Protein Docking by the Underestimation of Free Energy Funnels in the Space of Encounter Complexes

Similarly to protein folding, the association of two proteins is driven by a free energy funnel, determined by favorable interactions in some neighborhood of the native state. We describe a docking method based on stochastic global minimization of funnel-shaped energy functions in the space of rigid body motions (SE(3)) while accounting for flexibility of the interface side chains. The method, called semi-definite programming-based underestimation (SDU), employs a general quadratic function to underestimate a set of local energy minima and uses the resulting underestimator to bias further sampling. While SDU effectively minimizes functions with funnel-shaped basins, its application to docking in the rotational and translational space SE(3) is not straightforward due to the geometry of that space. We introduce a strategy that uses separate independent variables for side-chain optimization, center-to-center distance of the two proteins, and five angular descriptors of the relative orientations of the molecules. The removal of the center-to-center distance turns out to vastly improve the efficiency of the search, because the five-dimensional space now exhibits a well-behaved energy surface suitable for underestimation. This algorithm explores the free energy surface spanned by encounter complexes that correspond to local free energy minima and shows similarity to the model of macromolecular association that proceeds through a series of collisions. Results for standard protein docking benchmarks establish that in this space the free energy landscape is a funnel in a reasonably broad neighborhood of the native state and that the SDU strategy can generate docking predictions with less than 5 � ligand interface Ca root-mean-square deviation while achieving an approximately 20-fold efficiency gain compared to Monte Carlo methods.

Articulated Pose Estimation in a Learned Smooth Space of Feasible Solutions

A learning based framework is proposed for estimating human body pose from a single image. Given a differentiable function that maps from pose space to image feature space, the goal is to invert the process: estimate the pose given only image features. The inversion is an ill-posed problem as the inverse mapping is a one to many process. Hence multiple solutions exist, and it is desirable to restrict the solution space to a smaller subset of feasible solutions. For example, not all human body poses are feasible due to anthropometric constraints. Since the space of feasible solutions may not admit a closed form description, the proposed framework seeks to exploit machine learning techniques to learn an approximation that is smoothly parameterized over such a space. One such technique is Gaussian Process Latent Variable Modelling. Scaled conjugate gradient is then used find the best matching pose in the space of feasible solutions when given an input image. The formulation allows easy incorporation of various constraints, e.g. temporal consistency and anthropometric constraints. The performance of the proposed approach is evaluated in the task of upper-body pose estimation from silhouettes and compared with the Specialized Mapping Architecture. The estimation accuracy of the Specialized Mapping Architecture is at least one standard deviation worse than the proposed approach in the experiments with synthetic data. In experiments with real video of humans performing gestures, the proposed approach produces qualitatively better estimation results.

Fuzzy ART

Adaptive Resonance Theory (ART) models are real-time neural networks for category learning, pattern recognition, and prediction. Unsupervised fuzzy ART and supervised fuzzy ARTMAP synthesize fuzzy logic and ART networks by exploiting the formal similarity between the computations of fuzzy subsethood and the dynamics of ART category choice, search, and learning. Fuzzy ART self-organizes stable recognition categories in response to arbitrary sequences of analog or binary input patterns. It generalizes the binary ART 1 model, replacing the set-theoretic: intersection (∩) with the fuzzy intersection (∧), or component-wise minimum. A normalization procedure called complement coding leads to a symmetric: theory in which the fuzzy inter:>ec:tion and the fuzzy union (∨), or component-wise maximum, play complementary roles. Complement coding preserves individual feature amplitudes while normalizing the input vector, and prevents a potential category proliferation problem. Adaptive weights :otart equal to one and can only decrease in time. A geometric interpretation of fuzzy AHT represents each category as a box that increases in size as weights decrease. A matching criterion controls search, determining how close an input and a learned representation must be for a category to accept the input as a new exemplar. A vigilance parameter (p) sets the matching criterion and determines how finely or coarsely an ART system will partition inputs. High vigilance creates fine categories, represented by small boxes. Learning stops when boxes cover the input space. With fast learning, fixed vigilance, and an arbitrary input set, learning stabilizes after just one presentation of each input. A fast-commit slow-recode option allows rapid learning of rare events yet buffers memories against recoding by noisy inputs. Fuzzy ARTMAP unites two fuzzy ART networks to solve supervised learning and prediction problems. A Minimax Learning Rule controls ARTMAP category structure, conjointly minimizing predictive error and maximizing code compression. Low vigilance maximizes compression but may therefore cause very different inputs to make the same prediction. When this coarse grouping strategy causes a predictive error, an internal match tracking control process increases vigilance just enough to correct the error. ARTMAP automatically constructs a minimal number of recognition categories, or "hidden units," to meet accuracy criteria. An ARTMAP voting strategy improves prediction by training the system several times using different orderings of the input set. Voting assigns confidence estimates to competing predictions given small, noisy, or incomplete training sets. ARPA benchmark simulations illustrate fuzzy ARTMAP dynamics. The chapter also compares fuzzy ARTMAP to Salzberg's Nested Generalized Exemplar (NGE) and to Simpson's Fuzzy Min-Max Classifier (FMMC); and concludes with a summary of ART and ARTMAP applications.

