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Computational pan-genomics: status, promises and challenges
No full textMany disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case of Homo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic data sets. Instead, novel, qualitatively different computational methods and paradigms are needed. We will witness the rapid extension of computational pan-genomics, a new sub-area of research in computational biology. In this article, we generalize existing definitions and understand a pan-genome as any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations as graphs. We outline how this and other challenges from different application domains translate into common computational problems, point out relevant bioinformatics techniques and identify open problems in computer science. With this review, we aim to increase awareness that a joint approach to computational pan-genomics can help address many of the problems currently faced in various domains
Optimal Entropy-Transport problems and a new Hellinger-Kantorovich distance between positive measures
Get PDFWe develop a full theory for the new class of Optimal Entropy-Transport problems between nonnegative and finite Radon measures in general topological spaces.
They arise quite naturally by relaxing the marginal constraints typical of Optimal Transport problems: given a couple of finite measures (with possibly different total mass), one looks for minimizers of the sum of a linear transport functional and two convex entropy functionals, that quantify in some way the deviation of the marginals of the transport plan from the assigned measures.
As a powerful application of this theory, we study the particular case of Logarithmic Entropy-Transport problems and introduce the new Hellinger-Kantorovich distance between measures in metric spaces.
The striking connection between these two seemingly far topics allows for a deep analysis of the geometric properties of the new geodesic distance, which lies somehow between the well-known Hellinger-Kakutani and Kantorovich-Wasserstein distances
Markov state modeling reveals competing collective hydrogen bond rearrangements in liquid water
Get PDFWe construct a Markov state model for the dynamic rearrangement of the local hydrogen bond network in liquid water. The model is based on trajectories from classical molecular dynamics simulations and accounts for the dynamics of relative angular and separation coordinates of water molecules. We analyze first the conformational subspace of three water molecules and find five well separated dynamic modes with reaction times in the 2 - 5 ps range, which correspond to different interchanges of hydrogen bond donor and acceptors, followed by an entire continuum spectrum of modes. We then analyze the switching of one hydrogen bond between two water molecules and derive the complete transition network. The most probable pathway corresponds to a direct switch without an intermediate, in agreement with previous studies. However, a considerable fraction of paths proceeds along different intermediate states that involve alternative hydrogen bonds or unbound states
Dynamics of polar polarizable rotors acted upon by unipolar electromagnetic pulses: From the sudden to the adiabatic regime
No full textWe study, analytically as well as numerically, the dynamics that arises from the interaction of a polar polarizable rigid rotor with single unipolar electromagnetic pulses of varying length, , with respect to the rotational period of the rotor, . In the sudden, non-adiabatic limit, , we derive analytic expressions for the rotor's wavefunctions, kinetic energies, and field-free evolution of orientation and
alignment. We verify the analytic results by solving the corresponding time-dependent Schr\"odinger equation numerically and extend the temporal range of the interactions considered all the way to the adiabatic limit, , where general analytic solutions beyond the field-free case are no longer available. The effects of the orienting and aligning interactions as
well as of their combination on the post-pulse populations of the rotational states are visualized as functions of the orienting and aligning kick strengths in terms of populations quilts. Quantum carpets that encapsulate the evolution
of the rotational wavepackets provide the space-time portraits of the resulting
dynamics. The population quilts and quantum carpets reveal that purely
orienting, purely aligning, or even-break combined interactions each exhibit a
sui generis dynamics. In the intermediate temporal regime, we find that the
wavepackets as functions of the orienting and aligning kick strengths show
resonances that correspond to diminished kinetic energies at particular values
of the pulse duration
MSM/RD: Coupling Markov state models of molecular kinetics with reaction-diffusion simulations
Get PDFMolecular dynamics (MD) simulations can model the interactions between macromolecules with high spatiotemporal resolution but at a high computational cost. By combining high-throughput MD with Markov state models (MSMs), it is now possible to obtain long-timescale behavior of small to intermediate biomolecules and complexes. To model the interactions of many molecules at large lengthscales, particle-based reaction-diffusion (RD) simulations are more suitable but lack molecular detail. Thus, coupling MSMs and RD simulations (MSM/RD) would be highly desirable, as they could efficiently produce simulations at large time- and lengthscales, while still conserving the characteristic features of the interactions observed at atomic detail. While such a coupling seems straightforward, fundamental questions are still open: Which definition of MSM states is suitable? Which protocol to merge and split RD particles in an association/dissociation reaction will conserve the correct bimolecular kinetics and thermodynamics? In this paper, we make the first step towards MSM/RD by laying out a general theory of coupling and proposing a first implementation for association/dissociation of a protein with a small ligand (A + B C). Applications on a toy model and CO diffusion into the heme cavity of myoglobin are reported
Validation of numerical simulations by the exhaust flow of a PDC based high speed schlieren
