Geometric representation of neuroanatomical data observed in mouse brain at cellular and gross levels

This dissertation studies two problems related to geometric representation of neuroanatomical data: (i) spatial representation and organization of individual neurons, and (ii) reconstruction of three-dimensional neuroanatomical regions from sparse two-dimensional drawings. This work has been motivated by nearby development of new technology, Knife-Edge Scanning Microscopy (KESM), that images a whole mouse brain at cellular level in less than a month. A method is introduced to represent neuronal data observed in the mammalian brain at the cellular level using geometric primitives and spatial indexing. A data representation scheme is defined that captures the geometry of individual neurons using traditional geometric primitives, points and cross-sectional areas along a trajectory. This representation captures inferred synapses as directed links between primitives and spatially indexes observed neurons based on the locations of their cell bodies. This method provides a set of rules for acquisition, representation, and indexing of KESMgenerated data. Neuroanatomical data observed at the gross level provides the underlying regional framework for neuronal circuits. Accumulated expert knowledge on neuroanatomical organization is usually given as a series of sparse two-dimensional contours. A data structure and an algorithm are described to reconstruct separating surfaces among multiple regions from these sparse cross-sectional contours. A topology graph is defined for each region that describes the topological skeleton of the region’s boundary surface and that shows between which contours the surface patches should be generated. A graph-directed triangulation algorithm is provided to reconstruct surface patches between contours. This graph-directed triangulation algorithm combined together with a piecewise parametric curve fitting technique ensures that abutting or shared surface patches are precisely coincident. This method overcomes limitations in i) traditional surfaces-from-contours algorithms that assume binary, not multiple, regionalization of space, and in ii) few existing separating surfaces algorithms that assume conversion of input into a regular volumetric grid, which is not possible with sparse inter-planar resolution

MICRAT: A Novel Algorithm for Inferring Gene Regulatory Networks Using Time Series Gene Expression Data

Background: Reconstruction of gene regulatory networks (GRNs), also known as reverse engineering of GRNs, aims to infer the potential regulation relationships between genes. With the development of biotechnology, such as gene chip microarray and RNA-sequencing, the high-throughput data generated provide us with more opportunities to infer the gene-gene interaction relationships using gene expression data and hence understand the underlying mechanism of biological processes. Gene regulatory networks are known to exhibit a multiplicity of interaction mechanisms which include functional and non-functional, and linear and non-linear relationships. Meanwhile, the regulatory interactions between genes and gene products are not spontaneous since various processes involved in producing fully functional and measurable concentrations of transcriptional factors/proteins lead to a delay in gene regulation. Many different approaches for reconstructing GRNs have been proposed, but the existing GRN inference approaches such as probabilistic Boolean networks and dynamic Bayesian networks have various limitations and relatively low accuracy. Inferring GRNs from time series microarray data or RNA-sequencing data remains a very challenging inverse problem due to its nonlinearity, high dimensionality, sparse and noisy data, and significant computational cost, which motivates us to develop more effective inference methods. Results: We developed a novel algorithm, MICRAT (Maximal Information coefficient with Conditional Relative Average entropy and Time-series mutual information), for inferring GRNs from time series gene expression data. Maximal information coefficient (MIC) is an effective measure of dependence for two-variable relationships. It captures a wide range of associations, both functional and non-functional, and thus has good performance on measuring the dependence between two genes. Our approach mainly includes two procedures. Firstly, it employs maximal information coefficient for constructing an undirected graph to represent the underlying relationships between genes. Secondly, it directs the edges in the undirected graph for inferring regulators and their targets. In this procedure, the conditional relative average entropies of each pair of nodes (or genes) are employed to indicate the directions of edges. Since the time delay might exist in the expression of regulators and target genes, time series mutual information is combined to cooperatively direct the edges for inferring the potential regulators and their targets. We evaluated the performance of MICRAT by applying it to synthetic datasets as well as real gene expression data and compare with other GRN inference methods. We inferred five 10-gene and five 100-gene networks from the DREAM4 challenge that were generated using the gene expression simulator GeneNetWeaver (GNW). MICRAT was also used to reconstruct GRNs on real gene expression data including part of the DNA-damaged response pathway (SOS DNA repair network) and experimental dataset in E. Coli. The results showed that MICRAT significantly improved the inference accuracy, compared to other inference methods, such as TDBN, etc. Conclusion: In this work, a novel algorithm, MICRAT, for inferring GRNs from time series gene expression data was proposed by taking into account dependence and time delay of expressions of a regulator and its target genes. This approach employed maximal information coefficients for reconstructing an undirected graph to represent the underlying relationships between genes. The edges were directed by combining conditional relative average entropy with time course mutual information of pairs of genes. The proposed algorithm was evaluated on the benchmark GRNs provided by the DREAM4 challenge and part of the real SOS DNA repair network in E. Coli. The experimental study showed that our approach was comparable to other methods on 10-gene datasets and outperformed other methods on 100-gene datasets in GRN inference from time series datasets

Distributed, web-based microstructure database for brain tissue

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references (leaves 44-46).Issued also on microfiche from Lange Micrographics.A finite element model of the cerebral cortex enables a structured visualization of its gross anatomy and provides access to the neuronal databases associated with each unite element of tissue. Partitioned by finite elements, the distributed, web-based microstructure database serves as a tool for organizing neurons and neuronal forests, and for modeling local cortical microstructure by wiring up the forests. Embedding the database in XML adds structure and web-accessibility to the inherent information. When integrated with the brain tissue scanner, the distributed, web-based microstructure database serves as a comprehensive infrastructure for organizing brain tissue at three different hierarchical levels: volume, neuronal morphology, and network

An accelerated algorithm for discrete stochastic simulation of reaction–diffusion systems using gradient-based diffusion and tau-leaping

Stochastic simulation of reaction–diffusion systems enables the investigation of stochastic events arising from the small numbers and heterogeneous distribution of molecular species in biological cells. Stochastic variations in intracellular microdomains and in diffusional gradients play a significant part in the spatiotemporal activity and behavior of cells. Although an exact stochastic simulation that simulates every individual reaction and diffusion event gives a most accurate trajectory of the system's state over time, it can be too slow for many practical applications. We present an accelerated algorithm for discrete stochastic simulation of reaction–diffusion systems designed to improve the speed of simulation by reducing the number of time-steps required to complete a simulation run. This method is unique in that it employs two strategies that have not been incorporated in existing spatial stochastic simulation algorithms. First, diffusive transfers between neighboring subvolumes are based on concentration gradients. This treatment necessitates sampling of only the net or observed diffusion events from higher to lower concentration gradients rather than sampling all diffusion events regardless of local concentration gradients. Second, we extend the non-negative Poisson tau-leaping method that was originally developed for speeding up nonspatial or homogeneous stochastic simulation algorithms. This method calculates each leap time in a unified step for both reaction and diffusion processes while satisfying the leap condition that the propensities do not change appreciably during the leap and ensuring that leaping does not cause molecular populations to become negative. Numerical results are presented that illustrate the improvement in simulation speed achieved by incorporating these two new strategies