Biomedical subjects
Publications and source records attributed to N F Johnson.
We provide an analytic theory to explain Anghel et al's recent numerical finding whereby a maximum in the global performance emerges for a sparsely connected competitive population [Phys. Rev. Lett. 92, 058701 (2004)]. We show that the effect originates in the highly correlated dynamics of strategy choice, and can be significantly enhanced using a simple modification to the model.
The Platygastroidea comprises two families of parasitoids, Scelionidae and Platygastridae, and nearly 4500 described species. They parasitize a diverse array of insects as well as spiders. Idiobiont endoparasitism of eggs is the putative ground plan biology, as reflected by all scelionids, but most Platygastridae are koinobiont endoparasitoids of immature Auchenorrhyncha, Sternorrhyncha, and Cecidomyiidae. The superfamily is demonstrably monophyletic but its phylogenetic position remains uncertain. Relationships within the Platygastroidea are also poorly known and the group is in need of comprehensive phylogenetic study. Significant information is available on host relationships and biology, although much of this is biased to a few genera of Telenominae that are employed as biocontrol agents. Hosts for many genera are unknown, in particular those that inhabit leaf litter or parasitize solitary host eggs. The Trissolcus basalis-Nezara viridula parasitoid-host association has become a favored model system in ecological, behavioral, and physiological research on insects.
We formulate a theory of agent-based models in which agents compete to be in a winning group. The agents may be part of a network or not, and the winning group may be a minority group or not. An important feature of the present formalism is its focus on the dynamical pattern of strategy rankings, and its careful treatment of the strategy ties which arise during the system's temporal evolution. We apply it to the minority game with connected populations. Expressions for the mean success rate among the agents and for the mean success rate for agents with k neighbors are derived. We also use the theory to estimate the value of connectivity p above which the binary-agent-resource system with high resource levels makes the transition into the high-connectivity state.
We study a version of the minority game in which one agent is allowed to join the game in a random fashion. It is shown that in the crowded regime, i.e., for small values of the memory size m of the agents in the population, the agent performs significantly well if she decides to participate the game randomly with a probability q and she records the performance of her strategies only in the turns that she participates. The information, characterized by a quantity called the inefficiency, embedded in the agent's strategies performance turns out to be very different from that of the other agents. Detailed numerical studies reveal a relationship between the success rate of the agent and the inefficiency. The relationship can be understood analytically in terms of the dynamics in which the various possible histories are being visited as the game proceeds. For a finite fraction of randomly participating agents up to 60% of the population, it is found that the winning edge of these agents persists.
The dynamical evolution of many economic, sociological, biological, and physical systems tends to be dominated by a relatively small number of unexpected, large changes ("extreme events"). We study the large, internal changes produced in a generic multiagent population competing for a limited resource, and find that the level of predictability increases prior to a large change. These large changes hence arise as a predictable consequence of information encoded in the system's global state.
The minority game (MG) behaves as a stochastically disturbed deterministic system due to the coin toss invoked to resolve tied strategies. Averaging over this stochasticity yields a description of the MG's deterministic dynamics via mapping equations for the strategy score and global information. The strategy-score map contains both restoring-force and bias terms, whose magnitudes depend on the game's quenched disorder. Approximate analytical expressions are obtained and the effect of "market impact" is discussed. The global-information map represents a trajectory on a de Bruijn graph. For small quenched disorder, a Eulerian trail represents a stable attractor. It is shown analytically how antipersistence arises. The response to perturbations and different initial conditions is also discussed.
We show analytically how the fluctuations (i.e., standard deviation sigma) in the minority game can decrease below the random coin-toss limit if the agents use more general, stochastic strategies. This suppression of sigma results from a cancellation between the actions of a crowd, in which agents act collectively and make the same decision, and those of an anticrowd, in which agents act collectively by making the opposite decision to the crowd.
