Genes involved in complex adaptive processes tend to have highly conserved upstream regions in mammalian genomes

BACKGROUND:Recent advances in genome sequencing suggest a remarkable conservation in gene content of mammalian organisms. The similarity in gene repertoire present in different organisms has increased interest in studying regulatory mechanisms of gene expression aimed at elucidating the differences in phenotypes. In particular, a proximal promoter region contains a large number of regulatory elements that control the expression of its downstream gene. Although many studies have focused on identification of these elements, a broader picture on the complexity of transcriptional regulation of different biological processes has not been addressed in mammals. The regulatory complexity may strongly correlate with gene function, as different evolutionary forces must act on the regulatory systems under different biological conditions. We investigate this hypothesis by comparing the conservation of promoters upstream of genes classified in different functional categories.RESULTS:By conducting a rank correlation analysis between functional annotation and upstream sequence alignment scores obtained by human-mouse and human-dog comparison, we found a significantly greater conservation of the upstream sequence of genes involved in development, cell communication, neural functions and signaling processes than those involved in more basic processes shared with unicellular organisms such as metabolism and ribosomal function. This observation persists after controlling for G+C content. Considering conservation as a functional signature, we hypothesize a higher density of cis-regulatory elements upstream of genes participating in complex and adaptive processes.CONCLUSION:We identified a class of functions that are associated with either high or low promoter conservation in mammals. We detected a significant tendency that points to complex and adaptive processes were associated with higher promoter conservation, despite the fact that they have emerged relatively recently during evolution. We described and contrasted several hypotheses that provide a deeper insight into how transcriptional complexity might have been emerged during evolution.

Adaptive Routing of QoS-constrained Media Streams over Scalable Overlay Topologies

Current research on Internet-based distributed systems emphasizes the scalability of overlay topologies for efficient search and retrieval of data items, as well as routing amongst peers. However, most existing approaches fail to address the transport of data across these logical networks in accordance with quality of service (QoS) constraints. Consequently, this paper investigates the use of scalable overlay topologies for routing real-time media streams between publishers and potentially many thousands of subscribers. Specifically, we analyze the costs of using k-ary n-cubes for QoS-constrained routing. Given a number of nodes in a distributed system, we calculate the optimal k-ary n-cube structure for minimizing the average distance between any pair of nodes. Using this structure, we describe a greedy algorithm that selects paths between nodes in accordance with the real-time delays along physical links. We show this method improves the routing latencies by as much as 67%, compared to approaches that do not consider physical link costs. We are in the process of developing a method for adaptive node placement in the overlay topology, based upon the locations of publishers, subscribers, physical link costs and per-subscriber QoS constraints. One such method for repositioning nodes in logical space is discussed, to improve the likelihood of meeting service requirements on data routed between publishers and subscribers. Future work will evaluate the benefits of such techniques more thoroughly.

Informed Content Delivery Across Adaptive Overlay Networks

Overlay networks have emerged as a powerful and highly flexible method for delivering content. We study how to optimize throughput of large, multipoint transfers across richly connected overlay networks, focusing on the question of what to put in each transmitted packet. We first make the case for transmitting encoded content in this scenario, arguing for the digital fountain approach which enables end-hosts to efficiently restitute the original content of size n from a subset of any n symbols from a large universe of encoded symbols. Such an approach affords reliability and a substantial degree of application-level flexibility, as it seamlessly tolerates packet loss, connection migration, and parallel transfers. However, since the sets of symbols acquired by peers are likely to overlap substantially, care must be taken to enable them to collaborate effectively. We provide a collection of useful algorithmic tools for efficient estimation, summarization, and approximate reconciliation of sets of symbols between pairs of collaborating peers, all of which keep messaging complexity and computation to a minimum. Through simulations and experiments on a prototype implementation, we demonstrate the performance benefits of our informed content delivery mechanisms and how they complement existing overlay network architectures.

Adaptive Weighing Designs for Keyword Value Computation

Attributing a dollar value to a keyword is an essential part of running any profitable search engine advertising campaign. When an advertiser has complete control over the interaction with and monetization of each user arriving on a given keyword, the value of that term can be accurately tracked. However, in many instances, the advertiser may monetize arrivals indirectly through one or more third parties. In such cases, it is typical for the third party to provide only coarse-grained reporting: rather than report each monetization event, users are aggregated into larger channels and the third party reports aggregate information such as total daily revenue for each channel. Examples of third parties that use channels include Amazon and Google AdSense. In such scenarios, the number of channels is generally much smaller than the number of keywords whose value per click (VPC) we wish to learn. However, the advertiser has flexibility as to how to assign keywords to channels over time. We introduce the channelization problem: how do we adaptively assign keywords to channels over the course of multiple days to quickly obtain accurate VPC estimates of all keywords? We relate this problem to classical results in weighing design, devise new adaptive algorithms for this problem, and quantify the performance of these algorithms experimentally. Our results demonstrate that adaptive weighing designs that exploit statistics of term frequency, variability in VPCs across keywords, and flexible channel assignments over time provide the best estimators of keyword VPCs.

