2012, Alabart Lago, L. y Herrera, G., 2013) se intentó mostrar que el mecanismo interpretativo que propone la TR podría resultar adecuado como uno de los sistemas externos (también interpretativos) postulados por la GG, más precisamente, el sistema llamado CI. La relación que intentamos establecer tendrá en cuenta lo siguiente como marco teórico: a) En TR se afirma que la interpretación de un enunciado se deriva de las estructuras sintácticas, y esta derivación se realiza "en paralelo" con la derivación de estructuras llevada a cabo por las operaciones del componente sintáctico. b) En las últimas propuestas de la GG, extensiones y revisiones del PM propuesto en Chomsky (1995) no solo se dejan de lado los niveles de representación internos SP y ES sino también se considera prescindible la interfaz FL (Chomsky, 2005). Las estructuras generadas se transfieren a los sistemas externos en cuanto rasgos formales de las Categorías Funcionales son valorados. Mantendremos la noción de que el sistema computacional es relativamente irrestricto y que sus operaciones son condicionadas solo por Atracción y las llamadas "condiciones de legibilidad" impuestas por los sistemas externos, fundamentalmente el Principio de Interpretación Completa (PIC). c) Tendremos en cuenta la propuesta de Leonetti y Escandell Vidal (2004), que sostiene que las CCFF de la GG pueden considerarse equivalentes a las Categoría Procedimentales propuestas por la TR. En este sentido consideraremos válida la afirmación de Chomsky (1998) acerca de que las CCFF centrales (C, T, v y D) tienen propiedades semánticas. d) Otro factor que tendremos en cuenta es la noción de fase en la derivación, considerándola correcta en los términos expuestos en Chomsky (2001 y 2005) y Gallego (2007 y 2009), con ciertas modificaciones. Nuestra hipótesis puede resumirse en lo siguiente: Las operaciones de extracción de inferencias propuestas por TR se aplican durante la derivación sintáctica independientemente de que se haya transferido o no una fase. Es más, esperamos poder demostrar que algunos mecanismos inferenciales imponen ciertas condiciones que afectan a la valoración de los rasgos de las CCFF. Pretendemos también intentar mostrar que además de los núcleos de fase reconocidos, C y v, debe considerarse fase a SD, porque contiene rasgos específicos de cuyo cotejo y valoración se desprende el valor que recibirán otros rasgos en el curso de la derivación. Con estos fundamentos esperamos poder elaborar una descripción de cómo interactúan ambos sistemas en la derivación de una oración y la asignación (casi simultánea) de significado

Small molecules that mimic components of bioactive protein surfaces

Small molecules designed to mimic specific structural components of a protein (peptide strands, sheets, turns, helices, or amino acids) can be expected to display agonist or antagonist biological responses by virtue of interacting with the same receptors that recognize the protein. Here we describe some minimalist approaches to structural mimetics of amino acids and of strand, turn, or helix segments of proteins. The designed molecules show potent and selective inhibition of protease, transferase, and phospholipase enzymes, or antagonism of G-protein coupled or transcriptional receptors, and have potent anti-tumour, anti-inflammatory, or antiviral activity.

Interpretation of the temperature dependence of equilibrium and rate constants

The objective of this review is to draw attention to potential pitfalls in attempts to glean mechanistic information from the magnitudes of standard enthalpies and entropies derived from the temperature dependence of equilibrium and rate constants for protein interactions. Problems arise because the minimalist model that suffices to describe the energy differences between initial and final states usually comprises a set of linked equilibria, each of which is characterized by its own energetics. For example, because the overall standard enthalpy is a composite of those individual values, a positive magnitude for AHO can still arise despite all reactions within the subset being characterized by negative enthalpy changes: designation of the reaction as being entropy driven is thus equivocal. An experimenter must always bear in mind the fact that any mechanistic interpretation of the magnitudes of thermodynamic parameters refers to the reaction model rather than the experimental system For the same reason there is little point in subjecting the temperature dependence of rate constants for protein interactions to transition-state analysis. If comparisons with reported values of standard enthalpy and entropy of activation are needed, they are readily calculated from the empirical Arrhenius parameters. Copyright (c) 2006 John Wiley & Sons, Ltd.

