Modeling of hormone secretion-generating mechanisms with splines: a pseudo-likelihood approach

A flexible and robust approach is proposed for the investigation of underlying hormone secretion-generating mechanisms. Characterizing hormone time series is a difficult task as most hormones are secreted in a pulsatile manner and pulses are often masked by slow decay. We model hormone concentration as a filtered counting process where the intensity function of the counting process is modeled nonparametrically using periodic splines. The intensity function and parameters are estimated using a combination of weighted least squares and pseudo-likelihood based on the first two moments. Our method uses concentration measurements directly, which avoids the difficult task of estimating pulse numbers and locations. Both simulations and applications suggest that our method performs well for estimating the intensity function of the pulse-generating counting processes.     

Long distance dispersal and landscape occupancy in a metapopulation of the cranberry fritillary butterfly

Movements between habitat patches in a patchy population of the butterfly Boloria aquilonaris were monitored using capture-mark-recapture methods during three successive generations. For each data set, the inverse cumulative proportion of individuals moving 100 m distance classes was fitted to the negative exponential function and the inverse power function. In each case, the negative exponential function provided a better fit than the inverse power function. Two dispersal kernels were generated using both negative exponential and inverse power functions. These dispersal kernels were used to predict movements between 14 suitable sites in a landscape of 220 km². The negative exponential function generated a dispersal kernel predicting extremely low probabilities for movements exceeding 1 km. The inverse power function generated probabilities predicting that between site movements were possible, according to metapopulation size. CMR studies in the landscape revealed that long distance movements occurred at each generation, corresponding to predictions of the inverse power function dispersal kernel. A total of 26 movements between sites (up to 13 km) were detected, together with recolonisation of empty sites. The spatial scale of the metapopulation dynamics is larger than ever reported on butterflies and long distance movements clearly matter to the persistence of this species in a highly fragmented landscape.     

An approach to inverse scattering problems

There are several reasons for investigating the inverse scattering problem in medical image processing. A typical case, that of ultrasonic fields, is considered. Assuming that a plane wave illuminates a weakly inhomogeneous two-dimensional object, the fundamental equation is derived for the scattered waves in integral as well as in differential forms. It is shown that the scattered waves observed on a circle surrounding the object is sufficient to specify the structure of the object. This information is summarized in a single term, which is a function of the wavenumber as well as the angles of incidence and observation. A successive approximation is applied to reconstruct the image of the object from this function. Since no analytic solution is available, several methods of approximations are proposed, and examples of computations are shown for the case of a cylindrical object.     

The Pharmacology of the Cannabinoid System—A Question of Efficacy and Selectivity

Our knowledge of the function of the cannabinoid system in the body has been aided by the availability of pharmacological agents that affect its function. This has been achieved by the design of agents that either directly interact with the receptor (agonists and antagonist/inverse agonists) and agents that indirectly modulate the receptor output by changing the levels of the endogenous cannabinoids (endocannabinoids). In this review, examples of the most commonly used receptor agonists, antagonists/inverse agonists, and indirectly acting agents (anandamide uptake inhibitors, fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors) are given, with particular focus upon their selectivity and, in the case of the directly acting compounds, efficacy. Finally, the links between the endocannabinoid and cyclooxygenase pathways are explored, in particular, with respect to agents whose primary function is to inhibit cyclooxygenase activity, but which also interact with the endocannabinoid system.     

Estimation of integrated transition hazards and stage occupation probabilities for non-Markov systems under dependent censoring

We propose nonparametric estimators of the stage occupation probabilities and transition hazards for a multistage system that is not necessarily Markovian, using data that are subject to dependent right censoring. We assume that the hazard of being censored at a given instant depends on a possibly time-dependent covariate process as opposed to assuming a fixed censoring hazard (independent censoring). The estimator of the integrated transition hazard matrix has a Nelson-Aalen form where each of the counting processes counting the number of transitions between states and the risk sets for leaving each stage have an IPCW (inverse probability of censoring weighted) form. We estimate these weights using Aalen's linear hazard model. Finally, the stage occupation probabilities are obtained from the estimated integrated transition hazard matrix via product integration. Consistency of these estimators under the general paradigm of non-Markov models is established and asymptotic variance formulas are provided. Simulation results show satisfactory performance of these estimators. An analysis of data on graft-versus-host disease for bone marrow transplant patients is used as an illustration.     