Adaptive Reliable Multicast

An increasing number of applications, such as distributed interactive simulation, live auctions, distributed games and collaborative systems, require the network to provide a reliable multicast service. This service enables one sender to reliably transmit data to multiple receivers. Reliability is traditionally achieved by having receivers send negative acknowledgments (NACKs) to request from the sender the retransmission of lost (or missing) data packets. However, this Automatic Repeat reQuest (ARQ) approach results in the well-known NACK implosion problem at the sender. Many reliable multicast protocols have been recently proposed to reduce NACK implosion. But, the message overhead due to NACK requests remains significant. Another approach, based on Forward Error Correction (FEC), requires the sender to encode additional redundant information so that a receiver can independently recover from losses. However, due to the lack of feedback from receivers, it is impossible for the sender to determine how much redundancy is needed. In this paper, we propose a new reliable multicast protocol, called ARM for Adaptive Reliable Multicast. Our protocol integrates ARQ and FEC techniques. The objectives of ARM are (1) reduce the message overhead due to NACK requests, (2) reduce the amount of data transmission, and (3) reduce the time it takes for all receivers to receive the data intact (without loss). During data transmission, the sender periodically informs the receivers of the number of packets that are yet to be transmitted. Based on this information, each receiver predicts whether this amount is enough to recover its losses. Only if it is not enough, that the receiver requests the sender to encode additional redundant packets. Using ns simulations, we show the superiority of our hybrid ARQ-FEC protocol over the well-known Scalable Reliable Multicast (SRM) protocol.

SomeCast: A Paradigm for Real-Time Adaptive Reliable Multicast

SomeCast is a novel paradigm for the reliable multicast of real-time data to a large set of receivers over the Internet. SomeCast is receiver-initiated and thus scalable in the number of receivers, the diverse characteristics of paths between senders and receivers (e.g. maximum bandwidth and round-trip-time), and the dynamic conditions of such paths (e.g. congestion-induced delays and losses). SomeCast enables receivers to dynamically adjust the rate at which they receive multicast information to enable the satisfaction of real-time QoS constraints (e.g. rate, deadlines, or jitter). This is done by enabling a receiver to join SOME number of concurrent multiCAST sessions, whereby each session delivers a portion of an encoding of the real-time data. By adjusting the number of such sessions dynamically, client-specific QoS constraints can be met independently. The SomeCast paradigm can be thought of as a generalization of the AnyCast (e.g. Dynamic Server Selection) and ManyCast (e.g. Digital Fountain) paradigms, which have been proposed in the literature to address issues of scalability of UniCast and MultiCast environments, respectively. In this paper we overview the SomeCast paradigm, describe an instance of a SomeCast protocol, and present simulation results that quantify the significant advantages gained from adopting such a protocol for the reliable multicast of data to a diverse set of receivers subject to real-time QoS constraints.

An Adaptive Policy Management Approach to BGP Convergence

The Border Gateway Protocol (BGP) is the current inter-domain routing protocol used to exchange reachability information between Autonomous Systems (ASes) in the Internet. BGP supports policy-based routing which allows each AS to independently adopt a set of local policies that specify which routes it accepts and advertises from/to other networks, as well as which route it prefers when more than one route becomes available. However, independently chosen local policies may cause global conflicts, which result in protocol divergence. In this paper, we propose a new algorithm, called Adaptive Policy Management Scheme (APMS), to resolve policy conflicts in a distributed manner. Akin to distributed feedback control systems, each AS independently classifies the state of the network as either conflict-free or potentially-conflicting by observing its local history only (namely, route flaps). Based on the degree of measured conflicts (policy conflict-avoidance vs. -control mode), each AS dynamically adjusts its own path preferences—increasing its preference for observably stable paths over flapping paths. APMS also includes a mechanism to distinguish route flaps due to topology changes, so as not to confuse them with those due to policy conflicts. A correctness and convergence analysis of APMS based on the substability property of chosen paths is presented. Implementation in the SSF network simulator is performed, and simulation results for different performance metrics are presented. The metrics capture the dynamic performance (in terms of instantaneous throughput, delay, routing load, etc.) of APMS and other competing solutions, thus exposing the often neglected aspects of performance.