La contingence des faits linguistiques:réflexions sur la variation et le changement

This paper is a reflection on the role of contingent facts for the general understanding of language. Such facts are illustrated by the lacks of proportionality in the paradigm of French indefinites and the irregular correlations between the Null Subject Parameter and other hypothesised parameters. Such contingencies clearly go against the expectation raised by at least some versions of structuralism and the current chomskyan Minimalist Program. As demonstrated by alternative views being developed in various natural and social sciences, and as shown by recent research on formulaic language, contingency may be understood as the result of the expedient character of a medium geared towards action. A view of language as action may thus offer a perspective able to account both for the general default rules shaping a grammar and for the contingencies that entrench them in use, as both are integral and complementary aspects of language.

What nominal phrases are all about: the atypical case of indefinite pronouns with a determiner

This paper presents novel data that challenge the traditional categorial understanding of the nominal phrase. The established use of an indefinite pronoun with a determiner in French (ce quelqu'un, du n'importe quoi, un je ne sais quoi) contravenes assumptions both about pronouns, which should not be embedded, and nominal phrases, which should be headed by a noun. Analysed here for the first time, the embedding of a pronoun under a determiner is shown to find its justification in the semantic import of the construction. The anaphoric role guaranteeing referential continuity is promoted by a strong determiner; weak determiners typically contribute to constructing a designative use of the pronoun when a more precise characterisation cannot or will not be provided. How this construction would be analysed in the Minimalist Programme is presented to suggest that the phrase satisfies semantic requirements, which resolves the paradoxes of its traditional definition

Practical secure information flow in programming languages

If we classify variables in a program into various security levels, then a secure information flow analysis aims to verify statically that information in a program can flow only in ways consistent with the specified security levels. One well-studied approach is to formulate the rules of the secure information flow analysis as a type system. A major trend of recent research focuses on how to accommodate various sophisticated modern language features. However, this approach often leads to overly complicated and restrictive type systems, making them unfit for practical use. Also, problems essential to practical use, such as type inference and error reporting, have received little attention. This dissertation identified and solved major theoretical and practical hurdles to the application of secure information flow. ^ We adopted a minimalist approach to designing our language to ensure a simple lenient type system. We started out with a small simple imperative language and only added features that we deemed most important for practical use. One language feature we addressed is arrays. Due to the various leaking channels associated with array operations, arrays have received complicated and restrictive typing rules in other secure languages. We presented a novel approach for lenient array operations, which lead to simple and lenient typing of arrays. ^ Type inference is necessary because usually a user is only concerned with the security types for input/output variables of a program and would like to have all types for auxiliary variables inferred automatically. We presented a type inference algorithm B and proved its soundness and completeness. Moreover, algorithm B stays close to the program and the type system and therefore facilitates informative error reporting that is generated in a cascading fashion. Algorithm B and error reporting have been implemented and tested. ^ Lastly, we presented a novel framework for developing applications that ensure user information privacy. In this framework, core computations are defined as code modules that involve input/output data from multiple parties. Incrementally, secure flow policies are refined based on feedback from the type checking/inference. Core computations only interact with code modules from involved parties through well-defined interfaces. All code modules are digitally signed to ensure their authenticity and integrity. ^

Dynamics of spatial heterogeneity in a landfill with interacting phase densities:a stochastic analysis

A landfill represents a complex and dynamically evolving structure that can be stochastically perturbed by exogenous factors. Both thermodynamic (equilibrium) and time varying (non-steady state) properties of a landfill are affected by spatially heterogenous and nonlinear subprocesses that combine with constraining initial and boundary conditions arising from the associated surroundings. While multiple approaches have been made to model landfill statistics by incorporating spatially dependent parameters on the one hand (data based approach) and continuum dynamical mass-balance equations on the other (equation based modelling), practically no attempt has been made to amalgamate these two approaches while also incorporating inherent stochastically induced fluctuations affecting the process overall. In this article, we will implement a minimalist scheme of modelling the time evolution of a realistic three dimensional landfill through a reaction-diffusion based approach, focusing on the coupled interactions of four key variables - solid mass density, hydrolysed mass density, acetogenic mass density and methanogenic mass density, that themselves are stochastically affected by fluctuations, coupled with diffusive relaxation of the individual densities, in ambient surroundings. Our results indicate that close to the linearly stable limit, the large time steady state properties, arising out of a series of complex coupled interactions between the stochastically driven variables, are scarcely affected by the biochemical growth-decay statistics. Our results clearly show that an equilibrium landfill structure is primarily determined by the solid and hydrolysed mass densities only rendering the other variables as statistically "irrelevant" in this (large time) asymptotic limit. The other major implication of incorporation of stochasticity in the landfill evolution dynamics is in the hugely reduced production times of the plants that are now approximately 20-30 years instead of the previous deterministic model predictions of 50 years and above. The predictions from this stochastic model are in conformity with available experimental observations.