Inverse sampling of controls in a matched case control study

A method of inverse sampling of controls in a matched case-control study is described in which, for each case, controls are sampled until a discordant set is achieved. For a binary exposure, inverse sampling is used to determine the number of controls for each case. When most individuals in a population have the same exposure, standard case-control sampling may result in many case-control sets being concordant with respect to exposure and thus uninformative in the conditional logistic analysis. The method using inverse control sampling is proposed as a solution to this problem in situations when it is practically feasible. In many circumstances, inverse control sampling is found to offer improved statistical efficiency relative to a comparable study with a fixed number of controls per case.     

Sensitivity of the erythrocyte micronucleus assay: dependence on number of cells scored and inter-animal variability

Until recently, the in vivo erythrocyte micronucleus assay has been scored using microscopy. Because the frequency of micronucleated cells is typically low, cell counts are subject to substantial binomial counting error. Counting error, along with inter-animal variability, limit the sensitivity of this assay. Recently, flow cytometric methods have been developed for scoring micronucleated erythrocytes and these methods enable many more cells to be evaluated than is possible with microscopic scoring. Using typical spontaneous micronucleus frequencies reported in mice, rats, and dogs we calculate the counting error associated with the frequency of micronucleated reticulocytes as a function of the number of reticulocytes scored. We compare this counting error with the inter-animal variability determined by flow cytometric scoring of sufficient numbers of cells to assure that the counting error is less than the inter-animal variability, and calculate the minimum increases in micronucleus frequency that can be detected as a function of the number of cells scored. The data show that current regulatory guidelines allow low power of the test when spontaneous frequencies are low (e.g., < or =0.1%). Tables and formulas are presented that provide the necessary numbers of cells that must be scored to meet the recommendation of the International Working Group on Genotoxicity Testing that sufficient cells be scored to reduce counting error to less than the inter-animal variability, thereby maintaining a more uniform power of detection of increased micronucleus frequencies across laboratories and species.     

Sensitivity of the erythrocyte micronucleus assay: Dependence on number of cells scored and inter-animal variability

Until recently, the in vivo erythrocyte micronucleus assay has been scored using microscopy. Because the frequency of micronucleated cells is typically low, cell counts are subject to substantial binomial counting error. Counting error, along with inter-animal variability, limit the sensitivity of this assay. Recently, flow cytometric methods have been developed for scoring micronucleated erythrocytes and these methods enable many more cells to be evaluated than is possible with microscopic scoring. Using typical spontaneous micronucleus frequencies reported in mice, rats, and dogs we calculate the counting error associated with the frequency of micronucleated reticulocytes as a function of the number of reticulocytes scored. We compare this counting error with the inter-animal variability determined by flow cytometric scoring of sufficient numbers of cells to assure that the counting error is less than the inter-animal variability, and calculate the minimum increases in micronucleus frequency that can be detected as a function of the number of cells scored. The data show that current regulatory guidelines allow low power of the test when spontaneous frequencies are low (e.g., ≤0.1%). Tables and formulas are presented that provide the necessary numbers of cells that must be scored to meet the recommendation of the International Working Group on Genotoxicity Testing that sufficient cells be scored to reduce counting error to less than the inter-animal variability, thereby maintaining a more uniform power of detection of increased micronucleus frequencies across laboratories and species.     

