Despite decades of study of chromosome territories (CT) in the interphase nucleus of mammalian cells, our understanding of the global shape and 3-D organization of the individual CT remains very limited. Past microscopic analysis of CT suggested that, while many of the CT appear to be very regular ellipsoid-like shapes, there were also those with more irregular shapes. We have undertaken a comprehensive analysis to determine the degree of shape regularity of different CT. To be representative of the whole human genome, 12 different CT (~41% of the genome) were selected that ranged from the largest (CT 1) to the smallest (CT 21) in size and from the highest (CT 19) to lowest (CT Y) in gene density. Using both visual inspection and algorithms that measure the degree of shape ellipticity and regularity, we demonstrate a strong inverse correlation between the degree of regular CT shape and gene density for those CT that are most gene rich (19, 17, 11) and gene poor (18, 13, Y). CT more intermediate in gene density, showed a strong negative correlation with shape regularity but not with ellipticity. An even more striking correlation between gene density and CT shape was determined for the nucleolar associated NOR-CT. Correspondingly striking differences in shape between the X active and inactive CT implied that, aside from gene density, the overall global level of gene transcription on individual CT is also an important determinant of chromosome territory shape.
There is growing evidence that chromosome territories (CT) have a probabilistic non-random arrangement within the cell nucleus of mammalian cells including radial positioning and preferred patterns of interchromosomal interactions that are cell-type specific. While it is generally assumed that the three-dimensional (3D) arrangement of genes within the CT is linked to genomic regulation, the degree of non-random organization of individual CT remains unclear. As a first step to elucidating the global 3D organization (topology) of individual CT, we performed multi-color fluorescence in situ hybridization using six probes extending across each chromosome in human WI38 lung fibroblasts. Six CT were selected ranging in size and gene density (1, 4, 12, 17, 18 and X). In-house computational geometric algorithms were applied to measure the 3D distances between every combination of probes and to elucidate data-mined structural patterns. Our findings demonstrate a high degree of non-random arrangement of individual CT that vary from chromosome to chromosome and display distinct changes during the cell cycle. Application of a classic, well-defined data mining and pattern recognition approach termed the 'k-means' generated 3D models for the best fit arrangement of each chromosome. These predicted models correlated well with the detailed distance measurements and analysis. We propose that the unique 3D topology of each CT and characteristic changes during the cell cycle provide the structural framework for the global gene expression programs of the individual chromosomes.
The well-established human epidermal keratinocyte (HEK) differentiation model was investigated to determine possible alterations in chromosome territory (CT) association during differentiation. The seven human chromosomes (1, 4, 11, 12, 16, 17, and 18) selected for this analysis are representative of the chromosome size and gene density range of the overall human genome as well as including a majority of genes involved in epidermal development and differentiation (CT1, 12, and 17). Induction with calcium chloride (Ca(2+)) resulted in morphological changes characteristic of keratinocyte differentiation. Combined multi-fluorescence in situ hybridization (FISH) and computational image analysis on the undifferentiated (0 h) and differentiated (24 h after Ca(2+) treatment) HEK revealed that (a) increases in CT volumes correspond to overall nuclear volume increases, (b) radial positioning is gene density-dependent at 0 h but neither gene density- nor size-dependent at 24 h, (c) the average number of interchromosomal associations for each CT is gene density-dependent and similar at both time points, and (d) there are striking differences in the single and multiple pairwise interchromosomal association profiles. Probabilistic network models of the overall interchromosomal associations demonstrate major reorganization of the network during differentiation. Only ~40 % of the CT pairwise connections in the networks are common to both 0 and 24 h HEK. We propose that there is a probabilistic chromosome positional code which can be significantly altered during cell differentiation in coordination with reprogramming of gene expression.
The rupture of Intracranial Aneurysms is the most severe form of stroke with high rates of mortality and disability. One of its primary treatments is to use stent or Flow Diverter to divert the blood flow away from the IA in a minimal invasive manner. To optimize such treatments, it is desirable to provide an automatic tool for virtual stenting before its actual implantation. In this paper, we propose a novel method, called ball-sweeping, for rapid virtual stenting. Our method sweeps a maximum inscribed sphere through the aneurysmal region of the vessel and directly generates a stent surface touching the vessel wall without needing to iteratively grow a deformable stent surface. Our resulting stent mesh has guaranteed smoothness and variable pore density to achieve an enhanced occlusion performance. Comparing to existing methods, our technique is computationally much more efficient.
Endovascular coiling is a primary treatment for intra-cranial aneurysm, which deploys a thin and detachable metal wire inside the aneurysm so as to prevent its rupture. Emerging evidence from medical research and clinical practice has suggested that the coil configuration inside the aneurysm plays a vital role in properly treating aneurysm and predicting its outcome. In this paper, we propose a novel virtual coiling technique, called , for generating a coil configuration with ensured blocking ability. It can be used as an automatic tool for virtually simulating coiling before its implantation and thus optimizes such treatments. Our approach is based on integer linear programming and computational geometry techniques, and takes into consideration the packing density and coil distribution as the performance measurements. The resulting coiling is deployable (with the help of coil pre-shaping) and with minimized energy. Experimental results on both random and real aneurysm data suggest that our proposed method yields near optimal solution.
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