488943
A Combinatorial Toolbox for Protein Sequence Design and Landscape Analysis in the Grand Canonical Model
In modern biology, one of the most important research problems is to understand how protein sequences fold into their native 3D structures. To investigate this problem at a high level, one wishes to analyze the protein landscapes, i.e., the structures of the space of all protein sequences and their native 3D structures. Perhaps the most basic computational problem at this level is to take a target 3D structure as input and design a fittest protein sequence with respect to one or more fitness functions of the target 3D structure. We develop a toolbox of combinatorial techniques for protein landscape analysis in the Grand Canonical model of Sun, Brem, Chan, and Dill. The toolbox is based on linear programming, network flow, and a linear-size representation of all minimum cuts of a network. It not only substantially expands the network flow technique for protein sequence design in Kleinberg's seminal work but also is applicable to a considerably broader collection of computational problems than those considered by Kleinberg. We have used this toolbox to obtain a number of efficient algorithms and hardness results. We have further used the algorithms to analyze 3D structures drawn from the Protein Data Bank and have discovered some novel relationships between such native 3D structures and the Grand Canonical model.
32992816
A Combinatorial Toolbox for Protein Sequence Design and Landscape Analysis in the Grand Canonical Model
In modern biology, one of the most important research problems is to understand how protein sequences fold into their native 3D structures. To investigate this problem at a high level, one wishes to analyze the protein landscapes, i.e., the structures of the space of all protein sequences and their native 3D structures. Perhaps the most basic computational problem at this level is to take a target 3D structure as input and design a fittest protein sequence with respect to one or more fitness functions of the target 3D structure. We develop a toolbox of combinatorial techniques for protein landscape analysis in the Grand Canonical model of Sun, Brem, Chan, and Dill. The toolbox is based on linear programming, network flow, and a linear-size representation of all minimum cuts of a network. It not only substantially expands the network flow technique for protein sequence design in Kleinberg's seminal work but also is applicable to a considerably broader collection of computational problems than those considered by Kleinberg. We have used this toolbox to obtain a number of efficient algorithms and hardness results. We have further used the algorithms to analyze 3D structures drawn from the Protein Data Bank and have discovered some novel relationships between such native 3D structures and the Grand Canonical model.
2551048
Computers Are from Mars, Organisms Are from Venus
Biology and computer science share a natural affinity. Physicist Erwin Schrodinger envisioned life as an aperiodic crystal, observing that the organizing structure of life is neither completely regular, like a pure crystal, nor completely chaotic and without structure, like dust in the wind. Perhaps this is why biological information has never satisfactorily yielded to classical mathematical analysis. Machine computations combine elegant algorithms with brute-force calculations, which seems a reasonable approach to this aperiodic structure. Likewise, computing seeks to create a machine that can flexibly solve diverse problems. In nature, such plastic problem solving resides uniquely in the domain of organic matter. Thus, examining how organisms solve problems can lead to new computation and algorithm development approaches that devour the problems that are so easy to approach using a computer, yet so difficult to tackle in the laboratory. The paper discusses the two most successful uses of computers in biology, comparative sequence analysis and in silico cloning. It considers DNA computing and genetic algorithms.
1278377
A Tree Obscured By Vines: Horizontal Gene Transfer and the Median Tree Method of Estimating Species Phylogeny
A phylogeny is a tree graph representation of genealogical relationships between biological objects. It is of general interest to estimate the phylogeny of whole organisms (species trees) using bio-molecular sequences. When multiple sequences are available for each organism such as with whole genome data, individual phylogenies estimated by each molecule (gene trees) may not be concordant. The lack of concordance may be due to actual biological mechanisms such as horizontal transfer of the molecules. Here, we present a new phylogeny estimation method designed to estimate the species tree despite such horizontal transfer. It uses the idea that horizontal transfer distorts distance relationships between pairs of species but a median estimate of the distances is robust to such distortions. We demonstrate the utility of our method using a simulation study.
199137
Scaling of Accuracy in Extremely Large Phylogenetic Trees
The accuracy of phylogenetic inference was examined in simulated data sets up to nearly 10,000 taxa, the size of the largest set of homologous genes in existing molecular sequence databases. Even with a simple search algorithm (maximum parsimony without branch swapping), the number of characters needed to estimate 80% of a tree correctly can scale remarkably well at optimal substitution rates (on the order of log N, where N is the number of taxa). In other words, the number of taxa in an analysis can be doubled and only an arithmetic increase in the number of characters is required to maintain the same level of accuracy. Even substitution rates that are much higher than normally used in phylogenetic studies did not affect the scaling too adversely. However, scaling is usually worse than log N for more stringent levels of accuracy. Moreover, errors are not distributed randomly throughout the tree. Shallow nodes are remarkably easy to reconstruct and display favourable log-linear scaling. The deepest nodes are extremely difficult to reconstruct accurately, even with branch swapping, and the scaling is poor. Therefore, the strategy of sequencing large numbers of homologous genes may not always provide global solutions to extreme phylogenetic problems and alternative strategies may be required.