Accumulation of nuclear DNA damage or neuron loss: molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases

According to a long-standing hypothesis, aging is mainly caused by accumulation of nuclear (n) DNA damage in differentiated cells such as neurons due to insufficient nDNA repair during lifetime. In line with this hypothesis it was until recently widely accepted that neuron loss is a general consequence of normal aging, explaining some degree of decline in brain function during aging. However, with the advent of more accurate procedures for counting neurons, it is currently widely accepted that there is widespread preservation of neuron numbers in the aging brain, and the changes that do occur are relatively specific to certain brain regions and types of neurons. Whether accumulation of nDNA damage and decline in nDNA repair is a general phenomenon in the aging brain or also shows cell-type specificity is, however, not known. It has not been possible to address this issue with the biochemical and molecular-biological methods available to study nDNA damage and nDNA repair. Rather, it was the introduction of autoradiographic methods to study quantitatively the relative amounts of nDNA damage (measured as nDNA single-strand breaks) and nDNA repair (measured as unscheduled DNA synthesis) on tissue sections that made it possible to address this question in a cell-type-specific manner under physiological conditions. The results of these studies revealed a formerly unknown inverse relationship between age-related accumulation of nDNA damage and age-related impairment in nDNA repair on the one hand, and the age-related, selective, loss of neurons on the other hand. This inverse relation may not only reflect a fundamental process of aging in the central nervous system but also provide the molecular basis for a new approach to understand the selective neuronal vulnerability in neurodegenerative diseases, particularly Alzheimer's disease.     

Solvent effects on the stability of nifuroxazide complexes with cobalt(II), nickel(II) and copper(II) in alcohols

A spectrophotometric study of the complexation of nifuroxazide with cobalt(II), nickel(II) and copper(II) was carried out in different alcohols. The formation of a complex in each case is reported and their stability constants have been calculated. For a given solvent, the stability of the complexes increases from cobalt to copper. In the case of copper(II), the stability varies as an inverse function of the dielectric constant of the solvent. A possible structure of the complex is proposed.     

Accumulation of the cyclin-dependent kinase inhibitor p27/Kip1 and the timing of oligodendrocyte differentiation.

Many types of vertebrate precursor cells divide a limited number of times before they stop and terminally differentiate. In no case is it known what causes them to stop dividing. We have been studying this problem in the proliferating precursor cells that give rise to postmitotic oligodendrocytes, the cells that make myelin in the central nervous system. We show here that two components of the cell cycle control system, cyclin D1 and the Cdc2 kinase, are present in the proliferating precursor cells but not in differentiated oligodendrocytes, suggesting that the control system is dismantled in the oligodendrocytes. More importantly, we show that the cyclin-dependent kinase (Cdk) inhibitor p27 progressively accumulates in the precursor cells as they proliferate and is present at high levels in oligodendrocytes. Our findings are consistent with the possibility that the accumulation of p27 is part of both the intrinsic counting mechanism that determines when precursor cell proliferation stops and differentiation begins and the effector mechanism that arrests the cell cycle when the counting mechanism indicates it is time. The recent findings of others that p27-deficient mice have an increased number of cells in all of the organs examined suggest that this function of p27 is not restricted to the oligodendrocyte cell lineage.     

Dual-parameter optimisation of the elastic properties of skin

This paper presents a procedure for characterising the mechanical properties of skin using stochastic inverse identification. It is based on the minimisation of a cost function relative to the comparison between experimental suction experiments and their corresponding finite element models. Two different models are compared: a classical single-layer approach and a dual-layer medium which account for both the dermis and the hypodermis. Finite element results are used to construct the pre-optimisation database which is required for the inverse analysis. To compare the calculations, the entire identification is based on a dual-parameter optimisation procedure: for the single-layer approach a quadratic hyperelastic constitutive equation is used, whereas for the dual-layer medium a simple neo-Hookean potential is used. Theoretical conclusions, which are developed first, are then compared with actual case studies.     