A vueltas con la naturaleza del cambio fonético-fonológico: los casos de Nj y Lj

Las etapas del cambio fonético-fonológico han sido descritas desde hace décadas, especialmente desde un punto de vista articulatorio y casi siempre partiendo de los testimonios escritos de que se podía disponer. No obstante, recientemente han ido surgiendo nuevas teorías que defienden que el cambio puede ser explicado a través del estudio de la variación y los procesos fonéticos propios del habla actual, puesto que ambos están relacionados con fenómenos de hipo (e hiper) articulación y, a la postre, de coarticulación. Una de ellas es la Fonología Evolutiva (Blevins 2004), aun cuando no ofrece una explicación satisfactoria para la difusión del cambio. En este estudio, se ha recurrido a estas teorías para esclarecer las causas de la evolución de dos contextos de yod segunda: /nj/ y /lj/, que llevaron a la fonologización de // y //, en un primer estadio de la historia del español.

Contributos da tecnologia multimédia e do multissensorial nas artesn performativas Era Uma Vez

O presente projeto de intervenção artística com o nome “Era Uma Vez” tem como objetivo transformar Contos Tradicionais numa Performance interativa, recorrendo à tecnologia multimédia, no sentido de proporcionar ao público visitante uma viagem pelo mundo da fantasia, num ambiente multissensorial. Neste sentido, pretendeu-se implementar um espaço de lazer, de relaxamento e um convite ao mundo da fantasia, fazendo sonhar e maravilhando todos os públicos envolvidos. O local de realização da Performance foi um espaço não convencional, um prédio antigo, atualmente desabituado, na cidade de Viseu. Quanto à Performance pretendeu-se que os intérpretes e todo o espaço envolvente provocasse no público múltiplas sensações. Estas provocações poderiam libertar memórias, não fossem as histórias ou os contos muitas vezes responsáveis por incutir determinados sentimentos, valores morais e princípios ideológicos. O uso das tecnologias multimédia nas artes tem tido um crescimento exponencial. Atualmente são muitas as formas de arte que adotam a multimédia no seu processo criativo, este fator provém da necessidade de criar novas ideias, procurar ser original, tornar o produto mais atrativo. A afirmação de espaços multissensoriais ou MSE (Multi Sensory Environment - ambiente multissensorial) tem sido notável. A exploração desta metodologia de trabalho destina-se para além do desenvolvimento e aprendizagem, o querer proporcionar, bem-estar, prazer, exploração, relaxamento e encontrar equilíbrio. A metodologia aplicada para a criação deste projeto é a Metodologia Projetual de Bruno Munari. Tratando-se de um projeto artístico tem uma organização simples e minimalista que resulta de um esquema cujo a ordem é definida pelo autor do projeto mediante as suas necessidades. A Estreia teve como resultado um balanço muito positivo por parte dos participantes, a adesão e a participação do público interagindo com todo o ambiente criado superou as expectativas.

