We have built a stochastic model in the program MCell that simulates Ca2+ transients in spines from the principal molecular components believed to control Ca2+ entry and exit. Proteins, with their kinetic models, are located within two segments of dendrites containing 88 intact spines, centered in a fully reconstructed 6 × 6 × 5 μm3 cube of hippocampal neuropil. Protein components include AMPA- and NMDA-type glutamate receptors, L- and R-type voltage-dependent Ca2+ channels, Na+/Ca2+ exchangers, plasma membrane Ca2+ ATPases, smooth endoplasmic reticulum Ca2+ ATPases, immobile Ca2+ buffers, and calbindin. Kinetic models for each protein were taken from published studies of the isolated proteins in vitro. For simulation of electrical stimuli, the time course of voltage changes in the dendritic spine was generated with the desired stimulus in the program NEURON. Voltage-dependent parameters were then continuously re-adjusted during simulations in MCell to reproduce the effects of the stimulus. Nine parameters of the model were optimized within realistic experimental limits by a process that compared results of simulations to published data. We find that simulations in the optimized model reproduce the timing and amplitude of Ca2+ transients measured experimentally in intact neurons. Thus, we demonstrate that the characteristics of individual isolated proteins determined in vitro can accurately reproduce the dynamics of experimentally measured Ca2+ transients in spines. The model will provide a test bed for exploring the roles of additional proteins that regulate Ca2+ influx into spines and for studying the behavior of protein targets in the spine that are regulated by Ca2+ influx.

For 2D or 3D meshes that represent a continuous function to the reals, the contours-or isosurfaces-of a specified value are an important way to visualize it. To find such contours, a seed set can be used for the starting points from which the traversal of the contours can start. This paper gives the first methods to obtain seed sets that are provably small in size. They are based on a variant of the contour tree (or topographic change tree). We give a new, simple algorithm to compute such a tree in regular and irregular meshes that requires O(rt log n) time in 2D for meshes with n elements, and in 0( n2) time in higher dimensions. The additional storage overhead is proportiid to the maximum size of any contour (linear in the worst case, but typically less). Given the contour tree, a minimum size seed set can be computed in polynomial time and storage. Since in practice at most linear storage is allowed, we develop a simple approximation aIgorithm giving a seed set of size at most twice the size of the minimum. It requires O(n log2 n) time in 2D and 0(n2) time otherwise, and requires linear storage. We also give experimental results, showing the size of the seed sets and supporting the claim that sublinear storage is used.

We describe an approach to construct hexahedral solid NURBS (Non-Uniform Rational B-Splines) meshes for patient-specific vascular geometric models from imaging data for use in isogeometric analysis. First, image processing techniques, such as contrast enhancement, filtering, classification, and segmentation, are used to improve the quality of the input imaging data. Then, lumenal surfaces are extracted by isocontouring the preprocessed data, followed by the extraction of vascular skeleton via Voronoi and Delaunay diagrams. Next, the skeleton-based sweeping method is used to construct hexahedral control meshes. Templates are designed for various branching configurations to decompose the geometry into mapped meshable patches. Each patch is then meshed using one-toone sweeping techniques, and boundary vertices are projected to the lumenal surface. Finally, hexahedral solid NURBS are constructed and used in isogeometric analysis of blood flow. Piecewise linear hexahedral meshes can also be obtained using this approach. Examples of patient-specific arterial models are presented.

Ribosomes, constituting protein factories in living cells, translate genetic information carried by messenger RNAs into proteins, and are thus involved in virtually all aspects of cellular development and maintenance. The few available structures of the eukaryotic ribosome1–6 reveal its increased complexity compared to its prokaryotic counterpart7–8, manifested mainly in the presence of eukaryotic-specific ribosomal proteins and additional rRNA insertions, called expansion segments (ES)9. These structures also point out some differences among species, in part represented by the size and arrangement of these ESs. Such differences are extreme in kinetoplastids, unicellular eukaryotic parasites often infectious to humans. Here we present a high-resolution cryo-electron microscopy structure of the ribosome from Trypanosoma brucei, the parasite transmitted by the Tse-tse fly and causing African sleeping sickness. Our atomic model reveals the unique features of this ribosome, characterized mainly by the presence of extraordinarily large ESs and ribosomal proteins extensions leading to the formation of four additional intersubunit bridges, and additional rRNA insertions including one large rRNA domain nonexistent in other eukaryotes. The kinetoplastid large ribosomal subunit (LSU) rRNA chain is uniquely cleaved into six pieces10–12; our structure reveals the five cleavage sites and suggests the importance of the cleavage for the maintenance of the T. brucei ribosome in the observed structure. We discuss several possible implications of the large rRNA ESs for the translation regulation process. Our structure could serve as a basis for future experiments aiming at understanding the functional importance of these kinetoplastid-specific ribosomal features in the protein translation regulation, an essential step toward finding effective and safe kinetoplastid-specific drugs.

This paper describes an algorithm to extract adaptive and quality quadrilateral/hexahedral meshes directly from volumetric data. First, a bottom-up surface topology preserving octree-based algorithm is applied to select a starting octree level. Then the dual contouring method is used to extract a preliminary uniform quad/hex mesh, which is decomposed into finer quads/hexes adaptively without introducing any hanging nodes. The positions of all boundary vertices are recalculated to approximate the boundary surface more accurately. Mesh adaptivity can be controlled by a feature sensitive error function, the regions that users are interested in, or finite element calculation results. Finally, a relaxation based technique is deployed to improve mesh quality. Several demonstration examples are provided from a wide variety of application domains. Some extracted meshes have been extensively used in finite element simulations.