The Art of Seeing and Painting

The human urge to represent the three-dimensional world using two-dimensional pictorial representations dates back at least to Paleolithic times. Artists from ancient to modern times have struggled to understand how a few contours or color patches on a flat surface can induce mental representations of a three-dimensional scene. This article summarizes some of the recent breakthroughs in scientifically understanding how the brain sees that shed light on these struggles. These breakthroughs illustrate how various artists have intuitively understand paradoxical properties about how the brain sees, and have used that understanding to create great art. These paradoxical properties arise from how the brain forms the units of conscious visual perception; namely, representations of three-dimensional boundaries and surfaces. Boundaries and surfaces are computed in parallel cortical processing streams that obey computationally complementary properties. These streams interact at multiple levels to overcome their complementary weaknesses and to transform their complementary properties into consistent percepts. The article describes how properties of complementary consistency have guided the creation of many great works of art.

The Impact of AIDS on Government Service Delivery: The Case of the Zambia Wildlife Authority

Background: The loss of working-aged adults to HIV/AIDS has been shown to increase the costs of labor to the private sector in Africa. There is little corresponding evidence for the public sector. This study evaluated the impact of AIDS on the capacity of a government agency, the Zambia Wildlife Authority (ZAWA), to patrol Zambia’s national parks. Methods: Data were collected from ZAWA on workforce characteristics, recent mortality, costs, and the number of days spent on patrol between 2003 and 2005 by a sample of 76 current patrol officers (reference subjects) and 11 patrol officers who died of AIDS or suspected AIDS (index subjects). An estimate was made of the impact of AIDS on service delivery capacity and labor costs and the potential net benefits of providing treatment. Results: Reference subjects spent an average of 197.4 days on patrol per year. After adjusting for age, years of service, and worksite, index subjects spent 62.8 days on patrol in their last year of service (68% decrease, p<0.0001), 96.8 days on patrol in their second to last year of service (51% decrease, p<0.0001), and 123.7 days on patrol in their third to last year of service (37% decrease, p<0.0001). For each employee who died, ZAWA lost an additional 111 person-days for management, funeral attendance, vacancy, and recruitment and training of a replacement, resulting in a total productivity loss per death of 2.0 person-years. Each AIDS-related death also imposed budgetary costs for care, benefits, recruitment, and training equivalent to 3.3 years’ annual compensation. In 2005, AIDS reduced service delivery capacity by 6.2% and increased labor costs by 9.7%. If antiretroviral therapy could be provided for $500/patient/year, net savings to ZAWA would approach $285,000/year. Conclusion: AIDS is constraining ZAWA’s ability to protect Zambia’s wildlife and parks. Impacts on this government agency are substantially larger than have been observed in the private sector. Provision of ART would result in net budgetary savings to ZAWA and greatly increase its service delivery capacity.

Non-clinical outcomes of antiretroviral therapy for HIV/AIDS in developing countries: a systematic literature review