Previous studies showed that intratracheal instillation of endotoxin induces transient type II cell hyperplasia in the rat lung and described some of the mechanisms involved in the proliferative response of type II cells. The purpose of the present study was to investigate how long the type II cell hyperplasia persists and how it is resolved. The portion of epithelial cells in hyperplastic lesions of the rat lung expressing cyclin D1, an indicator for cells in the G1 phase of the cell cycle, was greatest at 3 d post instillation and decreased after 4 and 6 d. The fate of the proliferating epithelial cells was traced by injecting the rats with 5-bromo-2' deoxy uridine (BrdU) 2 d post instillation, the peak time point for maximum incorporation of BrdU. Exfoliated BrdU-positive epithelial cells were detected in the alveolar spaces in tissue sections from rats 4, 5, and 6 d post instillation. BrdU-positive epithelial cells showed flattened nuclei at 6 and 10 d post instillation. Expression of the 116 kD poly(ADP-ribose) polymerase (PARP) was low in type II cells from control rats, and was increased at 3, 4, and 6 d post instillation. In cells obtained by lavage, only a 35 kD cleavage product of PARP was detected, which is an indicator of necrotic cell death. In isolated type II cells from rats 3, 4, and 6 d post endotoxin instillation, progressive cleavage of the PARP to its 89 kD residual fragment was detected, which is a direct evidence for the activation of caspases. Furthermore, apoptotic epithelial cells with condensed nuclei were identified by electron microscopy in rats 4 d post instillation. These results indicate that apoptosis is an additional mechanism for the resolution of endotoxin-induced lung epithelial hyperplasias.
Repeated exposure to 0.5 ppm ozone (O3) induces mucous cell metaplasia in the nasal transitional epithelium (NTE) of rats. The cellular events which commit the NTE to undergo this phenotypic alteration occur during the first 3 days of exposure. To examine the kinetics of the early cellular responses of NTE to O3, F344 rats were exposed to filtered air or 0.5 ppm O3 for 8 hr and euthanized 2, 4, 6, 8, 12, 16, 20, 24, and 36 hr postexposure (PE). Two hours before euthanization, rats were injected with bromodeoxyuridine (BrdU) to label S-phase cells. The nasal cavities were fixed and processed for light microscopy. Sections from the anterior nasal cavity were immunostained to detect BrdU-labeled cells and analyzed to determine the numeric densities of NTE cells and intraepithelial neutrophils, and the labeling index (LI; [BrdU-labeled epithelial cells/total epithelial cells] x 100) and unit length labeling index (ULLI; BrdU-labeled epithelial cells/mm basal lamina) of the NTE overlying maxilloturbinates. O3 exposure induced a transient influx of neutrophils 2-4 hr PE and a significant (17%) loss of NTE cells 2-4 hr PE. An increase in epithelial DNA synthesis was first detected 12 hr PE. In this study, there was no difference in the sensitivity of the two measures of epithelial cell DNA synthesis. Both the LI and ULLI were greatest 20-24 hr PE and were reduced, but still greater than those of controls, by 36 hr PE. The numeric density of NTE cells returned to control levels 20-24 hr PE. This study has defined the kinetics of acute O3-induced NTE cell injury, loss, and proliferation in vivo. The transit time from Go to S, after O3-induced injury, was 12-20 hr and the duration of G2 + M was 8-12 hr. These data may be used to further explore the early cellular and molecular events that lead to ozone-induced mucous cell metaplasia.