An Adaptive Management Approach to Resolving Policy Conflicts

The Border Gateway Protocol (BGP) is the current inter-domain routing protocol used to exchange reachability information between Autonomous Systems (ASes) in the Internet. BGP supports policy-based routing which allows each AS to independently define a set of local policies on which routes it accepts and advertises from/to other networks, as well as on which route it prefers when more than one route becomes available. However, independently chosen local policies may cause global conflicts, which result in protocol divergence. In this paper, we propose a new algorithm, called Adaptive Policy Management Scheme(APMS), to resolve policy conflicts in a distributed manner. Akin to distributed feedback control systems, each AS independently classifies the state of the network as either conflict-free or potentially conflicting by observing its local history only (namely, route flaps). Based on the degree of measured conflicts, each AS dynamically adjusts its own path preferences---increasing its preference for observably stable paths over flapping paths. APMS also includes a mechanism to distinguish route flaps due to topology changes, so as not to confuse them with those due to policy conflicts. A correctness and convergence analysis of APMS based on the sub-stability property of chosen paths is presented. Implementation in the SSF network simulator is performed, and simulation results for different performance metrics are presented. The metrics capture the dynamic performance (in terms of instantaneous throughput, delay, etc.) of APMS and other competing solutions, thus exposing the often neglected aspects of performance.

Adaptive Neural Models of Queuing and Timing in Fluent Action

Temporal structure in skilled, fluent action exists at several nested levels. At the largest scale considered here, short sequences of actions that are planned collectively in prefrontal cortex appear to be queued for performance by a cyclic competitive process that operates in concert with a parallel analog representation that implicitly specifies the relative priority of elements of the sequence. At an intermediate scale, single acts, like reaching to grasp, depend on coordinated scaling of the rates at which many muscles shorten or lengthen in parallel. To ensure success of acts such as catching an approaching ball, such parallel rate scaling, which appears to be one function of the basal ganglia, must be coupled to perceptual variables, such as time-to-contact. At a fine scale, within each act, desired rate scaling can be realized only if precisely timed muscle activations first accelerate and then decelerate the limbs, to ensure that muscle length changes do not under- or over-shoot the amounts needed for the precise acts. Each context of action may require a much different timed muscle activation pattern than similar contexts. Because context differences that require different treatment cannot be known in advance, a formidable adaptive engine-the cerebellum-is needed to amplify differences within, and continuosly search, a vast parallel signal flow, in order to discover contextual "leading indicators" of when to generate distinctive parallel patterns of analog signals. From some parts of the cerebellum, such signals controls muscles. But a recent model shows how the lateral cerebellum, such signals control muscles. But a recent model shows how the lateral cerebellum may serve the competitive queuing system (in frontal cortex) as a repository of quickly accessed long-term sequence memories. Thus different parts of the cerebellum may use the same adaptive engine system design to serve the lowest and the highest of the three levels of temporal structure treated. If so, no one-to-one mapping exists between levels of temporal structure and major parts of the brain. Finally, recent data cast doubt on network-delay models of cerebellar adaptive timing.

KInNeSS: A Modular Framework for Computational Neuroscience

Making use of very detailed neurophysiological, anatomical, and behavioral data to build biological-realistic computational models of animal behavior is often a difficult task. Until recently, many software packages have tried to resolve this mismatched granularity with different approaches. This paper presents KInNeSS, the KDE Integrated NeuroSimulation Software environment, as an alternative solution to bridge the gap between data and model behavior. This open source neural simulation software package provides an expandable framework incorporating features such as ease of use, scalabiltiy, an XML based schema, and multiple levels of granularity within a modern object oriented programming design. KInNeSS is best suited to simulate networks of hundreds to thousands of branched multu-compartmental neurons with biophysical properties such as membrane potential, voltage-gated and ligand-gated channels, the presence of gap junctions of ionic diffusion, neuromodulation channel gating, the mechanism for habituative or depressive synapses, axonal delays, and synaptic plasticity. KInNeSS outputs include compartment membrane voltage, spikes, local-field potentials, and current source densities, as well as visualization of the behavior of a simulated agent. An explanation of the modeling philosophy and plug-in development is also presented. Further developement of KInNeSS is ongoing with the ultimate goal of creating a modular framework that will help researchers across different disciplines to effecitively collaborate using a modern neural simulation platform.

