SIEGE: Smoking Induced Epithelial Gene Expression Database

The SIEGE (Smoking Induced Epithelial Gene Expression) database is a clinical resource for compiling and analyzing gene expression data from epithelial cells of the human intra-thoracic airway. This database supports a translational research study whose goal is to profile the changes in airway gene expression that are induced by cigarette smoke. RNA is isolated from airway epithelium obtained at bronchoscopy from current-, former- and never-smoker subjects, and hybridized to Affymetrix HG-U133A Genechips, which measure the level of expression of ~22 500 human transcripts. The microarray data generated along with relevant patient information is uploaded to SIEGE by study administrators using the database's web interface, found at http://pulm.bumc.bu.edu/siegeDB. PERL-coded scripts integrated with SIEGE perform various quality control functions including the processing, filtering and formatting of stored data. The R statistical package is used to import database expression values and execute a number of statistical analyses including t-tests, correlation coefficients and hierarchical clustering. Values from all statistical analyses can be queried through CGI-based tools and web forms found on the �Search� section of the database website. Query results are embedded with graphical capabilities as well as with links to other databases containing valuable gene resources, including Entrez Gene, GO, Biocarta, GeneCards, dbSNP and the NCBI Map Viewer.

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.

Isoperimetric Partitioning: A New Algorithm for Graph Partitioning

Temporal structure is skilled, fluent action exists at several nested levels. At the largest scale considered here, short sequences of actions that are planned collectively in prefronatal 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 finer 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 precise acts. Each context of action may require a 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 patterns of analog signals. From some parts of the cerebellum, such signals control muscles. But a recent model shows how the lateral cerebellum may serve the competitive queuing system (frontal cortex) as a repository of quickly accessed long-term sequence memories. Thus different parts of the cerebellum may use the same adaptive engine design to serve the lowest and highest of the three levels of temporal structure treated. If so, no one-to-one mapping exists between leveels of temporal structure and major parts of the brain. Finally, recent data cast doubt on network-delay models of cerebellar adaptive timing.

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.

Emergence of Tri-Phasic Muscle Activation from the Non-linear Interactions of Central and Spinal Neural Network Circuits

The origin of the tri-phasic burst pattern, observed in the EMGs of opponent muscles during rapid self-terminated movements, has been controversial. Here we show by computer simulation that the pattern emerges from interactions between a central neural trajectory controller (VITE circuit) and a peripheral neuromuscularforce controller (FLETE circuit). Both neural models have been derived from simple functional constraints that have led to principled explanations of a wide variety of behavioral and neurobiological data, including, as shown here, the generation of tri-phasic bursts.

How Spinal Neural Networks Reduce Discrepancies between Motor Intention and Motor Realization

This paper attempts a rational, step-by-step reconstruction of many aspects of the mammalian neural circuitry known to be involved in the spinal cord's regulation of opposing muscles acting on skeletal segments. Mathematical analyses and local circuit simulations based on neural membrane equations are used to clarify the behavioral function of five fundamental cell types, their complex connectivities, and their physiological actions. These cell types are: α-MNs, γ-MNs, IaINs, IbINs, and Renshaw cells. It is shown that many of the complexities of spinal circuitry are necessary to ensure near invariant realization of motor intentions when descending signals of two basic types independently vary over large ranges of magnitude and rate of change. Because these two types of signal afford independent control, or Factorization, of muscle LEngth and muscle TEnsion, our construction was named the FLETE model (Bullock and Grossberg, 1988b, 1989). The present paper significantly extends the range of experimental data encompassed by this evolving model.