Przestrzenne formy upamiętniania Zagłady

This book is a synthesizing reflection on the Holocaust commemoration, in which space becomes a starting point for discussion. The author understands space primarily as an amalgam of physical and social components, where various commemorative processes may occur. The first part of the book draws attention to the material aspect of space, which determines its character and function. Material culture has been a long ignored and depreciated dimension of human culture in the humanities and social sciences, because it was perceived as passive and fully controlled by human will, and therefore insignificant in the course of social and historical processes. An example of the Nazi system perfectly illustrates how important were the restrictions and prohibitions on the usage of mundane objects, and in general, the whole material culture in relation to macro and micro space management — the state, cities, neighborhoods and houses, but also parks and swimming pools, factories and offices or shops and theaters. The importance of things and space was also clearly visible in exploitative policies present in overcrowded ghettos and concentration and death camps. For this very reason, when we study spatial forms of Holocaust commemoration, it should be acknowledged that the first traces, proofs and mementoes of the murdered were their things. The first "monuments" showing the enormity of the destruction are thus primarily gigantic piles of objects — shoes, glasses, toys, clothes, suitcases, toothbrushes, etc., which together with the extensive camps’ space try to recall the scale of a crime impossible to understand or imagine. The first chapter shows the importance of introducing the material dimension in thinking about space and commemoration, and it ends with a question about one of the key concepts for the book, a monument, which can be understood as both object (singular or plural) and architecture (sculptures, buildings, highways). However, the term monument tends to be used rather in a later and traditional sense, as an architectural, figurative form commemorating the heroic deeds, carved in stone or cast in bronze. Therefore, the next chapter reconstructs this narrower line of thinking, together with a discussion about what form a monument commemorating a subject as delicate and sensitive as the Holocaust should take on. This leads to an idea of the counter-monument, the concept which was supposed to be the answer to the mentioned representational dilemma on the one hand, and which would disassociate it from the Nazi’s traditional monuments on the other hand. This chapter clarifies the counter-monument definition and explains the misunderstandings and confusions generated on the basis of this concept by following the dynamics of the new commemorative form and by investigating monuments from the ‘80s and ‘90s erected in Germany. In the next chapter, I examine various forms of the Holocaust commemoration in Berlin, a city famous for its bold, monumental, and even controversial projects. We find among them the entire spectrum of memorials – big, monumental, and abstract forms, like Peter Eisenman’s Memorial to the Murdered Jews of Europe or Daniel Liebeskind’s Jewish Museum Berlin; flat, invisible, and employing the idea of emptiness, like Christian Boltanski’s Missing House or Micha Ullman’s Book Burning Memorial; the dispersed and decentralized, like Renata Stih and Frieder Schnock’s Memory Places or Gunter Demnig’s Stumbling Blocks. I enrich descriptions of the monuments by signaling at this point their second, extended life, which manifests itself in the alternative modes of (mis)use, consisting of various social activities or artistic performances. The formal wealth of the outlined projects creates a wide panorama of possible solutions to the Holocaust commemoration problems. However, the discussions accompanying the building of monuments and their "future life" after realization emphasize the importance of the social component that permeates the biography of the monument, and therefore significantly influences its foreseen design. The book also addresses the relationship of space, place and memory in a specific situation, when commemoration is performed secretly or remains as unrealized potential. Although place is the most common space associated with memory, today the nature of this relationship changes, and is what indicates popularity and employment of such terms as Marc Augé’s non-places or Pierre Nora’s site of memory. I include and develop these concepts about space and memory in my reflections to describe qualitatively different phenomena occurring in Central and Eastern European countries. These are unsettling places in rural areas like glades or parking lots, markets and playgrounds in urban settings. I link them to the post-war time and modernization processes and call them sites of non-memory and non-sites of memory. Another part of the book deals with a completely different form of commemoration called Mystery of memory. Grodzka Gate - NN Theatre in Lublin initiated it in 2000 and as a form it situates itself closer to the art of theater than architecture. Real spaces and places of everyday interactions become a stage for these performances, such as the “Jewish town” in Lublin or the Majdanek concentration camp. The minimalist scenography modifies space and reveals its previously unseen dimensions, while the actors — residents and people especially related to places like survivors and Righteous Among the Nations — are involved in the course of the show thanks to various rituals and symbolic gestures. The performance should be distinguished from social actions, because it incorporates tools known from religious rituals and art, which together saturate the mystery of memory with an aura of uniqueness. The last discussed commemoration mode takes the form of exposition space. I examine an exhibition concerning the fate of the incarcerated children presented in one of the barracks of the Majdanek State Museum in Lublin. The Primer – Children in Majdanek Camp is unique for several reasons. First, because even though it is exhibited in the camp barrack, it uses a completely different filter to tell the story of the camp in comparison to the exhibitions in the rest of the barracks. For this reason, one experiences immersing oneself in all subsequent levels of space and narrative accompanying them – at first, in a general narrative about the camp, and later in a specifically arranged space marked by children’s experiences, their language and thinking, and hence formed in a way more accessible for younger visitors. Second, the exhibition resigns from didacticism and distancing descriptions, and takes an advantage of eyewitnesses and survivors’ testimonies instead. Third, the exhibition space evokes an aura of strangeness similar to a fairy tale or a dream. It is accomplished thanks to the arrangement of various, usually highly symbolic material objects, and by favoring the fragrance and phonic sensations, movement, while belittling visual stimulations. The exhibition creates an impression of a place open to thinking and experiencing, and functions as an asylum, a radically different form to its camp surrounding characterized by a more overwhelming and austere space.