No full textThe book reports on the latest theoretical and experimental findings in the field of active flow and combustion control. It covers new developments in actuator technology and sensing, in robust and optimal open- and closed-loop control, as well as in model reduction for control, constant volume combustion and dynamic impingement cooling. The chapters reports oncutting-edge contributions presented during the fourth edition of the Active Flow and Combustion Control conference, held in September 19 to 21, 2018 at the Technische Universität Berlin, in Germany. This conference, as well as the research presented in the book, have been supported by the collaborative research center SFB 1029 on “Substantial efficiency increase in gas turbines through direct use of coupled unsteady combustion and flow dynamics”, funded by the DFG (German Research Foundation). It offers a timely guide for researchers and practitioners in the field of aeronautics, turbomachinery, control and combustion
Revisiting Francisella tularensis subsp. holarctica, Causative Agent of Tularemia in Germany With Bioinformatics: New Insights in Genome Structure, DNA Methylation and Comparative Phylogenetic Analysis
No full textFrancisella (F.) tularensis is a highly virulent, Gram-negative bacterial pathogen and the causative agent of the zoonotic disease tularemia. Here, we generated, analyzed and characterized a high quality circular genome sequence of the F. tularensis subsp. holarctica strain 12T0050 that caused fatal tularemia in a hare. Besides the genomic structure, we focused on the analysis of oriC, unique to the Francisella genus and regulating replication in and outside hosts and the first report on genomic DNA methylation of a Francisella strain. The high quality genome was used to establish and evaluate a diagnostic whole genome sequencing pipeline. A genotyping strategy for F. tularensis was developed using various bioinformatics tools for genotyping. Additionally, whole genome sequences of F. tularensis subsp. holarctica isolates isolated in the years 2008–2015 in Germany were generated. A phylogenetic analysis allowed to determine the genetic relatedness of these isolates and confirmed the highly conserved nature of F. tularensis subsp. holarctica
Change and Persistence of Gender Disparities in Academic Careers of Mathematicians and Physicists in Germany
No full textThis article discusses whether or not gender-related disparities exist within the academic fields of mathematics and physics regarding the application of career knowledge and the experiences of disadvantage in relation to recognition of performance, assessment of professional competencies, and integration into networks. To answer this question, primary data was collected with a structured online survey addressing graduates in both academic fields (n=5,174). The article considers a subsample of respondents working at a university or university of applied sciences (n=1,613). Apart from the gender perspective, other factors potentially influencing the academic careers of mathematicians and physicists, such as being in a certain subject, age cohort or having children, are also considered. Some of the key findings are: a) more gender differences occur in mathematics than in physics; b) the experiences of disadvantage in the workplace constitute a cross-disciplinary phenomenon caused by the gender differentiating academic culture; and c) more female than male academics in both disciplines accept constraints or abandon career goals due to child care
Grand canonical diffusion-influenced reactions: a stochastic theory with applications to multiscale reaction-diffusion simulations
Get PDFSmoluchowski-type models for diffusion-influenced reactions (A+B -> C) can be formulated within two frameworks: the probabilistic-based approach for a pair A, B of reacting particles and the concentration-based approach for systems in contact with a bath that generates a concentration gradient of B particles that interact with A. Although these two approaches are mathematically similar, it is not straightforward to establish a precise mathematical relationship between them. Determining this relationship is essential to derive particle-based numerical methods that are quantitatively consistent with bulk concentration dynamics. In this work, we determine the relationship between the two approaches by introducing the grand canonical Smoluchowski master equation (GC-SME), which consists of a continuous-time Markov chain that models an arbitrary number of B particles, each one of them following Smoluchowski's probabilistic dynamics. We show that the GC-SME recovers the concentration-based approach by taking either the hydrodynamic or the large copy number limit. In addition, we show that the GC-SME provides a clear statistical mechanical interpretation of the concentration-based approach and yields an emergent chemical potential for nonequilibrium spatially inhomogeneous reaction processes. We further exploit the GC-SME robust framework to accurately derive multiscale/hybrid numerical methods that couple particle-based reaction-diffusion simulations with bulk concentration descriptions, as described in detail through two computational implementations
Transition manifolds of complex metastable systems: Theory and data-driven computation of effective dynamics
No full textWe consider complex dynamical systems showing metastable behavior but no local separation of fast and slow time scales. The article raises the question of whether such systems exhibit a low-dimensional manifold supporting its effective dynamics. For answering this question, we aim at finding nonlinear coordinates, called reaction coordinates, such that the projection of the dynamics onto these coordinates preserves the dominant time scales of the dynamics. We show that, based on a specific reducibility property, the existence of good low-dimensional reaction coordinates preserving the dominant time scales is guaranteed. Based on this theoretical framework, we develop and test a novel numerical approach for computing good reaction coordinates. The proposed algorithmic approach is fully local and thus not prone to the curse of dimension with respect to the state space of the dynamics. Hence, it is a promising method for data-based model reduction of complex dynamical systems such as molecular dynamics