Three-dimensional modeling of single stranded DNA hairpins for aptamer-based biosensors.

Aptamers consist of short oligonucleotides that bind specific targets. They provide advantages over antibodies, including robustness, low cost, and reusability. Their chemical structure allows the insertion of reporter molecules and surface-binding agents in specific locations, which have been recently exploited for the development of aptamer-based biosensors and direct detection strategies. Mainstream use of these devices, however, still requires significant improvements in optimization for consistency and reproducibility. DNA aptamers are more stable than their RNA counterparts for biomedical applications but have the disadvantage of lacking the wide array of computational tools for RNA structural prediction. Here, we present the first approach to predict from sequence the three-dimensional structures of single stranded (ss) DNA required for aptamer applications, focusing explicitly on ssDNA hairpins. The approach consists of a pipeline that integrates sequentially building ssDNA secondary structure from sequence, constructing equivalent 3D ssRNA models, transforming the 3D ssRNA models into ssDNA 3D structures, and refining the resulting ssDNA 3D structures. Through this pipeline, our approach faithfully predicts the representative structures available in the Nucleic Acid Database and Protein Data Bank databases. Our results, thus, open up a much-needed avenue for integrating DNA in the computational analysis and design of aptamer-based biosensors

CplexA: a Mathematica package to study macromolecular-assembly control of gene expression

Summary: Macromolecular assembly vertebrates essential cellular processes, such as gene regulation and signal transduction. A major challenge for conventional computational methods to study these processes is tackling the exponential increase of the number of configurational states with the number of components. CplexA is a Mathematica package that uses functional programming to efficiently compute probabilities and average properties over such exponentially large number of states from the energetics of the interactions. The package is particularly suited to study gene expression at complex promoters controlled by multiple, local and distal, DNA binding sites for transcription factors. Availability: CplexA is freely available together with documentation at http://sourceforge.net/projects/cplexa/.Comment: 28 pages. Includes Mathematica, Matlab, and Python implementation tutorials. Software can be downloaded at http://cplexa.sourceforge.net

Stochastic dynamics of macromolecular-assembly networks

The formation and regulation of macromolecular complexes provides the backbone of most cellular processes, including gene regulation and signal transduction. The inherent complexity of assembling macromolecular structures makes current computational methods strongly limited for understanding how the physical interactions between cellular components give rise to systemic properties of cells. Here we present a stochastic approach to study the dynamics of networks formed by macromolecular complexes in terms of the molecular interactions of their components. Exploiting key thermodynamic concepts, this approach makes it possible to both estimate reaction rates and incorporate the resulting assembly dynamics into the stochastic kinetics of cellular networks. As prototype systems, we consider the lac operon and phage lambda induction switches, which rely on the formation of DNA loops by proteins and on the integration of these protein-DNA complexes into intracellular networks. This cross-scale approach offers an effective starting point to move forward from network diagrams, such as those of protein-protein and DNA-protein interaction networks, to the actual dynamics of cellular processes.Comment: Open Access article available at http://www.nature.com/msb/journal/v2/n1/full/msb4100061.htm

Dynamics-informed deconvolutional neural networks for super-resolution identification of regime changes in epidemiological time series

Inferring the timing and amplitude of perturbations in epidemiological systems from their stochastically spread low-resolution outcomes is as relevant as challenging. It is a requirement for current approaches to overcome the need to know the details of the perturbations to proceed with the analyses. However, the general problem of connecting epidemiological curves with the underlying incidence lacks the highly effective methodology present in other inverse problems, such as super-resolution and dehazing from computer vision. Here, we develop an unsupervised physics-informed convolutional neural network approach in reverse to connect death records with incidence that allows the identification of regime changes at single-day resolution. Applied to COVID-19 data with proper regularization and model-selection criteria, the approach can identify the implementation and removal of lockdowns and other nonpharmaceutical interventions with 0.93-day accuracy over the time span of a year.Comment: 18 pages, 5 figure

Multiprotein DNA looping

DNA looping plays a fundamental role in a wide variety of biological processes, providing the backbone for long range interactions on DNA. Here we develop the first model for DNA looping by an arbitrarily large number of proteins and solve it analytically in the case of identical binding. We uncover a switch-like transition between looped and unlooped phases and identify the key parameters that control this transition. Our results establish the basis for the quantitative understanding of fundamental cellular processes like DNA recombination, gene silencing, and telomere maintenance.Comment: 11 pages, 4 figure