6308143
Geometry of gene expression dynamics
MOTIVATION
A gene expression trajectory moves through a high dimensional space where each axis represents the mRNA abundance of a different gene. Genome wide gene expression has a dynamic structure, especially in studies of development and temporal response. Both visualization and analyses of such data require an explicit attention to the temporal structure.


RESULTS
Using three cell cycle trajectories from Saccharomyces cerevisiae to illustrate, we present several techniques which reveal the geometry of the data. We import phase-delay time plots from chaotic systems theory as a dynamic data visualization device and show how these plots capture important aspects of the trajectories. We construct an objective function to find an optimal two-dimensional projection of the cell cycle, demonstrate that the system returns to this plane after three different initial perturbations, and explore the conditions under which this geometric approach outperforms standard approaches such as singular value decomposition and Fourier analysis. Finally, we show how a geometric analysis can isolate distinct parts of the trajectories, in this case the initial perturbation versus the cell cycle.


CONTACT
junhyong.kim@yale.edu
6738575
Agent-oriented software modeling
Due to the increased applications of agents, agent-oriented software becomes large and complex. To support systematic developments of such software, the agent-oriented software development methodology needs to be developed. This paper focuses on the modeling phase of agent-oriented software development. For agent-oriented software modeling, the Agent Elicitation method, Intra and Inter Agent modeling method are proposed. Agent Elicitation shows how to extract agents from classes in the real world. Modeling methods of agent's characteristics-Goal, Belief, Plan and Capability-are proposed for Intra Agent modeling. Methods of agent's mobility and communication in multiagent systems are proposed for Inter Agent modeling.
62653029
The BlackWidow High-Radix Clos Network
This paper describes the radix-64 folded-Clos network of the Cray BlackWidow scalable vector multiprocessor. We describe the BlackWidow network which scales to 32K processors with a worstcase diameter of seven hops, and the underlying high-radix router microarchitecture and its implementation. By using a high-radix router with many narrow channels we are able to take advantage of the higher pin density and faster signaling rates available in modern ASIC technology. The BlackWidow router is an 800 MHz ASIC with 64 18.75Gb/s bidirectional ports for an aggregate offchip bandwidth of 2.4Tb/s. Each port consists of three 6.25Gb/s differential signals in each direction. The router supports deterministic and adaptive packet routing with separate buffering for request and reply virtual channels. The router is organized hierarchically [13] as an 8�8 array of tiles which simplifies arbitration by avoiding long wires in the arbiters. Each tile of the array contains a router port, its associated buffering, and an 8�8 router subswitch. The router ASIC is implemented in a 90nm CMOS standard cell ASIC technology and went from concept to tapeout in 17 months.
16116503
Evolutionary programming techniques for constrained optimization problems
Two evolutionary programming (EP) methods are proposed for handling nonlinear constrained optimization problems. The first, a hybrid EP, is useful when addressing heavily constrained optimization problems both in terms of computational efficiency and solution accuracy. But this method offers an exact solution only if both the mathematical form of the objective function to be minimized/maximized and its gradient are known. The second method, a two-phase EP (TPEP) removes these restrictions. The first phase uses the standard EP, while an EP formulation of the augmented Lagrangian method is employed in the second phase. Through the use of Lagrange multipliers and by gradually placing emphasis on violated constraints in the objective function whenever the best solution does not fulfill the constraints, the trial solutions are driven to the optimal point where all constraints are satisfied. Simulations indicate that the TPEP achieves an exact global solution without gradient information, with less computation time than the other optimization methods studied here, for general constrained optimization problems.
6280619
Prediction of subcellular localization of proteins using pairwise sequence alignment and support vector machine
Predicting the destination of a protein in a cell is important for annotating the function of the protein. Recent advances have allowed us to develop more accurate methods for predicting the subcellular localization of proteins. One of the most important factors for improving the accuracy of these methods is related to the introduction of new useful features for protein sequences. In this paper we present a new method for extracting appropriate features from the sequence data by computing pairwise sequence alignment scores. As a classifier, support vector machine (SVM) is used. The overall prediction accuracy evaluated by the jackknife validation technique reached 94.70% for the eukaryotic non-plant data set and 92.10% for the eukaryotic plant data set, which is the highest prediction accuracy among the methods reported so far with such data sets. Our experimental results confirm that our feature extraction method based on pairwise sequence alignment is useful for this classification problem.
5817098
Neural Network Normalization for Genetic Search
An arbitrary neural network has a number of functionally equivalent other networks. This causes redundancy in genetic representation of neural networks, which considerably undermines the merit of crossover in GAs [1]. This problem has received considerable attention in the past and has also been called the “competing conventions” problem [2].