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PubMed1978

Bidder's hypothesis revisited. Solution to some key problems associated with general molecular theory of ageing.

In this paper I consider three major difficulties associated with the general molecular theory of ageing, namely: (1) How can molecular damage accumulate in the face of the constellation of repair mechanisms that is found in cells? (2) How can the obvious programmatic nature of ageing be reconciled with underlying stochastic processes? (3) How do some organisms avoid ageing? As a solution to points 1 and 2, I propose that the repair mechanisms themselves deteriorate in a programmed fashion with age. However, I argue that this programming is unlikely to be a result of direct selection for life-shortening but, rather, is more likely to be a result of an indirect selection for other characters. This idea is very similar to the theory of senescence first formulated by Bidder. The solution to point 3 is that the repair mechanisms in systems which avoid ageing, in particular cellular and molecular turnover, are not impaired with age. The rejuvenating capacities of sexual and asexual reproduction are also discussed.

Aging↗
PubMed2006

Runtime analysis of the (mu+1) EA on simple Pseudo-Boolean functions.

Although Evolutionary Algorithms (EAs) have been successfully applied to optimization in discrete search spaces, theoretical developments remain weak, in particular for population-based EAs. This paper presents a first rigorous analysis of the (mu+1) EA on pseudo-Boolean functions. Using three well-known example functions from the analysis of the (1+1) EA, we derive bounds on the expected runtime and success probability. For two of these functions, upper and lower bounds on the expected runtime are tight, and on all three functions, the (mu+1) EA is never more efficient than the (1+1) EA. Moreover, all lower bounds grow with mu. On a more complicated function, however, a small increase of mu probably decreases the expected runtime drastically. This paper develops a new proof technique that bounds the runtime of the (mu+1) EA. It investigates the stochastic process for creating family trees of individuals; the depth of these trees is bounded. Thereby, the progress of the population towards the optimum is captured. This new technique is general enough to be applied to other population-based EAs.

Algorithms↗
PubMed1995

Models of delayed recovery.

After a biologic insult has impaired function of the developing central nervous system, recovery may not become apparent for years. Probability models adopted from the carcinogenesis, developmental neurobiology, learning decay, and stochastic process literatures are presented so that assumptions about apparent delays in the recovery process can be tested with data from longitudinal studies after a temporally circumscribed adverse event/exposure. This process of evaluating multiple models is exemplified with one data set. Nonlinear models of recovery are important because some children with early deficits first show improvement months to years later.

Brain↗
PubMed2003

Regulated secretion of glycosylated human ferritin from hepatocytes.

Serum ferritin has been used widely in clinical medicine chiefly as an indicator of iron stores and inflammation. Circulating ferritin also can have paracrine effects. Despite the clinical significance of serum ferritin, its secretion remains an enigma. The consensus view is that serum ferritin arises from tissue ferritins--principally ferritin light--which can be glycosylated. Ferritin heavy and light chains are cytosolic proteins that form cages of 24 subunits to store intracellular iron. We show that ferritin light is secreted when its expression is increased in stable, transfected HepG2 cells or adenovirus-infected HepG2 cells. Export occurs through the classical secretory pathway and some chains are N-glycosylated. Ferritins do not need to form cages prior to secretion. Secretion is blocked specifically, effectively, and rapidly by a factor in serum. The timing of this inhibition of ferritin secretion suggests that normally cytosolic ferritin L is targeted to the secretory pathway during translation despite the absence of a conventional signal sequence. Thus, secretion of glycosylated and unglycosylated ferritin is a regulated and not a stochastic process.

Adenoviridae↗
PubMed2006

Dominant negative retinoic acid receptor initiates tumor formation in mice.