A nonstationary Poisson point process describes the sequence of action potentials over long time scales in lateral-superior-olive auditory neurons

The behavior of lateral-superior-olive (LSO) auditory neurons over large time scales was investigated. Of particular interest was the determination as to whether LSO neurons exhibit the same type of fractal behavior as that observed in primary VIII-nerve auditory neurons. It has been suggested that this fractal behavior, apparent on long time scales, may play a role in optimally coding natural sounds. We found that a nonfractal model, the nonstationary dead-time-modified Poisson point process (DTMP), describes the LSO firing patterns well for time scales greater than a few tens of milliseconds, a region where the specific details of refractoriness are unimportant. The rate is given by the sum of two decaying exponential functions. The process is completely specified by the initial values and time constants of the two exponentials and by the dead-time relation. Specific measures of the firing patterns investigated were the interspike-interval (ISI) histogram, the Fano-factor time curve (FFC), and the serial count correlation coefficient (SCC) with the number of action potentials in successive counting times serving as the random variable. For all the data sets we examined, the latter portion of the recording was well approximated by a single exponential rate function since the initial exponential portion rapidly decreases to a negligible value. Analytical expressions available for the statistics of a DTMP with a single exponential rate function can therefore be used for this portion of the data. Good agreement was obtained among the analytical results, the computer simulation, and the experimental data on time scales where the details of refractoriness are insignificant. For counting times that are sufficiently large, yet much smaller than the largest time constant in the rate function, the Fano factor is directly proportional to the counting time. The nonstationarity may thus mask fractal fluctuations, for which the Fano factor increases as a fractional power (less than unity) of the counting time.     

Contractility and conformation

Contractility in fibers can arise from changes of macromolecular conformation caused by changes in some thermodynamic variable such as temperature, pH, or solvent composition. Illustrations are given of contractile processes in fibers and of changes in macromolecular conformation in dilute solution. These may involve order-disorder transitions, e.g. of the type exhibited by the helix-coil transition. A statistical mechanical treatment of the helix-coil transition involves the assignment of statistical weights to various states and the proper counting of these statistical weights in the formation and evaluation of the partition function; the thermodynamic properties of the system are derivable from the partition function. The counting procedure involved in the consideration of the α-helix and random coil is described. In addition, the factors affecting the relative stabilities of various helical conformations are discussed. These considerations of macromolecular conformation provide a basis for discussing contractile mechanisms in which changes of conformation are involved.     

Problem in liquid scintillation counting: adsorption of (14-C)pholyethylene glycol in dilute solutions.

[¹⁴C]polyethylene glycol is the method of choice for quantitating changes in intestinal water flux during drug absorption experiments in animals and man. This study points out some of the problems which can be encountered in using this method and provides ways to minimize these problems. Polyethylene glycol selectively binds to the glass wall of scintillation vials during counting and results in a decrease in counting efficiency as a function of time. The results obtained when using this method are determined by the choice of scintillation vial, scintillation cocktail, concentration of polyethylene glycol and the time period over which the samples are counted.     

Return of splenic function after splenectomy: how much tissue is needed?

Ninety patients whose spleen had been removed either because of trauma (41 cases) or as an elective procedure (49) were investigated for return of splenic function by counting pitted red cells and examining spleen scans made after injection of heat damaged 99mTc labelled red cells. There was no significant difference in the proportion of pitted red cells between the two groups of patients. Evidence of splenic tissue in scintiscans was not invariably associated with low pitted red cell values, suggesting that the presence of splenic tissue did not necessarily mean return of splenic function. In every patient whose proportion of pitted red cells was less than 16.2% the scintiscan showed splenic uptake. The proportion of patients with pitted red cell values below 16.2% was significantly higher in the group operated on for trauma, and it is concluded that this was due to splenosis. A high inverse correlation between pitted red cell counts and computed splenic volumes was found. Patients with pitted red cell values of less than 16.2% had computed volumes of 22-133 cm3; below this range the proportion of pitted red cells rose very sharply. These results confirm that splenosis occurs in adults, though less often than in children, and suggest that when splenic tissue is to be implanted a graft of at least 20-30 cm3 is needed to ensure satisfactory return of splenic function.     

