Dynamical Principles of Two-Component Genetic Oscillators

Genetic oscillators based on the interaction of a small set of molecular components have been shown to be involved in the regulation of the cell cycle, the circadian rhythms, or the response of several signaling pathways. Uncovering the functional properties of such oscillators then becomes important for the understanding of these cellular processes and for the characterization of fundamental properties of more complex clocks. Here, we show how the dynamics of a minimal two-component oscillator is drastically affected by its genetic implementation. We consider a repressor and activator element combined in a simple logical motif. While activation is always exerted at the transcriptional level, repression is alternatively operating at the transcriptional (Design I) or post-translational (Design II) level. These designs display differences on basic oscillatory features and on their behavior with respect to molecular noise or entrainment by periodic signals. In particular, Design I induces oscillations with large activator amplitudes and arbitrarily small frequencies, and acts as an “integrator” of external stimuli, while Design II shows emergence of oscillations with finite, and less variable, frequencies and smaller amplitudes, and detects better frequency-encoded signals (“resonator”). Similar types of stimulus response are observed in neurons, and thus this work enables us to connect very different biological contexts. These dynamical principles are relevant for the characterization of the physiological roles of simple oscillator motifs, the understanding of core machineries of complex clocks, and the bio-engineering of synthetic oscillatory circuits

A mathematical model for the rational design of chimeric ligands in selective drug therapies

Chimeric drugs with selective potential toward specific cell types constitute one of the most promising forefronts of modern Pharmacology. We present a mathematical model to test and optimize these synthetic constructs, as an alternative to conventional empirical design. We take as a case study a chimeric construct composed of epidermal growth factor (EGF) linked to different mutants of interferon (IFN). Our model quantitatively reproduces all the experimental results, illustrating how chimeras using mutants of IFN with reduced affinity exhibit enhanced selectivity against cell overexpressing EGF receptor. We also investigate how chimeric selectivity can be improved based on the balance between affinity rates, receptor abundance, activity of ligand subunits, and linker length between subunits. The simplicity and generality of the model facilitate a straightforward application to other chimeric constructs, providing a quantitative systematic design and optimization of these selective drugs against certain cell-based diseases, such as Alzheimer's and cancerThis work has been supported by the Ministry of Science and Technology of Spain via a Ramon y Cajal Fellowship (Ref. RYC-2010-07450) and a Project from Plan National framework (Ref. BFU2011-30303), and a Marie Curie International Reintegration Grant from the EU (Ref. 248346-NMSSBLS). V.D.M. acknowledges financial support to the Universidad Autónoma de Madrid for a FPI-UAM fellowshi

Global variability in gene expression and alternative splicing is modulated by mitochondrial content

Noise in gene expression is a main determinant of phenotypic variability. Increasing experimental evidence suggests that genome-wide cellular constraints largely contribute to the heterogeneity observed in gene products. It is still unclear, however, which global factors affect gene expression noise and to what extent. Since eukaryotic gene expression is an energy demanding process, differences in the energy budget of each cell could determine gene expression differences. Here, we quantify the contribution of mitochondrial variability (a natural source of ATP variation) to global variability in gene expression. We find that changes in mitochondrial content can account for ∼50% of the variability observed in protein levels. This is the combined result of the effect of mitochondria dosage on transcription and translation apparatus content and activities. Moreover, we find that mitochondrial levels have a large impact on alternative splicing, thus modulating both the abundance and type of mRNAs. A simple mathematical model in which mitochondrial content simultaneously affects transcription rate and splicing site choice can explain the alternative splicing data. The results of this study show that mitochondrial content (and/or probably function) influences mRNA abundance, translation, and alternative splicing, which ultimately affects cellular phenotypeThe authors would like to thank the Ministerio de Economia y Competitividad (Spain) (Grant numbers BFU2009-10792 and BFU2013-45918-R) and The Medical Research Council (U.K.) for supporting this work. We thank the Fundação Ciência e Tecnologia (Portugal) for funding R.P.N. A.R. held a postgraduate fellowship (FPU) from the Ministerio de Educación y Ciencia. The CBMSO receives an institutional grant from Fundación Ramón Arece

Análisis por técnicas morfológicas y secuenciación de ADN del polen atmosférico de la Comunidad de Madrid: estudios preliminares. Morphological analysis and DNA sequencing of atmospheric pollen in Madrid region: preliminary study