BACKGROUND: Retinoic acid suppresses cell growth and promotes cell differentiation, and pharmacological retinoic acid receptor (RAR) activation is anti-tumorigenic. This begs the question of whether chronic physiological RAR activation by endogenous retinoids is likewise anti-tumorigenic. RESULTS: To address this question, we generated transgenic mice in which expression of a ligand binding defective dominant negative RARalpha (RARalphaG303E) was under the control of the mouse mammary tumor virus (MMTV) promoter. The transgene was expressed in the lymphoid compartment and in the mammary epithelium. Observation of aging mice revealed that transgenic mice, unlike their wild type littermates, developed B cell lymphomas at high penetrance, with a median latency of 40 weeks. MMTV-RARalphaG303E lymphomas were high grade Pax-5+, surface H+L Ig negative, CD69+ and BCL6- and cytologically and phenotypically resembled human adult high grade (Burkitt's or lymphoblastic) lymphomas. We postulated that mammary tumors might arise after a long latency period as seen in other transgenic models of breast cancer. We tested this idea by transplanting transgenic epithelium into the cleared fat pads of wild type hosts, thus bypassing lymphomagenesis. At 17 months post-transplantation, a metastatic mammary adenocarcinoma developed in one of four transplanted glands whereas no tumors developed in sixteen of sixteen endogenous glands with wild type epithelium. CONCLUSION: These findings suggest that physiological RAR activity may normally suppress B lymphocyte and mammary epithelial cell growth and that global RAR inactivation is sufficient to initiate a stochastic process of tumor development requiring multiple transforming events. Our work makes available to the research community a new animal resource that should prove useful as an experimental model of aggressive sporadic lymphoma in immunologically uncompromised hosts. We anticipate that it may also prove useful as a model of breast cancer.

Animals↗
PubMed2005

Strengthening Medicare: will increasing the bulk-billing rate and supply of general practitioners increase access to Medicare-funded general practitioner services and does rurality matter?

BACKGROUND: Recent increases in the bulk-billing rate have been taken as an indication that the Federal government's Strengthening Medicare initiative, and particularly the bulk-billing incentives, are 'working'. Given the enduring geographic differences in the supply of general practitioners (GPs) it is timely to reconsider the impact that this increase in the provision of 'free care' will have on access to Medicare-funded GP services in rural and urban areas of Australia. Utilisation has been modelled as two different stochastic processes: the decision to consult and the frequency of consultation. RESULTS: In the decision to consult model the supply of FFS GPs is a more important predictor of utilisation than the bulk-billing rate. Paradoxically the modelling predicts that ceteris paribus increases in either GP supply or the bulk-billing rate appear to have perverse effects in some areas by decreasing utilisation. In the frequency of consultation model, GP density is not a predictor and increasing the bulk-billing rate will unambiguously increase the frequency of consultation across all areas. In both models, the positive impacts associated with changes in supply and cost are constrained outside the inner metropolitan area by reduced geographic accessibility to Medicare-funded GP services. The modelling also shows that people are more likely to consult a GP in areas of high socioeconomic disadvantage, although socioeconomic status is not a predictor of frequency of consultation. CONCLUSION: Bulk-billing rates and the supply of FFS GPs are important features of the Australian health care system that are, potentially, amenable to policy manipulation. The implications of this research are that government policies designed to achieve similarity in these characteristics across geographic areas will not result in equity of access because they fail to address problems caused by geographic inaccessibility in rural and remote areas. Attempting to increase bulk-billing rates in some of these areas may, in fact, reduce access to FFS GP services.

Journal Article↗
PubMed1998

Heart rate dynamics in low risk human fetuses.

Evaluation of nonlinear heart rate (HR) dynamics has received considerable attention in the pediatric literature because such analyses not only provide insight into underlying control mechanisms, but may also help to differentiate between normal and abnormal infants. The purpose of this study was to determine, in eight low risk human fetuses, if nonlinear HR dynamics could be identified by analyzing the dispersion of interbeat intervals at slow (Ds) and fast (Df) HRs. The fetal cardiac electrical signal was captured transabdominally at a resolution of +/- 1 ms. To test the null hypothesis, that the time series is the result of a linear stochastic process, Ds and Df for the original time series were compared with the values calculated for three linear models. The linear models were constructed to preserve the major statistical properties of the original time series, including the mean, SD, and the Fourier power spectrum. For each fetus, there was no evidence of nonlinear cardiac dynamics based on analyses of Ds and Df. In contrast, the distribution of adjacent R-R intervals and the pattern of change across three successive interbeat intervals both revealed significant nonlinearities in HR control in each fetus. If the difference between normal and abnormal infants is the result of aberrant control of nonlinear processes, then our findings indicate that parameters which describe the nonlinearity may be more useful then Ds and Df in assigning a risk status.

Apgar Score↗
PubMed2000

An upstream element of the TamS1 gene is a site of DNA-protein interactions during differentiation to the merozoite in Theileria annulata.

