1,721,025 research outputs found
MAPK's networks and their capacity for multistationarity due to toric steady states
Full text linkMitogen-activated protein kinase (MAPK) signaling pathways play an essential role in the transduction of environmental stimuli to the nucleus, thereby regulating a variety of cellular processes, including cell proliferation, differentiation and programmed cell death. The components of the MAPK extracellular activated protein kinase (ERK) cascade represent attractive targets for cancer therapy as their aberrant activation is a frequent event among highly prevalent human cancers. MAPK networks are a model for computational simulation, mostly using ordinary and partial differential equations. Key results showed that these networks can have switch-like behavior, bistability and oscillations. In this work, we consider three representative ERK networks, one with a negative feedback loop, which present a binomial steady state ideal under mass-action kinetics. We therefore apply the theoretical result present in [27] to find a set of rate constants that allow two significantly different stable steady states in the same stoichiometric compatibility class for each network. Our approach makes it possible to study certain aspects of the system, such as multistationarity, without relying on simulation, since we do not assume a priori any constant but the topology of the network. As the performed analysis is general it could be applied to many other important biochemical networks.Fil: Pérez Millán, Mercedes Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Matemática; Argentina. Universidad de Buenos Aires. Ciclo Básico Común; ArgentinaFil: Turjanski, Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentin
Structural bioinformatics: the drugs virtual reality game
Full text linkLa bioinformática estructural consiste, entre otras cosas, en realizar una simulación de del comportamiento de biomoléculas, principalmente proteínas y sus entornos, en diferentes situaciones. Al igual que un simulador de vuelo nos puede decir si un piloto se encuentra en condiciones de conducir con éxito un avión a su destino, la simulación con las biomoléculas puede establecer la capacidad de una droga para inhibir algunas enzimas o la posibilidad que dos proteínas puedan interactuar entre ellas. De este modo la bio informática contribuirá a un cambio en el paradigma del diseño de drogas permitiendo una mayor rapidez en su descubrimiento y en el proceso de optimización. Hay ejemplos exitosos de este nuevo paradigma como el caso de los inhibidores selectivos COX-2 como el Celecoxib usados en enfermedades inflamatorias crónicas, los inhibidores de la enzima convertidora de angiotensina (ECA) como el Captopril, empleados en el tratamiento de la hipertensión y diversos compuestos para el tratamiento del HIV.Palabras claves: bioinformática estructural – nuevo paradigma de desarrollo de medicamentos – diseño racional de fármacos – desarrollo de fármacos in silico.Structural Bioinformatics consist in simulating biomolecules, mainly proteins and their environment in different situations. And just like a flight simulator can tell us, if a pilot is able to bring the plane safely to destiny, biomolecular simulations can determine the ability of a drug to inhibit certain enzyme, or the possibility of two proteins to interact with each other. In this way structural bioinformatics contributed to a change in the drug development paradigm allowing a faster drug discovery and optimization process. Successful examples of the new paradigm are COX-2 selective inhibitors used in chronic inflammations, ACE inhibitor captopril and several compounds to treat HIV among others.Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Turjanski, Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentin
Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations
Full text linkIntrinsically disordered proteins (IDPs) are a set of proteins that lack a definite secondary structure in solution. IDPs can acquire tertiary structure when bound to their partners; therefore, the recognition process must also involve protein folding. The nature of the transition state (TS), structured or unstructured, determines the binding mechanism. The characterization of the TS has become a major challenge for experimental techniques and molecular simulations approaches since diffusion, recognition, and binding is coupled to folding. In this work we present atomistic molecular dynamics (MD) simulations that sample the free energy surface of the coupled folding and binding of the transcription factor c-myb to the cotranscription factor CREB binding protein (CBP). This process has been recently studied and became a model to study IDPs. Despite the plethora of available information, we still do not know how c-myb binds to CBP. We performed a set of atomistic biased MD simulations running a total of 15.6 μs. Our results show that c-myb folds very fast upon binding to CBP with no unique pathway for binding. The process can proceed through both structured or unstructured TS's with similar probabilities. This finding reconciles previous seemingly different experimental results. We also performed Go-type coarse-grained MD of several structured and unstructured models that indicate that coupled folding and binding follows a native contact mechanism. To the best of our knowledge, this is the first atomistic MD simulation that samples the free energy surface of the coupled folding and binding processes of IDPs.Fil: Ithuralde, Raúl Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Roitberg, Adrián. University of Florida; Estados UnidosFil: Turjanski, Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentin
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study
Full text linkMitogen-activated protein kinase (MAPK) signaling pathways play an essential role in the transduction of environmental stimuli to the nucleus, thereby regulating a variety of cellular processes, including cell proliferation, differentiation, and programmed cell death. The components of the MAPK extracellular activated protein kinase (ERK) cascade represent attractive targets for cancer therapy, as their aberrant activation is a frequent event among highly prevalent human cancers. To understand how MAPKs recognize and phosphorylate their targets is key to unravel their function. However, these events are still poorly understood because of the lack of complex structures of MAPKs with their bound targets in the active site. Here we have modeled the interaction of ERK with a target peptide and analyzed the specificity toward Ser/Thr-Pro motifs. By using a quantum mechanics/molecular mechanics (QM/MM) approach, we propose a mechanism for the phosphoryl transfer catalyzed by ERK that offers new insights into MAPK function. Our results suggest that (1) the proline residue has a role in both specificity and phospho transfer efficiency, (2) the reaction occurs in one step, with ERK2 Asp 147 acting as the catalytic base, (3) a conserved Lys in the kinase superfamily that is usually mutated to check kinase activity strongly stabilizes the transition state, and (4) the reaction mechanism is similar with either one or two Mg 2+ ions in the active site. Taken together, our results provide a detailed description of the molecular events involved in the phosphorylation reaction catalyzed by MAPK and contribute to the general understanding of kinase activity.Fil: Turjanski, Adrian. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Hummer, Gerhard. National Institutes of Health; Estados UnidosFil: Gutkind, J. Silvio. National Institutes of Health; Estados Unido
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Antibodies and cellular receptors interaction with the immunodominant antigenic site of the capsid of FMD virus: a computational study
Full text linkLa Fiebre aftosa (FA) es una de las principales enfermedades de origen viral que afecta muchas especies de animales domésticos y salvajes con pezuña hendida. La misma, no solo perjudica a los productores dueños de los rodeos sino que, a nivel global, ocasiona gastos y pérdidas económicas millonarias debido al costo de los programas de control y a las restricciones que se imponen en el comercio internacional. El agente etiológico es el virus de la fiebre aftosa (VFA) y su principal vía de entrada a la célula huésped es mediada por la interacción con receptores de membrana tipo integrinas (Ig). Fundamentalmente, el control del VFA es mediado por anticuerpos neutralizantes que reconocen regiones claves del virus como el referido sitio de interacción con las integrinas, en donde el motivo RGD (arginina-glicina-aspartato) resulta esencial. Toda esta región viral conforma el sitio antigénico inmunodominante que se ha denominado sitio A. Las interacciones VFA/Ac y VFA/Ig han sido estudiadas por difracción de cristales y caracterizadas a nivel cuasi-atómico para algunos complejos en particular, pero no existen investigaciones que extrapolen esta información hacia otros aislamientos del VFA, anticuerpos o integrinas de interés. A la vez, las frecuentes variaciones nucleotídicas en el genoma de un virus de ARN como el VFA, determinan una composición aminoacídica también variable que afecta en particular a las proteínas virales estructurales y sus sitios de contacto con los anticuerpos. Los elementos referidos sustentan la relevancia de las investigaciones centradas en la formalización y modelización de estos fenómenos de interacción para complejos entre Ac y otros VFA, posibilitando la generación de conocimiento que resultará de utilidad para el diseño de mejores antígenos y vacunas, así como para la comprensión de los elementos que determinan la especificidad de reconocimiento virus/célula en el modelo del VFA. En esta tesis evaluamos la efectividad de múltiples herramientas de diseño computacional, con diferentes simplificaciones físico-químicas, para modelizar los fenómenos de reconocimiento entre Ag del VFA de serotipo C y anticuerpos, y su variación ante las mutaciones del antígeno. Trabajamos con un primer conjunto de complejos de interacción, disponibles en el repositorio público de datos de estructura (PDB), entre dos Ac de referencia y variantes de un péptido que representa al sitio A del VFA. Modelizamos molecularmente todas las mutaciones puntuales posibles en todos los residuos aminoacídicos del referido péptido antigénico viral y generamos un perfil computacional de la influencia de estas mutaciones en la energía de interacción Ag/Ac. Realizamos además, modelizaciones del antígeno de cepas del VFA con mutaciones en múltiples residuos aminoacídicos representativas de brotes y aislamientos a campo, y obtuvimos una predicción de la interacción de estas variantes antigénicas con los referidos Ac monoclonales. Los resultados emergentes de esta etapa soportan la utilización de aquellos métodos computacionales, que hacen eje en las optimizaciones de las cadenas laterales y el uso de conjuntos de complejos de interacción como molde, para predecir la interacción Ag-Ac. En una 2da etapa clonamos la secuencia codificante de otros 2 Ac monoclonales obtenidos en Argentina