Hasta el momento, el estudio de las partículas biológicas en el aire que respiramos, se ha dirigido, principalmente, al conocimiento y control del polen y esporas, aeroalérgenos cuyo impacto en salud es bien conocido. Recientemente la comunidad científica ha sugerido que el aire es un ecosistema en sí mismo, que tendría su propia “aerobiota”, compuesta principalmente por virus, bacterias, esporas de hongos y polen. Para estudiar en conjunto toda esta biodiversidad en el aire urbano en la Comunidad de Madrid, surge el consorcio pluridisciplinar AIRBIOTA-CM, que integra a cinco grupos de investigación de áreas muy diferentes, que pretenden obtener una visión conjunta sobre la composición y dinámica de las partículas biológicas del aire, optimizando los sistemas de muestreo y análisis. Las propuestas más novedosas de las investigaciones iniciadas por este consorcio, son la utilización de técnicas innovadoras de génetica molecular como la secuenciación masiva aplicada en metagenómica (“Next Generation Sequencing”, NGS) y el uso de nuevas estrategias de captación, como el empleo de aeronaves no tripuladas, para muestrear a diferentes alturas y en localizaciones geográficas urbanas que a priori puedan tener una composición diferente de la biota y tengan una actividad humana relevante. El proyecto se inicia en otoño de 2014, y los resultados preliminares que presentamos son los obtenidos mediante el análisis morfológico tradicional y el análisis del ADN del polen de una misma muestra procedente de un captador Burkard. Estos resultados evidencian que los captadores tipo Hirst utilizados por las redes aerobiológicas pueden emplearse también en los estudios de metagenómica, y que los datos obtenidos mediante la aplicación de ambos métodos de análisis coinciden a grandes rasgos, lo que revela que esta nueva metodología constituye una buena aproximación y posible alternativa al análisis morfológico, aunque se necesitan más estudios comparativos para adaptar bien esta tecnología. So far, the study of the biological particles in the air we breathe has been mainly directed at knowing and controlling pollen and spores, aeroallergens with a well-known health impact., It has been recently suggested that the air is an ecosystem in itself, and that it probably has its own biota, which would be composed mainly of viruses, bacteria, fungal spores, and pollen. The main objective of the AIRBIOTA-CM project is to study this diverse set of biological particles present in the urban air in the Community of Madrid using a multidisciplinary, innovative and integrative approach. The project is collaboration between five research groups in very different fields, which aim is to get an overview on the composition and dynamics of biological particles in the air to optimize the methods of sampling and analysis. As a methodological innovation, there is an attempt to apply the breakthroughs in metagenomics to the study of bioaerosols. In addition, new collection strategies have been used, such as the use of unmanned aerial vehicles by designing or adapting new samplers for these vehicles, to sample at different altitudes and in urban geographic locations that might presumably have a different composition of the biota and relevant human activity. The project started in autumn 2014. The preliminary results presented here refer to the comparison of results obtained by means of traditional (light microscopy) and metagenomics methods on atmospheric pollen in the Community of Madrid. The data obtained by both analyses coincide broadly, revealing that the molecular methodology is a good and possible alternative approach to morphological analysis, although more comparative studies to adapt well this technology are needed

Análise por técnicas morfológicas e sequenciação de ADN do pólen atmosférico da Comunidade de Madrid: estudos preliminares