Apicomplexan parasites are major pathogens of humans and domesticated animals. A fundamental aspect of apicomplexan biology, which may provide novel molecular targets for parasite control, is the regulation of stage differentiation. Studies carried out on Theileria annulata, a bovine apicomplexan parasite, have provided evidence that a stochastic process controls differentiation from the macroschizont to the merozoite stage. It was postulated that this process involves the presence of regulators of merozoite gene expression in the preceding stage of the life cycle, and that during differentiation a quantitative increase of these factors occurs. This study was carried out to test these postulations. Nuclear run-on analysis showed that TamS1 expression is controlled, at least in part, at the transcriptional level. The transcription start site showed homology with the consensus eukaryotic initiator motif, and study of the 5' upstream region by the electrophoretic mobility-shift assay demonstrated that a 23 bp motif specifically bound factors from parasite-enriched nuclear extracts. Three complexes were shown to bind to a 9 bp core binding site (5'-TTTGTAGGG-3'). Two of these complexes were present in macroschizont extracts but were found at elevated levels during differentiation. Both complexes contain a polypeptide of the same molecular mass and may be related via the formation of homodimer or heterodimer complexes. The third complex appears to be distinct and was detected at time points associated with the transition to high level merozoite gene expression.

Adult↗
PubMed2002

Life cycle of MTs: persistent growth in the cell interior, asymmetric transition frequencies and effects of the cell boundary.

Microtubule dynamics were investigated in CHO and NRK cells by novel experimental approaches designed to evaluate the microtubule behavior in the cell interior. These approaches were: (1) laser photobleaching of a path through the centrosome; (2) direct observation of microtubules in centrosome-containing cytoplasts; (3) GFP-CLIP-170 expression as a marker for microtubule plus end growth; and (iv) sequential subtraction analysis. The combination of these approaches allowed us to obtain data where the density of microtubules had previously prevented conventional methods to be applicable. In the steady state, nascent microtubules grew persistently from the centrosome towards the cell margin. Frequently, they arrived at the cell margin without undergoing any transition to the shortening phase. In contrast to the growth of microtubules, shortening of the plus ends from the periphery was non-persistent; that is, rescue was frequent and the extent of shortening showed a distribution of lengths reflecting a stochastic process. The combination of persistent growth and a cell boundary led to a difference in apparent microtubule behavior in the cell interior compared with that near the cell margin. Whereas microtubules in the cell interior showed asymmetric transition frequencies, their behavior near the cell margin showed frequent fluctuations between phases of shortening and growth. Complete microtubule turnover was accomplished by the relatively rare episodes of shortening back to the centrosome. Release from the centrosome with subsequent minus end shortening also occurred but was a minor mechanism for microtubule turnover compared with the plus end pathway. We propose a life cycle for a microtubule which consists of rapid growth from the centrosome to the cell margin followed by an indefinite period of fluctuations of phases of shortening and growth. We suggest that persistent growth and asymmetric transition frequencies serve the biological function of providing a mechanism by which microtubules may rapidly accommodate to the changing shape and advancing edge of motile cells.

Animals↗
PubMed1979

Stem cell growth and differentiation in Hydra attenuata. II. Regulation of nerve and nematocyte differentiation in multiclone aggregates.

The differentiation of nerve cells and nematocytes from interstitial stem cells in Hydra has been investigated under conditions of changing stem cell density. Interstitial stem cells were cultured in a feeder layer system consisting of aggregates of nitrogen mustard-inactivated tissue. The aggregates were seeded with varying numbers of stem cells from 10 to 400 per aggregate; between 4 and 7 days later the rates of nerve and nematocyte differentiation were measured. Nerve differentiation was scored by labelling the stem cell population with [3H]-thymidine and counting nests of 4 proliferating nematoblasts. In both cases the numbers of differentiating cells were normalized to the size of the stem cell population. The results indicate that the rate of nematocyte differentiation increases as the concentration of stem cells increases in aggregates; under the same conditions the rate of nerve differentiation remains essentially constant. To calculate the numbers of stem cells entering each pathway per generation, a computer was programmed to simulate the growth and differentiation of interstitial stem cells. Standard curves were prepared from the simulations relating the rates of nerve and nematocyte differentiation to the fraction of stem cells committed to each pathway per generation. The rates of nerve and nematocyte commitment were then estimated from the experimentally observed rates of differentiation using the standard curves. The results indicate that nerve commitment remains constant at about 0.13 stem cells per generation over a wide range of stem cell concentration. Nematocyte commitment, by comparison, increases from 0.15 to 0.21 stem cells per generation as stem cell concentration increases in aggregates. The fact that the ratio of nerve to nematocyte commitment changes under our conditions suggests that stem cell commitment is not a stochastic process but subject to control by environmental stimuli.