que reconocen un sitio A similar pero del VFA A24 Cruzeiro, perteneciente al serotipo A. Para estos anticuerpos implementamos un protocolo de modelado de su estructura molecular y de su interacción con el Ag viral asistidos por la información de los perfiles mutacionales obtenidos en ensayos de ELISA con péptidos con mutaciones puntuales y de información bibliográfica. Por medio de estos resultados de ELISA desarrollamos un mapa diferencial y fino del epítopo funcional para Ac monoclonales anti serotipo A. Finalmente, trabajamos en las interacciones virus/integrinas y mediante las herramientas computacionales descritas, caracterizamos la estructura de dichos complejo de interacción y recapitulamos específicamente sobre los elementos de secuencia y estructura que determinan la especificidad de las integrinas bovinas por elmotivo RGD en el contexto aminoacídico viral. Este trabajo nos permitió detectar potenciales elementos claves en la especificidad de las integrinas αVβ6 por sus ligandos. Este trabajo de tesis demuestra la pertinencia y aplicabilidad de técnicas computacionales de predicción y modelado de la estructura y el acople molecular en fenómenos de interacción entre el sitio inmunodominante del VFA y moléculas del huésped como anticuerpos e integrinas.Foot-and-mouth disease (FMD) is one of the major animal diseases affecting many domestic and wild cloven-hoofed species. FMD not only affect stock farmers but, globally, causes loss of millions of dollars in economic expenses, control programs and the restrictions it imposes on international trade. Its etiologic agent is the foot-and- mouth disease virus (FMDV), whose main entry to the host cells is through the interaction with integrin (Ig)-like membrane receptors. The FMDV control is mainly exerted by neutralizing antibodies that recognize functional-relevant viral regions. Specifically, the major target for neutralizing antibodies lays in the vicinity of the viral recognition site for the integrins, the RGD motif of the immunodominant antigenic site called A. The FMDV/Ab and FMDV/Ig had been studied by crystal diffraction methods and characterized at a quasi-atomic level for some specific complexes, but there are no investigations that extrapolate this information to other FMDV strains, antibodies or integrins of interest. Furthermore, FMDV displays a high mutation rate, typical from RNA virus, which is often translated into structural protein amino acid changes affecting antibodies contact sites. These elements support the relevance of pursuing the formalization and modeling this phenomenon in order to study and generalize them from a structural biology point of view. This knowledge will be useful for better antigen (Ag) and vaccines design as well as the understanding of virus/cell specificity determinants in the FMDV model. In this thesis, we have evaluated the effectiveness of multiple computational programs with different physical-chemical simplifications to model the recognition phenomena between site A antigens of FMDV of serotype C and monoclonal antibodies (mAbs), and their variation facing Ag mutational changes. Initially, we worked with two of interaction complexes, available in the public repository of structure data (PDB), between two different mAbs and their antigenic partner, a FMDV RGD peptide. Specifically, we model all the possible point mutations through all the amino acid residues of the aforementioned viral antigenic peptide and generate a computational profile of the influence of these mutations on the Ag/mAb interaction energy. Secondly, we successfully challenged the computational approaches with a prediction experiment; by means of modeling multiple amino acid mutations representative of FMDV outbreaks and field isolates interacting with the referred mAbs. The emerging data from this module showed a good correlation between previous published experimental data and predictions produced in this work. These results supported the feasibility of using computational methods with foundations in the optimizations of the side chains and the use of an ensemble of interaction complexes as an input for the Ag/Ab interaction modeling pipeline. In a second module, we cloned the coding sequence of further two mAbs obtained in Argentina that also recognize and neutralize site A epitopes, mainly from serotype A FMDV (A24 Cruzeiro ). For these antibodies, we implemented a protocol for modeling their molecular structure as well as their interaction with viral Ag, assisted by the information of the mutational profiles obtained by us in peptide ELISA tests and bibliographic information. By means of the ELISA results we developed a differential and fine map of the functional epitope for those mAbs. Finally, we work on integrin/site A interactions using the computational tools previously described and recapitulate over published structural data for human integrins, which allowed us to detect potentially new key integrin specificity position for its ligands. We also model several bovine integrins molecules in complex with a viral RGD peptide and characterized it concerning the integrin ́s specificity determinants by the RGD motif in the viral amino acid context. This work demonstrates the relevance and applicability of the computational prediction techniques on molecular structure modeling and molecular docking in the interaction phenomena between the FMDV immunodominant site A and biotechnologically relevant host molecules, antibodies and integrins.Fil: Marrero Díaz de Villegas, Rubén. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