The impacts of antiretroviral therapy on quality of life, mental health, labor productivity, and economic wellbeing for people living with HIV/AIDS in developing countries are only beginning to be measured. We conducted a systematic literature review to analyze the effect of antiretroviral therapy (ART) on these non-clinical indicators in developing countries and assess the state of research on these topics. Both qualitative and quantitative studies were included, as were peer-reviewed articles, gray literature, and conference abstracts and presentations. Findings are reported from 12 full-length articles, 7 abstracts, and 1 presentation (representing 16 studies). Compared to HIV-positive patients not yet on treatment, patients on ART reported significant improvements in physical, emotional and mental health and daily function. Work performance improved and absenteeism decreased, with the most dramatic changes occurring in the first three months of treatment and then leveling off. Little research has been done on the impact of ART on household wellbeing, with modest changes in child and family wellbeing within households where adults are receiving ART reported so far. Studies from developing countries have not yet assessed non-clinical outcomes of therapy beyond the first year; therefore, longitudinal outcomes are still unknown. As ART roll out extends throughout high HIV prevalence, low-resource countries and is sustained over years and decades, both positive and adverse non-clinical outcomes need to be empirically measured and qualitatively explored in order to support patient adherence and maximize treatment benefits.

A Lower-Bound Result on the Power of a Genetic Algorithm

This paper presents a lower-bound result on the computational power of a genetic algorithm in the context of combinatorial optimization. We describe a new genetic algorithm, the merged genetic algorithm, and prove that for the class of monotonic functions, the algorithm finds the optimal solution, and does so with an exponential convergence rate. The analysis pertains to the ideal behavior of the algorithm where the main task reduces to showing convergence of probability distributions over the search space of combinatorial structures to the optimal one. We take exponential convergence to be indicative of efficient solvability for the sample-bounded algorithm, although a sampling theory is needed to better relate the limit behavior to actual behavior. The paper concludes with a discussion of some immediate problems that lie ahead.

Fuzzy ART Choice Functions

Adaptive Resonance Theory (ART) models are real-time neural networks for category learning, pattern recognition, and prediction. Unsupervised fuzzy ART and supervised fuzzy ARTMAP networks synthesize fuzzy logic and ART by exploiting the formal similarity between tile computations of fuzzy subsethood and the dynamics of ART category choice, search, and learning. Fuzzy ART self-organizes stable recognition categories in response to arbitrary sequences of analog or binary input patterns. It generalizes the binary ART 1 model, replacing the set-theoretic intersection (∩) with the fuzzy intersection(∧), or component-wise minimum. A normalization procedure called complement coding leads to a symmetric theory in which the fuzzy intersection and the fuzzy union (∨), or component-wise maximum, play complementary roles. A geometric interpretation of fuzzy ART represents each category as a box that increases in size as weights decrease. This paper analyzes fuzzy ART models that employ various choice functions for category selection. One such function minimizes total weight change during learning. Benchmark simulations compare peformance of fuzzy ARTMAP systems that use different choice functions.

Space, Time and Learning in the Hippocampus: How Fine Spatial and Temporal Scales Are Expanded into Population Codes for Behavioral Control

The hippocampus participates in multiple functions, including spatial navigation, adaptive timing, and declarative (notably, episodic) memory. How does it carry out these particular functions? The present article proposes that hippocampal spatial and temporal processing are carried out by parallel circuits within entorhinal cortex, dentate gyrus, and CA3 that are variations of the same circuit design. In particular, interactions between these brain regions transform fine spatial and temporal scales into population codes that are capable of representing the much larger spatial and temporal scales that are needed to control adaptive behaviors. Previous models of adaptively timed learning propose how a spectrum of cells tuned to brief but different delays are combined and modulated by learning to create a population code for controlling goal-oriented behaviors that span hundreds of milliseconds or even seconds. Here it is proposed how projections from entorhinal grid cells can undergo a similar learning process to create hippocampal place cells that can cover a space of many meters that are needed to control navigational behaviors. The suggested homology between spatial and temporal processing may clarify how spatial and temporal information may be integrated into an episodic memory.

ART 2-A: An Adaptive Resonance Algorithm for Rapid Category Learning and Recognition

This article introduces ART 2-A, an efficient algorithm that emulates the self-organizing pattern recognition and hypothesis testing properties of the ART 2 neural network architecture, but at a speed two to three orders of magnitude faster. Analysis and simulations show how the ART 2-A systems correspond to ART 2 dynamics at both the fast-learn limit and at intermediate learning rates. Intermediate learning rates permit fast commitment of category nodes but slow recoding, analogous to properties of word frequency effects, encoding specificity effects, and episodic memory. Better noise tolerance is hereby achieved without a loss of learning stability. The ART 2 and ART 2-A systems are contrasted with the leader algorithm. The speed of ART 2-A makes practical the use of ART 2 modules in large-scale neural computation.