So far, the study of the biological particles in the air we breathe has been mainly directed at knowing and controlling pollen and spores, aeroallergens with a well-known health impact. It has been recently suggested that the air is an ecosystem in itself, and that it probably has its own biota, which would be composed mainly of viruses, bacteria, fungal spores, and pollen. The main objective of the AIRBIOTA-CM project is to study this diverse set of biological particles present in the urban air in the Community of Madrid using a multidisciplinary, innovative and integrative approach.The project is collaboration between ve research groups in very different fields, which aim is to get an overview on the composition and dynamics of biological particles in the air to optimize the methods of sampling and analysis.As a methodological innovation, there is an attempt to apply the breakthroughs in metagenomics to the study of bioaerosols. In addition, new collection strategies have been used, such as the use of unmanned aerial vehicles by designing or adapting new samplers for these vehicles, to sample at different altitudes and in urban geographic locations that might presumably have a different composition of the biota and relevant human activity.The project started in autumn 2014. The preliminary results presented here refer to the comparison of results obtained by means of traditional (light microscopy) and metagenomics methods on atmospheric pollen in the Community of Madrid. The data obtained by both analyses coincide broadly, revealing that the molecular methodology is a good and possible alternative approach to morphological analysis, although more comparative studies to adapt well this technology are needed.Hasta el momento, el estudio de las partículas biológicas en el aire que respiramos, se ha dirigido, principalmente, al conocimiento y control del polen y esporas, aeroalérgenos cuyo impacto en salud es bien conocido. Recientemente la comunidad científica ha sugerido que el aire es un ecosistema en sí mismo, que tendría su propia “aerobiota”, compuesta principalmente por virus, bacterias, esporas de hongos y polen. Para estudiar en conjunto toda esta biodiversidad en el aire urbano en la Comunidad de Madrid, surge el consorcio pluridisciplinar AIRBIOTA-CM, que integra a cinco grupos de investigación de áreas muy diferentes, que pretenden obtener una visión conjunta sobre la composición y dinámica de las partículas biológicas del aire, optimizando los sistemas de muestreo y análisis. Las propuestas más novedosas de las investigaciones iniciadas por este consorcio, son la utilización de técnicas innovadoras de génetica molecular como la secuenciación masiva aplicada en metagenómica (“Next Generation Sequencing”, NGS) y el uso de nuevas estrategias de captación, como el empleo de aeronaves no tripuladas, para muestrear a diferentes alturas y en localizaciones geográficas urbanas que a priori puedan tener una composición diferente de la biota y tengan una actividad humana relevante.El proyecto se inicia en otoño de 2014, y los resultados preliminares que presentamos son los obtenidos mediante el análisis morfológico tradicional y el análisis del ADN del polen de una misma muestra procedente de un captador Burkard. Estos resultados evidencian que los captadores tipo Hirst utilizados por las redes aerobiológicas pueden emplearse también en los estudios de metagenómica, y que los datos obtenidos mediante la aplicación de ambos métodos de análisis coinciden a grandes rasgos, lo que revela que esta nueva metodología constituye una buena aproximación y posible alternativa al análisis morfológico, aunque se necesitan más estudios comparativos para adaptar bien esta tecnología.Até ao momento o estudo das partículas biológicas no ar que respiramos tem sido principalmente dirigido ao conhecimento e controlo de pólen e esporos, alergénicos cujo impacto na saúde é bem conhecido. Recentemente a comunidade científica tem sugerido que o ar é só por si um ecossistema, que tem a sua própria“aerobiota”composta principalmente por vírus, bactérias, esporos de fungos e pólen. Para estudar em conjunto toda esta biodiversidade no ar urbano, surge na Comunidade de Madrid o consórcio pluridisciplinar AIRBIOTA-CM que integra cinco grupos de investigação de áreas muito distintas, visando obter uma visão conjunta sobre a composição e dinâmica das partículas biológicas do ar, otimizando os sistemas de amostragem e análise. As propostas mais recentes de investigação iniciadas por este consórcio são a utilização de técnicas inovadoras de genética molecular como a sequenciação massiva aplicada em metagenómica (“NextGenerationSequencing”, NGS) e o uso de novas estratégias de captação, como a utilização de aeronaves não tripuladas para obtenção de amostras em diferentes alturas e localizações geográficas urbanas que a priori podem ter uma composição diferente da biota e tenham uma atividade humana relevante. O projeto foi iniciado no outono de 2014 e os resultados preliminares apresentados são os obtidos pela análise morfológica tradicional e a pela análise do ADN do pólen de uma mesma amostra procedente de um captador polínico Burkard. Os resultados evidenciam que os captadores tipo Hirst utilizados pelas redes aerobiológicas podem utilizar-se também em estudos de metagenómica e que os dados obtidos mediante a aplicação de ambos os métodos de análise coincidem amplamente, o que revela que esta nova metodologia constitui uma boa aproximação e possível alternativa à análise morfológica, ainda que sejam necessários mais estudos comparativos para uma melhor adaptação desta tecnologia