Animals↗
PubMed1988

Heterogeneity and cell cycle analyses from time-lapse studies of human keratinocytes in vitro.

We have analysed the behaviour of cultured epidermal keratinocytes using time-lapse video recordings. We have found evidence for heterogeneity in the behaviour of the cells. Some lines underwent extensive self-renewal, thus expanding the population, while others produced daughter cells that migrated suprabasally and are presumed to have undergone terminal differentiation. We also present kinetic data on the cell cycle times, mitotic durations and post-mitotic residence times. The latter is the time between a cell's birth and eventual suprabasal migration. The data suggest that the 'decision' to migrate is in some way 'programmed' but that the actual migration is a stochastic process. Time-lapse analysis is a very powerful technique for lineage and cell kinetic analysis.

Cell Cycle↗
PubMed1997

Spatial patterns of olfactory neurons expressing specific odor receptor genes in 48-hour-old embryos of zebrafish Danio rerio.

Olfactory neurons have a complex phenotype characterized by their expression of a specific odor receptor (OR) gene and their targeting of an equally specific locus in the olfactory bulb. In the adult fish, olfactory neurons expressing specific ORs are broadly distributed in the epithelium, intermingling with neurons expressing other OR phenotypes. This distributed adult pattern has led to the suggestion that olfactory neuron phenotype is determined by a stochastic process, independent of external positional cues. However, when the fish olfactory system is established during embryogenesis it is simple in its organization, with few olfactory neurons and an olfactory epithelium that has not yet folded into the adult morphology. It is possible that positional cues might act in the embryo to establish an initial population and pattern of olfactory neuron phenotypes and that subsequent morphogenesis and neuronal addition lead to the randomized distribution of neurons. To test this possibility, we examined the spatial patterns of olfactory neurons expressing specific OR genes in 48 h embryos, a time of relative simplicity in the developing olfactory epithelium. Three-dimensional plots of neuron distributions were made, and comparison of OR expression patterns were made between right and left epithelia, between individual animals and between different OR genes. The patterns of OR gene expression were not conserved in these comparison. Mathematical analysis of 21 epithelia for the degree of order in the distribution of olfactory neurons argued strongly that the neurons expressing given ORs are randomly distributed in the 48 h embryos. These results are consistent with those observed from adult tissue and support models suggesting that extrinsic positional cues do not have a major role in specifying olfactory neuron phenotypes.

Animals↗
PubMedDate not supplied

Mass screening models for contagious diseases with no latent period.

In this paper, a simplified model describing the stochastic process underlying the etiology of contagious and noncontagious diseases with mass screening is developed. Typical examples might include screening of tuberculosis in urban ghetto areas, venereal diseases in the sexually active, or AIDS in high risk population groups. The model is addressed to diseases which have zero or negligible latent periods. In the model, it is assumed that the reliabilities of the screening tests are constant, and independent of how long the population unit has the disease. Both tests with perfect and imperfect reliabilities are considered. It is shown that most of the results of a 1978 study by W.P. Pierskalla and J.A. Voelker for noncontagious diseases can be generalized for contagious diseases. A mathematical program for computing the optimal test choice and screening periods is presented. It is shown that the optimal screening schedule is equally spaced for tests with perfect reliability. Other properties relating to the managerial problems of screening frequencies, test selection, and resource allocation are also presented.

Communicable Diseases↗
PubMed2002

Cell signaling and cytotoxicity by peroxynitrite.

Reactive nitrogen species are now considered to play an important role in various pathologies. Although the pathological significance of these molecules, peroxynitrite in particular, has long been attributed to their abilities to react with any component of the cells, including lipids, proteins, and DNA, a paradigm shift has recently been occurring whereby reactive nitrogen species are appreciated as signaling molecules. The question therefore arises as to whether nitrosative stress is indeed the result of a random (stochastic) process of cell damage, as it has traditionally been viewed, or rather is a consequence of the specific activation of a cascade of signaling events. The above considerations have provided the bases for the research work performed in our laboratory, and the results obtained are illustrated in the present article. In particular, our results indicate that some effects of peroxynitrite are not directly mediated by the oxidant; rather, it appears that peroxynitrite triggers a signaling pathway that finally leads to cytotoxicity.

Apoptosis↗
PubMed2006

Estimating random errors due to shot noise in backscatter lidar observations.

