Bridge helix bending promotes RNA polymerase II backtracking through a critical and conserved threonine residue.

The dynamics of the RNA polymerase II (Pol II) backtracking process is poorly understood. We built a Markov State Model from extensive molecular dynamics simulations to identify metastable intermediate states and the dynamics of backtracking at atomistic detail. Our results reveal that Pol II backtracking occurs in a stepwise mode where two intermediate states are involved. We find that the continuous bending motion of the Bridge helix (BH) serves as a critical checkpoint, using the highly conserved BH residue T831 as a sensing probe for the 3'-terminal base paring of RNA:DNA hybrid. If the base pair is mismatched, BH bending can promote the RNA 3'-end nucleotide into a frayed state that further leads to the backtracked state. These computational observations are validated by site-directed mutagenesis and transcript cleavage assays, and provide insights into the key factors that regulate the preferences of the backward translocation

Exploring Temporal Networks with Greedy Walks

Temporal networks come with a wide variety of heterogeneities, from burstiness of event sequences to correlations between timings of node and link activations. In this paper, we set to explore the latter by using greedy walks as probes of temporal network structure. Given a temporal network (a sequence of contacts), greedy walks proceed from node to node by always following the first available contact. Because of this, their structure is particularly sensitive to temporal-topological patterns involving repeated contacts between sets of nodes. This becomes evident in their small coverage per step as compared to a temporal reference model -- in empirical temporal networks, greedy walks often get stuck within small sets of nodes because of correlated contact patterns. While this may also happen in static networks that have pronounced community structure, the use of the temporal reference model takes the underlying static network structure out of the equation and indicates that there is a purely temporal reason for the observations. Further analysis of the structure of greedy walks indicates that burst trains, sequences of repeated contacts between node pairs, are the dominant factor. However, there are larger patterns too, as shown with non-backtracking greedy walks. We proceed further to study the entropy rates of greedy walks, and show that the sequences of visited nodes are more structured and predictable in original data as compared to temporally uncorrelated references. Taken together, these results indicate a richness of correlated temporal-topological patterns in temporal networks

The Barrier Method: A Technique for Calculating Very Long Transition Times

In many dynamical systems there is a large separation of time scales between typical events and "rare" events which can be the cases of interest. Rare-event rates are quite difficult to compute numerically, but they are of considerable practical importance in many fields: for example transition times in chemical physics and extinction times in epidemiology can be very long, but are quite important. We present a very fast numerical technique that can be used to find long transition times (very small rates) in low-dimensional systems, even if they lack detailed balance. We illustrate the method for a bistable non-equilibrium system introduced by Maier and Stein and a two-dimensional (in parameter space) epidemiology model.Comment: 20 pages, 8 figure

Beyond Worst-Case Analysis for Joins with Minesweeper

We describe a new algorithm, Minesweeper, that is able to satisfy stronger runtime guarantees than previous join algorithms (colloquially, `beyond worst-case guarantees') for data in indexed search trees. Our first contribution is developing a framework to measure this stronger notion of complexity, which we call {\it certificate complexity}, that extends notions of Barbay et al. and Demaine et al.; a certificate is a set of propositional formulae that certifies that the output is correct. This notion captures a natural class of join algorithms. In addition, the certificate allows us to define a strictly stronger notion of runtime complexity than traditional worst-case guarantees. Our second contribution is to develop a dichotomy theorem for the certificate-based notion of complexity. Roughly, we show that Minesweeper evaluates $\beta$-acyclic queries in time linear in the certificate plus the output size, while for any $\beta$-cyclic query there is some instance that takes superlinear time in the certificate (and for which the output is no larger than the certificate size). We also extend our certificate-complexity analysis to queries with bounded treewidth and the triangle query.Comment: [This is the full version of our PODS'2014 paper.

An Overview of Backtrack Search Satisfiability Algorithms

Propositional Satisfiability (SAT) is often used as the underlying model for a significan

Computational Investigations on Polymerase Actions in Gene Transcription and Replication Combining Physical Modeling and Atomistic Simulations

Polymerases are protein enzymes that move along nucleic acid chains and catalyze template-based polymerization reactions during gene transcription and replication. The polymerases also substantially improve transcription or replication fidelity through the non-equilibrium enzymatic cycles. We briefly review computational efforts that have been made toward understanding mechano-chemical coupling and fidelity control mechanisms of the polymerase elongation. The polymerases are regarded as molecular information motors during the elongation process. It requires a full spectrum of computational approaches from multiple time and length scales to understand the full polymerase functional cycle. We keep away from quantum mechanics based approaches to the polymerase catalysis due to abundant former surveys, while address only statistical physics modeling approach and all-atom molecular dynamics simulation approach. We organize this review around our own modeling and simulation practices on a single-subunit T7 RNA polymerase, and summarize commensurate studies on structurally similar DNA polymerases. For multi-subunit RNA polymerases that have been intensively studied in recent years, we leave detailed discussions on the simulation achievements to other computational chemical surveys, while only introduce very recently published representative studies, including our own preliminary work on structure-based modeling on yeast RNA polymerase II. In the end, we quickly go through kinetic modeling on elongation pauses and backtracking activities. We emphasize the fluctuation and control mechanisms of the polymerase actions, highlight the non-equilibrium physical nature of the system, and try to bring some perspectives toward understanding replication and transcription regulation from single molecular details to a genome-wide scale

Topological Properties of Citation and Metabolic Networks

Topological properties of "scale-free" networks are investigated by determining their spectral dimensions $d_S$, which reflect a diffusion process in the corresponding graphs. Data bases for citation networks and metabolic networks together with simulation results from the growing network model \cite{barab} are probed. For completeness and comparisons lattice, random, small-world models are also investigated. We find that $d_S$ is around 3 for citation and metabolic networks, which is significantly different from the growing network model, for which $d_S$ is approximately 7.5. This signals a substantial difference in network topology despite the observed similarities in vertex order distributions. In addition, the diffusion analysis indicates that whereas the citation networks are tree-like in structure, the metabolic networks contain many loops.Comment: 11 pages, 3 figure