Trade-offs and Noise Tolerance in Signal Detection by Genetic Circuits

Genetic circuits can implement elaborated tasks of amplitude or frequency signal detection. What type of constraints could circuits experience in the performance of these tasks, and how are they affected by molecular noise? Here, we consider a simple detection process–a signal acting on a two-component module–to analyze these issues. We show that the presence of a feedback interaction in the detection module imposes a trade-off on amplitude and frequency detection, whose intensity depends on feedback strength. A direct interaction between the signal and the output species, in a type of feed-forward loop architecture, greatly modifies these trade-offs. Indeed, we observe that coherent feed-forward loops can act simultaneously as good frequency and amplitude noise-tolerant detectors. Alternatively, incoherent feed-forward loop structures can work as high-pass filters improving high frequency detection, and reaching noise tolerance by means of noise filtering. Analysis of experimental data from several specific coherent and incoherent feed-forward loops shows that these properties can be realized in a natural context. Overall, our results emphasize the limits imposed by circuit structure on its characteristic stimulus response, the functional plasticity of coherent feed-forward loops, and the seemingly paradoxical advantage of improving signal detection with noisy circuit components

"Bioinformática con Ñ v1.0": a collaborative project of young Spanish scientists to write a complete book about Bioinformatics

Here we present a project aiming to provide specialized educational bibliography on Bioinformatics for Spanish speakers. The idea of writing a book in Spanish language covering the most important topics in the field of Bioinformatics was born in the XIth Spanish Symposium on Bioinformatics in Barcelona two years ago. Different scientists have been involved in the project, from senior scientists to PhD students from different countries. The book intends to be the beginning of an open project, where all the chapters are susceptible of being updated and new topics can be incorporated in future versions. Current book version can be accessed online at http://goo.gl/UYG0o7.Peer Reviewe

Multistable Decision Switches for Flexible Control of Epigenetic Differentiation

It is now recognized that molecular circuits with positive feedback can induce two different gene expression states (bistability) under the very same cellular conditions. Whether, and how, cells make use of the coexistence of a larger number of stable states (multistability) is however largely unknown. Here, we first examine how autoregulation, a common attribute of genetic master regulators, facilitates multistability in two-component circuits. A systematic exploration of these modules' parameter space reveals two classes of molecular switches, involving transitions in bistable (progression switches) or multistable (decision switches) regimes. We demonstrate the potential of decision switches for multifaceted stimulus processing, including strength, duration, and flexible discrimination. These tasks enhance response specificity, help to store short-term memories of recent signaling events, stabilize transient gene expression, and enable stochastic fate commitment. The relevance of these circuits is further supported by biological data, because we find them in numerous developmental scenarios. Indeed, many of the presented information-processing features of decision switches could ultimately demonstrate a more flexible control of epigenetic differentiation

Dispersión caótica átomo-superficie

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química. Fecha de lectura: 2-7-199

Global variability in gene expression and alternative splicing is modulated by mitochondrial content

Noise in gene expression is a main determinant of phenotypic variability. Increasing experimental evidence suggests that genome-wide cellular constraints largely contribute to the heterogeneity observed in gene products. It is still unclear, however, which global factors affect gene expression noise and to what extent. Since eukaryotic gene expression is an energy demanding process, differences in the energy budget of each cell could determine gene expression differences. Here, we quantify the contribution of mitochondrial variability (a natural source of ATP variation) to global variability in gene expression. We find that changes in mitochondrial content can account for ∼50% of the variability observed in protein levels. This is the combined result of the effect of mitochondria dosage on transcription and translation apparatus content and activities. Moreover, we find that mitochondrial levels have a large impact on alternative splicing, thus modulating both the abundance and type of mRNAs. A simple mathematical model in which mitochondrial content simultaneously affects transcription rate and splicing site choice can explain the alternative splicing data. The results of this study show that mitochondrial content (and/or probably function) influences mRNA abundance, translation, and alternative splicing, which ultimately affects cellular phenotype.The authors would like to thank the Ministerio de Economia y Competitividad (Spain) (Grant numbers BFU2009-10792 and BFU2013-45918-R) and The Medical Research Council (U.K.) for supporting this work. We thank the Fundação Ciência e Tecnologia (Portugal) for funding R.P.N. A.R. held a postgraduate fellowship (FPU) from the Ministerio de Educación y Ciencia.Peer Reviewe