A biodosimetric approach to determine alpha-particle dose to the respiratory tract epithelium from known exposures to radon has been developed in the rat. Cytotoxicity assays have been used to obtain dose-conversion factors for cumulative exposures typical of those encountered by underground uranium miners. However, this approach is not sensitive enough to derive dose-conversion factors for indoor radon exposures. The expression of DNA damage-inducible genes is being investigated as a biomarker of exposure to radon progeny. Exposure of cultures of A549 cells to alpha particles resulted in an increase in the protein levels of the DNA damage-inducible genes, p53, Cip1, and Gadd45. These protein changes were associated with a transient arrest of cells passing through the cell cycle. This arrest was typified by an increase in the number of cells in the G1 and G2 phases and a decrease in the number of cells in the S phase. The effect of inhaled alpha particles (radon progeny) in rats was examined in the epithelial cells of the lateral well of the anterior nasal cavity. Exposures to radon progeny resulted in a significant increase in the number of cells in the G1 phase and a decrease in the number of cells in the S phase. These cell-cycle changes were concomitant with an increase in the number of cells containing DNA strand breaks. These results suggest a commonality between cell-cycle events in vitro and in vivo following exposure to ionizing radiation. In addition to ionizing radiation, A549 cells were exposed to 4-nitroquinoline-1-oxide, methyl methanesulphonate, crocidolite asbestos, and glass microfiber. These studies showed that physical and chemical agents induce different expression patterns of p53, Cip1, and Gadd153 proteins and they could be used to discriminate between toxic and nontoxic materials such as asbestos and glass microfiber. The measurement of gene expression in A549 cells may provide a means to identify a broad spectrum of physical and chemical toxicants encountered in the environment.
DNA damage induced by chemicals and ionizing radiation is associated with the expression of negative regulators of the cell cycle. The arrest of cells in G1 and G2 phases of the cell cycle provides time for DNA repair. Asbestos fibers are carcinogenic when inhaled by both humans and animals; however, the mechanism by which the fibers exert their effect is unknown. This work was undertaken to determine whether the expression of DNA damage-inducible genes differs between crocidolite, a fiber positive for lung tumors, and JM 100 glass microfiber, which is negative for lung tumors when inhaled by rats. Temporal and dose-related expressions of p53, Cip1, and Gadd153 proteins were determined in cultured A549 cells treated with either Union Internationale Contre le Cancer crocidolite or JM 100 for 20 hr and cultured in fresh media. Immunolabeled cells were analyzed by flow cytometry, and the increased number of protein-expressing cells was determined by subtracting the expression in unexposed cells from exposed cells. Crocidolite induced the expression of all three proteins with a maximum expression after approximately 18 hr in fresh media. At a similar time point, JM 100 did not markedly induce the three proteins. Crocidolite also induced a dose-dependent increase in the number of cells in the G2 phase of the cell cycle. These results show that asbestos behaves like ionizing radiation and genotoxic chemicals by inducing proteins associated with DNA damage and cell-cycle arrest. The clear difference in response between crocidolite and JM 100 may help elucidate the mechanism of action of toxic and nontoxic fibers.
We have reported that dogs exposed twice to aerosols of beryllium oxide (BeO) developed Be-specific immune responses within the lung, along with granulomatous and fibrotic lung lesions. To evaluate the specificity of the immune response, lymphocytes from lungs and blood of BeO-exposed dogs were co-cultured over an irradiated blood monocyte layer, alternately with interleukin 2 and BeSO4. Resultant cell lines were then tested for their response to different metal cations, common canine recall antigens, and BeSO4 in an in vitro cell proliferation assay. The cell lines responded to BeSO4 in a dose-dependent fashion, with mean stimulation indices of 7, 58, 119, and 112 at concentrations of 0.01, 1.0, 10, and 100 microM BeSO4 respectively. Cells not proliferate when incubated with ZnSO4 or NiSO4, or with canine distemper, leptospira, adenovirus 2, parvovirus, or parainfluenza antigens. Lymphocytes from normal vaccinated dogs proliferated markedly when cultured with these antigens. Cells from the cultured cell lines (91%) stained with Thy-1 (a pan T-cell marker) and 96% stained with DT2 (a helper T-cell marker). Furthermore, the Be-induced proliferative response was restricted by major histocompatibility (MHC) class II antigens. These data reinforce the premise that inhalation exposure of dogs to BeO produces lung lesions and MHC class II restricted immunologic responses mediated by Be-specific, helper T-Cells. These data further confirm the hypothesis that antigen localized to the lung results in the recruitment of T-cells to the lung, followed by localized antigen-specific, cell-mediated immune responses.
