The impact of "search precision" in an agent-based tumor model

Several cell surface receptors are overexpressed in malignant brain tumors and reportedly involved in tumor progression and invasion. It is unclear, however, whether such an improvement of cellular signal reception leads to a monotonic increase in the tumor system's average velocity during invasion or whether there is a maximum threshold beyond which the average velocity starts to decelerate. To gain more insight into the systemic effects of such cellular search precision modulations, this study proposes a two-dimensional agent-based model in which the spatio-temporal expansion of malignant brain tumor cells is guided by environmental heterogeneities in mechanical confinement, toxic metabolites and nutrient sources. Here, the spatial field of action is represented by an adaptive grid lattice, which corresponds to the experimental finding that tumor cells are more likely to follow each other along preformed pathways. Another prominent feature is the dual threshold concept for both nutrient level and toxicity, which determine whether cells proliferate, migrate, remain quiescent or die in the next period. The numerical results from varying the key parameters encoding the capability of tumor cells to invade and their ability to proliferate indicate an emergent behavior. Specifically, increasing invasiveness not only leads to an increase in maximum expansion velocity, but also requires a more precise spatial search process, corresponding to an improved cell signal reception, in order to obtain maximum velocity. To increase cellular invasiveness beyond the maximum that can be achieved by exclusively tuning the motility parameter, it requires an additional reduction in the cells' proliferation rate and prompts an even more biased search process. Most interestingly, however, a prominent phase transition suggests that tumor cells do not employ a 100 percent search precision to attain maximum spatial velocity. These findings argue for a selection advantage conferred by limited randomness in processing spatial search and indicate that our computational platform may prove valuable in investigating emergent, multicellular tumor patterns caused by alterations on the molecular level.     

A method to search for similar protein local structures at ligand-binding sites and its application to adenine recognition

We have developed a method of searching for similar spatial arrangements of atoms around a given chemical moiety in proteins that bind a common ligand. The first step in this method is to consider a set of atoms that closely surround a given chemical moiety. Then, to compare the spatial arrangements of such surrounding atoms in different proteins, they are translated and rotated so that the chemical moieties are superposed on each other. Spatial arrangements of surrounding atoms in a pair of proteins are judged to be similar, when there are many corresponding atoms occupying similar spatial positions. Because the method focuses on the arrangements of surrounding atoms, it can detect structural similarities of binding sites in proteins that are dissimilar in their amino acid sequences or in their chain folds. We have applied this method to identify modes of nucleotide base recognition by proteins. An all-against-all comparison of the arrangements of atoms surrounding adenine moieties revealed an unexpected structural similarity between protein kinases, cAMP-dependent protein kinase (cAPK), and casein kinase-1 (CK1), and D-Ala:D-Ala ligase (DD-ligase) at their adenine-binding sites, despite a lack of similarity in their chain folds. The similar local structure consists of a four-residue segment and three sequentially separated residues. In particular the four-residue segments of these enzymes were found to have nearly identical conformations in their backbone parts, which are involved in the recognition of adenine. This common local structure was also found in substrate-free three-dimensional structures of other proteins that are similar to DD-ligase in the chain fold and of other protein kinases. As the proteins with different folds were found to share a common local structure, these proteins seem to constitute a remarkable example of convergent evolution for the same recognition mechanism. Received: 9 December 1996 / Accepted: 7 February 1997     

A method for single pair mating in an obligate parasitic nematode

Parasitic nematode species have extremely high levels of genetic diversity, presenting a number of experimental challenges for genomic and genetic work. Consequently, there is a need to develop inbred laboratory strains with reduced levels of polymorphism. The most efficient approach to inbred line development is single pair mating, but this is challenging for obligate parasites where the adult sexual reproductive stages are inside the host, and thus difficult to experimentally manipulate. This paper describes a successful approach to single pair mating of a parasitic nematode, Haemonchus contortus. The method allows for polyandrous mating behaviour and involves the surgical transplantation of a single adult male worm with multiple immature adult females directly into the sheep abomasum. We used a panel of microsatellite markers to monitor and validate the single pair mating crosses and to ensure that the genotypes of progeny and subsequent filial generations were consistent with those expected from a mating between a single female parent of known genotype and a single male parent of unknown genotype. We have established two inbred lines that both show a significant overall reduction in genetic diversity based on microsatellite genotyping and genome-wide single nucleotide polymorphism. There was an approximately 50% reduction in heterozygous SNP sites across the genome in the MHco3.N1 line compared with the MoHco3(ISE) parental strain. The MHco3.N1 inbred line has subsequently been used to provide DNA template for whole genome sequencing of H. contortus. This work provides proof of concept and methodologies for forward genetic analysis of obligate parasitic nematodes.     

数量遗传学中一种新的求综合性状的方法

本文运用申农(Shannon)提供的最大熵原理,提出一种构成单一综合性状的新方法,并以此与数量遗传学中的多元统计法作了比较。在作多元遗传分析吋,常用多元统计法求出多个数量性状的综合性状,再对这些相互关联的基本性状作主成份分析或用典范相关进行遗传分析。本文提出了不同于多元统计学的另一种新的方法——最大熵法求出多个数量性状的单一综合性状值。它具有数学结构简单,过程明晰,结果简明等优点。     

A 3D interactive method for estimating body segmental parameters in animals: application to the turning and running performance of Tyrannosaurus rex