We discuss the estimation of random errors due to shot noise in backscatter lidar observations that use either photomultiplier tube (PMT) or avalanche photodiode (APD) detectors. The statistical characteristics of photodetection are reviewed, and photon count distributions of solar background signals and laser backscatter signals are examined using airborne lidar observations at 532 nm using a photon-counting mode APD. Both distributions appear to be Poisson, indicating that the arrival at the photodetector of photons for these signals is a Poisson stochastic process. For Poisson- distributed signals, a proportional, one-to-one relationship is known to exist between the mean of a distribution and its variance. Although the multiplied photocurrent no longer follows a strict Poisson distribution in analog-mode APD and PMT detectors, the proportionality still exists between the mean and the variance of the multiplied photocurrent. We make use of this relationship by introducing the noise scale factor (NSF), which quantifies the constant of proportionality that exists between the root mean square of the random noise in a measurement and the square root of the mean signal. Using the NSF to estimate random errors in lidar measurements due to shot noise provides a significant advantage over the conventional error estimation techniques, in that with the NSF, uncertainties can be reliably calculated from or for a single data sample. Methods for evaluating the NSF are presented. Algorithms to compute the NSF are developed for the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations lidar and tested using data from the Lidar In-space Technology Experiment.

Journal Article↗
PubMed2003

State-estimation approach to the nonstationary optical tomography problem.

We propose a new numerical approach to the nonstationary optical (diffusion) tomography (OT) problem. The assumption in the method is that the absorption and/or diffusion coefficients are nonstationary in the sense that they may exhibit significant changes during the time that is needed to measure data for one traditional image frame. In the proposed method, the OT problem is formulated as a state-estimation problem. Within the state-estimation formulation, the absorption and/or diffusion coefficients are considered a stochastic process. The objective is to estimate a sequence of states for the process when the state evolution model for the process, the observation model for OT experiments, and data on the exterior boundary are given. In the proposed method, the state estimates are computed by using Kalman filtering techniques. The performance of the proposed method is evaluated on the basis of synthetic data. The simulations also illustrate that further improvements to the results in nonstationary applications can be obtained by adjustment of the measurement protocol.

Models, Theoretical↗
PubMed1990

Estimating illuminant direction and degree of surface relief.

Many algorithms for deriving surface shape from shading require an estimate of the direction of illumination. This paper presents a new estimator for illuminant direction, which also generates an estimate of the degree of surface relief, that is measured by the variance of surface orientation (the partial derivatives of surface depth). Surfaces are considered to be samples of a stochastic process representing depth as a function of position in the image plane. We derive an estimator for illuminant tilt that is based only on some general assumptions about the process. The assumptions are that the process is wide-sense stationary, strictly isotropic; and mean-square differentiable and that the second partial derivatives of surface depth are locally independent of the first partial derivatives. We develop an estimator of illuminant slant and degree of surface relief in two stages. In the first, we develop a general format for an estimator based on the same assumptions that are used for the tilt estimator. The second stage is the actual implementation of the estimator and requires the specification of a functional form for the local probability distribution of surface orientations. This approach contrasts with previous ones, which begin their development with an assumption of a particular distribution for surfaces. The approach has the advantage that it separates the problems of surface modeling and light-source estimation, permiting one to easily implement specific estimators for different surface models. We implement the illuminant slant estimator for surfaces that have a Gaussian distribution of surface orientations and show simulation results. Degraded performance in the presence of self-shadowing is discussed.

Depth Perception↗
PubMed2005

Fate vs choice: the immune system reloaded.

Development can occur by either instructive or stochastic processes. My colleagues and I have studied the contributions of these processes to differentiation of naïve CD4+ T-cells to either a Th1 or Th2 phenotype. Our initial discovery that pathogens in our in vitro priming system led to the development of Th1 cells through the action of interleukin-12 was important evidence of a link between innate and adaptive immunity. Subsequent studies in our laboratory revealed an important role for GATA-3 autoactivation in Th2 development. Other interesting projects that have emerged as a result of our Th cell differentiation studies include understanding the role of the inhibitory immunoreceptor B- and T-lymphocyte attenuator in the immune response, as well as the role of the transcription factor ERM in both T-cells and spermatogenesis. We currently maintain our interests in the Th differentiation field by trying to understand the role of type 1 interferons in Th1 development and the role of alternate promoters for the GATA-3 gene, among other things, but are also actively embarking on studies related to the choice between divergent cell types during embryonic stem cell differentiation.

Allergy and Immunology↗