The validity of burrow counting in estimating the densities of Chiromantes dehaani and Ilyoplax deschampsi in tidal flat at Yangtze Estuary

It has been confirmed that the crabs play significant roles in the structure and function of coastal wetland ecosystems, such as mangroves and salt marshes. However it is not easy to estimate the abundance and density of burrowing crabs effectively, thus a further understanding of roles of crabs in these ecosystems has been lagged. Some studies have discussed the suitability of several census techniques, such as burrow counting method in estimating crab density in mangroves. The validities of burrow counting method and other census techniques in estimating crab density, however, has not been tested in salt marshes, especially where vegetation are dense. In this study, we tested the validity of burrow counting method in estimating the densities of Chiromantes dehaani and Ilyoplax deschampsi in tidal flat with dense vegetation of Phragmites australis and Zizania aquatica at Yangtze Estuary through comparing densities estimated by the burrow counting method and the excavation. Burrow counting averagely underestimated the density of C. dehaani by 15% and the degree of underestimation varied among vegetations and habitats (from an overestimate by 23% to underestimate by 41%). Burrow counting averagely overestimated the density of I. deschampsi by 43% and the degree of overestimate varied from 0% to 133% depending on the vegetations and habitats. The percentage of occupied burrows and the number of crabs sharing one burrow were important factors influencing the validity of estimating crab density through burrow counting method.     

The validity of burrow counting in estimating the densities of Chiromantes dehaani and Ilyoplax deschampsi in tidal flat at Yangtze Estuary

It has been confirmed that the crabs play significant roles in the structure and function of coastal wetland ecosystems, such as mangroves and salt marshes. However it is not easy to estimate the abundance and density of burrowing crabs effectively, thus a further understanding of roles of crabs in these ecosystems has been lagged. Some studies have discussed the suitability of several census techniques, such as burrow counting method in estimating crab density in mangroves. The validities of burrow counting method and other census techniques in estimating crab density, however, has not been tested in salt marshes, especially where vegetation are dense. In this study, we tested the validity of burrow counting method in estimating the densities of Chiromantes dehaani and Ilyoplax deschampsi in tidal flat with dense vegetation of Phragmites australis and Zizania aquatica at Yangtze Estuary through comparing densities estimated by the burrow counting method and the excavation. Burrow counting averagely underestimated the density of C. dehaani by 15% and the degree of underestimation varied among vegetations and habitats (from an overestimate by 23% to underestimate by 41%). Burrow counting averagely overestimated the density of I. deschampsi by 43% and the degree of overestimate varied from 0% to 133% depending on the vegetations and habitats. The percentage of occupied burrows and the number of crabs sharing one burrow were important factors influencing the validity of estimating crab density through burrow counting method.     

A neural net model for the α-rhythm

Pulse-interval distributions are obtained for a counting system in which there is a gradual, rather than abrupt, increase in excitability following the registration of a pulse (relative refractoriness). The results are applicable to systems in which Poisson counting would be observed in the absence of such effects, and in which the memory reaches back at most one pulse. Choosing a particular functional form for the recovery function, the theory fits the experimentally measured distribution for the maintained discharge in the cat's retinal ganglion cell. It is also consistent with the notion that Weber's Law emerges from refractoriness in the visual system, as first proposed by van der Velden.This work was supported in part by the National Science Foundation     

Use of methyl green-DNA agarose for detecting deoxyribonuclease activity in polyacrylamide gels

A liquid scintillation counting system is described that allows recovery of compounds for further study and analysis. For most classes of compounds tested (with the exception of steroids) the recovery was high (usually at least 90%) and in the case of nucleosides was accompanied by very little degradation of the sample. The counting method should be useful for the counting of samples where a high recovery of the compound is necessary.