We developed a method based on interactive B-spline solids for estimating and visualizing biomechanically important parameters for animal body segments. Although the method is most useful for assessing the importance of unknowns in extinct animals, such as body contours, muscle bulk, or inertial parameters, it is also useful for non-invasive measurement of segmental dimensions in extant animals. Points measured directly from bodies or skeletons are digitized and visualized on a computer, and then a B-spline solid is fitted to enclose these points, allowing quantification of segment dimensions. The method is computationally fast enough so that software implementations can interactively deform the shape of body segments (by warping the solid) or adjust the shape quantitatively (e.g., expanding the solid boundary by some percentage or a specific distance beyond measured skeletal coordinates). As the shape changes, the resulting changes in segment mass, center of mass (CM), and moments of inertia can be recomputed immediately. Volumes of reduced or increased density can be embedded to represent lungs, bones, or other structures within the body. The method was validated by reconstructing an ostrich body from a fleshed and defleshed carcass and comparing the estimated dimensions to empirically measured values from the original carcass. We then used the method to calculate the segmental masses, centers of mass, and moments of inertia for an adult Tyrannosaurus rex, with measurements taken directly from a complete skeleton. We compare these results to other estimates, using the model to compute the sensitivities of unknown parameter values based upon 30 different combinations of trunk, lung and air sac, and hindlimb dimensions. The conclusion that T. rex was not an exceptionally fast runner remains strongly supported by our models-the main area of ambiguity for estimating running ability seems to be estimating fascicle lengths, not body dimensions. Additionally, the craniad position of the CM in all of our models reinforces the notion that T. rex did not stand or move with extremely columnar, elephantine limbs. It required some flexion in the limbs to stand still, but how much flexion depends directly on where its CM is assumed to lie. Finally we used our model to test an unsolved problem in dinosaur biomechanics: how fast a huge biped like T. rex could turn. Depending on the assumptions, our whole body model integrated with a musculoskeletal model estimates that turning 45 degrees on one leg could be achieved slowly, in about 1-2s.     

A food web based hypothesis for the survival vs. weight relationship of rainbow trout in an experimental stream study with bleached kraft mill effluent

A series of experimental streams studies carried out with biologically treated bleached kraft mill effluent (BKME) and rainbow trout Oncorhynchus mykiss included a variety of fish health parameters. There was a pattern of larger but fewer fish in BKME exposed streams. To determine if reduced fish numbers was a detrimental effect, we examined the relationship between number and weight for control and BKME exposed streams for the 9‐month effluent exposures of 1.3–5.1% v/v. A regression analysis indicated that fish numbers decreased at a similar rate for corresponding fish size in both control and BKME‐exposed streams. A dose‐response relationship for effluent and fish number was not found, indicating that reduced fish number was not a direct expression of toxicity. The factors which induced BKME‐exposed fish populations to tend toward fewer but larger fish were not determined but are hypothesized to relate to BKME food web stimulation, a related enhancement in trout growth, and a corresponding reduction in fish number.     

A new trick for an old dog: The application of mifepristone in the treatment of adenomyosis

Adenomyosis is also called internal endometriosis and affects about 20% of reproductive‐aged women. It seriously reduces life quality of patients because current drug therapies face with numerous challenges. Long‐term clinical application of mifepristone exhibits wonderful therapeutic effects with mild side‐effects in many disorders since 1982. Since adenomyosis is a refractory disease, we investigate whether mifepristone can be applied in the treatment of adenomyosis. In this study, we investigated the direct effects of mifepristone on human primary eutopic endometrial epithelial cells and stromal cells in adenomyosis. We found that mifepristone causes cell cycle arrest through inhibiting CDK1 and CDK2 expressions and induces cell apoptosis via the mitochondria‐dependent signalling pathway in endometrial epithelial cells and stromal cells of adenomyosis. Furthermore, mifepristone inhibits the migration of endometrial epithelial cells and stromal cells through decreasing CXCR4 expression and restricts the invasion of endometrial epithelial cells via suppression of epithelial‐mesenchymal transition in adenomyosis. We also found that mifepristone treatment decreases the uterine volume, CA125 concentration and increases the haemoglobin concentration in serum for adenomyosis patients. Therefore, we demonstrate that mifepristone could serve as a novel therapeutic drug in the treatment of adenomyosis, and therefore, the old dog can do a new trick.     

A nuclear DNA barcode for eastern North American oaks and application to a study of hybridization in an Arboretum setting

DNA barcoding has proved difficult in a number of woody plant genera, including the ecologically important oak genus Quercus. In this study, we utilized restrictionsite‐associated DNA sequencing (RAD‐seq) to develop an economical single nucleotide polymorphism (SNP) DNA barcoding system that suffices to distinguish eight common, sympatric eastern North American white oak species. Two de novo clustering pipelines, PyRAD and Stacks, were used in combination with postclustering bioinformatic tools to generate a list of 291 potential SNPs, 80 of which were included in a barcoding toolkit that is easily implemented using MassARRAY mass spectrometry technology. As a proof‐of‐concept, we used the genotyping toolkit to infer potential hybridization between North American white oaks transplanted outside of their native range (Q. michauxii, Q. montana, Q muehlenbergii/Q. prinoides, and Q. stellata) into a horticultural collection surrounded by natural forests of locally native trees (Q. alba and Q. macrocarpa) in the living collection at The Morton Arboretum (Lisle, IL, USA). Phylogenetic and clustering analyses suggested low rates of hybridization between cultivated and native species, with the exception of one Q. michauxii mother tree, the acorns of which exhibited high admixture from either Q. alba or Q. stellata and Q. macrocarpa, and a hybrid between Q. stellata that appears to have backcrossed almost exclusively to Q. alba. Together, RAD‐seq and MassARRAY technologies allow for efficient development and implementation of a multispecies barcode for one of the more challenging forest tree genera.