Ab initio thermodynamic modeling of distal multisite transcription regulation

Transcription regulation typically involves the binding of proteins over long distances on multiple DNA sites that are brought close to each other by the formation of DNA loops. The inherent complexity of assembling regulatory complexes on looped DNA challenges the understanding of even the simplest genetic systems, including the prototypical lac operon. Here we implement a scalable approach based on thermodynamic molecular properties to model ab initio systems regulated through multiple DNA sites with looping. We show that this approach applied to the lac operon accurately predicts the system behavior for a wide range of cellular conditions, which include the transcription rate over five orders of magnitude as a function of the repressor concentration for wild type and all seven combinations of deletions of three operators, as well as the observed induction curves for cells with and without active catabolite activator protein. Our results provide new insights into the detailed functioning of the lac operon and reveal an efficient avenue to incorporate the required underlying molecular complexity into fully predictive models of gene regulation

Investigação na Sala de Aula: a aprendizagem dos números irracionais

This article describes an experience with the charaterization of mathematical thoughts of the 8th grade students. This is made through the investigation in the classroom for learning irrational numbers. The article is the result of an investigation for the construction of the concept of irrational numbers from the social practices and the interaction in the classroom from the students as well as the teachers. The research is based on group activities, where knowledge is given through interaction in the groups and from the exploration of the surroundings. To do the analysis several activities were made. This was made with a group of students where each one summarized the steps followed to develop the activity. The results obtained were analized highlighting the case stories presented, especially the ones related to irrational numbers. The results allow to define that the group work makes a better construction of learning mathematics.El presente artículo describe una experiencia con la caracterización del pensamiento matemático de los estudiantes de grado octavo, a través de investigación en el aula para el aprendizaje de los números irracionales. El artículo es el resultado de una investigación que tuvo como objetivo la construcción del concepto de número irracional a partir de prácticas sociales y la interacción en el aula, tanto de los alumnos como del docente. La investigación se fundamenta en actividades grupales, en donde el conocimiento se da a través de la interacción grupal y a partir de la exploración en el medio. Para realizar este análisis se hicieron varias actividades de tipo exploratorio, con grupos de estudiantes donde cada uno redactó los pasos que aplicaron al desarrollar dicha actividad. Para ello, se explican y se analizan los resultados obtenidos, destacando los relatos aportados, especialmente lo relacionado con los números irracionales. Los resultados obtenidos permiten establecer que el trabajo en grupo posibilita una mejor construcción del conocimiento en el aprendizaje de las matemáticas.Le présent article de réflexion décrit une expérience avec la caractérisation de la pensée mathématique des étudiants du huitième degré, à travers d’une recherche dans la salle pour l’apprentissage des nombres irraisonnables. L’article est le résultat d’une recherche qui a eu pour objectif la construction du concept de nombre irraisonnable à partir des pratiques sociales et l’interaction dans la salle, des élèves et de l’enseignant. La recherche repose dans des activités de groupe, où la connaissance se rend à travers de l’interaction groupale et à partir de l’exploration dans le milieu.Pour réaliser cette analyse quelques activités de type exploratoire ont été faites, avec groups d’étudiants où chacun a rédigé les pas qu’ils ont appliqués après avoir développé la dite activité. Pour cela, s’expliquent et s’analysent les résultats obtenus, en soulignant les récits apportés, spécialement le relatif aux nombres irraisonnables. Les résultats obtenus permettent d’établir que le travail en groupe facilite une meilleure construction de la connaissance dans l’apprentissage des mathématiques.O presente artigo de reflexão descreve uma experiência com a caracterização do pensamento matemático dos estudante de oitavo ano de Ensino Fundamental, a través da pesquisa na sala de aula para a aprendizagem dos números irracionais. O presente artigo é o resultado de uma investigação a qual teve como objetivo a construção do conceito de número irracional a partir das práticas sociais e da interação na sala de aula, quanto dos alunos como do professor. A investigação se fundamenta em atividades grupais, onde o conhecimento se dá por meio da interação grupal e a exploração do meio. Para a realização desta análise fizeram-se várias atividades de tipo exploratório com grupos de estudantes onde cada um deles escreveu os passos que foram aplicados para o desenvolvimento de esta atividade. Para isso, explicam-se e analisam-se os resultados obtidos, destacando os relatos aportados, especialmente, aquilo em relação com os números irracionais. Os resultados obtidos, permitem estabelecer que o trabalho em grupo possibilita uma melhor construção do conhecimento na aprendizagem das matemáticas

DNA looping: the consequences and its control

The formation of DNA loops by proteins and protein complexes is ubiquitous to many fundamental cellular processes, including transcription, recombination, and replication. Here we review recent advances in understanding the properties of DNA looping in its natural context and how they propagate to the cellular behavior through gene regulation. The results of connecting the molecular properties with cellular physiology indicate that looping of DNA in vivo is much more complex and easier than predicted from current models and reveals a wealth of previously unappreciated details