The overall purpose of this study was to produce a model of transient type II cell hyperplasia to enable comparisons of changes in gene expression in the remodelling epithelium with those in carcinogen-induced hyperplastic lesions. Rats instilled with endotoxin had increased numbers of neutrophils in the bronchoalveolar lavage fluid (BALF) by 3 hours that reached maximum levels at 48 hours and returned to background levels 168 hours after instillation. The number of macrophages in the BALF increased throughout the 168 hours following instillation. Epithelial cell hyperplasia was maximum at 96 hours post-instillation in areas of extensive inflammation. The number of alveolar epithelial cells that exhibited bromodeoxyuridine nuclear incorporation reached maximum levels 48 hours after endotoxin treatment and decreased to near background levels at 96 hours. Ultrastructural studies of hyperplastic cells showed the presence of lamellar bodies and condensed chromosomes, characteristics of type II cells in mitosis. At 168 hours after instillation, the hyperplasia regressed to form normal-appearing alveolar structure with few focal lesions. Specific immunostaining for the proto-oncogenes, EGF receptor and erbB-2, on tissue sections increased during the endotoxin-induced hyperplasia. Furthermore, the induction of the 170 kDa and 180 kDa glycoproteins in type II cells isolated from endotoxin-instilled rats was shown by Western analysis. These proto-oncogenes, often thought to be markers of early events during neoplasia, may, therefore, also be associated with wound repair mechanisms after hyperplasia.
OBJECTIVE: To find whether continuous ceramic filaments (CCFs) and silicon carbide whiskers (SiCWs), which are used in many industries as reinforcing materials in advanced ceramic composites, are carcinogenic in the intrapleural inoculation assay. METHODS: Samples of SiCWs, CCF, International Union Against Cancer crocidolite, or saline were injected into the pleural cavities of female F344/N rats to find whether the samples of SiCW and CCF had the potential to induce mesotheliomas after the direct application of the materials to the surface of the pleural mesothelium. RESULTS: Rats injected with two of the three individual samples of SiCW or the crocidolite had significantly reduced life spans compared with the rats treated with saline, CCFs, or the third SiCW sample. Rats treated with either of the two SiCW samples or crocidolite developed mesotheliomas. By contrast, rats treated with saline or CCF did not. The two SiCW samples that induced shortened life spans also induced a higher rate of mesothelioma (87%-90%), than the crocidolite (57%) and the third SiCW sample (23%). CONCLUSION: SiCWs but not CCFs could induce mesotheliomas after intrapleural injection in rats. The difference in biological activity between the SiCW samples could not be explained on the basis of their physical dimensions or biological activity toward cultured cells. Results from this study indicated that SiCWs should be handled with care as they might be carcinogenic if inhaled. However, there is controversy as to whether results of intrapleural injection assays are sufficient to determine a fibre's carcinogenic activity. The results also showed that a collection of fibrous materials such as SiCWs could have considerably different biological activities despite similar physical dimensions.
Identifying the causal events and temporal aspects of lung cancer development requires the ability to isolate target and nontarget cells for comparative analyses. Current methodology can either isolate only one pure specific cell population from a lung or multiple cell types at lower purity. Previous studies in our laboratory have identified the alveolar type II cell as the progenitor cell for tumor development in the A/J mouse. The purpose of this study was to develop new protocols for the isolation and culture of type II and Clara cells from the mouse lung. Both type II and Clara cells were obtained in high purity using a sequential centrifugal elutriation protocol. In the first elutriation, cell fractions were collected using a Standard chamber. The type II and Clara cell fractions were then elutriated separately (two different separations) using a Sanderson chamber. The final purity of the type II and Clara cell preparations was 73% and 76%, respectively. Colonies of 4 to 20 Clara cells exhibiting epithelial morphology were evident 1 wk after plating in low serum medium. The growth of type II cells required the addition of bronchioalveolar lavage fluid and acidic fibroblast growth factor to the medium. The isolation of viable mouse type II and Clara cells in high purity should facilitate the identification of cell-specific changes in gene expressions or in enzymatic pathways following in vivo or in vitro exposure to environmental carcinogens.