Spikes, Synchrony, and Attentive Learning by Laminar Thalamocortical Circuits

This article develops the Synchronous Matching Adaptive Resonance Theory (SMART) neural model to explain how the brain may coordinate multiple levels of thalamocortical and corticocortical processing to rapidly learn, and stably remember, important information about a changing world. The model clarifies how bottom-up and top-down processes work together to realize this goal, notably how processes of learning, expectation, attention, resonance, and synchrony are coordinated. The model hereby clarifies, for the first time, how the following levels of brain organization coexist to realize cognitive processing properties that regulate fast learning and stable memory of brain representations: single cell properties, such as spiking dynamics, spike-timing-dependent plasticity (STDP), and acetylcholine modulation; detailed laminar thalamic and cortical circuit designs and their interactions; aggregate cell recordings, such as current-source densities and local field potentials; and single cell and large-scale inter-areal oscillations in the gamma and beta frequency domains. In particular, the model predicts how laminar circuits of multiple cortical areas interact with primary and higher-order specific thalamic nuclei and nonspecific thalamic nuclei to carry out attentive visual learning and information processing. The model simulates how synchronization of neuronal spiking occurs within and across brain regions, and triggers STDP. Matches between bottom-up adaptively filtered input patterns and learned top-down expectations cause gamma oscillations that support attention, resonance, and learning. Mismatches inhibit learning while causing beta oscillations during reset and hypothesis testing operations that are initiated in the deeper cortical layers. The generality of learned recognition codes is controlled by a vigilance process mediated by acetylcholine.

KInNeSS: A Modular Framework for Computational Neuroscience

Making use of very detailed neurophysiological, anatomical, and behavioral data to build biologically-realistic computational models of animal behavior is often a difficult task. Until recently, many software packages have tried to resolve this mismatched granularity with different approaches. This paper presents KInNeSS, the KDE Integrated NeuroSimulation Software environment, as an alternative solution to bridge the gap between data and model behavior. This open source neural simulation software package provides an expandable framework incorporating features such as ease of use, scalability, an XML based schema, and multiple levels of granularity within a modern object oriented programming design. KInNeSS is best suited to simulate networks of hundreds to thousands of branched multi-compartmental neurons with biophysical properties such as membrane potential, voltage-gated and ligand-gated channels, the presence of gap junctions or ionic diffusion, neuromodulation channel gating, the mechanism for habituative or depressive synapses, axonal delays, and synaptic plasticity. KInNeSS outputs include compartment membrane voltage, spikes, local-field potentials, and current source densities, as well as visualization of the behavior of a simulated agent. An explanation of the modeling philosophy and plug-in development is also presented. Further development of KInNeSS is ongoing with the ultimate goal of creating a modular framework that will help researchers across different disciplines to effectively collaborate using a modern neural simulation platform.

Task-Irrelevant Perceptual Learning Specific to the Contrast Polarity of Motion Stimuli

Studies of perceptual learning have focused on aspects of learning that are related to early stages of sensory processing. However, conclusions that perceptual learning results in low-level sensory plasticity are of great controversy, largely because such learning can often be attributed to plasticity in later stages of sensory processing or in the decision processes. To address this controversy, we developed a novel random dot motion (RDM) stimulus to target motion cells selective to contrast polarity, by ensuring the motion direction information arises only from signal dot onsets and not their offsets, and used these stimuli in conjunction with the paradigm of task-irrelevant perceptual learning (TIPL). In TIPL, learning is achieved in response to a stimulus by subliminally pairing that stimulus with the targets of an unrelated training task. In this manner, we are able to probe learning for an aspect of motion processing thought to be a function of directional V1 simple cells with a learning procedure that dissociates the learned stimulus from the decision processes relevant to the training task. Our results show learning for the exposed contrast polarity and that this learning does not transfer to the unexposed contrast polarity. These results suggest that TIPL for motion stimuli may occur at the stage of directional V1 simple cells.

Adaptive Resonance Theory

SyNAPSE program of the Defense Advanced Projects Research Agency (Hewlett-Packard Company, subcontract under DARPA prime contract HR0011-09-3-0001, and HRL Laboratories LLC, subcontract #801881-BS under DARPA prime contract HR0011-09-C-0001); CELEST, an NSF Science of Learning Center (SBE-0354378)

Cerebellar Learning in an Opponent Motor Controller for Adaptive Load Compensation and Synergy Formation

This paper shows how a minimal neural network model of the cerebellum may be embedded within a sensory-neuro-muscular control system that mimics known anatomy and physiology. With this embedding, cerebellar learning promotes load compensation while also allowing both coactivation and reciprocal inhibition of sets of antagonist muscles. In particular, we show how synaptic long term depression guided by feedback from muscle stretch receptors can lead to trans-cerebellar gain changes that are load-compensating. It is argued that the same processes help to adaptively discover multi-joint synergies. Simulations of rapid single joint rotations under load illustrates design feasibility and stability.