Silicon carbide (SiC) whiskers are fiberlike materials with a wide range of industrial applications. Industrial hygiene samplings of the material are taken to monitor and control possible exposures to workers. This study characterizes an SiC whisker in detail, including its width-length distribution, aspect ratio, particle density, and aerodynamic size distribution. The SiC whiskers were aerosolized, and samples from a filter, cascade impactor, and aerosol centrifuge were taken. The diameter-length distribution of SiC fibers determined by electron microscopy from filter samples was found to follow the bivariate lognormal distribution. The aerodynamic size of a fiber aerosol depends not only on the particle dimension and density but also on the orientation of its axis with respect to flow. The results show that the aerodynamic size distribution obtained from the impactor was consistent with the predicted value, assuming the long axis of the fiber was parallel to the flow toward the collection substrate. On the other hand, the aerodynamic size in the aerosol centrifuge was consistent with results for a perpendicular orientation. A larger aerodynamic size (20-25%) was obtained in the case of impactor data as compared with centrifuge data. The respirable fraction estimated from the cascade impactor data was 65%, consistent with the estimate from bivariate analysis (67%) but smaller than the estimated fraction from the aerosol centrifuge (76%). The results show that the data obtained with the bivariate analysis of fiber dimensions had good correlation with the cascade impactor data, and this approach can be used to predict the aerodynamic size distribution and the size-selective fractions for fiber aerosols from filter samples.
Other investigators have shown that both sparsely ionizing and UV radiation cause cell cycle arrest that is associated with increased expression of wild-type p53 protein. The effect of exposure to alpha-particles from 238Pu on the induction of the p53 protein has now been examined in cultured lung epithelial cells derived from male F344 rats. The number of cells having increased levels of p53 protein was determined by flow cytometry after the cells had been stained with a monoclonal antibody to p53. alpha-Particle irradiation caused a dose-dependent increase in p53 protein levels detectable at doses as low as 0.6 cGy, with no evidence of a threshold. An increase in p53 protein also occurred in X-irradiated cells. However, no increase was seen in cells exposed to less than 10 cGy of X-rays, indicating the existence of a relatively higher DNA damage threshold for sparsely ionizing radiation. In addition, more cells exposed to low doses of alpha radiation had increased p53 protein levels than would be predicted based on the number of nuclei expected to be traversed by an alpha-particle, suggesting that alpha-particles cause genetic damage by mechanisms in addition to direct interactions with DNA.
A model of word recognition is proposed which assumes that when a word is encountered, the first available orthographic code activates all lexical entries that are positionally consistent with that information (i.e., the word's cohort). As subsequently encoded orthographic information becomes available, activation is withdrawn from lexical entries with which it is inconsistent, and the cohort is resolved when only a single candidate remains. The model is intended to characterize: (1) The initial encoding of the graphic information; (2) the recording of that information into an abstract orthographic form; (3) the manner in which the appropriate lexical entries are then activated; (4) the process whereby subsequent orthographic encoding resolves those activated entries to a single candidate; and finally (5) the way in which subjects use information for making decisions as it emerges during this processing. The model includes two critical points. The first is that letter identity information is encoded in the form of a complex orthographic unit termed a wickelgraph. A wickelgraph includes an encoding of the target letter's identity information as its core, plus, as a context, the identity of its two immediately adjacent letters. The set of possible wickelgraphs is assumed to instantiate the rules of orthography. The second point is that once a cohort is established, the perceiver can sample its status at any point during resolution and base a decision on the outcome of that sample. Some tasks (e.g., naming) may allow for a decision based on the initial status of the cohort, while others (e.g., lexical decision) can require its complete resolution. Six experiments are reported that illustrate some of these cohort effects in lexical access.